Diabetic macular oedema

Referral priority: Moderate

All patients with diabetic macular oedema should be referred semi-urgently to an ophthalmologist or a hospital, following local guidelines.

Click on one of the cards below to read more about the specific eye condition.

Written by
Marko Lukic
Edited by
Svein Tindlund and Jon Gjelle
Published
June 2023
Sections
01
Introduction

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02
Symptoms

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03
Clinical signs

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04
Diagnostic procedures

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05
Management and treatment

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06
References

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Atlas overview
Sections
01 Introduction
01

Introduction

The pandemic of diabetes mellitus represents a substantial global health challenge. Diabetes causes many long-term systemic complications that considerably impact the patient and society, as it typically affects individuals in their most productive years.(1) There are two types of diabetes, type 1 and 2. Type 1 diabetes mellitus (T1DM) is characterised by the destruction of beta cells in the pancreas by an autoimmune mechanism, whereas type 2 diabetes mellitus (T2DM) is a relationship between lifestyle and genetics.

The International Diabetes Federation published data that indicate that the prevalence of diabetes mellitus in Europe is 8.5% of people aged between 20 and 79 years, which means that 33 million people in the EUare affected by this silent and severe condition.(2) The total number of people diagnosed with diabetes mellitus worldwide is projected to rise to 366 million in 2030.(3)

One of the most significant and common complications of diabetes mellitus are diabetic retinopathy and diabetic macular oedema (DMO), the leading cause of visual loss in the working-age population.(4) According to The UK National Ophthalmology Database study, clinically significant macular oedema was present in 15.8–18.1% of eyes, and in 8.7–10.0% of eyes, this involved the central macula.(5) Then, the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) found that DME incidence over 25 years among people with type 1 DM (T1DM) was 29%.6 For people with type 2 DM (T2DM), the WESDR found that 25.4% of those who used insulin and 13.9% of those who did not use insulin had DME.(6)

There are established risk factors for DMO, which are similar to those for diabetic retinopathy; duration of diabetes mellitus (DM), poor control of DM with elevated haemoglobin A1c (HbA1c), hypertension, and hyperlipidemia, impaired renal function and use of thiazolidinediones.(7,8,9)

The role of glycated haemoglobin (HbA1c) in its correlation with the risk of developing and progressing diabetic retinopathy has been well established. The HbA1c is an important indicator of long-term glycemic control to reflect the cumulative glycemic history of the preceding two to three months.(10) There are two scales of HbA1c used in everyday clinical practice. The targets of diabetic patients under the old classification were between 6.5 and 7.5%, while the new measurement indicates 48-59 mmol/mol.(11) As per the Diabetes Control and Complications Trial (DCCT), and later on confirmed by The Epidemiology of Diabetes Interventions and Complications Study (EDICS), the intensive control of blood glucose levels, where the mean HbA1c was 7.2%, achieved a decrease in the incidence of diabetic retinopathy by 76% and slowing the progression of diabetic retinopathy by 54%.(12,13) Nonetheless, the publications give inconsistent conclusions about the role of HbA1c in cases of diabetic macular oedema.(14-18) However, due to undeniable evidence of HbA1c in the progression of diabetic retinopathy, its control is essential also in patients with diabetic macular oedema but primarily to prevent further progression of diabetic retinopathy.(19)

Diabetic macular oedema may appear at any stage of diabetic retinopathy but is more frequent at more severe stages.(20) Three significant events are involved in the pathomechanism of diabetic retinopathy and diabetic macular oedema: capillary leakage, capillary occlusion, and retinal ischaemia with its sequelae.(7) On the molecular level, hyperglycemia leads to the activation of alternative pathways of glucose metabolism such as the polyol pathway advanced glycation endproducts (AGEs) formation, protein kinase C (PKC) activation, hexosamine pathway flux, and Poly(ADP-ribose) polymerase activation.21,22 The result of these pathways is the activation of cytokines and growth factors, leading to vascular endothelial dysfunction, increased vascular permeability, and eventual microvascular occlusion.(21) In diabetic macular oedema, the AGEs play a role in causing damage to the blood-retinal barrier.  The damage leads to leakage of fluid within the interstitial space.(23)

02

Symptoms

Patients with diabetic macular oedema may present with decreased visual acuity, metamorphopsia, and changes in colour perception and reading. However, a significant number of patients may be asymptomatic. The clinical studies revealed a poor correlation between central foveal thickness and macular oedema.(24)

Always take a thorough medical history, including blood sugar and blood pressure control questions. Remind your patients of the importance of strict control of the metabolic status and being familiar with HbA1c.

03

Clinical signs

Macular oedema clinically represents macular thickening with or without lipid exudates. By appearance, it may be focal, multi-focal, or diffuse. However, there is inconsistency in using those terms in clinical practice.

The Early Treatment Diabetic Retinopathy Study (ETDRS) established criteria for so-called clinically significant macular oedema(25):

  • Retinal thickening at or within 500 μm of the centre of the fovea.
  • Hard exudates at or within 500 μm of the centre of the fovea if adjacent to an area of retinal thickening.
  • Retinal thickening of at least one disc area, any portion of which is within 1500 μm (approximately one disc diameter) from the centre of the fovea.

The above criteria are done based on a slit-lamp examination in the 1980s. Nowadays, OCT plays a crucial role in diagnosing and monitoring macular oedema. However, the abovementioned criteria are still significant in determining clinically significant macular oedema. If left untreated, this condition can potentially cause severe damage to vision.

Image 1. Colour fundus photo of diabetic maculopathy – note lipid exudates affecting fovea and parafoveal microaneurysms.
04

Diagnostic procedures

Slit lamp examination and colour fundus photography are classical examination methods where it is vital to be familiar with the clinical signs mentioned above.

Optical coherence tomography – it is a golden standard in diagnosing diabetic macular oedema and recognising early signs of diabetic maculopathy (macular changes secondary to diabetes without the presence of fluid). It is beneficial to monitor the relationship between fluid and fovea. Therefore, the International Council of Ophthalmology defined the below classification.(20)

  • Centre-involved DME: Retinal thickening in the macula that involves the central subfield zone (1 mm in diameter)
  • Non-centre-involved DME: Retinal thickening in the macula that does not include the central subfield zone (1 mm in diameter)
Image 2. Intraretinal fluid (cystoid spaces) involving the fovea.
Image 3. Lipid exudates and intraretinal hyperreflective dots represent signs of diabetic maculopathy. Note that there is no presence of fluid.

There are established OCT biomarkers in DMO that are important in vision prognosis and treatment response; disorganisation of inner retinal layers (DRIL), intraretinal hyperreflective foci, disruption of the ellipsoid zone, subfoveal neuroretinal detachment.(2,6) Their detailed elaboration is out of this article’s scope.

Optical coherence tomography angiography (OCTA) is a modern diagnostic tool for evaluating macular and retinal perfusion. It is essential to understand that OCTA is distinct from fluorescein angiography, and there are significant differences between these two modalities. Nevertheless, it is a non-invasive tool that quickly aids in investigating retinal perfusion.

Image 4. Mild macular fluid. Note the subfoveal disruption of the ellipsoid zone, which is a poor VA prognostic factor.
Image 5. Parafoveal macular oedema with intraretinal lipid exudates and intraretinal hyperreflective spots. Note subfoveal neuroretinal detachment.
05

Management and treatment

Patients must keep their metabolic status under control as best they can- This includes strict control of diabetes, blood pressure, and cholesterol.(27) it is important to modify the patient’s diet, lose body weight, and exercise The role of eye care specialists is to advise patients on the importance of disease control and to inform them about potential consequences in case of progressive disease.

The first treatment used for macular oedema was a macular laser. The Early Treatment Diabetic Retinopathy Study (ETDRS) was the first study to provide a treatment paradigm for this disease using laser therapy to reduce moderate vision loss in patients with clinically significant macular oedema by approximately 50%.(25)

At present, anti-VEGF agents are the first-line treatment for DMO requiring treatment. Since 2005, intravitreal bevacizumab has been used off-label for ocular conditions. The Food and Drugs Administration (FDA) approved ranibizumab for DME in 2012, aflibercept in 2014, and brolucizumab and faricimab in 2022.(20)

Numerous landmark clinical trials have proven the safety and efficacy of intravitreal anti-VEGF treatment.(28-60) There are some clinical considerations in treating DMO with intravitreal anti-VEGF injections. According to Protocol V study results, observation is recommended for eyes with centre-involving DMO and visual acuity of 20/25 or better.(61) -It’s worth noting that the recommendation mentioned earlier is only applicable if patients can consistently attend follow-up appointments and receive the necessary treatment during any clinical deterioration. Choosing the first-line anti-VEGF agent, as well as the protocol of treatment, varies among experts. However, it is important to understand that there is no perfect drug and that 40% of eyes still have persistent DMO (defined as never having a CST < 250μm through 6 months on time-domain OCT) over two years, according to Protocol I results.(62) Those patients who did not achieve desirable results may be switched to another anti-VEGF agent or steroids.

Steroids have an important role in the treatment of DMO, as it has been proven that inflammation plays a significant -part in the pathomechanism of the condition.(63) – Among steroids, a few agents have been used and proven to be effective in treating diabetic macular oedema (DMO), including intravitreal triamcinolone (labelled), intravitreal dexamethasone implant, and intravitreal fluocinolone acetonide implant.(28,35,64,65)

It is also possible to combine treatment and use a combination of steroids and anti-VEGF +/- focal macular laser. Diabetic macular oedema is a chronic condition, and its treatment is complex and chronic. An experienced retina specialist must do it.

06

References

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2 https://idf.org/our-network/regions-members/europe/welcome.html

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5 Keenan T, Johnston R, Donachie P, Sparrow J, Stratton I and Scanlon P. United Kingdom National Ophthalmology Database Study: Diabetic Retinopathy; Report 1: prevalence of centre-involving diabetic macular oedema and other grades of maculopathy and retinopathy in hospital eye services. Eye. 2013; 27: 1397.

6 Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin epidemiologic study of diabetic retinopathy XV: the long-term incidence of macular edema. Ophthalmology. 1995 Jan 1;102(1):7-16.

7 Ishibazawa A, Nagaoka T, Takahashi K, Takahashi A, Yokota H, Yoshida A. Association between diabetic macular edema and chronic kidney disease in patients with type 2 diabetes. Investigative Ophthalmology & Visual Science. 2013 Jun 16;54(15):2400-.

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11https://www.iddt.org/news/new-hba1c-units

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20 https://eyewiki.aao.org/Diabetic_Macular_Edema#cite_note-15

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48 Li X, Dai H, Li X, Han M, Li J, Suhner A, Lin R, Wolf S. Efficacy and safety of ranibizumab 0.5 mg in Chinese patients with visual impairment due to diabetic macular edema: results from the 12-month REFINE study. Graefe’s archive for clinical and experimental ophthalmology. 2019 Mar;257(3):529-41.

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52 Bressler NM, Beaulieu WT, Maguire MG, Glassman AR, Blinder KJ, Bressler SB, Gonzalez VH, Jampol LM, Melia M, Sun JK, Wells III JA. Early response to anti–vascular endothelial growth factor and two-year outcomes among eyes with diabetic macular edema in protocol T. American journal of ophthalmology. 2018 Nov 1;195:93-100.

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54 Terasaki H, Shiraki K, Ohji M, Metzig C, Schmelter T, Zeitz O, Sowade O, Kobayashi M, Vitti R, Berliner A, Shiraga F. EFFICACY AND SAFETY OUTCOMES OF INTRAVITREAL AFLIBERCEPT FOCUSING ON PATIENTS WITH DIABETIC MACULAR EDEMA FROM JAPAN. Retina (Philadelphia, Pa.). 2019 May;39(5):938.

55 Heier JS, Korobelnik JF, Brown DM, Schmidt-Erfurth U, Do DV, Midena E, Boyer DS, Terasaki H, Kaiser PK, Marcus DM, Nguyen QD. Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies. Ophthalmology. 2016 Nov 1;123(11):2376-85.

56 Brown DM, Schmidt-Erfurth U, Do DV, Holz FG, Boyer DS, Midena E, Heier JS, Terasaki H, Kaiser PK, Marcus DM, Nguyen QD. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015 Oct 1;122(10):2044-52.

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60 Wykoff CC, Abreu F, Adamis AP, Basu K, Eichenbaum DA, Haskova Z, Lin H, Loewenstein A, Mohan S, Pearce IA, Sakamoto T. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. The Lancet. 2022 Feb 19;399(10326):741-55.

61 Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, Grover S, Jampol LM, Jhaveri CD, Melia M, Stockdale CR. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a srandomised clinical trial. Jama. 2019 May 21;321(19):1880-94.

62 Elman MJ, Bressler NM, Qin H, Beck RW, Ferris III FL, Friedman SM, Glassman AR, Scott IU, Stockdale CR, Sun JK, Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011 Apr 1;118(4):609-14.

63 Whitcup SM, Cidlowski JA, Csaky KG, Ambati J. Pharmacology of corticosteroids for diabetic macular edema. Investigative ophthalmology & visual science. 2018 Jan 1;59(1):1-2.

64 Campochiaro PA, Brown DM, Pearson A, Chen S, Boyer D, Ruiz-Moreno J, Garretson B, Gupta A, Hariprasad SM, Bailey C, Reichel E. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012 Oct 1;119(10):2125-32.

65 Haller JA, Bandello F, Belfort Jr R, Blumenkranz MS, Gillies M, Heier J, Loewenstein A, Yoon YH, Jacques ML, Jiao J, Li XY. Randomised, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010 Jun 1;117(6):1134-46.