3rd Annual Retina Report
An Overview of Intravitreal Injection

Here, we examine the history and process of intravitreal injection as well as review your role in managing potential complications.

By Jay M. Haynie, O.D.

Goal Statement:

Because of the increased use of anti-VEGF therapy for wet AMD during the last several years, optometrists can expect to comanage these patients more than ever before. Therefore, we must be educated thoroughly about the process of intravitreal injection as well as how to properly manage potential secondary complications.

Faculty/Editorial Board:

Jay M. Haynie, O.D.

Credit Statement:

This course is COPE-approved for 2 hours of CE credit. COPE ID is 34784-PS. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Dr. Haynie has no relationships to disclose.

---

In my practice setting, I have been fortunate to observe and manage countless patients with various sight-threatening retinal conditions. Many years ago, I was given the opportunity to participate in a retinal fellowship in a surgical practice located in Tacoma, Wash. This position allowed me to work with several retinal surgeons as well as share patients, experience surgical trends, observe outcomes, and witness the evolution of retina care firsthand.

Currently, I serve as the clinical director of the practice where I completed my fellowship. In this setting, I have found it worthwhile to consider comanagement as an evolutionary process. From a historical perspective, it is clear that the current approach to optometric comanagement has taken significant time to emerge and differs greatly across various practice settings, states and local communities (for further reading, see "What is 'Integrated Eye Care?'" March 2012).

So, it seems logical to expect that the comanagement of intravitreal injections for retinal disease also will evolve over time and in different ways. This form of medical care likely will continue between retinal specialists and optometrists for several years to come. Therefore, optometrists must be educated thoroughly about the process of intravitreal injection as well as how to properly manage potential secondary complications.

The History of Intravitreal Injection

The administration of intravitreal injections has revolutionized the treatment of many visually devastating retinal diseases, including age-related macular degeneration (AMD), diabetic retinopathy and retinal occlusive disease as well as vitreoretinal surgery. There is no question that the number of intravitreal injections performed by retina specialists has increased dramatically. During the past decade, there has been a veritable explosion of new drugs, techniques and indications for intraocular injection.

At one time, intravitreal injection was limited to antibiotic agents that were intended to treat a discrete subset of patients with endophthal-mitis. Today, however, many subtypes of AMD and retinal vascular disorders are treated with intra-vitreal injections of anti-vascular endothelial growth factor (VEGF) agents. Because of the high frequency of reinjection associated with anti-VEGF therapy, it is inevitable that optometrists also will interface increasingly with these patients.

In the past, injections associated with the eye primarily were administered periocularly (e.g., frequent sub-Tenon's injections of steroids and antibiotics delivered following intraoperative surgery). Periocular injections of steroidal medications became a standard method for the management of uveitis patients. Additionally, several retina specialists determined that periocular steroid injections were extremely useful in the management of wet AMD (steroids helped limit the extent of fibrotic and inflammatory disease associated with neo-vascularization).¹

Subsequently, intravitreal steroid injection in an outpatient setting was attempted for a host of inflammatory conditions, including wet AMD and diabetic macular edema. Further, intravitreal ganciclovir injection also emerged as a technique for treating cytomegaloviral retinitis in patients with HIV. Over time, it became apparent that injection--both in and around the eye--was safe, efficient, practical and useful in helping patients with a variety of ocular conditions.

Understanding Pharmacotherapy Options

Anti-VEGF therapy has dramatically changed how eye care providers treat and manage sight-threatening retinal disease. During the last 15 years, we have witnessed a relative explosion in viable treatment options for our patients. Here is a look at several established and cutting-edge treatment options for advanced retinal disease:

* Laser therapy. Some of the earliest management strategies for significant retinal disease predominantly included the use of laser photocoagulation and photody-namic therapy. Although many clinical trials proved laser therapy to be beneficial for AMD, patients often experienced disease recurrence secondary to the continuous release of VEGF.²

VEGF is a protein produced by cells that stimulates angiogenesis. When unregulated by hypoxia, VEGF is released into the vitreous cavity, causing vascular permeability and associated retinal edema. Laser photocoagulation does not address the release of VEGF, and therefore underlying retinal disease continues to smolder in the background. Nonetheless, the ability to slow or suppress the release of VEGF has proven to be essential for long-term visual stability.²

* Macugen. In 2004, Macugen (pegaptanib sodium, Pfizer and OSI/Eyetech Pharmaceuticals, Inc.) was the first anti-VEGF agent to receive FDA approval for the treatment of neovascular AMD. Its development marked a clear breakthrough in modern AMD management.

Macugen is a selective anti-VEGF compound that is designed to inhibit one strain of VEGF. It should be administered via intravitreal injection every six weeks. Although the use of Macugen has declined with the release of newer anti-VEGF agents, such as Lucentis (ranibizum-ab, Roche/Genentech) and Avastin (bevacizumab, Roche/Genentech), it appears to be making a comeback because of its more favorable dosing frequency (e.g., every six weeks vs. every four weeks). Additionally, Macugen is associated with a lower risk of stroke than either Lucentis or Avastin.³

* Lucentis. In June 2006, the FDA approved Lucentis for the treatment of neovascular AMD and macular edema secondary to retinal vein occlusion (RVO). Unlike Macugen, Lucentis is thought to be effective against several strains of VEGF. It was the first compound shown to improve visual acuity in patients with wet AMD.⁴ The recommended dosing schedule for Lucentis is one injection per month until the patient stabilizes. Thereafter, Lucentis may be dosed on a p.r.n. basis.

* Avastin. Avastin is FDA-approved for the treatment of colorectal cancer. However, because the agent costs substantially less per dose than Lucentis, it has been widely used off-label since 2004 to treat several retinal diseases, including neovascular AMD. Recently, a major study supported by the FDA--the Comparison of Age-related Macular Degeneration Treatment Trials (CATT)--compared the safety and therapeutic efficacy of both Lucentis and Avas-tin for the treatment of neovascular AMD.⁵ CATT results confirmed that both compounds exhibit statistically equivalent safety and therapeutic benefit in the preservation of visual acuity. Most managing clinicians opt to administer one intraocular injection of Avastin per month until the patient's vision stabilizes, and then on a p.r.n. basis thereafter (figures 1 and 2), much like Lucentis.

1, 2. Note the multiple pockets of cystoid intraretinal edema seen in this patient with wet age-related macular degeneration (left). Following an injection of Avastin (bevacizumab, Roche/Genentech), the intraretinal edema resolved.

* Eylea. Also known as VEGF Trap-Eye, Eylea (aflibercept, Regeneron Pharmaceuticals) is the latest anti-VEGF agent to receive FDA approval for the treatment of neovascular AMD. Unlike Macu-gen, Lucentis and Avastin, Eylea is administered every other month (following a loading phase consisting of three monthly injections).

FDA approval for Eylea was secured following publication of the VIEW 1 and VIEW 2 clinical trials, which compared the agent's safety and efficacy profile to that of Lucentis.⁶ The primary endpoints of VIEW 1 and VIEW 2 were maintenance of visual acuity (defined as losing fewer than 15 ETDRS letters) for one year. Most importantly, the VIEW researchers concluded that subjects who revceived 2mg of Eylea every eight weeks exhibited comparable visual improvement to subjects who received 2mg of Lucentis every four weeks.⁶ These results suggest that, when compared to Lucentis, the reduced dosing frequency of Eylea likely will save patients not only time and money, but also significant discomfort.

* Kenalog. For years, intravitreal Kenalog (triamcinolone acetonide, Bristol-Myers Squibb) has been used either alone or as an adjunct to anti-VEGF therapy in patients with a variety of retinal conditions. Intravitreal Kenalog is especially effective at treating macular edema secondary to uveitis, diabetic reti-nopathy and RVO.^7,8

To date, the therapeutic impact of Kenalog on patients with neovas-cular AMD is not well understood. However, clinical experience suggests that Kenalog may potentially slow the rate of visual acuity loss, which could reduce the number of total anti-VEGF or laser treatments required to maintain serviceable vision throughout the patient's lifetime. The primary concern associated with intravitreal Kenalog is an increased risk of posterior subcap-sular cataract development and/or steroid-induced glaucoma.^7,8

* Ozurdex. Ozurdex (dexa-methasone intravitreal implant, Allergan), a biodegradable steroid implant, is FDA approved to treat edema associated with RVO and non-infectious uveitis. Clinical studies have shown a rapid reduction in retinal edema secondary to RVO (figures 3 and 4) as well as elimination of vitreous haze associated with uveitis within one to two months after Ozurdex implanta tion.⁹ The implant may remain in place up to four months; however, the exact duration varies depending on the presentation and/or therapeutic response. Much like Kenalog, Ozurdex may increase a patient's risk for subcapsular cataract development and/or steroid-induced glaucoma.^7,8

3, 4. At left, marked cystoid edema seen in a patient with an underlying central retinal vein occlusion prior to treatment with Ozurdex (dexamethasone intravitreal implant, Allergan). Following Ozurdex implantation, the cystoid edema rapidly cleared.

 

The Process of Intravitreal Injection

Although slight variations exist between eye care providers, the practice of intravitreal injection is fairly uniform. Notable procedural differences include: use of gloves by the clinician, use of a sterile drape, a preoperative/postoperative measurement of intraocular pressure and the use of postoperative topical antibiotics. Here is the standard, step-by-step process for the administration of intravitreal injection:¹⁰

• Instill topical tetracaine and topical antibiotics.
• Administer a subconjuctival injection of lidocaine for anesthesia.
• Apply a povidone iodine scrub to lid margin and lashes.
• Insert the lid speculum.
• Administer a povidone iodine drop (or apply another swab) to the conjunctiva in the area of injection site.
• Inject the pharmacologic agent into the superior temporal quadrant.
• Instill a topical antibiotic.
• Remove the lid speculum.
• Confirm hand motion vision and/or measure the patient's intra-ocular pressure.
• Rinse the eye and lid margin with sterile saline.
• Prescribe topical antibiotics for at-home patient use.

It is essential to mention that the retinal surgeon's primary concern is avoidance of infectious endo-phthalmitis following intravitreal injection.^11-15 Fortunately, strict adherence to the aforementioned injection administration protocol is believed to reduce this risk.^11-15

Adverse Reactions

The most common adverse reaction to intravitreal injection is superficial keratitis associated with the povidone iodine solution. Without question, this reaction is the sole reason for triage calls within the first 24 hours following injection. Patients are encouraged to use artificial tears regularly for symptoms of discomfort and irritation immediately following the injection.

More serious complications include both infectious and psue-do-endophthalmitis, intraocular hemorrhage, retinal tear, retinal detachment, cataract formation and increased intraocular pressure.^11,12,16,17

Secondary Complications

* Infectious endophthalmitis is the single complication that is most feared by all ophthalmic surgeons. Although the risk of endophthalmi-tis following intravitreal injection remains low, we must familiarize ourselves with the clinical signs and symptoms.

The symptoms of endophthalmitis following intravitreal injection may include: increased ocular discomfort, light sensitivity, pain, floaters and a marked decrease in visual acuity.¹⁸ The onset of symptoms may vary; however, patients generally experience such secondary complications within three to five days following injection.

Clinical signs of endophthalmitis include redness; cellular reaction of the anterior chamber and vitreous; the abundance or complete absence of fibrin in the anterior chamber and/or the vitreous; corneal edema and keratic precipitates; marked vitreous haze; and a possible hypo-pyon (figure 5). It is important to note that a patient does not have to exhibit all of these complications; just one or more clinical signs should raise immediate concern in any individual who recently received an intravitreal injection.

5. Anterior segment of a patient with infectious endophthalmitis. Note the global injection and steamy cornea in conjunction with the hypopyon.

 

* Pseudo-endophthalmitis also may occur following intravitreal injection, and it is believed to be a reaction to a preservative in the compound or to the compound itself. The signs of pseudo-endophthalmitis typically present within the first 24 hours following injection and will always be seen with an associated hypopyon (however, the vision may be intact and the level of discomfort usually is lower).

Compared to infectious endo-phthalmitis, the clinical appearance of eyes with pseudo-endophthal-mitis generally is less hyperemic (figure 6). The differential between infectious and pseudo-endophthal-mitis can be challenging, and may require increased clinical experience to confirm. As a safety measure, a vitreous tap with an injection of antibiotics often is performed if there is any concern that the presentation has an infectious etiology. To ensure patient safety, immediate referral back to the retinal surgeon is strongly advised should any symptoms of either infectious or pseudo-endophthalmitis manifest.

6. Anterior segment photograph of a patient with pseudo-endophthalmitis. Note how quiet the eye looks, despite the presence of the hypopyon.

 

* Increased intraocular pressure following intravitreal injection has been reported in up to 9.4% of cases; yet, just 5.5% developed sustained pressure elevation that required topical or surgical management. Keep in mind, however, that steroid-associated intra-ocular pressure elevation caused by inhibited aqueous outflow is far more common than pressure increases secondary to anti-VEGF therapy.^19-21

Managing Complications

The management of infectious endophthalmitis has evolved during recent years, and currently includes a vitreous biopsy (with or without vitrectomy) as well as an intravitreal antibiotic injection (i.e., vancomycin hydrochloride and/ or ceftazidime). Some retinal specialists advocate the use of 400mg gatifloxacin p.o. q.d. and 1gt topical gatifloxacin q.i.d. As a general guideline, consider the use of topical gatifloxicin for any patient who presents with a suspected case of endophthalmitis.

Patients who present with pseudo-endophthalmitis can be safely and effectively managed in a similar fashion to those individuals suspected of infectious endophthal-mitis. In the absence of intraocular fibrin, however, I will initiate topical fluoroquinolones and topical steroids q.i.d., and schedule the patient for 24-hour follow-up. If the patient experiences a decrease in visual acuity or an increase in intra-ocular inflammation, you should make a referral for vitreous biopsy and intravitreal antibiotics.

When managing increased intraocular pressure secondary to intravitreal steroid injection, we must familiarize ourselves with the duration/efficacy of the compound in the vitreous cavity. One study indicated that at least 0.1cc of tri-amcinolone per 4mg dose was mea surable in patients' vitreous cavities for up to three months following injection.²² In such cases, patients required the use of topical intra-ocular pressure medications for an average of eight months following injection.²³

When deciding how to manage any elevation in intraocular pressure, it really depends on the status of the optic nerve, the visual field and the retinal never fiber layer. A patient with a healthy optic nerve, for example, can withstand a transient pressure increase better than a patient with known compromise or damage.

Nonetheless, patients with glaucoma and coexisting retinal disease should undergo optic nerve head photography, visual fields testing and retinal nerve fiber layer analysis at baseline prior to intravitreal injection. These tests can help predict which patients are at the great est risk of further damage in the event of even a modest increase in intraocular pressure.

Given that the etiology of elevated intraocular pressure is a compromise in aqueous outflow facility, treatment should include the use of topical agents that increase aqueous outflow. These agents include Alphagan P (brimonidine tartrate 0.15%, Allergan), Timoptic (timo-lol 0.5%, Aton Pharma), Trusopt (dorzolamide 2.0%, Merck) and Azopt (brinzolamide 1.0%, Alcon). Keep in mind, however, that pros-taglandin analogues should not be used in patients with known macu-lar edema, because they may exacerbate the underlying condition.^24,25

The concept of measuring intraocular pressure one week following intravitreal injection is somewhat controversial, and can be tiring for the patient given the frequency of examinations at the retina specialist's office. However, patients with advanced glaucoma should be monitored closely for pressure increases following injection. You should inform the comanaging retina specialist of any documented intraocular pressure spikes.

The O.D.'s Role

So, where do we fit into all of this? Ultimately, our role in the comanagement of intravitreal injection still remains undefined; however, we will continue to provide primary eye care for these patients. Similar to cataract surgery, we have the responsibility of discussing potential treatment options with our patients prior to considering a referral.

Additionally, providing the retina specialist with pertinent ocular history as well as any documented contraindications to intravitreal injection, such as ocular hypertension or glaucoma, is extremely important.

7. Intraretinal cystoid edema in a patient with wet AMD (top).

8. Subretinal fluid seen in a patient who presented with wet AMD.

Further, completing a risk assessment of the patient is becoming more common, and it should include the following questions:

• Is there active blepharitis in either eye?
• Can the patient cooperate during intravitreal injection and not interfere with the sterile technique?
• Will the patient recognize symptoms of endophthalmitis and report them to you immediately?
• Can the patient instill topical antibiotics into the eye following the procedure?
• Is the patient going to return for scheduled follow-up appointments?

These are just a few baseline questions that can be asked of every patient being considered for intra-vitreal injection.

In addition to preparing the patient for a commitment to intra-vitreal injection, it is equally important to recognize signs of existing recurrent disease. Fortunately, we now have access to cutting-edge diagnostic technology, such as spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence, that more easily enables us to identify subtle characteristics of retinal disease that may be difficult to see clinically or even with conventional retinal photography. For example, SD-OCT is vital in the postoperative management of patients with AMD, because we can document intraretinal edema (figure 7) or subretinal fluid (figure 8), which may help identify a recurrent neovascular membrane in the absence of new symptoms.

Unlike cataract surgery, intravit-real injection often requires a series of re-treatments over the course of the patient's lifetime. For some individuals, this translates into several years of care with a retina specialist and comanagining O.D.

Although it is not our job to decide upon the actual treatment plan, we certainly can prepare our patients for what to expect. In this, we play an essential role in educating the patient about his or her condition as well as the most effective treatment options that could help maintain or even restore their vision.

Dr. Haynie is the executive clinical director at Retina & Macula Specialists, with office locations in Tacoma, Renton, Olympia and Kennewick, Wash.

References

1. Schmidt-Erfurth U, Michels S, Augustin A. Perspectives on verteporfin therapy combined with intravitreal corticosteroids. Arch Ophthalmol. 2006 Apr;124(4):561-3.
2. American Macular Degeneration Foundation. Treatments for Wet Macular Degeneration: Old and New. Available at: www.macular.org/ wettreat.html#vegf (accessed May 24, 2012).
3. Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease Surv Ophthalmol. 2011 Mar-Apr;56(2):95-113.
4. Genentech Product Information. Lucentis: Full Prescribing Information. Available at: www.gene.com/gene/products/information/tgr/lucentis/ (accessed May 24, 2012).
5. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevaci-zumab for neovascular age-related macular degeneration. N Engl J Med. 2011 May 19;364(20):1897-908.
6. Regeneron Pharmaceuticals, Inc. VEGF Trap-Eye (aflibercept ophthalmic solution) Briefing Document. Available at: www.fda. gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/ UCM259143.pdf (accessed May 24, 2012).
7. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular Edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report. Arch Ophthalmol. 2009 Sep;127(9):1115-28.
8. 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 Sep;127(9):1101-14.
9. Allergan Retina. About Ozurdex: Ozurdex for the Treatment of Noninfectious Posterior Segment Uveitis. Available at: www.ozurdex.com/ForUveitis.aspx (accessed May 24, 2012).
10. Ophthalmology Times. Meticulous intravitreal injection technique essential for minimizing endophthalmitis risk. February 23, 2006. Available at: http://ophthalmologytimes.modernmedicine.com/ophthalmologytimes/Clinical+Pharmacology/Meticulous-intravitreal-injection-technique-essent/ArticleStandard/Article/detail/309486 (accessed May 24, 2012).
11. Jonas JB, Spandau UH, Schlichtenbrede F. Short term complications of intravitreal injections of triamcinolone and bevacizumab. Eye (Lond). 2008 Apr;22(4):590-1.
12. Mezad-Koursh D, Goldstein M, Heilwail G, et al. Clinical characteristics of endophthalmitis after an injection of intravitreal antivas-cular endothelial growth factor. Retina. 2010 Jul-Aug;30(7):1051-7.
13. Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for Intravitreal Injections. Retina. 2004 Oct;24(5 Suppl):S3-19.
14. Moshfeghi AA, Flynn HW Jr. Complications of intravitreal injection. Rev Ophthalmol. 2004 Dec;11(12):64-7.
15. Scott IU, Flynn HW Jr. Reducing the risk of endophthalmitis following intravitreal injections. Retina. 2007 Jan;27(1):10-2.
16. Jonas JB, Kreissig I, Spandau UH, Harder B. Infectious and noninfectious endophthalmitis after Intravitreal high-dosage triamcino-lone acetonide. Am J Ophthalmol. 2006 Mar;141(3):579-80.
17. Choi DY, Ortube MC, McCannel CA, Sarraf D, et al. Sustained elevated intraocular pressures after intravitreal injection of bevaci-zumab, ranibizumab, and pegaptanib. Retina. 2011 Jun;31(6):1028-35.
18. Taban M, Behrens A, Newcomb RL, et al. Acute endophthalmitis following cataract surgery: a systematic review of the literature. Arch Ophthalmol. 2005 May;123(5):613-20.
19. Armaly MF. Effect of corticosteroids on intracocular pressure and fluid dynamics. II. The effect of dexamethasone in the glaucomatous eye. Arch Ophthalmol. 1964 May;71:636-44.
20. Mccarty GR, Schwartz B. Increased concentration of glucocor-ticoid receptors in rabbit iris-ciliary body compared to rabbit liver. Invest Ophthalmol Vis Sci. 1982 Oct;23(4):525-8.
21. Southern AL, Gordon CG, L'hommedieu D. 5B-dyhydrocortisol: possible mediator of the ocular hypertension in glaucoma. Invest Ophthalmology Vis Sci. 1985;26:393.
22. Beer PM, Bakri SJ, Singh RJ, et al. Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single injection. Ophthalmology. 2003 Apr;110(4):681-6.
23. Gillies MC, Simpson JM, Billson FA, et al. Safety of an intravit-real injection of triamcinolone: results from a randomized clinical trial. Arch Ophthalmol. 2004 Mar;122(3):336-40.
24. Hoyng PF, Rulo AH, Greve EL, et al. Fluorescein angiographic evaluation of the effect of latanoprost treatment on blood-retinal barrier integrity: a review of studies conducted on pseudophakic glaucoma patients and on phakic and aphakic monkeys. Surv Oph-thalmol. 1997 Feb;41 Suppl 2:S83-8.
25. Heier JS, Steinert RF, Frederick AR Jr. Cystoid macular edema associated with latanoprost use. Arch Ophthalmol. 1998 May;116(5):680-2.