Widening use of dexamethasone implant for the treatment of macular edema.

Sustained-release intravitreal 0.7 mg dexamethasone (DEX) implant is approved in Europe for the treatment of macular edema related to diabetic retinopathy, branch retinal vein occlusion, central retinal vein occlusion, and non-infectious uveitis. The implant is formulated in a biodegradable copolymer to release the active ingredient within the vitreous chamber for up to 6 months after an intravitreal injection, allowing a prolonged interval of efficacy between injections with a good safety profile. Various other ocular pathologies with inflammatory etiopathogeneses associated with macular edema have been treated by DEX implant, including neovascular age-related macular degeneration, Irvine-Gass syndrome, vasoproliferative retinal tumors, retinal telangiectasia, Coats' disease, radiation maculopathy, retinitis pigmentosa, and macular edema secondary to scleral buckling and pars plana vitrectomy. We undertook a review to provide a comprehensive collection of all of the diseases that benefit from the use of the sustained-release DEX implant, alone or in combination with concomitant therapies. A MEDLINE search revealed lack of randomized controlled trials related to these indications. Therefore we included and analyzed all available studies (retrospective and prospective, comparative and non-comparative, randomized and nonrandomized, single center and multicenter, and case report). There are reports in the literature of the use of DEX implant across a range of macular edema-related pathologies, with their clinical experience supporting the use of DEX implant on a case-by-case basis with the aim of improving patient outcomes in many macular pathologies. As many of the reported macular pathologies are difficult to treat, a new treatment option that has a beneficial influence on the clinical course of the disease may be useful in clinical practice.

Introduction

The sustained-release intravitreal (IV) 0.7 mg dexamethasone (DEX) implant (Ozurdex®, Allergan Pharmaceuticals, Irvine, CA, USA) is approved in Europe for the treatment of macular edema related to the following diseases: diabetic retinopathy, branch retinal vein occlusion or central retinal vein occlusion, and non-infectious uveitis.1

DEX is one of the 3 most commonly used intraocular corticosteroids together with triamcinolone acetonide (TA) and fluocinolone acetonide. However, compared with these, DEX differs in its pharmacokinetics and pharmacodynamics properties due to certain biological effectiveness: different glucocorticoid receptor binding affinity (DEX > fluocinolone > triamcinolone) and different anti-inflammatory activities (DEX = fluocinolone and is 5 times more active than triamcinolone).1,2 The advantage of a DEX implant, containing micronized, preservative-free DEX 0.7 mg in a biodegradable copolymer of polylactic-co-glycolic acid (which eventually breaks down into carbon dioxide and water), is the release of the active ingredient within the vitreous chamber for up to 6 months after an IV injection. All these aforementioned features allow reduction in the frequency of injections with benefit in terms of hospital and patient resource saving, including diminished complications related to injection procedure (eg, retinal detachment, endophthalmitis, lens iatrogenic injury, etc). However, in real life it has been shown that a shorter-interval re-treatment is required because of the loss of the drug’s effectiveness before 6 months, with a reported range varying from 4 to 5.9 months.3,4 Another relevant pharmacological aspect, as demonstrated by experimental studies, is the reduction of IV drugs half-life in vitrectomized eyes compared with non-vitrectomized ones, making their use ineffective.5 On the contrary, DEX implant has the advantage of maintaining the same half-life and, therefore, the same pharmacological properties in both vitrectomized and non-vitrectomized eyes.6–8

Regarding complications related to the use of DEX implant, pivotal studies and real-life studies have confirmed a good safety profile with only a few complications: cataract progression in the range from 29.8%9 to 67.9%,10 closely related to the number of implants received, and an increase of intraocular pressure (IOP) >10 mmHg from baseline reported in a range of 15.4%9 and 27.7%10 of cases. There are several reviews collecting literature data about the approved use of sustained-release DEX implants. However, there are various ocular pathologies with inflammatory etiopathogeneses associated with macular edema, such as: neovascular age-related macular degeneration (nAMD); Irvine–Gass syndrome (IGS); vasoproliferative retinal tumors (VPRTs); retinal telangiectasia and Coats’ disease; radiation maculopathy; retinitis pigmentosa; macular edema secondary to scleral buckling and pars plana vitrectomy (PPV), all of which have been treated by DEX implant.

The aim of this review was to provide a systematic collection of all of the diseases that benefit from the use of the sustained-release DEX implant alone or in combination with concomitant therapies in order to provide a valuable therapy option for these diseases in clinical practice.

Methods

MEDLINE databases for the period 2009 to September 2016 were searched by using the medical subject heading “Dexamethasone intravitreal implant/Ozurdex” and the keywords “macular edema, age-related macular degeneration, Irvine–Gass, pseudophakic cystoid macular edema, post-operative macular edema, PPV, scleral buckling, retinitis pigmentosa, prostaglandin, radiation macular edema, telangiectasia.” Studies were limited to the English language. Because randomized controlled trials on these topics were lacking, all studies (retrospective and prospective, comparative and non-comparative, randomized and nonrandomized, single center and multicenter, and case reports) were analyzed. Aims, and anatomical and functional outcomes, and complications after DEX implant were analyzed.

nAMD

Approved first-line therapy for nAMD is based on the use of anti-vascular endothelial grow factor (VEGF) IV injections such as pegaptanib, ranibizumab, and aflibercept. However, there are patients who have a non-complete response to anti-VEGF injections as well as patients who, after an optimal functional and anatomical response, develop tachyphylaxis.11 The explanation for this incomplete response lies in the multifactorial pathogenesis of AMD, which involves VEGF, inflammation, and oxidative stress, as seen in histological studies performed on neovascular membranes after their surgical excision. Neovascular membrane growth in the subretinal space is stimulated by activated macrophages (and other inflammatory cells secreting cytokines) and enzymes that can damage the Bruch’s membrane.12 Therefore, inflammation is another potential target of nAMD treatment that could be counteracted by the use of corticosteroids.

Combination therapy consisting of anti-VEGF therapy and a corticosteroid relies on the use of drugs with different mechanisms of action, and could allow the reduction of anti-VEGF IV injection frequency and therefore, improve long-term efficacy and safety while reducing scarring results.13–16 Using combination therapies to treat nAMD dates back to photodynamic therapy (PDT), when it was associated with the IV TA injection.17,18 However, side effects due to IV TA, such as cataract progression and increased IOP, sometimes resistant to medical therapy, halted these procedures despite anatomical and functional benefits.19 Cataract surgery has been reported in around 45.2% of eyes that underwent triamcinolone injection,19 and ocular hypertension (IOP >21 mmHg) in around 44.6% of eyes, with IOP-lowering surgery required in 0.3% of eyes.20

The LuceDex study21 was the first study using the IV DEX injections (500 mg in 0.05 mL), followed by IV ranibizumab (4 monthly injections of 0.5 mg in 0.05 mL) that was compared with IV ranibizumab monotherapy (Group 2; total 37 patients). After 4 consecutive months, in both groups, ranibizumab pro re nata treatment was administered if signs of lesion activity were present. The results of this study showed a clear benefit for combination therapy, with reduction in the dimension of the choroidal neovascular membrane, detected by fluorescein angiography, improvement in visual acuity, and reduced treatment frequency. Central macular thickness (CMT) and volume reductions were also observed, although these changes were not statistically significant.

After the approval of the DEX implant, several authors evaluated its efficacy in nAMD22–25 (Table 1). Compared with ranibizumab monotherapy, studies showed no long-term improvement of best corrected visual acuity (BCVA) and reduction of CMT;22–25 however, DEX implant in some cases allowed a reduced number of anti-VEGF injections.23,24

Table 1

Published studies on the use of DEX implant for age-related macular degeneration

Reference	Study design	No of eyes	Previous treatment	Treatment	Follow-up	Retreatment	BCVA	CMT	Complications
Calvo et al22	Retrospective	7 refractory	3 anti-VEGF	1 DEX + ranibizumab monthly	6 months	2 DEX (28.5%)	From 0.53±0.13 logMAR to 3 months: 0.45±0.3 (P=0.23)6 months: 0.52±0.2 (P=0.23)	From 273.14±50.94 μm to 3 months: 241.5±36.6 μm; (P=0.04)6 months: 260.71±58.51 μm (P=0.40)	3 ocular hypertension(42.8%)(27–32 mmHg)
Kuppermann et al 23	Prospective multicenter randomized	243	115 naïve:	58 DEX + ranibizumab vs 57 sham + ranibizumab PRN	6 months	3.15 DEX + ranibizumab PRN	NaïveChange from baseline:DEX: +0.3 to +2.7 L Sham:−0.5 to +2.6 L	NaïveChange from baseline: DEX:−12.61±96.4 μm Sham:−34.70±106.6 μm(P<0.05)	DEX18.2%IOP ≥25 mmHg
			128 prev treatment	65 DEX + ranibizumab vs 63 sham + ranibizumab PRN		3.37 sham + ranibizumab	Prev treatmentChange from baseline:DEX: +0.4 to +2.4 LSham: −0.3 to 2.6 L	Prev treatmentChange from baseline:DEX:−1.74±54.4 μmSham:+6.84±84.9 μm (P=ns)	Sham 5.1%IOP ≥25 mmHg(P=0.002)
Rezar-Dreindl et al24	Prospective randomized	40	5.6±3.4 ranibizumab	20 ranibizumab	12 months	7.95 ranibizumabP=0.042	From 62 to 68 L(P=0.2)	From 485 μm to 6 months: 426 μm12 months: 453 μm(P=0.38)	9% cataract surgery0% IOP >30 mmHg33% cataract surgery
			6.7±4.4 ranibizumab	20 ranibizumab + DEX		5.5 ranibizumab + 2 DEX (18 eyes)	68 to 71 L	From 439 μm to 6 months: 375 μm12 months: 368 μm	15% IOP >30 mmHg
Chaudhary et al25	Prospective multicenter randomized	10	NR	5 ranibizumab	6 months	6.2±2.3	Change from baseline:10.8±13.2 L3.0±10.5 L(P=0.331)	Change from baseline:31.7%±17.5% to 13.3%±27.0% (P=0.236)	1 IOP >30 mmHg
				5 ranibizumab + DEX		5.8±1.8 (P=0.766)

Abbreviations: BCVA, best corrected visual acuity; CMT, central macular thickness; DEX, dexamethasone implant; IOP, intraocular pressure; Naïve, previously untreated; NR, not reported; ns, not significant; prev treatment, previously treated; PRN, pro re nata; VEGF, vascular endothelial growth factor.

One study24 reported an incidence of cataract surgery of 9% in ranibizumab-treated eyes and 33% in eyes receiving 2 DEX implants. The incidence of ocular hypertension ranged from 15% to 42%,22–25 all treated with topical hypotonizing therapy.

IGS

The most likely physiopathological hypothesis for IGS is an inflammatory response instigated by the inflammatory mediators released during and after surgical procedures, causing alterations to the blood–retinal barrier. Many risk factors have been identified, such as posterior capsule rupture and vitreous loss, as well as the use of iris retractors, the presence of an epiretinal membrane, a vein occlusion, a history of uveitis or diabetes and the use of prostaglandin eye drops.26

First-line treatment for IGS involves the use of different therapies: topical nonsteroidal anti-inflammatory drugs (NSAIDs), oral acetazolamide, and topical corticosteroids. In patients resistant to such treatments, the following off-label treatment options have been tried:26–32

IV anti-VEGF

Subcutaneous interferon α2a injections

IV infliximab (anti-tumor necrosis factor-α)

Intra-, retro-, and peribulbar corticosteroids

PPV

Several authors have evaluated the efficacy of DEX implant for chronic IGS33–45 (Table 2).

Table 2

Published studies on the use of DEX implant for Irvine–Gass syndrome

Reference	Study design	No of eyes	Previous treatment	Treatment	Follow-up	Retreatment	BCVA	CMT	Complications
Williams et al33	Prospective multicenter randomized	41 uveitis + IGS (27)	Laser Medical therapy	DEX 0.7 mg or DEX 0.35 mg observation	6 months	NR	53.8% improvement ≥10 L after 3 months (P=0.029)41.7% improvement ≥10 L after 3 months (P=0.117)14.3% improvement ≥10 L after 3 months	NR	31% IOP >25 mmHg (0.7 mg)
Meyer and Schönfeld34	Case report	1	3 IVT 0.4 mg dexamethasone	1 DEX	4 months	NR	From 0.30 to 0.8 (for at least 3 months)	From 393 μm to 212 μm (for at least 3 months)	NR
Dutra Medeiros et al35	Retrospective	9	CAIsTopical NSAIDsCorticosteroidsIVT anti-VEGFIVT TA	1 DEX	6 months	NR	From 0.62±0.15 logMAR to 1 month: 0.47±0.21 (P=0.008)3 months: 0.37±0.24 (P=0.001)6 months: 0.37±0.26 (P=0.002)	From 542.22±134.78 μm to 1 month: 350.88±98.71 μm (P=0.001)3 months: 319.22±60.96 μm (P=0.002)6 months: 398.33±127.89 μm (P=0.031)	NR
Brynskov et al36	Case report	1	TA Sub-Tenon’s 5 Ranibizumab IVT	DEX	12	Second DEX (187 days later)	First DEX: from 78ETDRS letters to 76Second DEX: from 76ETDRS letters to 85	First DEX: from 541 to 219 μm (after 83 days)Second DEX: from 436 to 229 μm (after 56 days)	NR
Fenicia et al37	Case report	1 patient (2 eyes)	RE: topical NSAIDsOral indomethacin 3 peribulbar methylprednisolone	RE: DEX + Ranibizumab IVT (84 days later)	NR	RE: 1DEX +1 ranibizumab IVT (84 days later) +1 DEX (2 months later IVT ranibizumab)	RE: from 20/70 to 50 days 20/20	−369 μm after 7 days	NR
			LE: topical NSAIDs	LE: DEX
			Oral indomethacin				LE: from 20/40 to 80 days 20/20
			Ranibizumab IVT			2 DEX (5 months after)
Dang et al38	Prospective, nonrandomized, comparative	18	Topical steroidsTopical NSAIDs	DEX	6		1 month: VAI 44%P=0.625 vs TA2 months: VAI 39%P=0.941 vs TA3 months: VAI 39%P=0.553 vs TA6 months: VAI 33%P=0.856 vs TA	1 month: −175 μm (mean change), P=0.783 vs TA2 months: −145 μm (mean change), P=0.044 vs TA3 months: −126 μm (mean change), P=0.049 vs TA	DEX1 month: 6%IOP>21 mmHg2 months: 6%IOP>21 mmHg3 months: 6%IOP>21 mmHg6 months: 0%IOP>21 mmHg (P=0.044)
						NR
								6 months: −125 μm (mean change), P=0.812 vs TA
		25		TA		15 1 IVT TA9 2 IVT TA1 3 IVT TA	1 month: VAI 52%2 months: VAI 40%3 months: VAI 48%6 months: VAI 36%	1 month: −193 μm (mean change)2 months: −95 μm (mean change)3 months: −173 μm (mean change)6 months: −140 μm (mean change)	TA1 month: 12%IOP>21 mmHg2 months: 12%IOP>21 mmHg3 months: 20%IOP>21 mmHg6 months: 20%IOP>21 mmHg
Furino et al39	Retrospective	11	NR	1 DEX	6.27±0.47	NR	From 20/40 to 20/22(P<0.0001)	From 462±100 μm to 276±8 μm(P<0.0001)	IOP>20 mmHg
Al Zamil40	Retrospective	11	Oral CAIsTopical NSAIDsCorticosteroidsIVT anti-VEGFIVTA	1 DEX	6	NR	From 0.58±0.17logMAR to 1 month: 0.37±0.16logMAR (P=0.008)3 months: 0.20±0.13logMAR (P=0.001)6 months: 0.21±0.15logMAR (P=0.002)	From 513.8±134.9 μm to 1 month: 371.6±91.9(P=0.001)3 months: 302.6±50.9 μm(P=0.002)6 months: 308.0±54.5 μm(P=0.031)	NR
Khurana et al41	Prospective case series	6	Topical NSAIDs	1 DEX	NR		6 months: +14 L(P=0.03)	1 month: −100 μm(mean change)(P<0.01)6 months: −72 μm(mean change)(P=0.004)
Ortega- Evangelico and Diago Sempere42	Retrospective	4	NR	1 DEX	6		From 0.3 to 1 month: 0.575 logMAR (mean)3 months: 0.575logMAR (mean)	From 414 μm to 1 month: 330.25 μm(mean change)3 months: 346.75 μm (mean change)	NR
Mylonas et al43	Prospective randomized	29	NR	14 IVTA	6	19 second IVTA	From 63±13 L to 1 month: 73±11 L(P=0.001)3 months: 73±11 L(P=0.001)6 months: 71±13 L(P=0.001)	From 516±121 μm to 1 month: 355±59 μm(P=0.003)3 months: 389±89 μm(P=0.001)6 months: 365±74 μm(P=0.002)
				15 DEX			From 60±10 L to 1 month: 73±10 L(P<0.001)3 months: 72±11 L(P<0.001)6 months: 66±13 L(P=0.009)1 month: P=0.86 vs DEX3 months: P=0.80 vs DEX6 months: P=0.80 vs DEX	From 548±110 μm to 1 month: 357±69 μm(P<0.001)3 months: 391±102 μm(P<0.001)6 months: 504±159 μm(P=0.05)1 month: P=0.92 vs DEX3 months: P=0.94 vs DEX6 months: P=0.01 vs DEX
EPISODIC 2 study44	Retrospective	58 IGS of 100 overall	NR	1 DEX	24 months(25 eyes)	1.7 first year1.657 second year	Baseline mean58.5±15.6 L18 months: 66.9 (±18.3) L24 months: 62.3 L(±14.3)(P=0.0035)	Baseline 518.13±117.2 μm18 months: 346.9±115.7 μm−176 μm (P<0.001)24 months: 340.2±116 μm−182.7 μm (P<0.001)	6.2% IOP >25 mmHg
Sacchi et al45	Case report	1	Sub-Tenon’s betamethasone	1 DEX	6 months	NR	From 20/40 to 1 month: 20/30	NR	IOP >21 mmHg

Abbreviations: BCVA, best corrected visual acuity; CAIs, carbonic anhydrase inhibitors; CMT, central macular thickness; DEX, dexamethasone implant; ETDRS, Early Treatment Diabetic Retinopathy Study; IGS, Irvine-Gass syndrome; IOP, intraocular pressure; IVT, intravitreal; IVTA, intravitreal triamcinolone acetonide; L, ETDRS letters; LE, left eye; NR, not reported; NSAIDs, nonsteroidal anti-inflammatory drugs; RE, right eye; TA, triamcinolone acetonide; VAI, visual acuity improvement >10 L; VEGF, vascular endothelial growth factor.

Most of the studies had a 6-month follow-up; they showed a significant improvement in BCVA and a significant reduction in CMT with 1 DEX implant. Two prospective studies38,43 of DEX compared with IVTA showed similar functional effects and anatomical effects: one found a lower incidence of ocular hypertension in the DEX group (at 6 months 0% vs 20%, P=0.044).

A retrospective long-term study44 that included 58 cases of IGS in a total of 100 eyes found that efficacy was maintained at 24 months, after a mean number of 1.77 DEX implants in the first year and 1.70 in the second year. At 24 months, an IOP >25 mmHg was found in 6.2% of the patients, all treated with hypotensive eye drops and not requiring filtering surgery.44

VPRTs

Several approaches have been used to treat VPRTs, including cryotherapy, laser photocoagulation, PDT, IV anti-VEGF, plaque brachytherapy, and PPV.45–47

VPRTs treated by DEX and PDT were reported in 3 cases48 (Table 3). Total involution of the tumor was reported within 2 months and regression of exudates continued for several months, leaving fibrotic scar tissue in the inferior half of the retina.48

Table 3

DEX in vasoproliferative retinal tumors

Reference	Study design	No of eyes	Previous treatment	Treatment	Follow-up	Retreatment	BCVA	CMT	Complications
Cebeci et al48	Case report	3	IVT BEVLaser photocoagulation	DEX	12 months	1 DEX + PDT(1 week after)	From 20/25 to 20/40	NR	1 subcapsular cataract

Abbreviations: BCVA, best corrected visual acuity; BEV, bevacizumab; CMT, central macular thickness; DEX, dexamethasone implant; IVT, intravitreal; NR, not reported; PDT, photodynamic therapy.

Retinal telangiectasia and Coats’ disease

Retinal telangiectasia

Yannuzzi et al49 have recently classified different forms of idiopathic macular telangiectasia: aneurismal telangiectasia, idiopathic perifoveal telangiectasia, and occlusive telangiectasia. Although several approaches have been suggested for the treatment of idiopathic macular telangiectasia (including laser photocoagulation,50 PDT,51 IV anti-VEGF,52 PPV53), no treatment has yet been shown to provide a consistent effect on visual acuity. Also, corticosteroids have been used to treat these vascular pathologies due to their biological effect54 and DEX implant can be assumed to be an useful therapeutic device,55,56 which can also be administered in pediatric patients57 (Table 4).

Table 4

Published studies on the use of DEX implant for retinal telangiectasia

Reference	Study design	No of eyes	Previous treatment	Treatment	Follow-up	Retreatment	BCVA	CMT Complications
Sandali et al55	Case report	1	3 BEV IVT	DEX	15 months	2 DEX	From 20/32 to 1 month: 20/20	From 398 μm NR to 1 month:250 μm
Loutfi et al56	Case report	1	3 BEV IVT1 IVTA	DEX	NR	3 DEX	From 0.3 to 0.59 logMAR: 6 weeks after 1st DEX; from 0.3 to 0.64 logMAR: 6 weeks after 2nd DEX; from 0.3 to 0.78 logMAR: 2 weeks after 3rd DEX	From 397 μm NR to 286 μm:6 weeks after 1° DEX; 6 weeks after 2° DEX:279 μm; 2 weeks after 3° DEX:279 μm
Lei and Lam62	Retrospective	1	8 ranibizumabIVT + laser	DEX	17 months	4 DEX	From 1 to 52 weeks:0.5 logMAR	From 607 μm NR to 52 weeks: 346 μm

Abbreviations: BCVA, best corrected visual acuity; BEV, bevacizumab; CMT, central macular thickness; DEX, dexamethasone implant; IVT, intravitreal; IVTA, intravitreal triamcinolone acetonide; NR, not reported.

In these cases, with a longer follow-up, multiple DEX implants were performed, at each time successfully (leading to BCVA improvement and CMT reduction).56–58

Coats’ disease

In Coats’ disease, ablative therapy by laser photocoagulation and cryotherapy is the gold standard of treatment57 with photocoagulation preferred over cryotherapy in cases with little or no subretinal fluid.57 IV therapies such as anti-VEGF and steroids could be used to improve anatomic and visual outcomes,58,59 in particular, in combination with ablative therapies. IV corticosteroids, including DEX implant60–62 have been used to reduce intraocular inflammation, tighten capillary walls, and suppress cell proliferation, also having anti-VEGF properties,58 (Table 5).

Table 5

DEX implant in Coats’ disease

Reference	Study design	No of eyes	Previous treatment	Primary treatment	Follow-up	Retreatment	BCVA	CMT	Complications
Saatci et al60	Case report	2	5 ranibizumab IVT + laser photocoagulation in 1 eye	DEX in one patientDEX + laser photocoagulation in the other patient	12 months6 months	NR	UnchangedFrom 2/10 to 3/10	NR	IOP rise >25 mmHg in both eyes
Martínez-Castillo et al61	Case report	1	None	DEX + laser photocoagulation	12 months	NR	From 20/200 to 20/25	NR	None
Lei and Lam62	Retrospective chart review	1	3 BEV IVT + laser photocoagulation	DEX	16 months	3 DEX	From 1.3 to 52 weeks: 1.8 logMAR	From 821 μm to 52 weeks: 589 μm	None

Abbreviations: BCVA, best corrected visual acuity; BEV, bevacizumab; CMT, central macular thickness; DEX, dexamethasone implant; IOP, intraocular pressure; IVT, intravitreal; NR, not reported.

In one case, DEX implant led to a resolution of the exudative retinal detachment allowing laser photocoagulation of telangiectatic vessels.63 In other cases, final BCVA was influenced by subfoveal fibrosis, present at the time of the treatment58 or existing over a long-term.60

Radiation maculopathy

Several treatments have been proposed for radiation maculopathy, including laser photocoagulation, PDT, periocular injection of TA, IV anti-VEGF and, most recently, DEX implant (Table 6).63–68 All of these studies demonstrated a significant anatomical benefit with DEX implant in cases of recalcitrant radiation macular edema, with significant changes in visual acuity in most of the cases. Two comparative studies65,67 comparing DEX implant with anti-VEGF therapy, found no difference in outcomes, and a reduction in the number of injections in DEX-treated eyes.65

Table 6

Published studies on the use of DEX implant for radiation maculopathy

Reference	Study design	No of eyes	Previous treatment	Primary treatment	Follow-up	Retreatment	BCVA	CMT	Complications
Baillif et al63	Retrospective	5	None	DEX	6.4 months	3 eyes: 1 DEX2 eyes: 2 DEX	From 41 L to 2 months: 47 L	From 487.1 μm to 2 months: 331.2 μm	1 eye IOP >25 mmHg
Caminal et al64	Retrospective	12	2 laser2 VEGF IVT5 laser + anti-VEGFIVT	DEX	8.2±7.8 months	1 eye: 2 DEX	From 1±0.58 to 0.8±1.58logMAR(P=0.091)	From 416±263 to 254±170 μm(P=0.016)	1 eye cataract1 eye IOP rise
Russo et al65	Retrospective comparative	16	NR	8 DEX	Range 7–52 months	2.4±0.9 DEX(24 months)(P=0.018 vs ranibizumab)	DEX: from 0.45±0.18 to last follow-up: 0.27±0.15logMAR(P=0.011)	From 437±71 μm to last follow-up: 254±44 μm(P=0.012)	NR
				8 ranibizumab IVT
						6±1.8 ranibizumab(24 months)	Ranibizumab: from 0.49±0.14 to last follow-up: 0.34±0.13 logMAR(P=0.012)	From 459±81 μm to last follow-up: 243±58 μm(P=0.012) (P=0.721 vs ranibizumab)
Bui et al66	Retrospective	2	16 BEV IVT +4IVTA7 BEV +1 IVTA	DEX	NR	2 DEX	From 20/60 Snellen to 3 months: unchangedFrom 20/400 Snellen to 3 months: unchanged	From 456 to 238 μm after first DEX, 277 μm after second DEX From 618 to 336 μm	1 cataract surgery2 IOP rise
Seibel et al67	Retrospective comparative	5 DEX	None	DEX	At least 12 months	1–2 DEXBEV (range 1–10)IVTA (range 1–3)	DEX: 0.8 logMAR, unchangedBEV: 0.8 logMAR, 1 month, after last IVT0.7 logMARIVTA: 0.8 logMAR, unchanged	DEX: from 440 μm to 4 weeks 265 μm(P=0.049BEV: from 479 μm to 4 weeks 362 μm (P=0.01)IVTA: from 454 μm to 4 weeks 314 μm (P=0.034)	NR
		38 BEV		BEV
		35 IVTA		IVTA
Tarmann et al68	Retrospective	4	BEV IVT in 3 eyesBEV IVT + panretinal laser photocoagulation and IVTA in 1 eye	DEX	NR	NR	From 20/100 Snellen to 2–4 weeks 20/50 to 10 weeks 20/80 Snellen to 14–17 weeks: 20/100Snellen	From 616 μm to 2–4 weeks: 399 μm10 weeks: 393 μm14–17 weeks: 568 μm	1 eye IOP >25 mmHg

Abbreviations: BCVA, best corrected visual acuity; BEV, bevacizumab; CMT, central macular thickness; DEX, dexamethasone implant; IOP, intraocular pressure; IVT, intravitreal; IVTA, intravitreal triamcinolone acetonide; NR, not reported; VEGF, vascular endothelial growth factor.

IOP increased in some eyes,63,64,66 all successfully treated by topical hypotonizing therapy. Cataract development in these cases64–66 could be caused by DEX or the radiation therapy.

Retinitis pigmentosa

The exact pathogenesis of macular edema, whether it is related to chronic and low-grade inflammatory process69 or to autoimmune process as antiretinal antibodies70 or to the failure of the retinal pigment epithelium pumping mechanism, is unknown as yet.71 Treatments attempted include topical and systemic administration of CAI,71 NSAIDs, retinal laser photocoagulation, vitrectomy surgery,72 and IV anti-VEGF.73 Also, IV corticosteroids injections have been performed as these drugs may modulate the inflammatory mediators and the autoimmune process.74–76

The studies reporting on the use of DEX in macular edema related to retinitis pigmentosa consist of case report studies, which include only a few eyes (Table 7).77–80 Nevertheless, an anatomical and functional improvement has been shown, but a relapse of macular edema occurred before 6 months from the implant77 and an additional DEX was required in some cases.77,78 DEX implant proved to be safe with an IOP rise >21 mmHg recorded in only one eye.78

Table 7

DEX implant in retinitis pigmentosa

Reference	Study design	No of eyes	Previous treatment	Treatment	Follow-up	Retreatment	BCVA	CMT	Complications
Srour et al77	Retrospective	4	CAIs in all cases subtenon TA 1 caseNSAIDs in 2 cases	DEX	6 months	2 DEX in 2 eyes after 3 months	From 20/160 to 6 months: 20/125 after 1 DEX	From 443±185 μm to 6 months: 305±124 μm after 1 DEX	None
Ahn et al78	Case report	2 eyes of one patient	CAIsAnti-VEGF IVT	DEX	12 months	2 DEX in 1 eye 6 months after DEX	From 20/100 to 12 months: 20/60 REFrom 20/150 to 12 months: 20/100 LE	From 631 μm to 12 months: 531 μm REFrom 681 μm to 12 months: 499 μm LE	IOP riseIOP>21 mmHg
Saatci et al79	Case report	2 eyes of one patient	Topical CAIs	1 DEX	7 months	NR	From 2/10 to 1 week: 4/10 both eyes3 months: 2/10 both eyes	NR	None
Patil and Lotery80	Case report	1	Topical CAIsDepo-Medrone ParabulbarAnti-VEGF IVTIVTACryotherapy	1 DEX	10 months	NR	From 1.01 logMAR to 6 weeks: 0.89 logMAR	From 559 μm to 6 weeks: 271 μm	None

Abbreviations: BCVA, best corrected visual acuity; CAIs, carbonic anhydrase inhibitors; CMT, central macular thickness; DEX, dexamethasone implant; IOP, intraocular pressure; IVT, intravitreal; IVTA, intravitreal triamcinolone; LE, left eye; NR, not reported; NSAIDs, nonsteroidal anti-inflammatory drugs; RE, right eye; TA, triamcinolone acetonide; VEGF, vascular endothelial growth factor.

DEX implant in macular edema after retinal surgery

DEX implant was used also in case of macular edema secondary to PPV for epiretinal membrane or macular hole or scleral buckling (Table 8).81–85 In all cases, an anatomical and functional improvement was shown, even though in 2 cases, multiple DEX implants were performed because of recurrent macular edema.82 Additionally, the use of DEX allowed resolution of severe choroidal inflammation detected in 1 case following scleral buckle surgery.85

Table 8

Published studies on the use of DEX implant for other conditions

Reference	Study design	No of eyes	Previous treatment	Primary treatment	Follow-up	Retreatment	BCVA	CMT	Complications
Furino et al81	Retrospective	8 PPV + ILM peeling + cataract surgery	Diclofenac sodium and betamethasone drops	DEX	6.75±0.71 month	NR	From 20/50 to 20/23P<0.00001	From 438±45 μm to 296±49 μmP<0.00001	No eye IOP >18 mmHg
Taney et al82	Retrospective	5 PPV with ERM peeling	Topical prednisolone 1%Topical NSAIDsSubtenon TA IVTA in 1 eyeAnti-VEGF IVT in 3 eyesAnti-VEGF IVT 1 eye	DEX	NR	1 DEX in 3 eyes9 DEX in 1 eye7 DEX in 1 eye	3 Snellen lines improvement in 3 eyes at 4–6 weeks after DEX1 Snellen line improvement in 1 eye at 4–6 weeks after DEXNo BCVA improvement in 1 eye at 4–6 weeks after DEX	Mean CMT decrease of 106 μm (range 56–155 μm) in 4 eyes at 4–6 weeks after DEXNo CMT improvement in 1 eye at 4–6 weeks after DEX	1 eye IOP >25 mmHgCataract in 1 out of the 2 phakic eyes
Merkoudis and Granstam83	Case report	1 PPV + ILM peeling and C2F6 tamponade + cataract surgery	IVTATopical NSAIDsOral CAIAnti-VEGF IVT	1 DEX	10 months	NR	From 20/200 to 2 months: 20/40	Reduction of CMT 2 months after DEX	None
Georgalas et al84	Case report	1 PPV + ILM peeling cataract surgery	Topical steroidsSubtenon steroidsIntravitreal steroids	1 DEX	6 months	NR	From counting fingers to 1 week: 6/36	From 640 μm to 1 week: 383 μm	None
Bonfiglio et al85	Case report	1 scleral buckling + cryopexy	Oral prednisoloneOral CAITopical prednisoloneTopical NSAIDsTA Subtenon	1 DEX	6 months	NR	From 0.70 to 6 months: 0.20logMAR	From 510 μm to 6 months: 290 μm	None

Abbreviations: BCVA, best corrected visual acuity; CAI, carbonic anhydrase inhibitor; CMT, central macular thickness; DEX, dexamethasone implant; ERM, epiretinal membrane; ILM, inner limiting membrane; IOP, intraocular pressure; IVT, intravitreal; IVTA, intravitreal triamcinolone; NR, not reported; NSAIDs, nonsteroidal anti-inflammatory drugs; PPV, pars plana vitrectomy; TA, triamcinolone acetonide; VEGF, vascular endothelial growth factor.

Conclusion

The use of DEX implant for all of the aforementioned macular pathologies merits consideration, and the results reported can support the use of DEX implant on a case-by-case basis with the aim of improving patient outcomes in many macular pathologies.

In many of these cases, DEX implant allowed a reduction of CMT with an improvement of BCVA, even if, at long term, many eyes required retreatment because DEX implant started to lose its efficacy, sometimes at 3 months after the injection.

Many of these cases were refractory to previous treatments, and DEX implant was administered as the last treatment option. Consequently, the functional results provided may be influenced by the lateness of DEX implant use. Therefore, considering that many of the reported macular pathologies may be difficult to treat and that some of them are not especially uncommon, having an awareness of a new treatment option and its influence on the clinical course of the disease may represent a great assistance in clinical practice. Furthermore, the use of DEX remains the only solution in treating macular edema in vitrectomized eyes where the efficacy of other IV drug injections, such as anti-VEGF, is lost due to their pharmacokinetic properties.

DEX implant-related adverse events in this expanding-use scenario are consistent with those previously documented for the DEX treatment of diabetic macular edema, uveitis, and retinal vein occlusion.10,86,87 In the cases that we analyzed, cataract was reported in up to 33% of the eyes after 2 DEX implants,24 and the occurrence of ocular hypertension (IOP ≥25 mmHg) from 6%38 to 31%,32 all treated with topical therapy.

In conclusion, DEX implant may allow less frequent anti-VEGF treatment24,65 and therefore, the advantages for the patient are clear: the need to undergo stressful treatment is removed while ocular and systemic adverse effects are reduced.