AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Over the last several decades, there have been a few large-scale trials that have influenced the management of diabetic complications in the eye. Of these trials, only one, the Early Treatment Diabetic Retinopathy Study (ETDRS), identified macular edema as a study objective. To date, the ETDRS has presented the most comprehensive and detailed directives in the management of diabetic macular edema (DME). As a result, this article is based largely on the findings and conclusions of the ETDRS.

Pathophysiology

DME 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.

Frequency

United States

The World Health Organization (WHO) estimates that 15 million people have diabetes in the United States; one half of which are undiagnosed. 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 DME over another group.

Sex

No data describe the predilection of one sex developing DME over the other sex.

Age

Diabetic retinopathy (DR), not specifically DME, generally occurs in persons older than 40 years. It rarely occurs before puberty.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

Physical

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

• DME 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Cystoid macular edema
Hypotonic retinopathy
Macular pucker
Epinephrine use in aphakia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.
  • It 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 DME, ie, 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.
  • Quantitative measurement of macular thickness and subjective analysis of the foveal architecture allow a precise and reproducible way to monitor macular edema.
  • This is a relatively new imaging modality, which is being used mostly for research interests. OCT may have greater clinical use in the future.

Histologic Findings

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

Staging

See Physical for the differentiation between clinically significant and nonclinically significant DME.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.
  • These issues are best managed by primary care physicians and internists.
• Ocular
• • Intravitreal triamcinolone
    • Intravitreal triamcinolone (IVK) has been shown to significantly reduce macular edema and to improve visual acuity, particularly when the macular edema is pronounced.
    • Some studies advocate IVK as primary therapy, whereas others label it as adjunctive therapy to macular photocoagulation.
    • 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 side effects include a less than 1% chance of retinal detachment, cataract, and endophthalmitis.
  • VEGF inhibitors
    • Pegaptanib sodium, ranibizumab, and bevacizumab are 3 VEGF inhibitors that are currently being used to treat exudative age-related macular degeneration (ARMD).
    • The role of VEGF inhibitors in DME is still experimental; however, a few studies have demonstrated their benefit. Their role in the management of DME may increase.

Surgical Care

Laser treatment is clearly the first-line treatment of DR and DME. 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.

• Photocoagulation
• • Goals
    • Significant visual improvement is uncommon; the goal of macular laser treatment is to reduce progression.
    • Photocoagulation reduced the risk of doubling the visual angle from 24% to 12%, over all levels of visual acuity, over a period of 3 years (ETDRS).
  • Timing
    • Laser treatment is most effective when initiated before visual acuity is lost from DME; this emphasizes the need for diligent monitoring and follow-up care.
    • Laser treatment of DME should precede panretinal photocoagulation (PRP) by at least 6 weeks because PRP before this has been known to worsen DME. PRP should not be delayed in patients with very severe nonproliferative DR or high-risk proliferative DR.
  • 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 upconverted 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
• Vitrectomy
• • In eyes with diffuse DME without posterior vitreous detachment, vitrectomy with posterior vitreous detachment may be effective in resolving the DME and may lead to an increase in visual acuity.
  • Patients with refractory CSME and a taut posterior hyaloid face that have not responded to macular laser treatment may benefit from a vitrectomy with possible significant improvement in visual acuity.

Diet

Lifestyle modification as per primary care physician

Activity

Lifestyle modification as per primary care physician

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

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

Complications

• Side 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 DME in the ETDRS.
• • 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 DME
• 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.

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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Albert DM, Jakobiec FA. Principles and Practice of Ophthalmology. 2nd ed. Philadelphia: WB Saunders Co;2000.
• 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].
• Bonini-Filho MA, Jorge R, Barbosa JC, et al. 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].
• 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].
• Cunningham ET, 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].
• Fong DS, Segal PP, Myers F, et al. 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].
• Jonas JB, Martus P, Degenring RF, et al. Predictive factors for visual acuity after intravitreal triamcinolone treatment for diabetic macular edema. Arch Ophthalmol. Oct 2005;123(10):1338-43. [Medline].
• Kertes. Clinical Trials in Ophthalmology: Summary and Practice Guide. Lippincott Williams & Wilkins;1998:15-35.
• 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].
• 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].
• Tachi N, Ogino N. Vitrectomy for diffuse macular edema in cases of diabetic retinopathy. Am J Ophthalmol. Aug 1996;122(2):258-60. [Medline].
• 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].

Article Last Updated: Apr 14, 2006