1. AGE RELATED MACULAR DEGENERATION

2. 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 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.

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

4. 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.

5. 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)

6. AGE RELATED MACULAR DEGENERATION
The UN estimates the number of people with age related macular degeneration at 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

7. 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

8. 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%

9. HOW DOES NORMALVISION OCCURS

10. NORMAL MACULA

11. 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

12. MACULA: CROSS SECTION
Ref:

13. 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

14. 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

15. 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

16. WHAT GOES WRONG IN AMD?

17. 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

18. 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

20. 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

22. AGE RELATED MACULAR DEGENERATION TYPES
Dry macular degeneration
Wet macular degeneration

23. DRY MACULAR DEGENERATION
Accounts for about 90% of all cases
Also called atrophic, non exudative or drusenoid macular degeneration

24. 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

25. DRY MACULAR DEGENERATION: VISUAL

26. 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

27. WET MACULAR DEGENERATION: VISUAL

28. 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)

29. 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);

31. 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

32. AMD: SYMPTOMS VISUAL

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

35. AMD: EFFECT ON QUALITY OF LIFE

36. 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

37. 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!!!!)

38. 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

40. AMD: MANAGEMENT

41. DRY AMD: MANAGEMENT
Low vision aids
Antioxidants

42. 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 years

43. 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

44. 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

45. 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

46. Laser photocoagulation Photodynamic therapy
WET AMD: MANAGEMENT
Laser photocoagulation
Photodynamic therapy

47. 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

49. 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

50. 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

51. 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

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

54. 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

55. 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 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

56. 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

57. 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

58. 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

59. 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

60. Questions??
Thank you!!