Macular Degeneration

Multifactorial, incompletely understood aetiology

Risk factors

• Age (25% over 75)

• Female

• Smoking

• Hypertension

• Hypercholesterolaemia

• Diet:

  • High fat
  • Low omega 3 and 6

• Family history: there are two susceptibility genes

  • CFH: encodes complement factor H
  • ARMS2 (age-related maculopathy susceptibility 2): poorly understood function

• Cardiovascular disease

• Light iris colour

• Caucasian

• Hyperopia

Drusen

• Deposits of extracellular material (glycoconjugates, sialic acid, beta-galactose)

• Lie between the RPE and inner collagenous zone of Bruchs

• Small: <62 microns; intermediate: 63-124 microns; large: 125-249 microns

• FFA: may be hypo- or hyper-fluorescent

  • Hyperfluorescent: window defect due to RPE atrophy
  • Hypofluorescent: hydrophobic drusen

• Disease risk:

  • Hard drusen: dry ARMD
  • Soft drusen: wet ARMD

AREDS

• AREDS1

  • Defined risk factors for AMD progression

    • Presence of large drusen (see above)
    • RPE changes
    • Advanced disease in fellow eye

  • Found vitamin C, zinc oxide, cupric oxide and E provided some protection against progression

• AREDS2

  • Found beta-carotene associated with increased lung cancer risk in smokers
  • Addition of lutein and zeaxanthin reduced risk of progression by 10%

NICE Classification

• Early:

  • Low risk: medium drusen or pigmentary changes
  • Medium risk: large/reticular drusen (>125microns) or medium drusen with pigmentary changes
  • High risk: large/reticular drusen with pigmentary changes, or vitelliform lesion or atrophy

• Late (indeterminate):

  • RPE degeneration with fluid
  • Serous PED

• Late (wet):

  • CNV (classic, occult, mixed, RAP) or PCV

• Late (wet, inactive):

  • Fibrous scar
  • Sub-foveal atrophy due to RPE tear
  • Atrophy
  • Cystic degeneration

• Late (dry):

  • Geographic atrophy
  • Significant visual loss with dense/confluent drusen or advanced pigmentary changes or vitelliform lesion

Choroidal Neovascularization subtypes

• Type 1 (occult)

  • New vessels from the choriocapillaris emerge through a defect in Bruch’s and sit between Bruch’s and RPE
  • Leakage and bleeding lead to serous or fibrovascular PEDs (with irregular contour)
  • Poorly defined. Early stippled hyperfluorescence then with late staining on FFA.
  • Most common

• Type 2 (classic)

  • Vessels penetrate through the RPE (therefore lie between the RPE and outer retinal segments)
  • Lacy or grey appearance on fundoscopy
  • Well demarcated vascular pattern is seen early on FFA with dye then pooling into the subretinal space with progressive leakage

• Type 3 (‘RAP’) -an uncommon form of occult CNV

  • Vessels originating from deep capillary plexus of the retina then growing downward towards the RPE (rather than originating in choriocapillaris)
  • Patients tend to be older than in classic/occult CNV
  • Retinal angiomatous proliferations
  • Seen as red discoloration with exudation
  • FFA: early hyperfluorescence and progressive leakage
  • More aggressive: worse prognosis

FFA in AMD

• Drusen:

  • Autofluorescence
  • Staining
  • Hypo or hyperfluorescent

• RPE atrophy: window defect

• PED: pooling

• CNV:

  • Leaking
  • Masking (if haemorrhage)

• Scars: staining

Intravitreal anti-VEGF

• VEGF stimulates angiogenesis and CNV development

• Ranibizumab: recombinant humanised Ab fragment. 0.5mg/0.05ml

• Aflibercept: recombinant fusion protein of VEGF-binding portions. 2.0mg/0.05ml

• Bevacizumab: humanised full-length monoclonal antibody. 1.25mg/0.05ml

• Pegaptanib: not recommended for AMD use

• NICE indications for wet, active AMD

  • VA between 6/12 and 6/96 (although can be used if VA 6/96 or worse if benefit expected)
  • No structural damage to central fovea
  • Lesion is less than or equal to 12 disc areas in size
  • There is evidence of recent presumed progression eg on FFA or VA changes.

• ‘Active’ disease:

  • Retinal thickening
  • Intra or subretinal haemorrhage
  • Leakage on FFA
  • Increasing CNV size
  • Worsening VA

• PDT cannot be used unless in a clinical trial setting

• Stop anti-VEGF if the eye develops late inactive AMD without likely improvement and consider stopping in cases where VA is progressively deteriorating

• Complications

  • RD
  • Vitreous haemorrhage
  • Endophthalmitis
  • Uveitis
  • RPE tear
  • Stroke
  • MI

Polypoidal Choroidal Vasculopathy (IPCV)

• A distinct, idiopathic form of choroidal neovascularization with a predilection for the peripapillary area

• Classically associated with darkly-pigmented individuals

• Inner choroidal vascular networks develop outward projections

• Dilated choroidal vascular channels: ‘polyps’

• Polyps lead to multiple, recurrent serous and hemorrhagic retinal and RPE detachments and vitreous haemorrhage

• Minimal or no cystic change of the overlying retina andnottypically associated with drusen

• OCT signs

  • Peaked PED
  • Double layer sign
  • Subretinal fluid

• ICG angiography is more helpful the FA: longer wavelengths used in ICG are able to penetrate into the choroid and through dense hemorrhage

  • Demonstrates branching vascular network from choroidal circulation with polypoidal and aneurysmal dilations at the terminal branching vessels
  • ‘Bunch of grapes’ appearance

• Better prognosis than exudative ARMD

• Direct laser can be applied to the lesions (the EVEREST trial showed combination therapy of anti-VEGF with PDT was more effective).

College Contraindications to Ranibizumab

• Visual acuity <6/96
• Permanent structural damage (eg. macular scarring)
• Lesion >12 disc diameters in size
• Hypersensitivity to ranibizumab

AMD studies/trials

Trial	Gist	Result
AREDS 1 and 2	Vitamin supplementation for AMD	Vitamin C,E, zinc oxide and cupric oxide reduce risk of progression Beta carotene increases lung cancer risk
Macular photocoagulation study (MPS)	Compares laser to observation in CNV	Extra and juxtafoveal cases benefitted most from laser. Large subfoveal lesions did not benefit. Defined classic and occult CNV patterns
Treatment of AMD with PDT (TAP)	Evaluate PDT in classic CNV	PDT beneficial for predominantly classic CNV
Verteporfin in PDT (VIP)	Comparing PDT vs sham in occult CNV	PDT with verteporfin is more effective than placebo
VEGF inhibition in ocular neovascularisation (VISION)	Evaluate pegaptinib for subfoveal CNV	Pegaptinib better than sham and PDT
MARINA	Compared lucentis to sham for minimally classic/occult	Lucentis beneficial
anti-VEGF for classic CNV (ANCHOR)	Compared lucentis to PDT for classic CNV	Lucentis better than PDT for classic CNV
PIER	Compared quarterly lucentis dosing to sham	Lucentis better than sham but quarterly dosing less effective than in MARINA/ANCHOR (monthly dosing)
Comparison of AMD treatments trial (CATT)	Compared lucentis to avastin	Avastin was non-inferior to lucentis. Continuous treatment was better than PRN treatment
Inhibit VEGF in CNV (IVAN)	Compared lucentis and avastin	Avastin was non-inferior to lucentis and continuous was better than PRN
VIEW 1 and 2	Compared lucentis and eylea	Eylea non-inferior to lucentis
EVEREST	Compared PDT combined with lucentis with PDT alone and lucentis alone	Combined treatment was beneficial in PCV

Pathological myopia

• Axial length 32.5 or more; or -8.00D or more

• Ocular associations

  • ROP
  • Congenital glaucoma
  • Albinism
  • Ectopia lentils
  • RP
  • Wagner syndrome

• Systemic associations

  • Marfan’s
  • Stickler’s
  • Ehlers-Danlos
  • Alports
  • Down syndrome

• Fundus features

  • Tessellated fundus
  • Chorioretinal atrophy
  • Tilted disc with peripapillary atrophy
  • Staphyloma
  • Lacquer cracks
  • Foster Fuchs spot (raised pigmented scar)
  • Lattice degeneration

• Complications

  • Nuclear sclerotic cataract
  • POAG
  • Myopic macular degeneration with CNV
  • Macular hole
  • Retinal breaks/detachment
  • Cataract surgery: biometry difficult (eg. with staphyloma therefore optical coherence biometry preferable) and LIDRS