Diabetic macular edema 2011 (1)

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Novel Development in treatment of Diabetic Macular Edema, by Dr. Fritz Allen, presented at VO, Lecture Series 11, Feb 20, 2011 …

Novel Development in treatment of Diabetic Macular Edema, by Dr. Fritz Allen, presented at VO, Lecture Series 11, Feb 20, 2011
COPE Course ID: 30657-PS

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  • 1. Diabetic Macular Edema Where are we today? Fritz Allen, MD 2/20/2011 V.O.
  • 2. Introduction
    • Background:
    • The Early Treatment Diabetic Retinopathy Study (ETDRS) set the guidelines for treatment of DME : Glycemic control (DCCT), optimal BP control (UKPDS) and macular focal/grid photocoagulation reducing the risk of moderate vision loss by 50% (from 24% to 12% after 3 years).
    • New advances in pharmacotherapy and surgery have showed promise in Rx of DME
  • 3. Pathophysiology
    • DME is the result of microvascular changes in diabetes leading to incompetence of vessels, edema . Hypoxic state stimulate VEGF causing more CME
  • 4. Frequency
    • In the USA: The WHO estimates 15 million DM half undiagnosed and 50% of 8 million without eye care, 25-30% risk of vision loss from CSME
    • International: WHO estimates more than 150 million diabetic worldwide
  • 5. Mortality/Morbidity
    • DM is the leading cause of new blindness in the US in which CSME has a significant contribution .
    • Untreated , 25-30 % of CSME double their visual angle within 3 years
    • Treated ,the risk drops by 50%
  • 6. Race/Age/sex
    • DM is more common in Latinos, African Americans and Native Americans
    • Diabetic Retinopathy generally in older than 40 years, rare before puberty
    • No sex predilection
  • 7. Clinical
    • History
    • Ocular history
    • Diabetic history: type I or type II, duration of DM, age of patient , diabetic control (DCCT) (HbA1C less than 7%)
    • Renal disease: Proteinuria marker for DR
    • Systemic Hypertension
    • Triglycerides and Lipids level
    • Pregnancy
  • 8. Physical
    • Fundoscopy under stereopsis and high magnification , indirect is not enough to diagnose DME
    • DME: retinal thickening within 2DD from center of macula, asociated with exudate and microaneurysms
    • CSME (ETDRS): retinal thickening 500 microns from fovea , hard exudates within 500 microns from fovea with thickening, at least 1 DD of thickening with any part within 1 DD of fovea
  • 9.  
  • 10. Differential Diagnoses
    • ARMD, Exudative Branch Retinal Vein Occlusion Central Retinal Vein Occlusion Hypertension Macular Edema, Irvine-Gass Uveitis, Evaluation and Treatment
  • 11.  
  • 12.  
  • 13.  
  • 14.  
  • 15. Workup
    • Imaging studies
    • Fluorescein angiography (FA): not relevant in diagnosing CSME but should be performed if considering Rx, guides in laser Rx (focal vs diffuse leakage), identifies ischemic fovea
    • Fundus photos helps documenting changes
  • 16. Optical Coherence Tomography
    • OCT creates cross section of retina It has been able to demonstrates 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
  • 17. OCT
      • 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.
  • 18. 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.
    • These issues are best managed by primary care physicians and internists
  • 19. Ocular Rx
      • 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.
        • Some studies advocate IVTA 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 adverse effects include a less than 1% chance of retinal detachment, cataract, and endophthalmitis
  • 20. Ocular Rx
      • 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.
        • . 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
  • 21. Ocular Rx
        • . Bevacizumab : 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. A phase 3 trial would be needed for that purpose.
  • 22. 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.
  • 23. Future Therapies
        • 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.
  • 24. Future Therapies
    • Retisert, 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
  • 25. 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.
    • 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.
  • 26. 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.
      • Timing
        • Laser treatment is most effective when initiated before visual acuity is lost.
    • Laser treatment of diabetic macular edema should precede panretinal photocoagulation (PRP) by at least 6 weeks because PRP before 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
  • 27. Focal /Grid laser
      • 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.
  • 28. Pars plana vitrectomy
      • It is widely recognized that there have been recent advancements in small-gauge vitreoretinal surgery.
      • Many studies 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.
      • 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.
  • 29. Follow-up
    • Patients should be reassessed every 1-4 months depending on the severity of diabetic retinopathy.
  • 30. Complications of DME
    • Subretinal fibrosis is a vision-threatening condition, which occurred in 2% of eyes with diabetic macular edema (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 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.
  • 31. Conclusion
    • 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 is key
    • "The treatment is clearly effective, but has not been approved for DME by the FDA yet” ,
    • "Ranibizumab could be used off label for DME, but it is very expensive and until the FDA approves it for DME, Medicare and most insurance companies won't pay for it. As a result, many retina specialists are using bevacizumab, a less expensive VEGF antagonist, off label."