Various retinal disorders exhibit similar clinical features

Accurate diagnosis is critical, as their etiology and management will vary.

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Macular edema is the most common cause of visual disturbance and reduced vision in various retinal disorders. Although their clinical features are similar in appearance, their etiology and management may vary.

Pseudophakic cystoid macular edema

More than 3 million cataract surgeries are performed each year, with an average cost of $3,200 per eye, making it the most common ocular surgery in the U.S., according to Statistic Brain Research Institute. Remarkably, less than 1% of patients have severe postoperative complications, thus, most patients are happy with cataract surgery.

The two most common postoperative complications after cataract surgery are posterior capsular opacities (PCO) and pseudophakic cystoid macular edema (PCME). PCO can be managed by YAG capsulotomy, whereas PCME needs retina therapy. Ray Irvine Jr., in 1953, first described his patients with unexplained vision loss after intracapsular cataract extraction (ICCE). It was not until 1966 that Gass and Norton confirmed via angiographic study that cystoid macular edema was the cause of vision loss. Hence, Irvine-Gass syndrome is the name still being used by some clinicians as historical reference.

A classic perifoveal petalloid pattern of staining is often seen in the late stage on intravenous fluorescein angiography (IVFA). The incidence of angiographic PCME has decreased drastically as the advance of cataract surgery moved from ICCE (about 60%) to extracapsular cataract extraction and small-incision phacoemulsification (about 20% to 30%). The arrival of optical coherence tomography (OCT) has permitted an alternative, noninvasive way to image PCME in place of IVFA, thus introducing a new diagnostic technology that is highly sensitive in detecting macular edema.

A recent OCT study of 32 eyes of 32 patients who had uneventful phacoemulsification with implantation of a foldable IOL found that increases in retinal thickness reached a maximum at 6 weeks in 13 of 32 eyes (41%). At 30 weeks, all eyes had good visual acuity, but seven eyes (22%) still had macular edema. This finding suggests two possible diagnoses for PCME via OCT, clinical or subclinical PCME. Most patients with macular thickening on OCT post cataract surgery are asymptomatic or subclinical and resolve spontaneously over time. On the other hand, a small group of patients have clinical PCME and are symptomatic with vision loss of 20/40 or worse that requires medical treatment.

The incidence for clinical PCME is much lower today, hovering around 0.1% to 2.35%. PCME usually arises at 4 to 6 weeks, with the peak incidence of 6 weeks after surgery. It can be classified as acute PCME when it occurs within 6 months postoperatively and chronic PCME when it is present longer than 6 months after cataract extraction. Higher risks for PCME are associated with diabetes mellitus, hypertension, history of central retinal vein occlusion (CRVO), recent history of uveitis, pre-existing epiretinal membrane and possibly the use of prostaglandin analogs (Das et al.).

The exact pathogenesis of PCME remains to be fully elucidated, but a compromise in the blood-aqueous barrier or blood-retinal barrier must be responsible for the classic angiographic leakage findings. Surgical trauma and light toxicity can induce the release of phospholipids from the cell membrane that are converted into arachidonic acids by phospholipase A2. Arachidonic acids are catalyzed subsequently by cyclooxygenase (COX) and lipoxygenase (LOX) into inflammatory autacoids such prostaglandins and leukotrienes, respectively. Furthermore, the contraction of posterior hyaloid secondary to mechanical traction and chronic inflammation can loosen the perifoveal capillaries, manifesting in PCME.

Images: Koh LV

Various therapeutic approaches have been used in the management of PCME. As a part of perioperative management of cataract extraction, virtually all patients are prescribed a prophylactic topical fluoroquinolone such as gatifloxacin or moxifloxacin, a topical corticosteroid such as prednisolone acetate or difluprednate, and possibly a topical nonsteroidal anti-inflammatory drug (NSAID) such as nepafenac or bromfenac for a few weeks. Corticosteroids inhibit phospholipase A2 and the production of arachidonic acid, the precursor of prostaglandins and leukotrienes. Furthermore, corticosteroids also inhibit macrophage and neutrophil migration and decrease capillary permeability. Topical NSAIDs inhibit COX pathway and the production of prostaglandins and thromboxanes. Combination therapy of ketorolac tromethamine 0.5% and prednisone acetate 1% four times daily has been found to be more effective in resolving PCME than either ketorolac or prednisone alone. More patients in the combination group achieved a two-line or more improvement in Snellen acuity at a shorter treatment duration. Due to its potential effect in preventing postoperative PCME, many cataract surgeons recommend topical NSAID application for 2 days preop in patients with low risk and 1 week preop for those at high risk for PCME.

High-risk factors include diabetes mellitus, hypertension, history of CRVO, recent history of uveitis, preexisting epiretinal membrane or following complicated cataract surgery. Newer NSAIDs, Prolensa (bromfenac 0.07%) and Ilevro (nepafenac 0.3%), allow for convenient once-a-day dosing and are well tolerated and relatively safe. Although combination therapy of topical corticosteroid and NSAIDs is effective for most cases of PCME, for refractory PCME, intravitreal triamcinolone acetonide (IVTA) injections may be needed. But the downside is that up to half of the patients may experience significant elevation of IOP.

The discovery of antivascular endothelial growth factor (anti-VEGF) agents has revolutionized the management of wet AMD and other forms of macular edema, but they work only modestly in the treatment of refractory PCME and, hence, are not recommended as the first drug of choice for PCME. For those patients with refractory PCME secondary to vitreomacular traction, or retained lens nuclear material who do not respond to any medical treatment, pars plana vitrectomy can be an effective option.

Central serous chorioretinopathy

Central serous chorioretinopathy (CSCR) was first described by Von Graefe in 1866 as recurrent central syphilitic retinitis. Multiple names have been used for this condition over the years, but central serous retinopathy and CSCR are most often used currently. CSCR tends to occur more frequently in men between the ages of 20 and 50 years, but it can happen to older patients with signs similar to neovascular age-related macular degeneration, thus making it difficult to differentiate between the two conditions. The annual incidence was estimated at around 9.9 per 100,000 for men and 1.7 for women, sixfold more prevalent in men. Asians, Caucasians and Hispanics are suspected to have a higher incidence than African Americans who seem to suffer from a more severe form of CSCR with worse visual acuity. On the other hand, bilateral and multifocal forms of CSCR happen more frequently in the Asian population.

The most common symptoms that bring patients to the eye clinic are metamorphopsia, blurred vision and mild dyschromatopsia in the affected eye. A round, well-demarcated macular thickening is usually evident on fundus examination. Neurosensory detachment associated with focal pigment epithelial detachment (PED) is often detected on OCT, and an “ink blot” or “smoke stack” appearance of leakage that mimics a mushroom cloud can be seen via IVFA. Recently, enhanced-depth imaging (EDI) or swept-source OCT has made it possible to visualize and measure the full depth of the choroid. Increased choroidal thickness has been found in both affected and fellow eyes of CSCR patients. A 395-um choroidal thickness has been proposed as a sensitive threshold value for thick choroid or “pachychoroid.” Focal or diffuse dilation of large choroidal vessels has been suggested to account for a thicker choroid. Thick choroid has been hypothesized as a potential risk factor for CSCR, similar to thin cornea as a possible risk factor for glaucoma, but it is not pathognomonic of CSCR. It is difficult to compare choroidal thickness accurately because it changes with age, axial length and myopia and is thinner in females.

Another common association with CSCR is focal RPE barrier breakdown, which is present virtually in all CSCR-affected eyes. This breakdown disrupts the normal net outflow of fluid into the choroid, thus leading to the retention of ion and water in the sensory retina in the form of a fluid pocket and PED.

Various risk factors have been implicated in the pathophysiology of CSCR, but the pathogenesis of CSCR remains to be fully investigated. Type A personality characterized by a competitive drive, a sense of urgency and aggressive and hostile temperament has been reported by Yannuzzi as a risk factor for CSCR. Additionally, antipsychotic medication use and psychological stress were found as independent risk factors for CSCR. Clinicians can attest to this association, as CSCR patients tend to show up after a certain stressful event in their lives such as the recent start of a new job or family. In contrast, depressed patients were found to be more prone to recurrence. It could be that this group of individuals is more susceptible to stress-induced CSCR in their working environment but less likely to comply with therapy. Therefore, dysregulation of a neurotransmitter or neuromodulator is likely to play an important role in the pathogenesis of CSCR.

One particular neuromodulator that comes to mind is cortisol, which is widely known as a stress hormone. A growing body of evidence points to cortisol as a causing agent. For example, previous exposure to corticosteroid medications, regardless of the routes of administration, has been found as a risk factor for CSCR. Up to 5% of patients with endogenous Cushing syndrome have CSCR. Several studies reported the total 24-hour urine cortisol levels were higher in acute CSCR patients as compared to normal subjects. Hormonal changes associated with pregnancy, particularly during the third trimester, increased risk of CSCR by approximately seven times, suggesting the involvement of cortisol levels and possibly other hormones.

Another hormone related to cortisol is aldosterone, which may also be an accomplice in the etiology of CSCR, as the serum aldosterone levels were found to be low in one-third of the CSCR patients. Therefore, the dysregulation of glucocorticoid and mineralocorticoid hormones is involved in CSCR.

Catecholamines such as norepinephrine and epinephrine have also been implicated as a risk factor for CSCR. Concurrent use of steroids and catecholamines appeared to have additive effects, as is evident in multiple case reports of CSCR in organ transplant patients who were taking high doses of glucocorticoids and vasopressive catecholamines. Patients with hypertension were twice as likely to develop CSCR compared to control patients. In addition to hypertension, obstructive sleep apnea (OSA) is another risk factor for CSCR, as it has been reported in 22% of CSCR patients as compared to 2% to 4% reported in the general population.

Drugs other than corticosteroids that have been suspected to cause CSCR include pseudoephedrine and oxymetazoline combination sprays for nasal congestion, N-methyl-D-aspartate receptor (NMDA) and ephedra, and perhaps drugs for erectile dysfunction (sildenafil, tadalafil or vardenafil). MEK-inhibitors (binimetinib) for metastatic cancer can cause transient bilateral serous retinal detachments.

Most cases of CSCR present with mild to moderate loss of vision in the affected eye. Fortunately, the condition is self-limiting for the majority of patients with spontaneous resolution in a few months. Consequently, the first approach in managing acute CSCR is observation. The recurrence rates, however, are high, ranging from 15% to 50%. Recurrences necessitate prompt intervention because long-lasting serous retinal detachment (SRD) can cause photoreceptor damage and irreversible vision loss of worse than 20/40. Therefore, treatment is recommended for patients with persistent macular SRD for a few months, history of multiple recurrences and occupational requirement for a rapid recovery. The first step in management of CSCR is to eliminate the offending agent such as discontinuation of glucocorticoid intake, discussion of proper management of OSA and psychological support.

One intriguing aspect about CSCR is that macular edema is exacerbated rather than ameliorated by exposure to glucocorticoids, whereas macular edema caused by other etiologies tends to get better with steroid treatment. Therefore, inflammation is not likely involved in its pathophysiology, and another treatment modality is required.

If the leakage is found more than 500 um away from the fovea on IVFA, laser photocoagulation, green (514 nm) or yellow (580 nm), is a good option for acute CSCR. Laser seals the focal RPE defects, allowing for RPE to regain function and resume pumping fluids out into the choriocapillaris. Alternatively, photodynamic therapy (PDT) is also effective in sealing off leaks.

PDT works by using 693 nm light to activate verteporfin in the presence of oxygen to release free radicals in the choriocapillaris. Free radicals damage the choroidal vessels and occlude the leakages. For choroidal neovascularization (CNV), verteporfin is approved at a dose of 6 mg/m2 with a laser fluence of 50 J/cm2 that can cause significant side effects including choriocapillaris nonperfusion (40%), secondary CNV (5%), RPE atrophy (4%) and subsequent visual loss (1.5%). The side effects associated with this high dosage, however, may not be justified for CSCR patients with moderate impairment of vision. Fortunately, half-dose PDT (3mg/m2) and lower-fluence PDT (25J/cm2) have been shown to be highly effective in the treatment of SRD in CSCR. Although laser therapy is effective in certain cases of CSCR, it has many damaging side effects to the retina and choroid, so it is used only as indicated. Effective medical therapy is preferred if it is available. Although vascular endothelial growth factor (VEGF) is not associated with CSCR, several studies have been done to see if anti-VEGFs are effective in reducing choroidal hyperpermeability. The results to date are modest at best; therefore, anti-VEGF agent is not recommended for CSCR due to cost, unless CNV is apparent.

Numerous oral medications have been tested over the years with negative or poor evidence of benefits. These include carbonic anhydrase inhibitors (acetazolamide), beta-blockers (nadolol, propranolol), antibiotics (amoxicillin, metronidazole, clarithromycin) and proton pump inhibitors (omeprazole), imidazoles (ketoconazole), glucocorticoid-receptor antagonists (mifepristone), anti-platelets (aspirin), antimetabolites (methotrexate), 5 -reductase inhibitors (finasteride) and diarylheptanoids (curcumin). The only oral medication that shows a more convincing benefit is the aldosterone antagonists, spironolactone and eplerenone. Preclinical studies suggest that mineralocorticoid receptors are overexpressed in the vessels or higher levels of aldosterone and cortisol that cause choroidal and RPE changes lead to SRD.

In a retrospective study, 46 eyes of 36 patients with nonresolving CSCR after 4 months follow-up were treated with oral eplerenone or spironolactone (25 mg/d to 50 mg/d). After 3 months of treatment, macular and choroidal thickness were decreased significantly. These promising results have led to a double-masked, randomized clinical trial in 2015 to examine the treatment effect of spironolactone vs. placebo. Spironolactone appears to reduce macular thickness in eyes with CSC with persistent SRD, but it does not seem to improve visual acuity. Further studies are required to see whether it is effective in acute CSC.

Retinal vein occlusions

Retinal vein occlusion (RVO) is a common retinal vascular disorder. It is the second most common cause of visual loss after diabetic retinopathy. It was first described as retinal apoplexy and hemorrhagic retinitis in 1855, but the mechanism underlying its pathophysiology remains unclear. Nevertheless, significant progress has been made over the past decade in its management.

RVO is classified based on the location of obstruction in the retinal vasculature. The main types of RVO are CRVO, hemiretinal vein occlusion (HRVO) and branch retinal vein occlusion (BRVO).

CRVO blocks all venous outflow leading to widespread bleeding in the retina, often described as “blood and thunder” or “tomato ketchup” fundus. It is a manifestation of a red (hemorrhagic) infarct as opposite to white (ischemic) infarct in retinal arterial occlusion. HRVO blocks the superior or inferior (first-order) bifurcation of the retinal veins. Macular edema is frequently associated with CRVO and HRVO because extensive venous tributaries are occluded, leading to more extensive retinal edema that includes the macula. BRVO involves smaller branches of retinal veins that may or may not lead to macular edema, thus it can be classified as nonmacular or macular BRVO. In addition to location of obstruction, RVO can be categorized as ischemic or nonischemic type based on the extent of retinal nonperfusion via IVFA. Ischemic CRVO has poor perifoveal perfusion and peripheral capillary nonperfusion of greater than 10 disc areas. On the other hand, ischemic BRVO shows greater than 5 disc areas of nonperfusion.

In terms of incidence, BRVO is the most common form of RVO, a few times more common than CRVO, and HRVO is the least common. Most BRVOs affect patients older than 50 years, whereas CRVO occurs later, between 60 and 70 years old. The Eye Disease Case Control Study Group estimated nearly 200,000 cases of RVO in North America annually. HRVO was found to have similar outcomes as CRVO by the Central Venous Occlusion Study; therefore, the discussion of CRVO henceforth is relevant to HRVO. Virtually all patients with CRVO are symptomatic with visual impairment due to macular edema. In contrast, many patients with nonmacular BRVO are asymptomatic and unaware of their condition until incidental findings when they have their routine comprehensive eye exams. On the contrary, patients with macular BRVO have macular edema and are symptomatic. Impending or partial vein occlusions are sometimes detected incidentally via fundus examination and require closer monitoring.

RVO is another retinal condition that causes unilateral, painless loss of vision secondary to retinal hemorrhaging and macular edema. CRVO causes severe loss of vision, often worse than 20/200, and significant restrictions of peripheral visual field, whereas symptomatic BRVO tends to reduce visual acuity moderately, 20/60 or better. RVO increases intraluminal pressure up to 24 times, leading to transudation of blood from the veins as intraretinal hemorrhages and edema. Additionally, the release of inflammatory mediators, including VEGF, compromise the inner blood retinal barrier causing further leakages. Long-term retinal edema causes damages to the glial and RPE cells, and persistent infarction or ischemia leads to retinal neovascularization and tissue death. Development of collateral vessels is a common sequelae of RVO as an alternate route for venous outflow and is present in up to three-fourths of the cases.

Although many clinicians consider collateralization as a beneficial response to RVO, the final visual acuity in these patients tends to be worse. A possible explanation is that collateral vessels developed only as a result of severe cases of occlusion. In CRVO, collateral vessels are found at the optic nerve head, whereas in BRVO they are located temporal to the macula. Remarkably, four out of five BRVOs are located at arteriovenous (AV) crossings, and two-thirds of BRVOs occur in the temporal retina where higher AV crossings are located. Furthermore, superior temporal BRVOs are twice as more likely to cause macular edema than other quadrants; perhaps due to gravity and proximity to the macula.

In addition to edema, ischemia is another common sequelae of RVO. Retinal ischemia is known to induce neovascularization that can exacerbate retinal edema and cause other complications. For instance, neovascularization of the angle (NVA) can lead to neovascular glaucoma. Neovascularization of the iris (NVI) is detected in more than half of the patients with ischemic CRVO within the first 6 months. Additionally, neovascular glaucoma may appear in as many as 80% of these patients. Therefore, careful examination of the pupillary margin via slit lamp and gonioscopy are essential for early detection of NVI and NVA. Early treatment to prevent further progression of NVA is critical to minimize the effect of neovascular glaucoma that can cause blindness in 75% of cases and phthisis bulbi in one of four patients. In contrast, NVI and NVA rarely occur in HRVO and BRVO, but neovascularization elsewhere (NVE) in the retina can develop, leading to recurrent macular edema.

Despite being known for more than a century, the pathogenesis of RVO remains elusive. One of the main reasons is that it is a complex disorder with mutifactorial etiologies. Arterial disease, however, may be responsible for the majority of RVO incidences. Thickening of the arterial wall secondary to arteriosclerosis can nick and occlude the vein at the level of lamina cribrosa in CRVO and branch in BRVO. Common systemic diseases such as diabetes and hypertension are known to increase risk of RVO. Diabetes is associated more with CRVO, whereas hypertension is more relevant with BRVO. In addition, obstructive sleep apnea has been reported to double the risk of RVO. The Virchow’s triad of hypercoagulability, vascular turbulence and stasis, and endothelial injury, is thought to contribute to thrombosis in the body. These factors may also predispose retinal vein to clotting in some RVO. For example, carotid artery disease and other hypercoagulability-inducing factors such as dehydration, smoking and oral contraceptives have all been linked to RVO. Furthermore, bilateral CRVO in a young patient strongly indicates a hematologic disorder.

RVO most likely is caused by one or more systemic conditions and, hence, requires both systemic and ocular management to prevent life- and sight-threatening complications. It has been found to be associated with increased cardiovascular mortality. The 10-year relative risk of developing cardiovascular complications after RVO in male smokers is more than four times that of controls. Various treatment modalities have been attempted over the years with limited success. Isovolemic hemodilution was shown to increase blood velocity and improve visual acuity in some CRVO patients. On the contrary, a prospective study conducted over nearly 40 years reported that patients taking anticoagulants and/or aspirin at the time of CRVO showed more retinal hemorrhaging, worse visual acuity and more visual field loss as compared to patients who were not on these medications. Therefore, there is no solid evidence supporting the use of anticoagulants in the treatment of RVO.

Chorioretinal anastomosis connecting venous outflow to the choroidal bed can be created with direct venous puncture by laser to serve as an alternative drainage pathway. This approach works better for younger patients, but vitreous hemorrhage and choroidal neovascularization are common side effects. Separation of retinal artery and vein through cutting the common adventitial sheath via arteriovenous sheathotomy can relieve arterial compression of the vein in BRVO, but the procedure is invasive and complex. Laser photocoagulation was found to improve visual acuity modestly in the Branch Vein Occlusion Study (BRVOS). It was indicated for patients with persistent macular edema and visual acuity less than 20/40 for at least 3 months because some patients with macular BRVO may experience spontaneous resolution prior to 3 months. Furthermore, laser treatment is not recommended in the presence of significant hemorrhage and macular ischemia.

In contrast, grid laser photocoagulation was not found to be beneficial in macular edema secondary to CRVO, according to the Central Vein Occlusion Study (CVOS), hence observation had been the standard of care for CRVO-induced macular edema until the arrival of anti-VEGFs. Panretinal photocoagulation, however, is effective in shrinking ocular neovascularization induced by ischemic CRVOs. Therefore, it is important to detect any NVE, NVI or NVA and treat early to prevent neovascular glaucoma.

Similar to other forms of retinal edema with the exception of central serous chorioretinopathy, corticosteroids have been effective in treating macular edema secondary to RVO. Steroids are known to have multiple properties against edema such as anti-inflammatory, anti-angiogenic and anti-permeability. The Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE-CRVO) study found that 26% of CRVO patients treated with 1 mg or 4 mg triamcinolone acetonide, a synthetic glucocorticoid, were gaining 15 letters or more as compared to 7% in the control group at 12 month follow-up. The ocular side effects of steroids such as cataract formation and increase in IOP were significantly higher in the treated group than those of controls.

The subsequent SCORE-BRVO study confirmed that intravitreal triamcinolone (1 mg and 4 mg) was noninferior to grid laser photocoagulation in improving visual acuity and reducing retinal thickness. Again, the rates of cataract formation and IOP elevation were higher in steroid groups. Although intravitreal steroid works well in resolving macular edema, its ocular side effects has limited its widespread application. Therefore, clinician-scientists have worked over the past decade to come up with steroids with safer ocular profiles. They succeeded with the introduction of the retinal corticosteroid implant.

The Global Evaluation of Implantable Dexamethasone in RVO with Macular Edema (GENEVA) study found that 0.35 mg or 0.70 mg of dexamethasone achieved a 15-letter improvement in BCVA and reduced retinal thickness faster in a larger group of patients than the sham group. Furthermore, the implant lasts 4 to 6 months. Despite five times greater anti-inflammatory potency than triamcinolone acetonide, sustained-release formulation of dexamethasone implant (Ozurdex, Allergan) induces lower incidences of increased IOP and cataract formation than intravitreal triamcinolone injection.

Based on the GENEVA study, injectable Ozurdex biodegradable dexamethasone was the first steroid implant approved for the treatment of macular edema related to RVO. Additionally, other steroid implants have been introduced to the market. Fluocinolone acetonide (0.59 mg) intravitreal implant (Retisert, Bausch + Lomb) has been approved by the FDA for the treatment of chronic noninfectious uveitis affecting the retina with sustained release for up to 30 months. It is only used as last resort for macular edema due to RVO because of its universal cause of cataract formation and high incidence of IOP elevation.

Last, but not least, is the application of anti-VEGFs in the treatment of retinal edema. The discovery of the efficacy of anti-VEGF agents in the treatment of wet AMD in the past decade has ushered in a revolutionary armamentarium for the retinal specialist in the management of retinal disorders. There has been an explosion of publications on the application of anti-VEGF agents in eye care. In the interest of brevity, only relevant applications of anti-VEGF agents in the treatment of RVO are covered in this section.

Cumulative evidence confirms the increased presence of VEGF in RVO leading to neovascularization and vascular hyperpermeability. All three currently available anti-VEGF agents, bevacizumab, ranibizumab and aflibercept, have been investigated in the treatment of macular edema secondary to RVO. Bevacizumab (Avastin, Genentech) is a 149 kDa full-length recombinant humanized monoclonal antibody against VEGF that binds to all VEGF-A isoforms (121, 165, 189 and 206 amino acids) and was initially approved for the treatment of advanced carcinoma in 2004. Ranibizumab (Lucentis, Genentech) is a 48kDa fragment of bevacizumab that is still able to bind to all VEGF isoforms. Aflibercept (Eylea, previously known as VEGF-Trap Eye, Regeneron Pharmaceuticals) is a 115 kDa human recombinant fusion protein that blocks all isoforms of VEGF and the placental growth factor. Its affinity for VEGF-A is 100-fold greater than bevacizumab or ranibizumab.

The efficacy of anti-VEGF agents in the treatment of macular edema secondary to RVO has been shown in multiple studies such as BRAVO, CRUISE, HORIZON, RETAIN, COPERNICUS and GALILEO (see accompanying table on page 11). For example, 0.3 mg or 0.5 mg ranibizumab yielded significant improvement in visual acuity at 6 months in CRUISE and BRAVO. Similar findings were found with bevacizumab and aflibercept. Over the past decade, major advances in medical research have expanded the therapeutic options for effective management of macular edema secondary to RVO. Patients do not need to wait 3 months for spontaneous resolution, but can be treated with anti-VEGFs, corticosteroids or combination therapy of both anti-VEGFs and corticosteroids. Furthermore, prompt treatment of macular edema following RVO is associated with faster visual acuity improvement and minimizing irreversible damage to the retinal circuitry.

Diabetic macular edema

The last topic on the management of diabetic macular edema is similar to that of macular edema secondary to RVO. Therefore, only an essential account is presented on the management of DME. The definition of DME based on the Early Treatment Diabetic Retinopathy Study (ETDRS), also known as clinically significant macular edema (CSME), is: thickening of the retina at or within 500 mm of the center of the macula; hard exudates at or within 500 mm of the center of the macula, if associated with thickening of the adjacent retina; or a zone of retinal thickening 1 disc area, any part of which lies within 1 disc diameter of the center of the macula. A simplified version was later suggested by the Global Diabetic Retinopathy Project Group — mild DME: eyes with some edema or lipid in the posterior pole but distant from the center of the macula; moderate DME: eyes with edema or lipid approaching the center but not involving it; and severe DME: eyes with edema or lipid involving the center of the macula.

In 1985, ETDRS established that laser photocoagulation was the gold standard for treatment of CSME because laser photocoagulation was found to prevent up to 15 letters loss with prompt therapy. This gold standard lasted for almost three decades until 2013, when the Ranibizumab for Edema of the Macula in Diabetes 2 study showed that ranibizumab was more effective than laser treatment. Subsequently, a series of anti-VEGF studies, including RESTORE, RISE and RIDE, BOLT, DA VINCI, VIVID and VISTA, have ushered anti-VEGF agents as the standard first-line therapy in the management of DME (see accompanying table on page 12).

Furthermore, corticosteroids have also been shown to be more effective than laser treatment by studies like FAME and MEAD, but they have a high rate of adverse events such as cataract formation and glaucoma. Therefore, anti-VEGF agents and intravitreal steroids are preferred over laser photocoagulation for the treatment of DME. For DME that does not resolve completely after multiple intravitreal injections, combination therapy of anti-VEGFs and steroids or laser photocoagulation may be necessary. Finally, focal/grid laser photocoagulation, which was the gold standard treatment, is now reserved for non-center involving DME.

In summary, major medical advances have been made over the past decade in the management of macular edema. This article provides updates on retina therapy for the most common form of macular edema encountered by eye care providers. Topical NSAIDs and steroids are most effective for pseudophakic CME. Focal laser and photodynamic therapy are treatments of choice for persistent CSC, and aldosterone antagonists such as spironolactone may be an effective non-laser option for CSC. Anti-VEGF agents are the first line therapy for macular edema secondary to RVO and diabetes, but steroid implants are also good choices for many patients. Despite not being covered specifically in this article, all the aforementioned therapies are effective options in the management of wet AMD, with anti-VEGF agents being the first therapy of choice.

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• For your information:
• Len V. Koh, OD, PhD, MBA, FAAO, is assistant dean of clinical affairs and an associate professor at Midwestern University, Arizona College of Optometry in Glendale, Ariz. He can be reached at lkoh@midwestern.edu.

Disclosure: Koh reported no relevant financial disclosures.