AGE RELATED MACULAR DEGENERATION

An epidemic of “ageing” is impending in the Western world 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

Photoreceptor sit on a layer of RPE Contain pigment called Rhodopsin 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 Accounts for about 90% of all cases 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 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 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: Placebo Antioxidants alone Zinc alone 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

Laser photocoagulation Photodynamic therapy 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 Age-related 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

Monitor your vision daily with an Amsler grid 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!!