SURVEY OF OPHTHALMOLOGY VOLUME 58 � NUMBER 4 � JULY–AUGUST 2013

MAJOR REVIEW

Intraocular Pressure Monitoring Post IntravitrealSteroids: A Systematic ReviewWeerawat Kiddee, MD,1,2 Graham E. Trope, MB, PhD, FRCSC,1

Lisa Sheng, MD, MPH, PhD,3 Laura Beltran-Agullo, MD,1

Michael Smith, MBChB, FRCOphth,4 M. Hermina Strungaru, MD, PhD,1

Jasrajbir Baath, MD,5 and Yvonne M. Buys, MD, FRCSC1

1Department of Ophthalmology and Vision Sciences, Toronto Western Hospital, University of Toronto, Toronto, Canada;2Department of Ophthalmology, Faculty of Medicine, Prince of Songkla University, Hatyai, Songkhla, Thailand; 3Institutefor Clinical Evaluative Sciences, Toronto, Canada; 4Royal Devon and Exeter Hospital, Exeter, United Kingdom; and5Department of Ophthalmology, Faculty of Medicine, University of Ottawa, Ottawa, Canada

� 2013 byAll rights

Abstract. The use of intravitreal (IVT) corticosteroids for treatment of posterior segment diseases hasincreased significantly over the last decade. A commonly recognized complication of IVT steroids issecondary ocular hypertension (OHT) that can occur immediately secondary to direct intraocularvolume increase or weeks to months later as a result of increased outflow resistance. We performeda meta-analysis and found 32% (95% confidence interval, 28.2--36.3) of individuals developed OHTfollowing 4 mg IVT triamcinolone, 66% (50.2--78.8) and 79% (72.2--84.5) following 0.59 and 2.1 mgfluocinolone implant, respectively, and 11% (6.4--17.9) and 15% (9.2--24.3) following 0.35 and 0.7 mgdexamethasone implant, respectively. Risk factors included pre-existing glaucoma, higher baselineintraocular pressure (IOP), younger age, OHT following previous injection, uveitis, higher steroiddosage, and fluocinolone implant. Most cases of OHT can be controlled medically; up to 45%following fluocinolone implant require surgery, however. We suggest a protocol to monitor IOP afterIVT steroid injection/implantation that includes checking IOP within 30 minutes after injection,followed by 1 week after IVT triamcinolone and 2 weeks after implant insertion, then every 2 weeks forthe first month and monthly for up to 6 months after IVT triamcinolone and dexamethasoneimplantation and 9 months after fluocinolone implantation. (Surv Ophthalmol 58:291--310,2013. � 2013 Elsevier Inc. All rights reserved.)

Key words. ocular hypertension � steroid-induced glaucoma � intravitreal steroid injection �sustained-release intravitreal implants

I. Introduction

A. STEROIDS AND INTRAOCULAR PRESSURE

Exogenous steroids administered topically (byperi- and/or intraocular injection) or orally cancause secondary ocular hypertension (OHT).5,197

The risk of inhaled nasal sprays causing secondaryOHT is less clearly defined.200 The risk of steroid-

291

Elsevier Inc.reserved.

induced OHT varies by route of administration,duration of treatment, type of steroid, and pre-existing history of glaucoma, among other factors.For example, approximately 40% of the generalpopulation developed OHT after a 4--6 week courseof topical 0.1% dexamethasone, so-called steroidresponders, compared with nearly 100% of patients

0039-6257/$ - see front matterhttp://dx.doi.org/10.1016/j.survophthal.2012.08.003

292 Surv Ophthalmol 58 (4) July--August 2013 KIDDEE ET AL

with primary open-angle glaucoma (POAG) ornormal-tension glaucoma.3,4,138

The etiology of steroid-induced OHT has beenlinked to the myocilin gene that is upregulated bysteroid treatment in cultured trabecular meshworkcells.158 Stone et al reported that myocilin genemutations were also associated with development ofPOAG.180 Although steroid-induced OHT usuallyreverses after cessation of steroid administration, itremains an important risk factor for the developmentof glaucomatous optic neuropathy.3,196 Aprotocol forintraocular pressure (IOP) monitoring followingsteroid administration is essential to limit visualfunction loss secondary to steroid-induced glaucoma.

B. INTRAVITREAL STEROIDS

The use of intravitreal (IVT) corticosteroids hasincreased significantly over the past 10 years becauseof their beneficial effects on macular edema second-ary to uveitis, venous occlusive disease, diabetes, andchoroidal neovascularization.13,26,44,74,90,98,120,184,189

The two main methods of IVT steroid delivery areinjection and implantation of sustained-release de-vices. Despite the knowledge that IVT steroids maycause significant elevations of IOP, with 1--8% and upto 45% of patients reportedly requiring surgery foruncontrolled IOP after IVT triamcinolone acetonide(TA) injection and fluocinolone acetonide (FA)implantation, respectively, there is no consensusregarding the monitoring of IOP.23,156,191 There area few published reviews on IOP elevation followingIVT steroids; we found no systematic literaturereview or meta-analysis of this important topic,however.97,108,191

We provide the results of a systematic literaturereview and meta-analysis. Our objectives are todescribe the frequency, onset, duration, magnitude,management, and risk factors of IOP elevationfollowing IVT steroids and to develop a best-practicerecommendation for IOP surveillance following IVTsteroid administration.

II. Intravitreal Steroid Delivery Methods

A. INTRAVITREAL INJECTION

The injection of steroid directly into the vitreousallows a large bolus of drug to be administered toachieve a desired therapeutic level at the targettissue while minimizing systemic absorption andside effects. The most common steroids used for anIVT injection are TA and dexamethasone.

1. Triamcinolone Acetonide Intravitreal Injection

TA (Kenalog, Bristol-Myers Squibb, New York, NY)is a crystalline steroid that is minimally water soluble

injected in a suspension form. IVT TA had beenstudied in different doses: 1, 2, 4, 5, 6, 8, 10, 20, and25 mg.48,95--97,101--103,106,107,133,164 In most studies,a dose of 4 mg is used. The therapeutic responseand duration of action can last approximately 3months following 4 mg IVT TA.20

2. Dexamethasone Intravitreal Injection

Dexamethasone (dexamethasone sodium phos-phate, Weimer Pharma GmbH, Rastatt, Germany) ismore potent with a shorter duration of actioncompared with TA.199 When given intravitreally ithas been shown tobe safe indosages up to 1mg.72 IVTdexamethasone had been studied in two doses: 0.4and 0.8 mg.33 Although the short duration of actionof dexamethasone may minimize side effects it alsomay limit its therapeutic effect. A single injection ofIVT dexamethasone did not have a beneficial effecton diabetic macular edema (DME).33 There are fewstudies reporting IVT dexamethasone for treatmentof posterior segment diseases.

B. SUSTAINED-RELEASE INTRAVITREAL IMPLANT

(FIG. 1)

Given the short half-life of IVT steroids, repeatedinjections may be required to maintain therapeuticeffects, increasing the risk of injection-related compli-cations such as retinal detachment, vitreous hemor-rhage, and endophthalmitis.20,72 This has led to thedevelopment of sustained-release implants.60 IVTimplants are classified as either non-biodegradableor biodegradable. Non-biodegradable implants pro-vide more accurate drug release and longer durationof action than thebiodegradable implants, but requiresurgical removal.25,187

1. Triamcinolone Acetonide Sustained-ReleaseImplant

I-vation (SurModics, Eden Prairie, MN) (Fig. 1A)is a helical-shaped non-biodegradable metallicimplant designed to deliver TA for 24 months.Phase II trials of I-vation for DME were suspendedby Merck because photocoagulation was moreeffective than IVT TA as a treatment for DME.19,57

2. Fluocinolone Acetonide Sustained-releaseImplant

a. Retisert

Retisert (Bausch and Lomb, Rochester, NY)(Fig. 1B) is a non-biodegradable IVT FA implantthat is inserted via the pars plana. The device issutured to the sclera and releases FA at a controlledrate for approximately 30 months. Retisert had been

Fig. 1. Sustained-release intravitreal steroid implants. (A) I-vation (SurModics). (B) Retisert (with dime for sizecomparison). (Courtesy of Bausch and Lomb.) (C ) Iluvien (with grain for size comparison). (Courtesy of AlimeraSciences.) (D) Ozurdex (with an applicator). (Courtesy of Allergan Inc.)

INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID 293

studied in two doses: 0.59 and 2.1 mg. The UnitedStates Food and Drug Administration (U.S. FDA)approved 0.59 mg Retisert for the treatment ofnoninfectious posterior uveitis in 2005.91

b. Iluvien

Iluvien (Alimera Sciences, Alpharetta, GA)(Fig. 1C) is a non-biodegradable IVT FA implant thatis inserted into the vitreous cavity via the pars planathrough a transconjunctival self-sealing wound sim-ilar to an IVT injectionwith a 25-gaugeneedle. Iluvienimplant releases FA at a rate of 0.2 mg per day over 18months.110 Iluvien was shown to be effective fortreating DME in a phase III clinical trial. In 2011,however, the U.S. FDA failed to approve Iluvien totreat DME because of safety concerns.A

3. Dexamethasone Sustained-release Implant

Dexamethasone sustained-release implant (Ozur-dex, Allergan Inc., Irvine, CA) (Fig. 1D) (formerlycalled Posurdex) is a biodegradable sustained-release

device inserted into the vitreous cavity transconjuncti-vally through a 23-gauge needle releasing dexameth-asone over 6 months. Ozurdex had been studied intwo doses: 0.35 and 0.7 mg.74 The U.S. FDA approved0.7 mg Ozurdex for the treatment of macular edemafollowing retinal vein occlusion in June 2009. InSeptember 2010, 0.7 mg Ozurdex was U.S. FDA--approved to treat non-infectious intermediate andposterior uveitis.140 Ozurdex for treatment of DME iscurrently under investigation.26

III. Pharmacokinetics of IntravitrealSteroids

IVTsteroids are eliminated from the vitreous by twomain mechanisms: the anterior pathway via aqueoushumor that flows through the anterior chamberangle and a posterior pathway via permeationthrough the retina across the blood--retinal barrierinto retinal and choroidal microvasculature.56,60 Theduration of action of IVT-administered steroidsdepends on the retention, distribution, and rate of

294 Surv Ophthalmol 58 (4) July--August 2013 KIDDEE ET AL

excretion out of the vitreous. The longer the half-lifeof steroid injected in the vitreous cavity, the greater isthe duration of effect.47,187

A. INTRAVITREAL STEROID INJECTION

Dexamethasone sodium phosphate IVT injectionhas been studied since the 1980s.72,183 In a rabbiteye model maximum aqueous concentration oc-curred 1.5 hours after IVT injection with a half-lifeof approximately 3 hours. Clearance from thevitreous was within 72 hours.131 The short durationof dexamethasone limits its utility.

Triamcinolone acetonide is a crystalline steroidsuspension that is minimally water soluble. It formswhite crystals that settle in the inferior vitreous afterIVT injection.177 Owing to the minimal-water-soluble property, clearance of TA from the vitreousis slower in comparison with dexametha-sone.20,170,171,177 After IVT injection, TA initiallyconcentrates near the injection site before distrib-uting throughout the entire vitreous cavity. Humaneye studies show that, following a single injection ofTA, concentrations initially decrease rapidly in thefirst 2 months, followed by a subsequent prolongedrate of elimination. The fast phase of clearancereflects the elimination of water-soluble TA, and theslow phase reflects the slow dissolution of TA crystalsinto the vitreous.20,42

In addition to the pharmacokinetic properties ofIVT TA, dose, phakic, and vitrectomized status of theeye affect the duration of action. In animal modelsincreased dose of IVTTA (4, 6, 16, 20, and 25mg) wasdirectly related to increased half-life.100,109,117 Simi-larly, in human eyes 4 mg IVT TA has a reported half-life of 18.6 days in vitreous compared with 30 daysfollowing 20 mg IVT TA.20,42 In animal studies TAcrystals can be visualized in the nonvitrectomizedvitreous for up to 23--41 days. TA levels decreased 1.5times more rapidly in vitrectomized compared withnonvitrectomized eyes.45 In human eyes, the meanelimination half-life of TA in nonvitrectomized eyeswas 15.4--18.6 days compared with 3.2 days invitrectomized eyes.20 Studies suggest that 4 mg IVTTA has approximately 3--4 months duration oftherapeutic effect in nonvitrectomized eyes.8,20,145

The shortened mean elimination half-life invitrectomized and aphakic eyes can be explained byclearance mechanisms. Aphakia allows TA distribu-tion in the anterior chamber, facilitating clearance ofTA through the trabecular meshwork. In the vitrec-tomized eye, the vitreous cavity is filled with fluidinstead of normal-viscous vitreous gel, allowing thedrug to circulate more easily, distribute thoroughly,and therefore facilitate absorption and promoteclearance via the posterior pathway.45,56,60

B. SUSTAINED-RELEASE INTRAVITREAL IMPLANT

Retisert is a scleral-fixated, nonbiodegradableIVT FA implant. FA is a poorly water-solublesynthetic steroid. Logically, the lower water solubil-ity should allow longer drug retention in thevitreous. Each implant consists of a central elasto-mer core of 0.59 mg FA that is delivered at an initialrate of 0.6 mg/day over the first month, decreasingto a steady rate of 0.3--0.4 mg/day over approxi-mately 30 months.90,92 The pharmacokinetics ofRetisert depends on several factors, including drugsolubility, permeability of polymers, protein con-centration around the aqueous medium, and rateof drug clearance out of the vitreous.78

Ozurdex is a free-floating biodegradable IVTdexamethasone implant that consists of dexametha-sone embedded in a degradable polymer, resulting ingradual release of medication after the polymerundergoes hydrolysis to carbon dioxide and water.51

For this reason, dexamethasone is slowly distributedinto vitreous cavity over a sustained period andeventually no device remains. Animal studies showthat a peak concentration of dexamethasone in thevitreous at 2 months is followed by a relatively rapiddecline between 2 and 3 months. The IVT concentra-tion then reached a steady state through 6 months.36

The pharmacokinetics of 0.7 mgOzurdex is similar innonvitrectomized and vitrectomized eyes.37

IV. Mechanism of Intravitreal Steroid-induced Secondary Ocular Hypertension

Steroid-inducedOHT is emerging as an increasingproblem following IVT TA injection, IVT FA implan-tation, and IVT dexamethasone implantation.1,13,23,26,29--31,43,67,74--77,90,91,97,102,103,114,130,141,154--156,160,

162,165,167,176,178,184,191,195,198,199 Although the exactmechanism of steroid-induced secondary OHT isunknown, several theories exist. The immediateshort-term course of OHT after IVT injection couldbe explained by the direct increase of intraocularvolume. Physical obstruction of trabecular mesh-work by TA precipitate also occurs.39,149,173,176

Finally, long-term elevation of IOP following IVTinjection or implantation of sustained-release de-vices results from increased aqueous outflow re-sistance caused by steroid-induced trabecularmeshwork alteration.147,169,176,186,196

A. DIRECT VOLUME EFFECT

An acute increase in vitreous volume immediatelyfollowing IVT injection can induce a short-termincrease of IOP.21,34,83,84,115,118,126 Benz et al de-scribed the natural history of IOP within the first 30minutes after IVT injection of 0.1 mL of TA. If there

INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID 295

was vitreous reflux following IVT injection, the IOPdeclined immediately after injection and rapidlynormalized over 10 minutes. If no vitreous refluxwas observed, the mean IOP increased significantlyfrom 15.5 mm Hg at baseline to 45.8 mm Hgimmediately after injection and then graduallydeclined over 30 minutes. Approximately 90%(95% confidence interval [CI], 85.8-95.2) of pa-tients without vitreous reflux had an IOP !24 mmHg at 30 minutes post injection.21

A biomechanical model determining the effect ofintraocular volume changes on IOP showed thatimmediately after IVT injection of 4 mg of 0.1 mLTA, the mean IOP was 57.9 � 11.4 mm Hg. IOP wassignificantly elevated, with a mean of 40.6 � 12.1mm Hg compared with pre-injection. The meanIOP dropped to 9.4 � 4.9 mm Hg after paracentesis.In all eyes IOP was less than 20 mm Hg within 120minutes following IVT injection. The increase inIOP depends on the overall volume of the treatedeye. Smaller, hyperopic eyes had higher immediateIOP increase compared to larger, myopic eyes whenan equal amount of IVT TA was administered.126

The immediate increase in IOP is related to thevolume of medication injected. A total of 2.9% ofpatients had an IOP of $25 mm Hg at 30 minutesafter 0.05 mL IVT bevacizumab, compared with7.1% after 0.1 mL IVT TA.21,83 Bakri et al studiedIOP changes within 30 minutes after IVT injectionof 0.1 mL TA, 0.09 mL pegaptanib, and 0.05 mLbevacizumab. At 30 minutes post injection, meanIOP was highest in the TA group, followed by thepegaptanib and bevacizumab groups. The volumeinjected could explain this difference. The highestIOP recorded was 60 mm Hg, 10 minutes afterreceiving IVT TA. (There was no report of IOPimmediately after injection.) Seven percent (7%) ofeyes receiving IVT TA were treated with hypotensivetherapy. Eyes with pre-existing glaucoma (all in-jection types) were statistically significantly less likelyto have an IOP !35 mm Hg at 10 minutes postinjection.14

Kim et al recorded IOPs immediately after IVTTA injection and at 5-minute intervals thereafteruntil IOP was !30 mm Hg. Immediately afterinjection, mean IOP significantly increased from 14mm Hg at baseline to 44 mm Hg, with a maximumIOP of 87 mm Hg. An IOP of $30 mm Hg wasobserved in 79%. The incidence of IOP $30 mmHg fell to 30% within 5 minutes and by 30 minutesall eyes were !30 mm Hg. Eyes with pre-existingglaucoma had statistically significant IOP spikesand took longer to normalize. They also reportedthat significantly more IOP spikes were observedwith a smaller bore needle, likely due to less fluidreflux via the needle tract.118

A prospective randomized controlled trial (RCT)investigating the efficacy of paracentesis followingIVT TA found significantly elevated IOP immediatelyfollowing injection in the group randomized to noparacentesis (baseline 14.6� 2.7mmHg increased to46.7 � 8.3 mm Hg) compared with an immediatedecreased IOP in the paracentesis group (baseline15.3� 1.7 mmHg decreased to 7.8� 1.5 mmHg). At15 minutes, however, there was no statistical differ-ence in post-injection IOP between the groups. Theypostulated IOP normalized as a result of reducedaqueous formation and increased aqueous outflow.34

IOP following IVT injection of 0.1 mL of 4mg TA wassignificantly higher in phakic eyes than in pseudo-phakic eyes (p! 0.001) at 10, 20, 30, and 40 minutespost injection.115

In summary, a short-term course of OHT imme-diately following IVT TA can occur as a result ofa rapid increase in intraocular volume. Risk factorsinclude hyperopia, phakia, prior history of POAG,larger volume of injection, smaller bore needle, andno vitreous reflux during injection (see Table 2 insection V.B).14,21,83,115,118,126

Peak IOP typically normalizes within 15--120 min-utes after injection; this may take longer in cases ofpre-existing glaucoma, however.14,21,34,118,126 Thelong-term consequences of a high transient IOP riseare unclear. An acute IOP elevation can causeblockage of axonal transport, and the potential fordamage of ganglion cells should be considered,especially in patients with glaucomatous optic neu-ropathy.159 In addition there is a risk of vascularocclusive events secondary to elevated IOP.62 Presentlythere is no evidence to support using prophylactictopical antiglaucoma agents to prevent an immediateIOP spike following IVT injection but this is worthy ofconsideration until evidence becomes available. Para-centesis diminishes this risk of IOP spike34 and shouldbe considered in vulnerable eyes with preexistingglaucomatous optic neuropathy. Given the high pro-portion of elevated IOP immediately following in-jection, with the potential for ganglion cell or vascularcompromise, IOP should be checked 30minutes afterinjection, and, if elevated, consideration should begiven to hypotensive therapy or paracentesis withfurther close IOP monitoring.

B. PARTICULATE MATTER OBSTRUCTING THE

TRABECULAR MESHWORK

Fine white crystalline opacities in the inferioranterior chamber angle (pseudohypopyon)havebeenreported following IVT TA injection.39,40,149,151,168,173,175,176 The particulate matter can occlude thetrabecular meshwork and cause secondary OHT inearly period following IVT TA injection.176 The

296 Surv Ophthalmol 58 (4) July--August 2013 KIDDEE ET AL

reported prevalence of pseudohypopyon after IVT TAis 0.2--2%.99,149,151 It usually occurs within 3 days, asearly as the first day following injection, and resolveswithin 2--6 weeks.149,151 Pseudohypopyon occursmorefrequently in aphakic, pseudophakic, and vitrectom-ized eyes.149,151,175 The TA crystals presumably leakthrough the ruptured anterior hyaloid face into theanterior chamber between weak zonules.39

Pseudohypopyon secondary to IVT TA has beenassociated with elevated IOP with some casesrequiring a glaucoma drainage device to controlIOP.176 The presence of a hypopyon post IVT TAcan be a sign of endophthalmitis; in the absence ofother signs of inflammation, however, the possibilityof a pseudohypopyon should be considered withclose monitoring of IOP.

C. TRABECULAR MESHWORK DYSFUNCTION

Although the exact mechanism responsible forsteroid-induced outflow resistance is uncertain,possible mechanisms have been proposed.

1. Increased Extracellular Matrix Deposition inMeshwork

The trabecular meshwork consists of three regions:juxtacanalicular, corneoscleral, and uveal meshworks.The inner wall of Schlemm’s canal marks the outerborder of the juxtacanalicular meshwork whichserves as the major source of aqueous humor outflowresistance. The extracellular matrix (ECM) locatedbetween the layers of the juxtacanalicular meshworkcells is composed of type III collagen.196 Theoreti-cally, obstruction of trabecular beams or decrease inintratrabecular spaces could result in IOP elevation.

Steroids may alter the rate of protein synthesisand inhibit degradation of ECM, leading to aggre-gation of an excessive ECM.116,179,196 Morphologicaland histological studies of eyes with steroid-inducedglaucoma have shown an increased deposition ofECM in the trabecular meshwork causing increasedresistance to aqueous humor outflow and thedevelopment of OHT and secondary OAG.94,185,186,196 Recently, Kubota et al found that eyes thatdeveloped glaucoma following IVT steroid had ECMalterations resembling those after topical corticoste-roid treatment, with a decrease in intertrabecularspaces.129

2. Inhibition of Trabecular Meshwork CellFunctions

a. Inhibition of Phagocytosis

Trabecular meshwork cells are actively phagocyticand function in the removal of debris and pigmentmaterial from the outflow channels and also

facilitate ECM turnover.202 Reduction in phagocyticactivity is one possible mechanism of steroid-induced glaucoma by down-regulating one of itsbinding receptors.15,201,202 Dexamethasone inhibitsphagocytic activity of cultured trabecular meshworkcells, resulting in accumulation of debris andreduction of outflow facility.147

b. Stabilization of Lysosomes

Steroids stabilize lysosomes by strengthening themembrane, resulting in accumulation of polymer-ized and hydrophilic mucopolysaccharides. Theaccumulation of more polymerized and morehydrophilic mucopolysaccharides causes narrowingof the trabecular spaces and increased outflowresistance, consequently increasing IOP.3,61,176,194

In addition to inhibition of phagocytosis andstabilization of lysosomal membranes, steroids causea significant increase in trabecular cell and nucleussize, stacked arrangements of endoplasmic reticulum,and proliferation of the Golgi apparatus resulting inincrease outflow resistance.194

3. Alterations in Trabecular MeshworkCytoskeleton

The trabecular meshwork cytoskeleton functionsin regulating aqueous outflow.169 Steroids altertrabecular cytoskeletons, causing a progressive re-organization of microfilament into polygonal lattice-like cross-linked actin networks that are reversible onwithdrawal of steroids.52 The reorganization of thetrabecular cytoskeleton alters cell function by inhibit-ing trabecular cell migration and proliferation.52,53

4. Increase Cell Adhesion Molecules

Cell adhesion molecules are involved in cell-to-cell interactions. Steroid treatment causes gapjunctional complex realignment and increasedexpression of the tight junction protein or zonularoccludens. An alteration of trabecular tissue perme-ability causes reduction of hydraulic transendothe-lial flow through trabecular cells and could result inincreased aqueous outflow resistance.190

In conclusion, steroids cause an accumulation ofECM, inhibition of various trabecular cell functions,and alterations in trabecular cytoskeleton and celladhesion molecules. This results in chronic impair-ment of aqueous drainage and increased IOP.

V. Systematic Literature Review andMeta-analysis

We performed a systematic review utilizing thepreferred reporting practice for systematic reviews

INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID 297

and meta-analysis statement (see the Methods ofLiterature Search section).139

The quality of randomized trials was assessed usingthe Cochrane collaboration’s tool of assessing risk ofbias.80 The main outcome measure was the pro-portion of patients with an IOP elevation. Secondaryoutcomes included onset, duration, magnitude,management, and risk factors for IOP elevation.The results were subdivided by corticosteroid type,dose, mode of delivery (injection or implant) andunderlying diagnosis. Proportions were pooled usinga random-effects model if studies were homogenousas indicated by the heterogeneity test.

A. RESULTS

After screening 1,338 abstracts, 174 full textarticles were reviewed resulting in 129 eligiblestudies (115 TA injection, 1 dexamethasone in-jection, 7 FA implant, 6 dexamethasone implant)for the qualitative syntheses and meta-analysis.Figure 2 summarizes the results of the initial searchand publication selection.

1. Prevalence of OHT Post IVT Steroid (Table 1)

a. Triamcinolone Acetonide Intravitreal Injection

Four mg TA was the most common dosage anddrug reported with a pooled proportion of eyes withIOP $21 mm Hg or $10 mm Hg from baseline of32.1% (95% CI, 28.2--36.3). The results for the otherdoses are shown in Table 1. The risk of OHT wassignificantly greater for 25 mg IVT TA (45.9%; 95%CI, 36.9--55.3) compared with 4 mg.

b. Dexamethasone Intravitreal Injection

There was only one eligible study that reported16.7% of eyes receiving 0.8 mg IVT dexamethasoneand no eyes receiving 0.4 mg having an IOP O21mm Hg.33

c. Fluocinolone Acetonide Intravitreal Implant

FA implant has been studied in two doses: 0.59and 2.1 mg. The pooled proportion of patients witha $10 mm Hg rise from baseline or an IOP O21mm Hg was 65.9% (95% CI, 50.2--78.8) following0.59 mg and 79% (95% CI, 72.2--84.5) following 2.1mg FA implant. If OHT was defined as an IOP $30mm Hg, the pooled proportion of patients withOHT was 61.4% (95% CI, 54.4--68.0) following 0.59mg FA implant. There was no statistically significantdifference based on dose.

d. Dexamethasone Intravitreal Implant

An IOP rise from baseline $10 mmHg or an IOP$25 mm Hg occurred 10.9 % (95% CI, 6.4--17.9)

and 15.3% (95% CI, 9.2--24.3) following 0.35 and0.7 mg IVT dexamethasone implant, respectively.

2. Time Course of Ocular HypertensionFollowing Intravitreal Steroid

The time course of steroid-induced OHT varies bytype and dose of medication and method ofadministration.

a. Triamcinolone Acetonide Intravitreal Injection

Pooled results from eligible RCTs showed an onsetof OHT following IVT injection of 4 mg TA was 2--4weeks and from nonrandomized studies was 1--8weeks.9,10,28,32,40,49,54,86,112,135,144,146,148 Onset of OHTwas reported as early as 1 week following injection inseveral studies.9,10,28,86,111,137,151,176 Trabecular mesh-work occlusion by particulate matter could causeOHT within the first few days after injection.176 Anearly onset of OHT after 0.4 mg IVT TA was alsoshown in the Diabetic Retinopathy Clinical Research(DRCR) network’s study. OHT, defined as an IOPrise O10 mm Hg from baseline or an IOP $30 mmHg, occurred in 0.4% of eyes 4 � 3 days after initialinjection, with all requiring antiglaucoma medica-tion. Four percent (4%) of eyes receiving subsequentIVT TA injection developed OHT within 4 days andO50% needed IOP lowering treatment. According tothe DRCR network’s results, no TA precipitate wasdetected in the anterior chamber of these eyes. Noclear etiology of this early IOP elevation was pro-vided.57,137 Two retrospective studies found late onsetIOP elevation 10--14 weeks following injection.70,178

The latest onset of OHT after IVT TA was 20--24weeks in a small case series with IOPs of approxi-mately 50 mm Hg.193

For those eyes developing OHT following 4 mgIVT TA, the reported duration of OHT is 1--9months with maximum IOP within 2--12 weeks andreturning to baseline values within 4--9 months afterinjection.7,9,10,32,40,54,64,67,111,132,134,154,162

Few studies determined the time course of OHTafter 8 mg IVT TA. Ito et al found mean IOP startedto rise at 4 weeks following injection and reacheda maximum at 12 weeks.89 Duration of OHT is 6months, with mean IOP returning to baseline levelsat 6--9 months.89,152,153

For OHT following 20--25 mg IVT TA, thereported mean time of onset is 1--9 weeks afterinjection, with maximum IOP at 12 weeks.97,83 Themean time for IOP to return to baseline level is 5--9months.83,95,97,101--103,105--107,125

b. Dexamethasone Intravitreal Injection

There is only one study reporting OHT followingIVT dexamethasone injection. OHT occurred as

Fig. 2. Diagram showing article selection process.

298 Surv Ophthalmol 58 (4) July--August 2013 KIDDEE ET AL

early as the first day after injection and returned tobaseline values approximately 1 month afterinjection.33

c. Fluocinolone Acetonide Intravitreal Implant

Onset of OHT following IVT FA implant is within2--4 weeks, reaching a maximum at 24--28 weeks andreturning to baseline values approximately 9--12months after implantation.30,31,90,160

d. Dexamethasone Intravitreal Implant

There are no reports regarding the onset ofOHT following IVT dexamethasone implant; thetime to peak IOP, however, is 60 days followingimplantation, returning to baseline within 6months.26,75--77

B. RISK FACTORS (TABLE 2)

Several variables have been identified as possiblerisk factors for steroid-induced OHT, includingyounger age, uveitis, baseline IOP $15 mm Hg,pre-existing glaucoma, history of OHTwith previousIVT steroid, higher steroid dosage, and IVT FAimplant.

1. Patient-related Risk Factors

a. Age

A number of studies identify younger age as a riskfactor for OHT after IVT TA.27,81,90,101,136,154,164,174,197 Following 4 mg IVT TA the proportiondeveloping OHT was greater in those 45 years andyounger compared with those older than 45 years

TABLE1

Proportionof

EyesDevelopingOcularHypertension

Follow

ingIntravitreal

SteroidInjection/Implan

tation

Med

ication

Dose

Number

ofStudiesIncluded

Number

of

EyesIncluded

PooledPoint

Estim

atefor

ProportionofEyes

DevelopingOcu

lar

Hypertension(%

)95

%Confiden

ceInterval

Triam

cinoloneacetonide

4mg/

0.1mL

422,6,9--11,17,18,22,32,35,40--43,46,48--50,54,59,67,85,111,112,123,132--135,

144,148,150,154,161,164,165,172,174,178,182,183,188,190

3,65

432

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28.2--36.3

8mg/

0.2mL

489,133,152,153

319

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282,197

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114

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INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID 299

(p 5 0.006).174 Another study found that those 55years and younger had both a larger magnitude IOPelevation (p 5 0.02) and OHT less likely to becontrolled medically (p 5 0.009) than those olderthan 55.136 Roth et al reported a 16% reduction inOHT risk for every 10-year increase in age (p !0.001).164 Age, however, was not found to be a riskfactor in some studies.87,162,191

b. Sex

Reports on sex as a risk factor for OHT followingIVT steroids are controversial. One study found that,after adjusting for age, previous history of glaucoma,and retinal diseases, male sex was a significant riskfactor (odds ratio, 3.17; 95% CI, 1.38--7.27; p 50.006).136 A small prospective study also found malesex as a risk forOHT following 4or 25mg IVTTA(p50.029).27 Several studies, however, have not found sexwas a risk factor.2,97,101,154,191 Presently there isinsufficient data to make a conclusion.

c. Higher Baseline IOP

Several studies reported a baseline IOP $15 mmHg as a significant risk factor for OHT.12,153,165,191

Two studies determined the relative risk of OHTwith a baseline IOP $15 mm Hg as O2.178,179

Baseline IOP as a risk factor for OHT was notconfirmed in two other studies.27,87

d. History of Glaucoma

Patients with pre-existing glaucoma may have anincreased risk of OHT following IVT ste-roids12,153,165,191 and a higher peak IOP comparedwith nonglaucomatous eyes.191 A family history ofglaucoma may also be a risk factor for OHTfollowing IVT steroid.2

e. Underlying Ocular Disease

Among posterior segment diseases that requiredIVT steroid, only uveitis has been reported as a riskfactor for OHT after IVT TA injection.63,104

Our analysis of OHT following IVT TA injectionfound the highest prevalence of OHT in uveitispatients (42.7%; 95% CI, 28.4--58.3) followed bymacular degeneration (38.5%; 95% CI, 33.8--43.4),retinal vein occlusion (35.9%; 95% CI, 30.7--41.5),DME (32.3%; 95% CI, 27.5--37.5), and choroidalneovascular membrane (30.4%; 95% CI, 24.3--37.4).These differences, however, are not statisticallysignificant given the overlap of the 95% confidenceintervals. A similar conclusion was reached in twoother publications.81,178

Regarding underlying disease in those receivingIVT FA implants, defining OHT as an IOP rise of$10 mm Hg from baseline or an IOP O21 mm Hg,

TABLE 2

Risk Factors for Developing Ocular Hypertension Following Intravitreal Steroids

Risk Factors for OHT Immediately Following Injection Risk Factors for Later Onset OHT

Phakia Younger ageHyperopia UveitisPrior history of POAG Baseline IOP $15 mm HgSmaller bore needle Pre-existing glaucomaLarger volume of injection OHT following previous injectionNo vitreous reflux during injection Higher steroid dose

Fluocinolone acetonide intravitreal implantation

IOP 5 intraocular pressure; OHT 5 ocular hypertension; POAG 5 primary open angle glaucoma.

300 Surv Ophthalmol 58 (4) July--August 2013 KIDDEE ET AL

62.5% (95% CI, 55.1--69.4) and 79% (95% CI, 72.2--84.5) of uveitic eyes had OHT post 0.59 mg and 2.1mg FA implant, respectively. There were insufficientdata for a meta-analysis of other diseases. One studyreported 61.4% of DME eyes treated with 0.59 mgFA implant had an IOP $30 mm Hg.156

For eyes receiving dexamethasone IVT implants,there were insufficient studies to conduct a meta-analysis on eyes with uveitis or retinal vein occlusion.For DME, 15.7% (95% CI, 10.0--23.8) and 14.9%(95% CI, 10.2--21.3) developed OHT following 0.35mg and 0.7 mg dexamethasone IVT implant,respectively. In a RCT of chronic uveitis, 8.4% ofthe 0.35 mg group and 7.1% of the 0.7 mg grouphad OHT defined as an IOP $25 mm Hg.141 A 6-month RCT of dexamethasone IVT implant fortreating retinal vein occlusion showed that, of eyesreceiving single IVT implantation of 0.35 and 0.7mg, 3.9% and 4%, respectively, had an IOP $25 mmHg.75 An extended 12-month RCT by the same studygroup found that 32.8% of eyes with retinal veinocclusion were randomized to retreatment with 0.7mg had an IOP increase of $10 mm Hg frombaseline at any time point during the 1-year study.74

f. Underlying Systemic Disease

Diabetes is not usually considered a risk factor forOHT following IVT steroids.81,87,97,101,136 Jonasreported a rise of IOP O21 mm Hg post IVTinjection of 20 and 25 mg TA was statisticallyindependent of the presence of diabetes (p 5 0.74and p 5 0.37, respectively).97,101 Inatani et al alsodemonstrated that diabetes was not a risk for OHTfollowing 4 or 8 mg IVT TA (hazard ratio, 0.91; 95%CI, 0.47--1.61; p 5 0.760).87 One small retrospectivestudy however, proposed diabetes as a possible riskfactor for OHT following 4 mg IVT TA (p5 0.050).2

g. Secondary OHT after Repeat Intravitreal Steroid

Eyes with a history of OHT following IVT TA weremore likely to have OHT following a subsequentinjection.2,87,101,165,189 One study found the risk ofOHTwas three times greater in eyes with a history of

OHT following IVT steroids compared to those thatdid not develop OHT.165

h. Phakic/Pseudophakic and Vitrectomized/Nonvitrectomized Eye

Lens and vitrectomized status have not beenfound to be a risk factor for OHT following IVTsteroid.81,191

2. Medication-related Risk Factors

a. Type of Steroid

Our analysis showed that prevalence of OHT postIVT steroid was highest in FA implant groups,followed by IVT TA and IVT implantation ofdexamethasone (Table 1). Comparisons betweenstudies, however, are limited by the various defini-tions used for OHT.

b. Dosage of Steroid

We found a trend between increased dose ofsteroid and increased risk of OHT; this differencewas only statistically significant for 4 mg (32.1%;95% CI, 28.2--36.3) compared with 25 mg IVT TA(45.9%; 95% CI, 36.9--55.3), however.

c. Number of Injections

Roth reported a greater risk of OHT followingsubsequent injections, with 26.9% (95% CI, 14.1--29.9) developing OHT following a single injectioncompared with 34.7% (95% CI, 29.7--29.9) and42.6% (95% CI, 33.7--51.9) following two and threeIVT TA injections, respectively.165 Other investiga-tors reported that there was no difference in rates ofOHT for patients receiving multiple injectionsversus those receiving a single injection.81,178

C. MANAGEMENT

1. Medical Treatment

Most OHT following IVT TA injection can becontrolled medically.7,11,35,38,54,65,67,68,79,88,119,133,142

The reported proportion of patients requiring

INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID 301

hypotensive therapy to control IOP following 0.4 mgIVT TA is 15--64% of DME eyes, 30--41% of retinalvein occlusion eyes, 25--54% of choroidal neo-vascular membrane and macular degeneration eyes,and 15% of uveitic eyes.7,38,49,54,55,57--59,65--67,69,88,119,133,142,148,181 The mean number of topical antiglau-coma medications was 1.3 (range, 1--2.1).32,35,40,54,86,93,124,127,133,143,144,167,178

Following FA implantation, 49--78% of uveitic eyesrequired medical hypotensive therapy.29,90,91,155 Inone study of DME eyes, 61% required topicalantiglaucoma medication.156 A prospective non-randomized study reported 62% of retinal veinocclusion eyes required medical treatment for OHTafter FA implant.160 The mean number of topicalmedications prescribed following IVT FA was 3.3.91

In two studies, 6--16% of DME eyes receivedtopical hypotensive therapy following dexametha-sone implant.26,77 Twenty-six percent (26%) ofretinal vein occlusion eyes receiving 0.7 mg dexa-methasone IVT implant required medication totreat OHT at 6 months. At 12 months, an additional10% of patients whom received a second injection of0.7 mg implant were treated with antiglaucomamedication.74,75 There were no data regarding theproportion of uveitic eyes receiving medical treat-ment post dexamethasone implantation.141 Almostall patients developing OHT following dexametha-sone implants were controlled medically.26,75,76

2. Laser Treatment

Few studies have used argon laser trabeculoplastyforOHT following IVTsteroid.Most eyes still requiredtopical medication but were able to discontinue oralcarbonic anhydrase inhibitors.41,163,192

Five (5) of 7 eyes were successfully treated withselective laser trabeculoplasty in a noncomparativestudy of OHT following 4 mg IVT TA, but the othertwo required surgery—one required vitrectomy andone required Ahmed valve implantation.166 Anadditional two case reports described successfultreatment with selective laser trabeculoplasty.16,157

RCTs of 4 mg IVT TA for DME reported 0.4--2.4%of eyes receiving laser trabeculoplasty when topicalmedications failed to control OHT.57,66

In two retrospective studies, 2.5%ofeyeswere treatedwith selective laser trabeculoplasty, and4.8%with argonlaser trabeculoplasty, to control IOP following 0.4 mgIVT TA. In a study using 20 mg/0.2 mL, 4.7% receivedselective laser trabeculoplasty.81,83,136

Laser trabeculoplasty was carried out in 2.3% and0.8% of eyes after 0.5 and 0.2 microgram/dayIluvien FA implant, respectively.30 The use oftrabeculoplasty for treating OHT post dexametha-sone implants was reported in one study, but no

details were provided on the proportion of eyesreceiving this treatment.75

3. Surgical Management

Most patients with OHT after IVT steroid aresuccessfully managed with medical therapy, although1--8% require surgery utilizing various proceduressuch as trabeculectomy, trabeculotomy, nonpenetrat-ing glaucoma surgery, tube shunt surgery, cyclo-destructive procedures, and vitrectomy. 67,97,108

a. Surgical Management of OHT Following IVT TAInjection

Trabeculectomy is the most common surgicalprocedure for OHT after IVT TA—1-6% of patientsreceiving 4 mg IVT TA undergo trabeculectomycompared with 5% following 20 mg/0.2 mL58,59,69,83

and 1--8% following 25 mg/0.2 mL.95,101 Viscocana-lostomy has been reported in three cases.128 Glau-coma drainage devices (GDDs) and cyclodestructiveprocedures have also been described.57,73,122,167,176

Pars plana vitrectomy removal of TA is a treatmentoption for uncontrolled IOP following IVT TAeither alone or combined with trabeculectomy.1,113

Eight percent (8%) of eyes receiving 0.4 mg IVT TAunderwent vitrectomy for removal of TA. These eyeshad uncontrolled IOP despite maximal medicaltherapy at 4--8 weeks post injection. IOP decreasedfrom 70 mm Hg to !21 mmHg without medicationwithin 1--3 weeks post vitrectomy.1

b. Surgical Management of OHT Following IVT FAImplants

Glaucoma surgery was reported in a median of30% (range, 21--45%) of all study eyes receiving 0.59or 2.1 mg Retisert implants, compared with 4% and6% of eyes receiving 0.2 and 0.5 mg/day Iluvien,respectively.23,30,155,156,160 The 2-year cumulativeproportion of eyes undergoing surgery (no specificprocedure mentioned) in the Multicenter UveitisSteroid Treatment Trial was significantly higher inthe FA implant group than the systemic steroidgroup (26% vs 4%, hazard ratio, 8.4[95% CI, 3.4--20.8]; p ! 0.0001).114

Nineteen percent of posterior uveitis eyes, 20% ofDME eyes, and 8% of retinal vein occlusion eyesreceiving 0.59 or 2.1 mg FA implants underwenttrabeculectomy.23,156,160 GDDwere the initial surgicalprocedure for OHT following 0.59 or 2.1 mg FAimplant in a median of 26% of eyes (range, 8--31%).23,71,160

Among IOP-lowering surgeries, trabeculectomyand GDDs were the two most frequently performedsurgical interventions. A total of 42--76% of poste-rior uveitis eyes that need surgical management

Fig. 3. Algorithm for intraocular pressure monitoring following intravitreal steroid injection/implantation.

302 Surv Ophthalmol 58 (4) July--August 2013 KIDDEE ET AL

underwent trabeculectomy. GDDs were inserted in20--58% of surgically treated cases.23,71 Otherreported IOP-lowering surgical procedures includediode cyclodestruction (2%), nonpenetrating sur-gery, viscocanalostomy, and deep sclerotomy (1%),and implant removal.29,71,90,156

Hypotony (IOP !6 mm Hg) was the mostcommon postoperative complication following glau-coma surgery for treatment of OHT following IVTFA implants in patients with noninfectious posterioruveitis. Approximately half of eyes developedhypotony at O2 months after filtration surgery.There was no significant difference regardinghypotony in implanted eyes that underwent trabe-culectomy (45%) versus GDD (36%).71 There was,however, no significant difference in the proportionof FA implanted eyes that developed hypotony(43%) following glaucoma surgery versus thosewithout surgery (35%; p 5 0.09).24,71 These findings

suggest that uveitis itself may be a contributingfactor to hypotony.188

c. Surgical Management of OHT Following IVT Dexa-methasone Implants

Most OHT in eyes following 0.35 mg or 0.7 mgdexamethasone implants were successfully managedwith topical IOP-lowering medication. A reported0.6% of retinal vein occlusion eyes receivingdexamethasone implant required a laser or surgicalprocedure to reduce IOP (GDD insertion, deepsclerectomy, or cyclocryotherapy).75

VI. Recommendation for IntraocularPressure Surveillance

OHT is a common complication following IVTsteroids and may occur immediately following the

INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID 303

injection as a result of the mechanical effect ofintroducing extra volume into a fixed space or laterbecause of steroid effects on aqueous drainage.Identification of secondary OHT following IVTsteroid use is important since elevated IOP in mostcases is initially asymptomatic, and untreated mayresult in permanent vision loss. A systematicapproach to monitoring IOP is therefore required(Fig. 3). In addition, because steroid responders aremore likely to develop POAG than nonresponders,knowledge of steroid response is important forfuture glaucoma monitoring.121

A baseline assessment to determine and docu-ment the presence and degree of glaucoma isnecessary. In addition, risk factors, including base-line IOP $15 mm Hg, younger age, OHT followingprevious injection, uveitis, higher steroid dosage,and IVT FA implants, should be noted.

Based on our analysis of the data, we recommendchecking IOP and considering a paracentesis im-mediately following an IVT injection in eyes withpre-existing glaucomatous optic neuropathy be-cause of the risk of early volume-related pressurerise.118 IOP should also be checked within 30minutes following any type of IVT injec-tion.14,21,83,118 This is especially important wheninjecting a larger volume into small, hyperopic eyes,when using a small bore needle, and in cases of pre-existing glaucoma. Early pressure rises in most casescan be managed by paracentesis or medical therapy.

IOP should then be checked at 1 week after IVTTA and 2 weeks after IVT implantation of FA ordexamethasone followed by every 2 weeks for thefirst month and monthly for up to 6 months afterIVT TA injection and dexamethasone implant andfor 9 months after FA implant. If IOP O21 mm Hgor above target IOP in eyes with pre-existingglaucoma, or if IOP O28 mm Hg without pre-existing glaucoma, hypotensive therapy should beconsideredB with close subsequent monitoring ofIOP, optic disc, and visual fields. If IOP is 22-28mmHg without preexisting glaucoma, then IOP andoptic disc appearance should be checked at leastmonthly. If IOP O28 mmHg or glaucomatous diskchanges occur, hypotensive therapy should beconsidered followed by close monitoring.

Most cases of OHT can be controlled medically;a small proportion require surgery, however. Themost common operation is trabeculectomy; otherfiltration procedures or a vitrectomy to remove thesteroid/device may be considered, however. Trabe-culoplasty has also been successful in a smallnumber of cases.

For patients with pre-existing glaucoma inwhom IVT steroid therapy is recommended, co-management with a glaucoma specialist is a good

option. Limitations to this analysis, including thevariability of study designs and outcome reporting,resulted in a systematic literature review.

Our recommendations were established using thebest available evidence and are intended to provideguidance to supplement clinical judgment. We donot intend to establish a standard of care orsubstitute an algorithm for clinical judgment, as itis impossible to provide firm guidelines for allconceivable clinical situations.

VII. Conclusions

IVT steroids commonly cause secondary OHT.The majority of cases can be controlled medically;up to 45% of cases following IVT FA implants mayrequire surgery, however. All patients receiving IVTsteroid should be warned about this potential sideeffect, and those performing these procedures needto establish a protocol to monitor IOP followinginjection/implantation.

VIII. Methods of Literature Search

Prospective randomized trials, prospective cohortstudies, and retrospective studies that reportedsecondary OHT or glaucoma following IVT steroidinjection were searched using Medline, Embase andthe Cochrane Registry through August 2011 with thekeywords steroid, glucocorticoid, corticosteroid, fluocino-lone, triamcinolone, betamethasone, dexamethasone, kena-log, ozurdex, bevacizumab, avastin, pegaptanib, macugen,ranibizumab, lucentis, and IOP and IVT. Inclusioncriteria were prospective RCT, prospective cohortstudy and retrospective study, human participants 15years of age or older who required an IVT steroid foran ocular disorder, and English language publication.Exclusion criteria included case reports, literaturereviews, summaries, editorials, and letters, as well asnon-human studies. Those publications deemedeligible following review of the abstract were obtainedin full with two investigators independently reviewingeach article for eligibility and data extraction. Inaddition the references were reviewed for possiblepublications missed by the initial review. Results wereentered into standardized data collection sheets. Anydiscrepancies were resolved by consensus.

IX. Disclosure

Dr. Buys has received lecture fees and served onan advisory board for Allergan. The other authorshave no proprietary or commercial interest in anyproduct mentioned or concept discussed in thisarticle.

304 Surv Ophthalmol 58 (4) July--August 2013 KIDDEE ET AL

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Other Cited Material

A. Alimera Sciences receives complete response letter fromFDA for ILUVIEN [Internet]. 2011 [updated 2011 Nov 11;

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Reprint address: Yvonne M. Buys, MD, FRCSC, TorontoWestern Hospital, 399 Bathurst St, EW6-405, Toronto, Ontario,Canada M5T 2S8. e-mail: ybuys@utoronto.ca.

Outline

I. Introduction

A. Steroids and intraocular pressureB. Intravitreal steroids

II. Intravitreal steroid delivery methods

A. Intravitreal injection

1. Triamcinolone acetonide intravitrealinjection

2. Dexamethasone intravitreal injection

B. Sustained-release intravitreal implant(Fig. 1)

1. Triamcinolone acetonide sustained-release implant

2. Fluocinolone acetonide sustained-releaseimplant

a. Retisertb. Iluvien

3. Dexamethasone sustained-release implant

III. Pharmacokinetics of intravitreal steroids

A. Intravitreal steroid injectionB. Sustained-release intravitreal implant

IV. Mechanism of intravitreal steroid-inducedsecondary ocular hypertension

A. Direct volume effectB. Particulate matter obstructing the trabecu-

lar meshworkC. Trabecular meshwork dysfunction

1. Increased extracellular matrix depositionin meshwork

2. Inhibition of trabecular meshwork cellfunctions

a. Inhibition of phagocytosisb. Stabilization of lysosomes

3. Alterations in trabecular meshworkcytoskeleton

4. Increase cell adhesion molecules

V. Systematic literature review and meta-analysis

A. Results

1. Prevalence of OHT post IVT steroid(Table 1)

a. Triamcinolone acetonide intravitrealinjection

b. Dexamethasone intravitreal injectionc. Fluocinolone acetonide intravitreal implantd. Dexamethasone intravitreal implant

2. Time course of ocular hypertensionfollowing intravitreal steroid

a. Triamcinolone acetonide intravitrealinjection

b. Dexamethasone intravitreal injectionc. Fluocinolone acetonide intravitreal implantd. Dexamethasone intravitreal implant

B. Risk Factors (Table 2)

1. Patient-related risk factors

a. Ageb. Sexc. Higher baseline IOPd. History of glaucomae. Underlying ocular diseasef. Underlying systemic diseaseg. Secondary OHT after repeat intravitreal

steroidh. Phakic/Pseudophakic and vitrectomized/

nonvitrectomized eye

2. Medication-related risk factors

a. Type of steroid

310 Surv Ophthalmol 58 (4) July--August 2013 KIDDEE ET AL

b. Dosage of steroidc. Number of injections

C. Management

1. Medical treatment2. Laser treatment3. Surgical management

a. Surgical management of OHT followingIVT TA injection

b. Surgical management of OHT followingIVT FA implants

c. Surgical management of OHT followingIVT dexamethasone implants

VI. Recommendation for intraocular pressuresurveillance

VII. ConclusionsVIII. Methods of literature searchIX. Disclosure