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CLINICAL AND SURGICAL PRACTICE

Received: October 20^th 2014

Accepted: January 26^th 2015

Literature review: Diabetic macular edema. Repercussions and treatment

Luis Roberto Carmona-Moxica,^a Fabiola Hernández-Núñez^a

^aDivisión de Oftalmologia, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Luis Roberto Carmona-Moxica

Telephone:( 55) 3041 9655

Email: lrcm_587@hotmail.com

In our country there is a report of prevalence of Diabetes Mellitus in the adult population of a 10%, occupying one of the first causes of morbidity-mortality, also visual and labor incapacity. Macular edema is the first cause of lost vision in the diabetic patient. There are classic methods to detect it, as the examination with biomicroscope, indirect ophthalmoscopy, fluorangiography (FAR), and the new and gold standard method for diagnostic and sequence examination, Ocular Coherence Tomography (OCT). With OCT had been possible the study of distinct types of macular edema, that could represent distinct clinical states, with specific treatments. The protocol of treatment of macular edema, continues changing. The traditional methods as metabolic control and fotocoagulation with Laser now have more options as intravitreal injection of triamcinolone, or antiangiogenic substances, even surgical treatment with vitrectomy. There are many prospective and randomized studies evaluating this methods, so until now is difficult to determine wich treatment is the best.

Keywords: Macular edema; Diabetes mellitus

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Diabetes mellitus is an entity whose prevalence in the population of developed countries is between 6 and 8%,^1,2 In our country it is reported at 10% in the adult population, and it is also one of the leading causes of morbidity and mortality in the country, causing work disability in the economically active population, mainly due to impact on the eyesight of the patient.

Although both proliferative diabetic retinopathy and diabetic macular edema can cause vision loss, it is accepted that macular edema is the leading cause of vision loss in patients affected by this disease.^1,2

Dealing with this process presents several challenges to the ophthalmologist, first, concerning the diagnosis, it is clear that the classic methods for the detection of this disease, such as biomicroscopic examination, indirect ophthalmoscopy or fluorescein angiography (FA), have been overtaken by new methods such as optical coherence tomography (OCT). Some authors even suggest that different types of macular edema detected by OCT could represent different clinical entities that require specific treatment.³ But the therapeutic approach to diabetic macular edema is also unclear at present. To traditional methods of metabolic control^4,5 and laser photocoagulation,⁶ in recent years new alternatives have been added, such as the intravitreal injection of triamcinolone^7,8 and other antiangiogenic substances,^9,10 such as bevacizumab and ranibizumab, or surgical treatment by vitrectomy.^11,12 So far there are few prospective randomized studies to evaluate most of these therapies, making it even more difficult to determine the most appropriate treatment in each circumstance.  

Pathophysiology

The histological alteration found in diabetic macular edema is an accumulation of fluid in the Henle layer and the inner nuclear layer of the retina.

This fluid comes from intravascular compartment and its flow, as in other tissues, is modulated by the balance of hydrostatic pressure and osmotic pressure. But in the retina there is another structure, which is the blood-retinal barrier (BRB) which also acts to regulate vascular permeability.

The main mechanism leading to the extracellular accumulation of fluid in the retina is an alteration in the permeability of BRB.¹ It appears that prolonged hyperglycemia and hypoxia cause increased production of factor vascular endothelial growth factor (VEGF) on the part of glial, microglial and neuronal cells of the retina.¹³

VEGF, as well as being a substance with angiogenic capacity, has a very important permeabilizing activity and acts by increasing the permeability of the BRB and facilitating extravasation of fluid from the intravascular compartment.^13,14

Increased susceptibility to macular edema formation may be due to the fact that this area of ​​the retina has very few astrocytes. These cells synthesize factors that would increase protein synthesis of the tight bonds of the BRB and thus decrease permeability.

Systemic factors may also favor the development of diabetic macular edema. Hypertension causes an increase in hydrostatic pressure of the retinal capillaries.^4,5 Other circumstances such as hypoalbuminemia will decrease oncotic pressure. Both circumstances lead to increased vascular permeability and promote the development of edema.

Clinical manifestations

The main cause of visual loss in diabetic patients is diabetic macular edema.^1,2

The alteration that defines the appearance of diabetic macular edema is a thickening of the retina in the macular area caused by the extravasation of fluid into extravascular space.¹ This thickening can be detected in biomicroscopic examination or through diagnostic devices such as OCT. The thickening of the retina may be accompanied by hard exudates which consist of proteinaceous and lipidous material exuded by the vessels of the retina and deposited on the outer layers of the retina or even the subretinal space (Figure 1).

The most important clinical manifestation in diabetic macular edema is a central visual impairment associated with a deformation of images, which can appear in very early stages of disease.^1,2 Diabetic macular edema may develop associated with different degrees of diabetic retinopathy, which can range from mild nonproliferative diabetic retinopathy to advanced proliferative retinopathy.⁶

Classification

Until the appearance of OCT, diabetic macular edema was classified as focal or diffuse.^1,6 Focal edema is characterized by the appearance of hard exudates clustered around groups of microaneurysms. In FAG a focal escape is generally evidenced by microaneurysms. In diffuse edema the appearance of exudates or microaneurysms is not so obvious, and with FAG appears as a diffuse spread across the macular area (Figure 2).

The Early Treatment Diabetic Retinopathy Study (ETDRS)⁶ introduced the term of clinically significant diabetic macular edema, which is defined as:

• Retinal thickening 500 microns or less from the center of the fovea.
• Hard exudates 500 microns or less from the center of the fovea if associated with adjacent retinal thickening.
• Retinal thickening of at least one disc area, part of which is within one disc diameter of the center of the fovea.

According to ETDRS those patients whose edema could be framed as clinically significant would be those to benefit from laser treatment, hence the importance of this classification.

More recently the International Classification of Diabetic Retinopathy has been proposed,¹⁶ which sets forth three degrees in regard to diabetic macular edema:

• Mild: retinal thickening or hard exudates in posterior pole but far from the center of the macula.
• Moderate: proximity of thickening or exudates to the center of the macula.
• Severe: exudates or thickening affecting the center of the macula.

The introduction of OCT to the diagnosis of diabetic macular edema has made for new classifications proposed. Otani describes three types of edema found based on structural changes in the OCT:¹⁷

• The spongiform thickening of the retina is characterized by a moderate thickening of the macula and the emergence of areas of low reflectivity in the outer layers of the retina.
• Cystic macular edema shows large cystic spaces that occupy the entire thickness of the retina and cause a major distortion of macular anatomy.
• Subfoveal serous detachment manifests as a hyporeflective fusiform area in the subfoveal space.

Kim proposes a new classification that includes all three types described by Otani, although rather than calling it spongiform thickening, they choose diffuse thickening of the retina. They also add two other types, which are the posterior hyaloid traction without tractional retinal detachment, and posterior hyaloid traction with retinal detachment^18,19 (Figure 3).

Diagnosis

The method conventionally used to diagnose diabetic macular edema has been biomicroscopic examination. The problem with this method is that the information provided is solely qualitative and subjective, and it is insensitive because big changes are needed in the thickness of the retina so that they can be detected by biomicroscopic examination.¹⁸

FAG has also been used to diagnose diabetic macular edema.¹⁵ However, the interpretation of the results of this test is also subjective, and although useful for detecting vascular leakage, this is not always associated with thickening of the retina,⁶ which is what defines the presence or not of diabetic macular edema. FAG currently has two indications: the first is to identify focal points of leakage to guide the laser treatment, and the second is to assess the presence of macular ischemia, which is a factor of very poor prognosis as far as visual recovery is concerned.¹⁵  

Today OCT is the most useful to diagnose and diabetic macular edema.¹⁹ Tomographic cuts can objectively and accurately detect the presence of fluid in the layers of the retina, and features of the existence of areas of retinal thickening, which can also be measured, thus giving objective data to assess the evolution and response to treatment of these patients (Figure 4). It also allows one to examine in detail the vitreous-macular interface and detect possible abnormalities amenable to surgical treatment, very frequent in diabetic patients.^18,19

Treatment

To date only metabolic control 4,5 and laser photocoagulation^20-22 have conclusively shown efficacy in the treatment of diabetic macular edema in randomized prospective studies.

The ETDRS showed that focal laser photocoagulation was able to slow vision loss in patients with clinically significant macular edema.^20-22 It seems that the effect of the laser in diabetic macular edema is, on the one hand, to destroy photoreceptors in the macular area in order to reduce hypoxia in this area. The laser could also act to induce proliferation of endothelial cells and retinal pigment epithelial cells. Thus, cells destroyed by the laser would be replaced by new ones, with better functionality, thereby improving the efficiency of internal and external BRB in the control of edema.²⁰ Despite these seemingly good results obtained in the ETDRS, less than 3% of these patients experience improvement in their vision, 12% continue to lose visual acuity despite treatment and in 40% of them the edema persists more than 12 months.^20,22 It has also been found that patients whose edema was classified as diffuse type would be refractory to laser treatment.^21,22

The poor visual results obtained with the laser and its inability to deal with diffuse edema have raised treatment alternatives in recent years such as vitrectomy or intravitreal triamcinolone or other antiangiogenic substances.

One treatment that has aroused great interest and raised enormous expectations for the treatment of diabetic macular edema is intravitreal triamcinolona.^7,8 This substance would act temporarily to reduce the permeability of capillaries or to decrease production of VEGF,²⁸ but it does not act on hypoxia, which may be involved in the development of macular edema.

Among the disadvantages is that although short-term disappearance of edema and improvement of vision is obtained in a large percentage of patients, its effectiveness is temporary,²⁹ and medium term recurrence of the edema is the norm.³⁰ Moreover, a significant percentage of patients receiving this therapy develop elevated intraocular pressure or cataract. To try to improve the poor results obtained with isolated triamcinolone, it has been proposed to combine this treatment with laser photocoagulation.³²

A sequence is proposed in which first intravitreal triamcinolone injection is done and, a few weeks later when the edema has disappeared, grid photocoagulation is done in the macular area (Figure 5). In theory, this procedure would allow the laser to be applied more precisely and with less intensity when on a less thickened retina. This would increase the efficiency of the laser and prolong the effect of triamcinolone. Also, the results of these studies, which generally have included a small number of patients, have yielded conflicting data. While some find benefits in this combination therapy,^31,32 for others this option does not provide significant advantages.³²

With regard to vitrectomy, Lewis was the first to state that this was an effective treatment in cases where the edema had not responded to the laser and where it was associated with the presence of a thickened and tense posterior hyaloid.²³ Subsequently this therapy has also been applied to patients whose posterior hyaloid was not thickened,²⁴ and even in cases where it was detached.²⁵

Most recently the routine peeling of the internal limiting membrane (ILM) has been introduced in patients with diabetic macular edema who were treated by vitrectomy.^26,27 Most of the studies carried out to test the validity of this procedure included a small number of patients and yielded contradictory results. While some find anatomical and functional improvement,¹¹ others describe only improvement in the anatomical aspect of the macula, but no change in visual sharpness.¹² Probably, while no studies appear to prove otherwise, it seems reasonable to restrict the use of the vitrectomy for diabetic macular edema to those cases in which OCT demonstrates traction on the macular area or major alterations to the vitreoretinal interface (Figure 6).

Finally, with regard to the injection of antiangiogenic substances, both ranibizumab and pegaptanib are taking the lead in the number of Phase II-III randomized multicenter studies, showing their effectiveness in the short term to achieve the disappearance of edema without as many side effects as intravitreal triamcinolone.^9,10

We highlight some of these international reference studies regarding the use of antiangiogenics in the treatment of diabetic macular edema.¹⁴ The study RESTORE³³ evaluated the treatment of macular edema using antiangiogenic ranibizumab (Lucentis), anti-VGEF as monotherapy and combined with laser, compared with single laser treatment; the groups treated with ranibizumab alone or with laser gave better response in decreased macular edema and gained lines of visual acuity. READ-234 also concluded a gain in improved visual acuity and macular edema in patients in the monotherapy treatment with ranibizumab, relative to only laser photocoagulation or laser plus ranibizumab. The RESOLVE study evaluated the standardized dose response to ranibizumab compared to placebo, demonstrating a rapid and continuous improvement in visual acuity without significant adverse effects from the first month of treatment with ranibizumab.³⁵ RISE and RIDE studies evaluated 380 patients each with diabetic macular edema, in which they worked with 3 treatment groups based on ranibizumab at doses of 0.3 mg, 0.5 mg, and placebo, obtaining significant visual improvement and reduction of macular edema in the group of ranibizumab 0.5 mg, demonstrating effectiveness and safety in the treatment, given the absence of adverse effects at 1 and 2 years follow-up.³⁶

Currently, studies have also been conducted with aflibercept (VEGF TRAP),³⁷ a molecule that blocks the activity of all the families of VEGF, including factors of placental growth (PLGF1 and 2), hence its effectiveness with a lower concentration of the drug and longer duration; these include VIEW 1 and 2, as well as GALILEO and COOPERNICO DA VINCI,^38,39 conducted in patients with macular edema due to retinal vein occlusion such as in age-related macular degeneration, with potential future applications also for use in diabetic macular edema.³⁹

Conclusions

Diabetes is a major cause of morbidity and mortality worldwide, with special incidence and prevalence in our Mexican population. As part of the protocol addressing all diabetic patients, timely ophthalmologic evaluation is essential to detect changes related to this disease on a retinal level, such as diabetic macular edema, the main cause of visual decline in diabetic patients, and diabetic retinopathy in its different stages, the leading cause of blindness in diabetic patients. By doing this, it is possible to give treatment and timely follow-up to patients with this condition, and to offer a treatment from among those known and mentioned in this review, to reverse the changes and promote the preservation of visual acuity in patients, a tangible reflection of a better quality of life for patients with diabetes mellitus.

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