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