Macular Edema

Etiology

The primary underlying causes of macular edema are increased leakage from damaged retinal blood vessels, the growth of abnormal blood vessels in the deep retina, and the breakdown of the blood-retinal barrier. New blood vessels lacking normal tight junctions lead to abnormal serum leakage from the bloodstream into the retina. Other significant causes of macular edema include diabetes, branch and central retinal vein occlusion (RVO), choroidal neovascularization, posterior uveitis, postoperative inflammation, and central serous chorioretinopathy (see Image. Macular Edema Associated With Diabetes).

Additional causes of macular edema include Coats disease, retinal artery macroaneurysms, radiation retinopathy, hypertensive retinopathy, inflammatory disorders, medications, choroidal tumors, retinitis pigmentosa, nonarteritic anterior ischemic optic neuropathy (NAION), and Irvine-Gass syndrome.

Common causes of subfoveal fluid without intraretinal fluid include acute central serous chorioretinopathy, polypoidal choroidal vasculopathy, and uveitis, including Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, posterior scleritis, and choroidal granuloma.[8][9][10][11][12] In addition, foveoschisis with or without subretinal fluid characterizes optic disc pit maculopathy. 

Epidemiology

Among the global working population, macular edema is the primary cause of vision loss in patients with diabetic retinopathy.[13] Its occurrence in population-based investigations ranges from 4.2% to 7.9% for individuals with type 1 diabetes and 1.4% to 12.8% for those with type 2 diabetes.[14] Notably, 27% of patients affected by type 1 diabetes develop diabetic macular edema within 9 years of onset. 

RVO presents with varying prevalence rates of macular edema. Central RVO (CRVO) impacts approximately 0.1% to 0.2% of the population, whereas branch RVO (BRVO) affects nearly 0.5% to 2% of individuals.[15][16] In a Canadian cohort, the annual incidence of visual impairment, defined as visual acuity worse than 20/40 due to macular edema associated with BRVO, is 0.056%, and due to CRVO is 0.021%.[17] 

Prevalence rates for age-related macular degeneration increase with age. The annual incidence of age-related macular degeneration ranges from 0.3 per 1000 in people 55 to 59 to 36.7 per 1000 in individuals aged 55 to 59 to 36.7 per 1000 individuals in those aged 90 or older. Uveitis may lead to macular edema, with prevalence rates varying based on the underlying uveitic condition. The incidence of uveitis itself ranges from 10.5 to 52 per 100,000 person-years.[18]

The incidence of clinical Irvine-Gass syndrome, also known as pseudophakic cystoid macular edema, which manifests following uneventful cataract surgery, varies from 0.1% to 2.35%.[19] However, patients assessed with FFA and OCT reveal a notably higher incidence of 30% after extracapsular cataract surgery and 4% to 11% after phacoemulsification.[20][21] Risk factors for its development include systemic conditions such as diabetes and hypertension, preexisting ocular conditions such as diabetic retinopathy and RVO, as well as intraoperative complications such as posterior capsule rupture, surgical trauma, vitreous loss, use of high phacoemulsification energy, and prolonged surgical duration.[22]

In a study involving 25 eyes with NAION, OCT revealed subretinal fluid around the optic disc in 64% of eyes, with involvement extending to the fovea in 16% of cases.[23] However, this prevalence may be underestimated since not all patients with NAION undergo OCT routinely.[24] Macular edema may occur in 10% to 50% of patients with retinitis pigmentosa.[25]

Pathophysiology

General Pathophysiology

Intra- or subretinal fluid accumulation is due to a combination of dysregulation of the blood-retinal barrier, which permits proteins and other solutes that are usually retained in the blood to infiltrate the retinal tissue, increased leakage from damaged retinal blood vessels, and the growth of abnormal blood vessels in the deep retina. This fluid can accumulate diffusely in the central retina or within cysts.

Blood-Retinal Barrier

To promote optimal light transmission, the retinal interstitial spaces maintain a dry state through collaborative mechanisms that regulate fluid movement in and out. The relatively rigid macular framework provides resistance, limiting fluid influx from the vitreous cavity driven by intraocular pressure (IOP). Additionally, osmotic and hydrostatic forces within the retinal tissue and capillaries counterbalance each other. Choroidal osmotic pressure efficiently draws fluid out of the subretinal space, while active transport mechanisms in the retinal pigment epithelium pumps actively transport fluid from the subretinal space to the choroid.[5] 

The crucial element in maintaining this delicate equilibrium is the blood-retinal barrier.[26] This barrier prevents large molecules, such as proteins, from entering the retinal tissue. Any disruption of the blood-retinal barrier that allows proteins and other solutes, typically confined to the bloodstream, to infiltrate the retinal tissue can result in macular edema. Tight junctions form the inner blood-retinal barrier, or zonulae occludentes, among retinal capillary endothelial cells.

In contrast, the outer blood-retinal barrier comprises tight junctions between retinal pigment epithelial cells, adherens junctions, and desmosomes or maculae adherens. Although adherens junctions between photoreceptors and the external limiting membrane are not entirely impermeable to proteins, they restrict free protein movement. Pathological conditions that disrupt the blood-retinal barrier lead to macular edema by allowing proteins to enter the retinal tissue, initiating fluid accumulation through osmosis.[6]

Microvascular Changes

Vascular leakage involves various mechanisms, with inflammation of vessel walls playing a central role. A myriad of inflammatory mediators initiate a complex cascade of reactions. These mediators include VEGF, angiopoietin-2 (Ang-2), placental growth factor (PlGF), angiotensin II, prostaglandins, cytokines, chemokines, interleukins, matrix metalloproteinases, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, E-selectin, as well as inflammatory cells such as macrophages and neutrophils.[27][28] 

The inflamed vessel wall activates the renin-angiotensin pathway, leading to the generation of angiotensin. Angiotensin II contributes to the breakdown of the blood-retinal barrier through various mechanisms, including leukocyte infiltration, heightened vascular permeability, and extracellular matrix remodeling. Ischemia in the retina, combined with angiotensin II, inflammation, and other growth factors, triggers the secretion of VEGF. This cascade results in the breakdown of the blood-retinal barrier by initiating leukocyte infiltration, prompting structural alterations, and dissolving tight junctions among endothelial cells through processes such as phosphorylation of occludin protein, activation of protein kinase C, and induction of fenestrations. Similarly, prostaglandin E1 induces blood-retinal barrier breakdown by facilitating the opening of tight junctions.[29]

The subretinal fluid typically results from a combination of inner blood-retinal barrier breakdown and damage to the retinal pigment epithelium pump. Conditions such as exudative age-related macular degeneration, choroidal neovascularization, choroidal neovascular membrane, polypoidal choroidal vasculopathy, and retinal angiomatosis proliferation involve active exudation within the subretinal space due to abnormal choroidal vessels. Consequently, subretinal fluid accumulation is more pronounced in these diseases compared to those that primarily affect the blood-retinal barrier.[6][7] 

Disease Specific Pathophysiology

Macular edema in diabetes: Diabetic macular edema arises from microvascular alterations in the retina, characterized by basement membrane thickening and pericyte reduction. These changes increase retinal vascular permeability, causing leakage of plasma constituents into the surrounding retina and edema. Hypoxia resulting from this process can further stimulate VEGF production.[6][7]  

Retinal vein occlusions: Ischemia, raised hydrostatic pressure in the perifoveal capillaries, and turbulent blood flow disrupt the outer blood-retinal barrier.[5]

Macular neovascularization: The most common cause of macular neovascularization is wet age-related macular degeneration.[30] Choroidal neovascularization results in macular edema, as the newly formed blood vessels leak into the retina, causing fluid accumulation in the macula.[31]

Vitreomacular interface disorders: Vitreomacular interface disorders, including epiretinal membrane and vitreomacular traction due to incomplete posterior vitreous detachment, can cause macular edema through several effects. Researchers believe the traction causes increased local VEGF secretion and inflammation, causing blood-retinal barrier breakdown, vascular leakage, and macular edema. In addition, direct distortion of surrounding intraretinal vessels likely contributes to leakage, amplifies local VEGF secretion, and triggers the release of inflammatory factors such as basic fibroblast growth factor, further inducing local inflammation.[30]

Coats disease: Coats disease is an idiopathic ocular condition characterized by retinal telangiectasia, aneurysms, and exudation. Damage to the endothelium of the retinal vasculature and abnormal pericytes disrupt the inner blood-retinal barrier.[32] These abnormalities lead to multiple telangiectasias, aneurysmal dilation of vessels, and retinal ischemia.[33]

Retinal artery macroaneurysms: Retinal artery macroaneurysms are typically caused by chronic hypertension, arteriosclerosis, and focal ischemia of blood vessel walls. These factors lead to the weakening of the blood vessel wall and subsequent aneurysmal dilatation, resulting in macular exudation and hemorrhage.[34][35]

Radiation retinopathy: Macular edema is one of the earliest features of radiation retinopathy.[36] Initially, vascular damage occurs in capillaries due to free radicals, resulting in capillary nonperfusion and leakage.[37] Subsequently, retinal ischemia ultimately leads to macular edema, neovascularization, vitreous hemorrhage, and tractional retinal detachment.[36] Tissue tolerance doses (TD) are the total radiation doses that lead to complication rates of 5% (TD5/5) and 50% (TD50/5), respectively, at 5 years.[38][39] The TD5/5 and TD50/5 for the retina are 45 and 65 Gy, respectively.[38][40][41]

Hypertensive retinopathy: Hypertensive retinopathy is characterized by ischemic hypoperfusion of the choroid, disrupting the outer blood-retinal barrier and damaging the retinal pigment epithelium.[7]

Irvine-Gass syndrome: Irvine-Gass syndrome is typically triggered by surgical trauma during intraocular surgeries, which induces the breakdown of the blood-aqueous barrier through various mechanisms, including prostaglandin release.[42] The subsequent diffusion of inflammatory mediators into the vitreous cavity disrupts the blood-retinal barrier, leading to increased permeability of the perifoveal capillaries.[43]

Inflammatory disorders: Inflammatory disorders are characterized by the infiltration of inflammatory cells, such as lymphocytes and macrophages, within the retinal layers. Additionally, various factors, including prostaglandins, initiate inflammatory cascades that contribute to tissue damage and exacerbate the breakdown of the blood-retinal barrier.[22] Patients with inflammatory conditions like intermediate uveitis, anterior uveitis, birdshot retinochoroiditis, retinal vasculitis, and post-fever retinitis may exhibit cystoid macular edema (see Image. Cystoid Macular Edema, Uveitis).[44][45][46][47][48]

Panretinal photocoagulation: Macular edema following panretinal photocoagulation occurs as a secondary effect of the inflammation induced during the procedure, coupled with increases in macular blood flow secondary to the laser.[1][2][6]

Drug-induced macular edema: Drug-induced macular edema can be triggered by various medications. For instance, topical epinephrine has been associated with the breakdown of the blood-retinal barrier and subsequent macular edema.[49] Prolonged systemic use of tamoxifen can also lead to reversible macular edema.[50] In addition, systemic nicotinic acid disrupts the blood-retinal barrier through prostaglandin release and Müller cell toxicity.[51][52] Topical latanoprost may cause a blood-aqueous barrier disruption in early postoperative eyes.[53]

Choroidal tumors: Choroidal tumors such as choroidal hemangioma can be linked to cystoid macular edema and subretinal fluid due to abnormal leaking vessels. In rare cases, choroidal melanoma may also lead to these conditions secondary to the infiltration of chronic inflammatory cells within the choroid adjacent to the tumor.[54][55]

Retinitis pigmentosa and other inherited retinal diseases: Macular edema associated with inherited retinal diseases may occur through several mechanisms. These include the breakdown of the blood-retinal barrier caused by toxic products released from degenerating retinal cells, particularly the retinal pigment epithelial cells. Additionally, failure of the retinal pigment epithelial pumping mechanism and Müller cell dysfunction can contribute to its development.[25] Macular edema may be present in conditions such as gyrate atrophy of the retina and choroid, even without leakage on FFA.[56][57][58][59] 

Juvenile X-linked retinoschisis, resulting due to mutations in the retinoschisin 1 (RS1) gene, encoding retinoschisin—a protein crucial for intercellular adhesion and likely retinal cellular organization—is a significant cause of juvenile macular degeneration in males. This condition typically manifests in the first decade of life (see Image. Juvenile X-Linked Retinoschisis).

Nonarteritic anterior ischemic optic neuropathy: Macular edema is an uncommon finding associated with NAION.[60] Researchers speculate that fluid from the peripapillary choroid can percolate into the subretinal or intraretinal spaces.[24] Notably, subretinal fluid extending to the fovea or involving the fovea alone may be noted in other disorders causing optic disc edema, including neuroretinitis.[61]

Histopathology

Histopathological studies underscore the critical role of blood-retinal barrier breakdown in the pathogenesis of macular edema. Macular edema frequently manifests with vascular changes, including capillary dilation, microaneurysm formation, and endothelial cell hyperplasia.[62] In addition, structural changes, including the presence of cystoid spaces within the inner nuclear layer and disruption of the external limiting membrane, are common findings.[63] These morphological changes correspond with the clinical manifestation of cystoid macular edema observed in imaging studies.

An additional characteristic histopathological feature is the presence of lipid-laden exudates within the macular region, particularly evident in cases associated with vascular abnormalities such as macular edema associated with diabetes.[64] These exudates contribute to the disruption of retinal architecture and further compromise visual function. Moreover, chronic macular edema often exhibits histological alterations in the extracellular matrix, including collagen deposition and fibrous tissue proliferation. These changes may signify the advancement of macular edema to a more advanced and irreversible stage.[65]

History and Physical

Macular edema can sometimes be asymptomatic, but typical symptoms include metamorphopsia, where objects—specifically straight lines—appear warped, distorted, or bent, and micropsia, where patients perceive the external world as smaller than its actual size. Additional symptoms include blurred vision, central scotoma, and reduced contrast or color sensitivity. Visual impairment can range from mild to severe. In cases of central serous chorioretinopathy, patients commonly report experiencing central round or oval relative scotomas.

Retinal Vein Occlusion

Common symptoms of RVO include scotoma or visual field deficits, along with blurred or gray vision. Pain is typically absent as the retina lacks trigeminal innervation. In BRVO, patients may not exhibit symptoms or experience peripheral visual field defects. Blurred central vision arises if macular involvement or edema occurs. CRVO presents with an acute onset of broad, unilateral, painless, blurred vision, whereas patients with hemiretinal vein occlusion typically report blurred central vision.

Coats Disease

Coats disease, primarily impacting males aged 18 or younger and middle-aged men, commonly presents with diminished visual acuity, strabismus, and leukocoria. The condition can sometimes develop as a secondary response to a previous vascular event. Symptoms usually manifest unilaterally, and clinical examination often reveals subretinal lipid accumulation alongside abnormal telangiectatic vessels. Please see StatPearls' companion resource, "Exudative Retinitis (Coats Disease)," for further information.

Retinal Artery Macroaneurysms

Individuals with retinal artery macroaneurysms commonly experience a sudden onset of painless vision loss in an eye. The patient may remain asymptomatic if the central macula is spared or the aneurysm occurs without exudation or hemorrhage. See StatPearls' companion resource, "Retinal Macroaneurysm," for further information regarding the presentation and physical examination findings associated with retinal artery macroaneurysms.

Radiation Retinopathy

Radiation retinopathy is often asymptomatic and is typically discovered incidentally during fundoscopic examination. Clinical observations may include cotton-wool spots, hard exudates, retinal edema, telangiectasia, and perivascular sheathing. When symptomatic, symptoms of painless vision loss may manifest months to years after radiation therapy. Dilated funduscopic examination often reveals macular edema, exudates, microaneurysms, and vessel telangiectasias.

Irvine-Gass Syndrome

Decreased or blurry vision following cataract surgery is a common presentation of Irvine-Gass syndrome, often accompanied by optic disc edema as a characteristic funduscopic finding. 

Nonarteritic Anterior Ischemic Optic Neuropathy 

Affected patients typically present with monocular vision loss that occurs over hours to days. Common findings from the examination include reduced visual acuity, diminished color vision, an afferent pupillary defect, optic disc edema, peripapillary splinter hemorrhage, and a small optic cup in the unaffected eye. The optic disc is usually hyperemic. 

Evaluation

Historically, methods for evaluating macular edema included contact and non-contact slit lamp biomicroscopy, indirect ophthalmoscopy, FFA, fundus stereo photography, and OCT. Currently, OCT and FFA are the predominant investigative tools. Notably, measuring visual acuity in all patients is imperative, as while it may not directly aid in diagnosing macular edema, it serves as a crucial parameter for monitoring disease progression.

Slit-Lamp Biomicroscopy

The initial step in evaluating macular edema involves slit-lamp biomicroscopy, typically conducted using a 90D or 78D lens. The biomicroscopic examination method reveals the presence and location of macular thickening, exudates, and cystoid changes.[66] A distinctive stellate or radially oriented pattern of perifoveal cysts attributed to the oblique arrangement of the Henle fiber layer characterizes cystoid macular edema. Beyond the macular area, edema presents a honeycomb appearance due to the perpendicular alignment of the outer plexiform layer. A central cyst associated with cystoid macular edema may resemble a full-thickness macular hole; however, conducting the Watzke-Allen test during slit lamp biomicroscopy with a 90D lens reveals an intact vertical line without a central break.[67] Additionally, macular edema tends to reduce choroidal visibility compared to unaffected areas. Stereoscopic examination, facilitated by a 90D or macular contact lens, provides a 3-dimensional perspective, aiding in the identification of retinal elevation.

Fundus Fluorescein Angiography

FFA can delineate regions of retinal capillary leakage. The Early Treatment Diabetic Retinopathy Study (ETDRS) categorizes diabetic macular edema into diffuse and focal types based on the degree of fluorescein leakage associated with microaneurysms. According to the ETDRS criteria, focal diabetic macular edema exhibits 67% or more leakage associated with microaneurysms, intermediate demonstrates 33% to 66% leakage, and diffuse showcases less than 33% leakage associated with microaneurysms.[68] Larssen et al define diffuse diabetic macular edema as retinal thickening affecting 2 or more disk areas with involvement of the macular center. Focal diabetic macular edema, on the other hand, presents retinal thickening of less than 2 disk areas without affecting the macular center.[69] In FFA, focal macular edema is identified by fluorescein leakage from specific capillary regions. Ischemic diabetic macular edema appears as hypofluorescent areas within the macula (see Image. Multimodal Imaging of Diabetic Macular Edema).

Early-phase choroidal fluorescence can become partially obstructed in the presence of a considerable amount of edema, whether cystoid or non-cystoid, particularly if turbid due to lipid-laden macrophages. Dilation of the fine capillary network or telangiectatic retinal vessels around the fovea may be observed in the arteriovenous phase. Late-phase imaging reveals hyperfluorescence caused by dye accumulation leaking from retinal vessels, the extent of which depends on the dysfunctional retinal vascular endothelium. Hyperfluorescence may manifest as cystic or diffuse irregular staining, filling cystoid spaces rapidly in the presence of pronounced leakage or appearing late if not significant. Additionally, large retinal vessels may leak, termed perivascular staining, due to inflammation, traction, or occlusion. Cystoid macular edema typically presents as a petaloid leak at the macula during the late phase of FFA.[70]

Conditions in which an FFA leak is not evident despite the presence of macular edema include retinitis pigmentosa, gyrate atrophy of the retina and the choroid with foveoschisis, juvenile X-linked retinoschisis, Goldmann-Favre disease, phototoxicity, toxicity from antimicrotubule agents such as paclitaxel and docetaxel, and toxicity from nicotinic acid.[51][52][71] Foveoschisis and leaking cystoid macular edema can be distinguished through FFA, as foveoschisis does not exhibit leakage or induce the characteristic petaloid leak of cystoid macular edema. 

Optical Coherence Tomography

Clinicians use OCT to evaluate macular edema caused by diseases such as age-related macular degeneration, diabetic retinopathy, hereditary retinal degeneration, RVO after cataract surgery, epiretinal membrane, and uveitis. Owing to its excellent reproducibility, OCT has become the preferred diagnostic modality for diagnosing and monitoring cystoid macular edema. OCT enables clinicians to identify, localize, and quantify fluid collections, facilitating precise assessment and long-term monitoring. Additionally, OCT's capacity to classify various diseases supports prognostication, aiding in disease management, predicting patient outcomes, and treatment planning.

Diabetic macular edema: Different patterns of fluid accumulation appear on OCT in patients with diabetic macular edema:

• Diffuse retinal thickening: Characterized by retinal thickness greater than 200 μm in height and more than 200 μm in width with areas of lower reflectivity, especially in the outer retinal layers.

• Cystoid macular edema: Manifests as intraretinal fluid accumulation within well-defined spaces of low reflectivity, typically originating around the outer plexiform layer but potentially involving the photoreceptor and inner retinal layers.

• Posterior hyaloid traction or taut posterior hyaloid membrane: Identified by the presence of a highly reflective membrane on the inner retinal surface, causing tractional retinal elevation.

• Subretinal fluid: Identified as a dome-shaped dark region located between the neurosensory retina and the retinal pigment epithelium.

• Tractional retinal detachment: Characterized by a peak-shaped retinal detachment resulting from traction exerted by proliferative membranes over the retinal surface or within the vitreous.[41] This condition presents as a low signal area underlying the highly reflective border of the detached retina.

Radiation retinopathy: OCT enables clinicians to grade radiation retinopathy using a 5-point grading system, which correlates with visual acuity.

• Grade 1: Foveola-sparing non-cystoid macular edema

• Grade 2: Foveola-sparing cystoid macular edema

• Grade 3: Foveola-involving non-cystoid macular edema

• Grade 4: Mild-to-moderate foveola-involving cystoid macular edema

• Grade 5: Foveola-involving severe cystoid macular edema [40][41]

Juvenile X-linked retinoschisis: OCT findings can classify juvenile X-linked retinoschisis into distinct types, as mentioned below.

• Type 1 or foveal: Absence of both lamellar schisis on OCT and peripheral schisis on the ophthalmoscopy.

• Type 2 or foveolamellar: Presence of lamellar schisis on OCT without peripheral schisis on the ophthalmoscopy.

• Type 3 or complex: Lamellar schisis on OCT and peripheral schisis on the ophthalmoscopy.

• Type 4 or foveoperipheral: Presence of peripheral schisis on ophthalmoscopy without lamellar schisis on OCT.[72][73]

The hallmark finding of juvenile X-linked retinoschisis is the presence of a spoke-wheel pattern in the macula, particularly observable in high-magnification ophthalmoscopy in patients aged 30 or younger. Currently, spectral domain OCT serves as the primary diagnostic modality for this condition, allowing for the visualization of marked retinoschisis in various retinal layers. Clinicians may observe dilation of the fine capillary network or telangiectatic retinal vessels around the fovea.

On OCT, patients with uveitis typically exhibit diffuse macular edema, cystoid macular edema, and subretinal detachment. Clinicians may observe intraretinal fluid, accumulation of subretinal fluid, and pigment epithelial detachments in patients with choroidal neovascularization, as seen in wet age-related macular degeneration. Subretinal detachment is also evident in OCT scans of patients with BRVO. Vitreomacular traction manifests as foveal cavitation, while the posterior hyaloid often appears hyper-reflective and thickened on OCT. OCT angiography is a valuable tool for evaluating the vascular status of the posterior pole. 

Treatment / Management

A stepwise therapeutic approach is essential for managing macular edema, typically involving systemic and ocular pharmaceutical agents. Surgical intervention may also be required to address specific needs in certain cases.

Systemic Therapy

Given that many patients develop macular edema as a secondary manifestation of systemic health conditions such as diabetes, hypertension, dyslipidemia, or inflammatory conditions, addressing these underlying systemic issues is paramount. Research indicates that strict glycemic control can effectively delay the onset and progression of diabetic retinopathy in both type 1 and type 2 diabetes.[74][75] Additionally, managing associated disorders such as nephropathy and ischemic heart disease yields significant benefits.[76][77](A1)

Intravitreal Anti-Vascular Endothelial Growth Factor  

Intravitreal injections of anti-VEGF agents represent the primary treatment approach for macular edema across various pathologies. Pegaptanib, the initial medication approved for human use, is a 40-kDa aptamer and mRNA polyethylene glycol-linked molecule designed to specifically target VEGF165. However, it is no longer utilized for treatment.[78] (B3)

Currently, clinicians commonly administer 3 formulations of intravitreal anti-VEGF therapies:

• Bevacizumab, available at 1.25 mg/0.05 mL, is a 148-kDa humanized full-size monoclonal IgG1 antibody targeting all VEGF-A subtypes.

• Ranibizumab, available at 0.3 mg/0.05 mL and 0.5 mg/0.05 mL, is a 48-kDa humanized monoclonal antibody fragment also targeting all VEGF-A subtypes.

• Aflibercept, available at 2 mg/0.05 mL, is a 115-kDa fusion protein targeting VEGF-A, VEGF-B, and placental growth factors.

Diabetic macular edema: Findings from the Diabetic Retinopathy Clinical Research (DRCR) Retina Network Protocol H indicate that intravitreal bevacizumab may mitigate diabetic macular edema in select cases.[79] Similarly, the bevacizumab or laser therapy (BOLT) study demonstrates the favorable impact of intravitreal bevacizumab on center-involving clinically significant macular edema in eyes without advanced macular ischemia. The ETDRS defines clinically significant macular edema as retinal thickening within 500 μm of the macular center, hard exudates within 500 μm of the macular center with associated adjacent retinal thickening, or retinal thickening measuring 1 or more disc areas, a part of which lies within 1 disc diameter of the macular center.[80] (A1)

Results indicate that eyes receiving intravitreal bevacizumab experience a median increase of 8 letters on the ETDRS visual acuity chart. In comparison, those treated with laser therapy experience a median decrease of 0.5 letters after 1 year. The likelihood of gaining 10 or more letters on the ETDRS visual acuity chart is 5.1 times higher in the intravitreal bevacizumab cohort.[81] Notably, the use of intravitreal bevacizumab in this capacity is off-label. (A1)

The Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema (RESTORE) trial demonstrates that intravitreal ranibizumab 0.5 mg, either as monotherapy or combined with laser, yields greater visual improvement compared to standard laser alone.[82] Additionally, 2 parallel phase III trials indicate that intravitreal ranibizumab at both 0.3 and 0.5 mg doses outperforms sham injections in terms of visual improvement and reduction in central retinal thickness.[83] (A1)

The DRCR Retina Network Protocol I shows that 0.5 mg of intravitreal ranibizumab with prompt or deferred laser produces superior visual gain compared to 4 mg of intravitreal triamcinolone acetonide with laser and laser alone. Visual outcomes produced by intravitreal ranibizumab plus deferred laser are better than those from intravitreal ranibizumab plus prompt laser. Subgroup analysis reveals that intravitreal triamcinolone acetonide plus laser yields similar results to intravitreal ranibizumab plus laser in eyes with pseudophakic macular edema.[84](A1)

The diabetic macular edema and vascular endothelial growth factor trap-eye: Investigation of Clinical Impact (DA VINCI) study demonstrates that intravitreal aflibercept achieves superior anatomical and functional improvement compared to laser therapy.[85] In addition, 2 parallel phase III trials reveal that eyes treated with aflibercept exhibit significantly greater mean visual gain and edema resolution after 1 year compared to laser therapy.[86](A1)

All 3 medications demonstrate comparable efficacy when visual acuity exceeds 20/50. However, when the baseline visual acuity is 20/50 or worse, aflibercept exhibits superior improvement compared to ranibizumab and bevacizumab. The median number of injections and occurrence of adverse events remain consistent across all 3 medications.[87][88] (A1)

The DRCR Retina Network Protocol V shows no significant difference in visual loss at the end of 2 years among eyes with center-involving diabetic macular edema and a best corrected visual acuity of 20/25 or better, irrespective of the treatment. Consistent with current practice, the study proposes clinicians observe patients with good visual acuity and treat them with aflibercept only if the visual acuity worsens.[89](A1)

Retinal vein occlusion: In the Branch Retinal Vein Occlusion (BRAVO) trial, eyes with BRVO receiving 6 monthly intravitreal ranibizumab 0.3 or 0.5 mg injections show superior visual improvement compared to sham injections. Visual acuity at 1 year remains well-maintained even after shifting to as-needed dosing for the subsequent 6 months.[90] The Central Retinal Vein Occlusion (CRUISE) trial yields similar outcomes.[91](A1)

Studies demonstrate that administering 6 monthly aflibercept injections followed by bi-monthly injections results in superior visual benefit and reduced edema compared to macular grid laser in eyes with BRVO-related macular edema at 24 and 52 weeks.[92] Additionally, 2 other studies reveal that 6 monthly aflibercept injections followed by as-needed dosing help achieve more significant visual benefit and edema reduction than macular grid laser in eyes with ventral RVO-related macular edema.[93][94] Brolicizumab (6 mg/0.05 mL) and faricimab (6 mg/0.05 mL) are among the additional available anti-VEGF medications.[95][96] (A1)

Ocular Topical Medications

Nonsteroidal anti-inflammatory drugs: NSAIDs reduce the production of prostaglandins by inhibiting the enzyme cyclooxygenase. Most studies reveal that NSAIDs have a beneficial role in managing pseudophakic cystoid macular edema. However, further well-designed randomized control trials are necessary to establish their efficacy conclusively.[43][97] Bromfenac 0.09%, nepafenac 0.1%, diclofenac 0.1%, ketorolac 0.5%, flurbiprofen 0.03%, and indomethacin 1% have demonstrated efficacy in reducing postoperative inflammation following cataract surgery in randomized controlled clinical trials. Evidence suggests that combining topical NSAIDs with topical corticosteroids in patients with pseudophakic cystoid macular edema provides a synergistic effect (see Image. Pseudophakic Cystoid Macular Edema).

Recent studies indicate improved central subfield thickness in patients with diabetic macular edema who maintain good glycemic control. Patients treated with NSAIDs show more stable intraocular pressure compared to those receiving topical corticosteroids, suggesting a potential advantage. However, further research is needed to confirm these findings. The DRCR Retina Network Protocol R findings suggest that topical nepafenac 0.1% does not significantly affect OCT-measured retinal thickness in eyes with non-center involving diabetic macular edema after 1 year.[98]  (A1)

Topical carbonic anhydrase inhibitors: Carbonic anhydrase inhibitors (CAI) inhibit the enzymes carbonic anhydrase and γ-glutamyl transferase, increasing fluid transport from the sub-retinal space toward the choroid. These medications are particularly effective in disorders with diseased retinal pigment epithelium, such as retinal pigment-related macular edema.

Ocular Laser 

Ocular lasers can treat macular edema secondary to various diseases.

Diabetic macular edema: Laser therapy is recommended for patients with inadequate response to anti-VEGF therapy. Healthcare providers typically utilize double diode or YAG photocoagulation lasers to treat diabetic macular edema. The ETDRS reveals that laser reduces the risk of moderate visual loss, or a loss of 15 letters on the EDTRS visual chart or a doubling of the visual angle, at 36 months. After 6 weeks, clinicians can treat any untreated initial lesions. Repeat treatment should be scheduled at least 4 months after the initial session if no initial lesions remain.[99]

Diabetic macular edema treatment techniques: The various techniques to manage diabetic macular edema are listed below.

• Focal laser: Focal laser treatment involves addressing lesions situated within 500 to 3000 µm from the macular center using moderate-intensity burns sized 50 to 100 µm for durations of 50 to 100 ms. These lesions typically include microaneurysms, intraretinal microvascular abnormalities, and leaking short capillary segments observed on FFA. Treatment success is indicated by whitening or darkening of the focal lesions, serving as the end point.[100]

• Grid laser: Grid laser treatment targets regions displaying diffuse capillary leakage or nonperfusion observed on FFA within 500 to 3000 µm from the macular center. Clinicians apply burns sized 50 to 200 µm for durations of 50 to 500 ms, placing 2 burn widths apart. The end point of treatment is signified by mild retinal pigment epithelium whitening. Focal leaks within this region have also been addressed. The possible mechanisms of action include improved oxygen supply to the inner retina due to laser-induced damage to oxygen-consuming photoreceptors and retinal pigment epithelium, reduced autoregulatory vasoconstriction, and restoration of the retinal pigment epithelium barrier and pump.[100]

• Modified grid laser: This laser treatment ensures burns are not intense enough to alter the color of microaneurysms. Achieving mild gray-white burns beneath all microaneurysms is considered adequate for effective treatment.[100]

• Mild macular laser photocoagulation: This involves applying light burns that are barely visible or appear as light gray over the macula, including both thickened and normal retina. Microaneurysms are not directly treated during this procedure.[101]
(A1)

The DRCR Retina Network Protocol A reports that while the mild macular photocoagulation laser protocol may be less effective in reducing retinal thickness compared to the modified grid laser protocol, both protocols yield similar visual outcomes.[101] Protocol B demonstrates that the modified grid laser protocol is more effective and associated with fewer adverse effects than intravitreal triamcinolone injections over a 2-year period.[102](A1)

Branch retinal vein occlusion: The Branch Retinal Vein Occlusion, Associated Macular Edema study reports that nearly one-third of cases improve spontaneously within the first 3 months. Eyes with persistent macular edema, visual acuity of 20/40 or worse, and an absence of macular ischemia on FFA have better visual outcomes at 3 years when treated with macular grid laser than observation. Clinicians place the grid laser spots in the area of capillary leak located outside the edge of the foveal avascular zone and inside the significant vascular arcades.[103](B3)

Central retinal vein occlusion: The CRUISE trial demonstrates that macular grid laser treatment reduces angiographic evidence of macular edema in central retinal vein occlusion. However, it does not show any significant visual benefit.[104](A1)

Retinal artery macroaneurysm: Clinicians have several options for treating leaking retinal microaneurysms, including direct or indirect laser therapy, or a combination of both. Clinicians perform direct laser by applying 200 to 500 µm size, 200 to 500 ms duration burns over the microaneurysm to seal the aneurysm. However, this can weaken the already thin and distended wall of the aneurysm, potentially leading to complications such as aneurysm rupture, vitreous and preretinal hemorrhage, and arterial occlusion. Clinicians perform indirect laser treatment by applying 100 to 200 ms confluent burns around the lesion. This treatment may reduce the oxygen demand of the surrounding tissue, which subsequently may reduce the blood flow and pressure inside the aneurysm.

Intravitreal Steroids 

Fluocinolone acetate: A non-biodegradable intravitreal implant containing fluocinolone acetonide (0.59 mg; Retisert; Bausch and Lomb) is available. Studies reveal that implanting this device achieves better visual and anatomic outcomes than laser in eyes for diabetic macular edema. The rates of cataract progression and IOP elevation to 30 mm Hg or more are 91% and 61.4%, respectively.[105] An additional non-biodegradable, sustained-release device containing fluocinolone acetonide (0.19 mg; Iluvien; Alimera Sciences, Inc) is also available.(A1)

A phase III trial reveals that implantable devices containing either 0.2 or 0.5 μg/d produce superior visual improvement compared to sham injections for up to 3 years. Patients with chronic diabetic macular edema have superior outcomes. Almost all patients with phakic macular edema develop cataracts, but visual improvement is equivalent to pseudophakic macular edema following cataract surgery. The associated incidence of glaucoma is low at 7.6% in high-dose or 0.5 μg/d and 3.7% in the low-dose or 0.2 μg/d groups.[106](A1)

Intravitreal triamcinolone acetonide: The Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE) trial reveals that intravitreal triamcinolone acetonide at doses of 1 mg or 4 mg does not offer significant benefits compared to macular grid laser for macular edema related to BRVO, in terms of visual acuity or foveal thickness. Intravitreal triamcinolone acetonide treatment results in notable adverse effects such as cataracts and elevated IOP. Conversely, intravitreal triamcinolone acetonide demonstrates superiority over observation for macular edema associated with central RVO. Moreover, the safety profile of the 1 mg dose is preferable to the 4 mg dose.[107](A1)

Clinicians may use posterior subtenon triamcinolone injections to address various disorders leading to macular edema.[108] High-dose systemic steroids, including intravenous methylprednisolone, may aid in managing subfoveal fluid in acute Vogt-Koyanagi-Harada disease and sympathetic ophthalmia.[109](B3)

Dexamethasone: Implantable dexamethasone is available in a biodegradable 0.35 or 0.7 mg sustained-release device (Ozurdex; Allergan, Inc.). Studies reveal that the implant meets the primary efficacy end point for visual improvement without monthly injections. However, studies indicate that 67.9% of eyes in the 0.7 mg group develop cataracts, and 27.7% experience a 10-mm Hg or more elevation in IOP.[110] A study demonstrates superior anatomical and similar visual outcomes of the steroid implant compared to bevacizumab for diabetic macular edema with fewer injections.[111] Further research highlights its effectiveness in both BRVO and central RVO compared to sham treatment, with peak visual and anatomical improvement observed after 60 days before subsequent deterioration in vision.[112](A1)

The DRCR Retina Network Protocol U reveals that adding a dexamethasone implant to continued intravitreal ranibizumab therapy is not likely to improve visual acuity at 24 weeks compared to using intravitreal ranibizumab therapy alone in eyes with persistent diabetic macular edema. However, combining these treatments is expected to reduce retinal thickness while potentially increasing IOP.[113](A1)

Further studies comparing anti-VEGF therapy with dexamethasone implants have shown superior results with anti-VEGF injections compared to dexamethasone implants in treating macular edema due to diabetes and RVO. Although implants reduce injection frequency, they carry higher risks of cataracts and steroid-induced glaucoma. Therefore, dexamethasone or any implantable steroid is typically considered second-line therapy. Combination therapy with anti-VEGF medications is not likely superior to anti-VEGF injections alone. 

Differential Diagnosis

The differential diagnoses of macular edema include the following conditions:

• Vitreomacular traction and epiretinal membrane
• Autosomal dominant cystoid macular edema due to Müller cell dysfunction
• Juvenile X-linked retinoschisis [72][73] 
• Foveoschisis  
• Hypotony macular edema due to abnormal retinal capillary permeability secondary to reduced IOP [1][2]
• Congenital cavitary disc maculopathy, including optic nerve head pit or optic disc pit, morning glory anomaly, optic nerve coloboma, and extra-papillary cavitation [114] 
• Chronic central serous chorioretinopathy [114][115]
• Microcystic macular edema in advanced glaucoma and optic neuropathy [116]
• Berlin edema or commotio retinae (see Image. Commotio Retinae With Foveal Involvement)[117]
• Macular telangiectasia or idiopathic juxtafoveal telangiectasia [118] 
• Central retinal arterial occlusion [119] 

Prognosis

The prognosis of macular edema typically varies based on its underlying cause. Approximately 33% to 35% of individuals with diabetic macular edema experience spontaneous resolution within 6 months. With the advent of newer pharmacological agents for intravitreal injection, the prognosis of most retinal disorders has improved.

Several OCT biomarkers can aid in determining the prognosis of macular edema, as mentioned below. 

Disorganization of the inner retinal layers: This is characterized by the inability to distinguish boundaries between any 2 of the following—ganglion cell–inner plexiform layer complex, inner nuclear layer, or the outer plexiform layer in more than 50% of the foveal 1-mm zone defines disorganization of the inner retinal layers. A poor visual prognosis is anticipated when disorganization of the inner retinal layers affects 50% or more of the central foveal 1 mm.[120]

Hyperreflective retinal foci: These indicate subclinical lipoproteins or other materials that extravasate following the breakdown of the inner blood-retinal barrier. Their presence indicates a high chance of subfoveal hard exudate deposition after the resolution of macular edema.[121]

Intraretinal cystoid spaces: These serve as indicators of Müller cell malfunction, and their prognostic significance depends on their size. Small cysts measure less than 100 µm, whereas large ones range from 101 to 200 µm, and giant cysts exceed 200 µm. Additionally, their location and association with hyperreflective material, composed of fibrin and inflammatory by-products, further determine their prognostic significance, signifying severe blood-retinal barrier disruption. The hyperreflective material observed on OCT angiography manifests as an extravascular signal attributed to particulate Brownian motion, termed suspended scattering particles in motion. Typically located at the vascular-avascular junction, these signals often resolve with the formation of hard exudates.[122][123] Large cysts are usually associated with macular ischemia, whereas giant cysts tend to inflict damage on the outer nuclear layer and ellipsoid zone, resulting in poorer visual outcomes. 

Photoreceptor outer segment: This refers to the length between the junction of the inner and outer segments of the photoreceptor and the retinal pigment epithelium. Shorter lengths are often associated with poorer visual acuity.[124]

The integrity of the external limiting membrane and ellipsoid zone: The integrity of outer retinal layers indicates the health of photoreceptors and retinal pigment epithelium.[125]

Complications

If left untreated, macular edema can lead to irreversible vision loss.[126] Additional complications may include damage to the central retinal tissue, foveal atrophy, epiretinal membrane, macular ischemia, lamellar macular hole, and macular fibrosis. However, the various treatment modalities may also carry risks of additional complications. For instance, laser photocoagulation may lead to accidental foveal burns, subretinal fibrosis, scarring, and choroidal neovascular membranes. Intravitreal injections pose the risk of severe complications such as endophthalmitis, as well as vitreous hemorrhage, central retinal artery occlusion, and retinal tears.[127] Risks specific to anti-VEGF medications include cerebrovascular accidents, vasculitis with occlusion, and retinal occlusion, while corticosteroids may cause cataracts and steroid-induced glaucoma.