A Journey through the Eye Macular Degeneration Dr Dianne Sharp Ophthalmologist Retina Specialists, Auckland

What is the Macula? Normal Retina macula retina optic nerve

Progressive, chronic disease of central retina Loss of central vision Peripheral vision not affected Not black blind What is Macular Degeneration (AMD)?

Leading cause of severe vision loss Macular Degeneration in New Zealand Macular Degeneration Glaucoma Cataract Other

Macular Degeneration Facts and Figures Deloitte Access Economics 2011 and Macular Degeneration Foundation Australia

Macular Degeneration in NZ Australian pop 22 million: NZ pop 4.4million = approx. 1/5th  Macular Degeneration (MD) is a chronic disease with no cure 1  Cause of up to 50% of all blindness  Affects 1 in 7 people over 50 in some way: 1 o 170,000 have early MD in NZ o 33,400 have late MD in NZ. 7,000 are legally blind.  1 in 4 people over 80 have vision loss from MD 1  The number of people with MD will increase by 70% by ¹ Deloitte Access Economics

Prevalence of chronic diseases Australia 2010 – ref Deloitte

2x 4 to 8x 3x Risk of falls Risk of depression Risk of hip fracture Rate of social dependence 3yr Nursing home admission Employment The Impact of Macular Degeneration* Access Economics & AMDAI The impact of MD on quality of life is equivalent to cancer or coronary heart disease.

Cost of vision loss from Macular Degeneration $AU2.55 billion in 2010 in Australia $NZ 0.64 billion in NZ (Adjusted for population and currency) Deloitte Access Economics & Macular Degeneration Foundation 2011,

Optimal integrated model of care for Macular Degeneration (AMD) 1.Primary prevention 2.Early detection & timely diagnosis 3.Early & regular treatment with on-going monitoring for wet AMD 4.Rehabilitation & emotional support

Macular Degeneration symptoms

How does MD Develop? Macula Retina RPE Choroid Normal Retina

RETINA CHOROID RPE Healthy retina Bruch’s membrane

Early AMD -“Drusen”

Normal Retina Drusen Early AMD

Drusen Early AMD

Normally no symptoms but at risk of progression Lipid deposits (drusen) No treatment but progression slowed by diet and lifestyle modifications Early Stages of MD

Dry AMD Drusen Atrophy 7rs later

Dry AMD

Dry AMD: Atrophy of retinal tissue. Gradual loss of central vision over years end stage has significant vision loss Wet AMD: Formation leaky blood vessels under retina Rapid loss central vision Late Stages of AMD

Wet AMD

Advanced Wet AMD

Wet AMD

Dry MD: Atrophy of retinal tissue. Gradual loss of central vision over years end stage has significant vision loss Wet MD: Formation leaky blood vessels under retina Rapid loss central vision over weeks or months Late Stages of MD

Visual impairment by severity of vision loss

Optimal integrated model of care for Macular Degeneration (AMD) 1.Primary prevention 2.Early detection & timely diagnosis 3.Early & regular treatment with on-going monitoring for wet AMD 4.Rehabilitation & emotional support

Risk Factors for MD Age

Prevalence AMD (%) Blue Mountains Eye Study Age group Early AMD Dry Late AMD Wet Late AMD All Late AMD yr6%<0.5% yr11%<0.5%0.5% yr20%1%2%3% yr25%3%7%10% 90+ yr35%18%13%31% All 50 yr+13%0.7%1.5%

% Prevalence AMD by age

Risk Factors for MD Genetics % cases have a genetic link 50% risk of MD if a direct family history

AMD Principal genes CFH & ARMS2 Rotterdam Eye Study Early AMD 75% had one risk allele Late AMD 93% had one risk allele Risk of developing AMD by 85yrs increases with number of alleles

Genetics: Risk Alleles CFH Mainly dry AMD Inhibitory effect on complement pathway ? Less effective inhibition of inflammatory pathway ARMS2 Mainly wet MD Gene located in mitochondria ? Interferes with normal oxidation Rotterdam Eye Study

Modifying Genetic Risk Factors Smoking With 1 CFH allele Risk of AMD: Non smokers risk 12x Smokers risk 34x Diet 1 CFH &/or ARMS2 allele High dose Zn, omega 3, lutein rate close to no genetic risk

Risk Factors for MD Smoking  Smoking increases risk 3 to 4 times  Smokers get MD 10 years earlier, on average  BUT 20 years after quitting, a smoker’s risk is the same as a non-smoker

Eye test every 2 years or earlier if any new symptoms Recommend family members have eye test. Protect eyes from sun Healthy lifestyle: o Control weight o Exercise o Eat eye health foods o Consider a supplement Reduce Your Risk of MD

Eating for Eye Health Lutein Dark green and naturally yellow vegetables and fruit every day

Fish 2-3 times per week (salmon, sardines, mackerel, anchovies, tuna) Eating for Eye Health Omega 3

Handful of nuts per week (brazil nuts, almonds, walnuts, pine nuts) Limit fat intake Eating for Eye Health

Low Glycaemic Index foods Low GI Foods Break down more slowly Prolong energy release Leave less waste products in the eye

3 key supplements to consider: AREDS formulation Lutein Omega 3 (fish oil) What supplements?

Per day Zinc 80mg Vitamin C 500mg Vitamin E 400IU Copper 2mg ß-carotene 15mg AREDS Formula Age Related Eye Disease Study Daily dose = 2 tablets People who smoke, suffer from lung cancer or asbestosis should not take a supplement with beta- carotene. This is the reason it is removed from most AREDS supplement products. Macu-Vision

Diet supplements  AREDS Formulation: for intermediate or late AMD in one eye, reduces risk of progression by 20-25%  AREDS 2: trial in progress. Reducing Zn, removing beta-carotene, addition Lutein

Optimal integrated model of care for Macular Degeneration (AMD) 1.Primary prevention 2.Early detection & timely diagnosis 3.Early & regular treatment with on-going monitoring for wet AMD 4.Rehabilitation & emotional support

Symptoms of Macular Degeneration Early stages o Early MD may be asymptomatic. Eye tests are the key. Late stages o Difficulty distinguishing faces o Difficulty reading & fine vision o Distortion (straight lines appear wavy or bent) o Dark / blank patches in central vision

Use an Amsler grid (one eye at a time) Normal Lines distortedDark patches or empty spaces

Chronic disease Dry AMD: diet and lifestyle important Wet AMD: treatment available diet and lifestyle also important Treatments for AMD

Treatment for Wet MD Injection Lucentis or Avastin into the eye Average every 4–6 weeks Early treatment saves sight! Aim to stabilise vision and prevent further vision loss.

***p< vs. sham sham -3 Month ANCHOR +2 MARINA +1.5 PDT -2 Lines on vision chart AMD Treatment Trials (Anchor & Marina) Lucentis treatment: Mean gain in vision over 2yr

Current drug treatments Lucentis or Avastin o Normally given as monthly injections o Highly effective. CATT study: Comparing Lucentis and Avastin o Similar effect at 24 months o Still some unanswered questions re adverse events with Avastin

Optimal integrated model of care for Macular Degeneration (AMD) 1.Primary prevention 2.Early detection & timely diagnosis 3.Early & regular treatment with on-going monitoring for wet AMD 4.Rehabilitation & emotional support

AMD treatment trials (PIER) Subset analysis highlights need for individualised dosing No initial gain (no gain at month 3) (n=21, 34% total) Initial gain not maintained (n=24, 40% total & 60% initial gainers) Maintained initial gain (>0 at month 3) (n=16, 26% total & 40% initial gainers) BCVA, best corrected visual acuity

New Therapies on horizon Treatments that allow decreased Rx frequency Improved drug delivery methods (drops, oral) Therapies allowing self monitoring rather than doctor visits Combined drug therapies →improve efficacy & decreasing Rx burden Drugs that reverse disease process

Wet AMD: New treatments VEGF Trap-Eye o Similar effect to Lucentis / Avastin o lasts two months o Available later this year in NZ Pazopanib (Eye drop) o Used with anti-VEGF injections to help spread number of injections o In phase 3 trials

Dry AMD: New treatments Fenretinide A tablet, derived from Vitamin A Slows development of drusen Reduces risk of wet AMD by 2 fold In phase 3 trials Brimonidine An implant inside eye May protect against late dry AMD In phase 2 trials

Laser for early (dry) AMD Ellex 2RT (Laser) o Ultra-short duration, non-thermal laser o Appears to reduce formation of drusen o May improve waste transport in retina o Trials ongoing

Gene therapy for wet AMD Gene therapy inserts a ‘normal’ gene into cells to replace disease-causing genes. RetinoStat – gene-therapy to stop new blood vessel formation. Early clinical trials.

When retinal cells die Treatments that could directly replace lost retinal cells RPE cell transplantation from donor Stem Cell treatment Artificial (‘bionic’) vision –Only useful if total vision loss

Retinal cell transplantation Many animal studies, some human studies Only limited efficacy reported Very difficult surgery

Stem cells Stem cells have the ability to develop into different types of adult cells such as photoreceptor cells or RPE cells Possible sources: Embryonic stem cells (Most adaptable), Adult stem cells (more restricted) Please note: MDNZ recognises and respects different points of view concerning stem cell research. Our role is to simply report on all research occurring for your information.

Stem cell treatment

Artificial vision “Bionic eyes” An electronic prosthesis to replace the function of dead retinal cells. NOTE: Current ‘bionic eyes’ provide MUCH LESS vision than most people with end stage AMD already possess.

Pathogenesis of AMD for future treatments

Early AMD: Drusen OCT Infra red Auto fluorescence

Anti-inflammatory Pro-inflammatory Normal AMD Drusen

Complement inflammation pathways Membrane Attack Complex

Rattner and Nathans 7, 860–872 (November 2006) | doi: / nrn2007 Complement mediated inflammation in AMD Anti-C5b-9 Membrane Attack Complex C5 cleavage products beneath RPE. Drusen contain almost all alternative complement pathway proteins

Complement inflammation pathways CFH CFB Exercise

Complement inflammation pathways CFH Tobacco CFB Exercise CFH

Complement inflammation pathways CFH Tobacco CFB Exercise CFH High fat intake

Complement inflammation pathways CFH Tobacco HDL CFB Exercise CFH High fat intake Membrane Attack Complex

INTERACTION OF ENVIRONMENTAL AND GENETIC RISK FACTORS IN AMD Risk of AMD Genetic and environmental risk factors are not merely additive Resultant risk in some cases is greater than that conferred by each risk factor individually.

Potential Targets for AMD Therapy Membrane Attack Complex

AMD is a complex disease Medical research takes time and vast amounts of money. o New drug: 12 years and $500m - $1.2 billion o Other research:  New mechanisms  Identify risk and protective factors More research is needed!

Optimal integrated model of care for Macular Degeneration (AMD) 1.Primary prevention 2.Early detection & timely diagnosis 3.Early & regular treatment with on-going monitoring for wet AMD 4.Rehabilitation & emotional support

Optimal integrated model of care for Macular Degeneration (AMD) 1.Primary prevention 2.Early detection & timely diagnosis 3.Early & regular treatment with on-going monitoring for wet AMD 4.Rehabilitation & emotional support

Our Vision: To reduce the incidence and impact of Macular Degeneration in New Zealand

Our Objectives Education Awareness Representation Research Support Services

For more information 0800 MACULA Free call, NZ-wide Web:

The Ageing Eye: Integrated Care GP OptometristOphthalmologist

The Ageing Eye: Integrated Care GP OptometristOphthalmologist