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.

Ref: BMJ 2003; 326: 485-8

One major implication of this demographic change is the emergence of conditions that are directly related to ageing.

Ref: BMJ 2003; 326: 485-8

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.

Ref: Surveys of ophthalmology 32 (6) 1988: 375-413

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

Ref: BMJ 2003; 326: 485-8

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

1. Invest Ophthalmology vis. Sci 2001; 42: 2237-412. Am J. Epidemiology 1977; 106: 133

3. Ophthalmology 1992; 99; 933-434. Ophthalmology 1995; 102: 1450-60

5. Ophthalmology 1995; 102: 205-10

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%

1. Invest Ophthalmol Vis Sci (abstract) 2000; 41; 5119

2. Ind. J Ophthalmol 1984; 32: 343-6

HOW DOES NORMALVISION OCCURS

NORMAL MACULA

Ref: http://www/ahaf.org

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

NEJM; 342(7): 2000; 483-492

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 retinaFunctions of RPE includes maintainance of the photoreceptors, absorption of stray light, formation of the outer blood retinal barrier, phagocytosis and regeneration of visual pigmentBruch’s membrane separates the RPE from vascular choroid,

Function of Bruch’s membrane is to provide support to the retinaChoroid capillaries are a layer of fine blood vessels that nourishes the retina and provides O2

Ref: http://www.ahaf.orghttp://www.eyesight.org

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

Photoreceptor sit on a layer of RPE

Contain pigment called RhodopsinOpsin->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 understoodFlawed 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

BMJ 326, 2003; 485-488

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

AGE RELATED MACULAR DEGENERATION TYPES

Dry macular degeneration

Wet macular degeneration

Ref: NEJM, Vol. 342 (7): 483-492

DRY MACULAR DEGENERATION

1. Accounts for about 90% of all cases2. Also called atrophic, non exudative or

drusenoid macular degeneration

DRY MACULAR DEGENERATION

DrusenDrusen is an aggregation of hyaline material located between Bruch’s membrane and RPEDrusen are composed of waste products from photoreceptorsDrusen > 63 microns in diameter are statistically associated with visual pathology and are termed early ARMDHypo/hyper pigmentation of RPE may be present

NEJM, Vol 342 (7): 483-492

DRY MACULAR DEGENERATION: VISUAL

WET MACULAR DEGENERATION

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

http://www.blindness.org

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 vesselsLeakage of blood or serum as a result of choroidal neovascularization may occur precipitously and is often associated with the abrupt loss of visionPatients with CNV have a rapid decline in vision (20/200) within weeksMore frequently, visual acuity deteriorates more slowly and stabilises within 3 yearsOnce 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 symptomsBlurry visionDistorted visionStraight lines appear wavyObjects may appear as the wrong shape or sizeA dark empty area in the centre of vision

http://www.kellogg.umich.edu/

AMD: SYMPTOMS VISUAL

Macular_Update[1].swf

AMD: SYMPTOMS

Patient’s ability to perform normal daily tasks such as reading, sewing, telling the time, driving are greatly impaired.

http://www.medscape.com

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

NEJM; Vol. 342 (7): 2000: 483-492

AMD: DIAGNOSIS

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

Ref: http://www.visionchannel.net

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 centres11

No. of people4767 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 AMDCategory 3: intermediate AMDCategory 4: advanced AMD in one eye

Category 2, 3 and 4 randomized to receive: 1. Placebo2. Antioxidants alone3. Zinc alone4. 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

WET AMD: MANAGEMENT

Laser photocoagulation

Photodynamic therapy

LASER PHOTOCOAGULATION

Intravenous fluoroscein angiography is performedWell-circumscribed new blood vessels identified on the fluoroscein angiogramTreated with laser photo coagulation after topical or local anaesthesia

The Principle of Photodynamic therapy

In contrast with the conventional hot laserPDT helps to selectively close off subretinal new

vesselstwo 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 minutesCytotoxic reactive oxygen intermediates damage cellular proteins and cause microvascular thrombosis

PHOTODYNAMIC THERAPY (contd.)

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

Copy of PhotodynamicTherapyFinal[1].swf

INVESTIGATIONAL TREATMENTS

Submacular surgeryRetinal transplantation and transplantation of RPERetinal translocationGene therapyAngiogenesis inhibitors: like cytochalasin E, Anecortave acetate, Prinomastat

TIPS FOR ARMD PATIENTS

Monitor your vision daily with an Amsler gridTake a multi-vitamin with zincIncorporate dark leafy green vegetables into your dietAlways protect your eyes with sunglasses that have UV protectionQuit smokingExercise regularly

Thank you