Age related macular degeneration ( ARMD)

Dr. Amit Verma Deptt. Of ophthalmology

INTRODUCTION Age-related macular degeneration (AMD) is one of the most

common irreversible causes of severe loss of vision, including legal blindness, in the elderly population (usually over 60)

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.

The disorder is either referred to as age related maculopathy (ARM) or age related macular degeneration (AMD)

DEFINITION 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:

discrete whitish-yellow spots identified as drusen. increased pigment or hyperpigmentation

associated with drusen. sharply demarcated areas of depigmentation or

hypopigmentation of the retinal pigment epithelium and associated drusen.

PREVELANCE Age related macular degeneration (AMD) was

responsible for 8.7% of all blindness worldwide in 2007, and this figure is expected to double by 2020 as a result of population ageing.

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

Blue Mountains Eye Study (1995) provides 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

The most significant risk factor for AMD is age, but additional important risk factors have been identified. A positive family history, cigarette smoking and hypertension are risk factors that have been fairly consistently found as risk factors for the development of exudative AMD.

Additional risk factors include increased C-reactive protein, increased white blood cell count, increased intake of vegetable fat, mono- and polyunsaturated fatty acids, increased intake of linoleic acid, increased intake of fat , increased intake of baked goods , female gender, hyperopia and blue iris colour .

Black race ,increased intake of docosahexaenoic acid, higher intake of fish, nuts and dark green leafy vegetables, and higher levels of serum carotenoids have been associated with a lower risk.

Various associated risk factors for the development and progression of ARMD have been suggested, including:

● female sex ● positive smoking history ● positive family history ● hypertension ● raised cholesterol ● history of previous high exposure to ultraviolet light ● hypermetropia ● cataract surgery

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 .

Low antioxidants level The original AREDS study depicts beneficial effects of

high dose oral antioxidant vitamine A, C , Beta carotene and Zinc supplements in reducing progression of intermediate and advanced AMD in fellow eye by 25%.

Diet An increase risk was found in individuals taking diet high

in saturated fats and having high BMI.

Aspirin Beaver Dam study showed twice incidence of late AMD

in patients taking aspirin twice weekly for 10 years

GENETICS In the past several genes were identified that cause

diseases with clinical features that overlap with AMD (e.g.,

ABCA4,ELOVL4, FIBL-6, APOE, SOD2).

Recently,several independent research groups have identified a common variant (Y402H) of the complement factor H (CFH) gene that may explain about 50% of AMD cases. This observation is the first that shows a strong association of a single gene anomaly with the pathogenesis of AMD.

PATHOPHYSIOLOGY The pathophysiology of AMD is complex

and, in addition to genetic predispositions, at least four processes contribute to the disease, i.e

lipofuscinogenesis (with its linkage to oxidative stress),

drusogenesis, local inflammation neovascularization (in the case of wet form)

Most patients with dry, atrophic ARMD present with a gradual reduction in the central vision of both eyes, which affects their ability to read, to recognise faces, and to see clearly in the distance. Patients may notice mild distortion of their central vision (metamorphopsia) but characteristically retain a good peripheral visual field.

In the wet, exudative form of ARMD, patients present more acutely with a sudden change in their central vision (usually in one eye initially). They often experience marked central distortion (“straight lines have a bend in the middle”) or a precipitous fall in their vision.

TYPES OF AMD ARMD can be divided clinically into dry (atrophic) and wet

(exudative) forms.

Dry (atrophic, non-exudative) ARMD This is the common form of ARMD; about 85% of all ARMD is of this

type. It is characterised by widespread atrophic changes in the macular area and is bilateral. Dry ARMD usually progresses only slowly and with great variability and may result in severe visual impairment over five to ten years in some patients.

Wet (exudative, neovascular) ARMD Wet ARMD is a more aggressive disease and although only 15% of

all ARMD cases are of this type, the exudative form is responsible for 90% of all severe visual loss in ARMD. The clinical course of the disease is much more rapid than dry ARMD and 75% of patients will have a marked reduction in vision over about three years. The chance of second ey involvement in wet ARMD is very high.

DRY AMD Dry or atrophic macular degeneration accounts for 85% of AMD

cases and is equally common in males and females The earliest clinically detectable sign of dry ARMD is the

appearance of drusen in the macular region of both eyes. Drusen are tiny pinpoint, discrete yellow deposits, which

correspond histopathologically to focal accumulations of abnormal hyaline material located specifically at the interface of Bruch’s membrane and the retinal pigment epithelium(RPE).

Later atrophic changes occur in the macular area, causing a diffuse pale, mottled appearance. This appearance corresponds histopathologically to atrophy of the RPE and choroid, with some areas of secondary RPE hyperplasia.

In advanced geographical atrophy of the macula there is a large,well demarcated area of atrophy and it is possible to see clearly the underlying choroidal vessels.

Drusen, which may be transient, have been classified clinically as follows:

hard (hyaline) drusen: the typical discrete, yellowish lesions that are PAS-positive nodules composed of hyaline material between the RPE and Bruch membrane.

soft drusen: drusen with amorphous, poorly demarcated boundaries, usually >63 um in size; histologically, they represent cleavage of the RPE and basal laminar or linear deposits from the Bruch membrane.

basal laminar or cuticular drusen: diffuse, small, regular, and nodular deposits of drusenlike material in the macula.

calcific drusen: sharply demarcated, glistening, refractile lesions usually associated with RPE atrophy.

WET / EXUDATIVE AMD Wet or neovascular AMD is an alternative pathway of early AMD

progression where separation of the RPE and choroid layer alongside an increase in vascular endothelial growth factor (VEGF) stimulates angiogenesis of choroidal blood vessels into the retina beneath the macula.

Angiogenesis begins with vasodilatation and increases in vascular permeability, followed by activation and proliferation of vascular endothelial cells. Accompanying degradation of the surrounding extracellular matrix facilitates endothelial cell migration, which assemble to form cords and develop lumens. Further differentiation and remodelling to accommodate local requirements eventually forms a complex vasculature

As in dry ARMD, there are drusen and atrophic changes at the macula, but the distinctive signs of wet ARMD relate to the abnormal growth of new blood vessels and leakage of serous fluid and blood into the macula region.

Choroidal neovascularisation appears as a small, focal, pale pink-yellow or grey-green elevation at the macula. There may be associated exudation of serous fluid or blood in the subretinal or sub-RPE space.

Eyes with choroidal neovascularization (neovascular, wet, or exudative AMD) have fibrovascular tissue present between the inner and outer layers of the Bruch membrane,beneath the RPE, or in the subretinal space.

The new blood vessels leak fluid and may rupture easily. producing the exudative consequences of neovascular AMD, including macular edema, serous ret inal detachment, and sub retinal and intraretinal hemorrhages.

Wet ARMD is a more aggressive disease and although only 15% of all ARMD cases are of this type, the exudative form is responsible for 90% of all severe visual loss in ARMD. The clinical course of the disease is much more rapid than dry ARMD and 75% of patients will have a marked reduction in vision over about three years. The chance of second eye involvement in wet ARMD is very high.

AREDS CLASSIFICATION Age Related Eye Disease Study classified AMD as;

NO AMD (category 1) – included control groups with no or few small drusen <63 um diameter

EARLY AMD (category 2) –multiple small drusen,few intermediate drusen 63 to 124 um,or mild RPE abnormality

INTERMEDIATE AMD (category 3) – has any one of the following:

Numerous intermediate drusen At least one large drosen >125um Geographical atrophy: sharply demarcated,oval round area

of atrophy of RPE not involving center of fovea.

ADVANCED AMD (category 4) :one or more of following(in absence of other causes) in one eye

Geographical atrophy of RPE involving foveal center

Neovascular maculopathy that includes: - choroidal neovascularisation (CNV) -serous and/or hemorrhagic detachment of neurosensory retina/RPE -retinal hard exudates -subretinal/sub-RPE fibrovascular proliferation -disciform scar(subretinal fibrosis)

WET DISCIFORM AMD

INVESTIGATIONS

OPTICAL COHERENCE TOMOGRAPHY

DRY AMD

WET AMD

FUNDUS FLUORESCENT ANGIOGRAPHY Fundus fluorescein angiography (FFA),

sometimes augmented with indocyanine green angiography (ICG), is used to confirm the presence of an area of choroidal neovascularisation at the macula.

On the basis of fluorescein angiography,choroidal neovascularisation can be divided into classic (neovascularisation fully delineated) and occult (full extent of neovascularisation not visible). The classic form usually progresses faster than the occult form.

Multiple Drusen

Geographical atrophy

CNV with subretinal hemorrhage

Subfoveal choroidal neovascularisation—classic with no occult. Increasing “lacy” hyperfluorescent dye leakage from the abnormal blood vessels is clearly demarcated

Subfoveal choroidal neovascularisation—occult. Increasing diffuse hyperfluorescent dye leakage with the source of leakage unable to be clearly defined

FUNDUS AUTOFLUORESCENCE Useful in

geographical atrophy and to quantify lipfuscin in RPE

Ultrawide field (optomap) image of a patch of retinal atrophy exposing choroide

autofluorescence

INDOCYANINE GREEN (ICG) ICG is useful in

PED,poorly defined CNV ,ocult CNV ,lesions like retinal angiomatous proliferation or ideopathic polypoidal choroidal vasculopathy.

MANAGEMENT

Currently, there is no established effective treatment for DRY AMD and new investigational treatments are directed at CNV.

Treatments specifically for wet ARMD aim to close off blood flow through the area of choroidal neovascularisation, to allow resolution of the exudative changes at the macula and the restoration of central visual function.

Several different methods of ablation of choroidal neovascularisation are available for treating wet ARMD.

ANTIOXIDANT SUPPLIMENTS Doses used in AREDS study were: Vitamin C 500 mg Vitamin E 400 IU Leutein / zeoxanthin 10 mg / 2 mg Zinc oxide 80 mg Cupric oxide 2mg Results : - reduction of relative risk of advanced AMD was

25 % with a combination of antioxidants and zinc

Laser photocoagulation

The neovascularisation is occluded by direct laser photocoagulation. In the process of destroying the deeper abnormal vessel leakage, the overlying retina also sustains significant damage. This type of treatment is often used for extrafoveal and juxtafoveal choroidal neovascularisation that does not lie directly beneath the fovea. In subfoveal disease laser photocoagulation will result in an immediate reduction in vision.

Thermal laser photocoagulation (TLP) uses an argon laser (or other laser in the visible light spectrum).Before the advent of PDT, it was the only well established and widely accepted treatment for classic CNV secondary to AMD

Transpupillary thermotherapy (TTT) uses a longpulse 810 nm near-infrared diode laser which closes CNV via still unknown mechanism (the procedure is expected to locally rise temperature by 10°C on target tissue).It is an inexpensive and one of the few treatments available for occult CNV.

Photodynamic therapy (PDT)

This new technique uses a light activated photosensitiser (verteporfin), given intravenously.

An ophthalmic laser delivery system is used to generate the specific wavelength of light to activate the photosensitiser, which causes photochemical damage and vessel occlusion in the selected target area.

This makes it possible to cause vessel occlusion without damage to the retina, which has the advantage of preserving visual function, particularly with choroidal neovascularisation in the subfoveal region.

PDT has become the treatment of choice in subfoveal choroidal neovascularisation.

External beam radiation Precisely focused radiotherapy is used to ablate the

neovascular membrane. This treatment is currently undergoing evaluation in certain centres.

Agents that inhibit choroidal neovascularisation A variety of agents that may inhibit subfoveal choroidal

neovascularisation are being investigated. These include novel molecules such as antibodies and aptamers (RNA-like molecules).

The molecules neutralise growth factors such as vascular endothelial growth factor, which stimulates new vessel growth.

Anti-angiogenic steroids are also being tested

Submacular surgery This is an operation involving microsurgical vitrectomy to

remove the vitreous gel, combined with a retinal incision and then removal of the choroidal neovascularisation. This technique may be appropriate for selected cases.

Macular rotation or transposition surgery This is a complex surgical technique in which the macular

region of the retina is physically moved to overlie another area of healthy retinal pigment epithelium elsewhere in the adjacent retina. Subsequent strabismus surgery is need to rotate the macula back into the primary position

Anti-angiogenic agents attempt to block various steps in the pathway of angiogenesis in

CNV;they include:

• Pegaptanib sodium (Macugen) –

a pegylated modified RNA oligonucleotide of 28 bases in length that binds with a high affinity (in the picomolar range) to the major VEGF isoform, VEGF165.

A number of randomized, double-blind trials have recently been published, showing Macugen (tested in various doses up to 3 mg/eye) to be capable of producing a statistically significant and clinically meaningful benefit in the treatment of neovascular AMD.

Interestingly, dosages above 0.3 mg were not found to confer any additional benefit. In December 2004, the FDA approved Macugen to slow vision loss in eyes affected by all subtypes of neovascular AMD, with a recommended dose of 0.3 mg administered intravitreally once every 6 weeks

Bevacizumab (Avastin) – a 149 kDa full-length anti-VEGF-specific recombinant

humanized murine monoclonal antibody (rhumAb-anti-VEGF antibody) binds to all isoforms of VEGF-A. It is the first approved by the FDA antiangiogenesis-specific agent for cancer patients, originally recommended as a first-line treatment for patients with advanced, metastatic, colorectal cancer, preferably in a conjunction with standard chemotherapy (FDA, February 2004)

The recommended dose of Avastin (bevacizumab) is 5 mg/kg given once daily every 2 weeks as an intravenous infusion (iv). Bevacizumab, 5 mg/kg iv, has also been tested in neovascular AMD and in CNV secondary to pathological myopia, with a generally positive therapeutic outcomes (improved visual acuity and reduced, or even blocked leakage from CNV)

Although bevacizumab was not approved for ophthalmological neovascular diseases, it is available on the market, and thus can be used on an off-label basis.A commercially available bevacizumab (25 mg/ml sterile solution) can be utilized for neovascular AMD as a ready-for-use solution in a volume of 50 μl/eye which is equivalent to 1.25 mg dose.

Ranibizumab ( Lucentis) is a 48 kDa fragment of a humanized murine anti-VEGF antibody active

against all isomers of VEGF; the drug is prepared for intravitreal infusion.

Of the tested doses (0.05–2 mg/eye) the maximum tolerated single dose in neovascular AMD patients was 0.5 mg.Repeated, monthly, intravitreal injections of ranibizumab had a good safety profile, and were associated with improved visual acuity and decreased leakage from CNV. It is suggested to be used in combination with PDT.

Ranibizumab is not approved by the FDA to date.

Anecortave acetate (Retaane) – a novel steroid(a synthetic cortisone chemically modified into

cortisene) devoid of glucocorticoid activity with a potent anti-angiogenic potential (it inhibits the proteolysis required for vascular endothelial cell migration,thereby inhibiting ocular neovascularization.

-Anecortave acetate as a slow-release depot suspension may be delivered at a dose of 15 mg as an extraocular(juxtascleral; sub-Tenon retrobulbar) injection at six-month intervals. Retaane has not final FDA approval yet.

Triamcinolone acetonide – an intravitreal treatment option for various intraocular edematous

and proliferative disorders. In most studies the drug was used at a dosage of 4 mg/injection, although in some centers the tested dosage equaled 20–25 mg. Triamcinolone acetonide may be helpful as an adjunct therapy for exudative AMD, possibly in combination with PDT.

STEM CELL TREATMENT