Fig. 1
Ozurdex implant imaged in the vitreous immediately following injection in a patient with multifocal choroiditis
Ozudex was approved by the US FDA in 2010 as first-line therapy in the treatment of macular edema associated with noninfectious intermediate and posterior uveitis [50]. Drug diffusion and clearance from the vitreous cavity is more rapid in vitrectomized eyes; studies show the effect at 3 months is only maintained in a third of vitrectomized eyes which had improvement in CME at 1 month. Due to risk of migration into the anterior chamber and subsequent corneal decompensation, the implant should not be used in aphakic vitrectomized eyes [51].
A randomized clinical trial demonstrated excellent results in the reduction of vitreous haze for patients with noninfectious intermediate uveitis; however, the mean improvement in macular edema dissipated before 26 weeks, suggesting the need for reinjection to treat CME [52]. Other reports suggest the implant is effective at treating refractory uveitic ME refractory for a period of 3–4 months with most patients requiring repeat implants within 6 months for recurrent CME [51, 53].
Multiple implants were required in 63 % of eyes in one retrospective observational study of patients with active noninfectious uveitis, 91 % of which had CME, over a 17-month period [54]. The response to repeat Ozurdex implantation mirrors that seen after a single injection; improvement in visual acuity and macular edema is observed after 1 month. The effects of repeated injections have shown to be cumulative, with long-term improvement in best-corrected visual acuity and stabilization of central retinal thickness over 24 months [54].
Although studies suggest no statistically significant increase in the rate of cataract formation between treatment and sham patients following one dexamethasone implant [52], one study did report development of posterior subcapsular opacity following a third injection [54]. Lowder et al. described <5 % incidence of IOP ≥ 30 mg Hg following a single Ozurdex implantation, with no eyes requiring surgical intervention [52]. However, there is some evidence that, in clinical practice, IOP elevation secondary to the dexamethasone implant may be greater than that reported in the registration trials [55, 56].
Retisert
In 2005, the FDA approved a nonbiodegradable intraocular sustained-release implant containing fluocinolone acetonide (Retisert, Bausch and Lomb) for use in the treatment of noninfectious intermediate, posterior, and panuveitis [57] (Fig. 2). The implant is designed to deliver 590 μg of fluocinolone acetonide over a 2–3-year period with minimal systemic absorption [58, 59]. The device is surgically anchored to the pars plana in the operating room under sterile conditions and can be monitored in the office through the dilated pupil (Fig. 3).
Fig. 2
Retisert pellet and strut before implantation. This is the currently available implant
Fig. 3
Retisert imaged in position. Note the ability to see the pellet properly positioned on the strut. This is the model of implant that is no longer available, because of issues with pellet strut separation
A large multicenter trial has demonstrated a reduction in uveitis recurrences from 51 to 6 % over 34 weeks with improvement in visual acuity [60]. Further, the proportion of eyes with a reduction in CME was greater for implanted eyes (86 %) compared to nonimplanted eyes (28 %) at 1 year, and this effect was maintained at 3 years [58].
In another report, 92 % of patients using systemic medications to control intraocular inflammation were able to reduce their dose following implantation, and all eyes with preoperative CME had statistically significant reduced retinal thickness at 6 and 12 months [61]. In a randomized controlled parallel superiority study comparing the fluocinolone implant with systemic therapy, 46 % of the patients in the implant group with macular edema experienced resolution of CME compared to only 23 % of systemically treated patients [62].
Data from three large registration trials revealed that, over a 3-year treatment period, 74.8 % of eyes receiving a fluocinolone acetonide implant required intraocular pressure lowering therapy. Approximately 50 % of eyes experienced an IOP >30 mmHg, commonly occurring within the first year following implantation. Surgical intervention was required in one-third of patients based on uncontrolled IOP, visual field, or disk changes [60, 63, 64]. Baseline visual field testing and optic nerve imaging are therefore recommended for patients undergoing fluocinolone implant surgery [63]. The fluocinolone acetonide implant carries a nearly 100 % incidence of cataract progression [60, 64]. Studies have demonstrated the feasibility and success of combined cataract extraction with IOL insertion at the time of fluocinolone acetonide implantation [61].
Additional risks of implant surgery include vitreous hemorrhage, hyphema, retinal detachment, and endophthalmitis [61]. Spontaneous separation of the medication pellet from its attachment is a rare but potential complication that may require surgery [65–67]. Complications such as retinal commotio, retinal tear, and endothelial failure due to dislocation of the pellet into the anterior chamber have also been reported [66, 67].
Anti-vascular Endothelial Growth Factor Medications
Vascular endothelial growth factor (VEGF) has been found in the aqueous humor of patients with uveitis and plays a role in the loss of vascular integrity which ultimately causes CME [4, 68, 69]. VEGF expression is induced by inflammatory mediators and cytokines which are produced and abundantly present in the eyes of patients with uveitis [4, 68]. Further, VEGF concentrations have been shown to be higher in patients who had CME associated with uveitis as compared to those without CME [69].
The use of intravitreal anti-VEGF therapies bevacizumab and ranibizumab has recently been described as off-label treatment for inflammatory CME; however, their effects in this setting are not well established and results have been inconsistent [12, 70–76]. Numerous studies have observed statistically significant decrease in central retina thickness on optical coherence tomography [71–74], while others report limited to no change [75, 76]. One reason for this may be that anti-VEGF agents have not been shown to display anti-inflammatory properties, and therefore, studies which included patients with active uveitis at the time of treatment may have underestimated their effect on CME [75, 76].
Mackensen et al. showed statistically significant reduction in macular thickness beginning as early as 2 weeks following a single bevacizumab injection for patients with controlled uveitis but breakthrough CME refractory to steroid therapies. These effects, however, were sustained for only 6–8 weeks, and repeat injections were required [73]. Lott et al. observed a 40 % worsening of vision and no improvement in central retinal thickness for eyes treated with intravitreal bevacizumab only; however, most of the patients in this series had active uveitis at the time of treatment [75].
Acharya et al. demonstrated a positive effect of monthly ranibizumab injection in eyes with controlled uveitis and persistent CME in a small prospective, noncomparative, interventional case series [71]. Improvement in macular edema occurred as early as 1 week and was maintained at 3 months in all eyes. Approximately 60 % of eyes required repeat injection, and these results were preserved 3 months after cessation of treatment [71].
The ideal dosing and sequence for intravitreal anti-VEGF agents in the treatment of inflammatory CME has yet to be determined; however, their length of effect is shorter than for periocular or intravitreal steroid therapies [77]. These agents are much less likely to cause glaucoma or cataract progression compared to steroid therapies; however, serial injections (every 5 weeks) in patients with macular degeneration were shown to lead to sustained elevation of IOP in 3.5–4.5 % of patients following a mean of 20 injections [78]. Mild anterior uveitis has been reported as an adverse side effect following 0.14–1.57 % of bevacizumab injections and 1.38 % with ranibizumab [79, 80].
Intravitreal Methotrexate
Methotrexate (MTX) is a folate antagonist designed to competitively inhibit dihydrofolate reductase which is required for cellular proliferation [81]. It has long been used as a systemic immunomodulatory therapy. MTX has been increasingly used to treat various ophthalmic conditions both locally and systemically.
The off-label use of intravitreal methotrexate to treat uveitic cystoid macular edema was examined in a few small studies [82–84]. In one prospective case series, patients with unilateral active, noninfectious uveitis or inflammatory CME were given intravitreal injections of MTX (400 μg/0.1 ml). A rapid reduction in inflammation and macular thickness was observed within 1 week. Visual acuity improvement of at least two Snellen lines was achieved in 87 % of patients at 3 months. While the inflammation tended to relapse after 4 months, the reduction in macular thickness was maintained at 6 months in all patients where OCT was able to be performed [82].
Other reports have described promising results of intravitreal methotrexate on the control of uveitis with or without CME [84, 85]. One study describes its use for the treatment of refractory unilateral retinal vasculitis due to Behçet disease in patients intolerant of corticosteroids or in whom they were contraindicated [84]. Study eyes underwent monthly intravitreal injections of MTX until remission of intraocular inflammation and/or stable visual acuity was achieved. Increase in visual acuity by three or more Snellen lines was observed in 85 % of study eyes following an average of four injections. Intravitreal MTX therapy resulted in a decrease in aqueous humor levels of IL-6 and IL-8 in treatment eyes [84]. IL-6 has been associated with breakdown of the blood-retinal barrier in uveitic disease, while IL-8 is a mediator of the innate immune response and is thought to play a role in altered vascular permeability [86, 87]. Significant reduction in the levels of these cytokines was associated with clinical improvement in 87 % of eyes [84].
A larger, multicenter, international retrospective case series evaluated eyes with active uveitis or uveitic CME treated with intravitreal MTX. Following one injection, 79 % of eyes entered a period of remission averaging 17 months. Of those who relapsed after one injection, 87 % entered a period of extended remission following a second injection. There was an overall average reduction in macular thickness maintained over a range of 10–30 months. Half of the patients receiving oral corticosteroids at the time of TX injection were able to successfully reduce steroid doses following intravitreal MTX [85].
Based on limited available data, intravitreal MTX may be a reasonable and effective option for patients with active unilateral uveitis and/or inflammatory CME who are known steroid responders or those in whom an elevation of IOP could be immediately detrimental.
Subcutaneous Interferon Alpha
Interferon alpha (IFN) is a cytokine belonging to the subgroup of type I interferons that exert strong antiviral, antiproliferative, and various immunomodulatory effects [88]. The interferons influence both innate and adaptive immune responses and have been successful at treating Behçet disease and multiple sclerosis [89]. They are approved for the treatment of viral hepatitis and myeloproliferative syndromes. In recent years, systemic interferon alpha has been reported to be very successful in the treatment of Behçet disease and other cases of refractory uveitis [90, 91].
Dueter et al. reported resolution of chronic macular edema in a small series of patients treated with systemic interferon-α. All patients had otherwise inactive uveitis with CME that had been persistent for an average of 36 months and had failed to respond to corticosteroids. All patients were treated with an initial dose of three to six million IU subcutaneously based on body weight which was tapered in a stepwise fashion. Stable complete remission of CME was achieved in more than half of patients [92].
Common side effects of interferons are dose dependent and include flu-like illness, nausea, fatigue, diarrhea, rash, anemia, elevated liver transaminases, leucopenia, alopecia, dermatitis, and mild depression [93]. Some patients will develop neutralizing antibodies which render them unresponsive to this treatment. Interferon therapy, like all other systemic therapies except the recently approved TNF inhibitor, adalimumab, has not been US FDA approved for the treatment of uveitis.
Antitumor Necrosis Factor Alpha Medications
Tumor necrosis factor alpha (TNF α), one of the proinflammatory cytokines found to occur at high levels in eyes with uveitis, activates T cells and macrophages, thereby increasing the expression of endothelial adhesion molecules and other proinflammatory cytokines [94, 95]. Inhibition of TNF α provides an attractive opportunity for more targeted anti-inflammatory therapy.
Murphy et al. were the first to demonstrate efficacy of TNF inhibition in the treatment of refractory noninfectious posterior uveitis [96]. Several case series have reported resolution of coexisting CME following TNF-alpha treatment for noninfectious uveitis; however, their use must be weighed against the risk of possible side effects [97–101]. TNF inhibitors are increasingly used for the therapy of posterior uveitis and retinal vasculitis, and more data will likely be available regarding their effects on uveitic macular edema. As well, other biologic therapies are being used in the treatment of uveitis, and data on their efficacy is gradually becoming available. Adalimumab received US FDA approval for the treatment of adults with noninfectious intermediate, posterior, or panuveitis in June, 2016, making it the first FDA-approved non-corticosteroid therapy for uveitis. Data regarding its effects on CME in patients in the registration trials is not yet available.
Choosing the Right Treatment
The decision regarding how to approach the treatment of inflammatory CME should include a careful assessment of individual clinical factors. The first priority must always be to quiet the inflammation, followed by restoration of normal structural integrity. Therapy differs depending upon laterality, severity, coexisting conditions such as cataract and glaucoma, history of steroid response, systemic comorbidities, and patient age. Local therapy may be more appropriate for unilateral disease, while systemic medications are often favored for bilateral conditions. Pseudophakic patients with mild disease and normal intraocular pressure may be treated with topical or periocular steroids; phakic patients should be counseled on their risk of cataract progression. Refractory cases or those who develop a steroid response should be considered for alternate therapy. For patients with moderate to severe disease who would like to avoid systemic immunosuppression or in whom such therapy is contraindicated, steroid implants may be the preferred option. For patients on systemic therapy in whom intraocular inflammation is active at the time of CME diagnosis, adjustments to dosing or frequency of immunomodulatory therapy may be all that is required. In some patients, systemic therapy may need to be initiated.
Care must be taken when treating children with steroid therapy. The risks of developing cataract and glaucoma with topical or local steroid therapy may be higher in children, and the significance of these diagnoses also carries more weight in children. Intraocular pressure and optic disk health must always be monitored in children with uveitis, especially those treated with steroid therapy. Alternative treatment measures should be sought if signs of glaucoma are observed.
Finally, the clinician should also be alert to the presence of structural abnormalities such as vitreomacular traction, epiretinal membrane, and gliosis of the internal limiting membrane (ILM) which can contribute to chronic macular edema that is refractory to medical therapies and which may require surgery.
Our expanding knowledge regarding the pathophysiology of uveitis and the advent of enhanced imaging modalities have improved our ability to diagnose and develop novel therapeutic approaches to manage inflammatory CME. Despite this, the treatment continues to be challenging. There is no single preferred approach, and therapy should be tailored to the individual. Early and aggressive treatment is recommended to give the best potential for visual recovery.
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