corrected vision between the two groups. This perhaps underlines the issue that repeat injections are necessary for a sustained release, an approach that is being used less and less. The positives and negatives of this approach continue to be discussed, particularly with the significant increase in intraocular pressure and cataract formation.17 Regression of iris neovascularization has been reported using this approach as well.18 In one study of 113 patients treated with intravitreal triamcinolone for subretinal neovascularization, 30% developed an increase in intraocular pressure >5 mmHg within the first 3 months.19 In addition to an increase in pressure, a clinical picture resembling an endophthalmitis was reported, with the normal concern as to whether it was sterile or infectious. Further, the triamcinolone preparations currently being used contain alcohol, which has an unknown effect on the retina. An intraocular preparation free of such components is now available.

Fluocinolone acetonide (FA) intravitreous implants have been evaluated in several studies, and the results of a 3-year clinical trial have recently been published.20 In this study 110 patients received a 0.59 mg FA implant and 168 received a 2.1 mg FA implant, all placed intravitreously. Uveitis recurrence was reduced to 4%, 10%, and 20% during the 1, 2, and 3 year periods for the 0.59 mg implant. More implanted eyes had an improvement in vision than did nonimplanted eyes. However, glaucoma surgery was required in 40% of the implanted eyes, compared to 2% of the nonimplanted eyes. Additionally, 93% of the phakic eyes that were implanted needed cataract surgery, whereas only 20% of the nonimplanted eyes needed this surgery. The Retisert implant is FDA approved for use in uveitis. However, questions remain as to the overall use of this approach in uveitis patients.21 Because of equipoise in the community as a whole, the Multicenter Uveitis Steroid Treatment (MUST) trial was initiated. This is a phase IV randomized controlled clinical trial comparing two treatments, the FA implant versus standard therapy, for patients with vision-threatening noninfectious intermediate uveitis, posterior uveitis, or panuveitis. It is projected that the study will be complete in late 2011.

Ozurdex.  Ozurdex is a sustained-release biodegradable intravitreal implant containing dexamethasone. The implant is placed in the vitreous using a 22-gauge applicator and the biodegradable polymers break down into H2O and CO2 as dexamethasone is released. A clinical study comparing applicator and surgical placement of Ozurdex found that patients receiving applicator placement had a similar efficacy but a slightly lower rate of certain adverse effects than did those receiving surgical placement.22

Ozurdex is currently FDA approved for macular edema associated with retinal vein occlusion and is also being developed for both diabetic macular edema and uveitis. A recent study demonstrated that Ozurdex was well tolerated and produced improvements in visual acuity, macular thickness, and fluorescein leakage in patients with persistent macular edema despite laser treatment or medical therapy. Eligible causes of macular edema in this study were diabetic retinopathy, retinal vein occlusion, uveitis, and Irvine-Gass syndrome.23 In a subgroup analysis of patients in this study who had macular edema due to either Uveitis or Irvine-Gass syndrome,24 those receiving the 700 mg Ozurdex implant had significantly greater improvement in visual acuity than

Nonsurgical therapeutic options

did controls up to 6 month following a single application. Ozurdex was well tolerated, with no cases of endophthalmitis. The number of patients with an increase in intraocular pressure (IOP) ≥10 mmHg at any visit during the 6-month trial was 12% in the 350 g Ozurdex group, 17% in the 700 g Ozurdex group, and 3% in the control group. No patients required surgical treatment for glaucoma.23

Secondary Effects

The topical application of steroid induces an increase in IOP in a significant number of persons. This should be monitored closely. It has been our experience that some patients with uveitis are extremely sensitive to steroid therapy, with dramatic increases in IOP noted even when topical steroids are administered on a very modest schedule. The reactivation of corneal herpes simplex infection can occur with topical steroid therapy. This is of even greater import in those patients undergoing corneal grafting, as a large proportion of these persons are undergoing this procedure because of corneal herpes.

The periocular injection of steroid has secondary effects unique to the procedure as well. (1) Although periocular steroid injections are an effective therapy for childhood uveitis, they may require general anesthesia, with the potential inherent side effects. (2) Possible penetration of the globe with the needle should be a constant concern to the ophthalmologist.25 (3) Continued periocular injections can induce orbital problems, such as proptosis of the globe and fibrosis of the extraocular muscles. (4) Retinal and choroidal occlusions after a posterior sub-Tenon’s injection given to treat cystoid macular edema have been reported.26 (5) Severe or intractable glaucoma can occur after periocular injections. This can become particularly problematic when a depot injection has been used. In such cases the depot may need to be removed surgically, which is sometimes a major undertaking. In a retrospective review of 64 patients, Levin and colleagues27 found that in nonglaucomatous eyes a history of a steroid-induced increase in intraocular pressure is a relative contraindication to injection. In another study of 53 patients who had a total of 162 posterior sub-Tenon’s steroid injections, an increase in IOP was seen in 36%.28 (6) Reactions to the vehicle in which the steroid injection has been placed can also occur (Fig. 7-4). (7) In patients with scleritis and ocular toxoplasmosis, periocular injections can be problematic. In the former the injections could potentially inhibit new collagen growth to a point where perforation of the globe may occur. This theory is being questioned by some. With toxoplasmosis, the acutely high intraocular steroid dose may effectively prevent the body’s normal antitoxoplasma mechanisms, thereby causing an exacerbation of the ocular disease. Intraocular steroid injections or implants may also result in elevations of IOP in a large proportion of patients. The complications of intraocular steroid placement are just beginning to be reported. As mentioned earlier, they include increased IOP, endophthalmitis, and much rarer but always potential problems after any penetrating injury to the globe (i.e., vitreous hemorrhage and retinal detachment).

Systemic corticosteroids remain the initial drug of choice for most patients with severe bilateral endogenous sightthreatening uveitis. The striking exception to this rule is patients with Behçet’s disease (see Chapter 26). When initi-

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

Figure 7-4.  Allergic response in conjunctiva after periocular injection of steroid. The patient underwent skin testing and was found to have a profound allergic response to the vehicle.

ating systemic steroid therapy, one should keep in mind several considerations. It is imperative that the treating physician (to the best of his or her ability) rule out the possibility of infection or malignant disease as a cause for the intraocular inflammation. Uppermost is the clinical impression, based on the ocular examination, that there is an inflammatory response that requires systemic therapy. It is also important for the practitioner to set standards by which to decide whether the therapy is successful or not. A detailed explanation should be given to the patient before starting therapy. The subject matter should include duration of therapy, goals, and side effects.

We generally find it advisable to begin therapy with prednisone 1–1.5 mg/kg/day (Table 7-2). The relatively high dose and daily therapy appear to increase the efficacy of this approach, which takes into account the known effects of corticosteroids in humans, already described. The high doses of corticosteroids should be maintained until one sees a clinical effect, but it is clear that the treating physician must set a reasonable time limit to decide whether this form of therapy is truly worthwhile. If it is determined that the corticosteroids are having a beneficial effect, then a slow reduction of the therapeutic dose needs to be established. A too-rapid reduction can lead to recurrence. The slow-tapering plan permits the treating physician to see if the reduction will cause a reactivation, which frequently manifests as a mild ocular inflammation and perhaps a minimal decrease in visual acuity. Some patients may need only a periodic short course of systemic steroids, whereas others require long-term maintenance therapy. Antacids or other antiulcer medications and calcium supplements can be given to patients, particularly those receiving long-term therapy. We routinely give ranitidine, 150 mg once or twice a day, to all our patients receiving oral prednisone for any length of time.

Alternate-day therapy is certainly a logical goal to aim for because side effects of such administration are much less than those with daily dosing. Fauci7 has suggested that one way to attain this is to double the daily maintenance dosage and then slowly reduce the alternate-day dosage by 5 mg

Table 7-2  Common immunosuppressive agents used systemically to control intraocular inflammatory disease

*It is important to note that the dosages should ultimately be determined by a treating physician with experience using these medications on the basis of the medical state of the patient in question. Further, not all of these medications (or the route of therapy indicated) have been approved by various governmental agencies (i.e., U.S. Food and Drug Administration) for use in patients with uveitis. Therefore the physician needs to inquire about their specific use.

until zero is reached. In our experience those patients with severe inflammatory disease or persistent macular edema often do not do well with alternate-day therapy, but it still remains a logical goal. It is important to stress the method outlined by Fauci, because it has been our experience in ophthalmology that the plan is rarely followed. If a patient is taking prednisone 20 mg/day and the decision has been made to attempt an alternate-day approach, then the treating physician needs to double the daily amount of prednisone from 20 to 40 mg/day and then begin a slow taper every other day.

How long does one treat? What is a reasonable long-term dosage? These are not easy questions to answer. Each patient’s requirements, capacities, and willingness for treatment are very different. Obviously the best dosage of steroid is none at all. However, being realistic, we believe that a reasonable daily adult maintenance dose is from 10 to 20 mg of prednisone, or as low a dose as is possible. This of course varies from patient to patient. For many patients with severe inflammatory disease we commonly see undertreatment, with therapy lasting only for 3–4 weeks followed by

a rapid taper. Unfortunately, this therapeutic approach is wishful thinking and will not work in many patients. We will not consider lowering the steroid dosage below 10– 20 mg unless the ocular disease appears quiescent for an extended period, usually about 3 months. In some diseases, such as sympathetic ophthalmia (see Chapter 23), we have elected to treat with maintenance dosages for at least a year, fearing a recurrence if therapy were stopped earlier. As a general tapering schedule, if the dose of prednisone is >40 mg/day, then one can reduce by 10 mg/day every 1–2 weeks; if the dose is between 20 and 40 mg/day, one can reduce by 5 mg/day every 1–2 weeks; if the dose is between 10 and 20 mg/day, one can reduce by 2.5 mg/day every 1–2 weeks; and if the dose is <10 mg, one can reduce by 1–2.5 mg/day every 1–4 weeks.29 As soon as it is clear that long-term (i.e., >3 months) therapy will be needed, we begin to think about adding a second agent (see below).

Intravenously administered ‘pulse’ corticosteroid therapy can also be employed. We have used this approach in patients who have a severe bilateral process that needs to be treated as rapidly as possible, administering 1 g of methylprednisolone intravenously and repeating daily for 3 days. Patients are hospitalized and examined by an internist before the administration of this therapy. It is not yet clear whether this method indeed renders better results than does giving a high dose of oral prednisone, such as 80 mg/day, but in our experience it certainly reverses an acute process very rapidly. This approach has been used to treat the Vogt–Koyanagi– Harada syndrome as well as the ocular manifestations of Behçet’s disease.30

The potential side effects of corticosteroids should be familiar to those giving the medication. Some of the more common secondary problems are seen in Box 7-1. Other adverse reactions have included nonketotic hyperosmolar coma in young nondiabetic patients receiving systemic corticosteroids for a short time,31 and central serous retinopathy.32

The effects of long-term corticosteroid administration are a constant concern. Polito and coworkers33 studied the growth of 10 boys with glomerulonephritis who received prednisone (1.2 mg/kg) every other day for at least 2 consecutive years. They found that in six patients the peak growth velocity was delayed after age 15. However, after 16 years of age the growth velocity was significantly higher than expected and permitted these patients to reach their genetic height potential. We have also gained a heightened sensitivity to the development of osteoporosis with corticosteroid therapy. Corticosteroids affect many aspects of bone health, including calcium homeostasis, and sex hormones, which are inhibitors of bone formation, enhancing osteoclastmediated bone resorption and reducing osteoblast-mediated bone formation.34 The effects of steroids can be seen within the first 6 months of therapy. The prevalence of vertebral fractures in patients with asthma treated with corticosteroids for at least 1 year is 11%.34 Most experts will recommend 800 IU of vitamin D daily as well as 1500 mg of calcium. Exercise is important, and hormone replacement therapy can be considered in menopausal women. Finally, antiresorptive agents such as alendronate, etidronate, and risedronate should be considered, particularly if bone density studies demonstrate osteoporosis or if patients are receiving longterm steroid therapy.

Nonsurgical therapeutic options

Box 7-1  Secondary effects of corticosteroid therapy

FLUIDS, ELECTROLYTES

Sodium retention, potassium loss

Fluid retention

Hypokalemic alkalosis

Hyperosmolar coma

MUSCULOSKELETAL

Muscle weakness

Steroid myopathy

Osteoporosis

Aseptic necrosis of femoral and humeral heads

Tendon rupture

GASTROINTESTINAL

Nausea

Increased appetite

Peptic ulcer

Perforation of small and large bowel

Pancreatitis

DERMATOLOGIC

Poor wound healing

Easy bruisability

Increased sweating

NEUROLOGIC

Convulsions

Headaches

Hyperexcitability

Moodiness

Psychosis

ENDOCRINE

Menstrual irregularities

Cushingoid state

Suppression of growth in children

Hirsutism

Suppression of adrenocortical pituitary axis

Diabetes

OPHTHALMIC

Cataracts

Glaucoma

Central serous retinopathy

Activation of herpes (topical)

OTHER

Weight gain

Thromboembolism

A question that must be constantly asked is whether the desired effect warrants the potential or real side effects. There is no easy answer, and a dialogue between the patient and the physician is the only way this question can be addressed. Although corticosteroids remain the mainstay of therapy for uveitis, the condition in some patients is resistant to steroids. For those receiving long-term steroid therapy the risk of developing unacceptable side effects at the dosages that need to be given to control the disease are real. In those patients other immunomodulatory agents are added as steroid-sparing agents so that lower steroid doses (or none at all) can be used.

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