• Uveitis

    Introduction

    Regional drug delivery has the advantage of avoiding systemic effects; thus, periocular injections of corticosteroids have traditionally provided a useful therapeutic approach in many forms of uveitis. More recently, intraocular therapy in the form of intravitreal triamcinolone injection (IVTA) has gained acceptance for the treatment of severe uveitis and cystoid macular edema (CME), which has led to the development of longer-acting intravitreal steroid implants, several of which are now in clinical trials.

    Periocular corticosteroids

    Periocular steroid injections are a well-established treatment for vitritis and CME, and they are commonly used in posterior or intermediate uveitis to avoid the side effects associated with systemic immunosuppression, particularly in unilateral disease. These injections can also provide useful additional local immunosuppression to the worse eye in patients with asymmetric disease who are already taking systemic immunosuppressive agents. In anterior uveitis, they can be used to treat CME and occasionally can also be of use in severe disease, or they can provide a depot of corticosteroid if noncompliance is suspected.

    Various injection sites can be used, including the subconjunctival and sub-Tenon's spaces as well as the orbital floor, although posterior injection avoids the development of unsightly subconjunctival plaques resulting from anterior seepage of depot corticosteroid. Our practice is to use orbital floor methylprednisolone. Injection into the orbital floor is easily performed in the clinic with a 25 mm 25-gauge needle. It is well tolerated and carries only a very small risk of globe perforation, as the needle is directed away from the globe at all times.1 Others use posterior sub-Tenon's injections, typically of triamcinolone, which is equally effective but is better tolerated if the globe is penetrated during the procedure.

    Periocular steroid therapy is typically indicated if visual acuity is between 20/40 and 20/60. It has a duration of action of up to 3 months, but it can require 6 weeks to take full effect. This may not be fast enough for patients with severe vitritis or CME, in whom a more immediate therapeutic effect is desirable. In addition, some cases of vitritis and CME prove resistant even to repeated injections of periocular steroid; patients are declared refractory to treatment if they fail to respond to 3 separate injections given at 6-week intervals. Like other modes of corticosteroid delivery, periocular corticosteroids are linked with the development of elevated intraocular pressure (IOP) and cataract.

    Intravitreal corticosteroids

    IVTA injection is of particular use in 2 groups of patients: those with severe vitritis or CME that is unlikely to respond rapidly to periocular corticosteroids, and those with inflammation that has already proved refractory to such treatment. Indeed, small case series have demonstrated that IVTA has beneficial effects in the treatment of refractory CME associated with uveitis, including in patients previously treated with periocular corticosteroids and second-line immunosuppressive agents.2,3

    Owing to the increased risks associated with intraocular injections, IVTA is usually reserved for patients with a visual acuity of 20/80 or worse. However, when used, it takes effect rapidly and has a duration of action of 8-16 weeks. IVTA is also useful in establishing whether there is a reversible component to visual loss. Visual loss of inflammatory origin can be considered truly refractory to immunosuppression only if there is no improvement in response to IVTA, in which case discontinuing systemic therapy may be appropriate.

    However, the use of intravitreal corticosteroids can cause side effects. The most common adverse effect is increased IOP, which occurs in up to 40% of patients.4 This is usually temporary and can be managed with topical medication, although a few patients require surgical intervention. Cataract is a common complication of IVTA and occurs in up to 45% of patients within a year of injection.5 A prior history of corticosteroid response is often considered an absolute contraindication to intraocular corticosteroid therapy.  However, many clinicians now consider this only a relative contraindication, particularly with the advent of corticosteroid implants. Filtration surgery in these patients has a high success rate, probably owing to the corticosteroid influence, and the visual benefits of treatment may still outweigh the risks, at least in the short term.

    Infectious (culture-positive) endophthalmitis is rare, occurring in zero to 0.87% of cases,6 but culture-negative sterile endophthalmitis has also been reported. There is continuing debate regarding the contribution to this occurrence of the preservatives in the preparation, but we have found sterile endophthalmitis to be a rare development. Removing preservatives by washing prior to use also reduces the dose given7 and may increase the risk of bacterial contamination.

    There is also debate over the dosage: 2 mg, 4 mg, and 25 mg doses of triamcinolone have all been reported, although most of the 25 mg doses reported were subsequently washed, significantly reducing the actual dose delivered. We and others take triamcinolone directly from the vial, without prior washing, at a dose of 4 mg in 100 μl. We use 4 mg, as a 2 mg dose does not allow the treating clinician to determine whether a patient who fails to respond is refractory to treatment or has simply been undertreated, and larger doses appear to provide no discernable extra benefit.

    Corticosteroid sustained-release devices

    To avoid the need for recurrent intravitreal corticosteroid injections in patients with chronic disease, sustained-release devices have been developed, 2 of which are currently undergoing phase 4 trials. The Posurdex implant is an injected intravitreal biodegradable polymer that releases low-dose dexamethasone over a period of approximately 6 months, and the Retisert device is a surgically placed intravitreal insert that releases fluocinolone acetonide over a period of 2.5 years. Both can result in a significant rise in IOP; the Retisert implant is associated with a very high rate of cataract surgery and trabeculectomy. Essentially, the systemic side effects of traditional immunosuppression are exchanged for (treatable) local complications. The Posurdex trial is due to report in 2009, and 3-year data is starting to become available for the Retisert implant.8

    Summary

    While periocular corticosteroid injections remain the mainstay of treatment for unilateral vitritis or CME on the grounds of their relative safety, intravitreal therapy has made treatment possible of disease that had previously been considered refractory. The trend toward intravitreal treatment is likely to continue with the introduction into clinical practice of long-acting steroid implants that, it is hoped, will prove both effective and convenient for patients with chronic sight-threatening disease requiring long-term immunosuppression.

    References

    1. Ferrante P, Ramsey A, Bunce C, Lightman S. Clinical trial to compare efficacy and side-effects of injection of posterior sub-Tenon triamcinolone versus orbital floor methylprednisolone in the management of posterior uveitis. Clin Experiment Ophthalmol. 2004;32(6):563-568.

    2. Antcliff  RJ, Spalton DJ, Stanford MR, et al. Intravitreal triamcinolone for uveitic cystoid macular edema: an optical coherence tomography study. Ophthalmology. 2001;108(4):765-772.

    3. Kok H, Lau C, Maycock N, et al. Outcome of intravitreal triamcinolone in uveitis. Ophthalmology. 2005;112(11):1916.e1-7.

    4. Jonas JB, Degenring RF, Kreissig I, et al. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection. Ophthalmology. 2005;112(4):593-598.

    5. Thompson JT. Cataract formation and other complications of intravitreal triamcinolone for macular edema. Am J Ophthalmol. 2006;141(4):629-637.

    6. Westfall AC, Osborn A, Kuhl D, et al. Acute endophthalmitis incidence: intravitreal triamcinolone. Arch Ophthalmol. 2005;123(8):1075-1077.

    7. Spandau UH, Derse M, Schmitz-Valckenberg P, et al. Triamcinolone acetonide concentration after filtration of the solvent agent. Am J Ophthalmol. 2005;139(4):712-713.

    8. Goldstein  DA, Godfrey DG, Hall A et al. Intraocular pressure in patients with uveitis treated with fluocinolone acetonide implants. Arch Ophthal 1007 Nov; 125(11):1478-85.

    Author Disclosure

    The authors state that they have no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service.