AGE RELATED MACULAR
DEGENERATION
AGE RELATED MACULAR DEGENERATION
Age related macular degeneration (ARMD) is
the leading cause of severe visual loss in
the western world in people over 50 years
of age.
Ref: Surveys of ophthalmology 32 (6) 1988: 375-
413
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 to cataract as the cause
of severe visual loss
Ref: BMJ 2003; 326: 485-8
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
NEJM; 342(7): 2000; 483-492
Macula
The fovea – depression at
centre of macula with
diameter 1.5mm. Give rise
to oval light reflex
( thickness of retina and
internal limiting membrane
at its border)
The foveola – central floor of
fovea wf diameter 0.35mm.
Thinnest part-only consists
of cones and the nuclei.
The umbo – tiny depression
at very centre of foveola –
light reflex
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
Ref: http://www.ahaf.org
http://www.eyesight.org
Risk factor
Risk Factors
Genetic
Race
Gender
Age
Hypertension/Diabetes
Refractive error
Lens opacities
Sun exposure
Smoking
Risk Factors
Genetic
– Studies have demonstrated familial aggregation.
– ABCR gene (linked to Stargardt’s disease) has been
linked to some cases of AMD.
– Complement factor H Gene
• Proteins in CFH pathway found in drusen
deposits
• Two- to four fold increased risk if gene variant is
inherited from one parent
• Five- to seven fold increased risk from 2 parents
Risk Factors
Race
– NHANES III reported a higher frequency in whites compared with
blacks.
– In Baltimore Eye Survey AMD accounted for 30% of blindness
among whites and 0% of blindness among blacks.
Gender
– In the Beaver Dam study, only wet AMD was shown to be more
frequent in women.
Age
AMD Is Directly Related To Age
30%
16%
12%
55 to 64 65 to 74 Over 75
Incidence of AMD Increases With Age
1 Beaver Dam Study
Source: Yanoff: Ophthalmology, First Edition, 1999; Clinical Practice Guidelines, www.aoanet.org; www.allaboutvision.com
Risk Factors
Hypertension
– Role remains unclear
– Beaver Dam reported that systolic BP was associated with
incidence of RPE depigmentation.
– Macular Photocoagulation Study reported an increased
incidence of wet AMD associated with hypertension
Diabetes
– Beaver Dam showed no relation, however, literature on the
matter is otherwise scant.
Ocular Risk Factors
Refractive error
– Increased risk with hyperopia
Lens opacities
– Beaver Dam revealed nuclear sclerosis associated with
increased risk of early AMD but not late stages of the
disease.
– FES found no relationship.
Aphakia
– In studies of unilateral aphakia, surgical eye had more
advanced disease when compared to contralateral eye.
Environmental Risk Factors
Sun exposure – controversial risk factor
– Watermen study revealed a weak association between
advanced AMD and exposure to visible light.
– UV light did not seem to be related in the Beaver Dam,
Watermen and Blue Mountain studies.
Environmental Risk Factors
Smoking
– Strong positive association between smoking and
the dry and wet form.
– In the Nurses’ Health Study risk increased as pack
years of smoking increased indicating a dose
dependent relationship.
WHAT GOES WRONG IN ARMD?
AGE RELATED MACULAR DEGENERATION
TYPES
Dry macular degeneration
Wet macular degeneration
Ref: NEJM, Vol. 342 (7): 483-492
ARMD : Etiology
Etiology is complex and poorly understood
Angiogenesis is likely to be an early feature of
neovascular ARMD
DRY MACULAR DEGENERATION
1. Accounts for about 90% of all cases
2. Also called atrophic, non exudative or
drusenoid macular degeneration
3. As yet, there is still no proven effective therapy
for the non-neovascular form of AMD
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
BMJ 326, 2003; 485-488
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
NEJM, Vol 342 (7): 483-492
DRY MACULAR DEGENERATION
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
http://www.blindness.org
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
BMJ 326; 2003: 485-488
Wet ARMD
Subretinal Fibrosis
WET MACULAR DEGENERATION
FFA IN WET ARMD
Classic CNV (30%)
– Well defined membrane which fluoresces brightly
and leaks into subretinal space within 1-2min
– Classified as :
• Extrafoveal : CNV is more than 200Um from the centre of
FAZ
• Juxtafoveal : CNV is closer than 200Um from the centre
of FAZ but dosen’t involve that
• Subfoveal : centre of FAZ is involve
FFA IN WET ARMD
Occult CNV
– Poorly defined less precise on early frame but gives
rise to late, diffused or multifocal leakage
Fibrovascular PED
– Combination of CNV and PED. The CNV fluoresces
brighter (hot spot) than detachment. In other case
CNV may be obscured by the blood or turbid fluid.
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
Patients with CNV have a rapid decline in vision
within weeks
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
http://www.kellogg.umich.edu/
AMD: SYMPTOMS VISUAL
AMD: EFFECT ON QUALITY OF LIFE
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
AREDS Recommendations
Supplement
– Intermediate AMD
– Advanced AMD
Excellent Safety
– Avoid beta carotene in
Intermediate Advanced
smokers
– Encourage adherence
Data on file, AREDS.
14 Super Foods
Blueberries Spinach
Sardine Turkey Breast
Citrus Broccoli
Pumpkin Walnuts
Yogurt Tomato
Oats
Legumes Green Tea
Soy
Daily sunlight and/or 1000 IU vitamin D daily
also is very important for general health
WET AMD: MANAGEMENT
Photodynamic therapy
Anti-angiogenic therapy
– Intravitreal steroid
– Anti-vascular endothelium growth factor (anti-VEGF)
Surgery
– Submacular surgery
– Macular translocation
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
Wormald R
The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews
2009 I
Objectives
The aim of this review was to examine the effects of PDT in the
treatment of neovascular AMD.
STUDY SIZE
1022 participants.
Authors' conclusions
Photodynamic therapy in people with choroidal neovascularisation due
to AMD is probably effective in preventing visual loss though there is
doubt about the size of the effect. Outcomes and potential adverse
effects of this treatment should be monitored closely. Further
independent trials of verteporfin are required to establish that the
effects seen in this study are consistent and to examine important
issues not yet addressed, particularly relating to quality of life and cost.
However, the advent of new interventions for AMD make this unlikely
1
Anti-angiogenic therapy
Intravitreal steroid
– Triamcinolone mayb use alone or adjunct to PDT
– May improve retinal thickness and decrease vascular
exudation
ANTI-VEGF FACTORS IN ARMD
Intravitreal bevacizumab (Avastin) for age-related
macular degeneration: a critical analysis of literature
S Jyothi
Eye advance online publication 14 August 2009
PURPOSE: This study was undertaken to review the current literature on
bevacizumab for age-related macular degeneration and its value in
determining best clinical practice
Conclusions
There is sufficient scientific and statistical evidence to advocate the effective use of OCT-
guided administration of intravitreal bevacizumab for neovascular AMD. This is reflected in
our study outcome measures that are comparable to findings published from recent well-
conducted RCTs on intravitreal ranibizumab at the same time point.
5
S Sacu
Eye advance online publication, 23 January
2009
Purpose:To compare 1-year functional and anatomic outcomes of intravitreal
bevacizumab (IVB) & photodynamic therapy +intravitreal triamcinolone
(PDT+IVTA) combination in patients with neovascular age-related macular
degeneration (AMD).
STUDY SIZE
28 patients.
Conclusions:Patients treated with IVB showed a significant better VA outcome
compared with the PDT+IVTA group despite the fact that both modalities showed
equal potency in reducing CRT during a 12-month period.
14
INVESTIGATIONAL TREATMENTS
Submacular surgery
Retinal transplantation and transplantation of
RPE
Retinal translocation
Gene therapy
Angiogenesis inhibitors: like cytochalasin E,
Anecortave acetate, Prinomastat
SUBMACULAR SURGERY
The technique for CNV removal
After complete pars plana
vitrectomy
CNVM is removed from subretinal
space by making retinotomy
temporal to fovea & inducing
localized retinal detachment.
Fluid-air exchange is performed at
the end of surgery and gas
tamponade is given.
TIPS FOR ARMD PATIENTS
Monitor vision monthly 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
Thank you
