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Disorders of the Nervous System > Clinical aspects of retinal degeneration > Flashcards

Clinical aspects of retinal degeneration Flashcards

1
Q

what causes blindness?

A

refractive error
cataracts
both treatable
314 million people have impaired sight
outer retinal disease makes up most of blindess

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2
Q

what is the epidemiology of blindness in the uk?

A

retinal diseases make 70% of blindness in the uk

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3
Q

what are causes of retinal blindness?

A

age related macular degeneration
diabetic retinopathy
retinal vascular occlusions
hereditary retinal disease
retinal detachments
trauma

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4
Q

what is the choriocapillaris

A

supplying oxygen and nutrient to outer retina and providing metabolic exchange

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5
Q

what is the role of the inner retina

A

processing and output via ganglion cells to optic nerve and brain

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6
Q

what is the role of the outer retina

A

light detection and phototransduction to produce action potentials to inner retina

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7
Q

outline the retinal pigment epithelium

A
  • light absorption
  • epithelial transport
  • spatial buffering of ions
  • visual cycle
  • phagocytosis of photoreceptor outer segment
  • secretion
  • immune privelige of the eye
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8
Q

what does the retinal pigment epithelium secrete

A

large variety of signalling molecules including ATP, FGF, transforming growth factor -beta, VEGF and PEDF

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9
Q

what is the prevalence and incidence of age related macular degeneration

A

over 75s - 1/4 of them have AMD
late AMD = loss of vision
prevalent in aged population
11 million people with late AMD (6%)

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10
Q

what is OCT

A

optical coherence tomography - measures coherence while light gets reflected back
high resolution - 3 micron in axial plane

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11
Q

how is AMD classified

A

early - few small drusen
intermediate - larger and more frequent drusen , pigmentary changes in RPE
advanced - dry or geographic atrophy, and wet or neovascular

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12
Q

what is seen in early AMD

A

drusen normally in macular area but can be away from fovea
RPE is very bright on optical coherence tomograph - can see the drusen

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13
Q

what are drusen

A

lipid and microprotein deposits
top layer is the basement layer of Retinal pigment epithelium
they accumulate to form drusen on bruch’s membrane

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14
Q

outline intermediate AMD

A

bigger drusen and more frequent
pigmentary abnomarlities
NOT symptomatic - maybe just darkness e.g cant see where they are going at night but overall good vision

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15
Q

outline late AMD

A

new vessels of choroid vessels grow under and through Bruchs membrane

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16
Q

outline wet AMD

A

because the new choroid vessels grow under RPE or through Bruchs membrane under retina - this can leak and bleed and cause FIBROSIS
causing visual loss

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17
Q

what are the two types of late AMD and what are they also called

A

neovascular (wet) - treatment for some
geographic atrophy - no treatment until recently

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18
Q

outline dry amd

A

choroid and RPE atrophies occur coincidentally
loss of photoreceptor outer segments in that area
secondary photoreceptor atrophy

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19
Q

outline geographic atrophy (dry amd)

A

people with bilateral GA:
- 2/3 unable to drive within 2 years
- 1 in 5 registered blind at 6 years
GA is PLEOMORPHIC - faster progression in some subtypes
- extrafoveal and multifocal GA facter than central
= progressive atrophy of outer retinal layers

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20
Q

outline AMD aetiology

A

as we age, deposits of lipids between RPE and basement membrane, BRUCH’S membrnes thicker, - this has implications on transmission of nutrients and oxygen from choroid
drusen in bruchs - lipoproteins complement proteins, APOE
waste poroducts not recycled correctly

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21
Q

outline AMD pathogenesis

A

age and oxidative stress -> mtDNA damage -> impaired RPE phagocytosis and autophagy
leads to RPE cell dysfunction, accumulation of lipofuscin and alternate complement activation - drusen build up
leads to RPE cell death

22
Q

what is the macula highly vulnerable to

A

oxidative stress
it has a high blood supply and oxygen uptake coupled with light exposure to lipid rich outer segments of photoreceptors , hence oxidatively susceptible

23
Q

what are risk factors of AMD

A

age
environmental = smoking, diet, obesity, hypertension, UV exposure
genetic predispositions

24
Q

outline genetic predispositions of AMD

A

impaired autophagy
susceptibility to oxidative stress
polygenic and complex - sibling with AMD means increased risk 3-6x

25
outline complement dysregulation in AMD
drusen CFH, CFI. C3 C9 of complement system strongly associated with pathogenesis C3 and C5 proteins accumulate in drusen, sub-RPE and AMD. damage from stressors accumulatees with age = drusen and lipofuscin deposits
26
what is the complement system
immunological network 30 proteins - made in liver, abundant act as interface of inate and adaptive immune systems- activated in response to infection and injury - provides inflammation and immune cell recruitment eliminates diseasses cells and pathogens without injuring host
27
which complement pathway affects amd
ALTERNATE PATHWAY
28
what are the AMD genes
polygenic mutations in alternate complement pathway one of common risk factors is variant in FH = CHANGE OF TYROSINE TO HISTIDINE OF CFH gene on 1q - affects ability of 402H to bind less well to substrates in RPE rea = ineffective alternative complement suppression
29
how many single gene defect dystrophies have been identified
200
30
why is ciliary trafficking important
important in photoreceptor outer segment - if modified affect cilia so cilial genes are important in RPE and RPE function phototransduction cascade
31
outline retinitis pigmentosa
night blindness then progressive field constriction followed by central visual loss can start in 20s rods affected first, as rods die cones rely on them more to survive , if rods die then cones die spicules, arteriolar attenuation and pale discs
32
how is retinitis pigmentosa inherited
as AR AD or X-linked - and mitochondrially inherited aswell
33
what is Stargardt disease
example of macular dystrophy autosomal recessive, common 'flecks' of focal lipofuchsin build up ABCA4 gene - codes for protein in outer segment discs of photoreceptors - build up of abnormal phototransduction products in RPE = RPE and photoreceptor loss
34
outline gene therapy to correct simple loss of function defects
'luxturna' is liscensed uses AAV2 (adeno-associated) virus vector - injected subretinally to transfect RPE cells with wild type RPE65 gene successful but expensive to treat both eyes
35
what are the problems with using gene therapy
20-50% of cases gene defect is unknown a lot of defects not correctable gene therapy wont improve function if cells are dead complex and expensive
36
what is the main way to prevent progression for intermediate AMD
dietary supplements of antioxidants vitamins Lutein and Zeanthin (naturally occur in retina) green leafy vegetables - kale, broccoli stops oxidation for dry AMD
37
what is the main treatment for wet AMD?
anti VEGF (anti vascular endothelial growth factor) prevents further choroidal new vessel growth , causes vasoconstriction and reduces vascular leak e.g Ranibizumab, Bevacizumab stops neovascular growth 80% respond
38
what are the problems with anti-VEGF agents
dont remove scar (fibrosis) not 100% effective have to be repeated monthly dont reverse underlying degeneration
39
what are some other potential treatments for dry AMD
anti-complement therapies other anti-inflammatory agents visual cycle modulation neuroprotection cellular treatments for rescue and transplant
40
outline complement inhibition/modulation
dry AMD progression reduced by 30% agents which work at C3 level blocking C3b production and C5 going to C5a redued progression of geographic atrophy - monthly injection
41
outline anti-inflamamtory treatments for dry AMD
statins - lipid lowering agents with anti-inflammatory properties integrin inhibitors that target macrophages and decrease inflammasome activation unknown efficacy
42
outline visual cycle modulation for dry AMD
modulate visual cycle by disrupting conversion of retinol to rhodopsin - decreases toxic waste products such as lipofuchsin and A2E in RTE unknown efficacy
43
what can we do for late stage AMD
electronic implants and optogenetics
44
what could we do for early stage AMD patients so they maintain vision
replace RPE as it stimulates choriocapilaris growth so could restore that - either with suspension or sheet of cells
45
what is autologous RPE transplantation
e.g RPE patch works well in some eyes surgery - to harvest the patch
46
what are the 3 main sources of pluripotent stem cells
human embryonic nuclear transfer - take somatic cell nucleus and put into oocyte with no nucleus in induced - what researchers r concentrating on right now
47
outline what RPE cells are like
confluent cuboidal pigmented monolayer gene expression - RPE65, MERTK phagocytosis apical polarity transepithelial resistance fluid transport
48
how does eye develop
optic vesicle invagination forms optic cup embryonic eye
49
what is the potential role of retinal organoids
take skin or blood cells and reprogramme them to IPS cells (induced pluripotent stem cells)
50
what do we need to consider with pluripotent stem cell transplants?
immune reactivity impractical to produce IPSc for everyone

Disorders of the Nervous System (19 decks)

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