26

Macular Edema Associated with Ocular Inflammatory Diseases

J. Peter 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 (1–5). 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 uveitis-associated 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, 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, 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

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 (10–13). 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 (14–16). 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, 20–22). 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, 23–26). 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, 34–36). 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 (38–43). 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, 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).

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, 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, 52). The incidence and degree of cataract progression appears to be related to the duration of follow-up and the number of injections (26). It is important to note that these numbers are consistent with the rate of cataract progression with sub-Tenon’s injections of TA (26). In a randomized, controlled trial, Gillies et al. found that cataract surgery was performed in 29% of the eyes treated with IVTA compared with 5% in placebo (51). A recent review put the overall risk of endophthalmitis at 0.3% per injection, or 0.9% per eye, but noted that the risk varied based on technique. A distinction was also made between true bacterial endophthalmitis and “pseudo-endophthalmitis,” thought to be an inflammatory reaction to the preservative (26, 53).

Implantable Corticosteroids

Intraocular sustained released fluocinolone acetonide delivery devices have demonstrated great promise at controlling intraocular inflammation, providing high local concentration with minimal systemic toxicity, and a duration of action of more than two years (31). In recent phase III trial results, the 34-week recurrence rate decreased from 51.4% preimplantation to 6.1% postimplantation, with 87% of eyes experiencing an improvement in visual acuity (VA) and decreased fluorescein angiography (FA) hyperfluorescence (54). Of patients with evidence of CME at baseline, 25% demonstrated a ≥3-line increase in VA at 34 weeks. Overall, the adverse event profile is similar to IVTA and other routes of corticosteroid administration, with 51.1% of eyes requiring ocular hypertensive therapy, 5.8% of patients requiring glaucoma surgery, and 9.9% requiring cataract surgery (54). Currently, the major prohibition to the FA implant is the cost, which can exceed US$20,000 (31). However, one must take into consideration the cost of systemic medications employed in the management of uveitis, which often is significantly higher over the duration of the implant. In addition, one needs to consider the adverse events associated with systemic therapy compared to those associated with the implants. Longer term clinical trials are underway to evaluate the costs and benefits of this effective and longer acting, but expensive, therapy.

The dexamethasone delivery system (DDS) represents another promising therapeutic option. It consists of a biodegradable copolymer of lactic acid and glycolic acid that safely biodegrades in the eye over time, releasing a steady concentration of dexamethasone. A recent trial reported the results of a single 700 ug application of dexamethasone with promising results in patients with CME secondary to various causes, including uveitis (30, 55).

Traditional Nonsteroidal Immunomodulatory Therapy

Though corticosteroids are often the initial treatment in patients with intermediate and posterior uveitis and related CME, their long term use is seriously limited by their systemic side-effects (56–58). Nonsteroidal immunomodulators are often introduced in order to decrease the daily corticosteroid dose to acceptable systemic levels (less than 10 mg per day of prednisone or equivalent) (23, 56). These alternatives to corticosteroids can be classified into traditional immunosuppressive agents and the newer biological agents. The traditional agents are the antimetabolites, alkylating agents, and T-cell inhibitors. These agents are the most common second-line agents due to their long history and safety record, though they all have the potential for serious side effects, including bone marrow toxicity and neoplasm. The use of these medications is directed at the control of the underlying disease state. They would rarely, if ever, be used for the treatment of isolated CME in the absence of inflammation. This review will focus on those with proven benefit in the treatment of CME.

Antimetabolites

Methotrexate, azathioprine, and mycophenolate mofetil are the three main antimetabolites used in the treatment of uveitis (23, 56–59). Methotrexate is often used in the treatment of anterior uveitis associated with juvenile idiopathic arthritis and the seronegative spondyloarthropathies (60, 61). Its use in posterior and intermediate uveitis is institution-specific, but some believe that it should be the first line corticosteroid-sparing agent (23, 56, 62). Mycophenolate mofetil has largely replaced use of azathioprine due to its similar mechanism and efficacy and better side effect profile. There are several reports of its efficacy and safety in uveitis; however, there is insufficient evidence to support the role of antimetabolites in managing uveitic CME (63–65).

Alkylating Agents

Cyclophosphamide is rarely used except in severe cases of treatment-resistant uveitis, scleritis, ocular cicatricial pemphigoid, and ocular inflammation due to Wegener granulomatosis (23, 56, 57). Chlorambucil may also be useful in severe, treatment resistant ocular inflammation, especially in patients with Behcet’s-related uveitis (56, 57). Both agents suffer from severe systemic side effects including bone marrow suppression, teratogenicity, and risks of malignancy (23, 57).

T-Cell Inhibitors

Cyclosporine and tacrolimus have received much attention for the treatment of noninfectious posterior uveitis due to their inhibition of IL-2 in the inflammatory cascade. There are ­multiple reports of their efficacy in intermediate and posterior uveitis (23, 56). Low-dose cyclosporine is often considered as a first-line therapy, occasionally in conjunction with low-dose corticosteroids, in patients with ocular inflammation, such as birdshot chorioretinopathy (57). The advantage to tacrolimus is that it can be titrated to clinical effect, minimizing the side serious side effects of renal impairment, hypertension, and metabolic abnormalities that plague these therapies; however there are not as many reports of its use in uveitis (23, 57). Recent work has investigated the possibility of local delivery of T-cell inhibitors in these patients, whether by intravitreal injection or deep scleral implant (23). Sirolimus is a noncalcineurin T-cell inhibitor recently developed. It has shown early benefit in the treatment of uveitis, though the data are early and more validating work is needed (66).

Voclosporin is a newer generation of calcineurin inhibitor that is currently being investigated in three phase-3 ­randomized clinical trials as a potential therapeutic agent for controlling active posterior uveitis, intermediate uveitis, panuveitis, or anterior uveitis, or as an agent that can maintain the uveitis in remission after it has been controlled by corticosteroids or another immunomodulatory agent. Resolution of macular edema associated with the uveitis will be evaluated in the studies as one of the parameters of bioactivity of voclosporin.

Biologic Agents

There has been much recent interest in the role of biological agents in the management of uveitis (56–58, 61–62, 67–76). These agents are promising due to their selective inhibition of target mediators in the inflammatory cascade. The majority of the research has been in tumor necrosis factor (TNF) antagonists and the role of interferon, and in patients with therapy-resistant CME (23).

Biologic Agents: TNF-α Antagonists

There is good rationale for the use of TNF-α inhibitors in uveitis, based on their success in multiple rheumatologic diseases (23, 61, 67, 76). The efficacy of infliximab has been demonstrated in several recent reports on the treatment of anterior and posterior uveitis, with anatomic and functional improvement in eyes with chronic, refractory CME (56, 67, 71, 76). There is also growing interest in adalimumab due to the fact that it can be administered subcutaneously, every one to two weeks (23). It has demonstrated promise in JRA and ocular Behcet’s disease, though its role in treatment of CME in the absence of inflammation is unknown (77–79).

Biologic Agents: Interferon-α

IFN therapy has demonstrated similar efficacy to TNF-α antagonists in intermediate and posterior uveitis, especially in patients with ocular involvement due to Behcet’s disease, though the lack of head-to-head trials makes comparison difficult (23, 56, 57, 80–82). The main differences are in the route of administration and side-effect profile (23, 70). IFN-α-2 a is the most common formulation, and is given by subcutaneous injection. Side effects, including a flu-like syndrome, are severe enough to discontinue therapy in approximately 5% of patients (23).

Vascular Endothelial Growth Factor Antagonists

There is good reason to believe that VEGF antagonists may play a role in the treatment of uveitic CME. VEGF concentrations are higher in the aqueous of patients with uveitic CME than in that of patients with uveitis but no CME (12). Further, bevacizumab has already demonstrated efficacy in treating CME secondary to central retinal vein occlusion (CRVO) and diabetes. (83, 84) Cordero Coma et al. recently published the first report of intravitreal bevacizumab for treatment of uveitic CME, which demonstrated anatomic but not functional improvement (85). A second small case series reported similarly disappointing results (86). While these short-term safety and efficacy studies provide less than compelling clinical results, given the experience with bevacizumab and other VEGF antagonists in the treatment of diabetic macular edema (DME) and age-related macular degeneration (AMD), this therapy merits further evaluation in larger, randomized ­controlled trials (84).

Biologic Agents: Other

Rituximab is an anti-CD20 (B-cell antigen) monoclonal antibody that was developed for the treatment of B cell lymphomas, but has emerged as a promising therapy for a number of T cell-mediated autoimmune diseases, including rheumatoid arthritis, lupus, and Wegener granulomatosis; however, thus far its use in uveitis is limited to case reports (87, 88).

Several interleukin family mediators have received interest as potential therapeutic targets. Daclizumab is a monoclonal antibody against IL-2, which has shown mixed results in the treatment of resistant noninfectious intermediate and posterior uveitis (23, 56, 72, 89, 90). Its role in the primary treatment of uveitic CME has not been studied. Both anakinra (an IL-1 antagonist) and tocilizumab (an IL-6 receptor antagonist) have shown early promise in the treatment of rheumatologic disease, but neither has been evaluated in uveitis.

Abatacept is a CTLA-4 blocker that has been evaluated in patients with rheumatoid arthritis, but not in uveitis (87). There have also been a few published reports on the use of octreotide in uveitis and uveitic CME with promising results, in small studies (68, 74, 91). The authors emphasized the need for further study.

Following a report that trace microalbuminuria was associated with patients with uveitis and patients with CME, but not those without, van Kooij et al. investigated the potential efficacy of lisinopril in the treatment of uveitic CME (92, 93). In one of the few decent sized (n ∇ 40) randomized, double-blind, placebo-controlled trials in the field, they concluded that lisinopril had no effect on inflammatory CME or visual acuity, though it did lower blood pressure and decrease morning urinary albumin excretion (93).

Surgical Management

The literature on the use of vitrectomy for the treatment of uveitic CME has spanned more than twenty years (15, 94). Becker et al. recently reviewed the subject and found 44 articles published through early 2005; however the lack of standardization of inclusion/exclusion criteria, outcome measures, and follow-up limited the analysis, and there were no randomized controlled trials at the time (95). Nevertheless, the authors were able to draw some conclusions from the study. First, they concluded that pars plana vitrectomy (PPV) is indicated for the treatment of structural complications of uveitis, including cataract, retinal detachment, and epiretinal membrane. They found insufficient evidence to conclude that vitrectomy had an independent visual benefit in CME apart from the removal of debris in the vitreous. Second, as most of the literature focused on intermediate uveitic syndromes, the positive outcomes reported overall seem to generalize to these entities, but conclusions on specific syndromes were more difficult to make. They also noted that pediatric patients may respond especially well, an outcome confirmed in a recent retrospective study (96). Third, they noted that PPV was usually associated with visual improvement, though it was difficult to separate the effect of PPV from frequent concomitant surgical procedures such as cataract extraction. Fourth, no firm conclusions could be drawn regarding the disease modifying effect of the PPV, though there was some evidence that PPV decreased inflammation in some patients through removal of stimulants. Finally, the authors suggested that when the evidence for PPV from other etiologies of CME is included, it affirms the suggestive trend in the data that PPV may benefit some patients with uveitic CME. Without further comparative studies between PPV and medical therapy, however, it is impossible to work out the appropriate role of PPV in the management of uveitic CME.

Since that publication, Tranos et al. published the first prospective, interventional, randomized, controlled study on the effect of PPV on chronic CME associated with uveitis (97). They reported the results in 23 eyes of 23 patients with CME secondary to chronic intermediate or posterior uveitis unresponsive to medical treatment. 12 were randomized into a surgical group who underwent PPV, and 11 had standard medical therapy. Vision improved by two or more lines in 50% of the surgery group as opposed to 18% of the medical group, which was statistically significant despite the small sample size. There was also a trend for angiographic improvement in the vitrectomized eyes, though this was not statistically significant. It is important to note, however, that 66% demonstrated no angiographic improvement after 6 months of follow-up, again raising the question of the confounding effect of the vitreous clearing effect of PPV. The authors did not find a significant difference in the need for systemic medications between the two groups in the six months following randomization. This pilot study demonstrated the potential efficacy of PPV in chronic uveitic CME in a prospective, randomized controlled trial, and confirms the need for larger prospective ­trials in the future.

The current indications for vitrectomy are decreased visual acuity in chronic CME, visual obstruction from vitreous debris, macular pucker, retinal detachment, and proliferative tractional retinopathy (22, 98). PPV has demonstrated benefit for patients with these ocular complications of chronic uveitis (95). It may have further benefit as primary treatment of both uveitis and uveitic CME due to its role as a depot of inflammatory mediators, though this effect has yet to be convincingly demonstrated. Longer term, larger studies are needed to confirm this effect and comparative studies are needed to determine the appropriate role of vitrectomy in the management of these patients.

CONCLUSION

The management of uveitis associated macular edema can be frustrating and challenging for the patient and provider, but much work is currently being performed to provide superior treatment alternatives for this complex condition. Table 26-2 lists the currently ongoing clinical trials for the management of uveitis and/or uveitic CME demonstrating the diversity of therapeutic strategies being explored. There are two research questions that will impact the future management of uveitis associated CME. First, how can we better control the underlying uveitis syndromes? Many of the trials in Table 26-2 are targeting uveitis, rather than CME, as primary outcome measures. As new therapies are developed to better treat the various forms of ocular inflammatory disease, the incidence of associated CME may decrease. However, even with controlled uveitis we know that CME can occur and lead to visual loss and blindness. Thus, the second question is: in the patient with isolated CME, among all of the new biological molecules, delivery vehicles, and surgical options being explored, what is the optimal strategy to control a given patient’s CME, balancing efficacy, tolerability, convenience, and cost?

This review attempted to provide a broad consensus on the current answers to this second question. Figure 26-1 displays a typical management algorithm for a patient with uveitis-associated CME. For unilateral CME, local or regional therapy is preferred, with corticosteroids often as first-line, though biologics and VEGF antagonists may demonstrate utility as first-line agents. In cases of bilateral (or severe) CME, either local or systemic therapy (or a combination) may be used, depending on disease characteristics. In many cases, there are a plethora of treatment options with few demonstrating clear superiority (most often due to lack of adequate trials). As new therapies are developed, head to head trials are necessary to definitively guide therapeutic decision making. Until then, uveitis specialists will need to balance the hope in newer therapies with demonstrated efficacy of the better established options. With the many ongoing clinical trials, participation in a trial ought to be an option discussed with patients, especially for those who are poorly controlled and at high risk for vision loss.

TABLE 26-2 ONGOING CLINICAL TRIALS FOR UVEITIS AND/OR UVEITIC CME^a

Stay updated, free articles. Join our Telegram channel

Join