*4.6.2 Dexamethasone sustained-release implants*

Dexamethasone intravitreal (DEX) implant (0.7 mg) (Ozurdex, Allergan, Inc., Irvine, CA, USA) consists of micronized dexamethasone in a biodegradable copolymer of polylactic-co-glycolic acid, which slowly releases steroids into the vitreous for about 6 months [188, 189]. In 2014, based on the results of the MEAD study [190], the FDA and most European countries approved Ozurdex for the treatment

of DME. DEX is a potent anti-inflammatory agent; its potency is twice that of Fluocinolone acetonide (FA) and 5-fold more than Triamcinolone Acetonide (TA) [191]. In contrast to TA, the pharmacokinetics of the DEX implant were not significantly different in vitrectomized and nonvitrectomized animal eyes [192]. There have been reports of the benefits of using DEX implant in naive DME as a first-line option [193, 194] and the advantages of early switching in patients not responding to anti-VEGF [195].

### *4.6.3 Fluocinolone acetonide (FA) implant*

FA has a 25-fold higher anti-inflammatory potency than cortisol [196]. It has selective and potent agonist properties by binding to the cytosolic glucocorticoid receptor with high affinity; it is devoid of mineralocorticoid activity [197–199]. FA is available as an intravitreal implant. It is small (3.5 mm in length, 0.37 mm in diameter), non-biodegradable, and designed for injection using a 25-gauge injector via the pars plana into the vitreous cavity [200]. The approved implant (ILUVIEN®) contains 0.19 mg of FA initially released at 0.25 μg/day (average, 0.2 μg/day); it lasts 36 months [201]. The Fluocinolone Acetonide for Diabetic Macular Edema (FAME) studies evaluated the use of 2 different FA doses (0.2 vs. 0.5 μg/day) compared to sham injections [202, 203]. This study showed the efficacy of FA implants for chronic DME that is resistant to conventional treatment.

#### *4.6.4 Triamcinolone Acetonide (TA)*

TA has a 7.5-fold higher anti-inflammatory potency than cortisone [204]. It was the first widely used intravitreal injectable medication for DME [205]. Several clinical trials have shown the efficacy of TA in the treatment of DME [206–208]. TA Half-life in the vitreous of a nonvitrectomized eye has been reported as 18.6 days, in contrast to a much shorter duration in a vitrectomized eye, 3.2 days [209]. A single intravitreal injection of 4 mg of TA lasts approximately three months in the nonvitrectomized human eye [209, 210]. DRCR.net Protocol B investigated the efficacy and safety of 1 mg and 4 mg doses of TA compared with focal or grid laser photocoagulation and concluded that focal laser was superior to intravitreal triamcinolone [211, 212].

#### *4.6.5 Adverse effects*

Adverse effects of intravitreal steroids include ocular hypertension, cataract, infectious endophthalmitis, pseudo endophthalmitis, and sterile endophthalmitis [213]. A steroid-induced cataract is the most common adverse event of intravitreal corticosteroids [213]. Up to 50% of eyes injected with intravitreal corticosteroid will develop elevated intraocular pressure [214, 215]. Both the DEX and FA implants have been reported to migrate into the anterior chamber, potentially leading to corneal edema, corneal endothelial decompensation, and ocular hypertension [216, 217]. The DEX implant has been accidentally injected into the crystalline lens rather than into the vitreous cavity [218]. In terms of outcomes, Gillies et al. reported that the Dexamethasone implant (Ozurdex, Allergan) was as efficacious as Bevacizumab in reducing DME [219].

#### **4.7 Macular laser photocoagulation for DME**

#### *4.7.1 Macular laser photocoagulation (MLP)*

MLP was the first proven treatment for DME [220, 221]. Though its mechanism of action is not entirely understood, it improves DME through several proposed

#### *Current Management of Diabetic Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.100157*

mechanisms. Photoreceptors and retinal pigment epithelium RPE cells are destroyed via a photothermal mechanism, thus reducing oxygen consumption. The reduced oxygen consumption in the outer retina is postulated to increase oxygen flux from the choroid to the inner retina, causing arteriolar constriction and decreased hydrostatic forces that drive edema [222].

Photocoagulation also induces changes to the RPE cells, causing their proliferation and releasing cytokines such as transforming growth factor-beta TGF-β, which antagonize the effects of VEGF [223].

The Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated a 50% reduction in moderate vision loss in patients with clinically significant diabetic macular edema (CSME) who underwent immediate focal laser photocoagulation [221]. MLP causes iatrogenic tissue damage, subretinal fibrosis, choroidal neovascularization, and laser scar enlargement [224, 225].

The DRCR.net re-examined this coagulation technique and reported it as a modified (m) ETDRS focal/grid photocoagulation protocol [226], but the risk of macular tissue damage remained.

The DRCR.net Protocol A reported that mETDRS laser is better than modified macular grid laser for DME while DRCR.net Protocol B noted that mETDRS focal laser is superior to intravitreal triamcinolone for DME [227]. DRCR.net Protocol K also reported that 20–60% of eyes that initially respond to focal laser might continue to improve after four months, suggesting durability of effect [228]. The macular laser had been considered the gold standard for many years [229]. According to the European Society of Retina Specialists (EURETINA) guidelines, focal/grid laser is now reserved mostly for non-center-involving DME [78].

### *4.7.2 Subthreshold micropulse diode (SDM) laser photocoagulation*

SDM has been used in the treatment of DME [230–232]. Compared with conventional laser photocoagulation, SDM is a tissue-sparing technique: it avoids protein coagulation and prevents retinal scars, allowing retinal anatomic and functional preservation [233]. It has been hypothesized that SDM, by inducing a controlled thermal elevation of the retinal tissue, can selectively stimulate the retinal pigment epithelium (RPE) [234, 235]. Its advantages include the absence of RPE scarring, no subsequent choroidal neovascularization, and elimination of paracentral visual field scotomas [232, 236]. Its disadvantages include no visible endpoint for treatment, making it difficult to determine where treatment has and has not been applied. Furthermore, there is no standardized, consensus set of treatment parameters or guidelines for treatment within the foveal avascular zone. The reduction in macular edema after subthreshold laser photocoagulation occurs with a slower time course, and more treatments are necessary to eliminate edema [232]. Some randomized clinical trials have demonstrated that subthreshold grid laser treatment is as effective as conventional focal/grid laser photocoagulation, though slower in terms of resolution of DME, in achieving the same functional and anatomical effects [237, 238]. There have been reports of the benefits of combining SDM and intravitreal anti VEGFs in treating DME [239, 240].

#### *4.7.3 Selective retinal therapy (SRT)*

SRT is a laser procedure in which the RPE is selectively damaged without affecting the neural retina and choroid [241–243]. A microsecond pulsed laser is used to induce an instantaneous temperature rise just at the melanosomes

within RPE cells, which leads to the formation of microbubbles around these melanosomes. Their temporary expansion results in a cell volume expansion and eventually mechanical cellular disruption without increasing temperature in the surrounding tissue. Studies have shown that SRT is effective in treating DME [243, 244].

#### *4.7.4 Patterned scanned laser (PASCAL)*

In PASCAL, the shorter pulse duration is used in an array of multiple burns to provide speed, better spatial localization, and reduced collateral damage by providing more precise control of the depth of the impact [245]. PASCAL is an ideal laser method to place the accurate "subthreshold" (subvisible) focal-grid laser in DME in contrast to conventional laser therapy [246, 247]. The advantages of PASCAL over conventional laser therapy include shorter treatment duration, increased safety, uniform, and precise spot placement, accurate "subthreshold" grid-pattern placement, and reduced pain and visual field defect [248]. However, the efficacy of PASCAL laser appears to be diminished compared to conventional laser therapy when the same number of laser spots were delivered [249].

#### *4.7.5 Navigated laser (NAVILAS)*

NAVILAS is a fundus imaging and laser treatment device developed by Neubauer et al. (OD-OS GmbH, Teltow, Germany) [250, 251]. The device utilizes retina navigation via computerized image capture and tracking assistance with high precision and reproducibility of <60–110 um [250]. It appears that the rate of retreatment for DME is reduced with NAVILAS when compared to the conventional mETDRS focal laser technique [251].

A 92% hit rate of microaneurysm via NAVILAS compared to 72% in conventional laser focal coagulation has been reported [252]. Focal laser therapy using NAVILAS will have more impact in the future to improve visual acuity and reduce the burden of anti-VEGF injection numbers in patients [253, 254].

#### **4.8 Vitrectomy for DME**

Optical coherence tomography has shown that vitreomacular adhesion is a risk factor for DME [255], as illustrated in **Figure 5**. Complete separation of posterior hyaloid with Posterior Vitreous Detachment (PVD) is associated with a decreased rate of DME [256]. Vitrectomy removes traction, improves macular oxygenation, removes VEGF and pro-inflammatory cytokines, and allows additional endolaser and steroids placement [257]. It was introduced for treating eyes with a taut posterior hyaloid adherent to the macula, often associated with shallow traction macular detachment, which had failed previous focal/grid laser [258, 259], as can be seen in **Figure 5**. It has also been used to treat eyes with an attached but non-thickened, non-taut posterior hyaloid or for eyes with persistent DME despite previous focal laser or intravitreal triamcinolone injection regardless of the status of the posterior hyaloid [260, 261], Illustrated in **Figures 12** and **13**.

Vitrectomy has been used as a potential primary therapy in eyes with more severe edema and greater visual acuity loss at presentation [262, 263]. Reports on the outcome of vitrectomy for DME are conflicting; some reports suggest that vitrectomy reduces macular thickening but does not improve visual acuity [264, 265]. Others have report improved visual acuities simultaneous with decreases in macular thickening or lagging behind the reduction in macular thickness by a

*Current Management of Diabetic Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.100157*

#### **Figure 12.**

*This is a fundus photograph of the left eye in a patient who suffers a combination of DME and proliferative diabetic retinopathy (PDR). This eye has had vitrectomy with pan-retinal laser photocoagulation for the treatment of PDR. Notice residual fibrovascular proliferation within the superotemporal vascular arcade. Conspicuous hard exudates cluster in the foveomacula region, with few microaneurysms located inferio-nasal to the hard exudates. Retinal laser photocoagulation marks are present. There is also a pale cupped optic disc and sheathing of the retinal arteries and veins.*

#### **Figure 13.**

*OCT of the fundus photography in Figure 12. This shows significant thickening of the fovea and loss of the normal foveal depression, disorganization of the intraretinal microstructure, aggregation of hard exudates, intraretinal cystoid spaces, and epiretinal membranes. This patient would have benefited from peeling of the internal limiting membrane during the vitrectomy. Post vitrectomized eyes with persistent DME can benefit from intravitreal steroid injections, e.g., Orzudex implant. Intravitreal steroids are beneficial in pseudophakic and aphakic eyes, in which the risk of cataract formation does not exist.*

few months [266, 267]. There have also been reports of improved visual acuity in cases with macular traction but no visual improvement in cases without traction [268, 269].

#### **4.9 Plasma kallikrein inhibitors**

Plasma kallikrein is highly upregulated in vitreous patients with DME [270]. It is a mediator of vascular leakage and inflammation. There is evidence that it is involved in DME pathogenesis in VEGF independent fashion and VEGF interdependent mechanisms [271]. Several small molecules and bicyclic peptides targeting the plasma kallikrein/kinin system are currently under investigation for DME treatment via intravitreal, oral, and topical administrations [271]. These include KVD001 (KalVista Pharmaceuticals) a highly potent and selective plasma kallikrein inhibitor, currently being developed as an intravitreal therapy), THR-149 (Oxurion NV), RZ402 (Rezolute Bio), and VE-3539 (Verseon Corp) [271]. Orally administered plasma kallikrein inhibitors are efficacious in reducing retinal edema and preserving retinal function in preclinical models. Plasma kallikrein inhibition is emerging as a promising new treatment modality for DME [271].
