Download or age related macular degeneration (AMD)

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
WHO’s 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
Bruch’s membrane separates the RPE from vascular choroid,
Function of Bruch’s 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 Bruch’s 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 Bruch’s 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
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
Patient’s 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!!