Macular Edema Associated with Ocular Inflammatory Diseases
Peter J. Campbell
Diana V. Do
Quan Dong Nguyen
Cystoid macular edema (CME) is one of the most common causes of visual loss in patients with ocular inflammatory disease or uveitis (1, 2, 3, 4 and 5). Due to the chronic nature of uveitic inflammation, CME can be especially difficult to treat, and uncontrolled CME can lead to macular scarring, irreversible visual loss, and blindness. The primary treatment for uveitisassociated CME is therapy of the underlying disease, which varies by uveitis syndrome, though adjunctive therapy targeting CME is often needed. Oral and periocular corticosteroids have represented the mainstay of treatment for years, though the introduction of intravitreal triamcinolone acetate and the development of modern nonsteroidal immunomodulatory and biologic therapies may change the way that this sight-threatening complication is managed in the years to come.
The incidence of CME depends on the anatomic location of the uveitis syndrome (2,6 and 7). The rate of CME is highest in panuveitis (66%), intermediate uveitis (60%), and posterior uveitis (34%). Uveitis entities commonly associated with CME are: pars planitis, Adamantiades-Behçet’s disease, sarcoidosis, juvenile rheumatoid arthritis (JRA), birdshot chorioretinopathy, and HLA-B27 associated uveitis. Approximately one in three uveitis patients will develop serious visual impairment or legal blindness in at least one eye (2,3 and 7). In the majority of cases, CME is responsive to therapy, though it often becomes resistant to treatment (8,9). Table 26-1 lists the frequency of CME and visual loss by anatomic location and etiology. CME can complicate the course of uveitis at any stage of disease, including when the uveitic inflammation has been controlled. Treating physicians must be aware of this complication and aggressively pursue the etiology of decreased vision in patients with uveitis as CME may develop even in the absence of overt inflammation (6,9).
TABLE 26-1 UVEITIS ASSOCIATED WITH CYSTOID MACULAR EDEMA (CME)a | |||||||||||||||||||||||||||||||||||||||||||||
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PATHOGENESIS
The pathogenesis of uveitis-associated CME remains unclear but probably implicates a number of inflammatory mediators leading to a transient breakdown of the inner or outer blood retinal barrier (BRB) and vascular leakage. The involvement of multiple mediators and cascades has been proposed, including: free radicals, serotonin, prostaglandins, histamine, bradykinin substance P, leukotrienes, TNFα, multiple interleukins (IL-1, IL-6, IL-8), multiple cell adhesion molecules (sICAM, sVCAM), interferons and IP-10, vascular endothelial growth factor (VEGF) and other factors (10, 11, 12 and 13). Several cytokines have been implicated in the disruption of the blood-ocular barrier, which is the likely mechanism of uveitic CME; however, the lack of good experimental models has made elucidation of the exact mechanism difficult (10,11).
The vitreous may also contribute to uveitic CME through several possible mechanisms. Vitreomacular traction may contribute to mechanical dysfunction of the inner BRB as vitreous fibers connect to the Muller cells in the macular areas, which are responsible for maintaining fluid balance in the retina, and are known to be swollen and damaged in CME (14, 15 and 16). Supporting this concept, it has been demonstrated that in patients with uveitis, eyes with posterior vitreous detachments are significantly less likely to experience macular damage (10,17). The vitreous may also act as a depot for inflammatory mediators, allowing longer lasting physiological effects. In certain uveitic syndromes, e.g. Vogt-Koyanagi-Harada disease and sympathetic ophthalmia, choroidal inflammation may also contribute to retinal and macular edema (10).
MANAGEMENT
The management of uveitic CME is primarily targeted at the control of the underlying inflammation. Therapy has historically consisted of anti-inflammatory medications (corticosteroids, nonsteroidal immunomodulators, targeted biologic agents), carbonic anhydrase inhibitors, and vitrectomy. Specific therapy is based on ocular involvement (unilateral or bilateral), degree of visual symptoms, associated systemic disease, previous response to medications, and a patient’s history and preference. Recent advances in management have been in the delivery methods of conventional therapies such as intravitreal injection and implantation of corticosteroids. Given the high side effect profile of corticosteroids over the long term, corticosteroid-sparing immunomodulators have received much interest. New biologic agents targeting specific mediators in the inflammatory cascade have been developed and have shown early promise. As our understanding of the pathogenesis of uveitis grows, new potential therapeutic targets, such as intercellular adhesion molecule (ICAM) inhibitors, are frequently identified and much recent work has been focused on finding less toxic, more convenient, and more effective treatments.
Nonsteroidal Anti-Inflammatory Drugs
Although prostaglandins have been implicated in the pathogenesis of macular edema, the role of prostaglandin inhibitors in uveitis is unclear. It has been conventional wisdom that nonsteroidal anti-inflammatory drugs (NSAIDS) such as topical ketorolac, are of benefit in pseudophakic and aphakic macular edema, but less so in uveitis; however, a recent systematic review failed to find convincing evidence for the use of topical NSAIDS in either acute or chronic CME of any etiology (6,18).
Acetazolamide
Carbonic anhydrase enzymes attached to the pigment epithelium facilitate fluid removal from the retina. Carbonic anhydrase inhibitors can accelerate this process and have played a role in the management of CME in a variety of conditions (19,20). Acetazolamide has been shown to benefit patients with aphakic CME but has often failed to control uveitic CME in trials (6, 20, 21 and 22). A recent long-term study demonstrated a benefit to low dose acetazolamide in uveitic CME but mostly limited to the subgroup of patients with no active inflammation (19). Given its recognizable but often tolerable side effect profile, acetazolamide probably represents an appropriate treatment option in cases of uveitic CME with controlled inflammatory activity, approximately half of whom can be completely weaned off all medications (19). Its benefit in more severe cases, or as adjunctive therapy with immunomodulators, is not well established.
Corticosteroids
Corticosteroids have represented the mainstay of treatment for sight-threatening uveitis (9, 10, 23, 24, 25 and 26). They can be administered orally, topically, periocularly, intravitreally, or via steroid implant. The advantage to corticosteroids is their broad anti-inflammatory effect and rapid onset of action. Corticosteroids act on several pathways involved in intraocular inflammation and decrease both the cellular inflammatory response as well as the degree of vascular leakage (27,28). The effect of corticosteroids on the retinal vasculature is dose-related, favoring the trend towards local therapy with the highest intraocular concentrations. Local therapy, whether periocular injection, intravitreal injection, or intraocular implant, has the further advantage of minimizing the systemic side effects of corticosteroids. Unfortunately, high intraocular concentration of steroids raises the incidence of ocular side effects, predominantly elevated intraocular pressure (AOP) and cataract (24).
Oral Corticosteroids
Oral corticosteroids are utilized in the management of many uveitic syndromes and associated disease states. In the management of CME, oral prednisone is preferred in patients with bilateral uveitis or severe unilateral inflammation resistant to local or regional steroids. A recent trial comparing sub-Tenon’s corticosteroid injection (for unilateral CME) versus a short course of oral corticosteroids (for bilateral CME) found that the short course of oral corticosteroids results in significantly faster visual recovery, suggesting a possible role for oral corticosteroid in conjunction with sub-Tenon’s injection in unilateral cases (29,30). Patients who require high doses of systemic steroids for longer periods of time are often considered for immunosuppressive therapy with a nonsteroidal immunomodulator to decrease the risk of developing the myriad complications of systemic steroids.
Topical Corticosteroids
Topical corticosteroids are used most often in the treatment of anterior uveitis, less commonly in intermediate uveitis, and rarely for isolated uveitic CME (31). Effectiveness is limited by suboptimal posterior segment penetration and complicated dosing regimen. The combination of topical corticosteroids and topical NSAIDs can provide synergistic effects in managing CME and can yield better efficacy than either class alone. Given the high ocular morbidity of persistent macular edema, there should be a low threshold for use of periocular, intravitreal, or systemic therapy in patients with complicated or recurrent CME associated with anterior uveitis (7).
Periocular Corticosteroids
Periocular steroid injections have played a key role in the management of intermediate and posterior uveitis (32). The periocular approach provides a large bolus of steroid at the site of inflammation with extended duration of efficacy and minimal systemic toxicity. The sub-Tenon’s approach has been favored over the orbital floor approach due to its proximity to the macula (10,33). The majority of patients respond well to periocular corticosteroid injection; however patients may become resistant to therapy (26, 32, 34, 35 and 36). Complications of periocular injection include globe penetration, cataract, and increased intraocular pressure. A study of 53 patients by Dafflon et al. found that 23/64 eyes (36%) experienced an increase in IOP >8 mm Hg compared to baseline, with 6 (9%) requiring surgery (32). Though intravitreal injection has been gaining popularity in recent years, there is a paucity of randomized controlled data and risk-benefit analysis to confirm its superiority over periocular administration; the periocular approach will most likely remain a part of the management algorithm of macular edema (37).
Intravitreal Corticosteroids
Efficacy of intravitreal injection of steroids has been demonstrated in treating numerous intraocular complications, including choroidal neovascularization (CNV), often in conjunction with other therapies such as VEGF antagonists or photodynamic therapy, proliferative vitreoretinopathy (PVR), and CME from multiple etiologies (38, 39, 40, 41, 42 and 43). Although triamcinolone acetonide (TA) is most commonly used, other types of steroids, such as dexamethasone, can also be injected intravitreally. The clinical effect is usually seen for 8 to 12 weeks (for TA), though repeat injections are almost always necessary, which raises the risk of adverse events (26,44 and 45). On the other hand, intravitreal
TA (IVTA) often succeeds in controlling CME in patients who have failed other therapies and may justify the increased risk of intravitreal injection in these patients (26). The majority of patients with treatment-resistant uveitic CME respond rapidly to IVTA, though many will eventually relapse (26,40, 45-48). Patients who require chronic therapy for control of the underlying inflammation can often be weaned off (or to lower doses of) systemic corticosteroids and immunomodulators (49).
TA (IVTA) often succeeds in controlling CME in patients who have failed other therapies and may justify the increased risk of intravitreal injection in these patients (26). The majority of patients with treatment-resistant uveitic CME respond rapidly to IVTA, though many will eventually relapse (26,40, 45-48). Patients who require chronic therapy for control of the underlying inflammation can often be weaned off (or to lower doses of) systemic corticosteroids and immunomodulators (49).
The main adverse effects include elevated IOP, cataract, and a small risk of endophthalmitis. Increased intraocular pressure is common following IVTA injection (44,45,50 and 51). IOP elevations >21 mm Hg (absolute) are seen in 30% to 50% of patients, and can occur months after initial therapy (26,52). In most cases, the IOP elevation can be treated with topical medication, though some (<10%) may require filtering surgery (45,51 and 52). The incidence and degree of cataract progression appears to be related to the duration of follow-up and the number of injections (26
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