AGE-RELATED MACULARAGE-RELATED MACULAR DEGENERATIONDEGENERATION

AJAY KUMAR SINGHAJAY KUMAR SINGH•Department of Ophthalmology

•King George‘s Medical University, Lucknow (INDIA)

INTRODUCTION

• DEFINITION:– A common chronic degenerative

disorder of unknown pathogenesis that affects older individuals and features central visual loss. .

Age-related

maculardegeneration

EPIDEMIOLOGY

• An epidemic of “ageing” is impending in the Western world. According to the latest predictions released by the United Nations 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.

Ref: BMJ 2003; 326: 485-8

AMD: TERMINOLOGY

• 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).

• The UN estimates the number of people with AMD are about 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.

• Prevalence of AMD in >75 year age group varies from 1.2% to 29.3% in different populations.

Ref: BMJ 2003; 326: 485-8

AMD: PREVALANCE

• 3 population based studies; the Beaver Dam Eye Study, Blue Mountain Eye Study and the Rotterdam study report the over-all prevalence rates to be 1.7% in US, 1.4% in Australia and 1.2% in Netherlands respectively.

• In South India, the prevalence is 1.1% whereas, another study from North India reports the prevalence rate to be 4.7%.

1. Invest Ophthalmology vis. Sci 2001; 42: 2237-412. Am J. Epidemiology 1977; 106: 1333. Ophthalmology 1992; 99; 933-434. Ophthalmology 1995; 102: 1450-605. Ophthalmology 1995; 102: 205-10Invest Ophthalmol Vis Sci (abstract) 2000;

41; 51196. Ind. J Ophthalmol 1984; 32: 343-6

AMD: PREVALANCE

POSTULATED RISK FACTORS FOR AMD

• Ageing– The Framingham Eye study (1976) showed the

prevalence– 65-74 years- 11%– 75-85 years- 28%

• Gender– Blue Mountains study (2002) suggests that 5-year

incidence of neovascular AMD among women is double that of men.

• Smoking – The Beaver Dam Study (1992) disclosed a

relationship between the development of exudative lesions and a history of current cigarette smoking.  

• Cardiovascular Risk factors– Hypertension: Rotterdam study

(2003) suggests positive correlation between high blood pressure and increased incidence of AMD.

• Light– Initially postulated hypothesis: UV-

damage by photo-oxidative damage via reactive oxygen intermediates.

– The Blue Mountains Eye Study (2002) disclosed no relationship between light and AMD.

POSTULATED RISK FACTORS FOR AMD

• Nutrition– Several studies (including

AREDS) have described the beneficial effects of dietary carotenoids, anti-oxidants, Zn and omega-3 fatty acid in slowing the course of the disease.

• 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.

POSTULATED RISK FACTORS FOR AMD

GENETICS

• Family history of macular degeneration:– Autosomal dominant with variable penetration– In first degree relative with macular

degeneration, chances is about 2.5 times.

• Macular Degeneration Gene:– Few studies* have described the increased risk

of AMD associated with polymorphisms of complement factor H (HF1/CFH)

– single nucleotide polymorphisms on 1q32, 6p21, and 10q26 are the risk for development of AMD

– The odds of developing macular degeneration are increased by about 2.5 to 5.5 times if one has the CFH gene variant.

*Moshfeghi DM, Blumenkranz MS, Retina. 2007 Mar;27(3):269-75

HOW DOES PATIENT PRESENTHOW DOES PATIENT PRESENT

??????

AMD: SYMPTOMS

Initial symptoms:• Straight lines appear wavy• Blurry vision• Distorted vision• Objects may appear as the wrong shape or

size• A dark empty area in the centre of vision

AMD: SYMPTOMS

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

HOW DOES NORMAL VISION HOW DOES NORMAL VISION OCCUR ???OCCUR ???

Foveola

Fovea

MACULA

Para-foveal zonePeri-

foveal zone

MACULA: ANATOMY

Umbo

RETINAL PIGMENT EPITHELIUM

The retinal pigment epithelium (RPE) is a single layer of hexagonally shaped cells & attached to the photoreceptor layer.

Functions - 1.Maintain the photoreceptors2.Absorption of stray light 3.Formation of the outer blood retinal barrier4.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.

WHAT GOES WRONG IN AMDWHAT GOES WRONG IN AMD

??????

TYPES

DRY AMD

• Accounts for about 90% of all cases• Also called atrophic, non-exudative or

drusenoid macular degeneration

• Clinically , dry AMD may manifest-

Stage of drusen and/or hyperpigmentation

Stage of incipient atrophy (non geographic

atrophy)

Stage of geographic atrophy

DRY AMD

Drusen

Insufficient oxygen and nutrients damages photoreceptor molecules

With ageing, the ability of RPE cells to digest these molecules decreases

Excessive accumulation of residual metabolic debris and hyaline material (drusen)

RPE membrane and cells degenerate and atrophy sets in and central vision is lost

DRY AMD

Drusen:

• Drusen are aggregation of hyaline material located between Bruch’s membrane and RPE.

• Drusen are composed of metabolic waste products from photoreceptors.

• Hypo/hyper pigmentation of RPE may be present.

DRY AMD

• Types:– Small: <63 µ– Intermediate: 63-124 µ– Large: >125 µ

– Hard:• generally small (<63 µ), bright yellow, solid

appearing drusen with well defined margins• may be asymptomatic

– Soft:• larger (>63 µ), pale yellow, ill defined, fluffy margins• High risk for neovascular AMD

• Soft Drusen:– Membranous:

• 63-175 µ• Pale, shallow appearing drusens

– Granular:• About 250 µ• Solid appearing drusens

– Serous:• >500 µ• Have pooled serous fluid• blister like appearance• May result in serous PED

HISTOPATHOLOGY

• Drusen appear as focal areas of the eosinophilic material between the basement membrane of RPE & BM.

• Deposits on the internal side of RPE basement membrane called –basal laminar deposits & on its external aspects called – basal linear deposits.

• Basal linear deposits are believed to form soft drusen with the passage of time & are more common in eyes effected by neo-vascular AMD.

Drusen

• Diagnostic criteria*• Degenerative disorder in persons >50

years, characterized by the presence of any of the following:– Soft drusen (>63 µ)– RPE abnormalities- areas of

hypo/hyperpigmentation (excluding pigment surrounding small, hard drusen)

– Visual acuity (VA) is not a criterion for the diagnosis

*International Epidemiological Age-related Maculopathy study Group

DRY AMD

DRUSEN

GEOGRAPHIC ATROPHY

DRY AMD: COURSE AND VISUAL PROGNOSIS

• Patients with only drusen not have much loss of vision, but require additional magnification of the text and more intense lighting to read small points.

• Presence of large drusen (>63 microns in diameter) is associated with a risk of the late form of the disease like CNV.

• Geographic atrophy- severest form of the dry AMD, RPE atrophy >175 microns with exposure of the underlying choroidal vessels.

EXUDATIVE MACULAR DEGENERATION( WET OR NEOVASCULAR AMD )

• Accounts for about 10%

• The pathology of neovascular AMD is choroidal neovascularisation with the formation of a subretinal/choroidal neovascular membrane (SRNVM/CNVM) The CNVM lead to haemorrhage and fibrovascular proferation and subsequent scarring.

• 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.

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

WET AMD

Potential for rapid and severe visual damage

WET AMD

• Diagnostic criteria*• persons >50 years, characterized by

the presence of any of the following:– choroidal neovascularization– serous retinal pigment epithelial

detachment– hemorrhagic retinal pigment

epithelial detachment– fibrotic scar in the macula

WET AMD

*Takahashi K et al.Nihon Ganka Gakkai Zasshi. 2008 Dec;112(12):1076-84.

WET AMD

WET AMD

WET AMD

• CNV lesion is well demarcated & its location may be determined by closest point to the FAZ.

• Lesion location is classified angiograpically as follows:-1. Subfoveal: under the centre of FAZ2. Juxtafoveal: 1-199 µm from the centre of FAZ3. Extrafoveal: >200 µm & <2500 µm from the centre

of FAZ

• Types:– Type I: CNV beneath RPE– Type II: CNV above RPE

CLASSIC CNV

OCCULT CNV (TYPE-I)

OCCULT CNV (TYPE-II)

RPE DETACHMENT (PED)

PED (Pigment epithelium detachment)

• Depending on cause, it is of many types:– Drusenoid– Serous– Fibro vascular– Hemorrhagic

RPE DETACHMENT (PED)

RPE TEAR

• Spontaneously or on photocoagulation of CNV.

• Visual acuity abruptly fall

• Angiogram shows CNV in early & in late phase shows hypofluorescence corresponding to heaped-up RPE with hyperfluorescence over the torn area.

DISCIFORM SCAR

• Retinal angiomatosis proliferans– Has been termed Type-III CNVM– Characterized by predominantly intraretinal

neovascularization– 3 Stages:

• Stage 1– Intraretinal neovascularization

• Stage 2– Subretinal neovascularization

• Stage 3– CNV clearly determined clinically/angiographically.– RCA (retino-choroidal anastamoses) seen as “Hair-

pin” appearance on FFA.

VARIATION

WET AMD: COURSE AND VISUAL PROGNOSIS

• Leakage of blood or serum in CNV may occur precipitously and associated with the abrupt loss of vision.

• Patients with CNV shows rapid decline in vision (20/200) within weeks.

• Once CNV has developed in one eye, the other eye is at relatively high risk for the same change.

• More frequently, visual acuity deteriorates more slowly and stabilizes within 3 years.

• AREDS Categories:– No AMD (AREDS category 1)

• No or a few small (<63 micrometres in diameter) drusen.

– Early AMD (AREDS category 2)• Many small drusen or a few intermediate-sized (63-124

micrometres in diameter) drusen, or macular pigmentary changes.

– Intermediate AMD (AREDS category 3)• Extensive intermediate drusen or at least one large (≥125

micrometres) drusen, or geographic atrophy not involving the foveal centre.

– Advanced AMD (AREDS category 4)• Geographic atrophy involving the foveal centre (atrophic, or

dry, AMD)• Choroidal neovascularisation (wet AMD)• evidence for neovascular maculopathy (subretinal

haemorrhage, serous retinal or retinal pigment epithelium detachments, lipid exudates, or fibrovascular scar).

AMD: STAGING

WHAT TO DOWHAT TO DO

??????

• Visual acuity• Amsler grid test: Assesses

distorted or reduced vision and small irregularities in the central field of vision.

• Ophthalmoscopy: to detect drusen, as well as neovascularization

• Fluorescein and ICG angiography: Determines the presence and location of neovascularization.

• Aided by optical coherence tomography.

AMD: DIAGNOSTIC TOOLS

• Role of Antioxidants:• AREDS-1 study- use of high dose of

multivitamins & antioxidants decreases the risk of progression of ARM in those with high risk characteristics.

• Combination of antioxidants and zinc (AREDS-1 Formula)-– Vitamin C: 500 milligrams (mg)– Vitamin E: 400 international units (IU)– Beta carotene: 15 mg (equivalent to Vit.A 25000 IU)– Zinc: 80 mg– Copper (cupric oxide): 2 mg

AMD: MANAGEMENT

• AREDS-2 Study:– Lutein & zeaxanthin antioxidants micronutrients found in

human macula.– Diet rich in these give some protection against the disease.– omega-3 fatty acids, docosahexaenoic acid (DHA) and

eicosapentaenoic acid (EPA) have also been shown to help with AMD.

– AREDS-2 Formula-• Vitamin C - 500 mg• Vitamin E - 400 IU• Beta-Carotene - 15 mg• Zinc - 80 mg• Copper - 2 mg• Lutein - 10 mg• Zeaxanthin - 2 mg• DHA - 350 mg• EPA - 650 mg

AMD: MANAGEMENT

• Current treatment –

1.Antiangiogenic drugs

2.Photodynamic therapy

3.Laser photocoagulation

AMD: MANAGEMENT

ANTI ANGIOGENICS

• Anti-VEGFs:– reduce the growth of new blood vessels,

decrease the leakage through them.

• Bevacizumab (Avastin)• Ranibizumab (Lucentis)• Pegaptanib sodium (Macugen)• Aflibercept (VEGF Trap-Eye)

• Bevacizumab (Avastin)-

– Full-length monoclonal antibody (150 kD)

– Binds all isoforms of VEGF– Has FDA approval for i.v. use

in metastatic colorectal, metastatic breast and non-small cell carcinoma of lung

– Is being used off-label for choroidal neovascularization based on results of short-term studies

– Dose- 1-1.25 mg, repeated 6-8 weekly.

• Ranibizumab (Lucentis )

– Recombinant humanized immunoglobulin G1,

kappa isotype, antibody fragment (Fab) (48

kD)

– Binds to all isoforms of VEGF.

– Dose- First 3 injections of 0.5 mg (0.05 mL)

four weekly & further on physician's

assessment.

• Comparison of AMD Treatment Trials

(CATT)

– Multicentre clinical trial

– Compare safety and efficacy of ranibizumab

and bevacizumab

– Currently under way

• Pegaptanib sodium (Macugen)

– 28 base ribonucleotide aptamer– Binds to Heparin-binding domain

of VEGF-A– Inactivates VEGF-A 165,189 and

206 isoforms– Given 0.3 mg dose six weekly

minimum for two years.– VISION (VEGF Inhibition Study in

Ocular Neovascularization) (2002) has shown that pegaptanib (6 weekly injections) is superior to sham injections and as effective as PDT in teatment of CNV.

• Aflibercept (VEGF Trap-Eye)

– a fusion protein of key binding domains of human VEGFR-1 and 2 combined with a human IgG Fc fragment

– blocks all isoforms of VEGF-A– Also blocks placental growth

factors-1 and 2– Two Phase III clinical trials

(VIEW-1 and VIEW-2) comparing aflibercept to ranibizumab are currently ongoing.

COMPLICATIONS

• Common-– Raised intra-ocular pressure

• Occasional– Cataract Formation– Intra-ocular hemorrhage

• Rare– Endophthalmitis– Retinal Detachment

PHOTODYNAMIC THERAPY (PDT)

• PDT helps to selectively close off subretinal new vessels.

• Two stage treatment:• Injecting the photosensitiser drug (Verteporfin)•Applying cold laser (689 nm) to activate the

drug – Releases the singlet oxygen molecule that damages

the endothelium– Thrombosis of the capillaries

– New PDT drug under phase-3 trial: Purlytin (SnE2)– PDT with ICG has also been evaluated* using

diode laser (805 nm).

• TAP (Treatment of AMD with Photodynamic therapy) study (1999): In predominantly classic CNV, PDT is more effective than placebo in maintaining/improving visual acuity.

*Chang Kyoon Yoon et al. Korean J Ophthalmol. 2007 March; 21(1): 55–60.

• Many studies have shown that ranibizumab is superior to placebo/PDT for treatment of neovascular AMD.– MARINA (Minimally classic/occult trial of the Anti-VEGF

antibody Ranibizumab In the treatment of Neovascular AMD) (2007)

– ANCHOR (Anti-VEGF antibody for the treatment of predominantly classic Choroidal neovascularization in AMD) (2009)

– PIER (Phase III-b, multicentre, randomized, double-masked, sham injection controlled study of the efficacy and safety of ranibizumab in subjects with sub-foveal neovascularization with or without classic CNV) (2008)

– PrONTO (Prospective OCT Study with Lucentis for Neovascular Age-Related Macular Degeneration)(2009)

LASER PHOTOCOAGULATION• Macular Photocoagulation Study (MPS) (1993):

– A series of prospective randomized multicenter clinical trials– To determine the efficacy of laser photocoagulation surgery in CNV

caused by AMD, ocular histoplasmosis, and idiopathic causes.

• Modality for juxtafoveal & extrafoveal CNV associated with AMD.

• Beneficial in CNV lesions with well demarcated boundaries, <6.5 MPS disc area (1 MPS disc area= 2.54 mm2)

• Well-circumscribed new blood vessels identified on the fluorescein angiogram and lasered.

• Disadvantages-– Immediate significant fall in central vision– evolution of central scotoma

• Complications-– Hemorrhage, perforations of BM, RPE tear & arteriolar narrowing.– Persistent or recurrent CNV is common.

LASER PHOTOCOAGULATION

• First described by Oosterhuis et al. in 1998 for treatment of choroidal melanoma.

• The goal of TTT is to create and maintain tissue hyperthermia.

• The diode laser (810 nm, near infrared):– low absorption in xanthophyll, minimising nerve

fibre layer damage– poorly absorbed by haemoglobin, allowing

treatment through preretinal and subretinal blood– mainly absorbed in the choroid, enabling effective

treatment of choroidal lesions.

• In ongoing trials: 3 mm spot, 800 mW, 60 sec.

TRANSPUPILLARY THERMOTHERAPY (TTT)

• TELETHERAPY (EBRT):– Studies have shown equivocal results.– Adverse effects: Cataract, keratoconjunctivitis

siccs, epiphora

• BRACHYTHERAPY (Plaque Radiotherapy):– Published reports include use of Palladium-103

(103 Pd)1, Strontium-90 (90 Sr)2 and Ruthenium-106 (106 Ru)3

– These studies have shown less vision loss in study group than controls.

– Adverse effects: Radiation induced vasculitis, retinal edema, necrosis of adjacent tissue

RADIATION THERAPY

1. Finger et al. 20032. Jaakkola et al 1998 and 2005, Finger et al 19993. Berta et al. 1995

WHEN TO DO WHATWHEN TO DO WHAT

??????

Diagnosis Recommended Treatment

No clinical signs of AMD(AREDS category 1)

Observation with no medical orsurgical therapies

Early AMD(AREDS category 2)

Advanced AMD with bilateral subfoveal geographic atrophy or disciform scars

Intermediate AMD(AREDS category 3)

Antioxidant vitamin and mineralsupplements as recommendedin the AREDS reportsAdvanced AMD in one eye

(AREDS category 4)

Diagnosis Recommended Treatment

Subfoveal CNV Ranibizumab/Bevacizumab intravitrealinjection

Subfoveal CNV, new or recurrent, for predominantly classic lesions <12 MPS disc area in size

Pegaptanib sodium intravitrealinjection

Minimally classic, or occult with no classic lesions where the entire lesion is<12 disc areas in size, subretinal hemorrhage associated with CVN comprises <50% of lesion, and/or there is lipid present, and/or the patient has lost15 or more letters of visual acuity during the previous 12 weeks

Subfoveal CNV, new or recurrent, where the classic component is >50% of the lesion and the entire lesion is <5400 microns in greatest linear diameter

PDT with verteporfin

Occult CNV with vision <20/50 or if the CVN is <4 MPS disc areas in size when the vision is >20/50

Diagnosis Recommended Treatment

Extrafoveal classic CNV, new or recurrent,May be considered for juxtapapillary CVN

Thermal laser photocoagulationsurgery as recommended in theMPS reports

American Academy of Ophthalmology Summary Benchmarks, November 2010

• Submacular excision of CNV• Macular translocation• Retinal rotation• Homologous Iris/Retinal pigment

epithelium transplantation• Autologous RPE transplantation

SURGICAL OPTIONS

EMERGING TREATMENTS FOR AMD

• Retaane® (Anecortave acetate)– modified steroid promising in reducing the risk of

vision loss due to the growth of unhealthy blood vessels in wet AMD.

• AdPEDF : Adenovirus-based Pigment Epithelium Derived Factor– a gene that leads to the production of the protein

PEDF, which helps keep photoreceptors healthy, thereby preserving vision.

• siRNA (Bevasiranib)– silences the genes that lead to the growth of

unhealthy, vision-robbing blood vessels under the retina.

– safety and efficacy established in a Phase II study– Phase III clinical trial is planned

• ATG3 (mecamylamine)– a topical formulation that inhibits the nicotinic acetylcholine

receptors – Currently undergoing phase II human study

• EVIZON™ (squalamine lactate)– aminosterol with anti–angiogenic activity – Derived from the liver of the dogfish shark, administered

intravenously (no eye injection)– in a Phase III human study for the treatment of wet AMD

• OT-551 (antioxidant eye drops)– supplement the eye’s natural defense system against disease

and injury.– Protection against both cataract and dry AMD– currently in a clinical study for geographic atrophy (advanced dry

AMD)

 

EMERGING TREATMENTS FOR AMD (Contd.)

• Encapsulated Cell Technology (ECT)

– Developed by Neurotech,– tiny capsule (6 mm) implanted into the

eye, contains retinal cells that produce a vision-preserving protein ,Ciliary Neurotrophic Factor (CNTF)

– keep photoreceptors alive and healthy, preserving vision.

– currently in a Phase II human clinical trial for people with dry AMD.

EMERGING TREATMENTS FOR AMD (Contd.)

REHABILATATION

• Low vision aids-

– Individual who experiences untreatable visual loss & effects the daily life.

– Reading lamps & simple magnifiers may be beneficial.

– Closed circuit television & scanning devises are also available to provide electronic magnification & contrast enhancement.

TIPS FOR AMD PATIENTS

CONCLUSIONS

• AMD continues to be one of the leading causes of visual loss in aged people.

• New therapeutic strategies continue to be developed & tested.

• Anti-angiogenic drugs remain the mainstay of current treatment.

• Advancement in pharmacology, bio-technology and genetic engineering may dramatically change the treatment protocol with better outcome in near future.

• And, refinements in advanced surgical techniques may offer better results in future………..