Survey of ohptholmology meta-analysis


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Survey of ohptholmology meta-analysis

  1. 1. SURVEY OF OPHTHALMOLOGY VOLUME 58 NUMBER 4 JULY–AUGUST 2013 MAJOR REVIEW Intraocular Pressure Monitoring Post Intravitreal Steroids: A Systematic Review Weerawat 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 1 Department of Ophthalmology and Vision Sciences, Toronto Western Hospital, University of Toronto, Toronto, Canada; Department of Ophthalmology, Faculty of Medicine, Prince of Songkla University, Hatyai, Songkhla, Thailand; 3Institute for Clinical Evaluative Sciences, Toronto, Canada; 4Royal Devon and Exeter Hospital, Exeter, United Kingdom; and 5 Department of Ophthalmology, Faculty of Medicine, University of Ottawa, Ottawa, Canada 2 Abstract. The use of intravitreal (IVT) corticosteroids for treatment of posterior segment diseases has increased significantly over the last decade. A commonly recognized complication of IVT steroids is secondary ocular hypertension (OHT) that can occur immediately secondary to direct intraocular volume increase or weeks to months later as a result of increased outflow resistance. We performed a meta-analysis and found 32% (95% confidence interval, 28.2--36.3) of individuals developed OHT following 4 mg IVT triamcinolone, 66% (50.2--78.8) and 79% (72.2--84.5) following 0.59 and 2.1 mg fluocinolone implant, respectively, and 11% (6.4--17.9) and 15% (9.2--24.3) following 0.35 and 0.7 mg dexamethasone implant, respectively. Risk factors included pre-existing glaucoma, higher baseline intraocular pressure (IOP), younger age, OHT following previous injection, uveitis, higher steroid dosage, 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 after IVT 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 for the first month and monthly for up to 6 months after IVT triamcinolone and dexamethasone implantation and 9 months after fluocinolone implantation. (Surv Ophthalmol 58:291--310, 2013. Ó 2013 Elsevier Inc. All rights reserved.) Key words. ocular hypertension steroid-induced glaucoma sustained-release intravitreal implants I. Introduction intravitreal steroid injection induced OHT varies by route of administration, duration of treatment, type of steroid, and preexisting history of glaucoma, among other factors. For example, approximately 40% of the general population developed OHT after a 4--6 week course of topical 0.1% dexamethasone, so-called steroid responders, compared with nearly 100% of patients A. STEROIDS AND INTRAOCULAR PRESSURE Exogenous steroids administered topically (by peri- and/or intraocular injection) or orally can cause secondary ocular hypertension (OHT).5,197 The risk of inhaled nasal sprays causing secondary OHT is less clearly defined.200 The risk of steroid291 Ó 2013 by Elsevier Inc. All rights reserved. 0039-6257/$ - see front matter
  2. 2. 292 Surv Ophthalmol 58 (4) July--August 2013 with primary open-angle glaucoma (POAG) or normal-tension glaucoma.3,4,138 The etiology of steroid-induced OHT has been linked to the myocilin gene that is upregulated by steroid treatment in cultured trabecular meshwork cells.158 Stone et al reported that myocilin gene mutations were also associated with development of POAG.180 Although steroid-induced OHT usually reverses after cessation of steroid administration, it remains an important risk factor for the development of glaucomatous optic neuropathy.3,196 A protocol for intraocular pressure (IOP) monitoring following steroid administration is essential to limit visual function loss secondary to steroid-induced glaucoma. B. INTRAVITREAL STEROIDS The use of intravitreal (IVT) corticosteroids has increased significantly over the past 10 years because of their beneficial effects on macular edema secondary to uveitis, venous occlusive disease, diabetes, and choroidal neovascularization.13,26,44,74,90,98,120,184,189 The two main methods of IVT steroid delivery are injection and implantation of sustained-release devices. Despite the knowledge that IVT steroids may cause significant elevations of IOP, with 1--8% and up to 45% of patients reportedly requiring surgery for uncontrolled IOP after IVT triamcinolone acetonide (TA) injection and fluocinolone acetonide (FA) implantation, respectively, there is no consensus regarding the monitoring of IOP.23,156,191 There are a few published reviews on IOP elevation following IVT steroids; we found no systematic literature review or meta-analysis of this important topic, however.97,108,191 We provide the results of a systematic literature review and meta-analysis. Our objectives are to describe the frequency, onset, duration, magnitude, management, and risk factors of IOP elevation following IVT steroids and to develop a best-practice recommendation for IOP surveillance following IVT steroid administration. II. Intravitreal Steroid Delivery Methods A. INTRAVITREAL INJECTION The injection of steroid directly into the vitreous allows a large bolus of drug to be administered to achieve a desired therapeutic level at the target tissue while minimizing systemic absorption and side effects. The most common steroids used for an IVT 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 KIDDEE ET AL injected in a suspension form. IVT TA had been studied in different doses: 1, 2, 4, 5, 6, 8, 10, 20, and 25 mg.48,95--97,101--103,106,107,133,164 In most studies, a dose of 4 mg is used. The therapeutic response and duration of action can last approximately 3 months following 4 mg IVT TA.20 2. Dexamethasone Intravitreal Injection Dexamethasone (dexamethasone sodium phosphate, Weimer Pharma GmbH, Rastatt, Germany) is more potent with a shorter duration of action compared with TA.199 When given intravitreally it has been shown to be safe in dosages up to 1 mg.72 IVT dexamethasone had been studied in two doses: 0.4 and 0.8 mg.33 Although the short duration of action of dexamethasone may minimize side effects it also may limit its therapeutic effect. A single injection of IVT dexamethasone did not have a beneficial effect on diabetic macular edema (DME).33 There are few studies reporting IVT dexamethasone for treatment of posterior segment diseases. B. SUSTAINED-RELEASE INTRAVITREAL IMPLANT (FIG. 1) Given the short half-life of IVT steroids, repeated injections may be required to maintain therapeutic effects, increasing the risk of injection-related complications such as retinal detachment, vitreous hemorrhage, and endophthalmitis.20,72 This has led to the development of sustained-release implants.60 IVT implants are classified as either non-biodegradable or biodegradable. Non-biodegradable implants provide more accurate drug release and longer duration of action than the biodegradable implants, but require surgical removal.25,187 1. Triamcinolone Acetonide Sustained-Release Implant I-vation (SurModics, Eden Prairie, MN) (Fig. 1A) is a helical-shaped non-biodegradable metallic implant designed to deliver TA for 24 months. Phase II trials of I-vation for DME were suspended by Merck because photocoagulation was more effective than IVT TA as a treatment for DME.19,57 2. Fluocinolone Acetonide Sustained-release Implant a. Retisert Retisert (Bausch and Lomb, Rochester, NY) (Fig. 1B) is a non-biodegradable IVT FA implant that is inserted via the pars plana. The device is sutured to the sclera and releases FA at a controlled rate for approximately 30 months. Retisert had been
  3. 3. INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID 293 Fig. 1. Sustained-release intravitreal steroid implants. (A) I-vation (SurModics). (B) Retisert (with dime for size comparison). (Courtesy of Bausch and Lomb.) (C ) Iluvien (with grain for size comparison). (Courtesy of Alimera Sciences.) (D) Ozurdex (with an applicator). (Courtesy of Allergan Inc.) studied in two doses: 0.59 and 2.1 mg. The United States Food and Drug Administration (U.S. FDA) approved 0.59 mg Retisert for the treatment of noninfectious posterior uveitis in 2005.91 b. Iluvien Iluvien (Alimera Sciences, Alpharetta, GA) (Fig. 1C) is a non-biodegradable IVT FA implant that is inserted into the vitreous cavity via the pars plana through a transconjunctival self-sealing wound similar to an IVT injection with a 25-gauge needle. Iluvien implant releases FA at a rate of 0.2 mg per day over 18 months.110 Iluvien was shown to be effective for treating DME in a phase III clinical trial. In 2011, however, the U.S. FDA failed to approve Iluvien to treat DME because of safety concerns.A 3. Dexamethasone Sustained-release Implant Dexamethasone sustained-release implant (Ozurdex, Allergan Inc., Irvine, CA) (Fig. 1D) (formerly called Posurdex) is a biodegradable sustained-release device inserted into the vitreous cavity transconjunctivally through a 23-gauge needle releasing dexamethasone over 6 months. Ozurdex had been studied in two doses: 0.35 and 0.7 mg.74 The U.S. FDA approved 0.7 mg Ozurdex for the treatment of macular edema following retinal vein occlusion in June 2009. In September 2010, 0.7 mg Ozurdex was U.S. FDA-approved to treat non-infectious intermediate and posterior uveitis.140 Ozurdex for treatment of DME is currently under investigation.26 III. Pharmacokinetics of Intravitreal Steroids IVTsteroids are eliminated from the vitreous by two main mechanisms: the anterior pathway via aqueous humor that flows through the anterior chamber angle and a posterior pathway via permeation through the retina across the blood--retinal barrier into retinal and choroidal microvasculature.56,60 The duration of action of IVT-administered steroids depends on the retention, distribution, and rate of
  4. 4. 294 Surv Ophthalmol 58 (4) July--August 2013 excretion out of the vitreous. The longer the half-life of steroid injected in the vitreous cavity, the greater is the duration of effect.47,187 A. INTRAVITREAL STEROID INJECTION Dexamethasone sodium phosphate IVT injection has been studied since the 1980s.72,183 In a rabbit eye model maximum aqueous concentration occurred 1.5 hours after IVT injection with a half-life of approximately 3 hours. Clearance from the vitreous was within 72 hours.131 The short duration of dexamethasone limits its utility. Triamcinolone acetonide is a crystalline steroid suspension that is minimally water soluble. It forms white crystals that settle in the inferior vitreous after IVT injection.177 Owing to the minimal-watersoluble property, clearance of TA from the vitreous is slower in comparison with dexamethasone.20,170,171,177 After IVT injection, TA initially concentrates near the injection site before distributing throughout the entire vitreous cavity. Human eye studies show that, following a single injection of TA, concentrations initially decrease rapidly in the first 2 months, followed by a subsequent prolonged rate of elimination. The fast phase of clearance reflects the elimination of water-soluble TA, and the slow phase reflects the slow dissolution of TA crystals into the vitreous.20,42 In addition to the pharmacokinetic properties of IVT TA, dose, phakic, and vitrectomized status of the eye affect the duration of action. In animal models increased dose of IVT TA (4, 6, 16, 20, and 25 mg) was directly related to increased half-life.100,109,117 Similarly, in human eyes 4 mg IVT TA has a reported halflife of 18.6 days in vitreous compared with 30 days following 20 mg IVT TA.20,42 In animal studies TA crystals can be visualized in the nonvitrectomized vitreous for up to 23--41 days. TA levels decreased 1.5 times more rapidly in vitrectomized compared with nonvitrectomized eyes.45 In human eyes, the mean elimination half-life of TA in nonvitrectomized eyes was 15.4--18.6 days compared with 3.2 days in vitrectomized eyes.20 Studies suggest that 4 mg IVT TA has approximately 3--4 months duration of therapeutic effect in nonvitrectomized eyes.8,20,145 The shortened mean elimination half-life in vitrectomized and aphakic eyes can be explained by clearance mechanisms. Aphakia allows TA distribution in the anterior chamber, facilitating clearance of TA through the trabecular meshwork. In the vitrectomized eye, the vitreous cavity is filled with fluid instead of normal-viscous vitreous gel, allowing the drug to circulate more easily, distribute thoroughly, and therefore facilitate absorption and promote clearance via the posterior pathway.45,56,60 KIDDEE ET AL B. SUSTAINED-RELEASE INTRAVITREAL IMPLANT Retisert is a scleral-fixated, nonbiodegradable IVT FA implant. FA is a poorly water-soluble synthetic steroid. Logically, the lower water solubility should allow longer drug retention in the vitreous. Each implant consists of a central elastomer core of 0.59 mg FA that is delivered at an initial rate of 0.6 mg/day over the first month, decreasing to a steady rate of 0.3--0.4 mg/day over approximately 30 months.90,92 The pharmacokinetics of Retisert depends on several factors, including drug solubility, permeability of polymers, protein concentration around the aqueous medium, and rate of drug clearance out of the vitreous.78 Ozurdex is a free-floating biodegradable IVT dexamethasone implant that consists of dexamethasone embedded in a degradable polymer, resulting in gradual release of medication after the polymer undergoes hydrolysis to carbon dioxide and water.51 For this reason, dexamethasone is slowly distributed into vitreous cavity over a sustained period and eventually no device remains. Animal studies show that a peak concentration of dexamethasone in the vitreous at 2 months is followed by a relatively rapid decline between 2 and 3 months. The IVT concentration then reached a steady state through 6 months.36 The pharmacokinetics of 0.7 mg Ozurdex is similar in nonvitrectomized and vitrectomized eyes.37 IV. Mechanism of Intravitreal Steroidinduced Secondary Ocular Hypertension Steroid-induced OHT is emerging as an increasing problem following IVT TA injection, IVT FA implantation, 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 exact mechanism of steroid-induced secondary OHT is unknown, several theories exist. The immediate short-term course of OHT after IVT injection could be explained by the direct increase of intraocular volume. Physical obstruction of trabecular meshwork by TA precipitate also occurs.39,149,173,176 Finally, long-term elevation of IOP following IVT injection or implantation of sustained-release devices results from increased aqueous outflow resistance caused by steroid-induced trabecular meshwork alteration.147,169,176,186,196 A. DIRECT VOLUME EFFECT An acute increase in vitreous volume immediately following IVT injection can induce a short-term increase of IOP.21,34,83,84,115,118,126 Benz et al described the natural history of IOP within the first 30 minutes after IVT injection of 0.1 mL of TA. If there
  5. 5. INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID was vitreous reflux following IVT injection, the IOP declined immediately after injection and rapidly normalized over 10 minutes. If no vitreous reflux was observed, the mean IOP increased significantly from 15.5 mm Hg at baseline to 45.8 mm Hg immediately after injection and then gradually declined over 30 minutes. Approximately 90% (95% confidence interval [CI], 85.8-95.2) of patients without vitreous reflux had an IOP !24 mm Hg at 30 minutes post injection.21 A biomechanical model determining the effect of intraocular volume changes on IOP showed that immediately after IVT injection of 4 mg of 0.1 mL TA, the mean IOP was 57.9 Æ 11.4 mm Hg. IOP was significantly elevated, with a mean of 40.6 Æ 12.1 mm Hg compared with pre-injection. The mean IOP dropped to 9.4 Æ 4.9 mm Hg after paracentesis. In all eyes IOP was less than 20 mm Hg within 120 minutes following IVT injection. The increase in IOP depends on the overall volume of the treated eye. Smaller, hyperopic eyes had higher immediate IOP increase compared to larger, myopic eyes when an equal amount of IVT TA was administered.126 The immediate increase in IOP is related to the volume of medication injected. A total of 2.9% of patients had an IOP of $25 mm Hg at 30 minutes after 0.05 mL IVT bevacizumab, compared with 7.1% after 0.1 mL IVT TA.21,83 Bakri et al studied IOP changes within 30 minutes after IVT injection of 0.1 mL TA, 0.09 mL pegaptanib, and 0.05 mL bevacizumab. At 30 minutes post injection, mean IOP was highest in the TA group, followed by the pegaptanib and bevacizumab groups. The volume injected could explain this difference. The highest IOP recorded was 60 mm Hg, 10 minutes after receiving IVT TA. (There was no report of IOP immediately after injection.) Seven percent (7%) of eyes receiving IVT TA were treated with hypotensive therapy. Eyes with pre-existing glaucoma (all injection types) were statistically significantly less likely to have an IOP !35 mm Hg at 10 minutes post injection.14 Kim et al recorded IOPs immediately after IVT TA injection and at 5-minute intervals thereafter until IOP was !30 mm Hg. Immediately after injection, mean IOP significantly increased from 14 mm Hg at baseline to 44 mm Hg, with a maximum IOP of 87 mm Hg. An IOP of $30 mm Hg was observed in 79%. The incidence of IOP $30 mm Hg fell to 30% within 5 minutes and by 30 minutes all eyes were !30 mm Hg. Eyes with pre-existing glaucoma had statistically significant IOP spikes and took longer to normalize. They also reported that significantly more IOP spikes were observed with a smaller bore needle, likely due to less fluid reflux via the needle tract.118 295 A prospective randomized controlled trial (RCT) investigating the efficacy of paracentesis following IVT TA found significantly elevated IOP immediately following injection in the group randomized to no paracentesis (baseline 14.6 Æ 2.7 mm Hg increased to 46.7 Æ 8.3 mm Hg) compared with an immediate decreased IOP in the paracentesis group (baseline 15.3 Æ 1.7 mm Hg decreased to 7.8 Æ 1.5 mm Hg). At 15 minutes, however, there was no statistical difference in post-injection IOP between the groups. They postulated IOP normalized as a result of reduced aqueous formation and increased aqueous outflow.34 IOP following IVT injection of 0.1 mL of 4 mg TA was significantly higher in phakic eyes than in pseudophakic eyes (p ! 0.001) at 10, 20, 30, and 40 minutes post injection.115 In summary, a short-term course of OHT immediately following IVT TA can occur as a result of a rapid increase in intraocular volume. Risk factors include hyperopia, phakia, prior history of POAG, larger volume of injection, smaller bore needle, and no vitreous reflux during injection (see Table 2 in section V.B).14,21,83,115,118,126 Peak IOP typically normalizes within 15--120 minutes after injection; this may take longer in cases of pre-existing glaucoma, however.14,21,34,118,126 The long-term consequences of a high transient IOP rise are unclear. An acute IOP elevation can cause blockage of axonal transport, and the potential for damage of ganglion cells should be considered, especially in patients with glaucomatous optic neuropathy.159 In addition there is a risk of vascular occlusive events secondary to elevated IOP.62 Presently there is no evidence to support using prophylactic topical antiglaucoma agents to prevent an immediate IOP spike following IVT injection but this is worthy of consideration until evidence becomes available. Paracentesis diminishes this risk of IOP spike34 and should be considered in vulnerable eyes with preexisting glaucomatous optic neuropathy. Given the high proportion of elevated IOP immediately following injection, with the potential for ganglion cell or vascular compromise, IOP should be checked 30 minutes after injection, and, if elevated, consideration should be given to hypotensive therapy or paracentesis with further close IOP monitoring. B. PARTICULATE MATTER OBSTRUCTING THE TRABECULAR MESHWORK Fine white crystalline opacities in the inferior anterior chamber angle (pseudohypopyon) have been reported following IVT TA injection.39,40,149,151,168, 173,175,176 The particulate matter can occlude the trabecular meshwork and cause secondary OHT in early period following IVT TA injection.176 The
  6. 6. 296 Surv Ophthalmol 58 (4) July--August 2013 reported prevalence of pseudohypopyon after IVT TA is 0.2--2%.99,149,151 It usually occurs within 3 days, as early as the first day following injection, and resolves within 2--6 weeks.149,151 Pseudohypopyon occurs more frequently in aphakic, pseudophakic, and vitrectomized eyes.149,151,175 The TA crystals presumably leak through the ruptured anterior hyaloid face into the anterior chamber between weak zonules.39 Pseudohypopyon secondary to IVT TA has been associated with elevated IOP with some cases requiring a glaucoma drainage device to control IOP.176 The presence of a hypopyon post IVT TA can be a sign of endophthalmitis; in the absence of other signs of inflammation, however, the possibility of a pseudohypopyon should be considered with close monitoring of IOP. C. TRABECULAR MESHWORK DYSFUNCTION Although the exact mechanism responsible for steroid-induced outflow resistance is uncertain, possible mechanisms have been proposed. 1. Increased Extracellular Matrix Deposition in Meshwork The trabecular meshwork consists of three regions: juxtacanalicular, corneoscleral, and uveal meshworks. The inner wall of Schlemm’s canal marks the outer border of the juxtacanalicular meshwork which serves as the major source of aqueous humor outflow resistance. The extracellular matrix (ECM) located between the layers of the juxtacanalicular meshwork cells is composed of type III collagen.196 Theoretically, obstruction of trabecular beams or decrease in intratrabecular spaces could result in IOP elevation. Steroids may alter the rate of protein synthesis and inhibit degradation of ECM, leading to aggregation of an excessive ECM.116,179,196 Morphological and histological studies of eyes with steroid-induced glaucoma have shown an increased deposition of ECM in the trabecular meshwork causing increased resistance to aqueous humor outflow and the development of OHT and secondary OAG.94,185, 186,196 Recently, Kubota et al found that eyes that developed glaucoma following IVT steroid had ECM alterations resembling those after topical corticosteroid treatment, with a decrease in intertrabecular spaces.129 KIDDEE ET AL facilitate ECM turnover.202 Reduction in phagocytic activity is one possible mechanism of steroidinduced glaucoma by down-regulating one of its binding receptors.15,201,202 Dexamethasone inhibits phagocytic activity of cultured trabecular meshwork cells, resulting in accumulation of debris and reduction of outflow facility.147 b. Stabilization of Lysosomes Steroids stabilize lysosomes by strengthening the membrane, resulting in accumulation of polymerized and hydrophilic mucopolysaccharides. The accumulation of more polymerized and more hydrophilic mucopolysaccharides causes narrowing of the trabecular spaces and increased outflow resistance, consequently increasing IOP.3,61,176,194 In addition to inhibition of phagocytosis and stabilization of lysosomal membranes, steroids cause a significant increase in trabecular cell and nucleus size, stacked arrangements of endoplasmic reticulum, and proliferation of the Golgi apparatus resulting in increase outflow resistance.194 3. Alterations in Trabecular Meshwork Cytoskeleton The trabecular meshwork cytoskeleton functions in regulating aqueous outflow.169 Steroids alter trabecular cytoskeletons, causing a progressive reorganization of microfilament into polygonal latticelike cross-linked actin networks that are reversible on withdrawal of steroids.52 The reorganization of the trabecular cytoskeleton alters cell function by inhibiting trabecular cell migration and proliferation.52,53 4. Increase Cell Adhesion Molecules Cell adhesion molecules are involved in cell-tocell interactions. Steroid treatment causes gap junctional complex realignment and increased expression of the tight junction protein or zonular occludens. An alteration of trabecular tissue permeability causes reduction of hydraulic transendothelial flow through trabecular cells and could result in increased aqueous outflow resistance.190 In conclusion, steroids cause an accumulation of ECM, inhibition of various trabecular cell functions, and alterations in trabecular cytoskeleton and cell adhesion molecules. This results in chronic impairment of aqueous drainage and increased IOP. 2. Inhibition of Trabecular Meshwork Cell Functions a. Inhibition of Phagocytosis Trabecular meshwork cells are actively phagocytic and function in the removal of debris and pigment material from the outflow channels and also V. Systematic Literature Review and Meta-analysis We performed a systematic review utilizing the preferred reporting practice for systematic reviews
  7. 7. INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID and meta-analysis statement (see the Methods of Literature Search section).139 The quality of randomized trials was assessed using the Cochrane collaboration’s tool of assessing risk of bias.80 The main outcome measure was the proportion of patients with an IOP elevation. Secondary outcomes 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) and underlying diagnosis. Proportions were pooled using a random-effects model if studies were homogenous as indicated by the heterogeneity test. 297 and 15.3% (95% CI, 9.2--24.3) following 0.35 and 0.7 mg IVT dexamethasone implant, respectively. 2. Time Course of Ocular Hypertension Following Intravitreal Steroid The time course of steroid-induced OHT varies by type and dose of medication and method of administration. a. Triamcinolone Acetonide Intravitreal Injection FA implant has been studied in two doses: 0.59 and 2.1 mg. The pooled proportion of patients with a $10 mm Hg rise from baseline or an IOP O21 mm Hg was 65.9% (95% CI, 50.2--78.8) following 0.59 mg and 79% (95% CI, 72.2--84.5) following 2.1 mg FA implant. If OHT was defined as an IOP $30 mm Hg, the pooled proportion of patients with OHT was 61.4% (95% CI, 54.4--68.0) following 0.59 mg FA implant. There was no statistically significant difference based on dose. Pooled results from eligible RCTs showed an onset of OHT following IVT injection of 4 mg TA was 2--4 weeks and from nonrandomized studies was 1--8 weeks.9,10,28,32,40,49,54,86,112,135,144,146,148 Onset of OHT was reported as early as 1 week following injection in several studies.9,10,28,86,111,137,151,176 Trabecular meshwork occlusion by particulate matter could cause OHT within the first few days after injection.176 An early onset of OHT after 0.4 mg IVT TA was also shown in the Diabetic Retinopathy Clinical Research (DRCR) network’s study. OHT, defined as an IOP rise O10 mm Hg from baseline or an IOP $30 mm Hg, occurred in 0.4% of eyes 4 Æ 3 days after initial injection, with all requiring antiglaucoma medication. Four percent (4%) of eyes receiving subsequent IVT TA injection developed OHT within 4 days and O50% needed IOP lowering treatment. According to the DRCR network’s results, no TA precipitate was detected in the anterior chamber of these eyes. No clear etiology of this early IOP elevation was provided.57,137 Two retrospective studies found late onset IOP elevation 10--14 weeks following injection.70,178 The latest onset of OHT after IVT TA was 20--24 weeks in a small case series with IOPs of approximately 50 mm Hg.193 For those eyes developing OHT following 4 mg IVT TA, the reported duration of OHT is 1--9 months with maximum IOP within 2--12 weeks and returning to baseline values within 4--9 months after injection.7,9,10,32,40,54,64,67,111,132,134,154,162 Few studies determined the time course of OHT after 8 mg IVT TA. Ito et al found mean IOP started to rise at 4 weeks following injection and reached a maximum at 12 weeks.89 Duration of OHT is 6 months, with mean IOP returning to baseline levels at 6--9 months.89,152,153 For OHT following 20--25 mg IVT TA, the reported mean time of onset is 1--9 weeks after injection, with maximum IOP at 12 weeks.97,83 The mean time for IOP to return to baseline level is 5--9 months.83,95,97,101--103,105--107,125 d. Dexamethasone Intravitreal Implant b. Dexamethasone Intravitreal Injection An IOP rise from baseline $10 mmHg or an IOP $25 mm Hg occurred 10.9 % (95% CI, 6.4--17.9) There is only one study reporting OHT following IVT dexamethasone injection. OHT occurred as A. RESULTS After screening 1,338 abstracts, 174 full text articles were reviewed resulting in 129 eligible studies (115 TA injection, 1 dexamethasone injection, 7 FA implant, 6 dexamethasone implant) for the qualitative syntheses and meta-analysis. Figure 2 summarizes the results of the initial search and publication selection. 1. Prevalence of OHT Post IVT Steroid (Table 1) a. Triamcinolone Acetonide Intravitreal Injection Four mg TA was the most common dosage and drug reported with a pooled proportion of eyes with IOP $21 mm Hg or $10 mm Hg from baseline of 32.1% (95% CI, 28.2--36.3). The results for the other doses are shown in Table 1. The risk of OHT was significantly 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 reported 16.7% of eyes receiving 0.8 mg IVT dexamethasone and no eyes receiving 0.4 mg having an IOP O21 mm Hg.33 c. Fluocinolone Acetonide Intravitreal Implant
  8. 8. 298 Surv Ophthalmol 58 (4) July--August 2013 Fig. 2. KIDDEE ET AL Diagram showing article selection process. early as the first day after injection and returned to baseline values approximately 1 month after injection.33 c. Fluocinolone Acetonide Intravitreal Implant Onset of OHT following IVT FA implant is within 2--4 weeks, reaching a maximum at 24--28 weeks and returning to baseline values approximately 9--12 months after implantation.30,31,90,160 B. RISK FACTORS (TABLE 2) Several variables have been identified as possible risk factors for steroid-induced OHT, including younger age, uveitis, baseline IOP $15 mm Hg, pre-existing glaucoma, history of OHT with previous IVT steroid, higher steroid dosage, and IVT FA implant. 1. Patient-related Risk Factors d. Dexamethasone Intravitreal Implant a. Age There are no reports regarding the onset of OHT following IVT dexamethasone implant; the time to peak IOP, however, is 60 days following implantation, returning to baseline within 6 months.26,75--77 A number of studies identify younger age as a risk factor for OHT after IVT TA.27,81,90,101,136,154, 164,174,197 Following 4 mg IVT TA the proportion developing OHT was greater in those 45 years and younger compared with those older than 45 years
  9. 9. 28.2--36.3 31.8a 30.0a 39.8a 45.9a 65.9a 79.0a 10.9b 15.3b 319 53 396 114 190 168 650 746 (p 5 0.006).174 Another study found that those 55 years and younger had both a larger magnitude IOP elevation (p 5 0.02) and OHT less likely to be controlled medically (p 5 0.009) than those older than 55.136 Roth et al reported a 16% reduction in OHT risk for every 10-year increase in age (p ! 0.001).164 Age, however, was not found to be a risk factor in some studies.87,162,191 20.4--45.8 17.9--45.7 35.0--44.8 36.9--55.3 50.2--78.8 72.2--84.5 6.4--17.9 9.2--24.3 32.1a 3,654 299 b. Sex Reports on sex as a risk factor for OHT following IVT steroids are controversial. One study found that, after adjusting for age, previous history of glaucoma, and retinal diseases, male sex was a significant risk factor (odds ratio, 3.17; 95% CI, 1.38--7.27; p 5 0.006).136 A small prospective study also found male sex as a risk for OHT following 4 or 25 mg IVT TA (p 5 0.029).27 Several studies, however, have not found sex was a risk factor.2,97,101,154,191 Presently there is insufficient data to make a conclusion. % 5 percent of studied eyes developing ocular hypertension. Ocular hypertension defined as IOP $ 21 mm Hg or $ 10 mm Hg from baseline. b Ocular hypertension defined as IOP $ 25 mm Hg or $ 10 mm Hg from baseline. Dexamethasone implant a 489,133,152,153 282,197 596,105--107,182 395,101,103 329,155,160 129 475,77,130,141 626,75--77,130,141 Fluocinolone acetonide implant 4 mg/0.1 mL Triamcinolone acetonide 8 mg/0.2 mL 10 mg/0.2 mL 20 mg/0.2 mL 25 mg/0.2 mL 0.59 mg 2.1 mg 0.35 mg 0.7 mg 144,148,150,154,161, 164,165,172,174,178,182,183,188,190 c. Higher Baseline IOP 422,6,9--11,17,18,22,32,35,40--43,46,48--50,54,59, 67,85,111,112,123,132--135, 95% Confidence Interval Number of Eyes Included Number of Studies Included Dose Medication Proportion of Eyes Developing Ocular Hypertension Following Intravitreal Steroid Injection/Implantation TABLE 1 Pooled Point Estimate for Proportion of Eyes Developing Ocular Hypertension (%) INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID Several studies reported a baseline IOP $15 mm Hg as a significant risk factor for OHT.12,153,165,191 Two studies determined the relative risk of OHT with a baseline IOP $15 mm Hg as O2.178,179 Baseline IOP as a risk factor for OHT was not confirmed in two other studies.27,87 d. History of Glaucoma Patients with pre-existing glaucoma may have an increased risk of OHT following IVT steroids12,153,165,191 and a higher peak IOP compared with nonglaucomatous eyes.191 A family history of glaucoma may also be a risk factor for OHT following IVT steroid.2 e. Underlying Ocular Disease Among posterior segment diseases that required IVT steroid, only uveitis has been reported as a risk factor for OHT after IVT TA injection.63,104 Our analysis of OHT following IVT TA injection found the highest prevalence of OHT in uveitis patients (42.7%; 95% CI, 28.4--58.3) followed by macular 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 choroidal neovascular membrane (30.4%; 95% CI, 24.3--37.4). These differences, however, are not statistically significant given the overlap of the 95% confidence intervals. A similar conclusion was reached in two other publications.81,178 Regarding underlying disease in those receiving IVT FA implants, defining OHT as an IOP rise of $10 mm Hg from baseline or an IOP O21 mm Hg,
  10. 10. 300 Surv Ophthalmol 58 (4) July--August 2013 KIDDEE ET AL TABLE 2 Risk Factors for Developing Ocular Hypertension Following Intravitreal Steroids Risk Factors for OHT Immediately Following Injection Phakia Hyperopia Prior history of POAG Smaller bore needle Larger volume of injection No vitreous reflux during injection Risk Factors for Later Onset OHT Younger age Uveitis Baseline IOP $15 mm Hg Pre-existing glaucoma OHT following previous injection Higher steroid dose Fluocinolone acetonide intravitreal implantation IOP 5 intraocular pressure; OHT 5 ocular hypertension; POAG 5 primary open angle glaucoma. 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 2.1 mg FA implant, respectively. There were insufficient data for a meta-analysis of other diseases. One study reported 61.4% of DME eyes treated with 0.59 mg FA implant had an IOP $30 mm Hg.156 For eyes receiving dexamethasone IVT implants, there were insufficient studies to conduct a metaanalysis 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 0.35 mg and 0.7 mg dexamethasone IVT implant, respectively. In a RCT of chronic uveitis, 8.4% of the 0.35 mg group and 7.1% of the 0.7 mg group had OHT defined as an IOP $25 mm Hg.141 A 6month RCT of dexamethasone IVT implant for treating retinal vein occlusion showed that, of eyes receiving single IVT implantation of 0.35 and 0.7 mg, 3.9% and 4%, respectively, had an IOP $25 mm Hg.75 An extended 12-month RCT by the same study group found that 32.8% of eyes with retinal vein occlusion were randomized to retreatment with 0.7 mg had an IOP increase of $10 mm Hg from baseline at any time point during the 1-year study.74 f. Underlying Systemic Disease Diabetes is not usually considered a risk factor for OHT following IVT steroids.81,87,97,101,136 Jonas reported a rise of IOP O21 mm Hg post IVT injection of 20 and 25 mg TA was statistically independent of the presence of diabetes (p 5 0.74 and p 5 0.37, respectively).97,101 Inatani et al also demonstrated that diabetes was not a risk for OHT following 4 or 8 mg IVT TA (hazard ratio, 0.91; 95% CI, 0.47--1.61; p 5 0.760).87 One small retrospective study however, proposed diabetes as a possible risk factor for OHT following 4 mg IVT TA (p 5 0.050).2 OHT following IVT steroids compared to those that did not develop OHT.165 h. Phakic/Pseudophakic and Vitrectomized/ Nonvitrectomized Eye Lens and vitrectomized status have not been found to be a risk factor for OHT following IVT steroid.81,191 2. Medication-related Risk Factors a. Type of Steroid Our analysis showed that prevalence of OHT post IVT steroid was highest in FA implant groups, followed by IVT TA and IVT implantation of dexamethasone (Table 1). Comparisons between studies, however, are limited by the various definitions used for OHT. b. Dosage of Steroid We found a trend between increased dose of steroid and increased risk of OHT; this difference was 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 following subsequent injections, with 26.9% (95% CI, 14.1-29.9) developing OHT following a single injection compared with 34.7% (95% CI, 29.7--29.9) and 42.6% (95% CI, 33.7--51.9) following two and three IVT TA injections, respectively.165 Other investigators reported that there was no difference in rates of OHT for patients receiving multiple injections versus those receiving a single injection.81,178 g. Secondary OHT after Repeat Intravitreal Steroid C. MANAGEMENT Eyes with a history of OHT following IVT TA were more likely to have OHT following a subsequent injection.2,87,101,165,189 One study found the risk of OHT was three times greater in eyes with a history of 1. Medical Treatment Most OHT following IVT TA injection can be controlled medically.7,11,35,38,54,65,67,68,79,88,119,133,142 The reported proportion of patients requiring
  11. 11. INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID hypotensive therapy to control IOP following 0.4 mg IVT TA is 15--64% of DME eyes, 30--41% of retinal vein occlusion eyes, 25--54% of choroidal neovascular 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 antiglaucoma 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 eyes required medical hypotensive therapy.29,90,91,155 In one study of DME eyes, 61% required topical antiglaucoma medication.156 A prospective nonrandomized study reported 62% of retinal vein occlusion eyes required medical treatment for OHT after FA implant.160 The mean number of topical medications prescribed following IVT FA was 3.3.91 In two studies, 6--16% of DME eyes received topical hypotensive therapy following dexamethasone implant.26,77 Twenty-six percent (26%) of retinal vein occlusion eyes receiving 0.7 mg dexamethasone IVT implant required medication to treat OHT at 6 months. At 12 months, an additional 10% of patients whom received a second injection of 0.7 mg implant were treated with antiglaucoma medication.74,75 There were no data regarding the proportion of uveitic eyes receiving medical treatment post dexamethasone implantation.141 Almost all patients developing OHT following dexamethasone implants were controlled medically.26,75,76 301 details were provided on the proportion of eyes receiving this treatment.75 3. Surgical Management Most patients with OHT after IVT steroid are successfully managed with medical therapy, although 1--8% require surgery utilizing various procedures such as trabeculectomy, trabeculotomy, nonpenetrating glaucoma surgery, tube shunt surgery, cyclodestructive procedures, and vitrectomy. 67,97,108 a. Surgical Management of OHT Following IVT TA Injection Trabeculectomy is the most common surgical procedure for OHT after IVT TA—1-6% of patients receiving 4 mg IVT TA undergo trabeculectomy compared with 5% following 20 mg/0.2 mL58,59,69,83 and 1--8% following 25 mg/0.2 mL.95,101 Viscocanalostomy has been reported in three cases.128 Glaucoma drainage devices (GDDs) and cyclodestructive procedures have also been described.57,73,122,167,176 Pars plana vitrectomy removal of TA is a treatment option for uncontrolled IOP following IVT TA either alone or combined with trabeculectomy.1,113 Eight percent (8%) of eyes receiving 0.4 mg IVT TA underwent vitrectomy for removal of TA. These eyes had uncontrolled IOP despite maximal medical therapy at 4--8 weeks post injection. IOP decreased from 70 mm Hg to !21 mmHg without medication within 1--3 weeks post vitrectomy.1 2. Laser Treatment Few studies have used argon laser trabeculoplasty for OHT following IVTsteroid. Most eyes still required topical medication but were able to discontinue oral carbonic anhydrase inhibitors.41,163,192 Five (5) of 7 eyes were successfully treated with selective laser trabeculoplasty in a noncomparative study of OHT following 4 mg IVT TA, but the other two required surgery—one required vitrectomy and one required Ahmed valve implantation.166 An additional two case reports described successful treatment 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 topical medications failed to control OHT.57,66 In two retrospective studies, 2.5% of eyes were treated with selective laser trabeculoplasty, and 4.8% with argon laser trabeculoplasty, to control IOP following 0.4 mg IVT TA. In a study using 20 mg/0.2 mL, 4.7% received selective laser trabeculoplasty.81,83,136 Laser trabeculoplasty was carried out in 2.3% and 0.8% of eyes after 0.5 and 0.2 microgram/day Iluvien FA implant, respectively.30 The use of trabeculoplasty for treating OHT post dexamethasone implants was reported in one study, but no b. Surgical Management of OHT Following IVT FA Implants Glaucoma surgery was reported in a median of 30% (range, 21--45%) of all study eyes receiving 0.59 or 2.1 mg Retisert implants, compared with 4% and 6% of eyes receiving 0.2 and 0.5 mg/day Iluvien, respectively.23,30,155,156,160 The 2-year cumulative proportion of eyes undergoing surgery (no specific procedure mentioned) in the Multicenter Uveitis Steroid Treatment Trial was significantly higher in the FA implant group than the systemic steroid group (26% vs 4%, hazard ratio, 8.4[95% CI, 3.4-20.8]; p ! 0.0001).114 Nineteen percent of posterior uveitis eyes, 20% of DME eyes, and 8% of retinal vein occlusion eyes receiving 0.59 or 2.1 mg FA implants underwent trabeculectomy.23,156,160 GDD were the initial surgical procedure for OHT following 0.59 or 2.1 mg FA implant in a median of 26% of eyes (range, 8-31%).23,71,160 Among IOP-lowering surgeries, trabeculectomy and GDDs were the two most frequently performed surgical interventions. A total of 42--76% of posterior uveitis eyes that need surgical management
  12. 12. 302 Surv Ophthalmol 58 (4) July--August 2013 Fig. 3. KIDDEE ET AL Algorithm for intraocular pressure monitoring following intravitreal steroid injection/implantation. underwent trabeculectomy. GDDs were inserted in 20--58% of surgically treated cases.23,71 Other reported IOP-lowering surgical procedures include diode cyclodestruction (2%), nonpenetrating surgery, viscocanalostomy, and deep sclerotomy (1%), and implant removal.29,71,90,156 Hypotony (IOP !6 mm Hg) was the most common postoperative complication following glaucoma surgery for treatment of OHT following IVT FA implants in patients with noninfectious posterior uveitis. Approximately half of eyes developed hypotony at O2 months after filtration surgery. There was no significant difference regarding hypotony in implanted eyes that underwent trabeculectomy (45%) versus GDD (36%).71 There was, however, no significant difference in the proportion of FA implanted eyes that developed hypotony (43%) following glaucoma surgery versus those without surgery (35%; p 5 0.09).24,71 These findings suggest that uveitis itself may be a contributing factor to hypotony.188 c. Surgical Management of OHT Following IVT Dexamethasone Implants Most OHT in eyes following 0.35 mg or 0.7 mg dexamethasone implants were successfully managed with topical IOP-lowering medication. A reported 0.6% of retinal vein occlusion eyes receiving dexamethasone implant required a laser or surgical procedure to reduce IOP (GDD insertion, deep sclerectomy, or cyclocryotherapy).75 VI. Recommendation for Intraocular Pressure Surveillance OHT is a common complication following IVT steroids and may occur immediately following the
  13. 13. INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID injection as a result of the mechanical effect of introducing extra volume into a fixed space or later because of steroid effects on aqueous drainage. Identification of secondary OHT following IVT steroid use is important since elevated IOP in most cases is initially asymptomatic, and untreated may result in permanent vision loss. A systematic approach to monitoring IOP is therefore required (Fig. 3). In addition, because steroid responders are more likely to develop POAG than nonresponders, knowledge of steroid response is important for future glaucoma monitoring.121 A baseline assessment to determine and document the presence and degree of glaucoma is necessary. In addition, risk factors, including baseline IOP $15 mm Hg, younger age, OHT following previous injection, uveitis, higher steroid dosage, and IVT FA implants, should be noted. Based on our analysis of the data, we recommend checking IOP and considering a paracentesis immediately following an IVT injection in eyes with pre-existing glaucomatous optic neuropathy because of the risk of early volume-related pressure rise.118 IOP should also be checked within 30 minutes following any type of IVT injection.14,21,83,118 This is especially important when injecting a larger volume into small, hyperopic eyes, when using a small bore needle, and in cases of preexisting glaucoma. Early pressure rises in most cases can be managed by paracentesis or medical therapy. IOP should then be checked at 1 week after IVT TA and 2 weeks after IVT implantation of FA or dexamethasone followed by every 2 weeks for the first month and monthly for up to 6 months after IVT TA injection and dexamethasone implant and for 9 months after FA implant. If IOP O21 mm Hg or above target IOP in eyes with pre-existing glaucoma, or if IOP O28 mm Hg without preexisting glaucoma, hypotensive therapy should be consideredB with close subsequent monitoring of IOP, optic disc, and visual fields. If IOP is 22-28 mmHg without preexisting glaucoma, then IOP and optic disc appearance should be checked at least monthly. If IOP O28 mmHg or glaucomatous disk changes occur, hypotensive therapy should be considered followed by close monitoring. Most cases of OHT can be controlled medically; a small proportion require surgery, however. The most common operation is trabeculectomy; other filtration procedures or a vitrectomy to remove the steroid/device may be considered, however. Trabeculoplasty has also been successful in a small number of cases. For patients with pre-existing glaucoma in whom IVT steroid therapy is recommended, comanagement with a glaucoma specialist is a good 303 option. Limitations to this analysis, including the variability of study designs and outcome reporting, resulted in a systematic literature review. Our recommendations were established using the best available evidence and are intended to provide guidance to supplement clinical judgment. We do not intend to establish a standard of care or substitute an algorithm for clinical judgment, as it is impossible to provide firm guidelines for all conceivable 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 may require surgery, however. All patients receiving IVT steroid should be warned about this potential side effect, and those performing these procedures need to establish a protocol to monitor IOP following injection/implantation. VIII. Methods of Literature Search Prospective randomized trials, prospective cohort studies, and retrospective studies that reported secondary OHT or glaucoma following IVT steroid injection were searched using Medline, Embase and the Cochrane Registry through August 2011 with the keywords steroid, glucocorticoid, corticosteroid, fluocinolone, triamcinolone, betamethasone, dexamethasone, kenalog, ozurdex, bevacizumab, avastin, pegaptanib, macugen, ranibizumab, lucentis, and IOP and IVT. Inclusion criteria were prospective RCT, prospective cohort study and retrospective study, human participants 15 years of age or older who required an IVT steroid for an ocular disorder, and English language publication. Exclusion criteria included case reports, literature reviews, summaries, editorials, and letters, as well as non-human studies. Those publications deemed eligible following review of the abstract were obtained in full with two investigators independently reviewing each article for eligibility and data extraction. In addition the references were reviewed for possible publications missed by the initial review. Results were entered into standardized data collection sheets. Any discrepancies were resolved by consensus. IX. Disclosure Dr. Buys has received lecture fees and served on an advisory board for Allergan. The other authors have no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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  19. 19. INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID by glucocorticoid receptor-beta. Invest Ophthalmol Vis Sci. 2005;46:4607--16 202. Zhang X, Ognibene CM, Clark AF, et al. Dexamethasone inhibition of trabecular meshwork cell phagocytosis and its modulation by glucocorticoid receptor beta. Exp Eye Res. 2007;84:275--84 Other Cited Material A. Alimera Sciences receives complete response letter from FDA for ILUVIEN [Internet]. 2011 [updated 2011 Nov 11; 309 cited 2011 Dec 9]. Available from: http://investor. B. The Royal College of Ophthalmologists of the United Kingdom. Guidelines for the management of open angle glaucoma and ocular hypertension [Internet]. 2004 [cited 2011 Dec 9]. Available from: http://www.þ Guidelines. Reprint address: Yvonne M. Buys, MD, FRCSC, Toronto Western Hospital, 399 Bathurst St, EW6-405, Toronto, Ontario, Canada M5T 2S8. e-mail: Outline I. Introduction 3. Alterations in trabecular meshwork cytoskeleton 4. Increase cell adhesion molecules A. Steroids and intraocular pressure B. Intravitreal steroids II. Intravitreal steroid delivery methods V. Systematic literature review and meta-analysis A. Intravitreal injection A. Results 1. Triamcinolone acetonide intravitreal injection 2. Dexamethasone intravitreal injection B. Sustained-release (Fig. 1) intravitreal implant 1. Triamcinolone acetonide sustainedrelease implant 2. Fluocinolone acetonide sustained-release implant a. Retisert b. Iluvien 3. Dexamethasone sustained-release implant III. Pharmacokinetics of intravitreal steroids A. Intravitreal steroid injection B. Sustained-release intravitreal implant IV. Mechanism of intravitreal steroid-induced secondary ocular hypertension A. Direct volume effect B. Particulate matter obstructing the trabecular meshwork C. Trabecular meshwork dysfunction 1. Increased extracellular matrix deposition in meshwork 2. Inhibition of trabecular meshwork cell functions a. Inhibition of phagocytosis b. Stabilization of lysosomes 1. Prevalence of OHT post IVT steroid (Table 1) a. Triamcinolone acetonide intravitreal injection b. Dexamethasone intravitreal injection c. Fluocinolone acetonide intravitreal implant d. Dexamethasone intravitreal implant 2. Time course of ocular hypertension following intravitreal steroid a. Triamcinolone acetonide intravitreal injection b. Dexamethasone intravitreal injection c. Fluocinolone acetonide intravitreal implant d. Dexamethasone intravitreal implant B. Risk Factors (Table 2) 1. Patient-related risk factors a. b. c. d. e. f. g. Age Sex Higher baseline IOP History of glaucoma Underlying ocular disease Underlying systemic disease Secondary OHT after repeat intravitreal steroid h. Phakic/Pseudophakic and vitrectomized/ nonvitrectomized eye 2. Medication-related risk factors a. Type of steroid
  20. 20. 310 Surv Ophthalmol 58 (4) July--August 2013 b. Dosage of steroid c. Number of injections C. Management 1. Medical treatment 2. Laser treatment 3. Surgical management a. Surgical management of OHT following IVT TA injection KIDDEE ET AL b. Surgical management of OHT following IVT FA implants c. Surgical management of OHT following IVT dexamethasone implants VI. Recommendation for intraocular pressure surveillance VII. Conclusions VIII. Methods of literature search IX. Disclosure