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Medical Retina > Pathophysiology and Clinical Features of AMD > Flashcards

Pathophysiology and Clinical Features of AMD Flashcards

1
Q

name the 4 clinical features of AMD found on the retina

A

Drusen

Focal pigmentary changes

Geographic atrophy

CNV

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2
Q

name the 5 theories of the pathogenesis of AMD

A

Oxidative Damage
Inflammation
Hypoxia
Role of genetic variation
RPE – the fulcrum of AMD pathogenesis

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3
Q

name the 2 features that describes normal ageing changes of the macula

A

Druplets (small drusen ≤ 63 μm)

No AMD pigmentary abnormalities

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4
Q

what size are druplets

A

≤ 63 μm

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5
Q

name the 2 features that describes early AMD

A

Medium drusen >63 μm ≤ 125 μm

No AMD pigmentary abnormalities

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6
Q

what size are medium drusen

A

between >63 μm & ≤ 125 μm

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7
Q

name the 2 features that describes intermediate AMD

A

Large drusen >125 μm and/or

AMD pigmentary abnormalities

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8
Q

what size are large drusen

A

>125 μm

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9
Q

name the 2 features of late AMD

A

Neovascular AMD (wet AMD) and/or

Geographic Atrophy (dry AMD)

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10
Q

which 4 layers of the eye does AMD affect and which part is only affected at the disease progresses

A

choroidal circulation
Bruch’s membrane
RPE
Photoreceptors

The inner retina is only affected as the disease progresses

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11
Q

what are drusen and where are they found

A

Localised deposits between basement membrane of RPE
and Bruch’s membrane

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12
Q

how do hard drusen appear on the retina

when is it classed as normal

when and what of does it become a risk factor

A

As tiny yellow/white lesions (63μm)

In small numbers, part of normal ageing process

When numerous, risk factor for soft drusen and AMD

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13
Q

soft drusen is _______ in size

may be ________ or _________

may coalesce to form _________ drusen

A

soft drusen is larger in size

may be distinct or indistinct

may coalesce to form confluent drusen

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14
Q

what is soft drusen associated with

(that is not visible with ophthalmoscopy)

A

diffuse thickening of Bruch’s membrane

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15
Q

which layer does drusen cause the elevation of and how does this appear on OCT

A

RPE

appears as bumpiness of the hyper reflective RPE

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16
Q

what can numerous drusen result in

A

drusenoid pigment epithelial detachment (PED)

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17
Q

Annual risk of ____ or foveal ____ in people with bilateral drusen and good VA ~ __% per eye

~___% developed neovascular AMD (nAMD) in __ years

A

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

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18
Q

what are the 4 clinical ocular risk factors for progression to late AMD

A

Larger, greater number of, and more confluent drusen

Focal hyperpigmentation / areas RPE atrophy

Slow choroidal filling

Late AMD in fellow eye

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19
Q

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

A

~50% people drusen increase in volume

~10% regress

~40% stable

precede development of GA or CNV

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20
Q

what 2 features are not visible ophthalmoscopically, but often accompanied by secondary changes e.g. soft drusen, RPE disruption

A

Basal Laminar Deposit (BLamD)
and
Basal Linear Deposit (BLinD)

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21
Q

where in the retina is Basal Laminar Deposit (BLamD) found

A

as material between RPE plasma and basement membranes

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22
Q

what is not specific to AMD (present in normal ageing), but is a continuous layer always present in AMD

A

Basal Laminar Deposit (BLamD)

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23
Q

what is a specific marker for AMD - not found in a healthy ageing eye

A

Basal Linear Deposit (BLinD)

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24
Q

what is Basal Linear Deposit and where is it found

and what does a build up of this lead to

A

Granular, vesicular or membranous debris between RPE basement membrane and Bruch’s membrane.

Build up leads to soft drusen formation

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25
Q

what is the origin of Basal Laminar Deposit (BLamD) production

A

Where excess basement membrane is produced by RPE in response to stress

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26
Q

what is the origin of Basal Linear Deposit (BLinD)

A

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

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27
Q

what 2 things may drusen be derived from

A

clusters of hard drusen or from membranous debris

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28
Q

what 3 things is focal hyperpigmentation caused by

A

Increased melanin content of RPE

RPE cell proliferation

RPE cell migration

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29
Q

how does focal hypopigmentation appear as on the retina and what 3 things is it caused by

A

as small patches of mottled pigment

Reduced melanin content of RPE cells

RPE cell atrophy

RPE layer thinning

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30
Q

what risk does the progression of pigmentary changes cause

A

risk progression to nAMD

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31
Q

what is drusen regression often lead to

A

disruption of overlying RPE causing hypo/hyper pigmentation

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32
Q

what is geographic atrophy GA

A

Confluent areas (>175μm) of RPE cell death

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33
Q

how is visual loss caused by geographic atrophy

and what is affected in the later stages of GA

A

Photoreceptors are metabolically dependent on RPE, therefore die causing visual loss

the inner retinal layers

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34
Q

where does geographic atrophy often start first

A

in parafovea, sparing fovea until later - causing a horse show region of vision loss

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35
Q

as well as the RPE, what else becomes affected by GA and why

A

Underlying choriocapillaris also becomes atrophic as it relies on factors produced by RPE for its ongoing integrity

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36
Q

the onset of GA may be preceded by areas of….because…

A

increased autofluorescence as it may be associated with RPE lipofuscin

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37
Q

which 3 things can lead to the cause of GA

A

drusen regression
flattening of PED
or
on involution of CNV

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38
Q

GA is bilateral in how many % of people?

A

50 % of patients

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39
Q

how many % of people is GA responsible for in those with AMD

A

20%

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40
Q

what can GA co-occur with

A

choroidal neovascularisation

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41
Q

what is the description of a CNV

A

Growth of new blood vessels from choroid to proliferate beneath RPE, or in subretinal space

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42
Q

how is CNV seen on oct

A

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

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43
Q

what 4 other signs are common as a result of the fragile vessels found in a CNV

A

sub or intra retinal haemorrhages
hard exudates
intra-retinal fluid
or
pigment epithelial detachment common

This is how we tend to detect a CNV

44
Q

what forms a disciform scar seen as the end result of a CNV

A

Repeated leakage of blood, serum and lipid which stimulates fibroglial organisation

45
Q

what 4 things results in vision loss due to a CNV

A

presence of:

  • exudates and
  • haemorrhage
  • secondary cell death and
  • formation of disciform scar
46
Q

what visual consequence occurs with progression of a CNV if left untreated

A

1 line logMAR acuity loss in 3 months, 3 lines
by 1 year

47
Q

what is the incidence of someone with unilateral CNV developing in the fellow eye by 12 months and by 4 years

A

12% by 12 months

27% by 4 years

48
Q

what is the peak risk of CNV in the second eye - what is more of a risk thereafter

A

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)

49
Q

what are the 2 phases of chorioretinal neovascular stages

A

intrachoroidal phase
and
active phase

50
Q

what happens in the intrachoroidal phase of the chorioretinal neovascular stage

A

endothelial cells and enlarged pericytes display bud confined to choroidal capillaries

51
Q

what happens in the active phase of the chorioretinal neovascular stage

A

enlarged pericytes spread within BlinD, beneath the RPE and beneath the sub retinal space

52
Q

how can sub-RPE and sub-retinal CNV occur in the active phase of CNV

A

through breaks in Bruch’s membrane

53
Q

name the 3 stimuli for causing CNV and what can these 3 stressors lead to

A

ischaemia, oxidation and inflammation

the increased expression of proangiogenic growth factors such as VEGF-A

54
Q

where in the retina does a PED occur

A

between basement membrane RPE and inner collagenous zone of Bruch’s Membrane

55
Q

what 2 outcomes can a PED have

and what 2 things can it usually leave behind

A

May flatten over time, but may tear (in approx 1 in 10)

Usually leaves area of atrophy or subretinal fibrosis

56
Q

name the 3 types of PED

A

Drusenoid

Serous

Fibrovascular

57
Q

describe the characteristics of a drusenoid PED

A

irregular surface, often with overlying pigmentary changes, slow rate enlargement

58
Q

what 3 things can a drusenoid PED progress into and by what % chance in each

A

GA in 49%
CNV in 13%
persistent drusenoid PED in 38%

59
Q

describe the characteristics of a serous PED

A

smooth, sharply demarcated domeshaped PED

60
Q

how much % of serous PEDs is associated with CNV

A

>80% associated with CNV

61
Q

what 2 things causes an avascualar serous PED

A

thickening and increased hydrophobicity of Bruch’s membrane

Fluid impaired in flowing to choroid from vitreous accumulates beneath RPE

62
Q

A serous PED associated with CNV, may be due to…

A

leakage from new vessels

Or an existing avascular PED may promote CNV

63
Q

describe 3 characteristics of a fibrovascular PED

A

irregular appearance, and breaks in the RPE where underlying CNV exposed

Neovascular membrane mechanically elevates RPE

Often large areas subretinal fluid adjacent to PED

64
Q

what structural changes occurs to the photoreceptors in AMD

A

cell loss initially mainly parafoveal rods

cones lost at a later stage in disease progression

65
Q

what structural changes occur to the the RPE in AMD

A

Lipofuscin accumulation and RPE cell death

66
Q

what structural changes occur to Bruch’s membrane in AMD

A

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

67
Q

what structural changes occurs to the choroid in AMD

A

choroidal blood flow impaired. Choriocapillaris drop-out adjacent to areas of CNV and GA

68
Q

what are the 4 mechanisms involved in the pathogenesis of AMD

A

Genetic predisposition

Oxidation

Immune Response /inflammation

Ischaemia

69
Q

what is oxidation?

A

The removal of electron(s) from an atom / molecule

70
Q

describe the 3 steps of oxidation of a molecule

A

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

71
Q

what are Reactive Oxygen Species (ROS)?

and what 3 things are they made up of

A

Unstable species - extract electrons from other molecules, making them unstable in turn

free radicals

hydrogen peroxide

singlet oxygen

72
Q

how are Reactive Oxygen Species (ROS) produced

and what 5 factors causes an increase in production

A

Produced in cells as a side product of metabolism

irradiation

cigarette smoking

ageing

inflammation

high partial pressure of oxygen

73
Q

how are photoreceptors prone to oxidative damage

A

Photoreceptor outer segments packed with membranes full of polyunsaturated fatty acids (PUFAs)- particularly susceptible to oxidation by ROSs

74
Q

why is the retina so prone to oxidative damage

A

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.

75
Q

what is the mechanism by which ROS forms and oxidative damage occurs in the retina

A

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

76
Q

where is lipofuscin found and what are high levels of this associated with

A

the RPE

High levels associated with RPE and PR degeneration

77
Q

lipofuscin is derived from…

and in turn, this ends up…

A

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)

78
Q

lipofuscin is excited by…

which causes…

A

short wavelength light

causing ROS generation

79
Q

what molecule does lipofuscin contain and what does this cause as a result

A

Contains A2E

which inhibits lysosomal function, resulting in reduced capacity to process waste material and induces cell death by apoptosis

80
Q

which 2 ways does oxidative stress promote neovascularisation

A

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

81
Q

Oxidation of lipids forms…

A

advanced lipoxation end products which accumulate in RPE and Bruch’s membrane

82
Q

Lipid peroxidation results in…

A

degradation of cell membranes, and cell death

83
Q

Oxidation of nucleic acids…

A

contributes to ageing and age-related disease

84
Q

ROS production peaks at…

A

the macula

85
Q

which part of the RPE is particularly vulnerable to oxidative stress

A

RPE mitochondria

possible cause of early RPE dysfunction in AMD

86
Q

which pathway is the immune response linked to when it comes to the pathogenisis of AMD

A

complement pathway

87
Q

The complement pathway consists of…?

A

~30 proteins which are an important component of the innate immune response

88
Q

what can happen to the complement pathway if unregulated

A

can lead to direct damage to host tissue, and immune cells recruited to the vicinity

89
Q

how is the complement pathway linked to the oxidative mechanism

A

Oxidative stress causes upregulation of the complement pathway

90
Q

when it comes to CNV onset, what happens with the RPE in response to the complement proteins

A

The RPE releases proangiogenic VEGF-A in response to complement proteins

91
Q

what do complement proteins C3a and C5a result in with the immune response

A

proteins C3a and C5a results in the recruitment of proangiogenic leukocytes to the choroid - which causes the CNV in neovascular AMD

92
Q

what 3 molecules relating to the immune response in AMD are found in drusen

A

immune response proteins

choroidal dendritic cells

immune antigen presenting cells

93
Q

name the 2 proteins associated with the immune response

A

complement factor H

Membrane attack complex C5b-9

94
Q

what molecule is a systemic marker for subclinical inflammation

A

C-reactive Protein (CRP)

There is a significant association between high levels plasma CRP and AMD

95
Q

what 3 things are involved in CNV, RPE atrophy and breakdown of Bruch’s membrane

A

Macrophages, fibroblasts, leukocytes

96
Q

An increased number of macrophages is a…

A

a hallmark of CNV

some appear to be protective whilst some aggravate CNV growth

97
Q

which genetic variation is one of the most consistant association with AMD risk

and name 3 others that can also contribute

A

complement system genetic variation, especially CFH

CFB

C3

IL8

98
Q

how is the choroid and bruch’s membrane disrupted when it comes to hypoxia and ischaemia in the pathogenesis of AMD

A

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

99
Q

When it comes to hypoxia and ischaemia…

Choroidal non-perfusion is associated with…

A

the location of the CNV

100
Q

Link between delayed choroidal filling and…

A

Dry AMD

101
Q

Increased vascular abnormality associated with…

A

increased risk RPE changes, atrophy, and VA loss

102
Q

when in the retina is oxygen demand very high and why

A

in the dark adapted retina, due to dark current in 120 million rods

103
Q

where in the retina does the oxygen tension decrease to almost zero and when

A

at the photoreceptor inner segments in the dark

104
Q

what 3 things leads to outer retina hypoxia

A

drusen retinal elevation

choroidal ischaemia

vitreoretinal adhesion

105
Q

what does hypoxia lead to the production of in CNV membranes

how does this stimulate neovascularisation

how does this also possibly lead to GA

A

hypoxia-inducible factor (HIF)

HIF stimulates production of VEGF, which stimulates neovascularisation

HIF also causes cell death GA? (apoptosis): possible route to geographic atrophy

Medical Retina (17 decks)

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