Continuing Education Activity

Macular edema is a non-specific sign or sequelae for a myriad of intraocular and systemic diseases, which leads to significant visual loss. It is important to recognize the cause of visual loss as it may be the presenting sign of a number of systemic diseases. Also, timely intervention is necessary to prevent permanent visual loss. This CME activity reviews the evaluation and treatment of macular edema and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the various systemic and ocular diseases associated with macular edema.
• Summarise the basic mechanisms responsible for causing macular edema.
• Review the various modalities used for investigating macular edema.
• Outline the various treatment modalities used for managing macular edema by an interprofessional team.

Introduction

Macular edema is defined as a collection of localized swelling in the macular area, leading to increased central retinal thickness. In the initial stage, the fluid accumulates in the outer plexiform layer (OPL) and/or the inner nuclear layer (INL). Swelling of the Müller cells has also been noted. The accumulated fluid may involve the intracellular and/or extracellular retinal spaces. It is a non-specific sign or sequelae for a myriad of intraocular and systemic diseases.[1][2]

The macula is the most predisposed region for the development of edema due to its unique anatomical features. The various predisposing factors include a high rate of fluid production due to the high cell count in this region along with the high metabolic activity; low rate of extracellular fluid resorption due to the presence of a central avascular zone; and the peculiar arrangement of the Henle fiber layer which makes the region a potential fluid reservoir.[3][4]

Etiology

Diabetic macular edema (DME): The vascular dysfunction is initially caused by the breakdown of the inner BRB, while the outer BRB is compromised in the later stages. The damage occurs secondary to hyperglycemia (vascular endothelial cells are damaged due to their inability to regulate intracellular glucose levels), ischemia, enhanced reactive oxygen intermediates production, extracellular matrix degradation, and modulation caused (matrix metalloproteinases are activated), and abnormal autoregulation (capillary basement membrane thickening).[3][4]

Retinal vein occlusions: The outer BRB is disrupted due to ischemia, raised hydrostatic pressure in the perifoveal capillaries, and a turbulent blood flow.

Coat disease: The inner BRB is disrupted due to damage to the endothelium of the retinal vasculature and abnormal pericytes. These abnormalities lead to multiple telangiectasias (sausage-like vessels) and retinal ischemia.[5]

Retinal artery macroaneurysms (RAM): Chronic hypertension, arteriosclerosis, and focal ischemia of blood vessel walls cause weakening of the blood vessel wall and subsequent aneurysmal dilatation.[6]

Radiation retinopathy (RR): Macular edema is the earliest feature of RR. The free radicals cause vascular damage (initially capillaries), leading to capillary nonperfusion. The pathogenies and clinical features are similar to diabetic retinopathy. Tissue tolerance doses (TD and TD) are defined as the total radiation doses which lead to complication rates of 5% and 50%, respectively, at five years. The values of TD and TD for the retina are 45 and 65 Gy, respectively.[7][8]

Hypertensive retinopathy (stage IV): The outer BRB is disrupted due to ischemic hypoperfusion of the choroid, resulting in RPE damage.[4]

Irvine-Gass syndrome: The surgical trauma during intraocular surgeries causes the breakdown of the blood-aqueous barrier via prostaglandin release. The inflammatory mediators subsequently diffuse into the vitreous cavity and also disrupt the BRB; this increases the permeability of the perifoveal capillaries.[9]

Inflammatory disorders: BRB breakdown is mediated by the release of prostaglandins.[10]

Non-arteritic anterior ischemic optic neuropathy (NAION): It is assumed that fluid can percolate into the subretinal and/or intraretinal spaces from the peripapillary choroid.[11]

Edema after panretinal photocoagulation (PRP): This occurs secondary to the inflammation-induced during the procedure and increases in macular blood flow secondary to the laser.[1][2][3]

Drug-induced macular edema: Topical epinephrine (antiglaucoma medication) causes the breakdown of the BRB. Prolonged use of systemic tamoxifen can cause reversible macular edema.[12] Systemic nicotinic acid disrupts the BRB by prostaglandins release and/or Müller cells toxicity (causes intracellular fluid accumulation).[13][14] Topical latanoprost (antiglaucoma medication) causes blood-aqueous barrier disruption in early postoperative eyes.

Choroidal tumors: Cystoid macular edema and subretinal fluid may be seen in tumors like choroidal melanoma secondary to infiltration of chronic inflammatory cells within the choroid adjacent to the tumor; and choroidal hemangioma due to the abnormal leaking vessels, respectively.

Retinitis pigmentosa (RP): The possible mechanisms responsible include the breakdown of the BRB due to the ‘toxic products’ released from the degenerating retinal cells, especially the RPE cells; failure of the RPE pumping mechanism, and muller cell dysfunction.[15]

Epidemiology

Diabetic macular edema is one of the leading causes of visual loss among the working population worldwide. Its prevalence in population-based studies is around 4.2 to 7.9% among patients with type 1 diabetes and was 1.4 to 12.8 % among patients with type 2 diabetes.[16]

The incidence of Irvin Gass syndrome secondary to an uncomplicated surgery varies from 0.1 to 2%. The risk factors for its development include systemic conditions like diabetes and hypertension, pre-existing ocular conditions like diabetic retinopathy (DR), retinal vein occlusion, epiretinal membrane, uveitis, and intra-operative complications like posterior capsule rupture, surgical trauma, especially to iris, vitreous loss, use of high phacoemulsification energy during the surgery and long surgical duration.[10]

The incidence of SRF in eyes with NAION is approximately 10%. However, this may be an underestimation as all these patients are not routinely subjected to optical coherence tomography (OCT).[11]

Macular edema may occur in 10 to 50% of patients with RP.[15]

Pathophysiology

Under physiological conditions, the retinal interstitial spaces are kept dry by several forces which work together to move fluid out of the retinal and subretinal spaces. Firstly, the resistance offered by the relatively rigid macular framework limits the fluid-driven into the retina from the vitreous cavity due to the intraocular pressure (IOP). Secondly, the osmotic and hydrostatic forces of the retinal tissue and capillaries balance each other. Thirdly, the strong choroidal osmotic pressure draws fluid out of the subretinal space. Lastly, retinal pigment epithelium (RPE) actively pumps fluid out of the subretinal space towards the choroid.

The most important factor for maintaining this delicate balance is the blood-retinal barrier (BRB). The barrier prevents the entry of large molecules like proteins into the retinal tissue. Hence, the retinal tissue is devoid of proteins under physiological conditions. The inner BRB is formed by the tight junctions (zonulae occludentes) between the retinal capillary endothelial cells. The outer BRB is formed by the tight junctions between the RPE cells, adherens junctions, and desmosomes (maculae adherentes). The zonulae adherentes between the photoreceptors and the external limiting membrane (ELM) are not completely impermeable to proteins but do not allow free protein movement. Hence, the proteins (if they enter) inside the retinal tissue are retained for a certain period. Thus, the pathological conditions which cause BRB breakdown, leading to macular edema as proteins enter the retinal tissue, and subsequently, fluid retention starts in the retinal tissue secondary to osmosis.

The fluid does not usually collect in the subretinal space as the RPE pumps actively transport out. Hence, the presence of subretinal fluid (SRF) usually indicates a combination of BRB breakdown and RPE pump damage. In the diseases like exudative age-related macular degeneration (choroidal neovascularization/ CNVM, Polypoidal choroidal vasculopathy/ PCV, retinal angiomatosis proliferation/ RAP), active exudation occurs within the subretinal space due to the abnormal choroidal vessels. Hence, the SRF accumulation is higher compared to diseases damaging the BRB.[3][4]

Intracellular edema develops when the cell membrane transport systems, responsible for maintaining the delicate ion-water movement across the cell membrane, are damaged. This leads to cell death and the release of multiple excitotoxins and free radicals, leading to the disruption of the BRB. Such damage occurs secondary to any metabolic insult (e.g., ischemia).

Understanding the basic mechanisms responsible for causing macular edema is important to change the therapeutic approach from broad-symptomatic treatment to a targeted treatment. Hence, it may be possible to develop drugs that target the specific molecules involved in the pathophysiology of a particular disease. Several mechanisms are involved in vascular leakage; inflammation of the vessel walls plays a central role. Several inflammatory mediators produce a complex chain of reactions leading to vascular leakage. These mediators include vascular endothelial growth factor (VEGF), 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, and inflammatory cells like macrophages and neutrophils.

Angiotensin is produced in the inflamed vessel wall through the renin-angiotensin pathway. Angiotensin II is responsible for causing the breakdown of the BRB via several mechanisms, including leukocyte infiltration, increase in vascular permeability, and extracellular matrix remodeling. VEGF is expressed primarily in endothelial cells. Its release is stimulated by retinal ischemia, angiotensin II, inflammation, and other growth factors. It induces BRB breakdown by leucocyte infiltration, producing conformational changes and dissolution of endothelial cell tight junctions by phosphorylating the protein occludin; activation of protein kinase C; and induction of fenestrations. Similarly, prostaglandin E1 causes BRB breakdown by opening the tight junctions.[17]

History and Physical

The patients present with visual loss, which may vary from mild to severe. Some patients may have no visual loss but may complain of metamorphopsia.

The simplest method for diagnosing retinal thickening is slit-lamp examination. CME refers to a typical stellate configuration, i.e., radially-orientated perifoveal cysts. It occurs due to the characteristic oblique arrangement of the Henle fiber layer. Edema outside the macular region has a honeycomb appearance as the outer plexiform layer is arranged perpendicularly.

The early treatment diabetic retinopathy study (ETDRS) defined clinically significant macular edema (CSME) as retinal thickening within 500 microns of the macular center; hard exudates within 500 microns of the macular center with associated adjacent retinal thickening; or retinal thickening measuring ≥1 disc area (DA), a part of which lies within one disc-diameter (DD) of the macular center.[18] Larssen et al. defined diffuse DME as ≥2 DA retinal thickening with involvement of the macular center; and focal DME as retinal thickening <2 DA without affecting the macular center.[19]

Evaluation

Investigations can be grouped into three categories.

1. Detect disturbance of the BRB: FFA, vitreous fluorophotometry, and laser flare cell photometer.
2. Detect retinal tissue thickening: OCT, retinal thickness analyzer (RTA), and scanning laser ophthalmoscope.
3. Assess the impact on visual function: Contrast sensitivity, multi-focal electroretinogram, and microperimetry.

We will restrict our discussion to the important points related to FFA and OCT only as they are the most commonly used investigations.

Fundus fluorescein angiography: A significant amount of edema (cystoid or non-cystoid), especially if turbid (due to lipid-laden macrophages), partially blocks the early phase choroidal fluorescence. The arteriovenous phase may show dilation of the fine capillary network and/or telangiectatic retinal vessels around the fovea. The late phase shows hyperfluorescence due to the accumulation of dye leaking from retinal vessels. The amount of leakage depends on the amount of dysfunctional retinal vascular endothelium. The hyperfluorescence may be either cystic or diffuse irregular staining. If the leakage is pronounced, the cystoid spaces fill rapidly, and hyperfluorescence may appear within one minute of injection. The large confluent cysts that are occasionally seen with severe CME may fill late. In case the leakage is not marked, the hyperfluorescence tends to appear late. The large retinal vessels can also leak (called perivascular staining) in case of inflammation, traction (severe pull on a large retinal vessel), or occlusion. A large retina vessel may leak if it is partially occluded or traverses an area of occlusion (capillary nonperfusion).

Conditions where an FFA leak is not demonstrated, despite macular edema, include RP, JXLR, Goldmann-Favre disease, and nicotinic acid toxicity.[13][14]

ETDRS defined focal DME as ≥67% leakage associated with microaneurysms, intermediate as 33 to 66% leakage associated with microaneurysms, and diffuse as <33% leakage associated with microaneurysms.[20]

Optical coherence tomography: Owing to its excellent reproducibility, it is currently the investigation of choice for diagnosing CME and monitoring its treatment. OCT has also been used for classifying multiple diseases, which can help in prognosticating patients.

a) Diabetic macular edema: Kim et al. proposed five morphologic DME patterns.

• Diffuse retinal thickening (DRT) is defined as increased retinal thickness (>200 microns height and >200 microns width) with areas of lower reflectivity, especially in the outer retinal layers.
• CME is defined as low reflectivity intraretinal round- or oval-spaced spaces with high reflective septa separating them.
• Posterior hyaloid traction (PHT) or taut posterior hyaloid membrane (TPHM) is defined as a highly reflective membrane on the inner retinal surface, causing tractional retinal elevation.
• Subretinal fluid is defined as a dome-shaped dark area between the NSR and RPE.
• Tractional retinal detachment (TRD) is a peak-shaped retinal detachment caused due to traction produced by the proliferative membranes present over the retinal surface and/or in the vitreous.[21]

b) Radiation retinopathy: Horgan et al. proposed a five-point OCT-based grading that correlated with visual acuity. Grade 1 was defined as foveola sparing non-CME, grade 2 as foveola sparing CME, grade 3 as foveola-involving non-CME, grade 4 as mild-to-moderate foveola-involving CME, and grade 5 as foveola-involving severe CME.[7][8]

c) Congenital juvenile X-linked retinoschisis: Prenner et al. proposed a classification system based on clinical and OCT findings.

• Type 1 (foveal) was defined as the absence of both lamellar schisis on OCT and peripheral schisis on the ophthalmoscope.
• Type 2 (foveo-lamellar) as the presence of lamellar schisis on OCT without peripheral schisis on the ophthalmoscope
• Type 3 (complex) as the presence of both lamellar schisis on OCT and peripheral schisis on the ophthalmoscope
• Type 4 (foveo-peripheral) as the presence of peripheral schisis on ophthalmoscopy without lamellar schisis on OCT.[22][23]

Treatment / Management

The management of macular edema needs a stepwise therapeutic approach. Most of the cases can be treated with systemic and ocular pharmaceutical agents. Additionally, surgical management may be needed in selected cases.

1. Systemic therapy: The majority of the patients develop macular edema secondary to systemic health conditions like diabetes mellitus, high blood pressure, dyslipidemia, or inflammatory conditions. Therefore, systemic treatment is of prime importance. The Diabetes Control and Complications Trial (DCCT) showed that intensive therapy in type 1 diabetic patients decreased the incidence of CSME compared to conventional therapy. However, the difference did not reach statistical significance. It took nearly three years of intensive treatment for the beneficial effect to appear.[24]

The United Kingdom prospective diabetes study (UKPDS) showed that strict sugar and blood pressure control slows macular edema development in Type 2 diabetic patients.[25] The Wisconsin epidemiologic study of diabetic retinopathy (WESDR) found that a 10 mmHg rise in the diastolic blood pressure increased the 4-year risk of developing macular edema in type 1 and type 2 diabetic patients by 330% and 210%, respectively. It also found that the incidence or progression of macular edema was not associated with smoking.[26]

The action to control cardiovascular risks in diabetes (ACCORD) Lipid study found that a combination of fenofibrate and statins (increases high-density lipoprotein (HDL) and decreases low-density lipoproteins (LDL) levels) led to a more significant reduction in the incidence of macular edema compared to statins alone (reduce LDL levels).[27] Similarly, the fenofibrate intervention and event lowering in diabetes (FIELD) study showed that treatment with fenofibrate reduced the need for laser treatment required for macular edema compared to the placebo group.[28]

2. Ocular topical medications: a) Non-steroidal anti-inflammatory drugs (NSAIDs): They reduce the production of prostaglandins by inhibiting the enzyme cyclooxygenase. Most studies show that NSAIDs have a beneficial role in IG syndrome. However, further well-designed RCTs are needed to confirm this.[9][29] The Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol R (Phase II trial) showed topical nepafenac (0.1%) did not have a significant effect on OCT-measured retinal thickness in eyes with non-center involving DME at the end of one year.[30] b) Topical carbonic anhydrase inhibitors (CAI): CAI inhibits the enzymes carbonic anhydrase and γ-glutamyl transferase, which in turn increase the transport of fluid from the sub-retinal space towards the choroid. These drugs are particularly effective in disorders with diseased RPE like RP-related macular edema.

3. Ocular laser: The various types of laser treatment include:

a) Focal laser (Original ETDRS): The focal lesions located within 500-3000 microns from the macular center are treated with moderate intensity, 50-100 µm sized burns of 50-100 ms duration. The ETDRS defined ‘focal lesions’ as microaneurysms, intraretinal microvascular abnormalities (IRMA), and short capillary segments that leak on FFA. Whitening or darkening of focal lesions is considered the endpoint of treatment. Directly hitting the focal lesions reduces the leakage from them.[31]

b) Grid laser (Original ETDRS): The area with a diffuse leak or nonperfusion (on FFA) located within 500-3000 microns from the macular center is treated with 50 to 200 microns sized burns of 50 to 500 ms duration placed two burn widths apart. Mild RPE whitening is considered the endpoint of treatment. In addition, the focal leaks within this area are treated focally. The possible mechanisms of action include improved oxygen supply to the inner retina as laser damages the oxygen-consuming photoreceptors and RPE; decrease in autoregulatory vasoconstriction; and restoration of the RPE barrier and the RPE pump.[31]

c) Modified ETDRS grid laser (mETDRS): The only modification is that the burns should not be heavy to produce a change in the color of microaneurysms; merely mild gray-white burns evident beneath all microaneurysms is enough.[31]

d) Mild macular laser photocoagulation (MMG): Light burns (barely visible or light grey) are placed over the whole macula (both thickened and normal retina). Microaneurysms are not treated directly.[32]

The laser can be used for the treatment of macular edema secondary to various diseases.

a. Diabetic macular edema: The ETDRS showed that laser reduced the risk of moderate visual loss (VL) at 36 months. Moderate VL was defined as a loss of ≥15 ETDRS letters or doubling of the visual angle. It is recommended that a new treatment can be administrated after six weeks only if treatable lesions were missed during the initial treatment. Otherwise, repeat treatment should be administrated at least 4-months after the initial treatment.[33]

The DRCR.net Protocol A reported that the MMG laser protocol was less effective in reducing the retinal thickness than the mETDRS protocol. However, the visual outcome was similar with both protocols.[32] The DRCR.net Protocol B showed that mETDRS laser is more effective and produces fewer side effects compared to intravitreal triamcinolone (IVTA 1mg and 4mg) over two years.[34]

b. Branch retinal vein occlusion: The Branch vein occlusion study (BVOS) reported that nearly one-third of cases improve spontaneously within the first three months. It showed that the eyes with persistent macular edema, visual acuity ≤20/40, and absence of macular ischemia on FFA had better visual outcomes (3 years) if treated with macular grid laser compared to observation. The grid laser spots were placed in the area of capillary leak located outside the edge of the foveal avascular zone and inside the major vascular arcades.[35]

c.  Central retinal vein occlusion: Central vein occlusion study (CVOS) showed that macular grid laser reduced the angiographic evidence of macular edema. However, there was no visual benefit.[36]

d. Retinal artery macroaneurysm: Leaking RAM can be treated with either direct or indirect laser or a combination of both. Direct laser is performed by applying 200 to 500 microns 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 aneurysm rupture, causing vitreous and/or pre-retinal hemorrhage and arterial occlusion. Indirect laser is performed by applying 100 to 200 ms duration confluent burns around the lesion. This reduces the oxygen demand of the surrounding tissue, which subsequently reduces the blood flow and pressure inside the aneurysm.

e. Optic nerve head pit: Juxtapapillary laser has been tried to create a barrier against fluid migrating from the optic nerve. However, the success rates have been low.[37][38]

4. Intravitreal anti-VEGF injections are the current standard of treatment for macular edema for most of the pathologies. The various molecules include:

a) Pegaptanib was the first drug to be approved for use in humans. It is a 40-kDa aptamer, i.e., mRNA polyethylene glycol-linked molecule that targets only VEGF165. It is currently not used for treatment.[39]

b) Bevacizumab (1.25mg/0.05mL) is a 148-kDa humanized full-size monoclonal IgG1 antibody that targets all the subtypes of VEGF-A.

The DRCR.net Protocol H (Phase II trial) showed that intravitreal bevacizumab (IVB) could reduce DME in some eyes; however, the study was not designed to determine its beneficial role.[40] The bevacizumab or laser therapy (BOLT) study showed the beneficial role of IVB in center-involving CSME in eyes without advanced macular ischemia. The results showed that eyes in the IVB group gained (median, 8 ETDRS letters) while eyes in the laser group lost (median, 0.5 ETDRS letters) after 1-year of treatment. The odds of gaining ≥10 ETDRS letters were 5.1 times greater in the IVB group.[41]

c) Ranibizumab (0.3 mg and 0.5mg/ 0.05 mL) is a 48-kDa humanized monoclonal antibody fragment (Fab) that targets all the subtypes of VEGF-A.

Diabetic macular edema: The RESOLVE trial (phase II trial) showed the efficacy of intravitreal ranibizumab (IVR, 0.3 mg and 0.5 mg) over sham injections.[42] The RESTORE trial (phase III) showed that IVR (0.5 mg) either as monotherapy or combined with laser provided better visual gain than standard laser alone.[43] The US FDA approved the use of IVR for the treatment of DME based on the results of the RISE and RIDE trials (two parallel phase III trials). They showed that IVR (0.3mg and 0.5 mg) was superior to sham injection in terms of both visual improvement and central retinal thickness reduction.[44] The DRCR.net Protocol I showed that IVR (0.5 mg) with prompt or deferred laser-produced superior visual gain compared to both IVTA (4 mg) with laser and laser alone. The visual outcomes produced by IVR plus deferred laser were better than IVR plus prompt laser. Subgroup analysis showed that IVTA plus laser produced similar results as IVR plus laser in pseudophakic eyes.[45]

Retinal vein occlusion: The BRAVO trial (phase III trial) showed that the eyes with BRVO, which received six monthly IVR injections (0.3 mg and 0.5 mg), experienced superior visual improvement compared to sham injections. The visual acuity at 1-year was well maintained even after shifting to pro-re-nata (PRN) dosing for the next six months.[46] The design and results of the CRUISE trial (Phase III trial for CRVO) were similar to the BRAVO trial.[47]

d) Aflibercept (2mg/ 0.05mL) is a 115-kDa fusion protein, i.e., a combination of the Fc portion of a monoclonal antibody; and high-affinity extracellular domains of VEGF receptor type-1 (R1) and VEGFR2. It targets VEGF-A and B; and placental growth factor (PlGF).

Diabetic macular edema: The DA VINCI study (phase II trial) showed that intravitreal aflibercept (IVA) achieved better anatomical and functional improvement compared to laser.[48] The US FDA approved the use of IVA for the treatment of DME based on the results of VIVID-DME and VISTA-DME studies (two parallel phase III trials). Their results showed that the mean visual gain and edema resolution at the end of 1 year was significantly greater in eyes treated with aflibercept compared to laser therapy. Both the 2q4 and 2q8 regimes had similar efficacy.[49]

The DRCR.net Protocol T showed that there was no difference in the visual improvement at 1-year and 2-year among patients receiving either bevacizumab, ranibizumab, or aflibercept in case the initial best-corrected visual acuity (BCVA) was 20/32-20/40. However, if the initial BCVA was ≤20/50, aflibercept was the most effective till the end of 1-year, and ranibizumab and aflibercept were equally effective at the end of 2-years.[50][51]

The DRCR.net Protocol V showed that there was no significant difference in the visual loss at the end of 2-years among eyes with center-involving DME and BCVA≥20/25 irrespective of the treatment given (observation or laser or aflibercept). The study proposed that the eyes with good visual acuity should be observed and treated with aflibercept only if the visual acuity worsens.[52]

Retinal vein occlusion: The VIBRANT study showed that six monthly aflibercept injections followed by bi-monthly injections helped achieve greater visual benefit and edema reduction than macular grid laser in eyes with BRVO-related macular edema at 24 and 52 weeks.[53] The COPERNICUS and GALILEO studies (Two parallel phase III trials) showed that six monthly aflibercept injections followed by PRN dosing helped achieve greater visual benefit and edema reduction than macular grid laser in eyes with CRVO-related macular edema.[54][55]

e) Brolicizumab (6mg/ 0.05mL) is a 26-kDa single-chain variable fragment that targets all subtypes of VEGF-A.[56]

5. Intravitreal steroids: The molecules used include:

a) Fluocinolone acetate: Retisert (0.59mg) is a non-biodegradable implant. The implant was reported to achieve better visual and anatomic outcomes compared to laser in eyes with DME; however, the rates of cataract progression (91%) and IOP elevation (61.4% patients with IOP ≥30 mm Hg) was very high.[57] Iluvien (0.19mg) is another non-biodegradable, sustained-release device. The results of the FAME trial helped it gain US FDA approval for the treatment of DME in eyes that did not experience a steroid-induced IOP rise. The phase III trial showed that the implant showed superior visual improvement than sham injection up to 3 years. The patients with chronic DME had a better outcome. The incidence of glaucoma was low (7.6% in high-dose i.e., 0.5 μg/d and 3.7% in low-dose group i.e., 0.2 μg/d).[58]

b) IVTA: The Standard care vs. corticosteroid for retinal vein occlusion (SCORE) trial (2009) showed that IVTA (1mg or 4mg) did not provide any significant benefit over the standard treatment (at that time, i.e., macular grid laser) in eyes with BRVO-related macular edema in terms of either visual acuity or foveal thickness. A significant proportion of eyes receiving IVTA developed cataracts and raised IOP. However, in eyes with CRVO-related macular edema, IVTA was superior to the standard treatment (at that time, i.e., observation). The safety profile of the 1-mg dose was superior to the 4-mg dose.[59]

c) Dexamethasone: A biodegradable sustained-release device (0.7 mg) is implanted with the help of a 22-gauge injector. It received US FDA approval for the treatment of DME based on the results of the MEAD study. The study showed that the implant (0.7 mg and 0.35 mg) met the primary efficacy endpoint for visual improvement without the need for monthly injections. In the 0.7 mg group, 67.9% of eyes developed cataracts, 59.2% eyes underwent cataract surgery, 27.7% eyes had ≥10 mmHg IOP elevation, while only 2 required trabeculectomy surgery.[60] TThe BEVORDEX study showed that the steroid implant achieved superior anatomic and similar visual outcomes compared to bevacizumab for DME with fewer injections.[61] The GENEVA study showed that the eyes receiving the implant had better visual improvement than sham in eyes with BRVO- and CRVO-related macular edema. The peak visual and anatomical improvement was noted after 60 days, following which the vision deteriorated.[62]

The DRCR.net protocol U showed that adding dexamethasone implant to continued IVR therapy is not likely to improve visual acuity (24 weeks) compared to continued IVR therapy alone among the eyes with persistent DME. However, the combined therapy is likely to reduce the retinal thickness and cause IOP elevation.[63]

Differential Diagnosis

• Vitreomacular traction and epiretinal membrane: The mechanical forces caused by the vitreous traction on macula lead to the accumulation of fluid.
• Autosomal dominant cystoid macular edema (CME) occurs due to muller cell dysfunction and resultant leakage from the perifoveolar capillaries.
• Congenital juvenile X-linked retinoschisis (JXLR): It occurs due to mutation(s) of the retinoschisin 1 (RS1) gene, which is located on the X-chromosome’s short arm. The gene encodes for the protein retinoschisin, which is involved in cell-to-cell adhesion. The exact pathophysiology underlying the formation of schitic cavities is not completely understood.[22][23]
• Hypotony macular edema occurs due to abnormal retinal capillary permeability secondary to reduced IOP.[1][2]
• Congenital cavitary disc maculopathy: These include optic nerve head (ONH) pit, morning glory anomaly, optic nerve coloboma, and extrapapillary cavitation. Serous maculopathy occurs due to the disruption of the normal anatomic features of the ONH, which keep the potential subretinal space in a dry state. As a result, vitreous and/or cerebrospinal fluid travels down the pressure gradient and gets accumulated in the neurosensory retina (NSR) and/ or subretinal space.[37][38]
• Chronic central serous chorioretinopathy (cCSCR): Cystoid spaces may be seen within the NSR in eyes with cCSCR. This OCT finding is termed posterior cystoid retinal degeneration (PCRD). It occurs secondary to primary choroidopathy and RPE dysfunction. It is not associated with leakage on fundus fluorescein angiography (FFA).[64]
• Microcystic macular edema (MME) in advanced glaucoma and optic neuropathy occurs due to severe retinal ganglion cells atrophy secondary to retrograde transsynaptic cell loss.[65]
• Berlin edema or Commotio retinae is a misnomer. It is characterized by grey-white retinal discoloration secondary to blunt trauma. This characteristic appearance is caused by disruption of the outer segment of the photoreceptor layer.[66]

Prognosis

The prognosis of macular edema usually depends on the cause. With the advent of newer pharmacological agents for intravitreal injection, the prognosis of the disease is usually good. Several OCT biomarkers can help prognosticate the patients. These include:

1. Disorganization of the inner retinal layers (DRIL): It is defined at the horizontal extent of the retina (within the central 1 mm) where the boundaries between the ganglion cell-inner plexiform layer complex, INL, and OPL cannot be identified clearly. The visual prognosis has been poor if DRIL affects ≥ 50% of the central 1 mm.[67]
2. Hyperreflective retinal foci (HRF): They are the subclinical lipoproteins that extravasate after the breakdown of the inner BRB. These indicate a high chance of subfoveal hard exudate deposition after the resolution of macular edema.[68]
3. Intraretinal cystoid spaces: These indicate Müller cell malfunction. The prognostic significance depends on their size (small<100 microns, large 101-200 microns, giant > 200 microns), location, and association with hyperreflective material. The large cysts are usually associated with macular ischemia. The giant cysts tend to cause outer nuclear layer and ellipsoid zone (EZ) damage. The hyperreflective material represents the deposition of fibrin and inflammatory by-products and indicates severe BRB disruption. It is also associated with poor visual outcomes. The hyperreflective material on OCT angiography appears as an extravascular signal due to the particulate Brownian motion. This appearance is termed as suspended scattering particles in motion (SSPiM). It is usually found at the vascular-avascular junction and resolves with hard exudate formation.[69][70]
4. Photoreceptor outer segment (PROS): It is defined as the length between the junction of the inner segment/ outer segment of the photoreceptor and the RPE. The shorter length is associated with worse visual acuity.[71]
5. The integrity of external limiting membrane and EZ: The integrity of outer retinal layers indicates the health of photoreceptors and RPE.[72]

Complications

Macular edema per se is associated with progressive, irreversible loss of vision. The various treatment modalities also have their own share of complications. The most severe complication associated with laser photocoagulation is the accidental foveal burn. Therefore, a test burn should be given nasal to disc before starting the laser. Other complications include subretinal fibrosis/ scarring, burn expansion, paracentral scotoma, and choroidal neovascular membranes. Intravitreal injections have a higher rate of complication, and the most dreaded complication is endophthalmitis. Other complications include vitreous hemorrhage, cataract due to incorrect injection method, central retinal artery occlusion due to sudden increase in intraocular pressure, and retinal tears.

Deterrence and Patient Education

Patient education is critical for the management of macular edema. The American Academy of Ophthalmology recommends patients with type 1 diabetes should get an ophthalmic screening within five years of initial diagnosis, while patients with type 2 diabetes should be screened at the time of the initial diagnosis. Similarly, patients with DME should be advised to maintain strict metabolic control. Patient education and appropriate behavior can help prevent, delay, and limit the ocular and systemic effects of diabetes. Patients have to be explained that diabetes can affect multiple organ systems.

Enhancing Healthcare Team Outcomes

Systemic diseases like diabetes mellitus, hypertension, dyslipidemia have multiple ocular and systemic manifestations. Hence, the management of patients with these diseases needs a multi-disciplinary team. The management starts with patient education. The primary health care providers should make a sincere effort to describe the natural history and the ability of these diseases to affect the body's multiple systems and the consequences of poor systemic control. The ophthalmic and diabetes nurses play a key role in patient education. The ophthalmologists should emphasize the need for regular follow up with multiple specialty doctors and vice versa. The pharmacists can counsel the patients on the need for regular medications and the importance of lifestyle modifications.