eMedicine Specialties > Ophthalmology > Retina

Macular Edema, Diabetic

Emmanouil Mavrikakis, MD, PhD, Consultant Vitreoretinal Surgeon, Ophthalmology Department, Athens Medical Centre, Greece
Wai-Ching Lam, MD, FRCS(C), Associate Professor, Department of Ophthalmology and Vision Sciences, University of Toronto; Baseer U Khan, MD, Staff Physician, Department of Ophthalmology, University of Toronto, Canada

Updated: Sep 29, 2009

Introduction

Background

Pathophysiology

Diabetic macular edema is the result of retinal microvascular changes that occur in patients with diabetes. Thickening of the basement membrane and reduction in the number of pericytes is believed to lead to increased permeability and incompetence of retinal vasculature. This compromise of blood-retinal barrier leads to the leakage of plasma constituents in the surrounding retina, resulting in retinal edema.² The hypoxic state achieved through this mechanism can also stimulate the production of vascular endothelial growth factor (VEGF). There is evidence that VEGF is up-regulated in diabetic macular edema and proliferative diabetic retinopathy.³

Frequency

United States

The World Health Organization (WHO) estimates that 15 million people have diabetes in the United States; half of whom are undiagnosed. In addition, about 50% of the 8 million patients diagnosed with diabetes do not receive appropriate eye care. Untreated, there is a 25-30% risk of developing clinically significant macular edema (CSME) with moderate visual loss.

International

The WHO estimates that more than 150 million people worldwide have diabetes.

Mortality/Morbidity

Diabetes is the leading cause of new blindness in the United States, to which CSME (see Physical for definition) has a significant contribution.

• Untreated, 25-30% of patients with CSME exhibit a doubling of the visual angle within 3 years.
• Treated, the risk drops by 50%.

Race

• Diabetes is more common in Latinos, African Americans, and Native Americans.
• No data describe the predilection of one racial group developing diabetic macular edema over another group.

Sex

No data describe the predilection of one sex developing diabetic macular edema over the other sex.

Age

Diabetic retinopathy, not specifically diabetic macular edema, generally occurs in persons older than 40 years. It rarely occurs before puberty.

Clinical

History

• Ocular history
• Diabetic history - Specific inquiry should be made into risk factors for the development of diabetic retinopathy.
  • Type of diabetes - After 20 years of disease, nearly all patients with type I and 60% of patients with type II have some degree of retinopathy.
  • Duration of the diabetes - Increased risk of diabetic retinopathy
  • Age of patient - Diabetic retinopathy is more likely to present in patients older than 40 years.
  • Diabetic control - The Diabetes Control and Complication Trial (DCCT) clearly demonstrated that tighter control of blood sugar is associated with reduced incidence of diabetic retinopathy. (Glycosylated hemoglobin [HbA1c] should be less than 7%.)
  • Renal disease - Proteinuria is a good marker for the development of diabetic retinopathy; thus, patients with diabetic nephropathy should be observed more closely.
  • Systemic hypertension - Increased risk of retinopathy (diabetic retinopathy with superimposed hypertensive retinopathy)
  • Triglycerides and lipids - Normalization of lipid levels reduces retinal leakage and exudates deposition.
  • Pregnancy - Diabetic retinopathy can progress rapidly in pregnant women, especially those with preexisting diabetic retinopathy.

Physical

Funduscopy under stereopsis and high magnification should be performed on every patient with diabetes to assess for diabetic macular edema and diabetic retinopathy. An indirect ophthalmoscope does not provide adequate magnification for the ophthalmologist to diagnose diabetic macular edema.

• Diabetic macular edema is defined as retinal thickening within 2 disc diameters of the center of the macula.
  • Focal edema is associated with hard exudate rings resulting from leakage from microaneurysms.
  • Diffuse edema results from breakdown of blood-retinal barrier with leakage from microaneurysms, retinal capillaries, and arterioles.
• CSME, as defined by the ETDRS, exists with any of the following findings:
  • Retinal thickening within 500 µm of the center of the fovea
  • Hard, yellow exudates within 500 µm of the center of the fovea with adjacent retinal thickening
  • At least 1 disc area of retinal thickening, any part of which is within 1 disc diameter of the center of the fovea
• Other physical findings that should be noted include the following:
  • Visual acuity is an important parameter in following the progression of CSME, although it does not aid in the diagnosis of CSME because patients may have a visual acuity of 20/20.
  • The status of the posterior hyaloid; detached, taut, thickened

Causes

Causes include the following:

• After 20 years of the disease, nearly all patients with type I diabetes mellitus and 60% of patients with type II diabetes mellitus will have some degree of retinopathy.
• Poor control of blood sugar increases the risk of diabetic retinopathy.
• Renal disease can be a marker for the development of diabetic retinopathy.
• Systemic hypertension increases the risk of diabetic retinopathy.
• Elevated lipid levels increase the risk of leakage and exudate deposits.

Differential Diagnoses

ARMD, Exudative
Branch Retinal Vein Occlusion
Central Retinal Vein Occlusion
Hypertension
Macular Edema, Irvine-Gass
Uveitis, Evaluation and Treatment

Other Problems to Be Considered

Cystoid macular edema
Hypotonic retinopathy
Macular pucker
Epinephrine use in aphakia

Workup

Imaging Studies

• Fluorescein angiography
  • Fluorescein angiography is not relevant in aiding in the diagnosis of CSME but should be performed if treatment of CSME is being considered.
  • Fluorescein angiography distinguishes and localizes areas of focal versus diffuse leakage, thereby guiding the placement of laser photocoagulation.
  • The proximity of the leakage to the foveal avascular zone should be noted.
• Color stereo fundus photographs provide an opportunity to evaluate long-term changes in the retina.
• Optical coherence tomography
  • Optical coherence tomography (OCT) captures reflected light from retinal structures to create a cross-sectional image of the retina, which is comparable to histologic sections as seen with a light microscope.
  • It has been able to demonstrate a moderate correlation between retinal thickness and best-corrected visual acuity, and it has been able to demonstrate 3 basic structural changes of the retina from diabetic macular edema (DME), that is, retinal swelling, cystoid edema, and serous retinal detachment.
  • OCT is not currently required to establish a diagnosis and is not prescribed by current practice guideline; however, OCT has gained widespread acceptance as an additional modality to help identify and evaluate macular pathology.⁴
  • Quantitative measurement of macular thickness and subjective analysis of the foveal architecture allow a precise and reproducible way to monitor macular edema.

Histologic Findings

One study has demonstrated vascular endothelial growth factor (VEGF) to be strongly positive in cells and extracellular matrix taken from retinas exhibiting diabetic retinopathy and diabetic macular edema.

Staging

See Physical for the differentiation between clinically significant and nonclinically significant diabetic macular edema.

Treatment

Medical Care

• Systemic
  • Medical treatment should focus on optimizing diabetic and hypertensive control and lowering lipid levels. Optimizing diabetic, hypertensive, and lipid control has been shown to positively impact diabetic retinopathy.⁵
  • These issues are best managed by primary care physicians and internists.
• Ocular
  • Intravitreal triamcinolone acetonide 
    • Intravitreal triamcinolone acetonide (IVTA) has been shown to significantly reduce macular edema and to improve visual acuity, particularly when the macular edema is pronounced.^6,7,8
    • Some studies advocate IVTA as primary therapy, whereas others label it as adjunctive therapy to macular photocoagulation.⁹
    • Action is maximal at 1 week, lasting 3-6 months.
    • Patients should be counseled about the risk (30-40%) of increased intraocular pressure, of which virtually all can be medically controlled.
    • Other adverse effects include a less than 1% chance of retinal detachment, cataract, and endophthalmitis.
  • Intravitreal anti-VEGF agents
    • VEGF increases retinal vascular permeability, causes breakdown of the blood-retina barrier, and results in retina edema. VEGF is up-regulated in diabetic retinopathy.
    • Three currently available anti-VEGF agents are pegaptanib sodium, ranibizumab, and bevacizumab.
    • Pegaptanib sodium is a pegylated aptamer directed against the VEGF-A₁₆₅ isoform. It was the first FDA approved ophthalmologic anti-VEGF agent for the treatment of choroidal neovascularization (CNV) from age-related macular degeneration (ARMD). In a phase 2 prospective clinical trial, it appeared to improve anatomic and visual outcome in patients with diabetic macular edema (DME).¹⁰ Phase 3 trials of pegaptanib sodium for diabetic macular edema are being conducted.
    • Ranibizumab is a recombinant humanized antibody fragment that is active against all isoforms of VEGF-A. Intravitreal ranibizumab is FDA approved for the treatment of exudative ARMD. The RESOLVE study (phase 2, placebo-controlled, randomized, multicenter study) evaluated the effect of ranibizumab in patients with diabetic macular edema. The RESOLVE study is now concluded, and final data should be available soon. The RESTORE study (phase 3, laser-controlled, randomized, multicenter study) is designed to confirm the efficacy and safety of ranibizumab 0.5 mg as adjunctive therapy added to laser photocoagulation and/or as monotherapy in patients with diabetic macular edema. The Diabetic Retinopathy Clinical Research Network is planning two phase 3, prospective, randomized multicenter trials of ranibizumab for diabetic macular edema.
    • Bevacizumab is a full-length recombinant humanized antibody that is active against all isoforms of VEGF-A. It is FDA approved as an adjunctive systemic treatment for metastatic colorectal cancer. Small, nonrandomized pilot studies have documented some efficacy against diffuse diabetic macular edema. The Diabetic Retinopathy Clinical Research Network conducted a phase 2, prospective, randomized, multicenter clinical trial to determine the safety and possible benefits of this agent. They concluded that intravitreal bevacizumab can reduce diabetic macular edema in some eyes, but the study was not designed to determine whether the treatment was beneficial.¹¹ A phase 3 trial would be needed for that purpose.
  • Future therapies
    • The RIDE study is an ongoing placebo controlled trial evaluating the efficacy and safety of intravitreal ranibizumab 0.5 mg injection every 4 weeks for 24 months in patients with diabetic macular edema.
    • VEGF Trap-Eye is a soluble VEGF receptor fusion protein that binds all forms of VEGF-A and related placental growth factor (PGF). When administered as a single 4 mg intravitreal injection in a phase 1 study, a marked decrease in central retinal thickness and mean macular volume was noted.
    • The phase 3 FAME (fluocinolone acetonide in diabetic macular edema) trial is evaluating the Medidur fluocinolone-based injectable implant.
    • The phase 3 trial of Posurdex biodegradable implant (sustained delivery formulation of dexamethasone) for the treatment of diabetic macular edema is underway.
    • Retisert,¹² another steroid implant (fluocinolone acetonide), was evaluated in patients with diabetic macular edema with good results but a concerning adverse effect profile; 90% of patients developed cataracts, and 40% required glaucoma surgery within 3 years.

Surgical Care

Laser photocoagulation continues to be a well-proven therapy to reduce the risk of vision loss from diabetic macular edema.

The Diabetic Retinopathy Clinical Research Network reported results from a multicenter, randomized clinical trial, comparing focal/grid laser photocoagulation and intravitreal triamcinolone for the treatment of diabetic macular edema. They concluded that over a 2-year period focal/grid laser photocoagulation is more effective and has fewer adverse effects than 1-mg or 4-mg doses of preservative free intravitreal triamcinolone for most patients with diabetic macular edema.¹³

Studies on all other surgical modalities have been limited in the number of patients and the scope of disease being treated; therefore, these procedures have limited use and questionable efficacy.

• Focal/grid laser photocoagulation
  • Goals
    • Significant visual improvement is uncommon; the goal of macular laser treatment is to reduce progression.
    • Photocoagulation reduced the risk of moderate visual loss from diabetic macular edema by 50%, from 24% to 12%, 3 years after initiation of treatment.¹
  • Timing
    • Laser treatment is most effective when initiated before visual acuity is lost from diabetic macular edema; this emphasizes the need for diligent monitoring and follow-up care.
    • Laser treatment of diabetic macular edema should precede panretinal photocoagulation (PRP) by at least 6 weeks because PRP before this has been known to worsen diabetic macular edema. PRP should not be delayed in patients with very severe nonproliferative diabetic retinopathy or high-risk proliferative diabetic retinopathy.
  • Treatment
    • Area(s) of leakage can be identified by examination (areas of retinal thickening) or by fluorescein angiography.
    • Burns - 50-100 µm in diameter
    • Focal leakage - Treatment of leaking microaneurysms
    • Diffuse leakage - Grid pattern photocoagulation
    • Important to avoid foveal avascular zone
    • Argon green, krypton yellow, and 532 frequency up-converted diode - Laser to treat focal lesions
    • Scatter laser photocoagulation involves placement of multiple argon blue-green or green or krypton red laser burns.
  • Treatable lesions - Identified clinically or angiographically
    • Focal leaks greater than 500 µm from the foveal center are believed to cause retinal thickening or hard exudates.
    • Focal leaks 300-500 µm from the foveal center causing retinal thickening and hard exudates that persisted after a first treatment and a visual acuity of less than 20/40 provided that the perifoveal capillary network will not be destroyed
    • Areas of diffuse leakage; microaneurysms, intraretinal microvascular abnormality (IRMA), or diffusely leaking macular capillary bed
    • Thickened avascular zones, other than the normal foveal avascular zone
• Pars plana vitrectomy
  • It is widely recognized that there have been recent advancements in small-gauge vitreoretinal surgery.
  • Many studies^14,15 suggest that vitreomacular traction or the vitreous itself may play a role in increased retina vascular permeability. Removal of the vitreous or relief of vitreous traction with vitrectomy may, in some patients, be followed by resolution of macular edema and corresponding visual rehabilitation. However, this treatment may be applicable only to a specific subset of eyes with diabetic macular edema.
  • Patients with refractory CSME and a taut posterior hyaloid face who have not responded to macular laser treatment may benefit from a vitrectomy with possible significant improvement in visual acuity.¹⁴
  • In eyes with diffuse diabetic macular edema without posterior vitreous detachment, vitrectomy with posterior vitreous detachment may be effective in resolving the diabetic macular edema and may lead to an increase in visual acuity.¹⁵

Diet

Lifestyle modification as per primary care physician

Activity

Lifestyle modification as per primary care physician

Medication

Medical management should focus on optimizing diabetic and hypertensive control and lowering lipid levels. These issues are best managed by primary care physicians and internists.

Follow-up

Further Outpatient Care

• Patients should be reassessed every 1-4 months depending on the severity of diabetic retinopathy.

Complications

• Adverse effects and complications of laser use have been well documented and are beyond the scope of this article.
• Subretinal fibrosis is a vision-threatening condition, which occurred in 2% of eyes with diabetic macular edema (DME) in the ETDRS.¹⁶
  • Subretinal fibrosis is an elevated mound or flat sheet of grey or white tissue deep to the retina at or near the center of the macula.
  • Fluorescein angiography appearance is hyperfluorescent in the capillary phase with persistence into the late phase and diffusion of dye.
  • This complication is associated most strongly with very severe hard exudates. It also is associated with a poor lipid profile. A previously proposed association with laser treatment has not been demonstrated in studies.
  • Poor prognosis exists; generally refractive to focal laser therapy.
• Residual massive foveal hard exudates after the resolution of diabetic macular edema
• Visual loss can be profound and irreversible. In one study, aspiration of hard exudates following a small retinotomy and serous neurosensory detachment demonstrated an increase of visual acuity in 5 of 7 patients.¹⁷

Prognosis

• Untreated, 25-30% of patients with CSME exhibit a doubling of the visual angle within 3 years.
• Treated, the risk drops by 50%.

Patient Education

• Because patient lifestyle modification and compliance is essential in maintaining good health in the context of diabetes and cardiovascular health, it is imperative that patients understand that positive lifestyle modification can greatly reduce the development and progression of diabetic complication in the eye and other organs.
• For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article Diabetic Eye Disease.

Miscellaneous

Medicolegal Pitfalls

• Medical/legal issues fall under the following 2 general categories:
  • Proper follow-up care of patients: Patients should receive follow-up care according to standard practice guidelines. See the American Academy of Ophthalmology Preferred Practice Pattern for Diabetic Retinopathy.
  • Complications of laser photocoagulation: These are related to either misdirected light or excessive energy, both of which are generally preventable with operator familiarity with standard treatment parameters.

References

1. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. Jul 1987;94(7):761-74. [Medline].

2. Albert DM, Jakobiec FA. Principles and Practice of Ophthalmology. 2^nd ed. Philadelphia: WB Saunders Co; 2000.

3. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. Dec 1 1994;331(22):1480-7. [Medline].

4. Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol. Jun 1999;127(6):688-93. [Medline].

5. Chew EY, Klein ML, Ferris FL 3rd, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol. Sep 1996;114(9):1079-84. [Medline].

6. Bonini-Filho MA, Jorge R, Barbosa JC, Calucci D, Cardillo JA, Costa RA. Intravitreal injection versus sub-Tenon's infusion of triamcinolone acetonide for refractory diabetic macular edema: a randomized clinical trial. Invest Ophthalmol Vis Sci. Oct 2005;46(10):3845-9. [Medline].

7. Jonas JB, Martus P, Degenring RF, Kreissig I, Akkoyun I. Predictive factors for visual acuity after intravitreal triamcinolone treatment for diabetic macular edema. Arch Ophthalmol. Oct 2005;123(10):1338-43. [Medline].

8. Patelli F, Fasolino G, Radice P, et al. Time course of changes in retinal thickness and visual acuity after intravitreal triamcinolone acetonide for diffuse diabetic macular edema with and without previous macular laser treatment. Retina. Oct-Nov 2005;25(7):840-5. [Medline].

9. Avitabile T, Longo A, Reibaldi A. Intravitreal triamcinolone compared with macular laser grid photocoagulation for the treatment of cystoid macular edema. Am J Ophthalmol. Oct 2005;140(4):695-702. [Medline].

10. Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. Oct 2005;112(10):1747-57. [Medline].

11. Scott IU, Edwards AR, Beck RW, et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. Oct 2007;114(10):1860-7. [Medline].

12. Hsu J. Drug delivery methods for posterior segment disease. Curr Opin Ophthalmol. May 2007;18(3):235-9. [Medline].

13. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. Sep 2008;115(9):1447-9, 1449.e1-10. [Medline].

14. Lewis H, Abrams GW, Blumenkranz MS, Campo RV. Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction. Ophthalmology. May 1992;99(5):753-9. [Medline].

15. Tachi N, Ogino N. Vitrectomy for diffuse macular edema in cases of diabetic retinopathy. Am J Ophthalmol. Aug 1996;122(2):258-60. [Medline].

16. Fong DS, Segal PP, Myers F, Ferris FL, Hubbard LD, Davis MD. Subretinal fibrosis in diabetic macular edema. ETDRS report 23. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol. Jul 1997;115(7):873-7. [Medline].

17. Takagi H, Otani A, Kiryu J, Ogura Y. New surgical approach for removing massive foveal hard exudates in diabetic macular edema. Ophthalmology. Feb 1999;106(2):249-56; discussion 256-7. [Medline].

18. Kertes. Clinical Trials in Ophthalmology: Summary and Practice Guide. Lippincott Williams & Wilkins; 1998:15-35.

Keywords

diabetic macular edema, DME, diabetes, diabetic eye disease, diabetic eye complications, diabetic retinopathy, DR, retinal edema, macula

Contributor Information and Disclosures

Author

Emmanouil Mavrikakis, MD, PhD, Consultant Vitreoretinal Surgeon, Ophthalmology Department, Athens Medical Centre, Greece
Emmanouil Mavrikakis, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology and American Society of Retina Specialists
Disclosure: Nothing to disclose.

Coauthor(s)

Wai-Ching Lam, MD, FRCS(C), Associate Professor, Department of Ophthalmology and Vision Sciences, University of Toronto
Wai-Ching Lam, MD, FRCS(C) is a member of the following medical societies: American Academy of Ophthalmology, Canadian Ophthalmological Society, and Royal College of Physicians and Surgeons of Canada
Disclosure: Pfizer Grant/research funds Primary investigator; Novartis Honoraria Speaking and teaching; Novartis Honoraria Review panel membership

Baseer U Khan, MD, Staff Physician, Department of Ophthalmology, University of Toronto, Canada
Baseer U Khan, MD is a member of the following medical societies: Canadian Ophthalmological Society
Disclosure: Nothing to disclose.

Medical Editor

V Al Pakalnis, MD, PhD, Professor of Ophthalmology, University of South Carolina School of Medicine; Chief of Ophthalmology, Dorn Veterans Affairs Medical Center
V Al Pakalnis, MD, PhD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and South Carolina Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Steve Charles, MD, Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine; Adjunct Professor of Ophthalmology, Columbia College of Physicians & Surgeons; Clinical Professor Ophthalmology, Chinese University of Hong Kong
Steve Charles, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Retina Specialists, Club Jules Gonin, Macula Society, and Retina Society
Disclosure: Alcon Laboratories Consulting fee Consulting; OptiMedica Ownership interest Consulting

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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