2. Normal Retina
Fovea
Macula
Photoreceptors
RPE
Choroid

5. A range of visual defects with macular pathology
Neovascular AMD
Neovascular AMD
Distortion
Blur
Scotoma
Normal
DME with proliferative DR
DME
DME
Blur
Blur + scotomas 5

8. RISK FACTORS Age Smoking Positive family history Hypertension Females
Raised cholesterol
Light iris color

9. DIET
Vitamins – C 500 mg, E 400 IU
Micronutrients – Zinc 80mg with 2mg cupric oxide
Beta carotene 15mg – Avoid in smokers
Fish
Nuts

10. Lifestyle modification
Avoid smoking
Reduce obesity
Use sunglass & Hats
Avoid alcohol

11. VEGF Inhibition in AMD FDA approved Pegaptanib Ranibizumab Off label
Aptamer
Specific for VEGF-A isoform 1651
Ranibizumab
Recombinant, humanized antibody fragment
Blocks all VEGF-A isoforms
Off label
Bevacizumab
Recombinant humanized monoclonal antibody
1Gragoudas ES, et al. N Engl J Med. 2004;351:2805.

12. VEGF-A Is a Key Mediator of Angiogenesis
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 cell
activation3
VEGF-A is produced in response to a variety of stimuli, including environmental factors such as hypoxia and low pH as well as growth factors and hormones.
The receptors for VEGF-A (VEGFR-1 and VEGFR-2) belong to the tyrosine kinase family of cell surface receptors.
VEGFR-2 is the receptor that is largely responsible for propagating the angiogenic, mitogenic, and permeability-enhancing properties of VEGF-A.
The VEGF signaling pathway begins when VEGF binds to its receptor on the surface of an endothelial cell.
The receptor is thus activated, homodimerizes, and undergoes autophosphorylation of the intracellular domain, thereby initiating a signaling pathway that results in endothelial cell activation, proliferation, and migration, as we have just discussed.
VASCULAR LEAKAGE3
Endothelial cell activation, proliferation, migration4
ANGIOGENESIS3
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: Aiello LP, et al. Arch Ophthalmol. 1995;113:1538.
3. Ferrara N, et al. Nat Med. 2003;9: Griffioen AW and Molema G. Pharmacol Rev. 2000;52:237.

13. VEGF Inhibition in AMD FDA approved Pegaptanib Ranibizumab Off label
Aptamer
Specific for VEGF-A isoform 1651
Ranibizumab
Recombinant, humanized antibody fragment
Blocks all VEGF-A isoforms
Off label
Bevacizumab
Recombinant humanized monoclonal antibody
1Gragoudas ES, et al. N Engl J Med. 2004;351:2805.

14. Different gold standard diagnostics with common ancillary tests
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
1. Sickenberg M. Ophthalmologica 2001;215:247–253
2. The Royal College of Ophthalmologists. AMD: guidelines for management [accessed Sep 2009]
3. Bhagat N et al. Surv Ophthalmol 2009;54:1–32 14

15. Standard of care: improvement with neovascular AMD vs stabilization with DME
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
1. Schmidt-Erfurth UM et al. Acta Ophthalmol Scand 2007;85:486–494
2. Bhagat N et al. Surv Ophthalmol 2009;54:1–32
3. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796–1806
4. Furlani BA et al. Expert Opin Emerg Drugs 2007;12:591–603 15

16. Diabetes and vision loss
Diabetes mellitus (DM) is a prevalent disease. Most common complications are microvascular changes1
Diabetic retinopathy (DR) is a common microvascular complication of diabetes2
Diabetic macula edema (DME) is a common cause of blindness in people of working age2,3 and can develop in both Type 1 and 2 DM4
About 8% of diabetic patients develop DME with visual impairment5
Prevalence of diabetes* worldwide
According to data published in 2006 by the International Diabetes Federation (International Diabetes Federation. Diabetes Atlas. 3rd Edition; 2006), the number of people suffering from diabetes worldwide in 2007 was approximately 246 million. It is also projected that by 2025, this number will rise to over 380 million, with most of the increase occurring in developing countries.
*Type 2 diabetes mellitus represents ~90%–95% of cases.
1King et al. Diabetes Care 1998; 21: ; 2Royal College of Ophthalmology. Diabetic Retinopathy Guidelines Accessed February 2009; 3Watkins. BMJ 2003; 326: ; 4Klein et al. Ophthalmology 1998; 105: ; 5Calculated from: Ling et al. Eye 2002; 16: ; Broadbent et al. Eye 1999; 13: ; Knudsen et al. Br J Ophthalmol 2006; 90: ; Hove et al. Acta Ophthalmol Scand 2004; 82: ; Romero-Aroca et al. Arch Soc Esp Oftalmol 2007; 82: ; Zietz et al. Dtsch Med Wochenschr 2000; 125: ; Kristinsson. Acta Ophthalmol Scand Suppl 1997; 223: 1-76 16

17. DME: the main cause of central vision loss in DR
DME was shown to affect approximately 10% of the diabetic population
Klein et al. Ophthalmology 1995; 102: 7-16 17

18. VEGF165 in DR
Retinal VEGF165 levels are elevated in experimental diabetes
Increased VEGF165 levels are found in the vitreous of eyes with proliferative DR
Patients with DR have higher VEGF165 levels in the aqueous
There is an increasing number of studies implicating vascular endothelial growth factor (VEGF) in the pathogenesis of diabetic retinopathy, both in the formation of retinal neovascularization and macular edema.
There are increased levels of VEGF in the retina and in the vitreous.
Qaum et al. IOVS 2001; 42: ; Aiello et al. N Engl J Med 1994; 331: 18

19. Factors affecting DME Incidence of DME increases with
elevated levels of HbA1C
severity of DR
duration of DM
elevated diastolic blood pressure
gender (more frequent in females)
serum lipid levels
Klein et al. Ophthalmology 1998; 105: 19

20. DME: current treatment
Systemic treatment
glucose control
blood-pressure control
blood-lipid control
multifactorial metabolic interventions
Ocular treatment
laser photocoagulation (standard treatment for DR / DME)
vitrectomy
pharmacologic therapy
AAO Guidelines. Diabetic Retinopathy. Accessed February 2009
Royal College of Ophthalmology. Diabetic Retinopathy Guidelines Accessed February 2009 20 20

21. Treatment of neovascularizatio in PDR
DME: aims of therapy
Reduction in vessel hyperpermeability and leakage in macular edema
Treatment of neovascularizatio in PDR 21

22. Laser photocoagulation for DME
Standard treatment – helps to slow fluid leakage and reduce the amount of fluid in the retina (macula edema)
Aim of treatment is to stabilize / prevent further vision loss
Limitations of treatment include
does not eliminate possibility of further vision loss
improvement in visual acuity is uncommon
complications including permanent damage to the retinal pigment epithelium and secondary choroidal neovascularization
National Eye Institute, National Institutes of Health. Diabetic Retinopathy. Accessed February 2009
AAO Guidelines. Diabetic Retinopathy. Accessed February 2009
Royal College of Ophthalmology. Diabetic Retinopathy Guidelines Accessed February 2009

23. DR and DME: the unmet treatment needs
Despite the use of standard interventions for DR, vision loss as a result of the disease still occurs in many patients1
Good metabolic and blood-pressure control are often difficult to achieve in clinical practice, and sight-threatening DR still develops2
Laser treatment is destructive and cannot restore vision loss that has already occurred; it therefore cannot be regarded as an ideal treatment, and there is a need for better-tolerated and less-destructive therapies3
Defining the unmet treatment need in diabetic retinopathy (DR)
Despite the use of standard interventions for DR, vision loss as a result of the disease still occurs in many patients. Good metabolic and blood-pressure control are often difficult to achieve in clinical practice, and sight-threatening DR still often develops. Furthermore, laser treatment is destructive and cannot restore vision loss that has already occurred; therefore it cannot be regarded as an ideal treatment, and there is a need for better-tolerated and less-destructive therapies.
1Comer & Ciulla. Curr Opin Ophthalmol 2004; 15:
2The DIRECT Programme Study Group. J Renin Angiotensin Aldosterone Syst 2002; 3:
3Fong. Surv Ophthalmol 2002; 47: S238-S245 23 23

25. Intravitreal Ranibizumab Summary
Intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser had superior VA and OCT outcomes compared with focal/grid laser treatment alone.
~50% of eyes had substantial improvement (≥10 letters) while ~30% gained ≥15 letters
Substantial visual acuity loss (≥10 letters) was uncommon
Results were similar whether focal/grid laser was given starting with the first injection or it was deferred >24 weeks 25