Pathophysiology and Clinical Features of AMD Flashcards
name the 4 clinical features of AMD found on the retina
Drusen
Focal pigmentary changes
Geographic atrophy
CNV
name the 5 theories of the pathogenesis of AMD
Oxidative Damage
Inflammation
Hypoxia
Role of genetic variation
RPE – the fulcrum of AMD pathogenesis
name the 2 features that describes normal ageing changes of the macula
Druplets (small drusen ≤ 63 μm)
No AMD pigmentary abnormalities
what size are druplets
≤ 63 μm
name the 2 features that describes early AMD
Medium drusen >63 μm ≤ 125 μm
No AMD pigmentary abnormalities
what size are medium drusen
between >63 μm & ≤ 125 μm
name the 2 features that describes intermediate AMD
Large drusen >125 μm and/or
AMD pigmentary abnormalities
what size are large drusen
>125 μm
name the 2 features of late AMD
Neovascular AMD (wet AMD) and/or
Geographic Atrophy (dry AMD)
which 4 layers of the eye does AMD affect and which part is only affected at the disease progresses
choroidal circulation
Bruch’s membrane
RPE
Photoreceptors
The inner retina is only affected as the disease progresses
what are drusen and where are they found
Localised deposits between basement membrane of RPE
and Bruch’s membrane
how do hard drusen appear on the retina
when is it classed as normal
when and what of does it become a risk factor
As tiny yellow/white lesions (63μm)
In small numbers, part of normal ageing process
When numerous, risk factor for soft drusen and AMD
soft drusen is _______ in size
may be ________ or _________
may coalesce to form _________ drusen
soft drusen is larger in size
may be distinct or indistinct
may coalesce to form confluent drusen
what is soft drusen associated with
(that is not visible with ophthalmoscopy)
diffuse thickening of Bruch’s membrane
which layer does drusen cause the elevation of and how does this appear on OCT
RPE
appears as bumpiness of the hyper reflective RPE
what can numerous drusen result in
drusenoid pigment epithelial detachment (PED)
Annual risk of ____ or foveal ____ in people with bilateral drusen and good VA ~ __% per eye
~___% developed neovascular AMD (nAMD) in __ years
Annual risk of CNV or foveal GA in people with bilateral
drusen and good VA ~ 3% per eye
~10% developed neovascular AMD (nAMD) in 4 years
what are the 4 clinical ocular risk factors for progression to late AMD
Larger, greater number of, and more confluent drusen
Focal hyperpigmentation / areas RPE atrophy
Slow choroidal filling
Late AMD in fellow eye
name in % values, the 3 patterns of changes to drusen of the population who are affected by it in a 1 year period
and what can the regression of drusen do
~50% people drusen increase in volume
~10% regress
~40% stable
precede development of GA or CNV
what 2 features are not visible ophthalmoscopically, but often accompanied by secondary changes e.g. soft drusen, RPE disruption
Basal Laminar Deposit (BLamD)
and
Basal Linear Deposit (BLinD)
where in the retina is Basal Laminar Deposit (BLamD) found
as material between RPE plasma and basement membranes
what is not specific to AMD (present in normal ageing), but is a continuous layer always present in AMD
Basal Laminar Deposit (BLamD)
what is a specific marker for AMD - not found in a healthy ageing eye
Basal Linear Deposit (BLinD)
what is Basal Linear Deposit and where is it found
and what does a build up of this lead to
Granular, vesicular or membranous debris between RPE basement membrane and Bruch’s membrane.
Build up leads to soft drusen formation
what is the origin of Basal Laminar Deposit (BLamD) production
Where excess basement membrane is produced by RPE in response to stress
what is the origin of Basal Linear Deposit (BLinD)
Where the RPE expels damaged cell constituents through the basolateral membrane (which is what causes the waste material) this then forms BLinD and soft drusen
Initial RPE injury may be oxidative, inflammatory or ischaemic
what 2 things may drusen be derived from
clusters of hard drusen or from membranous debris
what 3 things is focal hyperpigmentation caused by
Increased melanin content of RPE
RPE cell proliferation
RPE cell migration
how does focal hypopigmentation appear as on the retina and what 3 things is it caused by
as small patches of mottled pigment
Reduced melanin content of RPE cells
RPE cell atrophy
RPE layer thinning
what risk does the progression of pigmentary changes cause
risk progression to nAMD
what is drusen regression often lead to
disruption of overlying RPE causing hypo/hyper pigmentation
what is geographic atrophy GA
Confluent areas (>175μm) of RPE cell death
how is visual loss caused by geographic atrophy
and what is affected in the later stages of GA
Photoreceptors are metabolically dependent on RPE, therefore die causing visual loss
the inner retinal layers
where does geographic atrophy often start first
in parafovea, sparing fovea until later - causing a horse show region of vision loss
as well as the RPE, what else becomes affected by GA and why
Underlying choriocapillaris also becomes atrophic as it relies on factors produced by RPE for its ongoing integrity
the onset of GA may be preceded by areas of….because…
increased autofluorescence as it may be associated with RPE lipofuscin
which 3 things can lead to the cause of GA
drusen regression
flattening of PED
or
on involution of CNV
GA is bilateral in how many % of people?
50 % of patients
how many % of people is GA responsible for in those with AMD
20%
what can GA co-occur with
choroidal neovascularisation
what is the description of a CNV
Growth of new blood vessels from choroid to proliferate beneath RPE, or in subretinal space
how is CNV seen on oct
disrupted, raised RPE, and presence of hyper-reflective membrane and can also see presence of intra or sub retinal fluid as dark hypo reflective pockets
what 4 other signs are common as a result of the fragile vessels found in a CNV
sub or intra retinal haemorrhages
hard exudates
intra-retinal fluid
or
pigment epithelial detachment common
This is how we tend to detect a CNV
what forms a disciform scar seen as the end result of a CNV
Repeated leakage of blood, serum and lipid which stimulates fibroglial organisation
what 4 things results in vision loss due to a CNV
presence of:
- exudates and
- haemorrhage
- secondary cell death and
- formation of disciform scar
what visual consequence occurs with progression of a CNV if left untreated
1 line logMAR acuity loss in 3 months, 3 lines
by 1 year
what is the incidence of someone with unilateral CNV developing in the fellow eye by 12 months and by 4 years
12% by 12 months
27% by 4 years
what is the peak risk of CNV in the second eye - what is more of a risk thereafter
4 years
Then there’s an increasing risk of GA
(if a CNV hasn’t developed in that eye by this time then the eye will remain dry)
what are the 2 phases of chorioretinal neovascular stages
intrachoroidal phase
and
active phase
what happens in the intrachoroidal phase of the chorioretinal neovascular stage
endothelial cells and enlarged pericytes display bud confined to choroidal capillaries
what happens in the active phase of the chorioretinal neovascular stage
enlarged pericytes spread within BlinD, beneath the RPE and beneath the sub retinal space
how can sub-RPE and sub-retinal CNV occur in the active phase of CNV
through breaks in Bruch’s membrane
name the 3 stimuli for causing CNV and what can these 3 stressors lead to
ischaemia, oxidation and inflammation
the increased expression of proangiogenic growth factors such as VEGF-A
where in the retina does a PED occur
between basement membrane RPE and inner collagenous zone of Bruch’s Membrane
what 2 outcomes can a PED have
and what 2 things can it usually leave behind
May flatten over time, but may tear (in approx 1 in 10)
Usually leaves area of atrophy or subretinal fibrosis
name the 3 types of PED
Drusenoid
Serous
Fibrovascular
describe the characteristics of a drusenoid PED
irregular surface, often with overlying pigmentary changes, slow rate enlargement
what 3 things can a drusenoid PED progress into and by what % chance in each
GA in 49%
CNV in 13%
persistent drusenoid PED in 38%
describe the characteristics of a serous PED
smooth, sharply demarcated domeshaped PED
how much % of serous PEDs is associated with CNV
>80% associated with CNV
what 2 things causes an avascualar serous PED
thickening and increased hydrophobicity of Bruch’s membrane
Fluid impaired in flowing to choroid from vitreous accumulates beneath RPE
A serous PED associated with CNV, may be due to…
leakage from new vessels
Or an existing avascular PED may promote CNV
describe 3 characteristics of a fibrovascular PED
irregular appearance, and breaks in the RPE where underlying CNV exposed
Neovascular membrane mechanically elevates RPE
Often large areas subretinal fluid adjacent to PED
what structural changes occurs to the photoreceptors in AMD
cell loss initially mainly parafoveal rods
cones lost at a later stage in disease progression
what structural changes occur to the the RPE in AMD
Lipofuscin accumulation and RPE cell death
what structural changes occur to Bruch’s membrane in AMD
Thickening and deposition of hydrophobic material occurs with age, and to an increased level in AMD 15.
Results in impaired transport of oxygen, fluid, growth factors, retinoids, waste products and other materials
what structural changes occurs to the choroid in AMD
choroidal blood flow impaired. Choriocapillaris drop-out adjacent to areas of CNV and GA
what are the 4 mechanisms involved in the pathogenesis of AMD
Genetic predisposition
Oxidation
Immune Response /inflammation
Ischaemia
what is oxidation?
The removal of electron(s) from an atom / molecule
describe the 3 steps of oxidation of a molecule
Once the removal of electron(s) from an atom / molecule takes place…
The oxidising agent B accepts these electrons, and is thereby reduced
Once oxidised, compound A needs to steal electrons to restabilise (so becomes an oxidising agent)
Oxidation leads to a change in the structure of cellular macromolecules to form abnormal materials - so are no longer able to be recognised and processed by the cell machinery, so they tend to accummulate as waste products
what are Reactive Oxygen Species (ROS)?
and what 3 things are they made up of
Unstable species - extract electrons from other molecules, making them unstable in turn
free radicals
hydrogen peroxide
singlet oxygen
how are Reactive Oxygen Species (ROS) produced
and what 5 factors causes an increase in production
Produced in cells as a side product of metabolism
irradiation
cigarette smoking
ageing
inflammation
high partial pressure of oxygen
how are photoreceptors prone to oxidative damage
Photoreceptor outer segments packed with membranes full of polyunsaturated fatty acids (PUFAs)- particularly susceptible to oxidation by ROSs
why is the retina so prone to oxidative damage
The retina experiences high cumulative levels of light irradiation. Short wavelength light is main culprit: prolonged exposure in animals causes retinal atrophy similar to AMD.
what is the mechanism by which ROS forms and oxidative damage occurs in the retina
Retina contains photosensitisers (chromophores) including rhodopsin and lipofuscin
Photosensitisers absorb light and cause a chemical reaction
The retina has highest O2 consumption of any tissue in the body
Phagocytosis by RPE of outer segments generates ROSs
where is lipofuscin found and what are high levels of this associated with
the RPE
High levels associated with RPE and PR degeneration
lipofuscin is derived from…
and in turn, this ends up…
incomplete degradation by RPE of abnormal oxidised material
reducing functional cytoplasmic space
(due to accumulation of the lipofuscin and causes mechanical damage to the RPE)
lipofuscin is excited by…
which causes…
short wavelength light
causing ROS generation
what molecule does lipofuscin contain and what does this cause as a result
Contains A2E
which inhibits lysosomal function, resulting in reduced capacity to process waste material and induces cell death by apoptosis
which 2 ways does oxidative stress promote neovascularisation
Oxidative stress causes RPE to upregulate the production of proangiogenic molecules such as VEGF-A
Photoxidative stress of the RPE also activates the complement pathway and results in deposition of complement proteins which promotes neovascularisation
Oxidation of lipids forms…
advanced lipoxation end products which accumulate in RPE and Bruch’s membrane
Lipid peroxidation results in…
degradation of cell membranes, and cell death
Oxidation of nucleic acids…
contributes to ageing and age-related disease
ROS production peaks at…
the macula
which part of the RPE is particularly vulnerable to oxidative stress
RPE mitochondria
possible cause of early RPE dysfunction in AMD
which pathway is the immune response linked to when it comes to the pathogenisis of AMD
complement pathway
The complement pathway consists of…?
~30 proteins which are an important component of the innate immune response
what can happen to the complement pathway if unregulated
can lead to direct damage to host tissue, and immune cells recruited to the vicinity
how is the complement pathway linked to the oxidative mechanism
Oxidative stress causes upregulation of the complement pathway
when it comes to CNV onset, what happens with the RPE in response to the complement proteins
The RPE releases proangiogenic VEGF-A in response to complement proteins
what do complement proteins C3a and C5a result in with the immune response
proteins C3a and C5a results in the recruitment of proangiogenic leukocytes to the choroid - which causes the CNV in neovascular AMD
what 3 molecules relating to the immune response in AMD are found in drusen
immune response proteins
choroidal dendritic cells
immune antigen presenting cells
name the 2 proteins associated with the immune response
complement factor H
Membrane attack complex C5b-9
what molecule is a systemic marker for subclinical inflammation
C-reactive Protein (CRP)
There is a significant association between high levels plasma CRP and AMD
what 3 things are involved in CNV, RPE atrophy and breakdown of Bruch’s membrane
Macrophages, fibroblasts, leukocytes
An increased number of macrophages is a…
a hallmark of CNV
some appear to be protective whilst some aggravate CNV growth
which genetic variation is one of the most consistant association with AMD risk
and name 3 others that can also contribute
complement system genetic variation, especially CFH
CFB
C3
IL8
how is the choroid and bruch’s membrane disrupted when it comes to hypoxia and ischaemia in the pathogenesis of AMD
Disruption of choroidal circulation in AMD
Thickened Bruch’s membrane + drusen
- further reduce oxygen availability
- forms barrier to VEGF-A transmission to choroid (required to maintain a healthy choroid)
- causes choroidal atrophy and thus further deposition in Bruch’s
and further hypoxia
When it comes to hypoxia and ischaemia…
Choroidal non-perfusion is associated with…
the location of the CNV
Link between delayed choroidal filling and…
Dry AMD
Increased vascular abnormality associated with…
increased risk RPE changes, atrophy, and VA loss
when in the retina is oxygen demand very high and why
in the dark adapted retina, due to dark current in 120 million rods
where in the retina does the oxygen tension decrease to almost zero and when
at the photoreceptor inner segments in the dark
what 3 things leads to outer retina hypoxia
drusen retinal elevation
choroidal ischaemia
vitreoretinal adhesion
what does hypoxia lead to the production of in CNV membranes
how does this stimulate neovascularisation
how does this also possibly lead to GA
hypoxia-inducible factor (HIF)
HIF stimulates production of VEGF, which stimulates neovascularisation
HIF also causes cell death GA? (apoptosis): possible route to geographic atrophy
