AGE RELATED MACULAR

DEGENERATION

An epidemic of ageing is impending in the

Western world. According to the latest
predictions released by the United Nations,
the number of people aged over 60 will triple
from 606 million worldwide in 2000 to nearly
2 billion by 2050. The increase in population
aged over 80 is expected to be more than five
fold, from 69 million in 2000 to 379 million by
2050.

One major implication of this demographic

change is the emergence of conditions that
are directly related to ageing.

AGE RELATED MACULAR DEGENERATION

Age related macular degeneration (AMD) is

the leading cause of severe visual loss in
the western world in people over 50 years
of age.

AMD: TERMINOLOGY
Degeneration is the change of a tissue to a less functionally
active form.
Referred as senile macular degeneration, a name given by
Haab as early as 1885,
Age Related macular degeneration has recently been named
by Professor A C Bird and coworkers who performed the
International ARM Epidemiological study group.
The disorder is either referred to age related maculopathy
(ARM) or age related macular degeneration (AMD)

AGE RELATED MACULAR DEGENERATION

The UN estimates the number of people with
age related macular degeneration at 20-25
million worldwide
WHOs estimate is 8 million people with
severe visual impairment
AMD was found to be second only to cataract
as the cause of severe visual loss

AMD: PREVALENCE
Prevalence of AMD varies from 1.2% to 29.3%
3 population based studies; the Beaver Dam Eye
Study, Blue Mountain Eye Study and the
Rotterdam study report the prevalence rates to be
1.7% in US, 1.4% in Australia and 1.2% in
Netherlands respectively

AMD: PREVALENCE IN INDIA

In South India, the prevalence is 1.1% whereas,
another study from North India reports the
prevalence rate to be 4.7%

HOW DOES NORMALVISION OCCURS

NORMAL MACULA

The macula is the posterior aspect of the retina

Has highest concentration of photoreceptors
which facilitate central vision and permit high
resolution visual acuity
The macula is an area up to 5.5 mm in diameter
with the fovea at its centre

MACULA: CROSS SECTION

Ref: http://www.eyesight.org

The retinal pigment epithelium (RPE) is a single layer of

hexagonally shaped cells. They reach out to the photoreceptor
layer of the retina
Functions of RPE includes maintainance of the photoreceptors,
absorption of stray light, formation of the outer blood retinal
barrier, phagocytosis and regeneration of visual pigment
Bruchs membrane separates the RPE from vascular choroid,
Function of Bruchs membrane is to provide support to the retina
Choroid capillaries are a layer of fine blood vessels that nourishes
the retina and provides O2

Vision in the retina depends on photoreceptor cells (rods and cones)

Photoreceptor sit on a layer of RPE
Contain pigment called Rhodopsin
Opsin->glycoprotein
Rhodopsin
Cis-retinal -> derivative of vit A
Cis-retinal in presence of light
Trans-retinal
Electric impulse destined for the brain is generated

Also, trans-retinal -> recycled to cis-retinal in

RPE.
This entire process requires oxygen and
nutrition supplied by the fine blood vessels
of the choriocapillaries

WHAT GOES WRONG IN AMD?

AMD : Etiology
Etiology is complex and poorly understood
Flawed transport between choroid vessels and
photoreceptors may be involved
Angiogenesis is likely to be an early feature of
neovascular ARMD

AGE RELATED MACULAR DEGENERATION

Insufficient oxygen and nutrients

damages photoreceptor molecules
With ageing, the ability of RPE cells to digest these molecules decreases
Excessive accumulation of residual bodies (drusen)
RPE membrane and cells degenerate and atrophy sets in and central vision
is lost

AGE RELATED MACULAR DEGENERATION

Alternatively the photoreceptors and pigment epithelium send a distress signal to
choriocapillaries to make new vessels
New vessels grow behind the macula
Breakdown in the Bruchs membrane
Blood vessels are fragile
Leak blood and fluid
Scarring of macula
Potential for rapid severe damage

AGE RELATED MACULAR DEGENERATION

TYPES
Dry macular degeneration
Wet macular degeneration

DRY MACULAR DEGENERATION

1. Accounts for about 90% of all cases
2. Also called atrophic, non exudative or
drusenoid macular degeneration

DRY MACULAR DEGENERATION

Drusen
Drusen is an aggregation of hyaline material located
between Bruchs membrane and RPE
Drusen are composed of waste products from
photoreceptors
Drusen > 63 microns in diameter are statistically
associated with visual pathology and are termed early
ARMD
Hypo/hyper pigmentation of RPE may be present

DRY MACULAR DEGENERATION: VISUAL

WET MACULAR DEGENERATION

Accounts for about 10%
Also called choroidal neovascularization, subretinal
neovascularization or disciform degeneration
Abnormal blood vessels grow beneath the macula
These vessels leak blood and fluid into the macula
damaging photo receptors
Progresses rapidly and can cause severe damage to
central vision

WET MACULAR DEGENERATION: VISUAL

AMD: COURSE AND VISUAL PROGNOSIS

Patients with only drusen (in one or both eyes)
typically do not have much loss of vision, but they
make require additional magnification of the text
and more intense lighting to read small point
Presence of large drusen (> 63 microns in diameter)
is associated with a risk of the late form of the
disease
Patients with large drusen are at relatively high risk
for choroidal neovascularization (CNV)

AMD: COURSE AND VISUAL PROGNOSIS

Geographic atrophy is the severest form of the dry macular degeneration
representing a zone of RPE atrophy 175 microns or greater in diameter
with exposure of the underlying choroidal vessels
Leakage of blood or serum as a result of choroidal neovascularization
may occur precipitously and is often associated with the abrupt loss of
vision
Patients with CNV have a rapid decline in vision (20/200) within weeks
More frequently, visual acuity deteriorates more slowly and stabilises
within 3 years
Once CNV has developed in one eye, the other eye is at relatively high
risk for the same change
NEJM; Vol. 342(7); 483-492

AMD: SYMPTOMS
Initial symptoms
Blurry vision
Distorted vision
Straight lines appear wavy
Objects may appear as the wrong shape or size
A dark empty area in the centre of vision

AMD: SYMPTOMS VISUAL

AMD: SYMPTOMS
Patients ability to perform normal daily tasks such
as reading, sewing, telling the time, driving are
greatly impaired.

AMD: EFFECT ON QUALITY OF LIFE

AMD: ESTABLISHED AND POSSIBLE RISK FACTORS

Established Risk Factors

Possible Risk Factors

Older age (> 60 years)

Female sex

Family history

Light-colored iris

Cigarette smoking

Cardiovascular disease

Low dietary intake or plasma

concentrations of anti-oxidant vitamins
and zinc

What are the Risk Factors for AMD?

There are currently 5 specific risk factors that are
strongly associated with the development of AMD:
1. Caucasian Ancestry
2. Genetic Component
3. Hypertension
4. Aging
5. Smoking
(SO QUIT NOW!!!!)

AMD: DIAGNOSIS
Visual acuity is tested using the standard eye chart. It measures
vision at various distances and can detect vision loss
Amsler grid test: Assesses distorted or reduced vision and small
irregularities in the central field of vision
Retinal examination: Done through slit lamp microscope
examination: to detect drusen, as well as neovascularization
Fluoroscein angiography: Determines the presence and location
of neovascularization

AMD: MANAGEMENT

DRY AMD: MANAGEMENT

Low vision aids

Antioxidants

AREDS STUDY
Aim
To evaluate the effect of anti-oxidant vitamins and zinc on
the progression of dry AMD. The study was initiated by
National Institutes of Health.
No. of centres
11
No. of people
4767 participants aged 55-80 years

AREDS STUDY (contd.)

Patients divided into 4 categories:

Category 1: little or no AMD -> randomized to antioxidants or placebo to determine any effect on lens changes
Category 2: early AMD
Category 3: intermediate AMD
Category 4: advanced AMD in one eye
Category 2, 3 and 4 randomized to receive:
1.
Placebo
2.
Antioxidants alone
3.
Zinc alone
4.
Antioxidants plus zinc (Vit. C: 500 mg, Vit. E: 400 IU, Betacarotene: 15 mg, Zn oxide: 80 mg, Copper:
2mg)
Category 2, 3, 4 were followed for visual loss for the development of advanced AMD
Patients followed up: 6.3 years

AREDS STUDY (contd.)

Results
For category 2, only 13% of patients progressed to advanced AMD.
For categories 3 and 4 (who are at greater risk for developing advanced AMD), it
was found that the combination of zinc and antioxidants were most effective in
reducing the progression to advanced AMD.
Conclusion
It was recommended that patients with intermediate or advanced AMD should
consider taking antioxidant vitamins and zinc

Preventative Approaches for AMD

The AREDS formulation should only be taken when
prescribed by a physician or a P.A.
AREDS is the treatment of choice for dry AMD
Eating fresh fruits and dark green, leafy vegetables
Maintaining a low fat & low cholesterol diet
Exercising regularly
Wearing sunglasses with UV protection
Avoiding exposure to second-hand smoke
Getting an eye exam regularly

WET AMD: MANAGEMENT

Laser photocoagulation
Photodynamic therapy

LASER PHOTOCOAGULATION

Intravenous fluoroscein angiography is

performed
Well-circumscribed new blood vessels identified
on the fluoroscein angiogram
Treated with laser photo coagulation after topical
or local anaesthesia

The Principle of Photodynamic therapy

In contrast with the conventional hot laser
PDT helps to selectively close off subretinal new
vessels
two stage treatment
Injecting the photosensitiser drug
Applying cold laser to activate the drug
Releases the singlet oxygen molecule that damages the
endothelium
Thrombosis of the capillaries

PHOTODYNAMIC THERAPY
PDT for AMD is a two stage process comprising a 10
minute intravenous infusion of 6 mg/kg verteporfin
followed by activation 5 minutes later by 689 nm diode
laser for 83 seconds at 503/cm2
The photosensitive verteporfin is selectively taken up by
rapidly proliferating endothelial cells within the target
CNV reaching its peak concentration at 15 minutes
Cytotoxic reactive oxygen intermediates damage cellular
proteins and cause microvascular thrombosis

PHOTODYNAMIC THERAPY (contd.)

The recent publication of the Treatment of Agerelated Macular Degeneration (TAP) report and
Verteporfin in Photodynamic Therapy (VIP) trials
For predominantly classic lesions the frequency
of stable/improved vision was: 12 months-67%
treated, 39% placebo

INVESTIGATIONAL TREATMENTS

Submacular surgery
Retinal transplantation and transplantation of
RPE
Retinal translocation
Gene therapy
Angiogenesis inhibitors: like cytochalasin E,
Anecortave acetate, Prinomastat

Current Treatments for AMD

Pegaptanib Sodium (MACUGEN)
Used to prevent further vision loss from wet AMD
Was first introduced in 2004
Was the first intravitreal injectable drug developed to treat wet AMD,
and requires monthly dosing
In the VISION (VEGF Inhibition Studies in Ocular
Neovascularization) clinical trials in 2003 and 2004, 70% of patients
treated with a small dose of Macugen (0.3mg) injected every 6 weeks
had < 15 letters of vision loss at the primary end point analysis,
compared to only 55% of the control group
Macugen has less adverse effects
and a better safety profile than either
laser photocoagulation or PDT

Current Treatments for AMD

Ranibizumab (LUCENTIS)
Approved by the FDA on June 30th, 2006
Intravitreal injection that requires monthly dosing
The only FDA-approved drug that not only drastically slows
vision loss due to AMD, but it also seems to actually restore
some visual acuity that has already been lost due to wet AMD
destruction
In the MARINA study in 2004-2005 researching Lucentis, out
of 716 patients enrolled, at 12 months 94.5% of the group given
0.3mg of Lucentis and 94.6% of those given 0.5mg lost < 15
letters, as compared with 62.2% of patients receiving the
control injections

Current Treatments for AMD

Mean increases in visual acuity were 6.5 letters in the 0.3mg
group and 7.2 letters in the 0.5mg group, as compared with a
decrease of 10.4 letters in the control injection group
Numbers seen in a similar study (ANCHOR) comparing
Lucentis against Verteporfin PDT were nearly identical to the
MARINA study, favoring Lucentis
Lucentis had no long-term effect on intraocular pressure, and
very few instances (<1%) of detached retina or uveitis were
reported
Endopthalmitis was also reported in <1% of the patients, but this
adverse effect was concluded to be caused by the injection
procedure alone

Investigational Treatments for AMD

Bevacizumab (AVASTIN)
Avastin was approved by the FDA in February 2004 for the treatment
of metastatic colorectal cancer in combination with chemotherapy
Incidentally, ranibizumab (Lucentis) is a chemically modified product
of bevacizumab (Avastin) that is affinity-matured to have a higher
affinity for VEGF, and it is made by the same laboratory, Genetech,
that also produces Avastin
After initial results in 2005
from clinical trials with Lucentis
became available, ophthalmologists
began using Avastin to treat AMD
because of its similar chemical
structure to Lucentis

Investigational Treatments for AMD

Avastin requires monthly intravitreal injections
Outcomes in patients treated thus far with Avastin
have been virtually identical to Lucentis, with no
serious ocular effects reported
It must be noted though that intravitreal treatment with
Avastin has not been proven effective and safe in
controlled clinical trials like Lucentis

TIPS FOR ARMD PATIENTS

Monitor your vision daily with an Amsler grid

Take a multi-vitamin with zinc
Incorporate dark leafy green vegetables into your
diet
Always protect your eyes with sunglasses that
have UV protection
Quit smoking
Exercise regularly

Questions??

Thank you!!