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DME
Current Treatment Options
Dr. Zia-Ul-Mazhry
FCPS(Pak),
FRCS(Edin),
FRCS(Glasgow),
CIC Ophth- (UK)
Assistant Professor
...
Diabetic Macular Edema
• What is DME?
• How to diagnose, investigate and classify?
• When to treat?
• What are the availab...
Introduction
• Historical Background:
– Diabetic Macular Edema (DME) was unrecognized
before invention of the ophthalmosco...
Introduction
• Historical Background (cont’d):
– In 1869 Noyes established a causal relationship between
the changes descr...
• Non-proliferative diabetic
retinopathy (NPDR)
– Mild non-proliferative diabetic retinopathy
– Moderate-to-severe non-pro...
NPDR
Typically asymptomatic, but may
have decreased or fluctuating
vision with fluctuation in blood
sugars
NPDR can affect...
Minimal NPDR
• At least 1
Microaneurysms (m)
• Microaneurysms
only
• Remainder of fundus
normal
Dr. Mazhry frcs,fcps 7
Mild NPDR
• Microaneurysms (m)
and Dot
hemorrhages (h)
• May also
demonstrate
macular edema and
lipid exudate (e)
Dr. Mazh...
Moderate NPDR
• Cotton wool spots (w),
Retinal hemorrhages
(h) (Dot-blot, Flame),
and Microaneurysms
(m)
• Hemorrhages,
Mi...
Diabetic Macular Edema (DME)
• Definition: Diabetic macular edema
is retinal thickening caused by the accumulation
of intr...
Pathogenesis
Normal retinal circulation is unique:
Retinal capillaries are non-fenestrated and capillary
endothelial cells...
Pathogenesis (cont.)
Thus, 2 key changes occur:
Vessel permeability
Damaged endothelial wall becomes more porous
Vessel le...
Microaneurysms
• focal dilatations of retinal capillaries,
• 10 to 100 microns in diameter, and.
• appear as red dots espe...
Hard exudates
( Intra-retinal lipid exudates )
Dr. Mazhry frcs,fcps 14
• Accumulations of
lipids leak from
surrounding
cap...
Epidemiology :
• International
– The WHO estimates that more than 150 million people
worldwide have diabetes.
• Untreated,...
DME-Legal Blindness
• Mortality/Morbidity
– Diabetes is the leading cause of new blindness in the
United States, to which ...
Diagnosis-History
• Ocular history
• Diabetic history
– Specific inquiry should
be made into risk
factors for the
developm...
Diagnosis-History
• Diabetic control
– The Diabetes Control
and Complication Trial
(DCCT) clearly
demonstrated that
tighte...
Diagnosis-History
• Systemic hypertension
– Increased risk of
retinopathy (diabetic
retinopathy with
superimposed
hyperten...
DME Diagnosis-Physical
• Funduscopy under stereopsis and high
magnification should be performed on every
patient with diab...
DME Diagnosis-Physical
• Important observations include:
– Location of retinal thickening relative to the fovea
– Presence...
Diabetic Macular Edema(DME)
Focal/Diffuse
Dr. Mazhry frcs,fcps 22
• Diabetic macular edema is defined as
retinal thickenin...
Clinically Significant Macular Edema
• Retinal thickening at or within
500 µm from the center of the
macula or
• Hard exud...
Dr. Mazhry frcs,fcps 24
• Visual acuity
– is an important
parameter in following
the progression of
CSME, although it does...
Differential Diagnoses
– ARMD, Exudative
– Branch Retinal Vein Occlusion
– Central Retinal Vein Occlusion
– Hypertension M...
Workup
Imaging Studies
• Color stereo fundus photographs
– provide an opportunity to evaluate long-term
changes in the ret...
Workup
Imaging Studies-FFA
• Fluorescine angiography
– Fluorescein angiography is
useful in demonstrating the
breakdown of...
Workup
Imaging Studies
• Fluorescine
angiography
– Fluorescine angiography
distinguishes and
localizes areas of focal
vers...
Fluorescine angiography
• Focal leakage:
• Well defined areas of leakage; e.g.,
microaneurysms
• FFA will clearly show the...
Workup
Imaging Studies
• Optical coherence
tomography
– Optical coherence
tomography (OCT) captures
reflected light from r...
Workup
Imaging Studies
• Optical coherence tomography
– It has been able to demonstrate a moderate
correlation between ret...
Workup
Imaging Studies
• Optical coherence
tomography
– OCT is not currently required to
establish a diagnosis and is not
...
Treatment
• Medical Care
– Primary Care Physicians And Internists.
• optimizing
– diabetic and
– hypertensive
– renal
– an...
Ocular Treatment
• Available Tools
– LASERs
– AntiVEGF Therapy
– Steroids
Dr. Mazhry frcs,fcps 34
Focal/grid laser photocoagulation
• Focal/grid laser photocoagulation
– Goals
• Significant visual improvement is uncommon...
Focal Photocoagulation for CSME
• Fluorescein angiography and Fundus photos are obtained prior to
initiation of laser ther...
Laser Treatment for CSME
• Focal:
– 50-100  spots to
areas of discrete
leakage
• Grid:
– 100-200  spots in
areas of diff...
Prognosis
Macular laser Rx
• ETDRS showed that in eyes with CSME, focal laser
photocoagulation reduces the risk of moderat...
LASER Photocoagulation for CSME
• Side Effects and Complications of Focal Laser
– Paracentral scotomata
– Transient increa...
Anti VEGF Therapy
• Intravitreal anti-VEGF agents
• VEGF increases retinal vascular permeability, causes
breakdown of the ...
Anti VEGF Therapy
• Pegaptanib sodium
– is a pegylated aptamer directed against the VEGF-A165 isoform. It was the first FD...
Intravitreal Steroids
• Intravitreal triamcinolone acetonide
• Intravitreal triamcinolone acetonide (IVTA) has been shown
...
Role of Vitrectomy Surgery
• Pars plana vitrectomy
– It is widely recognized that there have been recent advancements in
s...
Case Study EM
Dr. Mazhry frcs,fcps 44
Dr. Mazhry frcs,fcps 45
Dr. Mazhry frcs,fcps 46
Case Study EM
Dr. Mazhry frcs,fcps 47
Case Studies - Patient EM
• 59-year-old African-American male
• Type 2 DM x 11 yrs
• LEE: 1.5 yr
• Pt complaint “having tr...
Patient EM
• Cholesterol levels within normal limits
• Current Albumin/Creatine level =
231.6 µg/mg (Normal: 0 - 20 µg/mg)...
Case Study EM
Exam Findings
• VA OD 20/30+ OS 20/30
• Sensorimotor exam normal
• No distortion with Amsler grid
• Early NS...
Case Study EM
Plan
• Laser treatment for macular edema within
one to two weeks
• Control of BP and BG
Dr. Mazhry frcs,fcps...
Case Study EM
Treatment
• Focal laser treatment
– OD at 3 weeks
– OS at 7 weeks
• 4 month follow-up
Dr. Mazhry frcs,fcps 52
Case Study EM
Notes
• HTN, renal disease and dyslipidemia can affect onset
and progression of retinopathy
• Co-management ...
Case DG
• 35-year-old Caucasian male
• Type 1 DM 23 years
• VA: OD-20/30; OS-20/40
• Denies hypertension, renal disease,
h...
Patient DG
• Diagnosis:
– Moderate NPDR OU
– DME not CSME OD
– Clinically Significant Macular Edema OS
• Plan:
– FA to ide...
Prevention of Diabetic Retinopathy
• Prevention of diabetic retinopathy requires prevention of
diabetes
• Patients at high...
Role of Hypertension in DME
• WESDR - diabetic patients with HTN had
3 x incidence of DME.
• UKPDS__rigorous BP control wi...
Role of Renal Disease in DME
• Gross proteinuria associated with 95% increased
risk of DME (WESDR)
• Case reports of reduc...
Role of Serum Lipids in DR
• Elevated serum lipids are associated with
increased risk of retinal hard exudates
• Increased...
Role of Vitreous in DME
• Vitreomacular traction is believed to
be a contributor to the multifactorial
etiology of DME.
• ...
Vitrectomy Surgery
• New Indication:
– Persistent Diabetic Cystoid Macular Edema
– Vitrectomy surgery is often helpful in ...
Cataract Surgery in Diabetics
• Various studies suggest that DR may progress following
cataract surgery
• Patients who und...
Follow-Up Based Upon Retinopathy Findings
Retinal Abnormality Suggested Follow-Up
Normal or rare
microaneurysms
Mild NPDR
...
DRCR Network Overview
• Funding:
– National Eye Institute-sponsored cooperative
agreement initiated September 2002
• Objec...
DRCR Diabetic Retinopathy
Clinical Research
Dr. Mazhry frcs,fcps
Diabetic Retinopathy Clinical Research Network. A randomi...
DRCR
CURRENTLY RECRUITING STUDIES
• Randomized trial comparing intravitreal
triamcinolone acetonide and laser
photocoagula...
A Randomized Trial Comparing Intravitreal Triamcinolone
Acetonide and Laser Photocoagulation for Diabetic Macular
Edema
• ...
Study Design
• Phase 3, multicenter, randomized clinical trial
• Randomization to one of three treatment groups:
Dr. Mazhr...
Intraocular Formulation
Comparison with Kenalog
®
-40
Ingredient Allergan Form Kenalog® -40
Triamcinolone Acetonide 2 and ...
Formulation and Packaging
Allergan
• Sterile, prefilled (0.05ml),
single-dose, ready-to-use
syringe with attached 27-
gaug...
Clinical Experience
• >75 active sites in >20 states
• >40 sites with pending certification
• First patient 7/14/04
• >300...
Evaluation of Vitrectomy for Diabetic
Macular Edema
• To provide information on the following outcomes in eyes
with DME th...
Subclinical Diabetic Macular Edema
Study
• Primary Objective: To determine the incidence of progression
of subclinical dia...
STUDIES IN FOLLOW-UP PHASE
• Pilot study of laser photocoagulation for
diabetic macular edema
• Pilot study of peribulbar ...
Pilot study of laser photocoagulation for
diabetic macular edema
• Compare laser treatment as we now use it
(called “stand...
Pilot study of peribulbar triamcinolone acetonide for
diabetic macular edema
• To estimate the incidence of improvement of...
UPCOMING STUDIES
• A Phase 2 Evaluation of Anti-VEGF Therapy for
Diabetic Macular Edema: Avastin
– 200 patient, phase 2 ra...
COMPLETED STUDIES
• Temporal Variation in OCT Measurements of Retinal
Thickening in Diabetic Macular Edema
– Determine the...
Eye Research
• Determine basic mechanisms of disease
• Identify potential therapeutic targets
• Develop specific novel the...
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Diabetic macular edema-Current treatment Modalities

Title:
Choosing amongst current modalities to manage Diabetic Retinopathy
At Medical Retina Clinic, Eye Department WAPDA Teaching Hospital Complex Lahore

Objective:
1. To review the current management options for DR
2. To share author’s four years follow up from Jan 2008 to Nov 2011 at Medical Retina Clinic, Eye Department WAPDA Teaching Hospital Complex Lahore.
3. Discussion on future Trends in management of DR.
Synopsis:
Diabetic retinopathy is the leading cause of new blindness in the world,
Argon LASER treatment has established itself as a gold standard in the management of DR. Intravitreal therapies in the form anti VEGF agents and steroids are also being widely used nationally and internationally. These therapies do not replace but complement each other.
Author will share his four years experience at Medical Retina clinic WAPDA hospital complex Lahore. 125 patients with DR were enrolled during this period. Treatment modalities used, included Argon Green Laser, Intravitreal Anti VEGF (Bevacizumab), Intravitreal Triamcinolone and subtenon Triamcinolone. Staging and severity of the disease as well as response to the offered therapy were the parameters used to tailor the treatment options.

Dr. Zia ul Mazhry
FRCS (Edin), FRCS (Glasgow), FCPS, CICOphth (UK)
Asstt Professor Central Park Medical College Lahore.
Consultant Eye Surgeon and Head of Eye Department
Wapda Teaching Hospital Complex
210 Feroz Pur Road Lahore.
Website: www.EyeAcuity.com
mazhry@yahoo.com
03004401151

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Diabetic macular edema-Current treatment Modalities

  1. 1. DME Current Treatment Options Dr. Zia-Ul-Mazhry FCPS(Pak), FRCS(Edin), FRCS(Glasgow), CIC Ophth- (UK) Assistant Professor Central Park Medical college Lahore Consultant Eye Surgeon & Head of Department WAPDA Teaching Hospital Complex Lahore.
  2. 2. Diabetic Macular Edema • What is DME? • How to diagnose, investigate and classify? • When to treat? • What are the available tools and how to use them? • The Follow UP Dr. Mazhry frcs,fcps 2
  3. 3. Introduction • Historical Background: – Diabetic Macular Edema (DME) was unrecognized before invention of the ophthalmoscope (Helmholtz, 1851). – Jaeger in 1856 was the first to describe a “roundish or oval yellow spots and extravasations which permeate part or the whole thickness of the retina” in a patient with positive urine glucose test for Diabetes Mellitus. – That same year Von Graefe refuted any relationship of the eye findings to diabetes. Dr. Mazhry frcs,fcps 3
  4. 4. Introduction • Historical Background (cont’d): – In 1869 Noyes established a causal relationship between the changes described by Jaeger and Diabetes Mellitus (DM). – In 1872 Nettleship confirmed this theory in his treaties on the issue (“Noyes’ glucosuric retinitis”). – In 1875 Appolinaire in Paris reported these observations and described in addition, the accumulation of lipid in the retina which he designated “glucose induced amblyopia.” – Diabetic Macular Edema (DME) was thereafter recognized as a clinical entity. Dr. Mazhry frcs,fcps 4
  5. 5. • Non-proliferative diabetic retinopathy (NPDR) – Mild non-proliferative diabetic retinopathy – Moderate-to-severe non-proliferative diabetic retinopathy • Proliferative diabetic retinopathy – High risk • Maculopathy – Diffuse/focal – Clinically significant macular oedema (CSME ) – Ischaemic Maculopathy Dr. Mazhry frcs,fcps 5 A classification of diabetic retinopathy
  6. 6. NPDR Typically asymptomatic, but may have decreased or fluctuating vision with fluctuation in blood sugars NPDR can affect visual function through 2 mechanisms, both which affect the macula: Variable degrees of intraretinal capillary closure resulting in macular ischemia Increased retinal vascular permeability resulting in macular edema Dr. Mazhry frcs,fcps 6
  7. 7. Minimal NPDR • At least 1 Microaneurysms (m) • Microaneurysms only • Remainder of fundus normal Dr. Mazhry frcs,fcps 7
  8. 8. Mild NPDR • Microaneurysms (m) and Dot hemorrhages (h) • May also demonstrate macular edema and lipid exudate (e) Dr. Mazhry frcs,fcps 8
  9. 9. Moderate NPDR • Cotton wool spots (w), Retinal hemorrhages (h) (Dot-blot, Flame), and Microaneurysms (m) • Hemorrhages, Microaneurysms in at least 1 quadrant, and cotton wool spots or venous beading in 1 quadrant only • Less than Severe Dr. Mazhry frcs,fcps 9
  10. 10. Diabetic Macular Edema (DME) • Definition: Diabetic macular edema is retinal thickening caused by the accumulation of intraretinal fluid primarily in the inner and outer plexiform layers. It is believed to be a result of hyperpermeability of the retinal vasculature. • Can be present with any level of diabetic retinopathy (DR). Dr. Mazhry frcs,fcps 10
  11. 11. Pathogenesis Normal retinal circulation is unique: Retinal capillaries are non-fenestrated and capillary endothelial cells have tight junctions; normal retinal capillaries do not leak fluid, blood No lymphatic system in the retina In the presence of retinal pathology, leaking fluid can accumulate and cause edema or swelling Retina responds to ischemia by stimulating growth factors to produce new vessels (called neovascularization)
  12. 12. Pathogenesis (cont.) Thus, 2 key changes occur: Vessel permeability Damaged endothelial wall becomes more porous Vessel leaks fluid, lipids, erythrocytes Accumulation of the fluid results in edema (macular edema if located within the central region of the retina) Vessel closure Supply of oxygen and nutrients are decreased New fragile growth occurs (secondary to ischemia)
  13. 13. Microaneurysms • focal dilatations of retinal capillaries, • 10 to 100 microns in diameter, and. • appear as red dots especially temporal to the fovea. • first ophthalmoscopically detectable change in diabetic retinopathy. • Despite multiple layers of basement membrane, they are permeable to water and large molecules, allowing the accumulation of water and lipid in the retina. • Since fluorescein passes easily through them, many more microaneurysms are usually seen on fluorescein angiography than are apparent on ophthalmoscopy Dr. Mazhry frcs,fcps 13
  14. 14. Hard exudates ( Intra-retinal lipid exudates ) Dr. Mazhry frcs,fcps 14 • Accumulations of lipids leak from surrounding capillaries and micro aneurysms • they may form a circinate pattern.
  15. 15. Epidemiology : • International – The WHO estimates that more than 150 million people worldwide have diabetes. • Untreated, – there is a 25-30% risk of developing clinically significant macular edema (CSME) with moderate visual loss. • USA – 5.8 million people are known to have DM – 4 to 5 million Americans have DM that has not been diagnosed – 9% of diabetic population in US will have macular edema – Of these, 200,000 patients with “macular edema alone” are at risk of moderate visual loss • (Aiello and Ferris, 1987). Dr. Mazhry frcs,fcps 15 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
  16. 16. DME-Legal Blindness • Mortality/Morbidity – Diabetes is the leading cause of new blindness in the United States, to which CSME 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%. Dr. Mazhry frcs,fcps 16
  17. 17. Diagnosis-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. Dr. Mazhry frcs,fcps 17
  18. 18. Diagnosis-History • 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. Dr. Mazhry frcs,fcps 18
  19. 19. Diagnosis-History • 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. Dr. Mazhry frcs,fcps 19
  20. 20. DME Diagnosis-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. Dr. Mazhry frcs,fcps 20
  21. 21. DME Diagnosis-Physical • Important observations include: – Location of retinal thickening relative to the fovea – Presence and location of exudates – Presence of cystoid macular edema Dr. Mazhry frcs,fcps 21
  22. 22. Diabetic Macular Edema(DME) Focal/Diffuse Dr. Mazhry frcs,fcps 22 • 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. Often associated with cystoid macular edema
  23. 23. Clinically Significant Macular Edema • Retinal thickening at or within 500 µm from the center of the macula or • Hard exudates at or within 500 µm from the center of the macula if accompanied by thickening of the adjacent retina or • A zone of retinal thickening, 1 disc area or larger in size, located 1 disc diameter or less from the center of the macula – ETDRS demonstrated that eyes with CSME benefited from treatment with focal Argon laser Dr. Mazhry frcs,fcps 23 CSME diagnosed primarily at the slit lamp (to assess retinal thickening)
  24. 24. Dr. Mazhry frcs,fcps 24 • 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 Other physical findings
  25. 25. Differential Diagnoses – ARMD, Exudative – Branch Retinal Vein Occlusion – Central Retinal Vein Occlusion – Hypertension Macular Edema – Irvine-Gass – Uveitis – Other Problems to Be Considered • Cystoid macular edema • Hypotonic retinopathy • Macular pucker • Epinephrine use in aphakia Dr. Mazhry frcs,fcps 25
  26. 26. Workup Imaging Studies • Color stereo fundus photographs – provide an opportunity to evaluate long-term changes in the retina. Dr. Mazhry frcs,fcps 26
  27. 27. Workup Imaging Studies-FFA • Fluorescine angiography – Fluorescein angiography is useful in demonstrating the breakdown of the blood- retinal barrier by delineating retinal capillary leakage and capillary nonperfusion – Fluorescein angiography is not relevant in aiding in the diagnosis of CSME but should be performed if treatment of CSME is being considered. Dr. Mazhry frcs,fcps 27 CSME diagnosed primarily at the slit lamp (to assess retinal thickening)
  28. 28. Workup Imaging Studies • Fluorescine angiography – Fluorescine 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. Dr. Mazhry frcs,fcps 28
  29. 29. Fluorescine angiography • Focal leakage: • Well defined areas of leakage; e.g., microaneurysms • FFA will clearly show the source of leakage • Diffuse leakage: • Poorly demarcated widespread leakage • Destruction of the inner blood retinal barrier. • FFA will show widened intercapillary spaces, with diffusely dilated capillary bed, and diffuse leakage. • RPE dysfunction Dr. Mazhry frcs,fcps 29
  30. 30. Workup Imaging Studies • 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. Dr. Mazhry frcs,fcps 30 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
  31. 31. Workup Imaging Studies • Optical coherence tomography – 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. Dr. Mazhry frcs,fcps 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
  32. 32. Workup Imaging Studies • Optical coherence tomography – 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. Dr. Mazhry frcs,fcps Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol. Jun 1999;127(6):688-93
  33. 33. Treatment • Medical Care – Primary Care Physicians And Internists. • optimizing – diabetic and – hypertensive – renal – and lipid control – Diet • Lifestyle modification – Activity • Lifestyle modification – Optimizing diabetic, hypertensive, and lipid control has been shown to positively impact diabetic retinopathy. Dr. Mazhry frcs,fcps 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. 33
  34. 34. Ocular Treatment • Available Tools – LASERs – AntiVEGF Therapy – Steroids Dr. Mazhry frcs,fcps 34
  35. 35. Focal/grid laser photocoagulation • 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 2-6 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. Dr. Mazhry frcs,fcps 35
  36. 36. Focal Photocoagulation for CSME • Fluorescein angiography and Fundus photos are obtained prior to initiation of laser therapy • Ophthalmologist views the FA to guide treatment of CSME – For focal leakage, direct laser therapy using green-only Argon laser is applied to all leaking microaneurysms between 500 and 3000 µm from the center of the macula – For diffuse leakage or zones of capillary nonperfusion adjacent to the macula, a light-intensity grid pattern using green-only Argon laser is applied to all areas of diffuse leakage more than 500 µm from the center of the macula and 500 µm from the temporal margin of the optic disc • Multiple sessions spread out over many months are frequently necessary for resolution of DME Dr. Mazhry frcs,fcps 36
  37. 37. Laser Treatment for CSME • Focal: – 50-100  spots to areas of discrete leakage • Grid: – 100-200  spots in areas of diffuse leakage • “Focal-Grid”: – combination of the above Dr. Mazhry frcs,fcps 37 Laser photocoagulation continues to be a well-proven therapy to reduce the risk of vision loss from diabetic macular edema. Area(s) of leakage can be identified by examination (areas of retinal thickening) or by fluorescein angiography. Important to avoid foveal avascular zone Avoid confluent burns
  38. 38. Prognosis Macular laser Rx • ETDRS showed that in eyes with CSME, focal laser photocoagulation reduces the risk of moderate visual loss by 50% or more. • It also reported an increase in the chance of improvement on the final BCVA. • However, in all the studies, 15%-24% of eyes had moderate visual loss despite focal laser Rx. • These eyes generally had diffuse diabetic macular edema (DDME) or poor macular perfusion. Dr. Mazhry frcs,fcps 38
  39. 39. LASER Photocoagulation for CSME • Side Effects and Complications of Focal Laser – Paracentral scotomata – Transient increased edema/decreased vision – Choroidal neovascularization (new abnormal blood vessel growth beneath the retina) – Subretinal fibrosis – Photocoagulation scar expansion – Inadvertent foveolar burns Dr. Mazhry frcs,fcps 39
  40. 40. Anti VEGF Therapy • 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 Dr. Mazhry frcs,fcps 40
  41. 41. Anti VEGF Therapy • 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 , 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. Dr. Mazhry frcs,fcps 41
  42. 42. Intravitreal Steroids • 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 Dr. Mazhry frcs,fcps 42
  43. 43. Role of Vitrectomy Surgery • Pars plana vitrectomy – It is widely recognized that there have been recent advancements in small-gauge vitreoretinal surgery. – Many studies14,15 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 Dr. Mazhry frcs,fcps 43
  44. 44. Case Study EM Dr. Mazhry frcs,fcps 44
  45. 45. Dr. Mazhry frcs,fcps 45
  46. 46. Dr. Mazhry frcs,fcps 46
  47. 47. Case Study EM Dr. Mazhry frcs,fcps 47
  48. 48. Case Studies - Patient EM • 59-year-old African-American male • Type 2 DM x 11 yrs • LEE: 1.5 yr • Pt complaint “having trouble seeing” • PMHx: – Uncontrolled HTN – + proteinuria – Last HbA1c = 11.1% • Meds: insulin, antihypertensive Dr. Mazhry frcs,fcps 48
  49. 49. Patient EM • Cholesterol levels within normal limits • Current Albumin/Creatine level = 231.6 µg/mg (Normal: 0 - 20 µg/mg) • Triglycerides and LDL levels calculated but non- fasting Dr. Mazhry frcs,fcps 49
  50. 50. Case Study EM Exam Findings • VA OD 20/30+ OS 20/30 • Sensorimotor exam normal • No distortion with Amsler grid • Early NSC, PSC OU; early CC, vacuoles OS • IOP 14mmHg OU Dr. Mazhry frcs,fcps 50
  51. 51. Case Study EM Plan • Laser treatment for macular edema within one to two weeks • Control of BP and BG Dr. Mazhry frcs,fcps 51
  52. 52. Case Study EM Treatment • Focal laser treatment – OD at 3 weeks – OS at 7 weeks • 4 month follow-up Dr. Mazhry frcs,fcps 52
  53. 53. Case Study EM Notes • HTN, renal disease and dyslipidemia can affect onset and progression of retinopathy • Co-management with other health care providers • Lesions that may indicate nondiabetic etiology – Venous caliber abnormalities – Parapapillary cotton wool spots of similar onset – Flame-shaped hemorrhages – Diffuse retinal edema – White centered hemorrhages (Roth’s spots) Dr. Mazhry frcs,fcps 53
  54. 54. Case DG • 35-year-old Caucasian male • Type 1 DM 23 years • VA: OD-20/30; OS-20/40 • Denies hypertension, renal disease, hypercholesterolemia/dyslipidemia Dr. Mazhry frcs,fcps 54
  55. 55. Patient DG • Diagnosis: – Moderate NPDR OU – DME not CSME OD – Clinically Significant Macular Edema OS • Plan: – FA to identify treatable lesions OS – Focal laser photocoagulation OS Dr. Mazhry frcs,fcps 55
  56. 56. Prevention of Diabetic Retinopathy • Prevention of diabetic retinopathy requires prevention of diabetes • Patients at higher risk (i.e. family history, ethnicity) of developing diabetes can adjust modifiable risk factors Healthy diet Exercise Blood pressure control Tobacco cession Weight reduction (if obese) Dr. Mazhry frcs,fcps 56
  57. 57. Role of Hypertension in DME • WESDR - diabetic patients with HTN had 3 x incidence of DME. • UKPDS__rigorous BP control with ACE- inhibitor or -blocker reduced the risk of the two-step progression of DR significantly. Dr. Mazhry frcs,fcps 57
  58. 58. Role of Renal Disease in DME • Gross proteinuria associated with 95% increased risk of DME (WESDR) • Case reports of reduction of diabetic macular edema after dialysis • Type 1 patients with microalbuminuria have three-fold risk of PDR compared to those with normal levels Dr. Mazhry frcs,fcps 58
  59. 59. Role of Serum Lipids in DR • Elevated serum lipids are associated with increased risk of retinal hard exudates • Increased amounts of hard exudates are associated with increased risk of visual impairment • Elevated lipids, most notably triglycerides, are a risk factor for development of high-risk PDR Dr. Mazhry frcs,fcps 59 ETDRS Report # 18 and 22
  60. 60. Role of Vitreous in DME • Vitreomacular traction is believed to be a contributor to the multifactorial etiology of DME. • The role of the posterior hyaloid in a subset of eyes with diffuse macular edema has become increasingly recognised (Schepens et al, 1984). • Nasrallah et al observed that a posterior hyaloid separation was more common in diabetic eyes without M.E than with M.E (55% v/s 20.0%). Dr. Mazhry frcs,fcps 60 (Nasrallah et al, Ophthalmology vol 90: 1988)
  61. 61. Vitrectomy Surgery • New Indication: – Persistent Diabetic Cystoid Macular Edema – Vitrectomy surgery is often helpful in cases withdetectable posterior hyaloid traction, epiretinal, membrane, or macular striae. – May also be beneficial in other cases of persistent or worsening cystoid macular edema – Considered for diffuse leakage or exudate in foveal center with vision 20/70 or worse. Dr. Mazhry frcs,fcps 61
  62. 62. Cataract Surgery in Diabetics • Various studies suggest that DR may progress following cataract surgery • Patients who undergo cataract surgery with CSME, Severe NPDR, or PDR should be considered for photocoagulation prior to cataract removal • If density of cataract precludes adequate evaluation of the retina or precludes treatment, prompt post-operative retinal evaluation and treatment can be considered Dr. Mazhry frcs,fcps 62
  63. 63. Follow-Up Based Upon Retinopathy Findings Retinal Abnormality Suggested Follow-Up Normal or rare microaneurysms Mild NPDR Moderate NPDR Severe NPDR CSME PDR Annually Every 9 months Every 6 months Every 4 months Every 2-4 months (careful f/u) Every 2-3 months (careful f/u) Dr. Mazhry frcs,fcps 63
  64. 64. DRCR Network Overview • Funding: – National Eye Institute-sponsored cooperative agreement initiated September 2002 • Objective: – The development of a collaborative network to facilitate multicenter clinical research on diabetic retinopathy, diabetic macular edema and associated conditions. Dr. Mazhry frcs,fcps 64
  65. 65. DRCR Diabetic Retinopathy Clinical Research Dr. Mazhry frcs,fcps 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. 65 DRCR.net >150 sites overall >90 community >450 total PIs >1000 study personnel 40 States www.DRCR.net • 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
  66. 66. DRCR CURRENTLY RECRUITING STUDIES • Randomized trial comparing intravitreal triamcinolone acetonide and laser photocoagulation for DME • Evaluation of vitrectomy for DME • Observational study of development of DME following scatter laser photocoagulation • Subclinical DME study Dr. Mazhry frcs,fcps 66
  67. 67. A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Laser Photocoagulation for Diabetic Macular Edema • To determine whether intravitreal triamcinolone acetonide injections at doses of 1mg or 4mg produce greater benefit, with an acceptable safety profile, than macular laser photocoagulation in the treatment of diabetic macular edema. • To compare the efficacy and safety of the 1mg and 4mg triamcinolone acetonide doses Dr. Mazhry frcs,fcps 67
  68. 68. Study Design • Phase 3, multicenter, randomized clinical trial • Randomization to one of three treatment groups: Dr. Mazhry frcs,fcps 68 • Standard of care group: conventional treatment consisting of modified ETDRS photocoagulation • Intravitreal injection of 1mg of triamcinolone acetonide • Intravitreal injection of 4mg of triamcinolone acetonide • Duration of follow-up: Three years • Injection volume always = 0.05ml
  69. 69. Intraocular Formulation Comparison with Kenalog ® -40 Ingredient Allergan Form Kenalog® -40 Triamcinolone Acetonide 2 and 8% 4% Benzyl Alcohol - 0.99% Polysorbate 80 - 0.04% Sodium Chloride To Isotonicity To Isotonicity Sodium Phosphate 0.34% - Sodium Hydroxide/ Hydrochloric Acid to pH 7.3 to pH 5.0 -7.5 Dr. Mazhry frcs,fcps 69
  70. 70. Formulation and Packaging Allergan • Sterile, prefilled (0.05ml), single-dose, ready-to-use syringe with attached 27- gauge needle. • Shelf-stable and requires no shaking to re-suspend. • Homogeneous, white suspension, easily delivered. Dr. Mazhry frcs,fcps 70 Preservative & endotoxin free Isotonic and pH Balanced Single-unit Dosing
  71. 71. Clinical Experience • >75 active sites in >20 states • >40 sites with pending certification • First patient 7/14/04 • >300 patients enrolled Dr. Mazhry frcs,fcps 71
  72. 72. Evaluation of Vitrectomy for Diabetic Macular Edema • To provide information on the following outcomes in eyes with DME that undergo vitrectomy: visual acuity, retinal thickening, resolution of traction (if present), surgical complications. • To identify subgroups in which there appears to be a benefit of vitrectomy and subgroups in which vitrectomy does not appear to be beneficial. Dr. Mazhry frcs,fcps 72
  73. 73. Subclinical Diabetic Macular Edema Study • Primary Objective: To determine the incidence of progression of subclinical diabetic macular edema (DME) – Subclinical DME—no edema involving the center of the fovea as determined by biomicroscopy but with center point thickness on OCT of at least 200 microns but less than or equal to 299 microns – Progression—increase in center point thickness of at least 50 microns to > 300 microns • Secondary Objectives: – To evaluate factors predictive of the presence of subclinical macular edema – To determine indicators of risk for progression of subclinical DME Dr. Mazhry frcs,fcps 73
  74. 74. STUDIES IN FOLLOW-UP PHASE • Pilot study of laser photocoagulation for diabetic macular edema • Pilot study of peribulbar triamcinolone acetonide for diabetic macular edema Dr. Mazhry frcs,fcps 74
  75. 75. Pilot study of laser photocoagulation for diabetic macular edema • Compare laser treatment as we now use it (called “standard method”) with a similar laser treatment that is milder in intensity, but more extensive in number (called “mild macular grid” method) Dr. Mazhry frcs,fcps 75
  76. 76. Pilot study of peribulbar triamcinolone acetonide for diabetic macular edema • To estimate the incidence of improvement of DME following a posterior peribulbar 40 mg triamcinolone acetonide injection compared with laser. • To estimate the incidence of improvement of DME following an anterior peribulbar 20 mg triamcinolone acetonide injection compared with laser. • To estimate the incidence of intraocular pressure elevation and other complications with each type of injection. • To provide preliminary data comparing the incidence of improvement of DME with a peribulbar triamcinolone alone versus peribulbar triamcinolone followed by laser photocoagulation. Dr. Mazhry frcs,fcps 76
  77. 77. UPCOMING STUDIES • A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Avastin – 200 patient, phase 2 randomized, multi-center clinical trial. – Provide preliminary data on the dose and dose interval related effects of intravitreally adminstered Avastin on retinal thickness and visual acuity in subjects with Diabetic Macular (DME) to aid in planning a phase 3 trial. – Provide preliminary data on the safety of intravitreally administered Avastin in subjects with DME. Dr. Mazhry frcs,fcps 77
  78. 78. COMPLETED STUDIES • Temporal Variation in OCT Measurements of Retinal Thickening in Diabetic Macular Edema – Determine the proportion of eyes that demonstrate a potentially meaningful change in central retinal thickening measured on OCT throughout the day. – Establish the time course of change for the eyes that experience diurnal change in central retinal thickening. – Evaluate intra-observer and inter-observer variability on OCT measurements. Dr. Mazhry frcs,fcps 78
  79. 79. Eye Research • Determine basic mechanisms of disease • Identify potential therapeutic targets • Develop specific novel therapies • Evaluate at subcellular, cellular & organism level • Rigorous clinical trials • Opportunity to make today’s standard-of-care obsolete tomorrow Dr. Mazhry frcs,fcps 79

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