Diabetic Macular Edema
Diabetic Macular Edema
Diabetic Macular Edema (DME)
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.
Duration of Diabetes Mellitus (DM) Poor control of DM with chronically elevated hemoglobin A1c (HbA1c) Hypertension Hyperlipidemia, Kidney disease, pioglitazone
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.
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).
Strict control of DM and other systemic diseases
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.
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 DME is center involving (CST on Heidelberg's OCT is 305 microns or worse in women and 315 or worse in men) and the visual acuity is worse than 20/25. Focal laser treatment is considered in the presence of “clinically significant macular edema (CSME)” (Please see below for definition of CSME), if use of anti-VEGF is contraindicated.
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
DME may be asymptomatic Decreased visual acuity( usually there is moderate vision loss compared to severe vision loss which occurs after vitreous hemorrhage/ retinal detachment involving macula in proliferative diabetic retinopathy) Metamorphopsia
CSME is a clinical diagnosis and is defined bt the ETDRS (Early Treatment Diabetic Retinopathy Study) 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.
Thus CSME is a clinical diagnosis made by slit lamp examination using contact lens, and investigations are not needed to diagnose CSME, though these may be needed to plan management, prognosticate, and to document.
Center involving DME (CI-DME) is diagnosed using SD-OCT when the central subfoveal thickness, CST on the macular map is 305 or worse in women and 315 or worse in men on Heidelberg (or equivalent thicknesses on the other SD-OCT machines)
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 capillary leakage are present on the FA.
HbA1c (Glycated Hemoglobin), Hemoglobin (anemia exacerbates diabetic retinopathy, may be associated with diabetic nephropathy), Fasting Blood Sugar (FBS), Post Prandial Blood Sugar (PPBS), Urea, Creatinine, Lipid Profile, Blood pressure, urine microalbumin levels
Other causes of macular edema include: retinal vein occlusion, ruptured macroaneurysm, Irvine-Gass syndrome, radiation retinopathy, hypertensive retinopathy, subfoveal choroidal neovascularization, retinal vein occlusion.
The standard of treatment for CSME since 1985 has been 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. Macular grid is done for diffuse macular edema. Laser photocoagulation has been shown to decrease the risk of moderate visual loss from 24% to 12% by 3 years.
Since 2005 intravitreal bevacizumab is being used for ocular conditions. FDA approved ranibizumab for wet age related macular degeneration in 2006 and for diabetic macular edema in 2012. Aflibercept has been approved to treat DME by FDA since 2014. Thus, as of 2021, the experience with anti-vascular endothelial growth factor (anti-VEGF) agents is of at least 15 years. Anti-VEGF agents have become the mainstay of treatment of DME currently.
- 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). '2 year results of RISE and RIDE trials for ranibizumab in DME showed that 98% patients maintained vision (lost less than 15 letters) with 0.3mg monthly injections, 34-45% patients gained at least 15 letters; mean visual acuity gain was 10.9 to 12.5 letters. Only 45-49% patients needed macular laser compared with 91-94% in control group. No additional benefit was seen with 0.5mg monthly versus 0.3mg ranibizumab monthly.'
- Aflibercept/VEGF trap eye: In the Vinci study DME patients were assigned randomly to 1 of 5 treatment regimens: VEGF Trap-Eye 0.5 mg every 4 weeks (0.5q4); 2 mg every 4 weeks (2q4); 2 mg every 8 weeks after 3 initial monthly doses (2q8); or 2 mg dosing as needed after 3 initial monthly doses (2PRN), or macular laser photocoagulation. Mean improvements in BCVA in the VEGF Trap- Eye groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus -1.3 letters for the laser group. Proportions of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the VEGF Trap-Eye groups were 40.9%, 45.5%, 23.8%, and 42.2% versus 11.4% for laser. Mean reductions in Central Retinal Thickness (CRT) in the VEGF Trap-Eye groups at week 52 were -165.4 μm, -227.4 μm, -187.8 μm, and -180.3 μm versus -58.4 μm for laser.'
- 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.
- 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.
- Ozurdex- Dexamethasone 0.7mg biodegradable implant was noted to improve vision by at least 15 letters in 22% patients at 3 years in MEAD study.  Around 60% eyes in 0.7mg implant group had cataract surgery. Approximately 1/3rd of the patients had clinically significant rise in the intraocular pressure needing therapy.
- Iluvien (fluocinolone acetonide intravitreal implant) 0.19 mg is a sustained release intravitreal implant. FDA approved it. to treat diabetic macular edema (DME) in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. It is supposed to release submicrogram levels of fluocinolone acetonide (FAc), for 36 months.
- 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.
- 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. However, long term benefit with this combined therapy was not seen and was wrought with complications as cataract, ocular hypertension and glaucoma.
- Strict control of diabetes, hypertension, and hypercholesterolemia
- Diet Modification
- Weight Loss
- 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.
- 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.
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.
- Subretinal fibrosis
- Extension of the laser scar into the fovea
- Choroidal neovascular membrane
- Paracentral scotoma
- Decreased visual acuity
- Vitreous hemorrhage
- Retinal tears/detachment
- Increase in intraocular pressure
- Cataract (common after steroid intravitreal injections)
- Ocular Hypertension/Glaucoma (common after steroid intravitreal injections)
- Retinal tears and retinal detachment
- Vitreous hemorrhage
- Elevated intraocular pressure
Depends on the severity of DME. 25%-30% of eyes with CSME will have moderate visual loss within 3 years.
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- Sharma, Yog Raj, Koushik Tripathy, Pradeep Venkatesh, and Varun Gogia. “Aflibercept – How Does It Compare with Other Anti-VEGF Drugs?” Austin J Clin Ophthalmol 1, no. 3 (2014): 1016.
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- Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, Li XY, Cui H, Hashad Y, Whitcup SM; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014 Oct;121(10):1904-14. doi: 10.1016/j.ophtha.2014.04.024. Epub 2014 Jun 4. PubMed PMID: 24907062.