Age Related Macular Degeneration

A Photo-Essay for Health Professionals-2003

 

John G. O'Shea MD, Robert B. Harvey FRCSE

•Age related macular degeneration (AMD) accounts for almost 50% of those registered as blind or partially sighted. The development of management strategies is limited by the diverse nature of the age related changes and a lack of a clear understanding of the process of visual loss in the elderly.
 
Macular degeneration affects central vision only, peripheral, navigational vision is universally retained unless other pathology is also present.

Terminology

•Degeneration is the change of a tissue to a less functionally active form.  Until recently the syndrome was referred to as Senile Macular Degeneration, a name given to the condition by  Haab as early as 1885, the terminological change reflecting contemporary sensibility regarding diseases in ageing populations.
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Age related macular degeneration has recently been comprehensively morphologically  classified by Professor AC Bird and his co-workers who formed the  International ARM Epidemiological Study Group.The disorder is either  referred to as age related maculopathy (ARM) or  age related macular degeneration (AMD)

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Prevalence in UK about 1.64% of Population (Melton Mowbury )--•50,000 people may have end stage ARMD

Age Related Maculopathy

 

•The International Epidemiological Study Group defines Age Related Maculopathy (ARM) as a disorder of the macular area, most often clinically apparent after 50 years of age, characterised by:
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Discrete whitish-yellow spots identified as drusen.

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Increased pigment or hyperpigmentation associated with drusen.

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Sharply demarcated areas of depigmentation or hypopigmentation of the retinal pigment epithelium and associated drusen.

Common manifestations of macular degeneration

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The key lesion of ARM is the druse (pleural drusen) an aggregation of hyaline material located between Bruch’s membrane and  the  RPE.  It is associated with atrophy and depigmentation of the overlying RPE. Certain types of drusen are  associated  with sight threatening pathology.  Small,  hard drusen are referred to simply as drusen, soft drusen over 63 microns in diameter are statistically associated with visual pathology and are termed early ARM.
•Non Exudative Macular Degeneration Dry or non exudative ARM is due to a slow and progressive degeneration of the photoreceptors  and the RPE with  gradual failure of central vision. 
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•Geographic atrophy consists of one or more areas of RPE hypopigmentation with clearly visible choroidal vessels.  It  is the  severest  form of  the non exudative ARM representing a zone of  RPE atrophy 175 microns or greater in diameter with exposure of the underlying choroidal vessels.
•Exudative Macular Degeneration This type of macular degeneration  may have rapid and devastating effects upon vision. By contrast with patients with  non -exudative retinal degeneration in whom impairment of vision is gradual, central vision may be lost over the course of a few days. 
        The pathology of neovascular AMD is choroidal neovascularisation with the formation of a subretinal neovascular membrane. (SRNVM) The SRNVM lead to haemorrhage and disciform scarring. PEDs also form a part of the description.
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The Macula

•The macula subserves high resolution central and colour vision. It is horizontally oval, 5mm in diameter. The foveola forms the central floor. It has a diameter of 0.35mm. It is the thinnest part of the retina. Its entire thickness consists only of cone photoreceptors and it subserves the most acute vision.
•The retinal pigment epithelium (RPE) is a single layer of hexagonally shaped cells  They reach out to the photoreceptor layer  of the inner retina.  Bruch's membrane separates the RPE from the vascular choroid. 
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•Ultrastructurally  it is composed of five elements  and througout life can accumulate  metabolic debris related to the build up of lipofuscin  from the RPE. The functions of the RPE include the maintenance of the photoreceptors, absorbtion of stray light, formation of the outer blood retinal barrier, phagocytosis and regeneration of visual pigment.
 
•The macula has the highest concentration of photoreceptors  and is the the area where the RPE is most metabolically active and as a consequence most likely  to suffer the consequence of enzymatic failure over time with the accumulation of metabolic debris and lipofuscin .

Demonstrated above is the location of the macula in relation to other ocular structures.  In the photograph the pointer indicates the centre of the macula and  demonstrates its relationship to  the retinal blood vesels and the optic disc.

Epidemiological Overview of Macular Degeneration

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Major epidemiological studies have centred on  preventive aspects of the condition.  These studies indicate, however, that the condition may not be as responsive to lifestyle modification as are other diseases of the elderly,  for example, as is ischaemic heart disease,   it is imperative that however that  any relationship between AMD and treatable or  preventable pathology be fully explored

 

•The first major epidemiologic study was the Framingham Eye Study ( FES ).  

 The Framingham study , it will be recalled, had investigated a study  population in the town of  Framingham Massachusetts for the risk factors of coronary artery disease  since  1948. In the Eye Study  (1977)  2675 of the 3977 still living members of the initial study were given an eye examination.

•This study  showed that a prevalence of AMD of 11%  for those aged 65-74 years and 28% for those aged 75-85 years . A total prevalence in the population aged between 52-85 of 8.8% was recorded.  By contrast, the prevalence of age  related cataract was 15.5 %  and that of open angle glaucoma 3.3%. Other studies also show the disease to be extremely comon in the elderly. 
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Blue Mountains Eye Study  

Published in 1995, this study provided an accurate estimate for the age specific prevalence of  ARM.  

End stage macular degeneration was present in 1.9% of the elderly  population studied and was bilateral in 56% of this group. It was more frequently of the neovascular type ( ratio neovascular: atrophic 2:1)

 

•ARM rose in prevalence from 0% among people younger than 55 years to 18.5%  among those 85 years or older. Soft drusen were found in 13.3% of the surveyed population and retinal pigment abnormalities in 12.6%. 
•The sex ratio was 1.34 indicating a marked female preponderance.

Risk factors

•Smoking
•The Beaver Dam Study disclosed a relationship between the development of exudative lesions and  a history of current  cigarette smoking.The relative odds for exudative macular degeneration , in females  was 2.5 times increased risk  (95% confidence interval 1.01-6.20)  compared with those who are ex smokers or never smokers. For males it was 3.2  ( 95% confidence interval 1.03- 10.50)
•The Eye Case Control  Group also  found  smoking increases the risk of the exudative type of AMD 2.8 times in those who are current smokers.   Smoking cessation  lowers the  relative  risk of  AMD
 

•Nutrition

Several studies have described the beneficial effects of dietary carotenoids in  slowing the course of the disease.Vitamin A, C or  E  supplimenters  had  no demonstrable reduced risk of developing  AMD. Dietary  zinc supplements did not have any  beneficial effect and the use of  dietary  vitamin supplements was  identified as a strategy likely to prevent AMD in  a recent study.   

The current recommendation is for a balanced diet and for  the consumption of foods rich in dietary carotenoids, namely spinach and  collard greens.

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Exogenous Post Menopausal Oestrogen

•The use of exogenous supplements in post menopausal women lowered risk of AMD in a study  performed  by  the  Eye Case Control Study Group.  
 
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Genotype and  Ethnic Origin

Studies in siblings and probands support the belief that genetic factors influence age related changes in Bruch’s membrane more than do environmental factors

 

•Light

•The Blue Mountains Eye Study  disclosed no relationship between light and ARM.
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Unilateral AMD

With AMD-related visual loss affecting one eye the risk of losing vision in the fellow eye increases to between 7 and 10% annually.

 

•The five year risk is lowest in the absence of large drusen or pigment hyperplasia but increases with one of these risk factors to 30% or with both to over 50%.

•The highest risk is for those with a pigment epithelial tear in one eye for whom the annual risk of second eye involvement is closer to 40%.

Clinical Characteristics

 

•Age related macular degeneration has recently been comprehensively morphologically classified by Professor AC Bird and his co-workers who formed the  International ARM Epidemiological Study Group

The disorder is either  referred to as age related maculopathy (ARM) or  age related macular degeneration (AMD) if more severe in extent.

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 Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, de Jong PTVM, Klaver CCW, Klein R, Mitchell P, Sarks SH, Soubrane G ,Taylor HR , Vingerling JR ,  An International Classification and Grading System for Age-Related Maculopathy and Age Related Macular Degeneration Special Article, Survey of Ophthalmology (1995 ) ; 39 :367-374
 

Drusen and Age Related Maculopathy

•The key lesion of ARM is the druse (pleural drusen) most people over the age of 40 years have at least one druse.  The druse is an aggregation of hyaline material located between Bruch’s membrane and  the  RPE.  It is associated with atrophy and depigmentation of the overlying RPE. Certain types of drusen are  associated  with sight threatening pathology. Small,  hard drusen are referred to simply as drusen, soft drusen over 63 microns in diameter are statistically associated with visual pathology and are termed early ARM.
• Hyper or hypopigmentation of the RPE also constitutes part of the description of ARM.

 

The photographic sequence below illustrates the relationship between drusen  and macular degeneration.

 

Hard Drusen are very common. They are discrete, small and do not have any  relationship wth AMD

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Confluent drusen are associated with neovascular membranes

The right eye has soft drusen. The left eye  has a disciform scar due to neovascular AMD.

Age Related Macular Degeneration

Non Exudative ( Dry / Atrophic )  Macular Degeneration

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Dry or non exudative ARM is due to a slow and progressive degeneration of the photoreceptors  and the RPE with  gradual failure of central vision. It is also known as atrophic ARM. RPE changes, as manifested  by hypo or hyperpigmentation may be present. There may be thinning of the overlying retina.

•Geographic atrophy consists of one or more areas of RPE hypopigmentation with clearly visible choroidal vessels.  It  is the  severest  form of  the non exudative ARM representing a zone of  RPE atrophy 175 microns or greater in diameter with exposure of the underlying choroidal vessels.
•As yet, there is still no proven effective therapy for the non-neovascular form of AMD.

Exudative Macular Degeneration ( Wet or Neovascular AMD )

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The pathology of neovascular AMD is choroidal neovascularisation with the formation of a subretinal neovascular membrane. (CNV or SRNVM) The SRNVM lead to haemorrhage and disciform scarring.

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•Age related Bruch’s membrane change may be especially  important in exudative macular degeneration, this change includes thickening  of Bruch’s membrane, drusen and other metabolic accuminata such as lipids and loss of basal connections with the RPE.
•Pigment epithelial detachment may occur in relation to Bruch’s membrane change.
•Sub-retinal neovascularisation can occur throughout the fundus but rarely gives rise to complications save in the macular area where it is associated with visual loss. Angiographically well defined neovascular systems lying away from fixation may on occasions be modified by treatment. If untreated, visual loss may be rapid with neovascular extension under fixation in 75% of cases within a year such that 60% develop severe visual loss within 3 years.
• Less well defined neovascularisation is considered untreatable and grows more slowly, but still 40% develop severe visual loss within 2 years.
•Juxta papillary lesions tend to extend towards the macula but do not invariably cause visual loss as they grow more slowly and may involute spontaneously.
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Pigment epithelial detachment

 

•Pigment epithelial detachment in patients under the age of 55 years is not usually associated with significant visual loss but occurring in those over 55 is likely to result in visual loss within 4 years in the majority of patients.

 

• Such loss may reflect the presence of neovascularisation under the detachment.
 
•Pigment epithelial detachments do not usually benefit from laser treatment.

 

• Treatment is frequently complicated by rapid visual loss associated with a pigment epithelial tear or rapid progression of an unrecognised neovascular response.
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Overview of Investigation and Therapy of AMD

 

•General practitioners and optometrists need to be aware of the urgent nature of referrals for patients with recent onset of distortion and visual loss (less than a month) and who still have reasonably good vision (6/12 or better).

 

•Such patients may still have treatable disease and should be referred urgently to either the ophthalmic casualty department or to the outpatient clinic following discussion with the local ophthalmologist. This is particularly true for the second eye when the other eye is already involved.

 

•In the elderly population with AMD concurrent ophthalmic disease, such as cataract and glaucoma, may also frequently occur and needs to be identified and treated appropriately.

 

•Good control of hypertension may favourably influence the surgical treatment of neovascular membranes.
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The value of routine screening, given the lack of effective treatment, is unproven.

 

There may be a case for self assessment, using an Amsler Grid, in those patients with high risk of neovascular disease which includes those with large soft drusen and pigment hyperplasia and those with established exudative AMD in one eye.

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•Mild low risk disease (ARM) requires no special management and, coming on slowly, can be managed in the community. Optometrists would seem to be well placed to carry out routine examinations and offer advice about the value of magnification and lighting.

Optometrists can reassure patients with minimal symptoms or signs of ARM and should not refer further. Referral from the primary sector usually occurs when visual impairment begins to interfere with normal lifestyle.

•Management includes:

Diagnosis and assessment of macular disease including angiography and exclusion of other treatable causes of visual failure.

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Treatment by laser photocoagulation/ PDT or otherwise as appropriate.  Prophylactic Laser studies are also being undertaken.

 

•Rehabilitation including:

•a) provision of suitable optical aids in the primary or secondary sector and training in their use.
•b) Completion when appropriate of the form BD8 (BP1 in Scotland, A 655 in Northern Ireland) and referral to Social Services (Appendix 2).
 
•c) Counselling and rehabilitation within the hospital and statutory or voluntary services in the community.
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Rehabilitation

Provision of low vision aids.

•Visual handicap registration.
•Training and coping strategies.
•Explaining the management of AMD requires patience and sympathy. Patients with AMD greatly benefit from continuing support and information about their condition and all patients losing vision need hope and encouragement.
Statutory and voluntary support services in the community.
 

The BD8 Form ( United Kingdom 1948 National Assistance Act ) 

•Definitions: 

Blindness- ‘cannot do any work for which eyesight is essential.’

•Partial Sight- ‘substantially and permanently handicapped by defective vision.’
•( The  WHO definition of blindness is vision less than 3/60 in the better eye with best available spectacle correction )

Flourescein Angiographic Characteristics of Neovascular Membranes

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Angiography should be available with a minimum of delay particularly given the rapid growth potential of any neovascular lesion. As the angiographic features may progress rapidly, laser treatment should be undertaken within 48 hours of the latest angiogram if at all possible. Stereoscopic angiography is preferable.

•Indocyanine angiography has a role in the assessment of vascular systems under the pigment epithelium which may be ill defined on fluorescein angiograph, and in the assessment of the particular condition of polypoidal choroidopathy. How far it results in benefit in terms of management remains controversial.

Colour/ Red Free photography is routinely undertaken with angiography. It helps to determine the nature of changes seen of the angiogram particularly in defining exudative change and the cause of blocked fluorescence due to haemorrhage, pigment or other cause. Drusen are sometimes much more visible on angiography than colour photography and vice versa.

 

Membrane Terminology

 

•Classic – Early leakage from edge of membrane, lacy pattern. Ealy transit phase- some late leakage

•Occult type 1, probably fibrovascular PED, shows stippling, leakage at end of transit phase.
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Occult type 2- Undetermined late leakage

 

 

 

•The location and angiographic characteristics of neovascular systems are used in determining the approach to management. Away from the macula they are described as peripheral or juxtapapillary. In the macula, but lying more than 200 microns from fixation, they are defined as extrafoveal. They are juxtafoveal or subfoveal when immediately adjacent to, or under, the foveola. Neovascular systems with well defined leakage seen on fluorescein angiography are described as classical and those with ill defined leakage are considered occult. Some complexes are mixed with both classical and occult components.

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Treatment of• Choroidal Neovascularisation

•Choroidal neovascularisation is a major cause of visual loss in AMD and one that, when well defined, may be amenable to treatment.

Effective treatment protocols for laser photocoagulation have been published.

 

•Pending the confirmed results of the current prospective treatment trials of radiation and photodynamic therapy (PDT), and their approval for use if appropriate, the mainstay of interventional treatment is that of laser photocoagulation
 

 

Laser photocoagulation-Macular Photocoagulation ( MPS ) Study

 

•In 1982 three studies showed treatment benefit from argon laser photocoagulation when a well defined neovascular complex lay outside 200 microns from fixation.

This is most likely to be the case when the visual acuity is still good (6/12 or better) and the duration of symptoms short (less than a month).

•Such situations are, however, rare and occur in only 5-10% of those seen.
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Despite the initial hopes of treatment it is now recognised that continued growth of the membrane and recurrent disease are major limiting factors for success and occur in about 50% within 5 years after initial successful treatment.

•The recommended treatment protocol usually involves:
•Heavy confluent laser photocoagulation (514nm or 577nm) covering the whole of the angiographic lesion and a margin of 100 microns around it.
•Laser power setting and duration to achieve an intense white coagulum.
•A planned sequence of burns around and onto the lesion avoiding other structures.
•Location of the initial burns to minimise the risk of movement causing an exclamation mark burn up to fixation .
•Macular Photocoagulation Study Group. Laser photocoagulation for juxtafoveal choroidal neovascularization. Five year results from randomized clinical trials. Arch Ophthalmol 1994; 112:500-9.

Photodynamic Therapy

Verteporfin, a photosensitizer or light-activated drug, was approved patients with predominantly classic subfoveal CNV caused by AMD following  the recent publication of the Treatment of Age-related Macular Degeneration (TAP) report and Verteporfin in Photodynamic Therapy (VIP) trials.

•Photodynamic therapy (PDT) is a combination drug and device treatment process, which involves verteporfin, or another photosensitizer, and a laser source.

• This activation of the drug creates free radical formation, which causes cellular damage and eventually results in thrombosis of the vessels and slowing of the progression of CNV.

•A phase 1 and 2 investigation showed that a single treatment of PDT with verteporfin could stop fluorescein leakage from CNV for 1-4 weeks in patients with classic subfoveal CNV

•PDT for AMD is a two stage process comprising a 10 minute intravenous infusion of 6mg/kg verteporfin followed by activation 5 minutes later by 689nm diode laser for 83 seconds at 50J/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

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•Two 24-month randomized, double-masked, placebo-controlled Phase III trials known as the TAP (Treatment of AMD with Photodynamic therapy) Investigation were published in the October 1999 issue of Archives of Ophthalmology.

•Photodynamic therapy with verteporfin achieved short-term cessation of fluorescein leakage from CNV without loss of vision or growth of classic CNV in some patients with age-related macular degeneration. Except for nonperfusion of neurosensory retinal vessels at a light dose of 150 J/cm, no other adverse events were of concern.

•The primary finding of these trials showed that in 243 patients with predominantly classic CNV, vision remained stable or improved in 67% of patients treated with Visudyne therapy compared to 39% of patients on placebo (p is less than 0.001).

TAP Study Group. Photodynamic Therapy of subfoveal choroidal neovascularisation in age-related macular degeneration with verteporfin. One year results of 2 randomized clinical trials. TAP report 1. Arch. Ophathmol., 1999;117

 

Summary

• The leading cause of blindness and partial sightedness registrations in the UK is now  AMD.
• Despite this, with ancillary help,  many of the sufferers of AMD manage to live independent and fulfilling lives.

Macular degeneration affects central vision only, peripheral, navigational vision is universally retained.

•Treatment remains supportive for most patients with macular degeneration although a minority will  benefit from macular laser photocoagulation.
 
•Photodynamic therapy ( PDT ) may offer new therapeutic possibilities for those with subretinal membranes who have not yet lost their central vision. 

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Links

 

The Macular Disease Society
The Macular Disease Society
Darwin House
13a Bridge Street
Andover
Hampshire SP10 1BE

The Macular Disease Society is a self-help society for those suffering from any of the eye conditions encompassed by the overall name of Macular Disease.

The Society is dedicated to providing information and practical support so that those with the condition may make the most of their remaining vision.

Telephone

0800 - 328 - 2849 (within the UK - free phone)
+ 44 - 800 - 328 - 2849 (outside the UK)     

 

Contact Us

Author : John G. O'Shea MD

  Illustrations: Robert Harvey FRCSEd (from Practical Ophthalmology,  2002 Palmtrees Publishing)

 

     Rob Harvey

      E-mail Address  :  rob_harvey@msn.com

    

    

Correspondence to-

Birmingham and Midland Eye Centre, Dudley Rd,  Birmingham B18 7QH,  U.K.

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