Possible complications associated with intravitreal injections range from transient pain and discomfort to sight-threatening complications. Complications also may depend on whether it is anti-VEGF or steroid being administered into the vitreous.^1,2

ANTERIOR-SEGMENT INVOLVEMENT

The possible complications of intravitreal injection, regardless of the injected drug, can involve the anterior segment and include corneal abrasions and surface irritation. Other complications encompass cataract formation, retinal tear and detachment, vitreous hemorrhage, intraocular pressure elevation, intraocular inflammation, and endophthalmitis.^1-5 A recent study of 45,000 eyes found that the total rate of complications was lower than 2%, with most of them being minor (74%) and not requiring medical intervention, for example, subconjunctival hemorrhage, or irritation.³ Receiving antibiotics after an injection decreases the risk of irritation, likely by washing out the povidone iodine, and may be recommended to patients who are more prone to irritation.³ The ocular surface could also be irrigated after the injection. Povidone iodine use can be limited to the injection site to alleviate the sensitivity associated with its use. However, a recent review showed that Iodine allergy lacks scientific validation and that not administering it might result in increased risk of infection.⁶ Alternatively, in rare cases, when the patient is sensitive to povidone iodine, chlorhexidine gluconate 0.1%⁷ or topical polyhexanide might be considered for disinfection prior to injection.⁸ Patients who suffer from corneal abrasions can be treated with artificial tears, antibiotics, and a bandage contact lens. If these measures fail, cryopreserved amniotic membranes (Prokera; Biotissue) can be utilized.⁹

INTRAOCULAR PRESSURE SPIKE

A significant spike in intraocular pressure (IOP) can occur as a result of, and immediately after, intravitreal injection.^10-13 Generally, elevated IOP is associated with steroid therapy, due to increased aqueous humor outflow resistance.^14,15 Rates of this complication have been estimated at 30% to 60% following an injection of triamcinolone acetonide,^16-18 and between 30% and 50% after dexamethasone implant.^19-22 Chronic IOP elevation may occur due to anti-VEGF injections as well. This is theorized to be the result of reduced aqueous outflow and of acute pressure rise in a relatively closed space.¹⁰ Although the majority of IOP spikes resolve spontaneously, when the IOP is consistently high, topical antiglaucomatous drops may be administered, as well as an ocular massage. In an acute IOP spike causing pain and vision loss, an anterior-chamber paracentesis should be performed.

Intravitreal implants might cause extreme uncontrollable pressure (rising up to 60 mmHg to 70 mmHg) and sometimes a vitrectomy is needed to remove the implant as a result. Occasionally, the intravitreal drug migrates into the anterior chamber, requiring surgical intervention, because the implant in the anterior chamber may cause corneal swelling and decompensation. Implant migration may also occur via iris coloboma.²³ The rate of this complication is estimated at 0.63%^3,23 and is related to vitrectomized pseudophkaic eyes with zonular complex instability. The implant can be surgically removed from the anterior chamber using an anterior chamber maintainer and allowing the maintainer jet to navigate the implant to a second paracentesis in the cornea.²⁴ Another surgical solution is to grab the implant through a corneal tunnel with the use of a viscoelastic injection.²³ To avoid this complication, Mateo et al described an intravitreal scleral fixation of dexamethasone implementing a 10–0 nonabsorbable polypropylene suturing to the pars plana.²⁵

TRAUMATIC CATARACT

Traumatic cataract formation can occur as a result of intravitreal injections. Its incidence is relatively rare if the injection is performed 4 mm posterior to the limbus and is estimated at 0% to 0.8%.^4,5,26,27 If cataract appears, it may resolve spontaneously. However, if it continues to progress, surgery should be performed with caution to remove the lens, due to the possibility of an open posterior capsule and damage to the lens zonules.

VITREOUS HEMORRHAGE

Vitreous hemorrhage may occur secondary to intravitreal injection in 0.02% to 4.5% of cases.^3,5 In general, the vitreous hemorrhage can be secondary to a pre-existing ocular condition, and it may absorb spontaneously. However, close monitoring using B-mode ultrasound is needed to rule out the occurrence of a retinal tear or a retinal detachment. Retinal tear and retinal detachment are rare, they can occur directly from intravitreal injections (0% to 0.7%),^3-5 or as a result of a posterior vitreous detachment. Retinal tears and detachments are treated accordingly with laser, pneumatic retinopexy, pars plana vitrectomy, or a scleral buckle.

TRACTIONAL RETINAL DETACHMENT

Intravitreal injections of anti-VEGF agents may lead to the “crunch phenomenon” in eyes with neovascularization. This phenomenon might occur in eyes with proliferative diabetic retinopathy and lead to traction and tractional retinal detachment (TRD). Injection of anti-VEGF into the eye results in reduced levels of active VEGF, which leads to a rise in connective tissue growth factor and fibrosis.²⁸ Arevalo et al reported a prevalence of TRD in 11 (5.2%) of 211 eyes due to intravitreal injections.²⁹ The risk factors for TRD following a bevacizumab injection are uncontrolled diabetes, vitreous hemorrhage, and proliferative retinopathy resistant to panretinal photocoagulation. They tend to last longer and occur between the time of injection and vitrectomy.³⁰ This complication should be addressed also with pars plana vitrectomy, if the macula is involved or threatened.

INFLAMMATION

The incidence rate of inflammation differs depending on the drug administered. The inflammatory location can also vary from the anterior to intermediate to posterior segments. A review of vitreous inflammation associated with anti-VEGF therapy showed rates of inflammation from mild iridocyclitis to severe sterile endophthalmitis.³¹ One case series described a high percentage (35% to 78%) of sterile ocular inflammation from a single lot of anti-VEGF agents, which may be secondary to endotoxin contamination.³¹ A large retrospective review estimated the rate of sterile endophthalmitis with aflibercept at 0.16%, compared to 0.10% for bevacizumab and 0.02% for ranibizumab.³² Some studies report a high rate of intraocular inflammation from the recently approved drug brolucizumab (Beovu; Novartis) (4.4% vs 0.6% with aflibercept), resulting in severe vascular occlusions.^33,34

Inflammation can be also be observed with triamcinolone acetonide injection. In this case, to differentiate from endophthalmitis, the eye will be asymptomatic and the patient will not report any pain. However, these cases should be handled with a tap and inject, as one cannot rule out endophthalmitis, and the consequences of a missed diagnosis are horrendous. When using an extended-release steroid such as dexamethasone, the implant may put the patient at risk for cytomegalovirus retinitis, due to local immunosuppression.^35-36

Overall, endophthalmitis after injection is rare, with incidence ranging from 0.01% to 0.3% of cases.^2,37-39 However, the incidence of endophthalmitis after steroid injection is higher. The prevalence of culture-positive endophthalmitis following intravitreal injection of triamcinolone acetonide has been estimated at 0.6% to 0.16% due to infectious agents.² Because the intravitreal steroid might mask the signs of inflammation, caution should be implemented to facilitate diagnosis. Treatment guidelines are adopted from the Endophthalmitis Vitrectomy Study. If the patient has hand motion vision or better, they should receive a vitreous tap along with intravitreal injection of broad-spectrum antibiotics. Patients with worse vision should undergo pars plana vitrectomy with the same spectrum of antibiotics.⁴⁰

CONCLUSION

The complication rate of intravitreal injections is relatively low, with mostly minor complications, which tend to resolve spontaneously. To reduce the chance of endophthalmitis, precautions including proper usage of antisepsis are critical. Special measures should be implemented among certain populations, such as patients with diabetes and patients undergoing steroid injections. Diabetic patients with PDR may be prone to develop traction with the use of anti-VEGF, while in patients undergoing intravitreal steroid injections, the steroid may mask the effect of endophthalmitis. Patients receiving intravitreal steroid injections may also be prone to developing cytomegalovirus retinitis due to local immune suppression. RP

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