Part 3 • Medical Therapy and Surgical Intervention Chapter 7 Philosophy, Goals, and Approaches to Medical Therapy

Mode of Action

In humans, corticosteroids are not considered to be cytotoxic agents. Human immune cells are not susceptible to lysis by corticosteroid administration, even at the higher dosages usually employed, unlike some of the agents to be covered in this chapter. Mice, rats, and rabbits are considered to be corticosteroid-sensitive animals, with their lymphocytes showing a marked tendency toward lysis after the administration of corticosteroids. Therefore, extrapolation from animal experiments must take place only after careful evaluation.

The mechanism of entry into the cell by steroids has been evaluated by means of several systems. The underlying point for the action of all the steroid hormones is the need for cellular receptors. The steroid is met at the cell surface by the appropriate receptor and then complexes with it in the cytoplasm of the cell. This complex then migrates to the nucleus, where it exerts its effect on DNA transcription, leading to changes in RNA production. These RNA alterations result in changes in protein production and cell function. In steroidsensitive animals, such as the rat, cells with steroid receptors will be lysed. However, in humans this is not the case, and in vivo and in vitro testing is therefore needed to fully evaluate the effect of the hormone on the system in question.

The effects of steroids on the immune system are both local and systemic. Essentially all cellular components are affected. On the systemic level, a profound change is seen particularly with neutrophils and lymphocytes (Fig. 7-1). For lymphocytes, Clamen5 and Fauci6 showed that a large number of the lymphocytes in the intravascular space continuously recirculate with the extravascular lymphocyte pool in organs such as the bone marrow, spleen, and lymph nodes. The addition of steroids induces a change in the recirculation pattern, with a large number of T cells, particularly the helper T subset, sequestered out of the intravascular circulation. This phenomenon results in a break in the recruitment of immunoreactive cells to the site of the inflammatory reaction. The effect on neutrophils appears to be quite striking as well. Steroid therapy induces a larger number of neutrophils to be produced by the bone marrow. In addition to this increased production, the circulating halflife of these cells on reaching the intravascular space is prolonged. Concomitant with these effects is an impeding of neutrophil migration from this space to the site of inflam-

↓Neutrophil adherence to vascular endothelium

↓Bactericidal activity of neutrophils

↓Clearance of antibody coated particles

↓Production of Il-1 and TNFα

Figure 7-1.  Antiinflammatory effects of corticosteroids.

mation. Decreases in the number of circulating monocytes, eosinophils, and basophils have also been observed.

Although the changes in the immune system are profound, it is important to remember that they are temporary. Fauci7 demonstrated that T-cell subsets return to essentially the presteroid ingestion state after about 24 hours. This observation is most important in developing a strategy for the treatment of an acutely active inflammatory condition, whether in the eye or elsewhere.

Profound effects on cell function have been noted with the addition of a steroid. The effects on the various immune cell populations include a decrease in bactericidal activity, a decrease in delayed hypersensitivity reactions, a decrease in lymphokine production, and changes in immediate hypersensitivity reactions. In addition, steroid administration has a profound effect on local resident cells in an organ, particularly the vascular endothelium. A reduction in the leakage of fluid during an inflammatory episode from the capillary endothelium results from steroid administration, thereby reducing tissue swelling. Further, during an inflammatory response there is a decrease in the amount of intracellular fluid taken in by cells, thereby reducing cell swelling and avoiding the resultant decrease in function and ultimate lysis. The effect of steroids on lysosome membranes, thought at one time to be an important stabilizing factor, now remains unclear.

Other effects of steroids are beginning to become clear. Among the many factors involved in uveitis are the matrix metalloproteinases (MMPs). MMPs are a class of proteolytic enzymes that influence tissue architecture. Their products have been implicated in a wide range of physiologic and pathologic processes and diseases. MMPs have been described in the pathogenesis of blood–retinal barrier breakdown and increased vascular permeability. Furthermore, MMPs also have been shown to play a role in the breakdown of the blood–brain barrier and increased vascular leakage in experimental animal encephalomyelitis. Inflammatory cells themselves may also modulate the production of some MMPs, with some cytokines stimulating and others inhibiting their production. Some steroids, such as anecortave acetate, an angiostatic steroid which is presently under evaluation, inhibit the expression of some MMPs involved in angiogenesis.

Preparations, Dosage Schedules, and Complications

Many steroid preparations are now available. It should be remembered that they have varying potencies, and therefore sometimes quite different concentrations of each drug need to be used (Table 7-1 and Fig. 7-2).

Topical application of corticosteroids is an excellent way to treat certain uveitides. Our own preference has been the use of prednisolone formulations for severe intraocular inflammatory disease. The basis for this choice is not scientific but rather the result of usage and convenience, and hence knowing what to expect with this formulation. Although studies do show differences in corneal penetration between phosphate and acetate preparations of steroids, we have not noted a major difference in efficacy between the two preparations for treating active inflammation. When the diagnosis is made, it is imperative that initial treatment of the uveitis be aggressive. We frequently ask the patient to administer his or her drops every hour while awake. One

evidenced by a reduction in the flare and cells in the eye, we then see the patient often (every 2–3 days to once a week) and begin a very slow tapering of the drops. The schedule for tapering is unique to each patient, but persons who have had numerous attacks may need to receive one or two drops a day for weeks or even months.

A second option is to inject the corticosteroid periocularly. This method, which permits a relatively high concentration of material to be given rapidly, is an effective way to treat particularly severe inflammatory conditions. There is the general choice between long-acting preparations (in a depot vehicle) and shorter-acting soluble preparations. These injections can be given every 1–2 weeks for short periods. In addition to treatment of severe anterior segment disease in general, this is a useful approach for unilateral disease, at the time of surgery on an uveitic eye, and for patients in whom the systemic effects of steroids should be avoided. We have found this to be an effective way to treat cystoid macular edema, even in children, although the procedure may require that young children receive general anesthesia. In one study8 25 of 28 eyes given a sub-Tenon’s injection of 40 mg triamcinolone had improved vision at 6 weeks post injection. In another study by Bui Quoc and colleagues,9 61 patients with uveitis were given one or more periocular injections of triamcinolone. Intraocular pressure elevation was seen in 21% of patients and 52% of patients were thought to have effective therapy based on angiographic changes and an improvement in visual acuity.

Several approaches to periocular injections have been suggested, and it probably is best to use the approach with which one feels the most comfortable. The approach from the superotemporal aspect of the globe, as described by Schlaegel,10 is thought to reduce the possibility of penetration of the globe and to place the medication under Tenon’s capsule and in the region of the macula. Freeman and coworkers11 demonstrated that the temporal approach is efficient for placing the injected steroid close to the macula. Using any of these approaches, we rarely need to systemically premedicate an adult. Topical anesthetics are liberally used, and the area in which the injection is to be given (such as the superotemporal aspect of the globe) is further anesthestized with a cotton swab soaked in topical anesthetic (either 4% lidocaine or cocaine). If there are no contraindications, we generally inject triamcinolone (Kenalog) 40 mg in 1 mL because this preparation appears to cause less fibrosis. Some practitioners have suggested mixing the steroid preparation

Part 3 • Medical Therapy and Surgical Intervention Chapter 7 Philosophy, Goals, and Approaches to Medical Therapy

with a local anesthetic. We generally do not do this because the increased volume needed increases the pain of the procedure. An alternate approach that has become popular is to inject the steroid preparation directly through the lower lid or the inferior fornix (using a 25-gauge needle) while the patient looks upward. After the injection, for the patient’s comfort, we put a patch on the eye and give a mild analgesic. We have rarely found the need to inject the steroid anteriorly over the pars plana/peripheral retina, a technique that is thought to increase the chance of steroid-induced ocular hypertension. If the procedure is performed on an outpatient basis, the person will be observed for some time (30–90 minutes) to be sure there are no untoward problems. We will use periocular injections over a 4–12-week interval, giving a series of two to four injections before declaring this method ineffective (Fig. 7-3). Finally, anecortave acetate, a corticosteroid that has been modified so that its corticosteroid activity has been eliminated, is also injected periocularly. The interest in this molecule is related to its retardation of blood vessel growth through inhibition of endothelial cell migration.12

An additional local approach that has attracted great attention is the intraocular administration of corticosteroids.

To date this route of administration has been achieved using three approaches. The first is the direct injection, usually of triamcinolone (2–4 mg), into the vitreous; the second is the use of a soluble pledget placed into the anterior or posterior chamber; and the third is placement of a slow-release fluo­ cinolone acetonide-containing implant into the eye.

Intravitreal steroid injections have been reported to be effective for many intraocular problems, including choroidal neovascularization, CME secondary to uveitis, diabetes, central vein occlusion, and pseudophakia.13–15 In one study15 in which 2 mg of triamcinolone were injected into uveitic eyes with cystoid macular edema, five of six eyes showed a reduction in macular thickening in 1 week based on optical coherence tomographic measurements. Two of the five eyes could be maintained afterward with periocular injections. However, only a moderate improvement in visual acuity was seen despite the return of the macula to its anatomically normal configuration. In one 40-patient randomized study16 comparing orbital floor injection of steroid versus intra­ vitreal injections for CME, foveal thickness increased with orbital floor injections but decreased with intravitreal injections, with CME improving in that group in 50% of patients. However, at 6 months there was no difference in the best