Article Date: 3/1/2005

Careful Use of Intravitreal Triamcinolone
The use of intravitreal injections of triamcinolone acetonide as treatment for recalcitrant diabetic macular edema and other retinal conditions.
EDDIE F. KADRMAS, MD, PHD

In a fairly unprecedented fashion, retinal physicians around the world have embraced the technique of intravitreal injection of triamcinolone acetonide (IVTA) for a wide variety of retinal conditions. General acceptance of the efficacy of this treatment is in spite of the lack of large controlled studies to support this trend. Nonetheless, this treatment has been seen by a majority of retina specialists to be a great benefit to patients, many of whom would not have other options in the retinal armamentarium for treatment of potentially blinding conditions. Other retinal physicians are more cautious, citing potential complications with the routine use of this drug. In this article, I will review the current state of affairs regarding the use of IVTA and cite some of my own personal observations on the proper technique and use of IVTA, as well as the potential complications that may be encountered.

HOW IVTA WORKS

Corticosteroids are known to have an inhibitory effect on angiogenesis and inflammatory reactions by reducing the migration and activation of inflammatory cells. Up-regulation of the extracellular-matrix protein plasminogen activator inhibitor-1 by steroids has a direct angiostatic effect.1 Steroids also inhibit the production of vascular endothelial growth factor (VEGF). Corticosteroids are known to stabilize endothelial and basement membranes and reduce vascular permeability and vascular leakage through their inhibitory effect on plasmin. In addition, steroids down-regulate intercellular adhesion molecule expression, which is an important stimulus in the development of neovascular membranes and an inflammatory mediator released by photodynamic therapy (PDT).2

Therefore, theoretical reasons to expect that IVTA could potentially work for a number of retinal conditions characterized by inflammation, vascular leakage, and new blood vessel growth do exist. However, the exact mechanism of action in each of these situations remains to be determined.

RETINAL CONDITIONS TREATABLE WITH IVTA

IVTA has been advocated for use in a number of retinal diseases, but probably more so for treating recalcitrant diabetic macular edema (DME). Intravitreal injection of triamcinolone acetonide has shown to be effective in treating clinically diffuse DME that fails to respond to conventional therapy in nonrandomized clinical case series reports.3,4 In some individuals, the effect appears to be dramatic, but in others, visual improvement may be modest and/or the edema recurs, necessitating multiple injections of IVTA. Nonetheless, for some individuals in my patient population, this treatment has made the difference between being legally blind and having the visual acuity to pass a driver's license examination.

Some cases of choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) may benefit from IVTA in combination with PDT with verteporfin. At the 2003 Vitreous Society meeting, Luckie presented a nonrandomized case series of 72 patients where the combined treatment group of PDT and IVTA was seen to require fewer retreatments than those treated with PDT alone. This trend has since been substantiated by other case series.5-7 Since with each recurrence of CNV there is often a further loss of visual potential, it follows that a modality that decreases the rate of recurrence can be of benefit to the patient. Although promising, the ultimate benefit of this treatment technique remains to be determined. In my practice, I have found that this combination therapy can reduce the total number of PDT treatments by almost one half.

Intravitreal injection of triamcinolone acetonide may also be used for treating pseudophakic cystoid macular edema that fails to respond to conventional therapy.8 Cystoid macular edema from vascular occlusions that fail to respond to laser treatment have shown to be treatable with IVTA.9-13 In addition, IVTA has been shown to be effective in reducing cystoid macular edema in select patients with uveitis.14 Again, variable amounts of visual recovery can be observed, from dramatic responses to those cases that show little to no improvement despite the resolution of the edema.

Finally, IVTA may be a useful intraoperative adjunct therapy for patients undergoing vitrectomy, where macular edema is a component of their overall problem.

POTENTIAL IVTA COMPLICATIONS

Any intraocular injection carries some risk, such as infection, intraocular pressure (IOP) elevation, retinal detachment, vitreous hemorrhage, and cataract. Cataract may occur from direct contact with the lens during the procedure or from a paracentesis performed for elevated IOP. Although this is possible, it can be avoided by careful attention to technique. Cataract may also develop because of the steroid effect of the drug itself.15 This would more likely require multiple injections, but could occur in a susceptible eye sooner. Cataracts can be extracted rather easily, but doing so may aggravate the condition being treated by the IVTA.

Most of the attention on potential complications of IVTA has focused on induced ocular hypertension, infectious endophthalmitis, and noninfectious endophthalmitis.

A number of reports have described ocular hypertension after IVTA injection.4,15-17 Mild to moderate IOP elevation was seen in 28%­42% of patients, typically in the first 3 months following injection. This was usually controlled with topical agents alone. In these studies no patient required more aggressive (ie, surgical) treatment and the condition was generally self-limited. One study found no association between multiple IVTA injections and significant IOP elevation.17 The same study found that a history of open-angle glaucoma did not appear to increase the risk of significant IOP elevation following IVTA injection. However, it should be kept in mind that there is a known higher incidence of steroid responders in glaucoma patients than in the population in general. Recent case reports point out that IVTA injections need to be taken seriously regarding potential IOP complications. Three cases of intractable glaucoma were reported by Singh and colleagues18 following IVTA injection, which required surgical glaucoma intervention. A fourth patient required filtration surgery and vitrectomy to remove residual steroid.18 Although these cases are rare, these problems need to be kept in mind.

Infectious endophthalmitis, the most serious complication of IVTA injection, is fortunately rare, but was reported in 3 studies. In a retrospective, multicenter study, infectious endophthalmitis was identified in 8 of 922 (0.87%) eyes following IVTA injection.19 The cases in this study represented some of the very first patients treated with this technique at several different centers. It was postulated that this relatively high rate of infectious endophthalmitis may be attributed to the techniques used for injection. Nonetheless, after this publication, greater awareness of the importance of sterile methods followed, which has apparently decreased the perceived rate of infection. Nelson and colleagues published another series of 440 eyes in which 2 eyes (0.5%) developed infectious endophthalmitis.20 Finally, 1 case of Mycobacterium chelonae abscessus endophthalmitis was reported following IVTA in a diabetic patient who subsequently required enucleation.21 Most of these cases presented with painful, red eyes; however, the last 3 cases mentioned above did not have associated pain on presentation. It should be noted that in cases of infectious endophthalmitis following IVTA, the steroid itself may suppress the inflammation and pain associated with the infection, and may therefore make the correct initial diagnosis more difficult to pin down.

Several studies have described noninfectious endophthalmitis after IVTA injection.20, 22-25 According to reports this complication occurs in 0.2%­6.7% of eyes following treatment. Some cases appear to present with a pseudohypopyon after injection consisting of triamcinolone crystals in the anterior chamber. Other cases appear to represent an inflammatory reaction in the anterior chamber and the vitreous, also with hypopyon formation. Although, the latter cases may be difficult to differentiate from true infectious endophthalmitis, they typically did not present with pain or a red eye, and had onset 1­2 days after injection. The cases of infectious endophthalmitis on the other hand presented 4­14 days after injection. Fortunately, all of these cases resolved without any untoward outcomes. Migration of triamcinolone into the anterior chamber could be expected in patients who are aphakic or have anterior-chamber, intraocular lenses, and an open or absent posterior capsule. Inflammation from the injection itself has been postulated to occur due to a reaction to the vehicle present with the drug, although this has yet to be proven.

Currently several studies are underway that focus on the use of IVTA for some of the conditions described previously (Table). For enrollment information please refer to the Clinical Trials Update in this issue of Retinal Physician, which lists major retinal studies currently underway. Hopefully, these studies will help answer the questions regarding the efficacy of IVTA for treating retinal diseases.

My experiences with complications from IVTA injection are as follows. After 473 injections, no cases of infectious endophthalmitis were seen. One case of apparent vitreal inflammation at 1-day postinjection was encountered, which resolved spontaneously and without consequence. This DME patient had an overall recovery of 4 lines of best-corrected visual acuity. One case of acute vitreous hemorrhage was seen in a patient on aspirin for coronary artery disease. The hemorrhage resolved spontaneously without complication. Intraocular pressure elevation above 22 mm Hg occurred in 18% of patients (all patients prior to injection had an IOP less than 21 mm Hg). Approximately 1 in 10 patients required the use of topical aqueous suppressants, the vast majority controlled on only 1 agent. Twelve patients (2.5%) required more than 1 agent. Virtually all cases of IOP elevation resolved after 3­4 months postinjection. No cases required glaucoma filtering surgery. However, a single patient had an apparent profound steroid effect with uncontrolled pressures on maximal medical treatment. Since there was visible triamcinolone present in the vitreous cavity, a limited vitrectomy was performed to remove the agent. The patient's IOP rapidly returned to normal. Ultimately the patient's DME was seen to resorb and his visual acuity improved from 20/200 to 20/30. Almost 1 year later, the patient's visual acuity remains the same and there is no recurrence of the edema.

INJECTION TECHNIQUE

Several injection techniques were reported; however, the one I am going to discuss comes from personal experience and is supported by a very low incidence of complications. I have performed more than 470 IVTA injections over the past 3 years, and have found the following method to work best for me.

From the very beginning, I felt that attention to sterile technique was crucial. I treat each case of IVTA no different than that of a major retinal case. Patients are instructed to begin taking a fourth generation fluoroquinolone 4 times a day for 1 day prior to the procedure. I perform the injections either in a small procedure room or at my ambulatory surgery center (which is adjacent to my clinic). The lids and lashes are prepped with 10% povidone iodine, and 5% povidone iodine is directly instilled into the cul de sac. This preparation effectively sterilizes the eye. A sterile drape and speculum are used. Sterile tetracaine is administered topically. Additionally, a sterile cotton swab is soaked in tetracaine and is placed directly over the injection site with gentle pressure in the inferior temporal quadrant for 1 minute. I have found that this topical anesthesia technique is perfectly adequate to control any significant discomfort from the injection. I avoid doing a paracentesis prior to IVTA since I have found that 99% of eyes do not require this step, as the IOP elevation directly following the injection is transient. The injection is performed with the patient supine under an operating microscope. I find that this provides more control over inadvertent patient movement. In addition, I have never seen migration of the triamcinolone into the anterior chamber in aphakic eyes nor in eyes with anterior-chamber, intraocular lenses. Immediately prior to the injection, the suspension is shaken vigorously for approximately 1 minute. The injection is performed using a 27-g needle through the pars plana rather than a 30-g needle since I have found the particle size of the commercial preparation of triamcinolone acetonide (Kenalog) that I use to be variable, sometimes clogging the 30-g bore. The 27-g opening becomes self-sealing, although a small egress of liquid vitreous may occur immediately after the needle is removed. The injection site is tamponaded with a sterile cotton-tipped swab and the injection site is gently massaged with the same. The eye is examined for arterial perfusion and the IOP is checked 20 minutes after the procedure. Rarely do I perform an anterior-chamber paracentesis for arteriolar nonperfusion or for persistent IOP elevation above 30 mm Hg (4 /473). Immediately following the injection, the patient receives a drop of dorzolamide hydrochloride-timolol maleate ophthalmic solution (Cosopt) and brimonidine tartrate ophthalmic solution (Alphagan), as well as a topical antibiotic ointment. The patient is sent home with a topical antibiotic, which is used for 3 days (although this is probably unnecessary). A dilated retinal exam is performed 1 week after the injection. If a patient requires an additional injection, a minimum of 3 months between injections is recommended, because it appears the clinical effect of IVTA is at least this long, and theoretically one may be less likely to get into steroid-related IOP problems.

PERSONAL OBSERVATIONS OF IVTA INJECTIONS

In the first 2 years, I used a commercial preparation of triamcinolone acetonide (Kenalog), injecting 4 mg from single-use vials. Although some have advocated concentrating the active agent and potentially minimizing any toxicity of the vehicle by allowing the triamcinolone to precipitate in the syringe and discarding the supernatant, I have stuck to the standard concentration of 40 mg/mL. I have felt that until it is determined what the minimal effective dose that provides the desired clinical effect without increased complications is, I would rather error on the side of caution, using a known repeatable dose which would have, at least theoretically, a lesser chance of IOP elevation.

In the past year of my experience with IVTA, I have used a sterile preservative-free preparation obtained from a local compounding laboratory because of some concerns about the potential toxicity of the alcohol preservative in triamcinolone acetonide. I can say that I have not personally seen a difference in efficacy, ultimate outcome, or complications between the 2 preparations. When one considers the small amounts of drug formulation used, the supernatant represents less than 1% of the total eye volume. The benzyl alcohol preservative that has been a focus of concern is in a concentration of just less than 1%. With the dilution factor taken into consideration after injection into the eye, this lowers its concentration to less than 0.01%. It may be that even though a component of the suspension could have potential toxicity, the small-diluted concentration used may be clinically insignificant.

CONCLUSIONS

Is IVTA the "magic silver bullet?" I think probably not. However, those retina specialists who are routinely using IVTA know that it works well in certain eyes and in certain conditions, sometimes in dramatic fashion. In all of medicine, our treatments are based on assessing the relative risk vs. benefit. Sometimes there is a fine line that divides an efficacious treatment from one that is potentially harmful. With the potentially blinding conditions we deal with, some of which have no good current treatment, it may be reasonable to try new methods that show promise, given the informed consent of the patient. I know many of my patients are indeed grateful for the results of the intervention, rather than doing nothing and having their vision deteriorate further. Will there be new treatments to supplant IVTA? I hope very likely. The new long-acting corticosteroid implants containing fluocinolone acetonide or dexamethasone appear to have some initial promising results. These agents may be useful for recurring edema currently treated with multiple IVTA injections, as well as for chronic inflammatory problems with associated macular leakage, such as certain cases of uveitis. It will be exciting to see the results of the combined PDT and IVTA studies, as a multimodality approach to CNV, including the use of anti-VEGF agents, which may be what is ultimately effective. However, much still remains to be researched. It is our role as retinal physicians to keep abreast of the best treatment options out there at a particular moment in time and serve our patients' best interests as we move forward.

Address correspondence to: Eddie F. Kadrmas, MD, PhD, Post and O'Connor Eye Centers, 40 Industrial Park Road, Plymouth, MA 02360, Telephone: (508) 746-8600, Fax: (508) 747-0824, E-mail: EFK4PPV@aol.com.

From a private practice in Plymouth and Dartmouth, Mass. Dr. Kadrmas has no financial interest in any of the products mentioned in this article.

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Retinal Physician, Issue: March 2005