CYSTOID MACULAR EDEMA

Signs and Symptoms

Cystoid macular edema (CME), not a true diagnosis but a finding arising from numerous causes, is named for its intraretinal polycystic histopathologic appearance.1-6 The term is overly used by many to indicate Irvine-Gass syndrome, which is characterized by intraretinal swelling with a petaloid (like the petals of a flower) fluorescein angiographic appearance that results when fluid fills into intraretinal cystic spaces surrounding the macula postoperatively following complicated intracapsular cataract extraction with vitreous loss.2-5 Today, the term CME is used to describe this type of macular edema (easily confirmed with OCT) whenever it is discovered.6,7

Causative factors include ocular eye drop preservatives, topical prostaglandin analogs (rarely, and if there is an open posterior capsule), topical beta-blockers, retinal vein occlusion, diabetes mellitus, central serous chorioretinopathy, anterior or posterior uveitis, pars planitis, retinitis pigmentosa, radiation retinopathy, posterior vitreous detachment, epiretinal membrane formation, macular retinal telangiectasia, post Nd:YAG laser procedure and blunt trauma, to name a few.2-18 Given the broad base of potential causative pathologies, with the exception of cataract surgery where some hard predictive data exists, the epidemiology for the formation CME rests with the particulars of the inciting disease.2-18 After cataract surgery, the second most common cause of CME is diabetes.2

Historically speaking, pseudophakic cystoid macular edema (PCME) was first described in 1953 by A. Ray Irvine, Jr., who observed that some patients had unexplained visual loss following intracapsular cataract extraction.4,5 The underlying cause of the visual loss was later identified by Gass and Norton.2,4,5 They added to the work of Irvine, documenting a phenomenon exhibiting a perifoveal petaloid pattern of staining along with late leakage from the optic nerve upon intravenous fluorescein angiography (IVFA).4,5 The condition came to be known as Irvine-Gass syndrome.2 Today, the incidence of PCME has decreased significantly for several reasons: the transition from intracapsular to extracapsular cataract surgery; development of small-incision phacoemulsification; deployment of small incision foldable lenses; improved technology enabling less intraoperative energy use; faster surgical times with better intraoperative cushioning agents; initiation of preoperative anti-infective/anti-inflammatory agents, and the development and use of better topical anti-inflammatory agents. While the modern incidence of PCME-related symptoms (defined as symptomatic vision loss 20/40 or worse) is only approximately 0.1% to 2.35% of all cases, an estimated 20% to 30% of patients undergoing phacoemulsification will demonstrate some form of mild PCME on IVFA.4 The rate has been estimated to be as high as 41% using OCT.3 Fortunately, most patients who have PCME detected with IVFA or OCT imaging have no visual disturbances and require no intervention.4

The predominant symptoms caused by CME of any etiology is visual distortion (metamorphopsia) and acuity reduction.2-18 Visual acuity may be minimally reduced or can decrease to 20/400.3-18

The ophthalmoscopic appearance of perifoveal retinal thickening is difficult to observe. The normal appearance of retinal tissue should be transparent and flat. Edematous retinal tissue can be stereoscopically appreciated using indirect biomicroscopic technique as being raised, having depth and with an opalescence contributing to both the tissue’s cloudiness and an inability to discern underlying choroidal detail.2 In most cases, however, a frank petalloid appearance is not appreciable. In severe cases, intraretinal cysts and the gathering of luteal pigment can create a radiating or oval yellow nodule in the region of the macula.2 With indirect lighting, a honeycombed appearance may be discernable, corresponding to the delineation of the individual fluid-filled cysts.2 The compromise to the precise foveomacular retinal architecture often causes a loss of the foveal light reflex. The true petaloid appearance of CME is best appreciated with fluorescein angiography.2-4 OCT testing is preferred when possible, as it permits non-invasive observation of the cystic, fluid-filled spaces.6

Pathophysiology

Cystoid macular edema is not a specific disease, but rather a clinical feature occurring in a number of conditions. Intracellular fluid and Müller cell swelling produce the condition’s distinctive hexagonal appearance.2 When the fluid remains intracellular, the effects of the disruption remain reversible.2 Once the cellular membranes rupture, giving rise to extracellular leakage, the damage is both irreversible and more significant.2 Leaking perifoveal capillaries, subject to the pathophysiology of the underlying cause, go on to create the formation of intraretinal polycystic fluid-filled spaces which disrupt light from reaching the photoreceptors and retard efficient dialogue to the visual pathway.2-4 Exudative or transudative fluid collects in the loosely arranged outer plexiform layer of Henle (where the axons of the photoreceptors synapse with the dendrites of the horizontal, bipolar and amacrine cells). The fibers in Henle’s layer are horizontally arranged, allowing maximum light transmission. This is what creates the fovea’s parabolic shape with the thinnest region being the foveola. This anatomy, along with the sequential filling of cysts, fosters the petaloid appearance seen during fluorescein angiography.3,4

Various factors and mechanisms are involved in the pathogenesis of CME, including the release of endogenous inflammatory mediators such as prostaglandins.2-4 Light toxicity from the operating microscope and mechanical irritation of the internal ocular tissues are also provocative.2-4 Inflammatory mediators disrupt the blood/aqueous barrier (and blood/retinal barrier), leading to increased vascular permeability.2-4 Any disease process that can break down these barriers can induce CME.2-21 Surgical manipulation may lead to the excessive release of arachidonic acid from cell membranes with production of either leukotrienes via the lipooxygenase pathway or prostaglandins via the cyclooxygenase pathway.2-4 These inflammatory biomarkers can result in increased retinal vessel permeability and the development of CME.2-21 Light toxicity from the operating microscope may contribute to free radical release with subsequent prostaglandin synthesis.2-5 Prostaglandins contribute to tissue inflammation, increasing vasodilation and vasopermeability.2 Any contraction of the posterior hyaloid membrane as a result of epiretinal membrane formation secondary to surgical procedures, inflammation from disease processes, anomalous posterior vitreous detachment, or vitreomacular adhesions may lead to traction onto the perifoveal retinal capillaries and the vasogenic and cytotoxic factors that produce CME.2,21

In cases of CME occurring from any form of uveitis, it can logically be assumed that the inflammatory process initiated by released prostaglandins contributes to perifoveal capillary dilation with increased permeability with fluid exudation.2,7,20 The same reasoning can be extended to CME occurring secondary to prostaglandin analog use in the management of glaucoma. This is more prevalent in patients that have undergone incisional ocular surgery with an opened posterior capsule, which, theoretically, allows easier access deep into the eye.2,9,10 Chronic CME can permanently alter the macular architecture via rupture of the inner wall of the foveal cystoid spaces.24 This transformation is accompanied by a substantial reduction in macular thickness known as a lamellar macular hole (LH).2,21-24 LH typically does not lead to changes in visual function.24 There have been cases of full-thickness holes resulting from CME treatments with injectable steroids such as triamcinolone.25

Management

When CME is caused by conditions such as diabetes, retinal vein occlusion, retinitis pigmentosa or uveitis, the treatment is dictated by standards of care for the causative condition.2-34 Cases of CME arising from diabetic retinopathy or retinal vein occlusion would warrant consideration of focal/laser photocoagulation of the leaking perifoveal capillaries, alone or in combination with injections of anti-VEGF such as Avastin (bevacizumab, Genentech), Lucentis (ranibizumab, Genentech) or Eylea (aflibercept, Regeneron), intravitreal steroid injections or intravitreal steroid implants. In inflammatory diseases such as uveitis, pars planitis, scleritis and retinitis, topical cycloplegics such as atropine 1% BID-TID, along with topical and oral nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressants, laser photocoagulation and anti-VEGF agents are often considered.31-33

Medications for CME include the oral nonsteroidal medicines ibuprofen and indomethacin and the corticosteroid prednisone. Topical nonsteroidal medications such as ketorolac, nepafenac and bromfenac have also been successful. Topical corticosteroid drops such as prednisolone acetate, loteprednol etabonate and difluprednate can be added for unresponsive or more severe cases.2-5,34,35 Common dosing ranges from QID to Q2H. Often a loading dose of Q2H is initiated and then rapidly dropped to QID after several days. Duration of therapy may be several days to months, depending upon the severity of the CME.2-18,34,35

Oral carbonic anhydrase inhibitors (CAIs) like acetazolamide and methazolamide have been documented as helpful in recalcitrant cases of CME.36 These agents increase active transport by the retinal pigment epithelium to facilitate fluid movement from the retina through the choroid.36 They work best in cases caused by diffuse retinal pigment epithelial failure (retinal dystrophies).36 The use of these agents is limited to the patient’s ability to tolerate the medication’s side effects.36 Topical CAI agents have been tested, yielding reduction in retinal thickening without significant gains in visual acuity.36

The majority of cases of symptomatic CME following cataract surgery resolve spontaneously without intervention within eight months, and many cases resolve faster.2-6,34 In rare instances, CME can remain angiographically or tomographically detectable in excess of five years, though patients may not be visually disturbed.2

In cases where vitreous traction has induced or contributed to the formation of CME, surgical vitrectomy has demonstrated success.37 New endoscopic laser delivery systems allow surgeons the option of shaving the vitreous without having to complete removal.37 The effectiveness of vitreous surgery with internal limiting membrane (ILM) peeling stems from relief of posterior hyaloid membrane traction, removal of inflammatory cytokines and increasing preretinal oxygen pressure.37 It is hypothesized that the ILM is the basement membrane of the Müller cells and may act as a diffusion barrier decreasing transretinal fluid movement.37 New investigations seek to duplicate the results seen in vitrectomy using intravitreal pharmacologic agents.37 Vitreosolve (Innovations in Sight), a carbamide derivative, is currently being evaluated in Phase III randomized controlled trials in patients with nonproliferative diabetic retinopathy (NPDR).37 Jetrea (ocriplasmin, Thrombogenics), an intravitreally injected fragment of plasmin currently being used to treat vitreomacular traction syndrome, is also being studied as a treatment for DME in a sham-controlled trial.37 Surgeons have found synergistic effects by mixing radial sheath optic neurotomy, pars plana vitrectomy with ILM peeling and postoperative intravitreal triamcinolone injection for the treatment of continuing retinal vein occlusion-induced CME.37

Clinical Pearls

CME remains a potential complication of cataract extraction even in uncomplicated cases.

CME following a cataract procedure is more likely in cases when the capsule has been ruptured or the vitreous incarcerated.

Clinically significant macular edema (CSME) refers to the location of the perifoveal swelling as defined by the Early Treatment of Diabetic Retinopathy Study (ETDRS). The histopathology of the intraretinal fluid accumulation is polycystic.

When oral or topical steroids are used, intraocular pressure must be monitored. If the pressure rises, it must be treated with an ocular hypotensive that has a low risk for aggravating the condition. As such, avoid prostaglandin analogs.

Amsler grid home monitoring can be used to track the progress of recovery and ensure condition stability. OCT testing can be used in office.

Prostaglandin analogs should be used with caution in patients with a history of incisional ocular surgery, especially if there is also a broken posterior capsule.

A prime cause of vision reduction in posterior uveitis is CME.

If left untreated, CME may predispose the eye to form a macular cyst or lamellar hole.

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