Lana M. Rifkin, MD

Uveitis is defined as intraocular inflammation with potentially various causes. It is classified as anterior, intermediate, posterior, or panuveitis, based on the location of inflammation. Uveitis accounts for about 10% of legal blindness in the United States.¹ The most common cause of significant vision loss in patients with intraocular inflammatory disease is cystoid macular edema (CME), which occurs in more than 30% of uveitis patients.² Choroidal neovascularization (CNV) can also occur as a consequence of uveitis, but less commonly, in 2% to 3% of uveitis patients.³

Uveitic CME can occur in any type of uveitis. It is most commonly a sequelae of panuveitis, where more than 60% of patients get CME, followed by intermediate uveitis, which causes approximately 30% of uveitic CME. Ten percent to 15% of patients with anterior uveitis can also suffer from CME.⁴ CME may persist despite quiescence of uveitis and can lead to irreversible visual compromise if not adequately treated. The current gold standard for treating CME is corticosteroids. Topical steroids and nonsteroidal anti-inflammatory agents may not be effective in uveitic macular edema. Thus, oral steroids or injection of steroid into the subtenon or intravitreal space are often offered. Common side effects of steroid injection, which may be limiting for some patients, are intraocular pressure elevation and cataract progression.⁵ Oral steroids may cause significant side effects of weight gain, blood sugar fluctuations, psychiatric side effects, bruising, and osteoporosis, among others.⁶

The pathophysiology of uveitic CME is not completely understood but is postulated to be a consequence of increased vascular permeability. It has been suggested that vascular endothelial growth factor (VEGF) may be implicated in the pathogenesis of uveitic CME. Indeed, increased VEGF concentration has been observed in the aqueous humor of patients with uveitic CME when compared to uveitis patients without CME.⁷ Intravitreal VEGF levels have also been measured in uveitis patients and, in comparison, the mean concentrations of VEGF in the vitreous of diabetic patients are 5.5 times greater than that of patients with uveitis, as compared to a healthy control group, in whom the levels of VEGF are zero. Intraocular VEGF levels detected in the vitreous of patients with uveitis are similar to those described in patients with neovascular age-related macular degeneration.8

With these discoveries, anti-VEGF agents such as bevacizumab, ranibizumab, and aflibercept have begun to be employed in resistant cases of uveitic CME or CNV or in cases where corticosteroids are otherwise contraindicated. Large multicenter trials evaluating the safety and efficacy of intravitreal anti-VEGF, particularly when compared to triamcinolone injection, for uveitic CME and CNV have not yet been undertaken but several small studies and case reports do exist, noting the use of anti-VEGF agents as an alternative or perhaps adjunct to steroid therapy. However, these reports and series are retrospective in nature and have various limitations.

Bevacizumab in Uveitic Cystoid Macular Edema and Choroidal Neovascularization

Bevacizumab (Avastin), a recombinant humanized monoclonal antibody, was the first clinically available anti-VEGF agent used, albeit off-label, for the treatment of resistant-to-standard-therapy CME and CNV secondary to ocular inflammatory disease.

The earliest report of intravitreal bevacizumab for the treatment of uveitic macular edema (Figure 12-1) was in 2007, with Cordero Coma et al⁹ reporting that 62% of patients with CME secondary to intraocular inflammation showed an improvement in visual acuity after a single injection of bevacizumab. Intravitreal bevacizumab treatment was also shown to be fast acting and effective in the treatment of refractory macular edema in uveitis patients in another small pilot study.¹⁰ A decrease in central retinal thickness was seen within 2 weeks in some patients; however, improvement in visual acuity did not always correlate as these patients had long-standing CME, causing photoreceptor damage, and intravitreal bevacizumab was used as a last-resort measure. Additionally, the effect was transient and repeat injections were necessary. In contrast, that same year, Ziemssen et al¹¹ indicated that the response to intravitreal bevacizumab was weak and transient. In their report, none of their 6 patients with chronic macular edema as a sequelae of uveitis had significant improvement in visual acuity or a decrease in central retinal thickness. It was postulated that perhaps acute and previously untreated uveitic CME may respond more favorably.

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