Intravitreal Injection for Wet (Exudative) Age-Related Macular Degeneration (AMD)

Intravitreal injection with anti-vascular endothelial growth factor (anti-VEGF) therapy is the gold standard for treatment of choroidal neovascular membranes (CNVs) associated with age-related macular degeneration (AMD or ARMD). ^{[1, 2, 3, 4]} Treatment options in wet AMD include bevacizumab (Avastin, Genentech), which is a full-length anti-VEGF antibody; ranibizumab (Lucentis, Genentech), which is an affinity-matured fragment; pegaptanib (Macugen, OSI/Eyetech); aflibercept (Eylea, Regeneron), an anti-VEGF trap; brolucizumab (Beovu, Novartis Pharmaceuticals), a single-chain Fv antibody fragment; and faricimab, a bispecific monoclonal antibody (Vabysmo, Genentech). ^{[5, 6, 7, 8, 9]} With the exception of bevacizumab, which is used on an off-label basis, all the other aforementioned drugs are FDA-approved for AMD. 

The intravitreal administration of pegcetacoplan (Syfovre), a complement inhibitor, is indicated for treatment of for geographic atrophy (GA) secondary to age-related macular degeneration. 

Wet age-related macular degeneration (ARMD).

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Absolute contraindications to intravitreal injection are as follows:

• Active blepharitis or external ocular surface infection is an absolute contraindication for intravitreal injections. These conditions should be treated appropriately first. ^[10]

Relative contraindications to intravitreal injection are as follows:

• History of significant acute inflammation related to the agent injected ^[11]
• Recent history of adverse thromboembolic event such as stroke

Many patients take anti-platelet or anti-coagulant agents. It is not necessary to stop these before injection.

Equipment for intravitreal injection is as follows:

• Povidone/iodine 5% and/or 10%
• Speculum
• Scleral marker (calipers)
• Tuberculin syringe
• 30- or 32-gauge needle (27-gauge for triamcinolone)
• Cotton swab
• Sterile gloves (optional)
• Sterile drape (optional)
• Mask (optional)

Various sterile packs with required equipment are available.

In many countries, including United States, Canada, and Australia, performing intravitreal injection in a minor procedure room or examination room under sterile conditions is common practice. However, some countries or centers recommend this procedure in an operating room.

Preinjection antibiotics are not used in most cases. The frequency of conjunctival bacterial growth was found to be similar with or without a 3-day course of topical antibiotic, in the setting of preinjection povidone-iodine. ^[12]  

Commonly used methods for local anesthesia include the following ^[13] :

• Topical anesthetic drops
• Application of cotton swabs soaked in tetracaine or lidocaine
• Lidocaine 2% gel
• Subconjunctival lidocaine following the instillation of topical anesthetic

Confirm the eye undergoing treatment.

Apply anesthetic of choice.

Instill povidone-iodine solution to the conjunctival sac, lids, and lashes following the instillation of anesthetic. Generally a 10% solution is used on the lids and lashes and 5% solution is applied to the conjunctiva and ocular surface. After a few minutes, another drop is instilled over the injection site. As an alternative to povidone-iodine solution, chlorhexidine may be used. This is useful in patients who have an allergy or intolerance to povidone-iodine. ^[14]

Insert speculum. This is optional but prevents the lids from closing during the injection. If no lid speculum is to be used, the location of injection should be inferiorly to reduce the likelihood of the lids touching the needle.

After a subconjunctival injection of lidocaine 1% and topical anesthesia, a lid speculum is placed. A 5% povidone iodine solution is used to clean the conjunctival surface.

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Use the scleral marker to mark the injection site radially away from the limbus: 3.5 mm for a pseudophakic eye and 4 mm for a phakic eye. The most commonly-accepted sites include the superotemporal and inferotemporal quadrants.

Inject gently into the mid-vitreous. An oblique entry (tunneled approach) may reduce the risk for reflux and aid in the construction of a self-sealing wound. ^[15] This can be particularly relevant in vitrectomized eyes.

Optionally, apply the sterile cotton tip to tamponade the injection site following withdrawal of the needle for 10 seconds with a gentle rub. This helps reduce reflux. Alternatively, apply one post-injection drop of 5% betadine on the site of injection.

Check vision and central retinal artery perfusion.

Flush the eye with lubricants/balanced salt solution to remove any residual povidone-iodine to reduce post-injection irritation. Topical antibiotics are optional, although evidence is growing that they are unnecessary and potentially increase the risk for bacterial resistance. ^{[16, 17, 18]}

The patient needs to be aware that severe pain, visual loss, or marked hyperemia of the globe requires urgent re-assessment by the ophthalmologist. A mechanism must be in place to allow the patient to contact the treating ophthalmologist or a member of the team urgently after hours.

A recent survey of intravitreal techniques by retinal specialists in the United States found only one third of participants wear sterile gloves for intravitreal injections. ^[19] Most (83%) do not displace the conjunctiva prior to injection and use a 30-gauge needle for injection of ranibizumab or bevacizumab. Although most respondents in this study did not use prophylactic topical antibiotics pre-injection, 81% used topical antibiotics post-injection.

Avoid touching the hub of the needle or syringe when opening the packaging.

Allow sufficient time for the anesthetic to take effect.

Allow sufficient time for betadine to coat the ocular surface prior to injection. Some physicians will wait at least a few seconds and up to 30 seconds prior to injection. Extensive delay may cause corneal dessication.

Aim to reduce excessive time between speculum insertion and injection to reduce corneal exposure time. This may reduce the amount of corneal desiccation and epitheliopathy.

Acquire sufficient interpalpebral exposure as to avoid touching the eyelashes with any part of the needle when performing the injections.

Eye washout with normal saline following the procedure may reduce discomfort in patients sensitive to povidone-iodine and/or anesthetic.

Warn patients about subconjunctival hemorrhage, which otherwise can be anxiety-provoking.

Reduce the risk for endophthalmitis by wearing a mask or by not speaking during the procedure. In the era of COVID, universal masking of patients is commonly seen. Taping the superior margin of the patient's mask can reduce the risk for respiratory pathogens entering the sterilized ocular area. 

Bilateral injections increase efficiency and convenience to the patient with no apparent risk increase. ^[20]

Potential complications of intravitreal injection for age-related macular degeneration (AMD) are summarized as follows ^{[10, 21, 22]} :

• Retinal detachment: This complication is rare. ANCHOR and MARINA demonstrated a 0.01% per-injection detachment rate.
• Cataract
• Transient raised IOP and possible progression of glaucoma damage in susceptible eyes
• Hypotony
• Adverse thromboembolic events ^[23]
• Endophthalmitis: In recent multicenter clinical trials of anti-VEGF therapy, the incidence of endophthalmitis has ranged from 0.7% to 1.6%. Non-infectious (sterile) endophthalmitis can occur in response to anti-VEGF injections.
• Infection: The FDA issued a safety alert regarding repackaged intravitreal injections of bevacizumab (Avastin), an anti-VEGF antibody. Serious eye infections caused by Streptococcus endophthalmitis have been reported in 12 patients who received the injections. The infections were the result of contamination that occurred during the repackaging of bevacizumab from 100 mg/4 mL single-use, preservative-free vials into individual 1-mL syringes containing 1.25 mg of bevacizumab in 0.1 mL for off-label use to treat wet macular degeneration. ^[24]
• Occlusive vasculitis: this complication has been reported specifically with brolucizumab. ^{[25, 26]}