Fortunately, the risk of serious vision-threatening complications with IVT is quite low, and adherence to good technique should reduce this risk even further. During the informed consent process, the patient should be made aware of all of the possible complications. Patients also should be instructed that foreign body sensation is normal following an injection and may not start for several hours after the anesthetic begins to wear off. Subconjunctival hemorrhage can also occur and may exacerbate foreign body sensation. Foreign body sensation may also occur secondary to conjunctival irritation and superficial punctuate keratopathy from povidone-iodine. Patients may visualize the medicine as it is suspended within the vitreous cavity, particularly triamcinolone acetonide. If patients are reassured regarding medication “floaters,” foreign body sensation, and subconjunctival hemorrhage, anxiety is alleviated and the amount of nighttime or weekend triage is reduced. Despite necessary precautions being taken, complications do occur. The following briefly describes the potential post-injection complications and touches upon management.
Endophthalmitis can be visually devastating even if treated in an appropriate and timely manner. Presenting symptoms may include eye pain, red eye, and blurry vision, and clinically the eye can appear severely injected with evidence of anterior and posterior segment inflammation. Visual acuity assessment may or may not be helpful as patients receiving IVT injections may have conditions that predispose them to poor baseline visual acuities. Patients who present suspiciously for endophthalmitis are usually treated in accordance with the guidelines provided by the Endophthalmitis Vitrectomy Study. Patients with hand-motion vision or better receive a vitreous tap with IVT antibiotic administration; those with worse than hand-motion vision may require surgical intervention. Prophylactic and post-injection antibiotics are frequently used in order to reduce the likelihood of endophthalmitis; however, while prophylactic antibiotics may reduce ocular flora, povidone-iodine prep is considered more effective. Recently, results on 2009 patients receiving IVT triamcinolone acetonide in the Diabetic Retinopathy Clinical Research Network (DRCRnet) and the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) clinical trials were reported. All injections were performed in a standardized fashion without the use of preoperative antibiotics. Only 1 of the 2009 patients developed endophthalmitis. Fortunately, endophthalmitis following IVT injection is uncommon, with a prevalence of 0.2% per injection and 0.5% per eye.
In patients receiving triamcinolone acetonide, the conditions of pseudoendophthalmitis and sterile endophthalmitis can complicate the diagnosis. The term pseudoendophthalmitis should be reserved for cases in which a patient who has received triamcinolone acetonide has particles in the anterior chamber and vitreous that simulate inflammatory cells. The term sterile endophthalmitis should be reserved for the patient who presents with intense inflammation, possibly due to vehicles within the solution. It has been suggested that to reduce the incidence of sterile endophthalmitis, flushing the vehicle from the triamcinolone acetonide and resuspending it in sterile saline solution may be required.
In November 2007, the FDA approved Triesence (triamcinolone acetonide injectable suspension, 40 mg/ml, Alcon) as an intraocular agent to treat ophthalmic disease and for use as a visualizing agent during pars plana vitrectomy. Unlike other formulations of triamcinolone acetonide, Triesence lacks benzyl alcohol, thereby potentially reducing the risk of post-injection inflammation. Despite this theoretical advantage, administration of Triesence caused up to 2% of patients to develop endophthalmitis (sterile and nonsterile) and hypopyon. As it is a corticosteroid, cataract and ocular hypertension can develop.
A common mechanism for the development of a rhegmatogenous retinal detachment (RRD) is vitreoretinal traction, usually in the far periphery near the ora serrata, producing a retinal tear with subsequent entry of liquefied vitreous into the subretinal space. The use of small-gauge needles reduces the chance of vitreous traction at the vitreous base. Retinal detachment can also occur if the retina is perforated by the needle during IVT. For this reason, careful measurement of the injection site with a caliper is required. By performing this step, one can further reduce the risk of RRD. In patients receiving IVT gancyclovir for cytomegalovirus (CMV) retinitis, the incidence of RRD is 0.9% per injection. Such patients, however, are at significant increased risk of RRD due to their underlying condition. It should be noted that the risk of RRD in patients treated with IVT agents for AMD is much lower. In the VEGF Inhibition Study in Ocular Neovascularization (VISION) trial, only 4 RRDs developed over 7545 injections (0.05% per injection). A patient complaining of floaters, photopsias, or peripheral vision loss should receive prompt evaluation because the early recognition and treatment of retinal tears and retinal detachment potentially staves off further vision loss, particularly if the macula has not been compromised.
Following intraocular injection, a transient rise in IOP can be expected. In the normotensive patient, the IOP usually returns to baseline levels without further intervention. In patients who develop dangerously high IOP spikes, the use of ocular massage, topical IOP-reducing agents, oral medication, and possibly anterior chamber tap can be used as means to reduce IOP and thereby prevent optic nerve damage and possibly central retinal artery occlusion.
In patients who are steroid-responders or who have pre-existing primary open-angle glaucoma, IVT injection of triamcinolone acetonide should be used judiciously. Closer observation of this cohort is warranted as topical medical therapy may be required.
Underlying glaucoma or ocular hypertension should not be considered a contraindication to IVT injection, even with triamcinolone acetonide, because the damaging effects of macular disease may be irreversible and could increase the severity of vision loss when compounded with other underlying conditions. Although routine prophylactic paracentesis is not routinely recommended, it may be considered an option in patients with glaucomatous disease who could have retinal ganglion cell and optic nerve damage even from an acute spike in IOP.
Cataract formation is an uncommon acute complication following IVT injection; however, cataract is a longer-term complication in patients receiving triamcinolone acetonide. It has been reported that cataract progression following IVT triamcinolone acetonide does occur for nuclear sclerotic, cortical, and posterior subcapsular types. With repeated administration, the rate of progression of nuclear and cortical cataracts increased; however, this effect was not seen with posterior subcapsular cataracts. More than 50% of patients developed posterior subcapsular cataracts, many of whom required cataract surgery.
Intraocular inflammation is an uncommon complication of IVT injection but occurs most frequently in those patients receiving cidofovir, fomivirsen, and bovine hyaluronidase. Sterile endophthalmitis and pseudoendophthalmitis have been discussed above.
Patients receiving IVT medications often report seeing floaters, particularly in association with triamcinolone acetonide. Patients should be warned of this “blob” of medication and sleep with the head of the bed elevated for 1 or 2 days to allow “the blob” to settle out of the visual axis. These medication “floaters” are harmless and patients can be reassured, but caution must be observed if they occur in association with flashing lights or peripheral scotomata, which could indicate a retinal tear and/or retinal detachment.
Patients may call concerning a “bleeding eye” if not educated about the possible appearance of a subconjunctival hemorrhage following an injection. Reassurance that a bloodshot eye following injection is not dangerous can reduce patient anxiety; however, patients should be alert to any severe eye pain and/or worsening vision associated with a red eye following injection, as this may be the onset of endophthalmitis.
Serious adverse events such as systemic hypertension, arterial thromboembolic events (ATEs), or serious hemorrhagic events have been reported in patients receiving pan-VEGF inhibitors systemically. Recently, a retrospective study auditing the Medicare database revealed that patients with neovascular AMD had a statistically significant higher rate of risk factors for ATEs compared to age-, race-, and gender-matched controls; however, neovascular AMD patients did not have a greater rate of ATEs.
Although the risk for ATEs is not worse in patients with neovascular AMD, there is the concern that IVT anti-VEGF therapy may increase the risk of an adverse event. In large, randomized, prospective multicenter studies, neither pegaptanib sodium nor ranibizumab have been shown to be associated with an increased risk of ATE in patients with neovascular AMD compared to control groups.
At present, there is no published data from a long-term, multicenter prospective trial evaluating IVT bevacizumab; however, the Pan-American Collaborative Retina Study Group (PACORES) group did report cerebrovascular accidents, myocardial infarctions, and iliac artery aneurysms in patients receiving IVT bevacizumab (13/1265). It should be noted that this study was a retrospective, multicenter, open-label, uncontrolled case series and could not compare adverse event rates between a cohort receiving intervention versus placebo.
In summary, the neovascular AMD population does not have a greater risk of developing ATEs and treatment with either pegaptanib sodium or ranibizumab has not been shown to increase the rate of ATEs. It is not known at this time if the risk of ATEs is increased in patients receiving IVT bevacizumab.