Focus on Cataract Surgery

Evaluating and managing post-op CME

It can result in clinically significant visual loss, so tread carefully.

By Pradeep S. Prasad, MD, and Uday Devgan, MD

Cystoid macular edema (CME) is one of the most common causes of suboptimal visual acuity following uncomplicated intraocular surgery. Although clinicians have described postoperative CME in association with numerous ophthalmic surgical procedures, it is most commonly associated with cataract extraction. Termed pseudophakic CME or Irvine-Gass syndrome, this condition manifests via fluorescein angiography in nearly one in five patients who have undergone uncomplicated cataract extraction.¹

However, clinically significant vision loss associated with pseudophakic CME occurs at a rate of 0.1% to 2.35%.² This rate can rise significantly when cataract extraction is associated with complications including retained lens fragments and vitreous loss. The rate also rises in patients with underlying uncontrolled ophthalmic conditions, including uveitis and diabetic retinopathy.³

Thus it is crucial that the surgeon learn to identify the symptoms of CME and take decisive action in treating it. Here are the practices that we have found to work.

PATHOPHYSIOLOGY

The fluid factor

In CME, excess fluid accumulates within the macula, particularly within the outer plexiform layer. In normal fluid homeostasis, tight junctions of the retinal vascular endothelium and the retinal pigment epithelium (the inner and outer blood-retinal barrier [BRB]) prevent fluid extravasation into the macula by blocking the passage of macromolecules into the extravascular compartment.

A number of disorders can cause the compromise of the inner and outer BRB: metabolic disorders such as diabetes, ischemia, mechanical forces and pharmacologic effects, most notably from prostaglandin analogs as well as inflammation.⁴

Role of inflammation

Inflammation, whether secondary to surgery, uveitis or metabolic disease, leads to the production of inflammatory mediators, such as prostaglandins, interleukins, TNF-α, TGF-β and growth factors. These molecules then trigger a cascade of intracellular and extracellular changes, including breakdown of intercellular junctions. This breakdown increases vascular permeability and can result in disruption of fluid homeostasis in the macula.⁵

An inflammatory cascade of particular importance is the arachidonic acid pathway. In postoperative CME, surgical trauma results in the breakdown of membrane phospholipids, which phospholipase A2 converts into arachidonic acid. Arachidonic acid is then converted into inflammatory mediators: prostaglandins by cyclooxygenase-1 and -2 or leukotrienes by lipoxygenase.

NSAIDs block the activity of cyclooxygenase-1 and -2, decreasing prostaglandin production. Corticosteroids block the activity of phospholipase A2, decreasing the production of both prostaglandins and leukotrienes.⁶

RISK FACTORS AND SIGNS

When and why CME happens

Pseudophakic CME typically arises 2-12 weeks following cataract surgery, although in rare cases it may present months or years afterward. The peak incidence of visually significant CME is 4-6 weeks after surgery.⁷ Advances in modern surgical technique, including small-incision phacoemulsification, shorter surgical times and the use of foldable IOLs placed in the capsular bag, have all significantly decreased the incidence of pseudophakic CME.

On the other hand, intraoperative complications such as excessive iris trauma or prolapse, posterior capsule rupture, vitreous loss, vitreous incarceration in the corneal wound and retained lens fragments can significantly increase the risk of CME. Vitreous loss alone, for instance, can increase the prevalence of CME 10% to 20%.⁸ Sulcus-fixated IOLs, placement of an anterior chamber IOL and iris capture have all been implicated in the development of CME, likely due to repetitive irritation of iris uveal tissue.⁹

Uveitis and diabetes red flags

Two patient populations at particular high risk for developing postoperative CME are those with a history of uveitis or uncontrolled diabetes and diabetic retinopathy.¹⁰ Postoperative rates of CME in patients with uveitis, even when controlled preoperatively, can be greater than 35%.¹¹ CME in patients with diabetes, especially those with preexisting DR and DME, has been reported as high as 44% to 55%.^12,13

Research has shown increased duration of diabetic disease, degree of retinopathy, glycemic control and use of insulin all correlate with the development of postoperative CME. Investigators have yet to determine whether the increased rate of CME in patients with diabetes is due to progression of DR and DME, or if underlying retinal vascular endothelial dysfunction lowers the threshold for development of CME.¹⁴

Getting a picture

Diagnostic evaluation of patients with suspected pseudophakic CME involves dilated funduscopic biomicroscopy, fluorescein angiography and OCT. Funduscopic findings include loss of the foveal depression, yellow discoloration of the perifoveal area, intraretinal cysts and optic nerve head swelling.¹⁵

Fluorescein angiography demonstrates perifoveal hyperfluorescence in a petalloid pattern (Figure 1). In addition, late optic disc leakage or staining may appear, which can help distinguish pseudophakic macular edema from DME and distinguish macular edema of other etiologies.

Figure 1. Fluorescein angiogram in a pseudophakic patient demonstrating late petalloid perifoveal angiographic leakage and optic disc staining secondary to Irvine-Gass syndrome.
COURTESY: RALPH LEVINSON, MD

OCT, which allows for non-invasive, rapid, high-resolution cross-sectional imaging of the macula, has increasingly become the diagnostic modality of choice for CME. OCT findings include intraretinal cystoid changes and foveal distortion (Figure 2). Unlike DME, sub-neurosensory retinal fluid typically does not appear on OCT.¹⁶ OCT can also be useful to quantitatively measure response to treatment.

Figure 2: A. OCT demonstrating outer plexiform layer cystoid spaces in a pseudophakic patient with Irvine-Gass syndrome. B. OCT demonstrating significant improvement in macular edema following intravitreal injection of triamcinolone.
COURTESY: ALLAN KREIGER, MD

PREOPERATIVE ASSESSMENT AND PROPHYLAXIS

Background check

Preoperative evaluation of cataract patients should include an evaluation of risk factors for intraocular complications and postoperative CME. History-taking should include review of medications, including prostaglandin use for IOP control and oral medications that may increase the risk of intraoperative floppy iris syndrome (IFIS).

In patients with diabetes, coordinate preoperative glycemic control and optimization with their primary-care physician. Your ophthalmoscopic examination should include assessment of pupillary dilation, presence of pseudoexfoliative material, phacodonesis and posterior capsular compromise.

Prophylaxis strategies

Clinicians typically employ topical corticosteroids and NSAIDs perioperatively as prophylaxis against anterior segment inflammation, pain and CME. Research has shown these medications are of particular benefit in patients with diabetes.

Further, growing evidence indicates topical corticosteroids and NSAIDs can result in a significant reduction in the rate of postoperative CME in routine, uncomplicated cases.^17,18 Numerous topical NSAIDs are currently available including nepafenac (Ilevro and Nevanac, Alcon, Fort Worth, Texas), ketorolac, bromfenac (Prolensa, Bausch + Lomb, Bridgewater, N.J.) and diclofenac (Voltaren, Novartis, Basel, Switzerland).

The label indication for topical NSAIDs in the United States is for control of postoperative pain and inflammation. Outside the United States, nepafenac has an indication to reduce the risk of postoperative macular edema in diabetic patients. In trial data, at the 90-day mark after cataract surgery, nepafenac gave a fivefold reduction in the risk of macular edema (just 3.2%) compared to vehicle (16.7%).¹⁹

Although both topical corticosteroids and NSAIDs are generally well-tolerated, prolonged use in certain patients may be associated with adverse effects ranging from mild ocular surface discomfort to elevated IOP with corticosteroids, and corneal melt with NSAIDs. Surgeons using NSAIDs and steroids, whether on-label or off, should carefully monitor patients at the postoperative visits.

When uveitis is an issue

In patients with a history of uveitis, the anterior chamber should be quiet for at least three months before cataract surgery (with respect to cells). In some patients with uveitis, the anterior chamber may never fully be cleared of flare. Intermediate and posterior uveitis should also be under control, although anterior vitreous cells may be present even in quiescent disease.²⁰ The surgeon may also use perioperative systemic corticosteroids or aggressive topical corticosteroids and NSAIDs or both to mitigate postoperative inflammation.

Diabetes patients with evidence of DME or proliferative disease require treatment before cataract surgery. When the surgeon cannot adequately treat the patient preoperatively because of poor visualization or recalcitrant disease, studies have shown perioperative intravitreal injection of anti-VEGF agents can hasten visual recovery and result in significantly improved postoperative visual acuity.²¹

MANAGING PSEUDOPHAKIC CME

Look for a cause

Once you have established the diagnosis of pseudophakic CME, appropriate management hinges on identifying an underlying cause, if any. Carefully examine the patient for IOL malposition, vitreous or iris incarceration and retained lens fragments. In cases of poor IOL visualization, ultrasound biomicroscopy can help to identify displaced IOL haptics and iris chafing. If you see vitreous incarceration in the corneal wound, you can perform either Nd:YAG vitreolysis or vitrectomy.^22,23

In cases involving violation of the posterior capsule, the surgeon must thoroughly examine the posterior segment, including the vitreous base with scleral depression to rule out small retained nuclear fragments. These patients may require secondary pars plana vitrectomy to remove retained lens fragments, particularly those associated with visually significant CME.²⁴

Stepwise treatment approach

In the absence of an identifiable cause of pseudophakic CME, the surgeon can employ a step-wise approach in management. Postoperative CME is associated with an 80% rate of spontaneous resolution. However, delayed improvement in visual acuity can result in significant patient morbidity.²⁵ Here are the steps we recommend:

• First-line treatment typically comprises topical corticosteroids and NSAIDs. You may need to extend treatment from several weeks to several months.

• In the absence of clear improvement on OCT and FA, periocular or intravitreal corticosteroids are options. Sub-Tenon or intravitreal triamcinolone and intravitreal dexamethasone implant (Ozurdex, Allergan, Irvine, Calif.) injection have all demonstrated improved visual acuity and resolution of pseudophakic CME.^26-28 (“What about anti-VEGF agents?” page 36)

• For chronic, recalcitrant cases of pseudophakic CME, pars plana vitrectomy has been shown to result in significant improvement in visual acuity.²⁹ Other options include interferon alpha, intravitreal infliximab and intravitreal diclofenac, although evidence for their efficacy is limited to small case series.^30-32

Conclusion

Pseudophakic CME is a main cause of decreased visual acuity following uncomplicated cataract surgery, and can be a source of significant patient morbidity.

By identifying the risk factors for the development of CME, the surgeon can modify surgical techniques or perioperative prophylaxis regimens to mitigate postoperative inflammation and decrease the risk of postoperative CME.

Treatment of pseudophakic CME may require repositioning the IOL or performing pars plana vitrectomy in the setting of complicated cataract extraction. In uncomplicated cataract surgery, though, when cases of pseudophakic CME do not resolve spontaneously, the surgeon can address the problem with a stepwise approach that includes topical NSAIDs and corticosteroids, followed by periocular or intravitreal injection of corticosteroids.

REFERENCES

About the Authors
	Pradeep S. Prasad, MD, is chief of ophthalmology at Harbor UCLA Medical Center and assistant clinical professor at the Jules Stein Eye Institute, UCLA School of Medicine. His e-mail is psprasadmd@gmail.com. Disclosure: Dr. Prasad has no relevant financial disclosures.
	Uday Devgan, MD, is chief of ophthalmology at Olive View UCLA Medical Center and in private practice at Devgan Eye Surgery in Los Angeles and Beverly Hills, Calif. (www.DevganEye.com). His e-mail is devgan@gmail.com. Dislosures: Dr. Devgan is a paid consultant to Alcon and Bausch + Lomb/Valeant, and formerly to Allergan and Ista Pharma, all of whom make ophthalmic NSAIDs and/or steroids. He has no direct financial interest in the products mentioned.