Age Related Macular Degeneration.

Nitin Renge.

DEFINITION:

• A common, chronic, Progressive degenerative disorder of Macula that affects older individuals and features central visual loss as a result of abnormalities in Photoreceptor / Retinal pigment epithelium/ Bruch’s membrane/ Choroidal complex often resulting in Geographic atrophy &/or Neovascularization.

Introduction• Leading cause of irreversible visual loss in Industrialized countries.• Common in Caucasian populations-54%.• Key Features:-- Earliest signs rarely visible before 50 years. Bilateral disease ( 50% bilateral within 5 years of visual loss in first eye ) Drusen Hyperpigmentation of RPE Hypopigmentation of RPE Geographic Atrophy Detachment of RPE Macular choroidal Neovascularization

• Associated Features :--- Subretinal Fluid Intraretinal Fluid Subretinal Haemorrhage Intraretinal or Inner retinal Haemorrhage Lipid Exudation Subretinal Fibrosis ( Disciform scarring ) Specific genetic risk allels, particularly in gene controlling the Complement system.

Anatomy:--• Macula Diameter 5.5 mm, at post pole & temporal to optic disc.

• Fovea Centralis Depression of 1.85 mm diameter & 0.25mm thick.

• Foveola -- Central point of fovea 0.35 mm in diameter 3mm temporal,1mm inferior to optic disc Thinnest part of retina Cones only High levels of visual acuity

FoveolaRPE

Choroid

FoveolaFovea

MACULA

Para-foveal zonePeri-

foveal zone

MACULA: ANATOMY

Umbo

Classification:---• Conventionally Two forms: 1) Non-exudative, Non-neovascular (dry) Most common (90%) Geographic atrophy advanced stage of dry ARMD

2) Exudative, Neovascular (wet) Less common (10%) Associated with more rapid progression to advanced vision loss Main manifestations are CNV & PED

Clinical Classification:---Cetegory Defination, based on presence of

lesions within two disc diameters of the Fovea in either eye

No apparent ageing changes

No Drusen, No AMD pigmentary abnormalities

Normal ageing changes

Only Drupelets (drusen < 63 micro m), No AMD pigmentary abnormalities

Early AMD Medium drusen(>63 micro m & < 125 Micro m) , No AMD pigmentary abnormalities

Intermediate AMD

Large drusen (> 125micro m) , Any AMD pigmentary abnormalities

Late AMD Neovascular AMD &/or Any geographic atrophy

AMD: STAGING:-

• 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).

Risk Factors:---• Age• Race- Caucasians > African Americans• Heredity 1) CFH-Bilateral GA 2)HTRA1-risk of bilateral CNV 3)C3- GA>CNV• Smoking • Obesity• Hypertension & other cardiovascular risk factors• Dietary Factors• Aspirin- may increase risk of NV-AMD• Other Factors- Cataract Surgery, Blue iris colour, High sunlight exposure & Female

Gender

Pathogenesis• Progressive thickening of Bruch’s membrane with age• Interferes with RPE - photoreceptor metabolism• Metabolites from photoreceptors accumulate on Bruch’s membrane• Forms lipid deposits as basal linear & basal laminar deposits• Later forms Drusens (colloid bodies) Earliest clinical sign Lipid or collagen rich deposits (waste) Also contains Amyloid, Complement factors & additional cellular components Lie between Bruch’s membrane and RPE Further disruption of RPE/photoreceptor metabolism Cause variable amount of depigmentation and eventually atrophy of overlying RPE

Drusen

Bruch’s Membrane

RPE

Photoreceptors outer seg

Choroid capillaries

Neuron connected to optic nerve

Rods & Cones

1)Small Drusen (drupletes) <63 um Sometimes termed Hard Drusen Sharp, well demarcated boundaries, White-yellow Small localised collection of hyaline material within or on Bruch’s membrane4)Intermediate Drusen >63 < 125um Fairly well-defined, Yellow-white, deposits at level of RPE

3)Large Drusen > 125 um ( Soft Drusen ) Less well delineated, Yellow-white Larger/commonly become confluent Poorly demarcated boundaries

Involve overlying focal RPE detachment (Drusenoid RPE detachment)

Soft Drusen: 1) Membranous: 63-175 µ Pale, shallow appearing drusens 2) Granular: About 250 µ Solid appearing drusens 3) Serous: >500 µ Have pooled serous fluid blister like appearance May result in serous PED

Hard drusen

Pigment epithelium defects

Hard Drusen

Soft Drusen

Confluent Drusen Representing widespread RPE

abnormality Increase risk of vision loss

Calcified Drusen (glistening appearance)

Dystrophic Calcification may develop in all type of Drusen

RPE degeneration, seen as:• Focal areas of hypo- and hyper- pigmentation (‘stippling’)• Associated with progression to late AMD with Visual loss• Eventually areas of atrophy of the RPE revealing underlying

large & deep choriodal vessels ‘Geographic atrophy’ = end stage or Late advanced stage of Dry AMD

a) Drusen with Pigmentary abnormality b) Geographic Atrophy

Differential Diagnosis of Drusens 1) Donyne Honeycomb retinal dystrophy (Malattia

leventinese, Autosomal dominant radial drusen) 2) Cuticular Drusen- FA characteristics is ‘Star in the

Sky’ appearance 3) Type 2 Membranoproliferative Glomerulonephritis.

Age-related thickening of Bruch’s membrane

Interferes with photoreceptor/RPE metabolism

Causing deposition of metabolites / formation of drusen

Damage to overlying RPE/photoreceptors and underlying choriocapillaris

AMD: SYMPTOMSInitial 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• Patient’s ability to perform normal daily

tasks such as reading, sewing, telling the time, driving are greatly impaired.

Non-Exudative AMD• Symptoms:- Gradual mild to moderate impairment over months or years Both eyes usually affected but often asymmetrically Vision may fluctuate, & is often better in bright light• Signs:-

Intermediate-large soft drusen may confluent Focal hyper &/or hypopigmentation of RPE Slow/progressive atrophy of RPE and photoreceptors Drusenoid RPE detachment Advanced form = Geographic Atrophy

• Clinically , dry AMD may manifest:- Stage of drusen and/or hyperpigmentation Stage of incipient atrophy (non geographic atrophy) Stage of geographic atrophy• 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

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.

Geographic Atrophy (GA)• Clinical Features:- Soft drusen present in early stages (significant risk factor for GA – due to RPE detachment) Decreased retinal thickness and increased visualisation of choroidal vessels Sharply demarcated pale area Choroidal vessels sometimes white• Signs/Symptoms:- Marked decrease VA (unless foveal sparing) Central field loss (positive scotoma) Difficulty recognizing faces Difficulty reading if large scotoma Difficulty in dim light/adapting

GEOGRAPHIC ATROPHY

DD’s for dry ARMDHerediatry Diseases:- Pattern dystrophy, Stargardt disease, Best’s disease, Angioid streaks

Central serous chorioretinopathy

Macular telangiectasia type II

Multifocal choroiditis

Acute posterior multifocal placoid pigment epitheliopathy

Toxic lesions:- Chloroquin, Phenothiazines, Canthaxathin

Cuticular Drusen with or without a vitelliform lesion

Adult vitelliform dystrophy

Exudative AMD • Clinical Features:- Choroidal neo-vascularisation Exudative detachment of RPE, sub-RPE(type1) and/or subretinal (type2) Disciform scar• Choroidal Neo-vascularisation:- Proliferations of fibrovascular tissue from choriocapillaris through defects in Bruch’s membrane Sub-RPE or sub-retinal Membranes have a grey-green or pinkish-yellow hue in late stages• Tendency to leak:- Serous and blood Distorted or painless blurred vision, usually with metamorphopsia Red if sub-retinal, darker if sub-RPE Rarely vitreous haemorrhage

WET AMDPhotoreceptors 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 maculaPotential for rapid and severe visual damage

• 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• The hallmark of neovascular AMD is CNV & potential manifestations are-

Subretinal fluid Macular edema Retinal , subretinal ,or sub-RPE hemorrhage Retinal or subretinal lipid exudate Plaque like membrane or grey or yellow green discrete discoloration RPE detachment RPE tear Sub-retinal fibrosis or disciform scar

.

• 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

Wet AMD: A Rapid Descent

TIME

Wet AMD

Blindness

Severe Vision Loss

Early Intermediate Advanced(dry) (dry) (wet)

No Vision Loss

Today: many are diagnosed after

vision loss

There are no good predictors for who will develop Wet AMD or

when

Common Ophthalmic condition associated with CNVAge-related macular degeneration

Angoid streaks

Best’s disease

Choroidal Osteoma

Fundus Flavimaculatus

Idiopathic Causes

Multifocal Choroiditis

Ocular Histoplasmosis Syndrome

Optic disc drusen

Optic nerve head pits

Pathological ( Progressive ) Myopia

Pattern dystrophies

Photocoagulation

Sarcoidosis

Serpiginous or Geographic Choroiditis

Toxoplasmic Retinochoroiditis

Traumatic Choroidal Rupture

Polypoidal choroidal Vasculopathy

Pattern of CNV Hyper fluorescence on FA

Classic CNV (20%)-Well

demarcated boundaries (Lacy pattern) during early transit-Subsequently leaking into subretinal space over 1-2 min, with late staining of fibrous tissue

Occult CNV (80%)Type 1

-Fibro vascular PED-Irregular elevation RPE.-Boundaries may be well demarcated or poorly demarcated.-Persistent staining or leakage of dye at 10 min

Type 2-Late leakage of undetermined of source (LLUS)-Boundaries poorly demarcated-Source of late leakage can not be determined from earlier frames of angiograms

CLASSIC CNV

OCCULT CNV (TYPE-I)

OCCULT CNV (TYPE-II)

RPE DETACHMENT (PED) Depending on cause, it is of many types:

• Drusenoid• Serous• Fibro vascular• Hemorrhagic

RPE TEAR• Spontaneously or on photocoagulation of CNV or

after intravitreal injections.

• Visual acuity abruptly fall with foveal involvement.

• FA shows in late phase hypofluorescence corresponding to thickened folded RPE with adjacent hyperfluorescence over the torn area, two area often separated by a sharply defined border.

DISCIFORM SCAR

VARIATION• Retinal angiomatosis proliferans-10-20% of Neovascular AMD in

Caucasians.• Has been termed Type-III CNVM• Frequently Bilateral & Symmetrical• Characterized by predominantly intraretinal neovascularization• 3 Stages:

• Stage 1• Intraretinal neovascularization

• Stage 2• Subretinal neovascularization

• Stage 3• CNV clearly evident clinically/angiographically.• RCA (retino-choroidal anastamoses)• A Diciform scar will often form

• Polypoidal Choroidal Vasculopathy A variant of neovascular AMD MC in women (5:1) & relatively young , African & East Asian ethnic origin Often Bilateral & Asymmetrical Sudden onset of unilateral visual impairment Causes multiple recurrent serosanguineous retinal & RPE detachments Typical OCT findings in PCV may reveal a classic hyperreflectivity in the choroidal layers known as the "double-layer" sign

Investigations• History:- Gradual change = non-exudative Sudden change = exudative• Visual Symptoms:- VA for Distance and near & no improvement with pin-hole Difficulty in reading/recognising faces, driving Difficulty with changing light / adapting after bright light Distortion of images mostly with exudative changes Less common symptoms include night glare, photopsia (flickering or flashing lights), visual hallucinations (Charles Bonnet syndrome) & abnormal dark adaptation• Amsler grid test: Assesses distorted & scotoma , small irregularities in the central field

of vision ( 10degree)• Ophthalmoscopy: to detect drusen, as well as neovascularization• Fluorescein and ICG angiography: Determines the presence and location of

neovascularization• Optical coherence tomography

MANAGEMENT• Antioxidants: AREDS-1 study & follow-up AREDS-2 Study use of high dose of multivitamins & antioxidants decreases the risk of progression of ARMD in those with high risk characteristics as age >55 with one or more of following Extensive intermediate Drusen At least one large Drusen GA in one or both eyes Late AMD in one eye ( greatest benefit in AREDS1) Combination of antioxidants vitamins and minerals-

AREDS1 Formula AREDS2 FormulaVitamin E 400IU Vitamin E 400IUVitamin C 500mg Vitamin C 500mgBeta Carotene 15mg ( Vit A 2500IU) Leutin 10mgZinc 80mg Zeaxanthin 2mgCopper (Cupric Oxide) 2mg Zinc 25-80mg

Copper 2mg

Cont..• Dry ARMD:- 1) Antioxidant suplimentation & Risk factors modulation 2) Low Vision Aids 3) Anti-inflammatory drugs- Sirolimus (Rapamycin) antifungal, immunosuppressant & used as SC every 2 months. Intravitreal Steroids as FA implants (sustain release upto 36 months) 4) Complement Inhibition- POT-4 neutralize early AMD inflammatory component & it is a Intravitreal gel sustain release system ARC1905 a C5 inhibitor Aptamer prevents C5a production Eculizumab a Antibody against C5, currently approved only for PNH Lampalizumab a monoclonal antibody, used as intravitreal monthly 5) Neurotrophic Factors- NT501 a genetically modified RPE intravitreal implant, shown retinal thickness as early as 4 months. 6) AL-8309A- as topical solution, light induced oxidative damage

Cont.. 7) Reduction of Retinal Toxins- In Dry AMD lipofuscin (a waste products) accumulates at leading edge of lesion ACU-4429 & Fenretinide (Oral doses) prevents accumulation of lipofuscin 8) Choroidal Blood Perfusion Enchancers- MC-1101 as Topical drug, shown to increase mean choroidal blood flow 9) Other Options Photocoagulation of Drusen Saffron (20mg/day) a neuroprotective effect Intravitreal neuroprotective drug Brimonidine Surgery like Retinal translocation, Subretinal Stem cell Transplantation

Wet-ARMD• Anti-angiogenic Drugs (Anti-VEGFs)- 1) Bevacizumab (Avastin)- Dose- 1-1.25 mg(0.05ml), repeated 6-8 weekly 2) Ranibizumab (Lucentis)- Dose- First 3 injections of 0.5 mg (0.05 mL) four weekly & further on physician's assessment 3) Pegatanib (Macugen)- Given 0.3 mg dose six weekly minimum for two years 4) Aflibercept (Eylea)-2mg (0.05ml) First 3 injections monthly then every 2 months as maintenance regimen• Photodynamic Therapy (PDT)- was developed in the 1990s Includes IV Verteporfin & a red diode laser (689 nm wavelength) Verteporfin (a benzoporphyyrin derivative)- second generation potent photosensitizer of the tetrapyrrole group

Cont.. Absorbs light at 690 nm, a longer wavelength is important because it allows deep tissue penetration, through blood, pigments & fluid which could accumulate beneath the retina Plasma half-life ranges approximately from 5 to 6 hours & BPD-MA/Verteporfin is excreted mainly by the bile (90%) Administered intravenously as a liposomal preparation & partitions into the LDL phase of the lipoprotein fraction of the blood Endothelial cells which form the neovessels of tumors & neovascular membranes have been shown to have increased the population of LDL receptors that play a major role in the mechanism of the uptake & therefore the selectivity of the photosensitizer in these cells MOA- The target cells are light irradiated & the molecules of the dye gain energy passing from the ground state to an excited, highly reactive, short-lived triplet state which transfers the excess of energy by two pathways 1) The energy absorbed from the triplet state is transferred to other molecules leading to the generation of free radicals, which instantaneously oxidize a wide variety of biomolecules - Type I mechanism

Cont.. 2) The energy absorbed from the triplet state is transferred to oxygen generating high reactive short-lived oxygen - Type II mechanism which appears to play the major role in the effect seen in PDT The interactions of these highly reactive compounds cause cellular and vascular damage Associated with an immediate induction of acute inflammatory responses Leading to occlusion of the feeding vessels i.e neovascular capillaries Main Indication- Subfoveal predominantly Classic CNV with visual acuity of 6/60 or better The potential advantages of PDT are:- Scarring is unlikely, as collagen & elastin are unaffected, leaving organs intact Highly selective tissue necrosis & Resistance to treatment does not develop with repeated treatment

• Laser Photocoagulation- Includes Thermal blue-green Argon laser or diode laser ablation of CNV, now rarely used

Modality for juxtafoveal (well-defined choroidal neovascular lesions located 1 to 199 µ from the foveal centre, or 200 to 2500 µm from the foveal centre but showing blood or pigmentation less than 200 microns from the foveal centre) & extrafoveal (located 200 to 2500 µm from the foveal centre) CNV associated with AMD A fluorescein angiography (FA) should be performed 72 to 96 hours before photocoagulation in order to select treatable cases & to guide the ophthalmologist during treatment Patients should undergo treatment as quickly as possible, since neovascular lesions may grow 10 to 18µ per day Treatment should be performed so that a white lesion in the retina is obtained

Cont.. The neovascular lesion should be surrounded by laser marks with a diameter of 200µ and duration of 0.2 to 0.5 seconds After surrounding the perimeter of the neovascular lesion, its central part is covered with 200µ burns; the remaining lesion is covered with 200 to 500µ burns, with duration of 0.5 to 1.0 seconds Laser treatment should avoid retinal blood vessels and the optic nerve (treatment should start 10-200 µm from the optic nerve), as well as preserve at least 1.5 hours of the papillomacular bundle (no peripapillary treatment) Follow-up:- it is necessary to perform medical examinations and control FA 2 to 3 weeks, 4 to 6 weeks, 3 to 4 months and 6, 8, 9 and 12 months after treatment Recurrence is rare after 2 years The greater risks exist 6 weeks to 12 months after treatment

Cont.. Complications:- 1) Choroidal haemorrhage (rarer if spots ≥ 200 microns and time intervals ≥ 0.2 seconds are used) 2) Premacular fibrogliosis 3) Accidental treatment of the fovea in extrafoveal or juxtafoveal lesions 4) Rupture of the pigment epithelium (more frequent in cases of PED) 5) Atrophy of the RPE in the area adjoining the laser scar (immediately after treatment or years later)• Laser photocoagulation remains currently indicated for the treatment of well-

defined extrafoveal choroidal membranes• For classic juxtafoveal membranes, laser photocoagulation could theoretically be

considered as an option for cases in which the entire neovascular lesion can be treated without damaging the fovea

• TRANSPUPILLARY THERMOTHERAPY:- 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, minimum 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 So effectively treat subfoveal occult choroidal neovascular membranes and preserve vision

Cont..• TECHNIQUE:- delivered through a slit lamp using an antireflective Goldmann contact

lens & an infrared diode laser at 810 nm, specially modified to give a long pulse mode The slit lamp has a special large spot size adapter with an adjustable beam width of 0.5 mm, 0.8 mm, 1.2 mm, 2.0 mm & 3.0 mm The treatment is given using one spot that encompasses the entire lesion Laser parameters used are duration of 60 seconds, at power settings between 250 and 1000 mW, depending upon the spot size used For a 3 mm spot size, the initial power setting is 800 mW by keeping the power density around 10 W/ sq.cm The end point is an area of no visible colour change to a light grey appearance Full treatment results are usually seen within 2-3 months after the procedure

• Submacular excision of CNV• Macular translocation• Retinal rotation• Homologous Iris/Retinal pigment epithelium transplantation• Autologous RPE transplantation

SURGICAL OPTIONS

EMERGING TREATMENTS• 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• ATG3 (mecamylamine)- a topical formulation that inhibits the nicotinic acetylcholine receptors

• EVIZON (squalamine lactate)- aminosterol with anti–angiogenic activity derived from the liver of the dogfish shark, administered intravenously (no eye injection)• OT-551 (antioxidant eye drops)- supplement the eye’s natural defense system against disease & injury protection against both cataract and dry AMD• Encapsulated Cell Technology (ECT)- 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

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