Local Drug Delivery for Noninfectious Uveitis

Abstract

Ocular inflammation lends itself to local therapies as both anterior and posterior segments of the eye are easily accessible and complications remain localized. Delivery can be via the subconjunctival, periocular, or intravitreal routes, and longer-acting vitreous implants have garnered significant interest. Intraocular injections have the added advantage of allowing medications to directly bypass the blood–ocular barriers.

Corticosteroids are the cornerstone of uveitis management and remain the best studied for local therapy. However, there is burgeoning research into steroid-sparing drugs given in this route. Antivascular endothelial growth factors bevacizumab and ranibizumab have shown promise, particularly in treating inflammatory choroidal neovascularization. Intravitreal methotrexate has shown encouraging outcomes as a second-line agent, while intravitreal sirolimus has shown some potential. Tumor necrosis factor alpha inhibitors have demonstrated equivocal outcomes with the suggestion of increased inflammatory activity post-intravitreal injection, such that their use outside of clinical trials is currently not recommended.

Medical management aims to treat the inflammation, and the sequelae of cystoid macular edema and choroidal neovascularization. This chapter summarizes the literature surrounding the indications and outcomes of treatment, pharmacodynamics and pharmacokinetics, and the complications of local injectable uveitis medications.

Appendix 13.1: Summary of Local Ocular Drug Delivery Methods

Subconjunctival Injection (Anterior Sub-Tenon)

Method

• Anesthesia: topical anesthesia should be achieved with repeated applications of topical anesthetic such as proparacaine and oxybuprocaine. This can be augmented by placing a local anesthetic-soaked pledget on intended injection site for 5 minutes

• A 1 mL syringe with a 30 g needle is preferred; 27 g needle may be required for triamcinolone

• Insert the needle bevel toward the globe through the conjunctiva on the superior or inferior bulbar surface at a site that is usually covered by the upper or lower eyelid

• Inject up to 0.1 mL of medication (typically Kenalog®) to form a small bleb; injections may be placed at multiple sites, up to a total volume to 0.5–1.0 mL. A whitish deposit may be noted, hence the preference to place these injections at a site that would/will be covered by the eyelids

Subconjunctival administration offers an attractive alternative to peri- and intraocular injections as the needle tip is always visible and therefore theoretically safer. Consideration should be made to minimize cosmetic defects such as a visible deposit within the interpalpebral fissure and subconjunctival hemorrhage.

Periocular Triamcinolone (e.g. Kenalog®) Injection (Posterior Sub-Tenon, Orbital Floor, Peribulbar) [169]

There are several approaches to periocular injections. While each technique offers different advantages and risks, all aim to place the drug close to the post-equatorial globe. Retrobulbar injections are rarely performed, particularly in a clinic setting where treatment usually takes place. The most common usage is triamcinolone acetonide 20–40 mg given into the sub-Tenon or orbital floor space.

Anesthesia

Topical anesthesia is required for the sub-Tenon techniques. This can be augmented by the addition of a quick-acting local anesthetic mixed into the syringe containing the corticosteroid. Orbital floor and peribulbar injections typically do not require topical anesthesia.

• A 3 mL syringe is preferred

• All injections are given with the needle bevel facing the globe as to minimize engaging the sclera and inadvertent intraocular penetration

Posterior sub-Tenon injections can be delivered by either blunt cannula or sharp needle (Nozik) technique. The technique aims to deposit the drugs close to the macula.

Sub-Tenon Injection (Blunt)

The specialized cannula is a blunt, curved 19 g needle 25 mm long.

• Ask the patient to look away from the intended site of injection, which is typically inferonasal

• Blunt curved scissors are used to make a small circumcorneal incision about 8 mm from the limbus

• Dissect onto bare sclera and into the sub-Tenon space

• Slide the cannula posteriorly along this track until the hilt is reached

• Inject the drug. Forceps can be used to provide counter traction and to hold the conjunctival opening closed

Difficulties can be encountered in accessing sub-Tenon space and in preventing regurgitation along injection track.

Sub-Tenon Injection (Nozik)

• 1. Use a 25- or 27 g 5/8″ needle

• 2. Ask the patient to look inferonasally

• 3. Insert the needle bevel toward the globe through the conjunctiva at a point 3–4 mm in front of the superotemporal fornix

• 4. Advance the needle to the hilt with lateral sweeping motions to maintain close contact with the globe while avoiding scleral penetration and inject up to 1 mL (40 mg)

This technique minimizes unsightly cosmetic blemishes but can result in ptosis [26, 31, 34, 170, 171]. This may result from disinsertion of the levator aponeurosis, direct needle trauma to the levator complex, or muscle fiber atrophy due to the triamcinolone [26, 170]. Subconjunctival hemorrhage and chemosis are rarely experienced.

Peribulbar Injection

Peribulbar injections can be approached transconjunctivally or transcutaneously through the lower eyelid.

• 1. Use a 25 g 1″ needle and 3 mL syringe

• 2. Ask the patient to look straight ahead as a gaze directed superonasally brings the optic nerve closer to the orbital rim

• 3. The needle is inserted at the meeting point between the lateral third and medial two-thirds of the lower orbital rim

• 4. Direct the needle slightly up-and-in with a side-to-side motion until the needle reaches its hilt

• 5. 1 mL of drug is deposited into the extraconal space

Orbital Floor Injection

Orbital floor injections are favored in some centers as it is believed they have a lower risk of globe perforation. Rarely, herniation of orbital fat following multiple orbital floor injections has been reported [172].

• 1. Use a 27 g 0.5″ or 1″ needle

• 2. Ask the patient to look straight ahead

• 3. The needle is inserted transcutaneously at the meeting point between the lateral third and medial two-thirds of the lower orbital rim

• 4. Advance the needle directly posteriorly

• 5. The drug is deposited on the orbital floor

All sharp-needle techniques carry an intrinsic risk of inadvertent globe perforation, which itself increases the risk of intraocular complications such endophthalmitis and retinal tears.

Intravitreal Injection of Triamcinolone [173]

Method

• 1. Anesthesia: topical anesthesia is required and can be augmented by placing a local anesthetic-soaked pledget on intended injection site for 5 minutes or by a subconjunctival injection of local anesthetic

• 2. A 1 mL syringe with a 27 g or 30 g 0.5″ needle is preferred

• 3. Instill povidone-iodine 5% into the conjunctival sac

• 4. Place an eyelid speculum

• 5. Ask the patient to look away from the intended site of injection, typically superotemporal

• 6. Mark the site of injection with calipers: 3.5 mm from the limbus in pseudophakic patients, 4.0 mm in phakic patients

• 7. Insert the needle approximately halfway into the vitreous cavity, directing the tip toward the optic nerve

• 8. Inject 0.05–0.1 mL of the medication

• 9. Check gross visual acuity or perform indirect ophthalmoscopy to ensure adequate central retinal artery circulation

Serious procedure-related complications occur infrequently at <1–5% and include retinal tears, vitreous hemorrhage, and endophthalmitis. Floaters, subconjunctival hemorrhage, and ocular surface irritation are common but benign.