Survey of ohptholmology meta-analysis

674 views
558 views

Published on

Published in: Health & Medicine, Education
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
674
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
8
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

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 http://dx.doi.org/10.1016/j.survophthal.2012.08.003
  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.
  14. 14. 304 Surv Ophthalmol 58 (4) July--August 2013 References 1. Agrawal S, Agrawal J, Agrawal TP. Vitrectomy as a treatment for elevated intraocular pressure following intravitreal injection of triamcinolone acetonide. Am J Ophthalmol. 2004;138:679--80 2. Ansari EA, Ali N. Intraocular pressure following intravitreal injection of triamcinolone acetonide. Open Ophthalmol J. 2008;2:119--22 3. Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics. I. The effect of dexamethasone in the normal eye. Arch Ophthalmol. 1963;70:482--91 4. Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics. II. The effect of dexamethasone in the glaucomatous eye. Arch Ophthalmol. 1963;70: 492--9 5. Armaly MF. Statistical attributes of the steroid hypertensive response in the clinically normal eye. I. The demonstration of three levels of response. Invest Ophthalmol. 1965;4: 187--97 6. Atmaca LS, Yalcindag FN, Ozdemir O. Intravitreal triamcinolone acetonide in the management of cystoid macular edema in Behcet’s disease. Graefes Arch Clin Exp Ophthalmol. 2007;245:451--6 7. Audren F, Erginay A, Haouchine B, et al. Intravitreal triamcinolone acetonide for diffuse diabetic macular oedema: 6-month results of a prospective controlled trial. Acta Ophthalmol Scand. 2006;84:624--30 8. Audren F, Tod M, Massin P, et al. Pharmacokineticpharmacodynamic modeling of the effect of triamcinolone acetonide on central macular thickness in patients with diabetic macular edema. Invest Ophthalmol Vis Sci. 2004; 45:3435--41 9. Avci R, Kaderli B, Akalp FD. Intravitreal triamcinolone injection for chronic diffuse diabetic macular oedema. Clin Experiment Ophthalmol. 2006;34:27--32 10. Avci R, Kaderli B. Intravitreal triamcinolone injection for chronic diabetic macular oedema with severe hard exudates. Graefes Arch Clin Exp Ophthalmol. 2006;244:28--35 11. Avitabile T, Longo A, Reibaldi A. Intravitreal triamcinolone compared with macular laser grid photocoagulation for the treatment of cystoid macular edema. Am J Ophthalmol. 2005;140:695--702 12. Baath J, Ells AL, Crichton A, et al. Safety profile of intravitreal triamcinolone acetonide. J Ocul Pharmacol Ther. 2007;23:304--10 13. Bakri SJ, Beer PM. The effect of intravitreal triamcinolone acetonide on intraocular pressure. Ophthalmic Surg Lasers Imaging. 2003;34:386--90 14. Bakri SJ, Pulido JS, McCannel CA, et al. Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab. Eye. 2009;23:181--5 15. Bamberger CM, Bamberger AM, Wald M, et al. Inhibition of mineralocorticoid activity by the beta-isoform of the human glucocorticoid receptor. J Steroid Biochem Mol Biol.. 1997;60:43--50 16. Baser E, Seymenoglu R. Selective laser trabeculoplasty for the treatment of intraocular pressure elevation after intravitreal triamcinolone injection. Can J Ophthalmol. 2009;44:e21 17. Bashshur ZF, Terro AM, Haibi CPE, et al. Intravitreal triamcinolone acetonide: Pattern of secondary intraocular pressure rise and possible risk factors. Clin Ophthalmol. 2008;2:269--74 18. Batioglu F, Ozmert E, Parmak N, Celik S. Two-year results of intravitreal triamcinolone acetonide injection for the treatment of diabetic macular edema. Int Ophthalmol. 2007;27:299--306 19. Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127:245--51 KIDDEE ET AL 20. Beer PM, Bakri SJ, Singh RJ, et al. Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology. 2003; 110:681--6 21. Benz MS, Albini TA, Holz ER, et al. Short-term course of intraocular pressure after intravitreal injection of triamcinolone acetonide. Ophthalmology. 2006;113:1174--8 22. Bhurayanontachai P, Ratanasukon M, Ma-a-lee A. The response pattern of intravitreal triamcinolone injection for non-AMD macular edema. J Med Assoc Thai. 2009;92: 58--63 23. Bollinger K, Kim J, Lowder CY, et al. Intraocular pressure outcome of patients with fluocinolone acetonide intravitreal implant for noninfectious uveitis. Ophthalmology. 2011;118:1927--31 24. Bollinger KE, Smith SD. Prevalence and management of elevated intraocular pressure after placement of an intravitreal sustained-release steroid implant. Curr Opin Ophthalmol. 2009;20:99--103 25. Bourges JL, Bloquel C, Thomas A, et al. Intraocular implants for extended drug delivery: therapeutic applications. Adv Drug Deliv Rev. 2006;58:1182--202 26. Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. 2011;31:915--23 27. Breusegem C, Vandewalle E, Van Calster J, et al. Predictive value of a topical dexamethasone provocative test before intravitreal triamcinolone acetonide injection. Invest Ophthalmol Vis Sci. 2009;50:573--6 28. Cakir M, Dogan M, Bayraktar Z, et al. Efficacy of intravitreal triamcinolone for the treatment of macular edema secondary to branch retinal vein occlusion in eyes with or without grid laser photocoagulation. Retina. 2008;28:465--72 29. Callanan DG, Jaffe GJ, Martin DF, et al. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008;126: 1191--201 30. Campochiaro PA, Brown DM, Pearson A, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118:626--35 31. Campochiaro PA, Hafiz G, Shah SM, et al. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology. 2010;117:1393--9 32. Chan CK, Fan DS, Chan WM, et al. Ocular-hypertensive response and corneal endothelial changes after intravitreal triamcinolone injections in Chinese subjects: a 6-month follow-up study. Eye. 2005;19:625--30 33. Chan CK, Mohamed S, Lee VY, et al. Intravitreal dexamethasone for diabetic macular edema: a pilot study. Ophthalmic Surg Lasers Imaging. 2010;41:26--30 34. Chang W, Chung M. Efficacy of anterior chamber paracentesis after intravitreal triamcinolone injection. Eur J Ophthalmol. 2007;17:776--9 35. Chang YC, Wu WC. Elevation of intraocular pressure after intravitreal injection of triamcinolone acetonide in Taiwanese patients. Kaohsiung J Med Sci. 2008;24:72--7 36. Chang-Lin JE, Attar M, Acheampong AA, et al. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci. 2011;52:80--6 37. Chang-Lin JE, Burke JA, Peng Q, et al. Pharmacokinetics of a sustained-release dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes. Invest Ophthalmol Vis Sci. 2011;52:4605--9 38. Chaudhary V, Mao A, Hooper PL, et al. Triamcinolone acetonide as adjunctive treatment to verteporfin in neovascular age-related macular degeneration: a prospective randomized trial. Ophthalmology. 2007;114:2183--9 39. Chen SD, Lochhead J, McDonald B, et al. Pseudohypopyon after intravitreal triamcinolone injection for the treatment of pseudophakic cystoid macular oedema. Br J Ophthalmol. 2004;88:843--4
  15. 15. INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID 40. Chen SD, Sundaram V, Lochhead J, et al. Intravitreal triamcinolone for the treatment of ischemic macular edema associated with branch retinal vein occlusion. Am J Ophthalmol. 2006;141:876--83 41. Chen WL, Tsai YY, Chiang CC, et al. Argon laser trabeculoplasty for late glaucoma after intravitreal triamcinolone. Acta Ophthalmol. 2009;87:238--9 42. Cheng L, Banker AS, Martin M, et al. Triamcinolone acetonide concentration of aqueous humor after decanted 20-mg intravitreal injection. Ophthalmology. 2009;116: 1356--9 43. Chieh JJ, Carlson AN, Jaffe GJ. Combined fluocinolone acetonide intraocular delivery system insertion, phacoemulsification, and intraocular lens implantation for severe uveitis. Am J Ophthalmol. 2008;146:589--94 44. Chieh JJ, Roth DB, Liu M, et al. Intravitreal triamcinolone acetonide for diabetic macular edema. Retina. 2005;25: 828--34 45. Chin HS, Park TS, Moon YS, et al. Difference in clearance of intravitreal triamcinolone acetonide between vitrectomized and nonvitrectomized eyes. Retina. 2005;25:556--60 46. Choi YJ, Oh IK, Oh JR, et al. Intravitreal versus posterior subtenon injection of triamcinolone acetonide for diabetic macular edema. Korean J Ophthalmol. 2006;20:205--9 47. Choonara YE, Pillay V, Danckwerts MP, et al. A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases. J Pharm Sci. 2010;99:2219--39 48. Chuang LH, Yeung L, Wang NK, et al. Secondary ocular hypertension after intravitreal injection with 2 mg or 4 mg of triamcinolone in retinal vein occlusion. J Ocul Pharmacol Ther. 2010;26:325--8 49. Chung EJ, Freeman WR, Azen SP, et al. Comparison of combination posterior sub-tenon triamcinolone and modified grid laser treatment with intravitreal triamcinolone treatment in patients with diffuse diabetic macular edema. Yonsei Med J. 2008;49:955--64 50. Ciardella AP, Klancnik J, Schiff W, et al. Intravitreal triamcinolone for the treatment of refractory diabetic macular oedema with hard exudates: an optical coherence tomography study. Br J Ophthalmol. 2004;88:1131--6 51. Ciulla TA, Walker JD, Fong DS, et al. Corticosteroids in posterior segment disease: An update on new delivery systems and new indications. Curr Opin Ophthalmol. 2004; 15:211--20 52. Clark AF, Wilson K, McCartney MD, et al. Glucocorticoidinduced formation of cross-linked actin networks in cultured human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 1994;35:281--94 53. Clark AF, Wordinger RJ. The role of steroids in outflow resistance. Exp Eye Res. 2009;88:752--9 54. Dada T, Dhawan M, Garg S, et al. Safety and efficacy of intraoperative intravitreal injection of triamcinolone acetonide injection after phacoemulsification in cases of uveitic cataract. J Cataract Refract Surg. 2007;33:1613--8 55. Danis RP, Ciulla TA, Pratt LM, et al. Intravitreal triamcinolone acetonide in exudative age-related macular degeneration. Retina. 2000;20:244--50 56. Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems. A shift to the posterior segment. Drug Discov Today. 2008;13:135--43 57. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447--9 58. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117: 1064--77 59. Ding X, Li J, Hu X, et al. Prospective study of intravitreal triamcinolone acetonide versus bevacizumab for macular edema secondary to central retinal vein occlusion. Retina. 2011;31:838--45 305 60. Edelhauser HF, Rowe-Rendleman CL, Robinson MR, et al. Ophthalmic drug delivery systems for the treatment of retinal diseases: basic research to clinical applications. Invest Ophthalmol Vis Sci. 2010;51:5403--20 61. Francois J. Corticosteroid glaucoma. Ann Ophthalmol. ¸ 1977;9:1075--80 62. Frenkel MP, Haji SA, Frenkel RE. Effect of prophylactic intraocular pressure-lowering medication on intraocular pressure spikes after intravitreal injections. Arch Ophthalmol. 2010;128:1523--7 63. Galor A, Margolis R, Brasil OM, et al. Adverse events after intravitreal triamcinolone in patients with and without uveitis. Ophthalmology. 2007;114:1912--8 64. Gelston CD, Olson JL, Mandava N. Macular oedema in central retinal vein occlusion treated with intravitreal triamcinolone. Acta Ophthalmol Scand. 2006;84:314--8 65. Gillies MC, Kuzniarz M, Craig J, et al. Intravitreal triamcinolone-induced elevated intraocular pressure is associated with the development of posterior subcapsular cataract. Ophthalmology. 2005;112:139--43 66. Gillies MC, McAllister IL, Zhu M, et al. Intravitreal triamcinolone prior to laser treatment of diabetic macular edema: 24-month results of a randomized controlled trial. Ophthalmology. 2011;118:866--72 67. Gillies MC, Simpson JM, Billson FA, et al. Safety of an intravitreal injection of triamcinolone: results from a randomized clinical trial. Arch Ophthalmol. 2004;122:336--40 68. Gillies MC, Simpson JM, Luo W, et al. A randomized clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration: one-year results. Arch Ophthalmol. 2003;121:667--73 69. Gillies MC, Sutter FK, Simpson JM, et al. Intravitreal triamcinolone for refractory diabetic macular edema: twoyear results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology. 2006;113:1533--8 70. Goff MJ, Jumper JM, Yang SS, et al. Intravitreal triamcinolone acetonide treatment of macular edema associated with central retinal vein occlusion. Retina. 2006;26: 896--901 71. Goldstein DA, Godfrey DG, Hall A, et al. Intraocular pressure in patients with uveitis treated with fluocinolone acetonide implants. Arch Ophthalmol. 2007;125: 1478--85 72. Graham RO, Peyman GA. Intravitreal injection of dexamethasone. Treatment of experimentally induced endophthalmitis. Arch Ophthalmol. 1974;92:149--54 73. Gregori NZ, Rosenfeld PJ, Puliafito CA, et al. One-year safety and efficacy of intravitreal triamcinolone acetonide for the management of macular edema secondary to central retinal vein occlusion. Retina. 2006;26:889--95 74. Haller JA, Bandello F, Belfort R, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118:2453--60 75. Haller JA, Bandello F, Belfort R, et al. Randomized, shamcontrolled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117:1134--46 76. Haller JA, Dugel P, Weinberg DV, et al. Evaluation of the safety and performance of an applicator for a novel intravitreal dexamethasone drug delivery system for the treatment of macular edema. Retina. 2009;29:46--51 77. Haller JA, Kuppermann BD, Blumenkranz MS, et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010;128:289--96 78. Haupert CL, Jaffe GJ. New and emerging treatments for patients with uveitis. Int Ophthalmol Clin. 2000;40:205--20 79. Hauser D, Bukelman A, Pokroy R, et al. Intravitreal triamcinolone for diabetic macular edema: comparison of 1, 2, and 4 mg. Retina. 2008;28:825--30 80. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928
  16. 16. 306 Surv Ophthalmol 58 (4) July--August 2013 81. Hirano Y, Ito T, Nozaki M, et al. Intraocular pressure elevation following triamcinolone acetonide administration as related to administration routes. Jpn J Ophthalmol. 2009;53:519--22 82. Hogewind BF, Zijlstra C, Klevering BJ, Hoyng CB. Intravitreal triamcinolone for the treatment of refractory macular edema in idiopathic intermediate or posterior uveitis. Eur J Ophthalmol. 2008;18:429--34 83. Hollands H, Seif G, Hollands S, et al. A trial of topical prednisolone acetate before intravitreal triamcinolone acetonide decreases intraocular pressure spikes. Can J Ophthalmol. 2010;45:484--8 84. Hollands H, Wong J, Bruen R, et al. Short-term intraocular pressure changes after intravitreal injection of bevacizumab. Can J Ophthalmol. 2007;42:807--11 85. Hou J, Tao Y, Jiang Y-R, et al. Intravitreal bevacizumab versus triamcinolone acetonide for macular edema due to branch retinal vein occlusion: a matched study. Chin Med J. 2009;122:2695--9 86. Im L, Allingham RR, Singh I, et al. A prospective study of early intraocular pressure changes after a single intravitreal triamcinolone injection. J Glaucoma. 2008;17:128--32 87. Inatani M, Iwao K, Kawaji T, et al. Intraocular pressure elevation after injection of triamcinolone acetonide: a multicenter retrospective case-control study. Am J Ophthalmol. 2008;145:676--81 88. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127:1101--14 89. Ito M, Okubo A, Sonoda Y, et al. Intravitreal triamcinolone acetonide for exudative age-related macular degeneration among Japanese patients. Ophthalmologica. 2006;220: 118--24 90. Jaffe GJ, Martin D, Callanan D, et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology. 2006;113:1020--7 91. Jaffe GJ, McCallum RM, Branchaud B, et al. Long-term follow-up results of a pilot trial of a fluocinolone acetonide implant to treat posterior uveitis. Ophthalmology. 2005; 112:1192--8 92. Jaffe GJ, Yang CH, Guo H, et al. Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device. Invest Ophthalmol Vis Sci. 2000;41: 3569--75 93. Jea SY, Byon IS, Oum BS. Triamcinolone-induced intraocular pressure elevation: intravitreal injection for macular edema and posterior subtenon injection for uveitis. Korean J Ophthalmol. 2006;20:99--103 94. Johnson D, Gottanka J, Flugel C, et al. Ultrastructural ¨ changes in the trabecular meshwork of human eyes treated with corticosteroids. Arch Ophthalmol. 1997;115:375--83 95. Jonas JB, Akkoyun I, Budde WM, et al. Intravitreal reinjection of triamcinolone for exudative age-related macular degeneration. Arch Ophthalmol. 2004;122:218--22 96. Jonas JB, Akkoyun I, Kamppeter B, et al. Intravitreal triamcinolone acetonide for treatment of central retinal vein occlusion. Eur J Ophthalmol. 2005;15:751--8 97. Jonas JB, Degenring RF, Kreissig I, et al. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection. Ophthalmology. 2005;112:593--8 98. Jonas JB, Hayler JK, Panda-Jonas S. Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative vitreoretinopathy. Br J Ophthalmol. 2000;84:1064--7 99. Jonas JB, Hayler JK, Sofker A, et al. Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol. 2001;131:468--71 100. Jonas JB. Intraocular availability of triamcinolone acetonide after intravitreal injection. Am J Ophthalmol. 2004; 137:560--2 KIDDEE ET AL 101. Jonas JB, Kreissig I, Degenring RF. Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol. 2003;87:24--7 102. Jonas JB, Kreissig I, Hugger P, et al. Intravitreal triamcinolone acetonide for exudative age related macular degeneration. Br J Ophthalmol. 2003;87:462--8 103. Jonas JB, Kreissig I, Sofker A, et al. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol. 2003;121:57--61 104. Jonas JB, Schlichtenbrede F. Visual acuity and intraocular pressure after high-dose intravitreal triamcinolone acetonide in selected ocular diseases. Eye. 2008;22:869--73 105. Jonas JB, Spandau UH, Kamppeter BA, et al. Follow-up after intravitreal triamcinolone acetonide for diabetic macular edema. Eur J Ophthalmol. 2006;16:566--72 106. Jonas JB, Spandau UH, Kamppeter BA, et al. Repeated intravitreal high-dosage injections of triamcinolone acetonide for diffuse diabetic macular edema. Ophthalmology. 2006;113:800--4 107. Jonas JB, Spandau UH, Kamppeter BA, et al. Follow-up after intravitreal triamcinolone acetonide for exudative age-related macular degeneration. Eye. 2007;21:387--94 108. Jones R 3rd, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature. Curr Opin Ophthalmol. 2006;17:163--7 109. Kamppeter BA, Cej A, Jonas JB. Intraocular concentration of triamcinolone acetonide after intravitreal injection in the rabbit eye. Ophthalmology. 2008;115:1372--5 110. Kane FE, Burdan J, Cutino A, et al. Iluvien: a new sustained delivery technology for posterior eye disease. Expert Opin Drug Deliv. 2008;5:1039--46 111. Kang SW, Park SC, Cho HY, et al. Triple therapy of vitrectomy, intravitreal triamcinolone, and macular laser photocoagulation for intractable diabetic macular edema. Am J Ophthalmol. 2007;144:878--85 112. Karacorlu M, Ozdemir H, Karacorlu S, et al. Intravitreal triamcinolone as a primary therapy in diabetic macular oedema. Eye. 2005;19:382--6 113. Kaushik S, Gupta V, Gupta A, et al. Intractable glaucoma following intravitreal triamcinolone in central retinal vein occlusion. Am J Ophthalmol. 2004;137:758--60 114. Kempen JH, Altaweel MM, Holbrook JT, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology. 2011;118:1916--26 115. Kerimoglu H, Ozturk BT, Bozkurt B, et al. Does lens status affect the course of early intraocular pressure and anterior chamber changes after intravitreal injection? Acta Ophthalmol. 2011;89:138--42 116. Kersey JP, Broadway DC. Corticosteroid-induced glaucoma: a review of the literature. Eye. 2006;20:407--16 117. Kim H, Csaky KG, Gravlin L, et al. Safety and pharmacokinetics of a preservative-free triamcinolone acetonide formulation for intravitreal administration. Retina. 2006; 26:523--30 118. Kim JE, Mantravadi AV, Hur EY, et al. Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents. Am J Ophthalmol. 2008;146:930--4 119. Kim JE, Pollack JS, Miller DG, et al. ISIS-DME: a prospective, randomized, dose-escalation intravitreal steroid injection study for refractory diabetic macular edema. Retina. 2008;28:735--40 120. Kim JY, Park SP. Comparison between intravitreal bevacizumab and triamcinolone for macular edema secondary to branch retinal vein occlusion. Korean J Ophthalmol. 2009; 23:259--65 121. Kitazawa Y, Horie T. The prognosis of corticosteroidresponsive individuals. Arch Ophthalmol. 1981;99:819--23 122. Kocabora MS, Yilmazli C, Taskapili M, et al. Development of ocular hypertension and persistent glaucoma after intravitreal injection of triamcinolone. Clin Ophthalmol. 2008;2:167--71
  17. 17. INTRAOCULAR PRESSURE SURVEILLANCE POST INTRAVITREAL STEROID 123. Kogure A, Ohkoshi K, Kogure S, et al. Efficacy and retention times of intravitreal triamcinolone acetonide for macular edema. Jpn J Ophthalmol. 2008;52:122--6 124. Konstantopoulos A, Williams CP, Newsom RS, et al. Ocular morbidity associated with intravitreal triamcinolone acetonide. Eye. 2007;21:317--20 125. Kosobucki BR, Freeman WR, Cheng L. Photographic estimation of the duration of high dose intravitreal triamcinolone in the vitrectomised eye. Br J Ophthalmol. 2006;90:705--8 126. Kotliar K, Maier M, Bauer S, et al. Effect of intravitreal injections and volume changes on intraocular pressure: clinical results and biomechanical model. Acta Ophthalmol Scand. 2007;85:777--81 127. Kramar M, Vu L, Whitson JT, et al. The effect of intravitreal triamcinolone on intraocular pressure. Curr Med Res Opin. 2007;23:1253--8 128. Krishnan R, Kumar N, Wishart PK. Viscocanalostomy for refractory glaucoma secondary to intravitreal triamcinolone acetonide injection. Arch Ophthalmol. 2007;125: 1284--6 129. Kubota T, Okabe H, Hisatomi T, et al. Ultrastructure of the trabecular meshwork in secondary glaucoma eyes after intravitreal triamcinolone acetonide. J Glaucoma. 2006;15: 117--9 130. Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007;125:309--17 131. Kwak HW, D’Amico DJ. Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection. Arch Ophthalmol. 1992;110:259--66 132. Lam DS, Chan CK, Mohamed S, et al. A prospective randomised trial of different doses of intravitreal triamcinolone for diabetic macular oedema. Br J Ophthalmol. 2007;91:199--203 133. Lam DS, Chan CK, Mohamed S, et al. Phacoemulsification with intravitreal triamcinolone in patients with cataract and coexisting diabetic macular oedema: a 6-month prospective pilot study. Eye. 2005;19:885--90 134. Lam DS, Chan CK, Tang EW, et al. Intravitreal triamcinolone for diabetic macular oedema in Chinese patients: six-month prospective longitudinal pilot study. Clin Experiment Ophthalmol. 2004;32:569--72 135. Lang Y, Leibu R, Shoham N, et al. Evaluation of intravitreal kenalog toxicity in humans. Ophthalmology. 2007;114: 724--31 136. Lau L-I, Chen K-C, Lee F-L, et al. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection in a Chinese population. Am J Ophthalmol. 2008; 146:573--8 137. Lauer AK, Bressler NM, Edwards AR. Frequency of intraocular pressure increase within days after intravitreal triamcinolone injections in the diabetic retinopathy clinical research network. Arch Ophthalmol. 2011;129: 1097--9 138. Lewis JM, Priddy T, Judd J, et al. Intraocular pressure response to topical dexamethasone as a predictor for the development of primary open-angle glaucoma. Am J Ophthalmol. 1988;106:607--12 139. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and metaanalyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62: e1--34 140. London NJ, Chiang A, Haller JA. The dexamethasone drug delivery system: indications and evidence. Adv Ther. 2011; 28:351--66 141. Lowder C, Belfort R, Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011;129:545--53 142. Maberley D, Canadian Retinal Trials Group. Photodynamic therapy and intravitreal triamcinolone for neovascular age- 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 307 related macular degeneration: a randomized clinical trial. Ophthalmology. 2009;116:2149--57 Marticorena J, Gomez-Ulla F, Fernandez M, et al. Combined photodynamic therapy and intravitreal triamcinolone acetonide for the treatment of myopic subfoveal choroidal neovascularization. Am J Ophthalmol. 2006;142: 335--7 Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109:920--7 Mason JO 3rd, Somaiya MD, Singh RJ. Intravitreal concentration and clearance of triamcinolone acetonide in nonvitrectomized human eyes. Retina. 2004;24:900--4 Massin P, Audren F, Haouchine B, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology. 2004;111:218--24 Matsumoto Y, Johnson DH. Dexamethasone decreases phagocytosis by human trabecular meshwork cells in situ. Invest Ophthalmol Vis Sci. 1997;38:1902--7 Mirshahi A, Shenazandi H, Lashay A, et al. Intravitreal triamcinolone as an adjunct to standard laser therapy in coexisting high-risk proliferative diabetic retinopathy and clinically significant macular edema. Retina. 2010;30:254--9 Moshfeghi AA, Scott IU, Flynn HW Jr, et al. Pseudohypopyon after intravitreal triamcinolone acetonide injection for cystoid macular edema. Am J Ophthalmol. 2004;138: 489--92 Ozdek SC, Aydin B, Gurelik G, et al. Effects of intravitreal triamcinolone injection on macular edema and visual prognosis in central retinal vein occlusion. Int Ophthalmol. 2005;26:27--34 Ozkiris A, Erkilic K. Complications of intravitreal injection of triamcinolone acetonide. Can J Ophthalmol. 2005;40: 63--8 Ozkiris A, Evereklioglu C, Erkilic K, et al. Intravitreal triamcinolone acetonide for treatment of persistent macular oedema in branch retinal vein occlusion. Eye. 2006;20: 13--7 Ozkiris A, Evereklioglu C, Erkilic K, et al. Intravitreal triamcinolone acetonide injection as primary treatment for diabetic macular edema. Eur J Ophthalmol. 2004;14:543--9 Park HY, Yi K, Kim HK. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection. Korean J Ophthalmol. 2005;19:122--7 Pavesio C, Zierhut M, Bairi K, et al. Evaluation of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious posterior uveitis. Ophthalmology. 2010;117:567--75 Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology. 2011;118:1580--7 Pizzimenti JJ, Nickerson MM, Pizzimenti CE, et al. Selective laser trabeculoplasty for intraocular pressure elevation after intravitreal triamcinolone acetonide injection. Optom Vis Sci. 2006;83:421--5 Polansky JR, Fauss DJ, Chen P, et al. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Ophthalmologica. 1997;211:126--39 Quigley HA, Anderson DR. Distribution of axonal transport blockade by acute intraocular pressure elevation in the primate optic nerve head. Invest Ophthalmol Vis Sci. 1977;16:640--4 Ramchandran RS, Fekrat S, Stinnett SS, et al. Fluocinolone acetonide sustained drug delivery device for chronic central retinal vein occlusion: 12-month results. Am J Ophthalmol. 2008;146:285--91 Ramezani A, Entezari M, Moradian S, et al. Intravitreal triamcinolone for acute central retinal vein occlusion; a randomized clinical trial. Graefes Arch Clin Exp Ophthalmol. 2006;244:1601--6
  18. 18. 308 Surv Ophthalmol 58 (4) July--August 2013 162. Rhee DJ, Peck RE, Belmont J, et al. Intraocular pressure alterations following intravitreal triamcinolone acetonide. Br J Ophthalmol. 2006;90:999--1003 163. Ricci F, Missiroli F, Parravano M. Argon laser trabeculoplasty in triamcinolone acetonide induced ocular hypertension refractory to maximal medical treatment. Eur J Ophthalmol. 2006;16:756--7 164. Roth DB, Realini T, Feuer WJ, et al. Short-term complications of intravitreal injection of triamcinolone acetonide. Retina. 2008;28:66--70 165. Roth DB, Verma V, Realini T, et al. Long-term incidence and timing of intraocular hypertension after intravitreal triamcinolone acetonide injection. Ophthalmology. 2009; 116:455--60 166. Rubin B, Taglienti A, Rothman RF, et al. The effect of selective laser trabeculoplasty on intraocular pressure in patients with intravitreal steroid-induced elevated intraocular pressure. J Glaucoma. 2008;17:287--92 167. Ruiz-Moreno JM, Montero JA, Amat P, et al. Secondary elevated IOP and cataracts after high-dose intravitreal triamcinolone and photodynamic therapy to treat choroidal neovascularization. J Glaucoma. 2009;18:69--72 168. Ruiz-Moreno JM, Montero JA, Artola A, et al. Anterior chamber transit of triamcinolone after intravitreal injection. Arch Ophthalmol. 2005;123:129--30 169. Ryder MI, Weinreb RN, Alvarado J, et al. The cytoskeleton of the cultured human trabecular cell. Characterization and drug responses. Invest Ophthalmol Vis Sci. 1988;29: 251--60 170. Schindler RH, Chandler D, Thresher R, et al. The clearance of intravitreal triamcinolone acetonide. Am J Ophthalmol. 1982;93:415--7 171. Scholes GN, O’Brien WJ, Abrams GW, et al. Clearance of triamcinolone from vitreous. Arch Ophthalmol. 1985;103: 1567--9 172. Scorolli L, Morara M, Meduri A, et al. Treatment of cystoid macular edema in retinitis pigmentosa with intravitreal triamcinolone. Arch Ophthalmol. 2007;125:759--64 173. Sharma MC, Lai WW, Shapiro MJ. Pseudohypopyon following intravitreal triamcinolone acetonide injection. Cornea. 2004;23:398--9 174. Shukla D, Vidhya N, Prasad NM, et al. Evaluation of patient age as a risk factor for intraocular pressure elevation after intravitreal triamcinolone. Am J Ophthalmol. 2007;144: 453--4 175. Simon S, Gray T, Dhanapala M, et al. Pseudohypopyon following intravitreal triamcinolone acetonide injection in a phakic eye. Clin Experiment Ophthalmol. 2010;38: 76--7 176. Singh IP, Ahmad SI, Yeh D, et al. Early rapid rise in intraocular pressure after intravitreal triamcinolone acetonide injection. Am J Ophthalmol. 2004;138:286--7 177. Sivaprasad S, McCluskey P, Lightman S. Intravitreal steroids in the management of macular oedema. Acta Ophthalmol Scand. 2006;84:722--33 178. Smithen LM, Ober MD, Maranan L, et al. Intravitreal triamcinolone acetonide and intraocular pressure. Am J Ophthalmol. 2004;138:740--3 179. Snyder RW, Stamer WD, Kramer TR, et al. Corticosteroid treatment and trabecular meshwork proteases in cell and organ culture supernatants. Exp Eye Res. 1993; 57:461--8 180. Stone EM, Fingert JH, Alward WL, et al. Identification of a gene that causes primary open angle glaucoma. Science. 1997;275:668--70 181. Sutter FKP, Simpson JM, Gillies MC. Intravitreal triamcinolone for diabetic macular edema that persists after laser treatment: Three-month efficacy and safety results of a prospective, randomized, double-masked, placebo-controlled clinical trial. Ophthalmology. 2004;111:2044--9 182. Tammewar AM, Cheng L, Kayikcioglu OR, et al. Comparison of 4 mg versus 20 mg intravitreal tri- KIDDEE ET AL 183. 184. 185. 186. 187. 188. 189. 190. 191. 192. 193. 194. 195. 196. 197. 198. 199. 200. 201. amcinolone acetonide injections. Br J Ophthalmol. 2008;92:810--3 Tano Y, Chandler D, Machemer R. Treatment of intraocular proliferation with intravitreal injection of triamcinolone acetonide. Am J Ophthalmol. 1980;90: 810--6 Tao Y, Hou J, Jiang YR, et al. Intravitreal bevacizumab vs triamcinolone acetonide for macular oedema due to central retinal vein occlusion. Eye. 2010;24:810--5 Tawara A, Tou N, Kubota T, et al. Immunohistochemical evaluation of the extracellular matrix in trabecular meshwork in steroid-induced glaucoma. Graefes Arch Clin Exp Ophthalmol. 2008;246:1021--8 Tektas OY, Lutjen-Drecoll E. Structural changes of the ¨ trabecular meshwork in different kinds of glaucoma. Exp Eye Res. 2009;88:769--75 Thrimawithana TR, Young S, Bunt CR, et al. Drug delivery to the posterior segment of the eye. Drug Discov Today. 2011;16:270--7 Tran VT, Mermoud A, Herbort CP. Appraisal and management of ocular hypotony and glaucoma associated with uveitis. Int Ophthalmol Clin. 2000;40:175--203 Tuncer S, Yilmaz S, Urgancioglu M, Tugal-Tutkun I. Results of intravitreal triamcinolone acetonide (IVTA) injection for the treatment of panuveitis attacks in patients with Behcet disease. J Ocul Pharmacol Ther. 2007;23:395--401 Underwood JL, Murphy CG, Chen J, et al. Glucocorticoids regulate transendothelial fluid flow resistance and formation of intercellular junctions. Am J Physiol. 1999;277: 330--42 Vasconcelos-Santos DV, Nehemy PG, Schachat AP, et al. Secondary ocular hypertension after intravitreal injection of 4 mg of triamcinolone acetonide: incidence and risk factors. Retina. 2008;28:573--80 Viola F, Morescalchi F, Staurenghi G. Argon laser trabeculoplasty for intractable glaucoma following intravitreal triamcinolone. Arch Ophthalmol. 2006;124: 133--4 Williams CP, Konstantopoulos A, Rowley SA, et al. Late intraocular pressure rise following intravitreal triamcinolone injection. Clin Experiment Ophthalmol. 2007;35: 385--6 Wilson K, McCartney MD, Miggans ST, et al. Dexamethasone induced ultrastructural changes in cultured human trabecular meshwork cells. Curr Eye Res. 1993; 12:783--93 Wingate RJ, Beaumont PE. Intravitreal triamcinolone and elevated intraocular pressure. Aust NZ J Ophthalmol. 1999; 27:431--2 Wordinger RJ, Clark AF. Effects of glucocorticoids on the trabecular meshwork: towards a better understanding of glaucoma. Prog Retin Eye Res. 1999;18:629--67 Yamamoto Y, Komatsu T, Koura Y, et al. Intraocular pressure elevation after intravitreal or posterior subTenon triamcinolone acetonide injection. Can J Ophthalmol. 2008;43:42--7 Yamashita T, Uemura A, Kita H, et al. Intraocular pressure after intravitreal injection of triamcinolone acetonide following vitrectomy for macular edema. J Glaucoma. 2007;16:220--4 Yeung CK, Chan KP, Chan CK, et al. Cytotoxicity of triamcinolone on cultured human retinal pigment epithelial cells: comparison with dexamethasone and hydrocortisone. Jpn J Ophthalmol. 2004;48:236--42 Yuen D, Buys YM, Jin YP, et al. Effect of beclomethasone nasal spray on intraocular pressure in ocular hypertension or controlled glaucoma. J Glaucoma [Internet]. 2011 Jun 28. [cited 2012 Jan 10];Available from: http://www.ncbi. nlm.nih.gov/pubmed/21716127. Zhang X, Clark AF, Yorio T. Regulation of glucocorticoid responsiveness in glaucomatous trabecular meshwork cells
  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. alimerasciences.com/releasedetail.cfm?ReleaseID5623128. 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. rcophth.ac.uk/page.asp?section5451sectionTitle5Clinicalþ Guidelines. Reprint address: Yvonne M. Buys, MD, FRCSC, Toronto Western Hospital, 399 Bathurst St, EW6-405, Toronto, Ontario, Canada M5T 2S8. e-mail: ybuys@utoronto.ca. 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

×