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 Table of Contents  
Year : 2017  |  Volume : 29  |  Issue : 1  |  Page : 4-8

Update on clinical characteristics and management of uveitic macular edema

1 Department of Uveitis and Ocular Pathology, Sankara Nethralaya, Chennai, Tamil Nadu, India
2 Department of Ophthalmology, Sri Ramachandra University, Chennai, Tamil Nadu, India
3 Department of Retina, Ispahani Islamia Eye Institute and Hospital, Dhaka, Bangladesh

Date of Web Publication19-Jun-2017

Correspondence Address:
Jyotirmay Biswas
Department of Uveitis and Ophthalmic Pathology, Sankara Nethralaya, Chennai - 600 006, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/kjo.kjo_52_17

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Cystoid macular edema is a complication of uveitis which can lead to severe visual impairment if left untreated. Uveitic macular edema occurs when the balance between the water entering the eye and pumped out of the eye is altered thus losing equilibrium in the physiologic function of the retina. Edema has a negative impact on visual recovery in patients with uveitis and may continue to exist despite control of uveitis. This delayed resolution of edema observed clinically and by imaging is most frequent following intermediate uveitis, birdshot retinochoroidopathy, sarcoid uveitis, panuveitis, and iridocyclitis associated with human leukocyte antigen B27. Literature about management of uveitic macular edema is limited, and no consensus has been reached with regard to management protocol. Several treatment options exist including corticosteroids, nonsteroidal anti-inflammatory drugs, immunomodulatory agents, implants, and surgery. These therapies can be administered through various routes such as oral, topical, periocular, or intravitreal injections. A response to treatment is seen as decrease in macular thickness and improvement in visual acuity.

Keywords: Corticosteroids, cystoid macular edema, immunomodulators, uveitic macular edema, vitrectomy

How to cite this article:
Biswas J, Annamalai R, Islam M. Update on clinical characteristics and management of uveitic macular edema. Kerala J Ophthalmol 2017;29:4-8

How to cite this URL:
Biswas J, Annamalai R, Islam M. Update on clinical characteristics and management of uveitic macular edema. Kerala J Ophthalmol [serial online] 2017 [cited 2022 Jun 30];29:4-8. Available from: http://www.kjophthal.com/text.asp?2017/29/1/4/208490

  Introduction Top

Cystoid macular edema (CME) is one of the most common causes of permanent visual loss in uveitis. Anatomical and structural alterations can cause photoreceptor disruption and retinal disorganization thus decreasing central vision. Macular edema due to inflammation can occur in anterior, intermediate, posterior, or panuveitis. It may develop in idiopathic, autoimmune etiology, or be associated with other systemic diseases. Water balance and metabolism in the retina require a balance, and when this equilibrium between influx and efflux of fluid is lost, acute or chronic CME can develop. Therapeutic strategies should be aimed at controlling the inflammation and reestablishing homeostasis. The preferred modality of treatment is with corticosteroids (CSs) and nonsteroidal anti-inflammatory drugs (NSAIDs). Therapy with immunomodulatory drugs, biologics, anti-vascular endothelial growth factors (VEGFs), and pars plana vitrectomy (PPV) are being used increasingly now.

  Clinical Features Top

Uveitic macular edema (UME) is one of the common causes of vision loss in adult uveitis. Patients with macular edema can be asymptomatic or present with inflammation, swelling, and defective central vision.[1] Clinical examination is done using slit lamp biomicroscopy, direct or indirect ophthalmoscopy. An increase in thickness at the macula, loss of foveal reflex, and cystic spaces may be seen. Green light helps to visualize the edema and cystic spaces better. Subclinical edema is described as <300 μm and is better seen by imaging. Iridocyclitis, vitritis, retinochoroiditis, vasculitis, and disc edema can be associated features. Chronic CME can lead to epiretinal membrane (ERM) formation, and the patient may present with metamorphopsia.

UME occurs when the balance between the water entering the eye and pumped out of the eye is altered thus losing equilibrium in the physiologic function of the retina. This may occur in some diseases such as panuveitis, birdshot retinochoroidopathy, intermediate uveitis, sarcoidosis, and acute anterior uveitis due to human leukocyte antigen (HLA)-B27.[2] In the chronic stages of uveitis, CME can still occur due to atrophy or fibrosis when retinal cells have been irreversibly damaged. Contrast sensitivity, near vision reading, and speed of reading are affected more than distant visual acuity in patients with UME. These parameters need to be checked in the initial visit and during each review to follow-up on the progress of the disease. A persistence of edema can be seen long after the clinical and angiographic disappearance of uveitis. CME that results from immune recovery uveitis contributes to a major cause of visual loss in HIV-infected patients on highly active antiretroviral therapy.[3] A presentation of cytomegalovirus retinitis is associated with UME along with ERMs. In immune recovery uveitis, there is production of interleukin-12 (IL-12), and this causes more severe edema than observed in other types of uveitis.

In the pediatric population, the prevalence of UME has been reported as 30% at 3 years from initial presentation.[4] CME is not common in children probably due to higher resistance of tissues to external damage in younger age groups. Factors that would predict prognosis would be the stage of disease if acute or chronic, involvement of one eye or both, the duration of edema, the thickness of the macula, and visual acuity.

  Pathogenesis Top

Fluid accumulation may be secondary to increased vascular permeability and to dysfunctional inner or outer blood–retinal barriers. Inflammation is mediated by cytokines such as interferon-gamma, ILs, tumor necrosis factor (TNF), and prostaglandins.[5] Patients with UME have higher concentrations of VEGF compared to those without CME, and VEGF is known to induce vascular permeability. Chronic or persistent UME can cause irreversible damage to the photoreceptors and produce profound visual loss. Damage to inner nuclear and plexiform layers can result in macular edema, and when the retinal pigment epithelium (RPE) is affected, serous detachment or significant structural changes with the development of large cysts in the retina develop.[6] Loss of Muller cells can also cause decreased visual acuity but can be salvaged to an extent by restoring Muller cell activity and its pump mechanism.

There is a breakdown of the blood–retinal barrier. Infections and any form of trauma activate the innate and adaptive response. The extent of oxidative damage and immune response will determine the amount of healing or permanent damage. Inflammation can cause dysfunction of RPE which also contributes to fluid accumulation. The resulting macular thickening if left untreated leads to fibrosis. After this stage has been reached, treatment is futile, and no form of therapy can reverse the disease.

  Investigations in Uveitic Macular Edema Top

Optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) are the two most useful investigations to identify the amount of fluid, extent of leakage, and confirm the diagnosis of UME.

FFA is very useful to examine retinal perfusion and to detect vascular hyperpermeability. It will show a progressive leakage of dye in the macular region seen as increasing hyperfluorescence.[7] There is late accumulation of dye in the parafoveal cystic spaces giving a characteristic petaloid pattern [Figure 1]a and [Figure 1]b. There is no association between the amount of leakage and visual acuity, and FFA alone cannot be used to detect response to therapy.
Figure 1: (a) RPE alteration and mild swelling in the macula. (b) Hyperfluorescence in the macular region. Late accumulation of dye in the parafoveal cystic spaces giving a characteristic petaloid pattern

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OCT has several more advantages and is useful in UME after the blood–retinal barrier has been breached. It is noninvasive and provides high-resolution cross-sectional images of localized accumulation of fluid seen as increase in retinal thickness. It detects macular thickening even before CME is visible clinically or by angiography and correlates well with visual acuity [8] [Figure 2]a and [Figure 2]b.
Figure 2: (a) Accumulation of fluid with intraretinal cystoid spaces with increased foveal thickness. (b) Subside of fluid and decrease foveal thickness after getting treatment after intravitreal triamcinolone

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Its biggest advantage is that it measures the axial distribution of fluid, detects vitreomacular traction, subclinical serous retinal detachment, and identifies complications of chronic UME such as macular hole and ERM. Serous macular detachment has been reported in association with UME in 50% of patients.

Spectral domain OCT is helpful to assess the visual potential in UME. Disorganization of retinal inner layers, intraretinal cyst area, disruption of the ellipsoid zone, hyperreflective foci, and central subfield thickness when measured by spectral domain OCT show high levels of correlation with the visual acuity.[9]

A comparative analysis to judge the role of FFA and OCT showed that each was as useful as the other in patients with UME. Indocyanine green angiography and FFA together would help to study vasculitis, ischemia, neovascularization, and subretinal neovascular membranes. Vitreous fluorometry is not as frequently used but has been tried and reported as a reliable investigation in detection of UME in aphakia and pseudophakia.[10]

  Treatment Top

Treatment of uveitic CME has recently seen several trials and advancements. The complex nature of the disease requires prolonged treatment with combined therapy. The outcome of treatment is largely dependent on the age of the patient, the duration of CME, and the pretreatment visual acuity. Clear regimens for the treatment of UME have not yet been established. Anti-inflammatory agents in the form of CSs and NSAIDS are the mainstay of treatment.

  Nonsteroidal Anti-Inflammatory Drugs Top

NSAIDS are less harmful and very reliable alternatives to CS treatment. They act by inhibition of the cyclooxygenase enzymes and prostaglandin synthesis thus reducing inflammation.[11] NSAIDS can be administered as topical eye drops or as oral medications. Their use in isolation for UME may not be sufficient but when added to intravitreal injections of bevacizumab or triamcinolone acetonide, significantly improve visual acuity and reduce the central macular thickness. An improvement of vision is most noted with 0.1% nepafenac eye drops in idiopathic anterior uveitis and HLA-B27-associated uveitis.[12] Oral NSAIDs such as tablet indomethacin 50 mg once daily when used for a long duration have a similar effect to that of steroid periocular injections.

  Corticosteroids Top

CS are fast acting, efficient, and cheap compared to other modalities, and this makes them an initial choice after infections have been ruled out. They act by suppressing the constant release of inflammatory mediators, decrease vascular permeability, strengthen the epithelial tight junctions, and maintain the blood–ocular barriers.[13] An improvement in visual acuity can be noted as early as 6 days on OCT. Various routes are used for of delivery CS. Topical, periocular, intravitreal, oral, and intravenous routes of steroid administration are associated with well-known serious side effects both ocular and systemic. However, they provide immediate decrease in inflammation and quicker resolution of edema. Hence, the benefits of treatment have to be weighed against adverse effects especially while treating children and immunosuppressed. Topical preparation of 1% prednisolone acetate is used most often in UME. Topical difluprednate 0.05%, four times daily for 3 weeks, is a well-tolerated and effective treatment for noninfectious UME with decreased central foveal thickness, mild improvement in visual acuity, and elevation of intraocular pressure observed in a few patients.[14] Topical steroids are of more benefit in aphakia as the drug can reach the posterior pole more effectively.

Systemic oral CSs are given in the dose of 1 mg/kg/body weight of prednisolone, but the patient has to be monitored for ocular and systemic complications of steroids. They have an overall beneficial effect while treating uveitis and are particularly indicated in bilateral UME.

  Periocular Injections Top

This route of drug administration of CS is very useful because of local delivery, immediate action and has the advantage of fewer systemic side effects. They are indicated for asymmetric cases. They can be administered to the subconjunctival space, the orbital floor, or the retrobulbar posterior sub-Tenon's space.[15] The preparations used are methylprednisolone or triamcinolone 4 mg in 0.1 ml. It has been reported that there is an improvement in visual acuity which lasts for a month after treatment. Complications are rare with this procedure, but cataract, glaucoma, ptosis, globe perforation, optic nerve injury, hemorrhage, or occlusions can occur with repeated injections.

CSs are used in the form of intravitreal implants to treat persistent macular edema. The drugs used in these preparations are dexamethasone and fluocinolone acetonide. Postinjection analysis has shown that there is a reduction in macular thickness and an improvement in visual acuity, but the long-term efficacy has not been studied. The multicenter uveitis steroid treatment trial showed that fluocinolone acetonide implants when compared to systemic therapy produced greater reductions in macular edema at the end of 6 months.[16] Implants with a longer duration of action which can be inserted easily in patients with UME are under trial now. Similar results were obtained with dexamethasone implants and have been reported as beneficial.

  Intravitreal Triamcinolone Acetonide Top

Intravitreal triamcinolone acetonide is efficient in treating noninfectious UME in both children and adults.[17] However, both cataracts and glaucoma are common in both age groups.

  Intravitreal Corticosteroid Top

Intravitreal CS in the form of dexamethasone implant 0.7 mg (Ozurdex) has the advantage of high levels of drug concentration in the retina as it bypasses the blood–retinal barrier.[18] It achieves a sustained and longer lasting effect in both postsurgical and uveitic CME and is cost effective. The drug is released slowly over a 6-month period with levels peaking at about 2 months.[19] The efficacy of Ozurdex is of maximum benefit in the treatment of noninfectious posterior uveitis where localized targeted therapy is possible without causing systemic side effects. However, they are associated with ocular side effects such as cataract, glaucoma, endophthalmitis, and retinal detachment. It has been widely used in noninfectious intermediate and posterior uveitis [Figure 3].
Figure 3: Intravitreal corticosteroid in the form of dexamethasone implant 0.7 mg (Ozurdex)

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A suprachoroidal approach for CS injection using triamcinolone acetonide is being explored. It has the advantage of minimizing the anterior segment to steroids and lowers side effects as repeated injections are required in UME.

  Immunomodulator Therapy in Uveitic Macular Edema Top

Immunosuppressive drugs are used only when there is no response or intolerance with steroids. Systemic immunosuppressive drugs such as mycophenolate mofetil, azathioprine, methotrexate, and cyclosporine A are also used in the treatment of UME, especially in patients with an underlying systemic condition. Anti-TNF-alpha agents showed a greater improvement in vision and macular thickness when compared to conventional immunosuppressive agents. A maximum improvement in visual acuity was seen in 3 months, and a decline noted at the end of 12 months.[20] In those with an underlying noninfectious, systemic disease azathioprine, methotrexate and cyclosporine A have been tried with some success. Mycophenolate mofetil however did not show any benefit in UME. The role of intravitreal methotrexate is being evaluated. A new drug, tocilizumab, which is a humanized antibody binds to IL-6 receptors is under trial. It may find a role in the treatment of UME that has not responded to conventional therapy and biologics. Interferon alpha and beta have been used and are currently under trial with a bigger sample size.

  Anti-Vascular Endothelial Growth Factors Top

Intravitreal injections of bevacizumab provide short-term improvement of UME in patients resistant to other anti-inflammatory drugs.[21] In UME refractory to other forms of treatment, it is therapeutically beneficial either in isolation or in combination with intravitreal triamcinolone acetonide. Complete and sustained resolution of macular edema with a single intravitreal injection of aflibercept has also been used with some benefit in intermediate uveitis.

  Pars Plana Vitrectomy Top

PPV is an option when medical therapy fails. It is a highly recommended form of treatment in patients with uveitic CME as prolonged medical therapy which is required in the majority of these patients is associated with side effects.[22] It has a beneficial effect on the course of uveitis and associated CME especially when associated with vitreomacular traction or ERM. A marked improvement in visual acuity was noted along with reduction in fluid when compared to medical management. When PPV is combined with internal limiting membrane peeling and intravitreal triamcinolone, there is a transient improvement, but cataract and glaucoma are the side effects. The exact indication for vitrectomy in CME is not defined but it certainly helps in tapering the dose of immunosuppressive agents used in chronic CME. Concomitant systemic immunosuppressive therapy after vitrectomy provides long-term remission.

Alternate forms of therapies such as acetazolamide, hyperbaric oxygen, octreotide, and interferons can be tried if conventional treatment with anti-inflammatory agents fails.

Oral acetazolamide has been reported to be beneficial in about 25% of patients, but recurrence occurs after treatment is stopped.[23] Carbonic anhydrase inhibitors (CAI) act by actively transporting fluid from the retina across the RPE into the choroid. This reverses the polarity of ionic transport in the RPE and thus decreases edema. The improvement in vision is very limited with CAI and hence not a preferred mode of management.

Hyperbaric oxygen acts mainly on the inner blood–retinal barrier to reduce the edema, and its use is based on the belief that hypoxia plays a role in the pathogenesis of UME.

Laser photocoagulation produced best results in young patients who had a shorter duration of uveitis. The edema following grid showed reduction on FFA but did not produce any improvement in vision.

Octreotide, a somatostatin analog, has been reported to be useful in reducing UME but again recurrence has been noted. The dose is 100 mg of octreotide acetate as subcutaneous injections three times a week.[24] It has been found to be very effective in the treatment of CME. Somatostatin is an immunomodulator and acts by inhibiting vascular endothelial proliferation. It acts on the receptors present in the RPE and is an inhibitor of growth hormone.

Transconjunctival cryopexy of the peripheral retina reduces snow banking and neovascularization at the vitreous base along with decrease in CME. This finding in intermediate uveitis was noted even after treatment with laser photocoagulation thereby decreasing the need for CSs. The enlargement of laser scars can produce visual field defects, and this has to be considered during treatment of patients with failing vision.

  Conclusion Top

Progress of CME in uveitis is always unpredictable. It would depend on the stage, etiology, and duration of uveitis. Sometimes, several months of treatment may be required long after the active inflammation has subsided. In most patients, poor visual outcome is because of delayed initiation of treatment, and irreparable damage to photoreceptors has already occurred. Visual recovery following uveitic CME is influenced by the amount of residual fluid, the extent of resolution of edema, residual macular changes secondary to fluid accumulation such as photoreceptor damage, pigment epithelial detachment, and other sequelae. The most widely used intravitreal agents are triamcinolone acetonide a synthetic CS and bevacizumab an anti-VEGF agent. In chronic CME, it is recommended to treat even patients with full visual acuity because of the danger of destruction of photoreceptors. CME of <6 months duration with uveitis in the remission phase is associated with the best prognosis.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Yoganathan K. Cystoid macular edema secondary to immune recovery uveitis in a man with cytomegalovirus retinitis and AIDS. Clin Ophthalmol 2010;4:1065-7.  Back to cited text no. 3
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