Macular degeneration treatments - an update for orthoptists

Treatment of Macular Degeneration

Orthoptic study day26th April 2013

• What is macular degeneration?• Current treatments• Future developments

Aims

Basic retinal anatomy

• Nerve layer (Neuro-retina)• Pigment layer (retinal pigment epithelium or

RPE)• Blood vessel layer (choroid)

Nerve layer (Neuro-retina)• Rods and cones

– Converts light energy into electrical impulses to transmit to the brain.

– Most energy dependent of all tissue in body

• Bipolar cells• Ganglion cells• Nerve fibre layer

– 1.1 million nerve fibres per eye

Pigment layer

• Recycles material from rods and cones– Recycling needed to maintain efficient function

• Contains pigment to stop internal reflections– Prevents “glare” inside the eye– Melanin pigment

• Single layer of cells

Blood vessel layer (choroid)

• Supply oxygen and nutrients to photoreceptors and RPE (outer retina)

• Highest blood flow per unit area of any tissue in the body

• Why vision goes just before you faint• Retina is always working very hard!

Is light bad for the eyes ?

• Form of electromagnetic radiation• Look what happens with excess sunlight on

the skin• Eye is an optical system that exposes retina

to radiation all the time• Light focused on the macula

What harm does light do to the retina?

• Reacts with fat in cell membranes• Produces reactive oxygen (free radicals)• Damages the DNA in the cells• Repair mechanisms

– Skin – repairs DNA all the time, new cells form– Brain – cannot create new cells as has to store

memory

– Retina – part of brain so cannot create new cells

How does retina protect itself from light?

• Luteal (yellow) pigment at macular protects against high energy blue light

• Rods and cones have “outer segments”• Although a “non dividing system” these outer

segment cell membranes are constantly shed then recycled by the RPE to form new cell membranes

How does macular degeneration start?

• Chronic damage to cells from high energy light– Damage to DNA (and cannot repair)

• Recycling becomes less effective with age– Accumulation of “waste products” of metabolism

• Toxins– Smoking

• Genetic make up– Complement factor H

Demographics

• AMD - most common cause of visual loss in patients over 55 in Western world

• Diabetic eye disease most common cause of visual loss in patients under 55 in Western world

• Ageing population in UK – 20 million > age 50

Types of AMD

• Dry– Most common form– Gradual loss of central vision– Not total blindness

• Wet– 10-15% of AMD– Sudden loss of central vision– Not total blindness but often more severe central visual

loss

Symptoms of AMD

Charles Bonnet syndrome

• Brain make up its own images• Can be colours or shapes• Can be formed visual hallucinations

Optical coherence tomographyNormal anatomy

Dry AMD• Build up of waste products due to poor

recycling (Drusen)• Changes in melanin pigment in the RPE

• Geographic atrophy

Dry AMD

Drusen“Lumpy bumpy” RPE

Wet AMD• Abnormal blood vessels grow into retina from

choroid and haemorrhage and leak• Vascular endothelial growth factor (VEGF)

stimulates this blood vessel growth

Fundus fluorescein angiography• Dye injected into vein in arm• Abnormal blood vessels leak the dye• Choroidal neovascular membrane (CNV)

Visual loss with wet AMD

• No treatment (natural history)– Loss of 5 lines of Snellen acuity in 2 years

• Most of the loss of vision will take place within the first 6 months

• Like a cut on the skin– First there is inflammation with swelling

and haemorrhage– Then a scar forms (disciform scar)

Injection treatments for wet AMD

• Developed from cancer research• Vascular endothelial growth factor

– Produced by the retina– Stimulates formation of abnormal, leaky blood

vessels

• Anti-VEGF– Lucentis, Avastin, Eylea– Blocks VEFG molecule therefore stops leakage

from the blood vessels

Judah Folkman MD

• Prof of Paediatric Surgery at Harvard• 17 Honorary degrees• His lab discovered angiogenesis molecules that

stimulate blood vessel formation to allow tumour growth

• Anti-angiogenesis drugs inhibit tumour growth• AntiVEGF treatment has developed from his

studies

Landmark Marina and Anchor studies

• Lucentis injected every month for 2 years• Average improvement of vision 10 letters• Maintained vision in most patients• If frequency of injections less than every

month reduced effect noted• Most UK practice is now 3 loading injection

over 3 months then as needed injections

Source: HORIZON data. Genentech.

Treated-Initial (n=388) Untreated (n=33)

ETD

RS

Lett

ers

-20

-15

-10

-5

0

5

10

15

3 6 9 12 15 18 21 24

HORIZON StudyHORIZON Study

+5.1

-6.7

+2.0

-6.9

24

MonthInitial baseline

Marina/Anchor StudiesMarina/Anchor Studies+10.2

-3.2

Average number of injections and costs

• 8 injections in the first year• 6 injections in the second year• Each injection costs £1,750 to the NHS

– £750 for Lucentis• The first 2 years cost the NHS £24,000• Average life expectancy from diagnosis

– 10 years

Costs – Avastin vs. Lucentis

INJECTING

First nurse-delivered injections service in UK, 2008

• Peter Simcock, Brian Kingett, Nicola Mann• 7,000 injections to date

Problems with injections• Does not address fundamental cause of wet

AMD• Multiple injections for elderly patients• VEGF may be needed to help improve

circulation – Avoid if high risk of or recent stroke or heart

attack• Risk of injection itself

– Infection of eye (endophthalmitis) 1 in 1,000

How to reduce frequency of injections

• Radiation damages proliferating cells– Endothelial cells (forming the abnormal blood

vessels– Inflammatory cells (causing damage to tissue)– Fibroblasts (causing scar tissue formation)

• Internal beam – Merlot study

• External beam – Intrepid study

MERLOT – first “portfolio study” in WEEU, 2010

• Finished recruiting, results awaited• Vitrectomy + beta irradiation from strontium

source

Intrepid study

• Similar to MERLOT but external beam irradiation

• X rays delivered via contact lens• IRay system from Oraya theraputics Inc• Reduced injection rate by one third in study • Await “real world” results

Eylea

• Anti-VEGF treatment• Aflibercept• May be more powerful than Lucentis• Less frequent injection?• Good for patients that have responded poorly

to Lucentis

What about dry AMD?

• Main treatment remains low visual aids• Stem cell treatment• Neuro-protection• Intraocular telescopes

– VIP IOL– Implantable miniature telescope– ARGUS II (digital camera in glasses

communicates with retinal chip)

What about diet and AMD ?

• Eat fresh fruit, dark green leaved vegetables• Vitamins supplements only if severe

Vitamins and AMD• Antioxidant treatments to “mop up” free

radicals• AREDS (Age related eye disease study)

– Vit C 500mg, E 400IU, Beta carotene 15mg and zinc 80mg

– Decreased risk of progression of AMD with subgroup analysis only

• AREDS 2 study (ongoing)– Investigating the benefits of lutein, zeaxanthin and

omega 3 fatty acid supplementation

Other macular degenerations• Epiretinal membrane / Cellophane maculopathy

– Scar tissue on surface of macula– Surgical treatment with vitrectomy and peel

• Vitreomacular traction– Surgical treatment with vitrectomy– New medical treatment with Ocriplasmin (Jetrea)

• Macular holes– (Phaco)Vitrectomy with gas and limited posturing– ? Jetrea in small holes

Epiretinal membrane

Vitreomacular traction

Macular holes