Clinical aspects of retinal degeneration Flashcards
what causes blindness?
refractive error
cataracts
both treatable
314 million people have impaired sight
outer retinal disease makes up most of blindess
what is the epidemiology of blindness in the uk?
retinal diseases make 70% of blindness in the uk
what are causes of retinal blindness?
age related macular degeneration
diabetic retinopathy
retinal vascular occlusions
hereditary retinal disease
retinal detachments
trauma
what is the choriocapillaris
supplying oxygen and nutrient to outer retina and providing metabolic exchange
what is the role of the inner retina
processing and output via ganglion cells to optic nerve and brain
what is the role of the outer retina
light detection and phototransduction to produce action potentials to inner retina
outline the retinal pigment epithelium
- light absorption
- epithelial transport
- spatial buffering of ions
- visual cycle
- phagocytosis of photoreceptor outer segment
- secretion
- immune privelige of the eye
what does the retinal pigment epithelium secrete
large variety of signalling molecules including ATP, FGF, transforming growth factor -beta, VEGF and PEDF
what is the prevalence and incidence of age related macular degeneration
over 75s - 1/4 of them have AMD
late AMD = loss of vision
prevalent in aged population
11 million people with late AMD (6%)
what is OCT
optical coherence tomography - measures coherence while light gets reflected back
high resolution - 3 micron in axial plane
how is AMD classified
early - few small drusen
intermediate - larger and more frequent drusen , pigmentary changes in RPE
advanced - dry or geographic atrophy, and wet or neovascular
what is seen in early AMD
drusen normally in macular area but can be away from fovea
RPE is very bright on optical coherence tomograph - can see the drusen
what are drusen
lipid and microprotein deposits
top layer is the basement layer of Retinal pigment epithelium
they accumulate to form drusen on bruch’s membrane
outline intermediate AMD
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
outline late AMD
new vessels of choroid vessels grow under and through Bruchs membrane
outline wet AMD
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
what are the two types of late AMD and what are they also called
neovascular (wet) - treatment for some
geographic atrophy - no treatment until recently
outline dry amd
choroid and RPE atrophies occur coincidentally
loss of photoreceptor outer segments in that area
secondary photoreceptor atrophy
outline geographic atrophy (dry amd)
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
outline AMD aetiology
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
outline AMD pathogenesis
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
what is the macula highly vulnerable to
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
what are risk factors of AMD
age
environmental = smoking, diet, obesity, hypertension, UV exposure
genetic predispositions
outline genetic predispositions of AMD
impaired autophagy
susceptibility to oxidative stress
polygenic and complex - sibling with AMD means increased risk 3-6x
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
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
which complement pathway affects amd
ALTERNATE PATHWAY
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
how many single gene defect dystrophies have been identified
200
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
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
how is retinitis pigmentosa inherited
as AR AD or X-linked - and mitochondrially inherited aswell
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
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
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
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
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
what are the problems with anti-VEGF agents
dont remove scar (fibrosis)
not 100% effective
have to be repeated monthly
dont reverse underlying degeneration
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
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
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
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
what can we do for late stage AMD
electronic implants and optogenetics
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
what is autologous RPE transplantation
e.g RPE patch
works well in some eyes
surgery - to harvest the patch
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
outline what RPE cells are like
confluent cuboidal pigmented monolayer
gene expression - RPE65, MERTK
phagocytosis
apical polarity
transepithelial resistance
fluid transport
how does eye develop
optic vesicle
invagination forms optic cup
embryonic eye
what is the potential role of retinal organoids
take skin or blood cells and reprogramme them to IPS cells (induced pluripotent stem cells)
what do we need to consider with pluripotent stem cell transplants?
immune reactivity
impractical to produce IPSc for everyone
