Diabetic Macular Edema, Clinicopathologic and Keys for Management

Abstract

Diabetic retinopathy (DR) is one of the leading causes of blindness worldwide. It usually begins several years after the onset of diabetes. In the early stages, there are relatively mild retinal changes, the most important of which, regarding visual acuity (VA) affection, is diabetic macular edema (DME). Recently, the development of optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) greatly changed the treatment strategy of this part of diabetic retinopathy, particularly with the development of more advanced laser technologies as micropulse laser and more effective and longer acting anti-VEGF and steroid intravitreal medications and the advances in pars plana vitrectomy (PPV) techniques. In this chapter, all those points will be highlighted with how to prevent the progression of retinopathy to save as much as could be saved of the visual function.

1. Introduction

Diabetic retinopathy (DR) is one of the most handicapping complications of diabetes, as it threatens the vision of about 5–10% of patients suffering from diabetes, many of whom are in the working age group [1, 2, 3, 4]. In the following sections, we shall concentrate on the pathogenesis, diagnosis and management of the early visually threatening complication of diabetic retinopathy, namely diabetic macular edema (DME).

2. Early preclinical changes of diabetic retinopathy

Chronic hyperglycemia affects both the microvascular and neural components of the retina by increasing the oxidative stress, inflammation and hypoxia (Figure 1) [5]. As a type of metabolic autoregulation, the earliest changes that occur in the retinal microvasculature secondary to hyperglycemia are retinal blood vessel dilatation and blood flow changes. Pericyte apoptosis secondary to hyperglycemia is also an early event in this pathology, and because pericytes provide structural support to the retinal capillary walls, outpouching of the capillary walls occurs forming microaneurysms, the earliest clinical sign that can be overlooked in very early stages [6, 7]. Glial cell activation and neural apoptosis lead to ganglion cell death, with consequent thinning of the ganglion cell layer preclinical to the signs of diabetic retinopathy seen on fundus examination [8]. Using optical coherence tomography angiography (OCT angiography) (OCTA), the foveal avascular zone (FAZ) in both the superficial and deep capillary plexuses (SCP and DCP) was found to be larger and irregular due to perifoveal capillary loss with more tortuosity, beading and focally dilated endings of capillaries. These findings were found to be more pronounced when diabetes was associated with hypertension [8].

Figure 1.

Early preclinical changes of diabetic retinopathy.

3. Diabetic macular edema (DME)

3.1 Pathogenesis

3.1.1 The normal blood retinal barrier (BRB) in healthy subjects

The inner and outer retinal barriers keep the retina immune privileged and regulate fluid and molecular entry and drainage into and to the outside of the retina keeping the retina in a dehydrated state [9].

The inner blood retinal barrier (retinal blood vessel walls) is formed by tight junctions (zonula occludens (ZO)) between endothelial cells, adherens junctions between pericyte cytoskeleton and endothelial cells and glial cell processes wrap around retinal capillaries [10]. Astrocytes and Müller cells stabilize the tight junctions between endothelial cells and ensheath vascular plexuses [11]. Finally, microglia produce soluble factors important for vesicular communication necessary for the maintenance of the inner blood retinal barrier [12, 13].

The outer blood retinal barrier is formed of junctional complexes between retinal pigment epithelial (RPE) cells formed of tight, adherens and gap junctions separating the neurosensory retina from the fenestrated choriocapillaris. It controls the transport of fluid and solutes into and to the outside of the retina to maintain its integrity [14, 15].

3.1.2 Pathologic alterations in diabetic macular edema

Microglia monitor the physiological microenvironment in the retina and can detect early signs of hyperglycemia leading to their activation [16]. Activation of microglial cells is usually associated with perivasculitis with consequent release of inflammatory mediators, including vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemotactic protein-1 (MCP-1), resulting in extension of the inflammation from the inner retina to all retinal layers with breakdown of the blood retinal barrier, increased vascular permeability and retinal neuronal damage [17, 18, 19, 20].

Hyperglycemia upregulates intercellular adhesion molecule-1 (ICAM-1) which together with vascular cell adhesion molecule mediate leukocyte adhesion to the vascular endothelium (leukostasis), resulting in vascular damage and capillary nonperfusion. Additionally, leukocytes share in microvascular damage by the release of cytokines and superoxide [21].

Inflammation and hypoxia adversely affect the functions of Müller cells, altering their potassium channels with consequent accumulation of intracellular fluids [22, 23]. Both inflammation and hypoxia also stimulate retinal Müller cells to produce VEGF, tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β) and prostaglandins, all of which contribute to the increased vascular permeability [24, 25]. On the other hand, Müller cells aggravate inflammation through stimulation of cluster of differentiation (CD) 40 and through the release of adenosine triphosphate (ATP) which promotes microglial inflammation [26].

Vascular endothelial growth factor, a main factor in the progression of DME and proliferative diabetic retinopathy (PDR) (Figure 2), is upregulated through several pathways, particularly the activation of hypoxia-inducible factor 1 (HIF-1) [27] and phospholipase A2 (PLA2) [28]. VEGF both increases vascular permeability by promoting phosphorylation of tight junction proteins, such as occludin and zonula occludens-1 (ZO-1) [29], in addition to its effect in promoting angiogenesis through the activation of mitogen-activated protein (MAP) [30].

Figure 2.

VEGF in DME and PDR.

Other angiogenic factors, particularly angioprotein 2 (Ang-2), an antagonist to endothelial receptor tyrosine kinase (Tie2), has been shown to promote vascular leakage in diabetic retina (Figure 3) [31].

Figure 3.

Role of angioprotein-2 in increasing vascular permeability and DME.

Reactive oxygen species (ROS) are an important link between hyperglycemia and the main pathways responsible for hyperglycemic damage. Although mitochondrial production is an important source of ROS [32], yet more recently it was proved that ROS derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is involved to a higher extent in the process of pericyte apoptosis on exposure to high glucose levels [33]. High glucose could stimulate ROS production through protein kinase C (PKC) β-dependent phosphorylation of the p47phox (the phagocyte NADPH oxidase/NOX₂ organizer) subunit (involved in the activation of NADPH oxidase) [34].

Diabetic macular edema is also associated with RPE dysfunction and impaired control of transport of water from the subretinal space into the choriocapillaris and vice versa [14].

3.2 Pretreatment evaluation of DME

3.2.1 Screening

All diabetic patients should perform baseline screening with full ophthalmological examination and imaging (fluorescein angiography (FA) together with OCT). Although FA has long been used for the diagnosis of diabetic retinopathy (DR), yet the intravenous dye injection can cause some side effects [35]. In addition, FA does not identify or separate the pathologies in the superficial and deep capillary networks of the retina and the leaking fluorescein dye may obscure the alterations in vascular morphology. All FA drawbacks are recently solved by the use of OCTA [36].

In type 1 diabetes mellitus (type 1 DM), it is usually advised to do the first ophthalmologic examination 5 years after the discovery of diabetes mellitus (DM), while in type 2 diabetes mellitus (type 2 DM), the examination is done once DM is diagnosed, then annually or earlier as needed [37].

3.2.2 Classifications of DME

Several attempts have been carried out to classify DME. A summary of these classifications is given as follows:

1. Center-involved vs. noncenter-involved DME [38].

2. Vasogenic vs. nonvasogenic DME: [6]

   1. The vasogenic type was defined as retinal thickening with visible retinal vascular abnormalities detectable on biomicroscopy and fundus photography (focally grouped microaneurysm and dilated capillaries) at the macular region usually associated with lipid exudates.

   2. The nonvasogenic type, on the other hand, was defined as retinal thickening with no visible vascular dilations and probably no lipid exudates detectable on biomicroscopy and fundus photography.

   3. Mixed type: It is either a vasogenic or a nonvasogenic type associated with retinal thickening and detectable traction on OCT examination (Figure 4).

3. Optical coherence tomography (OCT) classification (conventional OCT imaging):

Figure 4.

Mixed type of DME.

Three types of optical coherence tomography are recognized:

1. Diffuse thickening type (sponge-like diffuse retinal thickening) (Figure 5), which results from increased vascular permeability and breakdown of the inner blood retinal barrier secondary to inflammation and oxidative stress [14].

2. Cystoid macular edema (CME) type (thickening of fovea with intraretinal cystoid changes) (Figure 6) produced by a combination of production of prostaglandins and inflammatory cytokines together with ischemia, particularly in the deep capillary plexus around the cystoid spaces (demonstrated by OCTA) and finally necrosis of Müller cells [22].

3. Serous retinal detachment (SRD) type (thickening of fovea with subretinal fluid) (Figure 7): Probably, detachment begins by increased permeability of the choriocapillaris (evidenced by thickened subfoveal choroid) followed by a breakdown of the outer blood retinal barrier and damage of the external limiting membrane (ELM) secondary to inflammation (as evidenced by the elevation of interleukin 6 (IL-6) levels in this subtype [14]).

1. Spectral domain optical coherence tomography grading system of diabetic maculopathy (Table 1) [38].

2. En face image-based classification of diabetic macular edema using swept source optical coherence tomography: [35]

Figure 5.

Diffuse thickening type of DME.

Figure 6.

Cystoid macular edema (CME) type.

Figure 7.

Serous retinal detachment (SRD) type.

Parameter	Grade	Description
Thickening	0	Less than 10% increase above upper normal values
	1	More than 10% but less than 30% increase above upper normal values
	2	More than 30% increase above upper normal values
Cysts (round, minimally reflective spaces within the neurosensory retina)	0	Absent
	1	Mild
	2	Moderate
	3	Severe
Ellipsoid zone (EZ) and/or ELM status (the first and the second hyperreflective bands of the four outermost layers on OCT, respectively)	0	Intact
	1	Disrupted
	2	Absent
Disorganization of the inner retinal layers (DRIL) (loss of clear demarcation between the ganglion cell-inner plexiform layer complex, the inner nuclear layer and the outer plexiform layer in the central fovea)	0	Absent
	1	Present
Hyperreflective foci (1) reflectivity similar to that of nerve fiber layer; (2) absence of backshadowing; and (3) <30 μm diameter	0	Less than 30 in number
	1	More than 30 in number
Subretinal fluid (subfoveal neurosensory hyporeflective detachment due to fluid accumulation)	0	Absent
	1	Present
Vitreoretinal relationship	0	Absence of any visible adhesion or traction between vitreous cortex and retina
	1	Incomplete posterior vitreous detachment
	2	Posterior vitreous detachment
	3	Vitreomacular traction
	4	Epiretinal membrane

Table 1.

Optical coherence tomography (OCT) grading of diabetic macular edema (DME).

The idea of this classification is to construct en face images from three-dimensional (3D) images to visualize and localize the extent of the area of fluid at a specific retinal depth in cases of DME (Table 2).

Segment	Layers included	Parameter
Segment 1	Comprises inner nuclear layer, outer plexiform layer including Henle’s fiber layer	No fluid
		Foveal cystoid space
		Parafoveal cystoid space
		Diffuse fluid
Segment 2	Mainly comprises the outer nuclear layer	No fluid
		Diffuse fluid
		Subretinal fluid
		Diffuse fluid with subretinal fluid

Table 2.

En face image-based classification of diabetic macular edema.

Conclusions drawn from this classification were as follows:

First, the presence of fluid in Segment 2 resulted in a significantly worse visual outcome as compared to cases without fluid in this area, which is probably because of the disturbed oxygenation and elimination of metabolites from the layer of photoreceptors.

Second conclusion was that the extent of fluid in Segment 1 did not affect the final visual acuity (VA) in DME [35].

3.2.3 Baseline predictors for a good treatment response based on OCT findings

Several pretreatment criteria were found to be of prognostic value as regards better vision gain posttreatment, and these predictors include; less subretinal fluid (SRF) and few intraretinal cystoid spaces (IRC) and no vitreomacular traction (VMT) (Figure 8) [39].

Figure 8.

Base line predictors for an unfavorable treatment response based on OCT findings.

Better vision gain is also achieved if there was no disruption or disorganization of the inner retinal layers (DRIL) [40] and if there was preservation of the ellipsoid zone (EZ) and external limiting membrane (ELM) [41].

A thin subfoveal choroid at baseline may predict unfavorable posttreatment visual acuity, while eyes with a thicker baseline subfoveal choroidal thickness had better short-term anatomic and functional responses [42].

Several OCTA biomarkers have been found to be valuable in the determination of the degree of retinal ischemia and these include two FAZ biomarkers, namely foveal avascular zone area (FAZ-A) and the irregularity in the contour of the foveal avascular zone contour irregularities (FAZ-CI) and three vessel biomarkers, namely the tortuosity of retinal vessels (VT), the average vessel caliber (AVC) and the density of retinal vessels (VD) [43].

3.2.4 Pretreatment systemic monitoring

Systemic risk factors for progression of diabetic macular edema should be controlled to provide a suitable environment for ocular treatment to give better and longer lasting favorable results;

Multiple randomized clinical trials demonstrated the benefits of both controlled blood sugar level and arterial blood pressure in the reduction of retinopathy progression [44, 45, 46, 47, 48, 49]. The American Diabetes Association mentioned that the glycated hemoglobin (HbA1c) level should not exceed 7%, while the arterial blood pressure level should be kept under 130/80 mmHg and total lipids under 100 mg/dL [50], in addition, however, treatment should not be delayed to correct all systemic parameters [51, 52, 53].

Other parameters that are also to be taken into consideration are smoking cessation [54, 55], weight loss if required for a normal body mass index [55], renal impairment [54, 55] and sleep apnea [55], as all of those factors have an impact on the results of management of DME.

3.3 Treatment options

3.3.1 Laser treatment

For diabetic macular edema, laser photocoagulation was the gold standard for treatment until the introduction of anti-VEGF therapy.

3.3.1.1 Focal/grid laser

According to the Early Treatment Diabetes Retinopathy Study (EDTRS), focal/grid macular laser was shown to be effective in marked macular edema reduction or cure, in addition to the reduction of the risk of moderate visual loss by 50% at the termination of the 3-year follow-up trial [56]. More recent clinical trials following ETDRS showed a similar result of reduction of moderate visual loss by 50% with a gain of ≥10 letters of visual acuity in 28% of DME eyes [57].

Focal laser applied to leaking microaneurysms at least 300–500 μm from the center of the macula and guided by FA in noncenter-involving DME remains a gold standard for treatment of this subset of DME [43, 58].

In grid laser, mild power laser marks are made with a spot size of 50 μm to 200 μm, to treat widespread and diffuse edema [59], particularly in cases of resistance or contraindication to the use of anti-VEGF drugs [60].

Combining laser photocoagulation with anti-VEGF injections for DME has been described in several studies. Combined treatment was found to be more effective in improving visual acuity in DME patients. With combined treatment, 10 to 40% of patients gained ≥15 letters in their VA [61, 62, 63].

The mechanism of action of focal/grid photocoagulation is not clear, although direct closure of leaking microaneurysms in focal laser and the destruction of the high oxygen consuming photoreceptors, reduction of retinal tissue and improvement of oxygenation together with restoration of the function of retinal pigment epithelial cells in grid laser are postulated mechanisms [64, 65, 66] (Figure 9).

Figure 9.

Possible mechanism of action of grid laser in the management of DME.

3.3.1.2 Micropulse laser

The basis of micropulse laser (diode laser 810 μm and yellow laser 577 μm) unlike the conventional continuous-wave laser is to apply the minimum laser irradiance (watts per square meter). The aim is to raise the temperature of the RPE cells leading to their activation, but without exceeding the protein denaturation threshold in the neural retina which is thus not injured by the laser application.

In the traditional continuous-wave mode, the preset laser energy is delivered totally in a single laser pulse of 0.1–0.5 s. In the micropulse mode, a train of repetitive short laser pulses (each pulse is 100–300 μs) is delivered within an envelope of laser energy having a width of 0.1–0.5 s [67].

The Diabetic Macular Edema and Diode Subthreshold Micropulse Laser (DIAMONDS) trial found that the subthreshold micropulse laser was noninferior to the traditional continuous-wave laser (focal/grid) in terms of functional (VA improvement) and anatomical (optical coherence tomography central macular thickness (OCT CMT)) improvement [68].

3.3.2 Anti-VEGF drugs

The two anti-VEGF drugs Food and Drug Administration (FDA) approved and most commonly used are ranibizumab and aflibercept.

1. Ranibizumab: (Lucentis®, Genentech, South San Francisco, CA, USA/Roche, Basel, Switzerland) Ranibizumab was the first FDA-approved anti-VEGF. It is a humanized monoclonal antibody that acts by interrupting the functions of VEGF isoforms [43].

2. Aflibercept: (Eylea®, Regeneron, Tarrytown, NY, USA) [69]. Aflibercept is a 115-kDa, glycosylated, recombinant, fusion protein with native vascular endothelial growth factor receptor (VEGFR) ligand-binding sequences attached to the fragment crystallizable (Fc) segment of a human immunoglobulin G1 (IgG1). Aflibercept differs from the other anti-VEGF drugs, in that in addition to its binding capability to all isoforms of vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor B (VEGF-B), it also binds to placental growth factor (PlGF) [70].

3. Brolucizumab: (Beovu®; Novartis) Brolucizumab is a humanized single-chain antibody fragment, and it is the smallest functional subunit of an antibody approved for intravitreal use. Results from recent phase III trials showed the superior efficacy of brolucizumab in both reducing retinal thickness and retinal fluid reduction as compared to Aflibercept. Those results present an additional therapeutic option in the DME treatment. In addition to its superior efficacy, it can reduce both the financial and social treatment burden in patients with DME with increased intertreatment intervals up to 16 weeks. Caution with its use should be taken, however, regarding the post-FDA-approval side effects discovered, particularly intraocular inflammation, retinal vasculitis and retinal vascular occlusion (an increased risk for intraocular inflammatory events (0.3–4.7% compared to 0.6–1.7% with Aflibercept)) [71].

4. Bevacizumab: (Avastin®, Genentech, South San Francisco, CA, USA/Roche, Basel, Switzerland) Bevacizumab is FDA-approved only to treat local and metastatic solid cancers but because of its cheaper price and treatment efficiency, it has been used off-label for treatment of DME [72, 73]. It is a high-affinity, 149-kDa, recombinant, humanized, full-length murine antibody that binds all isoforms of VEGF-A. Being a cheaper alternative, it is extensively used off-label as an intravitreal injection for the treatment of DME [73, 74].

5. Faricimab: Faricimab is a bi-specific antibody, i.e., a single molecule that functions by a dual mechanism, and it has the advantage of blocking both angiopoietin-2 (Ang-2) and VEGF-A. (Ang-2) is an antagonist to endothelial receptor tyrosine kinase (Tie2) (Figure 3), when blocked, the vascular structure is stabilized inhibiting continuous loss of pericytes with less inflammation [75, 76].

In the BOULEVARD trial, the patients who received 6.0 mg of faricimab did not need frequent re-treatments as compared to the group of patients who received ranibizumab [77].

In the YOSEMITE and RHINE trials, faricimab administered at 8- and at 16-week intervals was not inferior to Aflibercept administered every 8 weeks as regards visual improvement [78, 79, 80, 81].

Several studies compared the efficacy of anti-VEGF drugs and laser treatment:

In all trials comparing Ranibizumab with sham injection (RESOLVE, RISE and RIDE), or with laser treatment (READ-2 and RESTORE), or in association with prompt and deferred laser (DRCR.net Protocol I), it was proved that Ranibizumab had better outcomes as compared to laser treatment for DME.

Similarly, studies with Aflibercept as DA VINCI (DME and VEGF trap-eye: investigation of clinical impact), Vision Impairment due to DME (VIVID-DME) and Study of Intravitreal Aflibercept Injection in Patients with Diabetic Macular Edema (VISTA-DME), also proved a better response with Aflibercept as compared to laser in the management of DME [82].

3.3.3 Steroids

1. Triamcinolone acetonide (TA): Intravitreal triamcinolone acetonide has not yet been approved for DME, however, in several studies its intravitreal use provided good visual acuity and anatomical improvements [83, 84, 85].

In pseudophakic eyes, the efficacy of Triamcinolone acetonide combined with laser therapy was found to be comparable to that of combined ranibizumab and laser therapy [86, 87].

The high incidence of glaucoma (about 44%) and cataract development (about 54%) make its use unsatisfactory [86, 87].

1. Dexamethasone intravitreal implant (DEX implant; Ozurdex; Allergan, Inc., Irvine, CA, USA):

OZURDEX® (dexamethasone intravitreal implant) 0.7 mg is a biodegradable implant injected into the vitreous to treat diabetic macular edema. Ozurdex was approved for treatment of diabetic macular edema in late 2014 [88].

In the MEAD trials, a great percentage of patients achieved a visual gain of ≥15-letters from baseline with improved central retinal thickness (CRT) by OCT [89].

In the PLACID trial, comparing Ozurdex monotherapy to laser monotherapy, a higher percentage of patients treated with dexamethasone achieved at least 10 letters better improvement as compared to those treated with laser monotherapy [90].

Dexamethasone has lower lipophilic properties than other corticosteroids, with consequent lower binding affinity to the trabecular meshwork. Thus, dexamethasone implants are associated with lower risks of glaucoma and cataract as compared to other steroids used for treatment of DME [91].

1. Fluocinolone acetonide (FA) intravitreal implant: It is a nonerodible implant approved for the treatment of diabetic macular edema (DME). The injectable intravitreal implant releases fluocinolone acetonide at a rate of about 0.2 μg/day for a duration of about 36 months [92].

The Fluocinolone Acetonide in Diabetic Macular Edema (FAME) trials showed that, in patients with center-involved DME previously treated with laser photocoagulation, FA intravitreal implant was superior as compared to sham injection in improving VA more than 15 letters at 24 months and at 36 months [93, 94].

The two commonest side effects of the drug were cataract (86%) and nearly all of them required cataract extraction and intraocular pressure (IOP) elevation (37%). Raised IOP was mostly treated with antiglaucoma medications, with <5% of eyes requiring glaucoma surgery [95].

3.4 Guidelines for treatment

3.4.1 Subclinical DME (SCME)

Subclinical macular edema is defined as thickening of the center of the macula identified by OCT but not detected on clinical examination [96].

Monitoring the progression of subclinical DME (SCME), the Diabetic Retinopathy Clinical Research Network (DRCR.net) showed that about a quarter to half of eyes would progress to clinically significant macular edema (CSME) within 2 years, and are 12 times more prone to the development of CSME as compared to eyes without SCME, particularly if there is increased retinal thickening within the outer ring of the ETDRS grid. This is an important indicator that SCME is an important biomarker for development of center-involving diabetic macular edema (CIME) and this was also found to be commoner in female patients [96, 97].

On the other hand, there is a controversy as to whether the level of HBA1c is related to the progression of SCME to CIME or not [97, 98].

The management of subclinical DME is mainly the prevention of its progression to CSME. Scheduled follow-up visits, with OCT performed together with glycemic control, and strict control of the other systemic risk factors mentioned above are recommended [43].

3.4.2 Treatment recommendations for non-center-involving DME (non-CIME)

Noncenter-involving DME represents a precursor to the development of center-involved clinically significant ME. If not treated, it was found that 38% of eyes will gain at least 50 μm in CMT over 2 years [96].

Laser treatment is recommended for this subset of DME by most authors.

A modified ETDRS (mETDRS) laser treatment was recommended by the Diabetic Retinopathy Clinical Research (DRCR) net study and was based on treating areas of thickened macula (as shown by OCT imaging) and areas of nonperfusion (detected by OCTA and FA) and leaking microaneurysm (detected by FA) with less intense and smaller burns than in the original ETDRS treatment. Results of this study showed a gain of 15 letters in 25% of the patients [99]. Complications of this technique however include central scotomata and loss of central vision caused by progressive enlargement of the laser scars [100].

Focal laser is another option adopted where focal laser is applied to all leaking microaneurysms 500–3000 μm away from the fovea. Results of this line of treatment showed improvement of visual acuity (VA) in 21% of eyes and stabilization of baseline VA in 61% of eyes [101].

One study, however, recommended either observation until involvement of the center of the macula or alternatively initiating anti-VEGF therapy or focal laser photocoagulation [58].

3.4.3 Treatment recommendations for center-involved DME

Most of the guidelines for center-involved DME recommend anti-VEGF intravitreal injections as the first line of treatment, unless contraindicated as in cases of a recent cardiovascular or cerebrovascular event within the previous 3–6 months, breast feeding and pregnancy [43, 58, 102, 103, 104].

Anti-VEGF injection is currently loaded by following one of the following protocols:

1. Treat and extend protocol (T&E)

With Ranibizumab, after the initial 3-monthly loading doses, the patient is switched to a T&E regimen if there were no signs of disease activity as indicated by OCT images and the best-corrected visual acuity (BCVA) was either the same or better as compared to that at the last visit. In this regimen, follow-up visits were extended by a 4-week interval so long as there was no disease activity for a maximum duration of 24 weeks. If signs of activity appeared (recurrence of intraretinal or subretinal fluid or CRT more than 300 μm), a new injection is given and the follow-up duration is shortened by 4 weeks to a minimum interval of 4 weeks between the visits [105].

For aflibercept, the recommended regimen is five loading monthly injections followed by one injection every 2 months for the first year. Once stabilized, the duration could be extended as above [106].

1. Pro re nata (PRN) regimen

In this regimen, the patient received the usual loading dose followed by monthly injections until there was no disease activity by OCT and the best-corrected visual acuity (BCVA) was either stabilized or improved as compared to the previous visit. Patients then were scheduled for regular follow-ups every 1–3 months and received no further injections, unless recurrence of disease activity was noted on OCT [105].

In a recent meta-analysis comparing T&E and PRN protocols for DME, there was no clear advantage in reducing the number of injections between the two groups; however, there were, in the T&E regimen, limited gains in visual and anatomical outcomes. The T&E regimen also allows for fewer patient visits, thereby reducing treatment burden [107].

All guidelines agree that nonresponders to anti-VEGF treatment (after the first 3–6 injections) should be switched to another anti-VEGF or to steroids. The definition of (nonresponders), however, differed in various guidelines. In one post hoc analysis exploring the relationship between early retinal anatomical (CMT on OCT imaging) and functional (visual acuity) responses (after 12 weeks) and long-term same anatomical and visual outcomes (weeks 52 and 156) in eyes treated with ranibizumab plus prompt or deferred laser (in Protocol I study), a conclusion was set that a reduction of less than 20% in central retinal thickness or less than 5-letter improvement in VA is to be categorized as (nonresponder) [108, 109].

The criteria of (nonresponders) in the American Delphi Panel guidelines were however different, they considered that failure to achieve a visual acuity of 20/40 or better or failure to achieve a reduction of at least 50% of excess macular thickness on OCT after the initial 3–6-month loading dose is to be considered nonresponsiveness [102].

The Spanish Delphi panel also had different criteria for nonresponders. They considered a less than 10% reduction in CRT or a less than 5 letter improvement in VA a criterion for nonresponsiveness [103].

For nonresponders, a switch to another anti-VEGF is recommended if the patient is phakic, to lower the incidence of cataract and glaucoma development. If the DME remained without responding, a switch to steroids is recommended [43]. Dexamethasone implant is the first choice in the steroid group followed by fluocinolone acetonide intravitreal implant in case of steroid nonresponsiveness [110].

A steroid dexamethasone implant (DEX implant; Ozurdex) can be used as a first-line treatment if anti-VEGF is contraindicated, in the above-mentioned conditions, or if there is poor compliance with the anti-VEGF regimen (because of the frequent visits or social or economic issues), and may also be recommended in patients who are vitrectomized, pseudophakic (because cataract development is not now an issue) or with chronic DME [111, 112]. IOP measurement and monitoring the development of cataract should be regularly checked in patients in whom a steroid implant is used [112].

One study suggested that DME associated with an increased inflammatory response, especially the cystoid and the sensory neural detachment types, as mentioned above, may resolve better with steroids as compared to anti-VEGFs [14].

3.4.3.1 Management of center-involved DME in pregnancy

Early Diabetic Treatment Retinopathy Study (ETDRS) recommended the use of grid or focal laser for clinically significant macular edema (CSME) in general. This was, however, before the era of anti-VEGFs and steroids [113]. ETDRS guidelines were, however, not specific for pregnancy, but two studies [114, 115] supported the use of macular laser at the earliest to prevent irreversible damage. Another study [116] recommended the use of micropulse laser for foveal involvement, as it is safer.

Anti-VEGF and triamcinolone are better to be avoided during pregnancy for fear of teratogenicity in cases where there is refractory DME. Since steroids were proven to be more effective in improving VA after 4 months of follow-up as compared to laser as proved by the Diabetic Retinopathy Clinical Research (DRCR) Network [117], it is therefore recommended to use dexamethasone implant for DME that developed before pregnancy [43].

Observation is a reasonable management option for pregnant patients with mild diabetic macular edema (DME) or DME developing during pregnancy since the edema may well resolve after delivery [43, 118].

The American Academy of Ophthalmology Preferred Practice Patterns recommend that pregnant diabetic patients undergo dilated fundus examination in the first trimester, with subsequent follow-up determined by the severity of retinopathy, as per every 3–6 months for moderate nonproliferative diabetic retinopathy (NPDR) and those with severe NPDR or worse should be examined every 1–3 months. Postpartum follow-up should continue during the first year [117].

3.4.3.2 Management of diabetic macular edema associated with proliferative diabetic retinopathy

In patients with noncenter-involved DME associated with PDR, a focal laser is a good option to be used to treat the DME [119].

If the PDR is presented with center-involved DME, anti-VEGF therapy is recommended, it will improve the DME and cause regression of the neovascularization, then, PRP can be applied. Both ranibizumab and aflibercept were equally effective in improving visual acuity and reducing CRT in eyes with DME and PDR after 2 years; however, the number of microaneurysms, supplementary laser PRP and micropulse laser sessions were higher in the Ranibizumab group [120].

3.4.3.3 Surgical management of DME

Currently, the indication of pars plana vitrectomy (PPV) in eyes with DME is the presence of vitreomacular traction or the persistence of macular edema following intensive intravitreal injection with anti-VEGF or steroids [121, 122].

The performance of internal limiting membrane (ILM) peeling is, however, a matter of controversy. Complications from ILM peeling in cases of DME when the retinal architecture is disorganized and weakened by a longstanding and chronic DME, such as rupturing intraretinal cystoid spaces, might be expected. In one study, the functional results as regards improvement of VA did not differ whether the ILM was peeled or not [122].

As regards the preoperative OCT findings, it was found that eyes with neurosensory detachment had the best postoperative VA improvement following PPV, while eyes with sponge-like diffuse retinal thickening (SDRT) did not show any VA improvement following PPV [123].

Although from the theoretical point of view, PPV reduces VEGF and other DME-promoting cytokine concentration in the premacular area [124] and increases oxygen supply to the ischemic retina further suppressing VEGF production with consequent reduction of DME, yet there is no universal agreement in the performance of PPV for cases of DME without traction [125, 126].

Results of clinical trials appear controversial [121, 122, 123]. Although a limited improvement of function and a short-term improvement in macular thickness reduction following surgery were reported by some authors [121, 127], others demonstrated a significant benefit [128, 129].

3.4.3.4 Cataract extraction in the presence of DME

It is usually recommended to give anti-VEGF 1–2 weeks before cataract extraction to stabilize DME prior to surgery. A less preferred option is to give the anti-VEGF during the surgery [130, 131].

3.5 Newer advances to solve the unmet needs in the management of DME

1. Predictive medicine:

This subset of medicine detects the occurrence of a disease before its manifestations appear in an individual, as per population-based cross-sectional studies linked to clinical data. People at risk can therefore have personalized treatment plans with better treatment outcomes [132, 133].

1. Solving the problems of delayed diagnosis, referral and screening

   1. The advent of new nonmydriatic ultrawide field fundus cameras to facilitate examination and documentation through miotic pupils [134].

   2. The use of handheld devices to facilitate screening and is also cost effective [135].

   3. The use of artificial intelligence (AI) to analyze the fundus photographs can overcome the deficiency of healthcare workers [136].

   4. Measuring the level of retinal flavoprotein fluorescence, which was found to be elevated in diabetic eyes with retinopathy, as compared to diabetic eyes without retinopathy. This was recently introduced using a noninvasive imaging machine [137].

2. Reducing the burden of monthly anti-VEGF injections

A Ranibizumab port delivery system, which is a sustained delivery refillable implant, is described in ongoing studies for approval. It can be implanted over the pars plana without sutures. It is now in phase II trial (LADDER, ClinicalTrials.gov identifier: NCT02510794) [135].

1. Overcoming the poor response to anti-VEGFs:

Newer pathway drugs are recently under investigation for the treatment of DME (Table 3).

Agent	Mechanism of action	Route of administration	Current development status
Pharmacological agents targeting the angioprotein/Tie pathway [138]
Razuprotafib (AKB-9778)	Small-molecule inhibitor of VE-PTP	Subcutaneous injection	Completed phase 2 for DME and DR
Nesvacumab	Fully human IgG1 monoclonal antibody inhibiting Ang-2	Intravitreal injection as a co-formulation with aflibercept	Completed phase 2 for DME development currently discontinued
Faricimab (Vabysmo)	Bispecific IgG1-based antibody inhibiting both Ang-2 and VEGF simultaneously	Intravitreal injection	Completed phases 2 and 3 for DME and nAMD. Approved by the US FDA for the treatment of DME and nAMD
AXT107	Type IV collagen-derived peptide that activates Tie-2 and inhibits VEGF-A and VEGF-C	Intravitreal injection	Ongoing phase 1/2a for DME and nAMD
Pharmacologic agents with an anti-inflammatory action: [139]
APX3330	Redox factor-1 (Ref-1) inhibition; can potentially reduce proinflammatory and hypoxic signaling	Small-molecule oral tablet	Phase 2
LKA651	Erythropoietin inhibitor	Intravitreal injection	Phase 2
Endothelial dysfunction blockers: [139]
AR-13503	Active metabolite of netarsudil and inhibitor of Rho kinase (ROCK) and protein kinase C (PKC)	Implant	Phase 1
CU06–1004	Inhibitor of vascular leakage and inflammation, as shown in various animal models	Oral capsule	Phase 1
THR-149	Bicyclic peptide inhibitor targeting plasma kallikrein AAV8 vector	Intravitreal injection	Phase 2
Gene therapy [139]
RGX-314	AAV8 vector containing a transgene for anti-VEGF fab	Intravitreal injection	Phase 2

Table 3.

Recently, pathway drugs under investigation are used for the treatment of DME.

4. Conclusion

Diabetes mellitus (DM) and its complications are a major public health burden worldwide. Diabetic macular edema is a vision-threatening complication of DR and a major cause of vision loss in diabetic patients.

The pathogenesis of diabetic macular edema is very diverse and consequently, the results of treatment are sometimes not satisfactory. Available treatment options include retinal laser photocoagulation, antivascular endothelial growth factor (anti-VEGF) agents, intravitreal corticosteroids and vitreoretinal surgery.

More drug options utilizing different pharmacologic pathways are now being investigated to improve the visual results posttreatment and decrease the economic and social burden the patients are experiencing.

Conflict of interest

“The author declares no conflict of interest.”