Interventions for the treatment of uveitic macular edema: a systematic review and meta-analysis
HAART therapy was started at month 6 and macular oedema with reduced vision was noted by month 8. described, and there are reports of iritis8 in patients on intravitreal cidofovir. . Uveitis and Macular Edema: A Complex Relationship. So much of uveitis happens in the draining lymph nodes and doesn't happen in the eye Uveitis and Macular Edema: A Complex Relationship. HANNOVER, Germany — Response to vitrectomy in uveitis varies according to the type vitrectomy (PPV) for cystoid macular edema (CME) in different forms of uveitis, Uveitis and Macular Edema: A Complex Relationship.
The duration of the sustained release is shorter than with the fluocinolone acetonide implant. The HURON study data showed the dexamethasone implant significantly improved visual acuity 15 or more letters and reduced inflammation with a relatively good safety profile. A subgroup analysis for patients with persistent ME greater than 90 days showed that the overall study results applied to this group as well. The evidence is suggestive that intravitreal dexamethasone implants may be developed to become a viable intervention for uveitic ME.
The two implants were equivalent in their ability to prevent recurrence of non-infectious uveitis, improve visual acuity, and reduced inflammation, but that the side effect profile was more favorable for the dexamethasone intravitreal implant.
Systemic Corticosteroids Oral prednisone is often used to treat patients with significant vision-threatening uveitis bilateral inflammatory ME and for ME refractory to topical treatment. When this stage is reached, steroid-sparing medications are started and the corticosteroids are tapered slowly. OCT studies have documented a more rapid decrease of ME with oral than with periocular corticosteroid treatment, making oral therapy the preferred route for some clinicians, especially if rapid recovery is essential.
Acetazolamide and Somatostatin Analogues Acetazolamide is a carbonic anhydrase inhibitor. One sub-type of carbonic anhydrase, known as isoenzyme IV, is thought to be a membrane-bound fraction found in the atypical region of the RPE cell. Inhibition of carbonic anhydrase reduces aqueous production and possibly also reduces leakage from the RPE.
However, patients under 55 years appeared more likely to benefit from treatment than older patients. Elevated liver enzymes, pain, and gastrointestinal distress have also been reported.
Octreotide is a somatostatin analog that works as a potent inhibitor of growth hormone releases as well as release of certain other agents. Studies suggest that somatostatin is synthetized by RPE housing receptors.
VEGF is an endothelial cell-specific mitogen, an angiogenic inducer, and a highly potent agent favoring retinal vascular permeability. The data on anti-VEGF efficacy in inflammatory ME are primarily derived from small clinical series and anecdotal reports based on a limited number of patients. In most cases, bevacizumab was injected into eyes with persistent ME, and quiescent uveitis.
Three reports comprising 51 eyes, showed a significant but transient reduction in central retinal thickness in most patients. Possible explanations include contamination of the medications with bacterial endotoxins, formation of antibodies against immunogenic anti-VEGF molecules, and leaching of contaminants from disposable syringes, packaging materials or impurities.
Whether patients with uveitis have an increase risk on developing uveitis as a result of anti-VEGF activity remains to be further examined. Due to the transient nature of anti-VEGF intraocular injections, this treatment modality is less suitable for ME in active chronic uveitis, and more practical in patients with persistent ME and quiescent uveitis. Given the safety profile of anti-VEGF further prospective randomized intervention studies of longer follow-up and larger sample size are needed before this agent can be broadly recommended as a treatment for uveitic macular edema.
Immunomodulatory Drugs Immunomodulatory drugs have been explored in the management of uveitis complicated by macular edema with a view to greater efficacy and for an opportunity to reduce side effects from corticosteroids. There are no randomized controlled trials towards the efficacy of these agents in treatment of uveitic ME. The most common endpoint reviewed in the studies that do exist has been to reduce the use of systemic costicosteroids and to achieve a remission of uveitis.
One study focused on ME in 19 uveitic patients who were unresponsive to standard immunosuppressive therapy and were then treated with mycophenolate mofetil. Many immunologic biologics are attractive treatment options because they offer a targeted suppression of immune effector response. In autoimmune diseases, INFs appear as double agents, involved in both supportive and suppressive action.
Side effects wee common and dose dependent.
Patients commonly experienced flu-like symptoms, fatigue, and increased liver enzymes. Severe depression has also been reported. The authors suggested that the mode of action of INFs in improving macular edema might be enhancement of the barrier function of the vascular endothelium. High intraocular levels of TNF have been observed in experimental autoimmune and human uveitis.
Etanercept is considered pro-inflammatory in the eye and is not recommended for use in patients with uveitis.Cataract Surgery - Tip for Improved Results
It goes without saying that these agents require further study before being considered safe or effective treatment options, but immunologic agents represent an exciting new frontier. Intraocular Immunosuppressive Therapy Intravitreal Methotrexate was given in 15 eyes to treat ME, 12 of 15 patients completed the final follow-up.
At 6 months both mean visual acuity and macular thickness improved. Vitamin E Nussenblatt et al reported no effect over month follow-up for 4 months of IU of vitamin E as an intervention compared to placebo.
Incidence of Visual Improvement in Uveitis Cases with Visual Impairment Caused by Macular Edema
Macular Grid Laser A case series of 6 eyes where macular grid laser was used to treat uveitic macular edema showed that best corrected visual acuity improved significantly for one eye, was stable in 3, and deteriorated in 2. Theoretically, the case for PPV in inflammatory ME is sound since many inflammatory mediators accumulate in the vitreous and a removal of these mediators may have good effect on ME.
In addition, fibrosis of the vitreoretinal interface occurs often and may result in the formation of epiretinal membranes, and subsequently, macular edema. The presence of an epiretinal membrane is a known factor associated with medical treatment failure Removal of this membrane can help to reduce ME.
In practice, results a not clear cut. The control of the uveitis is critical to prevent and treat the ME.
Despite new treatment options, and expanding knowledge on the pathophysiology of inflammatory ME, treatment remains challenging.
Uveitic Macular Edema: Treatment Update
Uveitis is a heterogeneous, relatively uncommon condition. As such it is difficult to conduct prospective randomized clinical trials. Clinical judgment and our understanding of the disease process suggest that more aggressive treatment earlier in the disease process, improves results.
Being mindful of, and striving to prevent the permanent structural changes and subsequent macular atrophy which regularly develop in patients with long-standing ME will generally lead to better results. Because of the unpredictable outcome, many potential pitfalls, and the need for sometimes, prolonged costly treatment which may have significant side effects patient counseling is imperative. Patients with uveitis can sometimes be paralyzed by the complexity of the choices presented to them, and often fail to accurately understand the significance of their condition, the mechanism their medications work through, need for compliance, and nature of adverse effect profiles.
The most important aspect of the discussion regarding different treatment options, and something that should be clear to all clinicians as they consider treatment options is the natural history of the condition without adequate treatment.
Traditionally, modern treatment of uveitic ME has been achieved mainly through immunosuppression with steroid therapy. The dexamethasone implant has duration to 3 to 5 months, and may currently represent the most promising long acting steroid based implant option.
Intravitreal triamcinolone acetonide is less potent than dexamethasone, but can last 3 months or longer. Because of their relatively high cost, and the fact that neither their efficacy or safety profiles have been well established, it would be prudent to reserve these agents for truly refractory cases, preferably at centers for uveitis so that further knowledge can be effectively gathered.
PPV offers potential for select cases with pathologic vitreoretinal interface and deserves further investigation in clinical trials. In unilateral ME in which structural changes can be demonstrated, treatment with PPV should be entertained before long-term treatment with immunosuppressive drugs is initiated.
Several papers acknowledged that despite best efforts, there is no way of differentiating treatment-induced disease quiescence from spontaneous disease remission.
Thus, current interventions are typically long duration and slow withdrawal. All patients need continued observation. As we gain more experience and follow-up with the newer treatments that have become available, outcomes should improve. The medical literature provides tools for clinical judgment, but as yet no clear silver bullet for therapy.
Treatment plans may rely on clinical judgment until better data and more definitive treatment options are available. Footnotes Raquel Goldhardt declares that she has no conflict of interest. Bradley Simon Rosen Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. Update on treatment of inflammatory macular edema. Ocular immunology and inflammation. They propose an algorithm for the treatment of uveitic macular edema pointing out the individual risk-benefit ratio when systemic immunosuppressive therapy is used.
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Nonsteroidal anti-inflammatory drugs in ophthalmology. Bromfenac alone or with single intravitreal injection of bevacizumab or triamcinolone acetonide for treatment of uveitic macular edema. Intravitreal triamcinalone acetonide for refractory uveitic cystoid macular oedema: Comparison of the efficacy and safety of different methods of posterior subtenon injection. Periocular triamcinolone acetonide injections for cystoid macular edema complicating noninfectious uveitis. Triamcinolone-induced intraocular pressure elevation: Other causes of visual impairment in uveitis include glaucoma, optic nerve involvement, vitreous opacification from the inflammatory response, and cataract formation usually attributed to both the disease process and chronic steroid use.
The exact pathology of macular edema is complicated and uncertain. The autoimmune theory is acceptable in patients who have been identified as genetically susceptible to uveitis. Inner and outer blood—retinal barrier breakdown in the central retina due to prolonged or severe inflammation leads to macular edema. The retinal vascular endothelium changes with activation of adhesion molecules and lymphocytes.
The fluid is predominantly located in the outer plexiform layer, as seen on OCT scanning. Development of an epiretinal membrane is also a consequence of chronic macular edema. Thus it is important to treat macular edema early. Further chronic macular edema may become more difficult to treat. Refractory macular edema usually occurs in patients with chronic or recurrent uveitis. Epidemiology Most of the epidemiological data is related to developed countries.
The estimated annual incidence of uveitis is 17—52 cases perUveitis is predominately a disease of adults between 20 and 60 years. The mechanism of action of steroids involves the inhibition of prostaglandin and leukotriene synthesis, as well as downregulation of cell adhesion and major histocompatibility molecules. However, it is associated with systemic side effects. Long-term use of steroids can cause peptic ulceration, osteoporosis, and necrosis of the hip, weight gain, muscle weakness, hyperglycemia, and systemic hypertension, progression of glaucoma, and progression of cataracts.
Less commonly, intravenous methyl prednisolone is used typically at much higher doses than that given orally, such as — mg doses repeated over 2—3 days. Forms of periocular injections include subconjunctival, orbital floor, and sub-Tenon. A steroid-filled syringe is advanced with the bevel facing towards the globe, superotemporally along the curve of the globe.
The needle is advanced until the hub touches the conjunctiva. The plunger is slightly withdrawn to rule out injecting steroids within a vessel. Conjunctiva along with Tenon is lifted approximately 10 mm away from the limbus using blunt serrated forceps. A gauge cannula is inserted and advanced 3 mm within the episcleral space.
The cannula is advanced about 12—14 mm in the sub-Tenon space with the stylet withdrawn. The syringe is then loaded with the steroid and injected.
It has been used to treat macular edema from a variety of other etiologies, including retinal vein occlusion, diabetic retinopathy, pseudophakic CME, and exudative macular degeneration. It is injected into the vitreous using an injector. Dexamethasone is then released over 3—6 months. It can be inserted in the clinic, in contrast to nonbiodegradable implants, which require a surgical procedure in the operating theater.
It is licensed in the US for posterior uveitis. The implant itself is a 1. The implant is surgically placed into the vitreous cavity. Pharmacokinetic studies in rabbits have demonstrated the delivery of constant levels of the corticosteroid to the posterior pole.
Although there is a reduction in systemic side effects, there are significant local side effects, including increased intraocular pressure requiring filtration surgery and cataract progression. Carbonic anhydrase catalyzes the hydration of carbon dioxide to bicarbonate, which dissociates to form hydrogen ions and bicarbonate. One subtype of carbonic anhydrase is isoenzyme IV, which is thought to be a membrane-bound fraction found in the apical region of the RPE cell.
Inhibition of carbonic anhydrase reduces aqueous production and possibly fluid leaking from the RPE. It is a potent inhibitor of the release of growth hormone and other hormones.
Incidence of Visual Improvement in Uveitis Cases with Visual Impairment Caused by Macular Edema
It is most commonly used for the treatment of acromegaly, carcinoid tumors, and vasoactive intestinal polypeptide-secreting tumors.
Given the receptors are housed in the RPE, somatostatin may play a role in fluid and ion-transport balance. Somatostatin may also inhibit the immune response and have a role in controlling inflammation. Hence, octreotide has been hypothesized as a potential treatment for uveitic macular edema.
Aptamers are oligonucleotide ligands that are selected for high-affinity binding to molecular targets. VEGF has been shown to be an endothelial cell-specific mitogen, an angiogenic inducer, and is also known to increase retinal vessel permeability.