Diabetic Macular Edema Diabetic Macular Edema

Where are we today?Where are we today?

Fritz Allen, MD Fritz Allen, MD

2/20/2011 V.O.2/20/2011 V.O.

Introduction Introduction Background:Background: The Early Treatment Diabetic Retinopathy The Early Treatment Diabetic Retinopathy

Study (ETDRS) set the guidelines for Study (ETDRS) set the guidelines for treatment of DME : Glycemic control treatment of DME : Glycemic control (DCCT), optimal BP control (UKPDS) and (DCCT), optimal BP control (UKPDS) and macular focal/grid photocoagulation macular focal/grid photocoagulation reducing the risk of moderate vision loss reducing the risk of moderate vision loss by 50% (from 24% to 12% after 3 years).by 50% (from 24% to 12% after 3 years).

New advances in pharmacotherapy and New advances in pharmacotherapy and surgery have showed promise in Rx of surgery have showed promise in Rx of DMEDME

PathophysiologyPathophysiology

DME is the result of microvascular DME is the result of microvascular changes in diabetes leading to changes in diabetes leading to incompetence of vessels, edema . incompetence of vessels, edema . Hypoxic state stimulate VEGF Hypoxic state stimulate VEGF causing more CMEcausing more CME

FrequencyFrequency

In the USA: The WHO estimates 15 In the USA: The WHO estimates 15 million DM half undiagnosed and million DM half undiagnosed and 50% of 8 million without eye care, 50% of 8 million without eye care, 25-30% risk of vision loss from CSME25-30% risk of vision loss from CSME

International: WHO estimates more International: WHO estimates more than 150 million diabetic worldwidethan 150 million diabetic worldwide

Mortality/MorbidityMortality/Morbidity

DM is the leading cause of new DM is the leading cause of new blindness in the US in which CSME blindness in the US in which CSME has a significant contribution . has a significant contribution .

Untreated , 25-30 % of CSME double Untreated , 25-30 % of CSME double their visual angle within 3 yearstheir visual angle within 3 years

Treated ,the risk drops by 50%Treated ,the risk drops by 50%

Race/Age/sexRace/Age/sex

DM is more common in Latinos, DM is more common in Latinos, African Americans and Native African Americans and Native Americans Americans

Diabetic Retinopathy generally in Diabetic Retinopathy generally in older than 40 years, rare before older than 40 years, rare before pubertypuberty

No sex predilection No sex predilection

ClinicalClinical

HistoryHistory Ocular historyOcular history Diabetic history: type I or type II, duration Diabetic history: type I or type II, duration

of DM, age of patient , diabetic control of DM, age of patient , diabetic control (DCCT) (HbA1C less than 7%)(DCCT) (HbA1C less than 7%)

Renal disease: Proteinuria marker for DRRenal disease: Proteinuria marker for DR Systemic Hypertension Systemic Hypertension Triglycerides and Lipids levelTriglycerides and Lipids level PregnancyPregnancy

Physical Physical

Fundoscopy under stereopsis and high Fundoscopy under stereopsis and high magnification , indirect is not enough to magnification , indirect is not enough to diagnose DMEdiagnose DME

DME: retinal thickening within 2DD from DME: retinal thickening within 2DD from center of macula, asociated with exudate center of macula, asociated with exudate and microaneurysmsand microaneurysms

CSME (ETDRS): retinal thickening 500 CSME (ETDRS): retinal thickening 500 microns from fovea , hard exudates within microns from fovea , hard exudates within 500 microns from fovea with thickening, at 500 microns from fovea with thickening, at least 1 DD of thickening with any part least 1 DD of thickening with any part within 1 DD of foveawithin 1 DD of fovea

Differential DiagnosesDifferential Diagnoses

ARMD, ExudativeARMD, ExudativeBranch Retinal Vein OcclusionBranch Retinal Vein OcclusionCentral Retinal Vein OcclusionCentral Retinal Vein OcclusionHypertensionHypertensionMacular Edema, Irvine-GassMacular Edema, Irvine-GassUveitis, Evaluation and Treatment Uveitis, Evaluation and Treatment

WorkupWorkup

Imaging studiesImaging studies Fluorescein angiography (FA): not Fluorescein angiography (FA): not

relevant in diagnosing CSME but relevant in diagnosing CSME but should be performed if considering should be performed if considering Rx, guides in laser Rx (focal vs Rx, guides in laser Rx (focal vs diffuse leakage), identifies ischemic diffuse leakage), identifies ischemic fovea fovea

Fundus photos helps documenting Fundus photos helps documenting changeschanges

Optical Coherence TomographyOptical Coherence Tomography

OCT creates cross section of retina It OCT creates cross section of retina It has been able to demonstrates has been able to demonstrates correlation between retinal thickness correlation between retinal thickness and best-corrected visual acuity, and and best-corrected visual acuity, and it has been able to demonstrate 3 it has been able to demonstrate 3 basic structural changes of the retina basic structural changes of the retina from diabetic macular edema (DME), from diabetic macular edema (DME), that is, retinal swelling, cystoid that is, retinal swelling, cystoid edema, and serous retinal edema, and serous retinal detachment detachment

OCTOCT

• OCT is not currently required to establish a OCT is not currently required to establish a diagnosis and is not prescribed by current diagnosis and is not prescribed by current practice guideline; however, OCT has gained practice guideline; however, OCT has gained widespread acceptance as an additional widespread acceptance as an additional modality to help identify and evaluate macular modality to help identify and evaluate macular pathology.pathology.

• Quantitative measurement of macular Quantitative measurement of macular thickness and subjective analysis of the foveal thickness and subjective analysis of the foveal architecture allow a precise and reproducible architecture allow a precise and reproducible way to monitor macular edema.way to monitor macular edema.

Treatment Treatment

Medical CareMedical Care SystemicSystemic

• Medical treatment should focus on optimizing Medical treatment should focus on optimizing diabetic and hypertensive control and lowering diabetic and hypertensive control and lowering lipid levels. Optimizing diabetic, hypertensive, lipid levels. Optimizing diabetic, hypertensive, and lipid control has been shown to positively and lipid control has been shown to positively impact diabetic retinopathy.impact diabetic retinopathy.

These issues are best managed by primary These issues are best managed by primary care physicians and internists care physicians and internists

Ocular Rx Ocular Rx

• Intravitreal triamcinolone acetonide Intravitreal triamcinolone acetonide  Intravitreal triamcinolone acetonide (IVTA) has been Intravitreal triamcinolone acetonide (IVTA) has been

shown to significantly reduce macular edema and to shown to significantly reduce macular edema and to improve visual acuity, particularly when the macular improve visual acuity, particularly when the macular edema is pronounced.edema is pronounced.

Some studies advocate IVTA as primary therapy, Some studies advocate IVTA as primary therapy, whereas others label it as adjunctive therapy to whereas others label it as adjunctive therapy to macular photocoagulation.macular photocoagulation.

Action is maximal at 1 week, lasting 3-6 months.Action is maximal at 1 week, lasting 3-6 months. Patients should be counseled about the risk (30-40%) Patients should be counseled about the risk (30-40%)

of increased intraocular pressure, of which virtually of increased intraocular pressure, of which virtually all can be medically controlled.all can be medically controlled.

Other adverse effects include a less than Other adverse effects include a less than 1% chance of retinal detachment, 1% chance of retinal detachment, cataract, and endophthalmitiscataract, and endophthalmitis

Ocular RxOcular Rx

• Intravitreal anti-VEGF agentsIntravitreal anti-VEGF agents VEGF increases retinal vascular permeability, causes VEGF increases retinal vascular permeability, causes

breakdown of the blood-retina barrier, and results in breakdown of the blood-retina barrier, and results in retina edema. VEGF is up-regulated in diabetic retina edema. VEGF is up-regulated in diabetic retinopathy.retinopathy.

Three currently available anti-VEGF agents are Three currently available anti-VEGF agents are pegaptanib sodium, ranibizumab, and bevacizumab.pegaptanib sodium, ranibizumab, and bevacizumab.

. The RESTORE study (phase 3, laser-controlled, . The RESTORE study (phase 3, laser-controlled, randomized, multicenter study) is designed to randomized, multicenter study) is designed to confirm the efficacy and safety of confirm the efficacy and safety of ranibizumab ranibizumab 0.5 mg as adjunctive therapy added to laser 0.5 mg as adjunctive therapy added to laser photocoagulation and/or as monotherapy in patients photocoagulation and/or as monotherapy in patients with diabetic macular edema. The Diabetic with diabetic macular edema. The Diabetic Retinopathy Clinical Research Network is planning Retinopathy Clinical Research Network is planning two phase 3, prospective, randomized multicenter two phase 3, prospective, randomized multicenter trials of ranibizumab for diabetic macular edema trials of ranibizumab for diabetic macular edema

Ocular RxOcular Rx

. . BevacizumabBevacizumab: Small, nonrandomized : Small, nonrandomized pilot studies have documented some efficacy pilot studies have documented some efficacy against diffuse diabetic macular edema. The against diffuse diabetic macular edema. The Diabetic Retinopathy Clinical Research Diabetic Retinopathy Clinical Research Network conducted a phase 2, prospective, Network conducted a phase 2, prospective, randomized, multicenter clinical trial to randomized, multicenter clinical trial to determine the safety and possible benefits of determine the safety and possible benefits of this agent. They concluded that intravitreal this agent. They concluded that intravitreal bevacizumab can reduce diabetic macular bevacizumab can reduce diabetic macular edema in some eyes, but the study was not edema in some eyes, but the study was not designed to determine whether the treatment designed to determine whether the treatment was beneficial. A phase 3 trial would be was beneficial. A phase 3 trial would be needed for that purpose.needed for that purpose.

Future TherapiesFuture Therapies The RIDE study is an ongoing placebo The RIDE study is an ongoing placebo

controlled trial evaluating the efficacy and controlled trial evaluating the efficacy and safety of intravitreal ranibizumab 0.5 mg safety of intravitreal ranibizumab 0.5 mg injection every 4 weeks for 24 months in injection every 4 weeks for 24 months in patients with diabetic macular edema.patients with diabetic macular edema.

VEGF Trap-Eye is a soluble VEGF receptor VEGF Trap-Eye is a soluble VEGF receptor fusion protein that binds all forms of VEGF-A fusion protein that binds all forms of VEGF-A and related placental growth factor (PGF). and related placental growth factor (PGF). When administered as a single 4 mg When administered as a single 4 mg intravitreal injection in a phase 1 study, a intravitreal injection in a phase 1 study, a marked decrease in central retinal thickness marked decrease in central retinal thickness and mean macular volume was noted.and mean macular volume was noted.

Future TherapiesFuture Therapies

The phase 3 FAME (fluocinolone The phase 3 FAME (fluocinolone acetonide in diabetic macular edema) acetonide in diabetic macular edema) trial is evaluating the Medidur trial is evaluating the Medidur fluocinolone-based injectable implant.fluocinolone-based injectable implant.

The phase 3 trial of Posurdex The phase 3 trial of Posurdex biodegradable implant (sustained biodegradable implant (sustained delivery formulation of delivery formulation of dexamethasone) for the treatment of dexamethasone) for the treatment of diabetic macular edema is underway.diabetic macular edema is underway.

Future TherapiesFuture Therapies

Retisert, another steroid implant Retisert, another steroid implant (fluocinolone acetonide), was (fluocinolone acetonide), was evaluated in patients with diabetic evaluated in patients with diabetic macular edema with good results but macular edema with good results but a concerning adverse effect profile; a concerning adverse effect profile; 90% of patients developed cataracts, 90% of patients developed cataracts, and 40% required glaucoma surgery and 40% required glaucoma surgery within 3 yearswithin 3 years

Surgical CareSurgical Care Laser photocoagulationLaser photocoagulation continues to be a well- continues to be a well-

proven therapy to reduce the risk of vision loss from proven therapy to reduce the risk of vision loss from diabetic macular edema.diabetic macular edema.

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

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

Focal/grid laser photocoagulationFocal/grid laser photocoagulation

• GoalsGoals Significant visual improvement is uncommon; the goal of Significant visual improvement is uncommon; the goal of

macular laser treatment is to reduce progression.macular laser treatment is to reduce progression. Photocoagulation reduced the risk of moderate visual loss Photocoagulation reduced the risk of moderate visual loss

from diabetic macular edema by 50%, from 24% to 12%, 3 from diabetic macular edema by 50%, from 24% to 12%, 3 years after initiation of treatment.years after initiation of treatment.

• TimingTiming Laser treatment is most effective when initiated before Laser treatment is most effective when initiated before

visual acuity is lost.visual acuity is lost. Laser treatment of diabetic macular edema should precede Laser treatment of diabetic macular edema should precede

panretinal photocoagulation (PRP) by at least 6 weeks panretinal photocoagulation (PRP) by at least 6 weeks because PRP before has been known to worsen diabetic because PRP before has been known to worsen diabetic macular edema. PRP should not be delayed in patients with macular edema. PRP should not be delayed in patients with very severe nonproliferative diabetic retinopathy or high-very severe nonproliferative diabetic retinopathy or high-risk proliferative diabetic retinopathy risk proliferative diabetic retinopathy

Focal /Grid laserFocal /Grid laser• TreatmentTreatment

Area(s) of leakage can be identified by examination (areas Area(s) of leakage can be identified by examination (areas of retinal thickening) or by fluorescein angiography.of retinal thickening) or by fluorescein angiography.

Burns - 50-100 µm in diameterBurns - 50-100 µm in diameter Focal leakage - Treatment of leaking microaneurysmsFocal leakage - Treatment of leaking microaneurysms Diffuse leakage - Grid pattern photocoagulationDiffuse leakage - Grid pattern photocoagulation Important to avoid foveal avascular zoneImportant to avoid foveal avascular zone Argon green, krypton yellow, and 532 frequency up-Argon green, krypton yellow, and 532 frequency up-

converted diode - Laser to treat focal lesionsconverted diode - Laser to treat focal lesions Scatter laser photocoagulation involves placement of Scatter laser photocoagulation involves placement of

multiple argon blue-green or green or krypton red laser multiple argon blue-green or green or krypton red laser burns.burns.

• Treatable lesions - Identified clinically or Treatable lesions - Identified clinically or angiographicallyangiographically

Focal leaks greater than 500 µm from the foveal center are Focal leaks greater than 500 µm from the foveal center are believed to cause retinal thickening or hard exudates.believed to cause retinal thickening or hard exudates.

Pars plana vitrectomyPars plana vitrectomy

• It is widely recognized that there have been recent It is widely recognized that there have been recent advancements in small-gauge vitreoretinal surgery.advancements in small-gauge vitreoretinal surgery.

• Many studies suggest that vitreomacular traction or the Many studies suggest that vitreomacular traction or the vitreous itself may play a role in increased retina vascular vitreous itself may play a role in increased retina vascular permeability. Removal of the vitreous or relief of vitreous permeability. Removal of the vitreous or relief of vitreous traction with vitrectomy may, in some patients, be followed by traction with vitrectomy may, in some patients, be followed by resolution of macular edema and corresponding visual resolution of macular edema and corresponding visual rehabilitation. However, this treatment may be applicable only rehabilitation. However, this treatment may be applicable only to a specific subset of eyes with diabetic macular edema.to a specific subset of eyes with diabetic macular edema.

• Patients with refractory CSME and a taut posterior hyaloid face Patients with refractory CSME and a taut posterior hyaloid face who have not responded to macular laser treatment may who have not responded to macular laser treatment may benefit from a vitrectomy with possible significant benefit from a vitrectomy with possible significant improvement in visual acuity.improvement in visual acuity.

• In eyes with diffuse diabetic macular edema without posterior In eyes with diffuse diabetic macular edema without posterior vitreous detachment, vitrectomy with posterior vitreous vitreous detachment, vitrectomy with posterior vitreous detachment may be effective in resolving the diabetic macular detachment may be effective in resolving the diabetic macular edema and may lead to an increase in visual acuity.edema and may lead to an increase in visual acuity.

Follow-upFollow-up

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

ComplicationsComplicationsof DMEof DME

Subretinal fibrosis is a vision-threatening condition, which occurred in 2% Subretinal fibrosis is a vision-threatening condition, which occurred in 2% of eyes with diabetic macular edema (DME) in the ETDRS.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 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.to the retina at or near the center of the macula.• Fluorescein angiography appearance is hyperfluorescent in the capillary phase Fluorescein angiography appearance is hyperfluorescent in the capillary phase

with persistence into the late phase and diffusion of dye.with persistence into the late phase and diffusion of dye.• This complication is associated most strongly with very severe hard exudates. It 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 also is associated with a poor lipid profile. A previously proposed association with laser treatment has not been demonstrated in studies.laser treatment has not been demonstrated in studies.

• Poor prognosis exists; generally refractive to focal laser therapy.Poor prognosis exists; generally refractive to focal laser therapy. Residual massive foveal hard exudates after the resolution of diabetic Residual massive foveal hard exudates after the resolution of diabetic

macular edemamacular edema Visual loss can be profound and irreversible. In one study, aspiration of Visual loss can be profound and irreversible. In one study, aspiration of

hard exudates following a small retinotomy and serous neurosensory hard exudates following a small retinotomy and serous neurosensory detachment demonstrated an increase of visual acuity in 5 of 7 patients.detachment demonstrated an increase of visual acuity in 5 of 7 patients.

ConclusionConclusion Untreated, 25-30% of patients with CSME exhibit Untreated, 25-30% of patients with CSME exhibit

a doubling of the visual angle within 3 years.a doubling of the visual angle within 3 years. Treated, the risk drops by 50%.Treated, the risk drops by 50%. Patient Education is keyPatient Education is key "The treatment is clearly effective, but has not been "The treatment is clearly effective, but has not been

approved for DME by the FDA yet” , approved for DME by the FDA yet” , "Ranibizumab could be used off label for DME, but it "Ranibizumab could be used off label for DME, but it

is very expensive and until the FDA approves it for is very expensive and until the FDA approves it for DME, Medicare and most insurance companies won't DME, Medicare and most insurance companies won't pay for it. As a result, many retina specialists are pay for it. As a result, many retina specialists are using bevacizumab, a less expensive VEGF using bevacizumab, a less expensive VEGF antagonist, off label."antagonist, off label."