Diabetic Macular Edema

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Disease Entity[edit | edit source]

Diabetic Macular Edema

Disease[edit | edit source]

Diabetic Macular Edema (DME)

Etiology[edit | edit source]

Chronic hyperglycemia is the major risk factor of diabetic macular edema. The incidence of DME over a 10 year period is 20% in patients with younger onset diabetes versus approximately 40% in older onset diabetes.

Risk Factors[edit | edit source]

Duration of Diabetes Mellitus (DM) Poor control of DM with chronically elevated hemoglobin A1c (HbA1c) Hypertension Hyperlipidemia

General Pathology[edit | edit source]

Chronic hyperglycemia-related accumulation of advanced glycated end products (AGEs) causes disruption of the blood retinal barrier (BRB) and an altered vitreo-retinal interface. Altered BRB leads to interstitial fluid accumulation within the retina and, in some cases, cyst formation, particularly in the perifoveal retina.

Pathophysiology[edit | edit source]

The exact pathogenesis of DME is still unclear. Recent evidence indicates that diabetic retinopathy (DR) is a neurovascular disease of the retina. Retinal neuronal abnormalities are present well before the retinal microvascular injury. Increased vasopermeability occurs as a result of breakdown of the BRB due to many factors: altered glial cells, loss of pericytes, endothelial cell death, leukostasis in the retinal vasculature, poor function of the tight junctions in the retinal vasculature, activation of the AGE receptor, upregulation of the expression of vascular endothelial growth factor (VEGF) and protein kinase C (PKC), and altered vitreo-retinal interface with a thickened taut, posterior hyaloid with persistent vitreo-macular traction (VMT).

Primary prevention[edit | edit source]

Strict control of DM

Diagnosis[edit | edit source]

History[edit | edit source]

A detailed history including the approximate date of onset of diabetes, the use of insulin vs. oral antihyperglycemic agents, and the quality of metabolic control (e.g., HbA1c level) should be elicited. Any associated medical problems such as hypertension, hypercholesterolemia should be identified.

Physical examination[edit | edit source]

Patients undergo a detailed biomicroscopic examination using the slit lamp as well as indirect ophthalmoscopy. DME is diagnosed stereoscopically as retinal thickening or hard exudates within one disc diameter of the center of the macula using detailed biomicroscopic contact lens examination of the macula. Treatment is recommended only when “clinically significant macular edema (CSME)” is present. (Please see below for definition of CSME.)

Signs[edit | edit source]

Macular thickening with or without hard exudates as judged with stereobiomicroscopy; thickening can occur in various patterns: focal, multifocal, and diffuse areas of retina thickening Hard exudates (consisting of lipoproteins) in various patterns, e.g., circinate rings

Symptoms[edit | edit source]

CSME may be asymptomatic Decreased visual acuity Metamorphopsia

Clinical diagnosis[edit | edit source]

CSME is a clinical diagnosis and is defined as: Retinal thickening within 500 µm of the macular center. Hard exudates within 500 µm of the macular center with adjacent retinal thickening. One or more disc diameters of retinal thickening, part of which is within one disc diameter of the macular center.

Diagnostic procedures[edit | edit source]

Optical coherence tomography (OCT) OCT shows three basic structural changes: retinal swelling, cystoid macular edema, and subretinal fluid. OCT is a more sensitive method for objective evaluation of vitreo-macular traction and for measurement of macular thickness. OCT can also be used to calculate the standardized change in macular thickness. OCT is more sensitive at detecting retinal thickening than is biomicroscopy. Experienced examiners generally cannot detect retinal thickening until retinal thickness is ≥ 300 µm. Fluorescein Angiography (FA) FA is performed to identify leaking microaneurysms or capillaries and areas of retinal ischemia. Leakage on the angiogram is not synonymous with retinal edema. Focal CSME is characterized by focal leakage from microaneurysms or capillaries is present on the FA, whereas diffuse DME is diagnosed when poorly demarcated areas of leakage are present on the FA.

Laboratory test[edit | edit source]

HbA1c

Differential diagnosis[edit | edit source]

Other causes of macular edema include: retina vein occlusion, ruptured macroaneurysm, Irvine-Gass syndrome, radiation retinopathy, hypertensive retinopathy, subfoveal choroidal neovascularization.

Management[edit | edit source]

General treatment[edit | edit source]

a. Laser Photocoagulation: The standard of treatment for CSME since 1985 has been focal laser photocoagulation since the results of Early Treatment for Diabetic Retinopathy study (ETDRS) were published. In “focal” CSME, a focal laser pattern is used to treat leaking microaneurysms identified on the FA that contribute to the retinal edema. In “diffuse” CSME, intraretinal leakage is noted on the FA from dilated retinal capillary beds or intraretinal microvascular abnormalities (IRMA) without isolated, discrete foci of leakage. Laser photocoagulation has been shown to decrease the risk of moderate visual loss from 24% to 12% by 3 years.



b. Pharmacotherapy : Other pharmacologic treatments are being investigated in prospective trials currently. These include anti-VEGF and corticosteroid intravitreal therapy. Long term (at least 3-year follow-up) is needed to assess the long-term efficacy and safety of this approach. Also, strict evaluation of the ideal dose, frequency, and duration of treatment, and the potential superiority of combination treatments in comparison to the focal/grid laser treatment is warranted.

i. Ranibizumab: Intravitreal ranibizumab (0.5 mg) with prompt focal/grid laser (within one week) has been found to be more effective compared with focal/grid laser alone for the treatment of DME involving the central macula (OCT central subfield thickness of ≥250 um) at 2-year follow-up (DRCRnet study).

ii. Bevacizumab: Intravitreal Bevacizumab (1.25 mg) at 6 week intervals has been reported to be more effective than modified ETDRS focal/grid laser in terms of improvement in visual acuity at 12 months (BOLT study). Intravitreal bevacizumab doses of 1.25 to 2.5 mg have shown improvement in best-corrected visual acuity and in reducing macular thickness on OCT at 24 months in The Pan-American Collaborative Retina Study Group.

iii. Steroid: Triamcinolone (4 mg) intravitreal injection has not been found to be superior to focal/grid photocoagulation at 2-years follow-up (DRCR net study). Fluocinolone acetonide and dexamethasone DDS intravitreal implants are being studied to evaluate their efficacy in treating DME.

c. Combined therapy

i. Intravitreal ranibizumab with laser: Intravitreal ranibizumab with prompt (within 1 week) or deferred (after 24 weeks) laser has been shown to be more effective compared to focal/grid laser alone for the treatment of DME involving the central macula (DRCRnet study). Ranibizumab is injected intravitreally at baseline with prompt laser, followed by monthly ranibizumab injections for 4 months followed by continuation of injections at 16 weeks if the OCT central subfield thickness is >/=250 um with visual acuity worse than 20/20.

ii. Steroid with laser: Intravitreal triamcinolone (4 mg) with focal/grid laser within a week has been shown to be more effective than laser alone (DRCR net) at 1 year only in pseudophakic eyes.

Medical therapy[edit | edit source]

  • Strict control of diabetes, hypertension, and hypercholesterolemia
  • Diet Modification
  • Weight Loss
  • Exercise

Medical follow-up[edit | edit source]

a. After laser treatment, the follow-up examination is at three months. If residual CSME is noted, OCT and FA may be performed to evaluate the benefit and location of repeat laser treatment.

b. Intravitreal injections (partially based on the DRCR net studies on ranibizumab): Patients follow-up every 4 weeks for intravitreal anti-VEGF injections during the first 4 months. At 16 and 20 weeks follow-up, the injections are given only if the OCT central subfield thickness is still >=250um. At 24 weeks and thereafter, monthly injections may be considered only if at least 1 line improvement of Snellen VA is noted or 10% improvement central subfield macular thickness on OCT from baseline. The retreatment at this point is at physician’s discretion.

Surgery[edit | edit source]

Pars plana vitrectomy (PPV) for removal of VMT may be considered. Identification of VMT is based on both clinical examination and OCT findings. The posterior hyaloid is removed along with any posterior cortical vitreous strands to the foveal edge and any visually significant epiretinal membrane. 50% of eyes will have reduction in central subfield thickness to < 250 um. As per the DRCR net study, only 28%-49% of such eyes will have improvement of visual acuity, and between 13% and 31% may have worsening of visual acuity. The effectiveness of PPV for DME in the absence of VMT is unclear.

Surgical follow up[edit | edit source]

Post-operative day (POD) #1, post-operative week (POW) #1, post-operative month (POM) #1, POM #3, POM #6, POM#12.

Complications[edit | edit source]

A. Laser Photocoagulation a. Subretinal fibrosis b. Extension of the laser scar into the fovea c. Choroidal neovascular membrane d. Paracentral scotoma e. Decreased visual acuity

B. Intravitreal injections a. Endophthalmitis b. Vitreous hemorrhage c. Retinal tears/detachment d. Increase in intraocular pressure e. Cataract (common after steroid intravitreal injections) f. Glaucoma (common after steroid intravitreal injections)

C. PPV a. Retinal tears and retinal detachment b. Vitreous hemorrhage c. Elevated intraocular pressure d. Endophthalmitis e. Cataract

Prognosis[edit | edit source]

Depends on the severity of DME. 25%-30% of eyes with CSME will have moderate visual loss within 3 years.

Additional Resources[edit | edit source]

References[edit | edit source]

a. Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and treatment. 2009 Jan-Feb;54(1):1-32

b. Diabetic Retinopathy Clinical Research Network Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology June 2010; 117(6):1064-1077.

c. Early Treatment Diabetic Retinopathy Study R: Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 103:1796-1806, 1985.

d. Michaelides M, Kaines A et al A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12 month data. Ophthalmology June 2010; 117(6):1059-1060.

e. Schachat AP. A new approach to the management of diabetic macular edema. Ophthalmology 2010 June;117(6):1059-1060.