Fundus photo of the right eye in a patient with cystoid macular edema.
Cystoid macular edema (CME) is a painless condition in which swelling or thickening occurs of the central retina (macula) and is usually associated with blurred or distorted central vision. Less common symptoms include metamorphopsia, micropsia, scotomata, and photophobia.
CME is a relatively common condition and is frequently associated with various ocular conditions, such as age-related macular degeneration (ARMD), uveitis, epiretinal membrane, vitreomacular traction, diabetes, retinal vein occlusion, medicine-related, or following ocular surgery. When CME develops following cataract surgery and its cause is thought to be directly related to the surgery, it is referred to as Irvine-Gass syndrome or pseudophakic CME.
Postcataract CME is usually self-limited, but for chronic CME or in cases of multiple recurrences, photoreceptor damage with permanent impairment of central vision may result.
The primary cause of cystoid macular edema (CME) depends on the underlying disease process, but most pathways eventually lead to vascular instability and breakdown of the blood-retinal barrier. The Müller cells in the retina become overwhelmed with fluid leading to their lysis. This results in an accumulation of fluid in the outer plexiform and inner nuclear layers of the retina. Diabetes and retinal vein occlusion can both lead to CME by causing vascular instability directly (vascular endothelial cell damage). Alternatively, CME associated with uveitis or following cataract surgery is most likely caused by the cytokines released by activated inflammatory cells. These molecules lead to breakdown of the blood-retinal barrier and capillary leakage.[1]
In the inflammatory pathway, the enzyme phospholipase causes the release of arachidonic acid. Subsequently, cyclooxygenase converts arachidonic acid to prostaglandin. Prostaglandins can cause breakdown of the blood-retinal barrier, including vasodilation, increased capillary permeability from compromise of tight endothelial junctions in the retinal capillaries, and decreased removal of fluid by the retinal pigment epithelium (RPE). The enzyme phospholipase can be inhibited by steroids and thereby blocks the formation of prostaglandins and their effects. The cyclooxygenase pathway is specifically inhibited by aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs).
Another product of arachidonic acid breakdown involves the enzyme lipoxygenase, which alternately converts arachidonic acid to leukotriene, a chemotactic agent. The exact role of leukotriene in CME remains unclear, and, currently, no lipoxygenase specific blocking agents are approved for use in the treatment of CME.
Patients with systemic disorders, such as diabetes or renal failure, may develop CME from breakdown of the blood-retinal barrier primarily due to vascular compromise. In diabetes, endothelial cells are damaged by advance glycosylation end-products. In addition, cytokines, such as vascular endothelial growth factor (VEGF), accumulate in the vitreous cavity of diabetic patients and lead to capillary leakage. CME can also be caused by mechanical forces (ie, epiretinal membrane, vitreomacular traction) pulling on the retinal surface, leading to vascular compromise and breakdown of the blood-retinal barrier.
Patients with a history of retinal vein occlusion (RVO), epiretinal membrane (ERM), and even prostaglandin analogs were found to have increased rates of pseudophakic CME.[2, 3, 4]
Other ocular conditions, such as exudative ARMD, cause CME by the growth of neovascular membranes, which are inherently leaky.
United States
The incidence following cataract surgery (Irvine-Gass syndrome) of clinically significant CME with decreased vision is only 0.2-1.4% after modern phacoemulsification surgery. The frequency was more common in older types of cataract surgery, where CME could occur in 20-60% of patients. Using more sensitive methods to detect macular edema such as optical CT (OCT) current rates have been estimated between 4-40%.[5, 6]
A 2014 study by Hunter et al found the incidence of pseudophakic CME at 1.5% of those patients undergoing routine cataract surgery at an academic center, and, interestingly, 27% of these patients had a best-corrected vision of less than 20/20 even after resolution of the CME.[7]
The frequency varies when other comorbidities such as diabetes are included. For example, patients with wet ARMD typically have some component of CME. Diabetic macular edema is the most common cause of vision loss in patients with nonproliferative diabetic retinopathy, and patients with a history of diabetic macular edema have higher rates of macular edema following cataract surgery.[8] CME is also a common cause of vision loss in patients with uveitis.
International
Studies have reported a similar incidence of CME and Irvine-Gass syndrome worldwide.[9, 10, 11]
CME following cataract surgery, although usually treated medically, has been shown to often resolve spontaneously within 6 months. Ninety percent of eyes improve to a visual acuity of 20/40 or better in cases with a posterior chamber intraocular lens (IOL). However, remissions and exacerbations of macular edema can result in photoreceptor damage with permanent impairment of vision.
CME due to diabetes, retina vein occlusion, or chronic uveitis tends to be chronic with periods of remission and exacerbation.
No significant racial predilection exists.
No sexual predilection exists.
CME can occur at any age depending on the etiology. Advanced age has been reported as a risk factor for the development of Irvine-Gass syndrome.
The majority of patients who have pseudophakic CME eventually achieve vision of 20/30 or better. Other cases of CME can be chronic, requiring long-term treatment.
For excellent patient education resources, visit eMedicineHealth's Eye and Vision Center. Also, see eMedicineHealth's patient education article How to Instill Your Eyedrops.
Patients with cystoid macular edema (CME) usually present with decreased or blurry vision.
Patients presenting with CME often have a history of cataract surgery, diabetes, retinal vein occlusion, or uveitis. Medication history is important to rule out potential toxic maculopathy from such agents as niacin, Avandia (in diabetics) or fingolimod (Gilenya®). Topical prostaglandins have also been associated with pseudophakic CME.[12] The need to stop prostaglandin use prophylactically has not been established.[13]
Slit lamp biomicroscopy reveals blunted or irregular foveal light reflex, retinal thickening, and/or intraretinal cysts in the foveal region.
Additional examinations can help elicit the cause for CME.
For uveitis, evidence of intraocular inflammation manifested by anterior chamber cells and flare and vitreous cells may be present in some cases.
For epiretinal membrane/macular pucker, dilated fundus examination can help reveal the membrane on the retinal surface.
Retinal examination can reveal diabetic retinopathy associated with the diabetic retinal edema.
Optic disc edema is also classically present in Irvine-Gass syndrome.
The following risk factors resulting from previous ocular surgical procedures, systemic diseases, drug toxicity, and other eye conditions have been associated with cystoid macular edema (CME):
Persistent macular edema or multiple remissions and exacerbations can result in foveolar photoreceptor damage with permanent impairment of vision.
Laboratory studies are guided by the suspected etiology. Fluorescein angiography is useful to establish the diagnosis of Irvine-Gass syndrome and typically shows leakage from the optic nerve as well as petaloid leakage within the macula. Optical CT is useful for quantifying the amount of edema and to monitor response to treatment.
Fasting blood sugar, blood pressure, and lipid profile are indicated if diabetes or retinal vein occlusion is suspected.
Further workup for hypercoagulable state may be initiated based on the suspected etiology.
Fluorescein angiography (FA) remains the criterion standard in imaging to demonstrate the presence of CME. FA is able to detect the exudative fluid (dye) in the macula.
Optical coherence tomography (OCT) has rapidly become the most popular method to detect and follow CME. More specifically, high-resolution spectral-domain OCT (SD-OCT) has become increasing valuable and is used routinely to follow these patients.[14]
Note some patients have CME evidenced by OCT that is not detectable by FA, and, vice versa, some patients have CME detectable by FA that is not evident on OCT imaging.
Treatment is aimed at the underlying etiology; however, several of the common treatments may help different causes of cystoid macular edema (CME).
Corticosteroids directly inhibit the enzyme phospholipase, blocking the formation of prostaglandins and leukotrienes. They are considered the primary treatment of CME in many instances, specifically in the treatment of CME secondary to uveitis. Corticosteroids can be administered topically or orally; they can also be injected intravitreally (off-label use) or injected into the sub-Tenon space (off-label use).[15, 16] However, corticosteroids have many ocular adverse effects, including cataract formation or elevated IOP. Therefore, some patients cannot tolerate them.
Patients with diabetes may benefit from a dexamethasone intravitreal implant (0.7 mg).[17] This treatment has also shown benefit in patients without diabetes.[18, 19]
NSAIDs inhibit the enzyme cyclooxygenase and can be used in the prevention and treatment of CME.[20] They are usually administered topically for approximately 3-4 months and on an as-needed basis. Topical NSAIDs have not been found to cause elevated IOP or cause cataract formation.
In a large, multicenter, prospective, double-masked, study of ketorolac versus placebo in the treatment of 120 patients with chronic aphakic or pseudophakic CME, a statistically significant improvement in visual acuity occurred in patients who received ketorolac versus placebo.[21]
Newer NSAIDs, such as bromfenac, may increase compliance and efficacy, as it requires only once-a-day dosing.
Nepafenac is unique because it is a prodrug and is activated only after diffusing into the vitreous of the eye. This drug has been shown in animal models to have higher ocular penetration.[22] The clinical benefit of this increased penetration has yet to be shown, as comparative large clinical trials have yet to be done.
A Cochrane review of 7 studies examined the effectiveness of NSAIDs in the treatment of CME following cataract surgery. Two of the studies demonstrated a positive effect of ketorolac on chronic CME. However, none of the remaining 5 trials revealed a significant difference between comparative groups.[23]
The RPE is important in the maintenance of the blood-retinal barrier and in the prevention of a surplus of extracellular and intracellular fluid within the retina. The enzyme carbonic anhydrase is present on the apical and basal surfaces of the RPE cell membrane. CAIs, such as acetazolamide, enhance the pumping action of RPE cells, facilitating the transport of fluid across the RPE.[24]
If the macular edema is associated with diabetic retinopathy, the therapy is targeted at the causative molecule vascular endothelial growth factor (VEGF). VEGF is a known mediator of capillary leakage implicated in the pathogenesis of diabetic retinopathy and exudative age-related macular degeneration.
Anti-VEGF therapy (ie, ranibizumab) has been shown in many clinical trials to be superior to laser alone for diabetic macular edema.[25]
Anti-VEGF therapy (bevacizumab) has been used for the treatment pseudophakic CME. Bevacizumab is a monoclonal antibody able to inactivate the effects of VEGF. The role VEGF has in pseudophakic CME is not clear, yet several authors have reported resolution of CME after administration of bevacizumab for their patients retrospectively. However, one report by Spitzer et al did not see any beneficial effects with this treatment.[26] Prospective studies are needed. More recently, combination therapy (intraocular steroids with anti-VEGF agents) can be effective in treating refractory pseudophakic CME.[27]
When vitreous is captured in the corneal wound following complicated cataract surgery, YAG laser lysis of the vitreous strands has been used with some success.
If vitreous adhesion to the surgical wound is evident, YAG laser to sever these connections can be helpful. Alternately, pars plana vitrectomy (PPV) is useful in the treatment of cystoid macular edema (CME) in several instances, as follows:
Multiple studies have reported improvement of CME after PPV in cases of aphakic, pseudophakic, chronic, or uveitis-related CME.[28, 29] Some surgeons advocate the peeling of the internal limiting membrane during the PPV. Proceed to Medication.
While diets high in antioxidants have been shown to be beneficial to the retina in age-related macular degeneration, no dietary change has been shown to influence the resolution of postoperative pseudophakic macular edema. Active diabetic retinopathy and the dietary implications of uncontrolled hyperglycemia have been associated with higher rates of diabetic macular edema, which can be worsened by the inflammation of cataract surgery causing more significant pseudophakic CME.
The risk of cystoid macular edema (CME) can be decreased by avoiding intraoperative complications, such as posterior capsule rupture, vitreous loss, vitreous to the wound, iris prolapse, or dislocated lens.
Perioperative and preoperative NSAIDs may decrease the incidence of CME associated with cataract surgery.[30]
Many studies have shown that preoperative and perioperative drops and medications can decrease the incidence of postoperative pseudophakic cystoid macular edema. Specifically, topical steroids and NSAIDs can be effective at decreasing the occurrence of CME.[31] Additional studies have shown that intraocular steroid injections (anti-VEGF) are very effective in high-risk patients, such as those with diabetic retinopathy.
Patients with cystoid macular edema (CME) are treated on an outpatient basis with regular follow-up visits to monitor for any signs of clinical improvement.
If steroids are used as a treatment, it is critical to closely monitor intraocular pressure, as glaucoma is a serious complication.
Medical therapy of Irvine-Gass syndrome includes NSAIDs, corticosteroids, and carbonic anhydrase inhibitors.
Clinical Context: Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which in turn decreases formation of prostaglandin precursors. Commonly used in the treatment of CME and for postoperative inflammation in patients who have undergone cataract extraction.
Clinical Context: Inhibits prostaglandin synthesis by decreasing activity of the enzyme, cyclooxygenase, which results in decreased formation of prostaglandin precursors, which in turn results in reduced inflammation.
Clinical Context: Nepafenac is a pro-drug of amfenac, a potent NSAID. Nepafenac undergoes amide hydrolysis by intraocular hydrolases to form the pharmacologically active amfenac. Amfenac inhibits both cyclooxygenase COX-1 and COX-2 activity. Therefore, its effects are intraocular (CME) and have less effect (or side-effect) on the ocular surface.
Clinical Context: This new NSAID blocks prostaglandin synthesis by inhibiting cyclooxygenase 1 and 2 and is unique in its once-a-day dosing and effective penetration to the posterior pole.
NSAIDs inhibit enzyme cyclooxygenase and also can be used in the prevention of CME. NSAIDs are administered topically, usually for 3-4 months. This class of drops have not been thought to cause elevated IOP (glaucoma) or cataract formation.
Clinical Context: Facilitates the transport of water across the retinal pigment epithelium from the subretinal space to the choroid. Has been found to be useful in cases of CME, but is more commonly used for lowering IOP in the therapy of glaucoma.
Carbonic anhydrase is present on both the apical and basal surfaces of the RPE cell membrane. CAIs enhance the pumping action of RPE cells and change ion flux, which affects the cellular environment in the retina.
Clinical Context: Indicated in several conditions of steroid-responsive intraocular inflammation including CME.
Clinical Context: Indicated in several conditions of steroid-responsive intraocular inflammation and CME.
Clinical Context: Indicated in several conditions of steroid-responsive intraocular inflammation and CME. Approved for macular edema in patients with diabetes.
Clinical Context: Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is a commonly used oral agent. Prednisolone is used for an oral taper of steroids, which may reduce the emotional effects of steroid withdrawal and the risk of the development of adrenocortical insufficiency.
Clinical Context: Triamcinolone is used in the treatment of inflammatory disorders responsive to steroids. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability.
Clinical Context: Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.
Inhibit the enzyme phospholipase and have a primary role in treatment of CME secondary to uveitis. Can be administered topically, orally, or injected in the sub-Tenon space.
Fundus photo of the right eye in a patient with cystoid macular edema.
Fluorescein angiography of the right eye (late phase) showing central macular leakage in cystic spaces around the fovea.
Optical coherence tomography (OCT) of the right eye showing central macular cystic spaces in cross-section.
Fundus photo of the right eye in a patient with cystoid macular edema from diabetic retinopathy.
Fluorescein angiography of the right eye (late phase) showing central macular leakage in cystic spaces around the fovea.
Optical coherence tomography (OCT) of the right eye showing central macular cystic spaces in cross-section.
