Photoreceptors
Choroid
RPE
Normal RetinaNormal Retina
Fovea
Macula
A range of visual defects with macular pathologyA range of visual defects with macular pathology
DME
Neovascular AMDNeovascular AMD
DME with proliferative DRDME
Distortion Blur Scotoma
Blur
Normal
Blur + scotomas
RISK FACTORSRISK FACTORSAgeAge
SmokingSmoking
Positive family historyPositive family history
HypertensionHypertension
FemalesFemales
Raised cholesterolRaised cholesterol
Light iris colorLight iris color
DIETDIET
Vitamins – C 500 mg, E 400 IUVitamins – C 500 mg, E 400 IU
Micronutrients – Zinc 80mg with 2mg Micronutrients – Zinc 80mg with 2mg cupric oxidecupric oxide
Beta carotene 15mg – Avoid in smokersBeta carotene 15mg – Avoid in smokers
FishFish
NutsNuts
Lifestyle modificationLifestyle modificationAvoid smoking Avoid smoking
Reduce obesityReduce obesity
Use sunglass & HatsUse sunglass & Hats
Avoid alcoholAvoid alcohol
VEGF Inhibition in AMDVEGF Inhibition in AMDFDA approvedFDA approved
PegaptanibPegaptanib– AptamerAptamer– Specific for VEGF-A isoform 165Specific for VEGF-A isoform 16511
RanibizumabRanibizumab– Recombinant, humanized antibody fragmentRecombinant, humanized antibody fragment– Blocks all VEGF-A isoformsBlocks all VEGF-A isoforms
Off labelOff labelBevacizumabBevacizumab– Recombinant humanized monoclonal antibodyRecombinant humanized monoclonal antibody– Blocks all VEGF-A isoformsBlocks all VEGF-A isoforms
1Gragoudas ES, et al. N Engl J Med. 2004;351:2805.
Endothelial cell activation, proliferation, migration4
VEGF-A Is a Key Mediator of VEGF-A Is a Key Mediator of Angiogenesis Angiogenesis
ANGIOGENESIS3 VASCULARLEAKAGE3
Environmental factors1
(hypoxia,2 pH)Growth factors,
hormones1 (EGF, bFGF, PDGF, IGF-1, IL-1, IL-6,
estrogen)
VEGF-A binding and activation of VEGF
receptor3
Endothelial cellactivation3
VEGF-A = vascular endothelial growth factor A; EGF = epidermal growth factor; bFGF = basic fibroblast
growth factor; PDGF = platelet-derived growth factor; lGF = insulin-like growth factor; IL= interleukin.
1. Dvorak HF. J Clin Oncol. 2002;20:4368. 2. Aiello LP, et al. Arch Ophthalmol. 1995;113:1538.
3. Ferrara N, et al. Nat Med. 2003;9:669. 4. Griffioen AW and Molema G. Pharmacol Rev. 2000;52:237.
VEGF Inhibition in AMDVEGF Inhibition in AMDFDA approvedFDA approved
PegaptanibPegaptanib– AptamerAptamer– Specific for VEGF-A isoform 165Specific for VEGF-A isoform 16511
RanibizumabRanibizumab– Recombinant, humanized antibody fragmentRecombinant, humanized antibody fragment– Blocks all VEGF-A isoformsBlocks all VEGF-A isoforms
Off labelOff labelBevacizumabBevacizumab– Recombinant humanized monoclonal antibodyRecombinant humanized monoclonal antibody– Blocks all VEGF-A isoformsBlocks all VEGF-A isoforms
1Gragoudas ES, et al. N Engl J Med. 2004;351:2805.
Early detection of neovascular AMD is possible with an Amsler grid1
FA is essential to confirm diagnosis of neovascular AMD, and to identify the location and composition of the CNV1
Ancillary tests:2
ICGA – delineation of choroidal vessel morphology
OCT – measurement of retinal thickness
Neovascular AMD
DME is diagnosed stereoscopically as retinal thickening in the macula using fundus contact lens biomicroscopy3
Ancillary tests:3
FA – identification and evaluation of fluid leakage from lesions
OCT – measurement of retinal thickness
DME
Different gold standard diagnostics with Different gold standard diagnostics with common ancillary testscommon ancillary tests
1. Sickenberg M. Ophthalmologica 2001;215:247–2532. The Royal College of Ophthalmologists. AMD: guidelines for management. 2009.
http://www.rcophth.ac.uk/docs/publications/AMD_GUIDELINES_FINAL_VERSION_Feb_09.pdf [accessed Sep 2009]3. Bhagat N et al. Surv Ophthalmol 2009;54:1–32
Standard of care: improvement with Standard of care: improvement with neovascular AMD vs stabilization with DMEneovascular AMD vs stabilization with DME
1. Schmidt-Erfurth UM et al. Acta Ophthalmol Scand 2007;85:486–4942. Bhagat N et al. Surv Ophthalmol 2009;54:1–32
3. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796–18064. Furlani BA et al. Expert Opin Emerg Drugs 2007;12:591–603
Ocular treatment – Anti VEGFs IVI1
• Maintenance of vision can be expected in 90–95% of patients
• Improvement of vision by ≥3 lines can be expected in 30–40% of patients
Neovascular AMD
Ocular treatment – laser photocoagulation2–4
• Rarely provides visual improvement
• In the 1985 ETDRS, VA improved in 16%, was unchanged in 77% and worsened in 7% of patients
Systemic treatment4
• Glucose control• Blood-pressure control• Blood-lipid control• Multifactorial metabolic
interventions
DME
Diabetes mellitus (DM) is a prevalent disease. Most Diabetes mellitus (DM) is a prevalent disease. Most common complications are microvascular changescommon complications are microvascular changes11
Diabetic retinopathy (DR) is a common microvascular Diabetic retinopathy (DR) is a common microvascular complication of diabetescomplication of diabetes2 2
Diabetic macula edema (DME) is a common cause of Diabetic macula edema (DME) is a common cause of blindness in people of working ageblindness in people of working age2,32,3 and can develop and can develop in both Type 1 and 2 DMin both Type 1 and 2 DM44
About 8% of diabetic patients develop DME with About 8% of diabetic patients develop DME with visual impairmentvisual impairment55
1King et al. Diabetes Care 1998; 21: 1414-1431; 2Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005. http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf . Accessed February
2009; 3Watkins. BMJ 2003; 326: 924-926; 4Klein et al. Ophthalmology 1998; 105: 1801-1815; 5Calculated from: Ling et al. Eye 2002; 16: 140-145; Broadbent et al. Eye 1999; 13: 160-165; Knudsen et al. Br J Ophthalmol 2006; 90: 1404-1409; Hove et al.
Acta Ophthalmol Scand 2004; 82: 443-448; Romero-Aroca et al. Arch Soc Esp Oftalmol 2007; 82: 209-218; Zietz et al. Dtsch Med Wochenschr 2000; 125: 783-788; Kristinsson. Acta Ophthalmol Scand Suppl 1997; 223: 1-76
Diabetes and vision lossDiabetes and vision loss
DME: the main cause of central DME: the main cause of central vision loss in DR vision loss in DR
DME was shown to affect approximately DME was shown to affect approximately 10% of the diabetic population 10% of the diabetic population
Klein et al. Ophthalmology 1995; 102: 7-16
VEGF165 in DRVEGF165 in DRRetinal VEGF165 Retinal VEGF165 levels are elevated in levels are elevated in experimental diabetesexperimental diabetes
Increased VEGF165 Increased VEGF165 levels are found in the levels are found in the vitreous of eyes with vitreous of eyes with proliferative DR proliferative DR
Patients with DR have Patients with DR have higher VEGF165 higher VEGF165 levels in the aqueouslevels in the aqueous
Qaum et al. IOVS 2001; 42: 2408-2413; Aiello et al. N Engl J Med 1994; 331: 1480-1487
Factors affecting DMEFactors affecting DMEIncidence of DME increases with Incidence of DME increases with – elevated levels of HbA1elevated levels of HbA1CC
– severity of DRseverity of DR– duration of DMduration of DM– elevated diastolic blood pressureelevated diastolic blood pressure– gender (more frequent in females)gender (more frequent in females)– serum lipid levelsserum lipid levels
Klein et al. Ophthalmology 1998; 105: 1801-1815
DME: current treatmentDME: current treatmentSystemic treatmentSystemic treatment– glucose controlglucose control– blood-pressure controlblood-pressure control– blood-lipid controlblood-lipid control– multifactorial metabolic interventionsmultifactorial metabolic interventions
Ocular treatmentOcular treatment– laser photocoagulation (standard treatment for DR / laser photocoagulation (standard treatment for DR /
DME)DME)– vitrectomyvitrectomy– pharmacologic therapypharmacologic therapy
AAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005.
http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf . Accessed February 2009
Reduction in vessel hyperpermeabilityReduction in vessel hyperpermeabilityand leakage in macular edemaand leakage in macular edema
DME: aims of therapyDME: aims of therapy
Treatment of neovascularizatio in PDR
Laser photocoagulation for DMELaser photocoagulation for DMEStandard treatment – helps to slow fluid leakage Standard treatment – helps to slow fluid leakage and reduce the amount of fluid in the retina and reduce the amount of fluid in the retina (macula edema)(macula edema)
Aim of treatment is to stabilize / prevent further Aim of treatment is to stabilize / prevent further vision lossvision loss
Limitations of treatment includeLimitations of treatment include– does not eliminate possibility of further vision lossdoes not eliminate possibility of further vision loss– improvement in visual acuity is uncommonimprovement in visual acuity is uncommon– complications including permanent damage to the retinal pigment complications including permanent damage to the retinal pigment
epithelium and secondary choroidal neovascularizationepithelium and secondary choroidal neovascularizationNational Eye Institute, National Institutes of Health. Diabetic Retinopathy.
http://www.nei.nih.gov/health/diabetic/retinopathy.asp#4a Accessed February 2009AAO Guidelines. Diabetic Retinopathy. http://www.aao.org/ppp. Accessed February 2009
Royal College of Ophthalmology. Diabetic Retinopathy Guidelines 2005. http://www.rcophth.ac.uk/docs/publications/publishedguidelines/DiabeticRetinopathyGuidelines2005.pdf . Accessed February
2009
DR and DME: DR and DME: the unmet treatment needsthe unmet treatment needs
Despite the use of standard interventions for DR, vision Despite the use of standard interventions for DR, vision loss as a result of the disease still occurs in many loss as a result of the disease still occurs in many patientspatients11
Good metabolic and blood-pressure control are often Good metabolic and blood-pressure control are often difficult to achieve in clinical practice, and sight-difficult to achieve in clinical practice, and sight-threatening DR still developsthreatening DR still develops22
Laser treatment is destructive and cannot restore vision Laser treatment is destructive and cannot restore vision loss that has already occurred; it therefore cannot be loss that has already occurred; it therefore cannot be regarded as an ideal treatment, and there is a need for regarded as an ideal treatment, and there is a need for better-tolerated and less-destructive therapiesbetter-tolerated and less-destructive therapies33
1Comer & Ciulla. Curr Opin Ophthalmol 2004; 15: 508-5182The DIRECT Programme Study Group. J Renin Angiotensin Aldosterone Syst 2002; 3: 255-261
3Fong. Surv Ophthalmol 2002; 47: S238-S245
Intravitreal Ranibizumab Intravitreal Ranibizumab SummarySummary
Intravitreal ranibizumab with prompt or deferred Intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser had superior VA and (≥24 weeks) focal/grid laser had superior VA and OCT outcomes compared with focal/grid laser OCT outcomes compared with focal/grid laser treatment alone.treatment alone.
~50% of eyes had substantial improvement ~50% of eyes had substantial improvement (≥10 letters) while ~30% gained ≥15 letters (≥10 letters) while ~30% gained ≥15 letters Substantial visual acuity loss (≥10 letters) Substantial visual acuity loss (≥10 letters) was uncommonwas uncommonResults were similar whether focal/grid laser Results were similar whether focal/grid laser was given starting with the first injection or it was given starting with the first injection or it was deferred was deferred >>24 weeks24 weeks