Clinical aspects of retinal degeneration

Question 1

what causes blindness?

Answer 1

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

Question 2

what is the epidemiology of blindness in the uk?

Answer 2

retinal diseases make 70% of blindness in the uk

Question 3

what are causes of retinal blindness?

Answer 3

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

Question 4

what is the choriocapillaris

Answer 4

supplying oxygen and nutrient to outer retina and providing metabolic exchange

Question 5

what is the role of the inner retina

Answer 5

processing and output via ganglion cells to optic nerve and brain

Question 6

what is the role of the outer retina

Answer 6

light detection and phototransduction to produce action potentials to inner retina

Question 7

outline the retinal pigment epithelium

Answer 7

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

Question 8

what does the retinal pigment epithelium secrete

Answer 8

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

Question 9

what is the prevalence and incidence of age related macular degeneration

Answer 9

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

Question 10

what is OCT

Answer 10

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

Question 11

how is AMD classified

Answer 11

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

Question 12

what is seen in early AMD

Answer 12

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

Question 13

what are drusen

Answer 13

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

Question 14

outline intermediate AMD

Answer 14

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

Question 15

outline late AMD

Answer 15

new vessels of choroid vessels grow under and through Bruchs membrane

Question 16

outline wet AMD

Answer 16

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

Question 17

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

Answer 17

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

Question 18

outline dry amd

Answer 18

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

Question 19

outline geographic atrophy (dry amd)

Answer 19

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

Question 20

outline AMD aetiology

Answer 20

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

Question 21

outline AMD pathogenesis

Answer 21

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

Question 22

what is the macula highly vulnerable to

Answer 22

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

Question 23

what are risk factors of AMD

Answer 23

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

Question 24

outline genetic predispositions of AMD

Answer 24

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

Question 25

outline complement dysregulation in AMD

Answer 25

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

Question 26

what is the complement system

Answer 26

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

Question 27

which complement pathway affects amd

Answer 27

ALTERNATE PATHWAY

Question 28

what are the AMD genes

Answer 28

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

Question 29

how many single gene defect dystrophies have been identified

Answer 29

200

Question 30

why is ciliary trafficking important

Answer 30

important in photoreceptor outer segment - if modified affect cilia so cilial genes are important in RPE and RPE function phototransduction cascade

Question 31

outline retinitis pigmentosa

Answer 31

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

Question 32

how is retinitis pigmentosa inherited

Answer 32

as AR AD or X-linked - and mitochondrially inherited aswell

Question 33

what is Stargardt disease

Answer 33

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

Question 34

outline gene therapy to correct simple loss of function defects

Answer 34

‘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

Question 35

what are the problems with using gene therapy

Answer 35

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

Question 36

what is the main way to prevent progression for intermediate AMD

Answer 36

dietary supplements of antioxidants vitamins
Lutein and Zeanthin (naturally occur in retina)
green leafy vegetables - kale, broccoli
stops oxidation
for dry AMD

Question 37

what is the main treatment for wet AMD?

Answer 37

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

Question 38

what are the problems with anti-VEGF agents

Answer 38

dont remove scar (fibrosis)
not 100% effective
have to be repeated monthly
dont reverse underlying degeneration

Question 39

what are some other potential treatments for dry AMD

Answer 39

anti-complement therapies
other anti-inflammatory agents
visual cycle modulation
neuroprotection
cellular treatments for rescue and transplant

Question 40

outline complement inhibition/modulation

Answer 40

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

Question 41

outline anti-inflamamtory treatments for dry AMD

Answer 41

statins - lipid lowering agents with anti-inflammatory properties
integrin inhibitors that target macrophages and decrease inflammasome activation
unknown efficacy

Question 42

outline visual cycle modulation for dry AMD

Answer 42

modulate visual cycle by disrupting conversion of retinol to rhodopsin - decreases toxic waste products such as lipofuchsin and A2E in RTE
unknown efficacy

Question 43

what can we do for late stage AMD

Answer 43

electronic implants and optogenetics

Question 44

what could we do for early stage AMD patients so they maintain vision

Answer 44

replace RPE as it stimulates choriocapilaris growth so could restore that - either with suspension or sheet of cells

Question 45

what is autologous RPE transplantation

Answer 45

e.g RPE patch
works well in some eyes
surgery - to harvest the patch

Question 46

what are the 3 main sources of pluripotent stem cells

Answer 46

human embryonic
nuclear transfer - take somatic cell nucleus and put into oocyte with no nucleus in
induced - what researchers r concentrating on right now

Question 47

outline what RPE cells are like

Answer 47

confluent cuboidal pigmented monolayer
gene expression - RPE65, MERTK
phagocytosis
apical polarity
transepithelial resistance
fluid transport

Question 48

how does eye develop

Answer 48

optic vesicle
invagination forms optic cup
embryonic eye

Question 49

what is the potential role of retinal organoids

Answer 49

take skin or blood cells and reprogramme them to IPS cells (induced pluripotent stem cells)

Question 50

what do we need to consider with pluripotent stem cell transplants?

Answer 50

immune reactivity
impractical to produce IPSc for everyone