PIZZIMENTI, JOSEPH J. OD, FAAO; NICKERSON, MARITZA M. OD; PIZZIMENTI, CLAIRE E. OD, FAAO; KASTEN-AKER, ANN G. MD
Intravitreal injection of triamcinolone acetonide has increasingly been used for the treatment of neovascular, inflammatory, and edematous intraocular diseases. These conditions include, but are not limited to, exudative age-related macular degeneration,1 macular edema resulting from retinal vascular occlusion,2 cystoid macular edema,3 diabetic macular edema,4 chronic uveitis,5 proliferative diabetic retinopathy,6 neovascular glaucoma,7 and proliferative vitreoretinopathy.8 The clinical effectiveness of intravitreal triamcinolone acetonide for these conditions is based on its direct application into the posterior segment.
A common and widely reported side effect of this treatment is a steroid-induced elevation of intraocular pressure.5,9,10 Triamcinolone acetonide has been found in aqueous humor and in silicone oil of treated eyes up to 18 months after the intravitreal injection.11,12 This extended time period delays the clearing of the drug in steroid-susceptible patients.
In most cases of intravitreal triamcinolone-induced rise in intraocular pressure, the patient can be successfully treated topically, using monotherapy or a combination of agents.12 In some cases, however, neither topical nor systemic medications will adequately control the intraocular pressure, or the patient may be intolerant to ocular and systemic adverse effects from these drugs. In a meta-analysis of previously reported cases, those eyes that could not be successfully treated with maximal medical therapy, including systemic carbonic anhydrase inhibitors, have been treated with filtering surgery.12
The use of laser surgical treatment for increased intraocular pressure secondary to intravitreal triamcinolone is not widely reported in the literature. In fact, little has been published on the use of laser surgical treatment for steroid-induced glaucoma in general.
There are two forms of laser trabeculoplasty: argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT). ALT is a mainstay in the treatment of primary open-angle glaucoma, and in most cases, it is used before incisional surgery. The mechanism by which ALT increases aqueous outflow and decreases intraocular pressure is unclear. Thermal scarring of the trabeculum occurs at the site where the laser energy is absorbed. The spaces between the laser burns are widened and freed of debris. It has been speculated that a mechanical tightening of the trabecular ring increases aqueous outflow. Evidence also exists of increased cell division, increased phagocytosis, and alteration of the extracellular matrix, all of which can improve trabecular function.13
SLT is a therapeutic procedure that targets pigmented trabecular cells in a nonthermal manner, thus sparing the meshwork coagulative damage.14 SLT causes a proliferation of trabecular and endothelial cells, the release of cytokines, the recruitment of macrophages, and phagocytosis. The ultimate result is increased aqueous outflow, thereby lowering intraocular pressure.14
This report presents a case of intraocular pressure elevation after intravitreal triamcinolone acetonide injection that was successfully treated with SLT.
A 63-year-old white man presented with brow ache on the right side of 2 weeks’ duration. The onset of this symptom began approximately 3 months after he received an intravitreal injection of 4 mg triamcinolone acetonide for diabetic macular edema in the right eye. The patient reported a history of both cataract and diabetic retinopathy in each eye. He indicated that he received laser treatment to the left retina 3 years previously. At the time of his examination, the patient was using one drop of latanoprost 0.005% (Xalatan; Pfizer U.S. Pharmaceutical Group, New York, NY) administered nightly in the right eye. His optometrist, who referred the patient to us for further evaluation and treatment of the intraocular pressure, prescribed this medication.
The patient wore 1-year old bifocal spectacles for distance and near vision and had no history of wearing contact lenses. He reported a history of systemic hypertension and type 2 diabetes mellitus, both of approximately 10 years’ duration. The patient also reported a having a “slow heart rate.” His current systemic medications included repaglinide (Prandin; Novo Nordisk, Princeton, NJ), pioglitazone HCl (Actos; Takeda, Lincolnshire, IL), amlodipine besylate (Norvasc; Pfizer, New York, NY), losartan potassium (Cozaar; Merck, Whitehouse Station, NJ), and torsemide (Demadex; Roche, Nutley, NJ).
On this visit, the patient’s best-corrected visual acuity with his spectacles was 20/400 in the right eye and 20/60 in the left. A mild afferent pupillary defect was noted in the right eye. Biomicroscopy revealed grade 2 nuclear sclerotic cataracts in the lens of each eye. Applanation tonometry revealed an intraocular pressure of 45 mm Hg in the right eye and 15 mm Hg in the left. The right eye’s intraocular pressure was, most likely, higher than our measurement of 45 mm Hg before the patient was started on topical medication, thus accounting for his symptom of brow ache. Gonioscopic evaluation of the iridocorneal angle and associated structures revealed grade 4 angles in the nasal, superior, temporal, and inferior quadrants of each eye with each angle exhibiting a wide open approach and mild/moderate trabecular pigment (Shaffer’s system was used for grading angle widths).15 There was no evidence of mechanical obstruction of the right eye’s trabeculum by the corticosteroid material. The patient had a resting heart rate of 56 beats per minute. His blood pressure was 128/81 mm Hg.
Dilated funduscopy of the right eye revealed a cup to disc ratio of .5H/.55V and clinical features of moderate, nonproliferative diabetic retinopathy. A large area of clinically significant macular edema, with associated disturbances of the pigment epithelium, was present in the right eye. This extensive macular dysfunction was, most likely, the cause of the afferent papillary defect. There was no evidence of glaucomatous notching or nerve fiber dropout in the right eye. Dilated funduscopy of the left eye revealed a cup to disc ratio of .45H/.5V and clinical features of moderate, nonproliferative diabetic retinopathy. Laser treatment scars were present in the left eye as was an epiretinal membrane in the macular region. There was no evidence of clinically significant macular edema in the left eye.
In an effort to lower the intraocular pressure in the right eye, both brimonidine 0.15% (Alphagan-P; Allergan, Inc., Irvine, CA) and dorzolamide 2% (Cosopt; Merck) were instilled, and the patient was monitored in-office until a tonometry measurement of 29 mm Hg was obtained. Topical beta-blockers were avoided given the patient’s measured pulse and reported history of reduced heart rate. Latanoprost 0.005% (1 gt OD at bedtime) (Xalatan; Pfizer U.S. Pharmaceutical Group), brimonidine 0.15% (1gt OD tid) (Alphagan-P; Allergan, Inc.), and dorzolamide 2% (1gt OD twice a day; Merck) were prescribed, and the patient returned in 2 weeks for follow up. On the return visit, acuities were unchanged and the intraocular pressure measured 18 and 12 mm Hg for the right and left eyes, respectively. Automated threshold perimetry was attempted, but poor fixation and low reliability rendered the findings invalid.
The patient returned in 4 weeks with palpitations shortly after instilling the brimonidine on several occasions, leading him to discontinue its use 1 week before the visit. He reported that since discontinuing the brimonidine, the palpitations stopped but the unilateral, right side brow ache returned. The patient reported good compliance with his two other topical medications. Acuities were unchanged from the previous visit, and the intraocular pressure measured 38 and 14 mm Hg for the right and left eyes, respectively.
At this point, the elevated intraocular pressure required more aggressive treatment. Topical beta-blockers and alpha-adrenergic agonists were poor options for our patient given his low heart rate and previous adverse reaction to brimonidine. Systemic carbonic anhydrase inhibitors were also suboptimal options as a result of their well-documented side effects, including blood dyscrasias, malaise, fatigue, renal calculi, nausea, and transient myopia.16 In addition, diabetics susceptible to ketoacidosis should avoid long-term carbonic anhydrase inhibitor use. For these reasons, surgical treatment of the patient’s intraocular pressure was considered a viable option.
Because laser trabeculoplasty is a relatively safe, effective procedure with less common and relatively milder complications (than incisional glaucoma surgery), we recommended it as the initial surgical treatment in this case. Within 1 week, the patient underwent SLT in the right eye. The eye received approximately 180° of treatment with SLT. Within 2 months of treatment with SLT, an intraocular pressure of 16 mm Hg was measured in the involved eye without topical medication. Using the measurement of 45 mm Hg from the initial visit as our baseline, this is approximately a 66% reduction in pressure. Now, 6 months postlaser treatment, the intraocular pressure in the involved eye is stable at 15 mm Hg without topical medication, and there has been no evidence of progressive glaucomatous cupping or nerve fiber dropout. The patient has experienced no side effects from the SLT procedure to date.
Corticosteroids have long been known to reduce inflammation and to suppress proliferation of cells. At the cellular level, corticosteroids have the ability to reduce or inhibit manifestations of the inflammatory response, including edema, fibrin deposition, lymphocyte proliferation, migration of neutrophils, release of mediators such as histamines and bradykinins, and synthesis of prostaglandins and leukotrienes.16
Intravitreal corticosteroids are increasingly being used and studied as a therapeutic modality for neovascular, inflammatory, proliferative, and edematous posterior segment diseases.9,12 Researchers have found that intravitreal injection allows delivery of the drug to its target tissues in a most direct fashion.3,11 Triamcinolone acetonide has been the most commonly used intravitreal steroid and is usually administered as a 4-mg bolus injection through the pars plana, typically with a 27-gauge or 30-guage needle. Triamcinolone acetonide is a synthetic glucocorticoid with mechanisms of action similar to those of naturally occurring glucocorticoids.11,17
The pharmacokinetics occurring after the injection of triamcinolone acetonide into the vitreous humor of humans have been described in previous work.11 The drug in suspension showed logarithmic, rather than linear, release kinetics, producing high initial levels of available drug. This was followed by a logarithmic decline in concentration. The intraocular pharmacokinetics and concentration after a single intravitreal injection of triamcinolone acetonide result in a persisting therapeutic effect. Short of undergoing a vitrectomy, eyes receiving this treatment will retain the drug for a prolonged period of several months.
Macular edema is the main cause of visual impairment in patients living with diabetes.18 Previous reports have shown that intravitreal triamcinolone was beneficial for diffuse diabetic macular edema.4,19 The specific mechanism of corticosteroid action on diabetic macular edema remains unclear. One hypothesis is that corticosteroids reduce retinal capillary permeability by increasing the activity and/or density of the tight junctions in the retinal capillary endothelium. Another theory is that corticosteroids inhibit the metabolic pathway of vascular endothelial growth factor (VEGF).19
Elevated intraocular pressure is a common and now well-documented side effect of intravitreal injection of triamcinolone. In a meta-analysis of previously reported data, researchers found that of 272 patients receiving an intravitreal injection of 20 mg triamcinolone acetonide, intraocular pressure readings higher than 21 mm Hg, 31 mm Hg, 35 mm Hg, and 40 mm Hg were measured in 112 (41.2%) patients, 31 (11.4%) patients, 15 (5.5%) patients, and 5 (1.8%) patients, respectively, at least 3 months after the injection.12 In a retrospective observational case series study on 89 patients receiving 4 mg triamcinolone acetonide, investigators found that 36 patients (40.4%) experienced a pressure elevation to 24 mm Hg or higher at a mean of 100.6 days (standard deviation = 83.1 days) after injection.9,12,17 Other investigators published an interventional case series in which 12 patients, all with bilateral diabetic macular edema unresponsive to laser treatment, received a triamcinolone acetonide injection in one eye, whereas the fellow eye served as a control. In this study, a dosage of 4 mg triamcinolone acetonide was used as the intervention. Although the results showed an overall dramatic anatomic improvement (reduced macular thickness) in diabetic macular edema, 6 of the 12 (50%) injected eyes had intraocular pressure that exceeded 25 mm Hg at intervals ranging between 2 days and 6 weeks after injection.4
The mechanism of this intraocular pressure rise is not fully understood, but there is evidence of glucocorticoid induction of a gene promoting synthesis of a new protein/glycoprotein,20 which is deposited in a manner consistent with steroid-induced glaucoma and distinct from primary open-angle glaucoma.21 It is also thought that biochemical and morphologic changes in the trabecular meshwork cause increased outflow resistance, thus increasing the intraocular pressure.22 In cases of a rapid rise in intraocular pressure (within 1 week) after treatment with intravitreal triamcinolone acetonide, mechanical obstruction of the trabecular meshwork by the corticosteroid material, vehicle, or both could contribute to the mechanism.10
In addition to increased intraocular pressure, other significant, although less common, side effects and complications of treatment with intravitreal triamcinolone acetonide include retinal detachment, vitreous hemorrhage, cataract, and endophthalmitis. Therefore, clinicians should engage the patient in a frank discussion about these potential risks, as well as possible benefits, of this treatment. Previous authors have recommended that clinicians assess steroid responsiveness in all candidates for intravitreal injection of triamcinolone acetonide by administering a topical steroid suspension several times daily during the weeks before the procedure.9 Others have gone so far as to suggest that those patients with a history of glaucoma or steroid response should not be given intravitreal triamcinolone. It has been suggested that repeated injections of triamcinolone acetonide, if indicated, be spaced at least 4 months apart. It may be prudent for clinicians to check the intraocular pressure within the first week after triamcinolone injection and to perform an initial gonioscopic examination to look for abnormal material in the angle.10
Treatment of the intraocular pressure rise as a result of intravitreal triamcinolone acetonide is typically accomplished in one of two ways: with pharmacotherapy or with incisional surgery. The previously cited meta-analysis showed that in all but 3 of the 272 (1.1%) postinjection patients with elevated intraocular pressure, adequate treatment was accomplished using antiglaucoma medications, most often topical drops. Filtering surgery was performed on the three cases that had intraocular pressure over 40 mm Hg despite maximal medical treatment, including oral carbonic anhydrase inhibitors.12
In an observational case series, authors reported adequate pressure-lowering after performing Ahmed valve placement surgery on three patients with elevated intraocular pressure after they received intravitreal triamcinolone acetonide.10 Others have advocated addressing the cause of the pressure rise by performing a vitrectomy and removing the triamcinolone from the vitreous cavity.23
Laser trabeculoplasty may provide an effective, safer alternative to incisional glaucoma surgery. It can be accomplished either with ALT or SLT techniques. The two procedures are technically similar, with ALT using argon laser and SLT using nonthermal laser technology. Both ALT and SLT are used as a primary treatment for patients with ocular hypertension and open-angle glaucoma.24 Although less invasive than filtering surgery, laser trabeculoplasty is not without possible side effects. These may include postlaser treatment intraocular pressure spikes, iritis, and peripheral anterior synechiae.13,24
We used SLT to treat our patient. SLT is a therapeutic procedure that targets pigmented trabecular meshwork cells without producing collateral damage to adjacent nonpigmented cells or structures. SLT uses a Q-switched 532 Nd:YAG (neodymium:yttrium–aluminum–garnet) laser to selectively target the pigmented cells in a nonthermal manner, increasing fluid outflow and thereby lowering intraocular pressure.14 SLT can be repeated several times, if necessary. Previous studies reported a 30% to 35% reduction in intraocular pressure using SLT as primary glaucoma therapy.14,24
The SLT laser system produces a 3-ns pulse with a 400-μm beam diameter. The short pulse of the laser does not permit time for heat transfer to collateral cells and tissue. SLT induces an immediate biologic response in the trabecular meshwork that involves the release of cytokines that trigger macrophage recruitment, the release of gelatinases, and other changes leading to enhanced aqueous outflow.14
It should be noted that in cases of a rapid rise in intraocular pressure (within 1 week) after treatment with intravitreal triamcinolone acetonide, in which the mechanism may be mechanical obstruction of the trabecular meshwork by the corticosteroid material, vehicle, or both laser trabeculoplasty may not be as effective as it was in our case.
As intravitreal injection of triamcinolone acetonide and other corticosteroids gains in popularity as a therapeutic option for retinal disease, clinicians and their patients should be aware of common side effects, including steroid-induced elevation of intraocular pressure. In patients with preexisting glaucoma, or a family history of glaucoma, it may be prudent to assess the presence or absence of this corticosteroid response in candidates for the procedure by instilling topical steroids to the eye and monitoring the pressure over several weeks before making a final recommendation.
For those patients who undergo intravitreal injection of triamcinolone acetonide, we recommend close initial follow up in the subsequent days and weeks, routinely checking for intraocular pressure elevation and other complications. In most patients presenting with a postinjection rise in intraocular pressure, topical treatment with antiglaucoma medications will achieve a desirable result. In some cases, however, neither topical nor systemic medications will adequately control the intraocular pressure, or the patient may be intolerant to ocular and systemic adverse effects from these drugs. Our case report illustrates the potential for laser trabeculoplasty to be implemented as a surgical option for steroid-induced glaucoma after intravitreal injection of triamcinolone acetonide.
Joseph J. Pizzimenti
College of Optometry
Nova Southeastern University
3200 South University Drive
Ft. Lauderdale, FL 33328-2018
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