Nonpseudophakic Cystoid Macular Edema

Introduction

Background

Although the most common cause of cystoid macular edema (CME) is due Ioirvine-Gass syndrome of CMEafter cataract extraction or other intraocular surgery, numerous other conditions are associated with the clinical appearance of fluid-filled, cystoid spaces in the macular region. CME is a final common pathway of many intraocular diseases, usually involving the retinal vasculature. The appearance can differ somewhat, depending on the etiology; however, CME can appear as a nonspecific clinical finding. If the cause of CME is not obvious, detailed ophthalmoscopy and, occasionally, ancillary testing may be necessary to identify the cause.

Pathophysiology

Macular edema is excessive fluid within the layers of the retina, distinct from the accumulation of fluid under or between the retinal layers (eg, subsensory fluid, serous retinal detachment). The amount of fluid normally present in the retina is maintained according to osmotic and hydrostatic pressures between the retina and the surrounding vasculature, which are compartmentalized by the blood-retinal barrier. A breakdown in the blood-retinal barrier allows for fluid to accumulate in cystoid spaces within the retina. Pathologic evidence of cell loss and Müller cell abnormalities may contribute to the resulting CME.

Several mechanisms have been proposed to explain how CME develops. The characteristic distribution of vascular leakage and retinal edema may be explained best by the diffusion of mediators (eg, prostaglandins) released in the eye. This theory is supported by evidence that cyclooxygenase inhibitors (eg, indomethacin, other nonsteroidal anti-inflammatory drugs) reduce the incidence of angiographic CME. However, this finding has only been shown conclusively in pseudophakic CME associated with surgical trauma to the anterior segment.

Another mechanism emphasizes the role of mechanical factors, such as tractional forces on the macula from disruption of the normal vitreoretinal interface. Even according to this theory, it is believed that local forces induce a release of mediators that lead to a breakdown of the blood-retinal barrier, resulting in the clinical appearance of CME.

Photic injury has been implicated in the development of pseudophakic CME; however, there is no scientific evidence that light damage to the retina causes CME.

Frequency

United States

Frequency of CME that is unassociated with cataract surgery varies widely, both in the United States and internationally, depending on the etiology or underlying condition leading to CME. The incidence figures vary because of the difficulty of observing subtle CME clinically, the surgeon bias in reporting CME, and the fact that fluorescein angiography (FA) or optical coherence tomography (OCT) that would detect CME is often not performed.

Mortality/Morbidity

CME from any etiology often leads to significant central visual loss, typically in the 20/40 to 20/200 range.

Race

No racial predilection has been associated with CME.

Sex

CME is distributed equally among males and females.

Age

Age of incidence of nonpseudophakic CME varies according to etiology.

Clinical

History

CME typically presents with a complaint of painless visual loss in one eye. It can be bilateral, depending on the etiology. The onset of symptoms is usually gradual; however, patients often only notice it suddenly, when they check one eye separately. Different causes of CME have different clinical presentations. The most common entities are discussed below.

• Diabetic maculopathy
• Diabetic maculopathy affects the capillaries in the macular region, leading to macular edema. Occasionally, a CME component of the macular edema develops, with cystoid changes in the foveal region. This is more common in cases of diffuse and chronic diabetic macular edema, and the vision may be reduced to the 20/200 level.
• When eyes with clinically significant macular edema (ie, edema overwhelming the homeostasis of the retina causing noticeable thickening) are treated early, before the onset of diffuse edema, CME possibly can be avoided if the patient maintains excellent control of the underlying medical problems.
• CME, in association with diabetic macular edema, has also been correlated to the presence of an attached posterior hyaloid, whereas patients with a posterior vitreous separation are much less likely to develop a component of CME. This may support a mechanical mechanism of the development of CME, where tractional forces induce the formation of cystoid spaces in the macula. Alternatively, the traction on the macula may lift the retina away from the RPE pump, causing CME. Occasionally, even in the absence of an attached posterior hyaloid, a preretinal membrane can exert tractional forces and lead to CME.
• Age-related macular degeneration
• Age-related macular degeneration (ARMD) can present in 1 of 2 forms: atrophic or exudative (dry or wet). Atrophic macular degeneration without exudative changes does not generally lead to CME. The exudative form of ARMD, with choroidal neovascularization, can cause a serous detachment of the overlying retina and resultant CME.
• CME is more common if the serous detachment of the macula has been present for 3-6 months or if the choroidal neovascular membrane has involved most of the subfoveal region. In such cases, the likelihood of restoring good vision is low.
• Retinal vein occlusions
• Retinal vein occlusion, a branch retinal vein occlusion (BRVO), or a central retinal vein occlusion (CRVO) can cause macular edema resulting from breakdown of the capillary endothelium associated with increased intravascular hydrostatic pressure. The damaged vessels leak fluid into the intercellular spaces, and, eventually, intraretinal cystoid spaces can be seen. This form of CME can be associated with further visual loss and usually results in some permanent visual loss if the situation persists for more than 6 months. However, it can improve with earlier resolution of the macular edema.
• Recovery of the macular edema can occur after laser therapy (even if the edema persists >6 mo) or with development of collateral vessels. Although laser grid photocoagulation has been shown to improve visual outcome in patients with BRVO, patients with CRVO do not appear to benefit from laser photocoagulation to treat macular edema. Although the edema may resolve, the visual outcome is unchanged.
• Newer approaches to treating macular edema associated with retinal vein occlusions include intraocular steroids and vascular endothelial growth factor (VEGF) inhibitors.
• Epiretinal membranes can cause surface wrinkling of the underlying retina resulting from contracture of the membrane. Occasionally, macular edema may develop due to distortion and traction on the surrounding intraretinal vessels. If the edema persists, breakdown of the intraretinal architecture can lead to cystoid spaces. This breakdown may be related to mechanical traction leading to edema, or it may be caused by the loss of apposition between the retina and the RPE pump. Ideally, surgical removal of a significant epiretinal membrane causing surface wrinkling retinopathy and macular edema reducing vision to the 20/60 to 20/80 level should be performed before irreversible CME develops.
• Choroidal tumors, such as malignant melanoma, choroidal nevus, or capillary hemangioma, have been associated with CME. These cystoid changes can occur overlying the tumor and in the macula, even when the tumor is located some distance from the macula, a phenomenon known as the Wise theory of macular accentuation. The source of CME at the level of the retinal capillary network results from intraretinal microvascular abnormalities resembling endothelial cell proliferation.
• Chronic uveitis, especially pars planitis, is associated with CME, most likely because of a breakdown in the blood-retinal barrier. The chronic inflammation disrupts the competence of the perimacular blood vessels, allowing for the development of the cystoid spaces. A clinical entity distinct from pars planitis has been described, characterized by CME, retinal periphlebitis, and vitreous inflammation. This condition typically is bilateral, affecting middle-aged women. Most patients maintain good vision over a prolonged time period.
• Radiation retinopathy, a condition of vascular damage from prior radiation treatment to the eye or orbit, can mimic diabetic retinopathy in its appearance. A form of macular edema often develops that is quite similar to diabetic macular edema and may manifest as CME.
• Perifoveal retinal telangiectasis or Coats disease typically presents with irregularly dilated and incompetent retinal vessels. These telangiectatic changes can occur at the level of the arterioles, venules, or capillaries. The closer the findings are to the macula, the earlier symptoms present. A clinical picture of CME may occur due to leakage from incompetent retinal vessels. Idiopathic juxtafoveal telangiectasis is a milder form of retinal telangiectasis, typically involving the temporal macula. CME is less common in this condition.
• CME without leakage on FA has been reported in middle-aged men on high doses of niacin for treatment of hypercholesterolemia.
• The presence of CME after successful retinal reattachment surgery has been reported to range from 30-43% during the first 4-6 weeks postoperatively. In aphakic eyes, incidence may be as high as 64%. Older patients are at a higher risk to develop CME after retinal detachment repair.
• CME has been reported after corneal relaxing incisions for astigmatism.
• CME after penetrating keratoplasty ranges from 20-43%. Aphakic eyes are at a much higher risk to develop postoperative CME. If an anterior vitrectomy was performed at the time of surgery, the risk of CME is 8-9 times more likely to occur.
• Retinitis pigmentosa (RP) is associated with CME. Studies have found an increased permeability of the retinal pigment epithelium (RPE) and perifoveal capillaries to fluorescein in eyes with RP. A study found an increased presence of circulating antiretinal antibodies in patients who presented with RP and CME. This suggests a possibility of an autoimmune process mediating the development of CME in patients with RP.
• Birdshot retinochoroidopathy presents with multiple, small, round or oval hypopigmented spots at the level of the choroid or RPE. Vitreous cells, disc edema, and leakage of fluorescein from retinal vessels are common features. CME can occur in conjunction with this condition.
• CME has been reported in association with orbital pseudotumor. The edema resolved after treatment of the orbital condition.
• Glaucoma treatment with latanoprost has been associated with the development of CME. The prostaglandin-like effect of latanoprost is believed to cause CME. CME typically resolves after discontinuation of the drug. In a study by Moroi et al of 7 patients with CME, after starting latanoprost therapy, all 7 patients had coexisting ocular conditions that may have placed these eyes at risk for prostaglandin-mediated blood-retinal barrier vascular insufficiency.
• CME has been associated with cytomegalovirus (CMV) retinitis in patients with the acquired immunodeficiency syndrome (AIDS) and immunocompetent patients. In some patients, CME develops specifically while the CMV retinitis resolves. A separate entity of CME has been described in patients with inactive CMV retinitis after immune recovery and improvement of their CD4 counts because of highly active antiretroviral therapy (HAART).
• CME inducing visual loss has been reported after the use of topical echothiophate iodide therapy.
• Retinal neovascularization and CME have been reported in patients with punctata albescens retinopathy.
• Dominantly inherited CME has been described as a macular dystrophy with an onset at middle age and a slow progression over ensuing decades. Pathologic studies of eyes with this condition suggest that the predominant changes occur in the inner nuclear layer and that this entity may present as a primary disease of the Müller cell.
• Foveal X-linked retinoschisis has been mistakenly described as CME.

Differential Diagnoses & Workup

Laboratory Studies

• Laboratory studies for CME vary depending on the presumed etiology of the edema.
• If findings suggestive of diabetes are present, the patient should have blood glucose testing or a glucose tolerance test.
• In the presence of uveitis, an appropriate evaluation for chronic uveitis should be initiated. See Uveitis, Evaluation Treatment for details.

Imaging Studies

• OCT is the criterion standard in the identification of CME. OCT is a noninvasive imaging modality that can determine the presence of CME by visualizing the fluid-filled spaces in the retina. The amount of CME can be monitored over time by quantifying the area of cystoid spaces on a cross-sectional image through the macula.
• Studies have reported OCT to be comparable to FA in the evaluation of CME, especially with newer, high-resolution OCT scanners. OCT is beneficial by quantifying the thickness of the retina and by allowing quantitative measurements of macular edema over time. This noninvasive method is especially useful in monitoring the response to treatment.
• Newer software for OCT has increased the resolution of this imaging modality and has led to the identification of specific patterns of CME.
• FA is an alternative imaging study to evaluate CME. Fluid accumulation may be delayed in certain conditions; thus, late phase fluorescein photos, sometimes as long as 20 minutes or more, may be required to properly evaluate the CME. Associated findings on FA may help determine the etiology of CME.
• If leaking microaneurysms are present in the setting of diabetic retinopathy, then diabetes likely is the cause.
• Vascular collaterals crossing the horizontal raphe on FA can help determine that the etiology of the edema (and retinal hemorrhages if present) is likely due to a vascular occlusion.
• The absence of leakage from CME on FA suggests a diagnosis of nicotinic acid retinopathy, Goldmann-Favre disease, or X-linked juvenile retinoschisis.
• FA also is helpful to verify the presence of CME when it is difficult to establish clinically.

Other Tests

• In the appropriate clinical setting, an electroretinogram may be indicated to confirm a diagnosis of RP with associated CME.

Procedures

• Occasionally, in cases of uveitis with associated CME, a diagnostic vitreous biopsy or vitrectomy can aid in determining the correct diagnosis. The vitreous fluid can be sent for the appropriate laboratory tests based upon the clinical picture. It is beyond the scope of this article to discuss the full laboratory workup for uveitis.
• In cases of orbital pseudotumor, an incisional biopsy for the purpose of confirming a diagnosis is indicated; however, CME rarely is associated with this condition.

Treatment

Medical Care

The treatment of nonpseudophakic CME varies greatly, depending on the etiology causing the edema.

• In drug-induced cases, such as CME associated with latanoprost, echothiophate iodide, or nicotinic acid, discontinuation of the drug usually causes reversal of CME.
• Topical steroids and nonsteroidal anti-inflammatory agents have been used in the treatment of CME, especially when associated with uveitis. Most studies have evaluated the efficacy of these drugs in the presence of pseudophakic CME after cataract surgery. However, the effect of these medications in stabilizing the blood-retinal barrier may aid in the treatment of other forms of CME.
• Injections of long-acting depot steroids (eg, triamcinolone) into the sub-Tenon space usually are more effective and commonly are used in the treatment of noninfectious uveitis. Peribulbar injections have a greater risk of intraocular injection than a subconjunctival approach; however, the drug delivery to the retina is superior when administered into the posterior sub-Tenon space.
• Intraocular triamcinolone acetonide has been found to effectively reverse CME in eyes with many conditions, including pseudophakic CME, retinal vein occlusions, diabetic macular edema, uveitis, and juxtafoveal telangiectasis. Clinical trials are underway to study the long-term benefit and safety of this treatment approach.
• Research implicates VEGF as an important mediator of vascular permeability and CME. Therefore, clinical trials are being conducted to evaluate the benefit of VEGF inhibitors in treating CME associated with different conditions, such as diabetic macular edema and retinal vein occlusions.
• Oral steroids also are a commonly used modality of stabilizing the blood-retinal barrier for the treatment of inflammation and CME in patients with intermediate or posterior uveitis. Oral steroids should be avoided unless necessary because of the associated complications of systemic use (eg, aseptic necrosis of the femoral head).
• When CME is associated with diabetic macular edema, focal laser photocoagulation according to the guidelines of the Early Treatment of Diabetic Retinopathy Study (ETDRS) should be followed (seeMacular Edema,Diabetic). However, CME in the setting of diabetic macular edema often suggests chronicity of the condition and will not respond adequately to laser treatment. Some physicians advocate the use of posterior sub-Tenon or intraocular injection of triamcinolone with or without macular laser photocoagulation to treat diabetic macular edema associated with CME.
• CME associated with choroidal neovascularization in ARMD is a secondary response to the presence of subretinal neovascularization. It is present most commonly in eyes with significant subsensory fluid in the macula and a poor prognosis for central vision. Fortunately, current treatments of exudative ARMD reduce the incidence of disciform scarring and associated CME.
• Macular edema is a common cause of visual loss in eyes with BRVO or CRVO. CME also can be associated with this form of macular edema. Macular laser photocoagulation has been shown to be effective in improving vision in patients with BRVO for greater than 4 months duration and a visual acuity of 20/40 or worse. However, the Central Vein Occlusion Study (CVOS) did not show any visual benefit from laser photocoagulation in eyes with CRVO and macular edema.
• Intravitreal triamcinolone has been reported to be effective in reversing CME in BRVO and nonischemic CRVO. The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study, a clinical trial sponsored by the National Institutes of Health (NIH), is evaluating the benefit of intraocular triamcinolone acetonide in retinal vein occlusions.
• Concurrently, the Posurdex Study is evaluating the benefit of an injectable dexamethasone implant for the treatment of macular edema in retinal vein occlusions.
• Many other causes of CME are treated by addressing the underlying condition. CME associated with CMV retinitis is treated by managing the retinitis with antiviral agents (eg, ganciclovir, foscarnet, cidofovir).
• CME associated with immune recovery in patients with inactive CMV retinitis and a stronger immune system are treated with steroids, either oral or posterior sub-Tenon injection of long-acting depot steroids.
• When malignant intraocular tumors are associated with CME, the priority is to treat the tumor. Systemic malignancies, such as multiple myeloma, have been observed to be associated with CME. Systemic treatment of the myeloma is the priority and usually addresses the CME. However, sub-Tenon injection of steroid may enhance resolution of the CME in such cases. Depending on the nature of the disease, CME associated with intraocular tumors requires treatment of the tumor (eg, laser photocoagulation, cryotherapy, radiation, thermotherapy, enucleation).
• CME secondary to juxtafoveal telangiectasis in Coats disease has been shown to respond to laser photocoagulation, with resolution of the edema and improvement in visual acuity.
• Orbital pseudotumor is treated effectively with oral steroids, and, in the case reported to be associated with CME, the macular edema resolved with treatment of the orbital pseudotumor.
• Other forms of CME have been reported to respond to treatment with acetazolamide. CME after scleral buckling procedures, CME in some forms of uveitis, and CME associated with RP may respond to acetazolamide therapy.

Surgical Care

Surgical treatment is not available for CME. However, situations exist in which an ocular condition associated with CME can be treated with surgery.

• An epiretinal membrane can induce a surface wrinkling retinopathy with CME. Surgical removal of the epiretinal membrane often can result in resolution of the CME and improved visual acuity.
• The vitreomacular traction syndrome is caused by traction of the vitreous on the macula. It can manifest with CME, and relieving the traction with vitrectomy surgery often can lead to resolution of the macular edema. Some authors advocate performing a vitrectomy for the treatment of CME without evidence of obvious vitreomacular traction (usually in patients after cataract surgery). This approach may be beneficial in select patients.
• In cases of CME associated with Coats disease or peripheral lesions of pars planitis, cryotherapy to these peripheral areas of exudation can induce the cystoid macular changes to dry up.

Medication

The most common drugs used to treat CME include steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetazolamide.

Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Modify the body's immune response to diverse stimuli. Used to stabilize the blood-retinal barrier and to induce resolution of macular edema.

Prednisone (Deltasone, Orasone, Meticorten)

Used rarely for severe inflammatory conditions with associated CME. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity

Follow-up

Further Outpatient Care

• Typically, patients with CME are evaluated 1-3 months after intervention to evaluate the efficacy of treatment.

Complications

• Complications associated with the treatment of CME are infrequent. When a posterior sub-Tenon injection of triamcinolone is given, patients can occasionally experience a transient ptosis or subconjunctival hemorrhage. Retinal arterial occlusion after sub-Tenon steroid injections has been reported due to intravascular injection of the drug.
• Intravitreal triamcinolone has been associated with ocular hypertension, cataract progression, retinal tear or detachment, infectious and noninfectious endophthalmitis, and lens damage.

Prognosis

• Visual prognosis in eyes with CME depends on the etiology of the CME. If the CME resolves with treatment, visual acuity of 20/40 or better is common. However, in long-standing CME, vision is often 20/100 to 20/200.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize CME can lead to failure to diagnose an associated disease. This can severely limit the visual prognosis if the condition is treatable. Usually, a characteristic fundus appearance allows the ophthalmologist to recognize conditions associated with CME, such as diabetic retinopathy, branch vein occlusion, or an epiretinal membrane. However, in the absence of an obvious associated condition, especially in a phakic eye, care should be taken to rule out such pathology as uveitis or a tumor. Missing such a diagnosis can have devastating consequences.
• The use of commercially available triamcinolone acetonide is not approved for intraocular injection; however, triamcinolone acetonide is commonly used at the discretion of the treating physician as an off-label use. This use has become accepted clinical practice and has an acceptably low-risk profile. Nevertheless, specific ophthalmic preparations of triamcinolone and other long-acting steroid implants are being developed.

Multimedia

Media file 1: Fundus photograph of left eye with branch retinal vein occlusion and cystoid macular edema. Visual acuity was 20/50, and the patient was treated with a modified grid laser photocoagulation and posterior sub-Tenon injection of triamcinolone.

Fundus photograph of left eye with branch retinal vein occlusion and cystoid macular edema. Visual acuity was 20/50, and the patient was treated with a modified grid laser photocoagulation and posterior sub-Tenon injection of triamcinolone.

Media file 2: Fundus photograph of nonproliferative diabetic retinopathy with clinically significant macular edema and cystoid macular edema.

Fundus photograph of nonproliferative diabetic retinopathy with clinically significant macular edema and cystoid macular edema.

Media file 3: Fluorescein angiogram of same eye as in Media file 2, revealing both cystoid macular edema and leakage from microaneurysms associated with diabetic retinopathy.

Fluorescein angiogram of same eye as in Media file 2, revealing both cystoid macular edema and leakage from microaneurysms associated with diabetic retinopathy.

Media file 4: Ocular coherence tomographic image of cystoid macular edema in a patient with uveitis.

Ocular coherence tomographic image of cystoid macular edema in a patient with uveitis.

Media file 5: Cystoid macular edema in patient with diabetic retinopathy.

Cystoid macular edema in patient with diabetic retinopathy.

Media file 6: Eye in previous image with diabetic CME after injection with 4 mg of intravitreal triamcinolone.