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Survey of ohptholmology meta-analysis
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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 304
Surv Ophthalmol 58 (4) July--August 2013
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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. 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
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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