Histopathology of Diabetic retinopathy Flashcards
where in the retina are Arterioles and venules (and some capillaries) found
found within the nerve fibre layer/ganglion cell layer
where in the retina are Capillaries only found
at the level of the inner nuclear layer
what is the capillary wall made up of and how are adjacent capillaries linked
Capillary wall made up of a layer of endothelial cells and pericytes surrounded by a shared basement membrane
(pericytes lie outside the endothelial cells)
Capillaries are non - fenestrated and adjacent endothelial cells are linked by tight junctions
what do capillary pericytes:
form
provide and
inhibit
Pericytes form a discontinuous layer outside the endothelium
Pericytes provide mechanical support to the capillary wall and may play a role in the regulation of capillary blood flow
Pericytes have also been shown to inhibit endothelial cell division in culture
what to capillary pericytes and endothelial cells both share
the same basement membrane
what do capillary pericytes and endothelial cells both share
the same basement membrane
what 2 things is the capillary basement membrane composed of
collagen glycoproteins and proteoglycans
what is the capillary basement membrane a determinant of
vascular permeability and also plays a role in the angiogenesis process
what is the homeostasis of the blood-retinal barrier maintained by
the selective permeability of retinal vessels and tight junctions between RPE cells = outer blood retinal barrier
which type of examining method is the clinical integrity of the blood-retinal barrier assessed by
fluorescein angiography
what is there a causal link of with diabetic retinopathy
between hyperglycaemia and diabetic retinopathy
high HBA1C levels
list the 3 classifications of DR
Non-proliferative
– Background
– Pre-proliferative
Proliferative
Maculopathy
list 3 clinical features of background retinopathy
Microaneuryms • Haemorrhages • Hard exudates
list 3 structural microscopic changes in micro vessels
Basement membrane thickening
Selective pericyte loss
Endothelial damage
what is an early histological feature of the disease
Basement membrane thickening
how much change in thickness and what is the 2 possible causes of basement membrane thickening
3-5X increase in thickness
caused by increased production or reduced degradation
what may a thickened basement membrane impede
may impede endothelial:pericyte and endothelial:glial interaction
what is a unique feature of diabetic retinopathy that is not seen in any other retinopathy
Selective pericyte loss
what is the endothelial cell:pericyte ratio in a normal and in a diabetic person
normal = 1:1
diabetic = 4:1
what may capillary pericyte loss influence
local blood-flow control
what does the endothelial changes in diabetes result in and what does endothelial damage result in
Loss of ability of endothelial cells to respond to changes in perfusion pressure
Endothelial damage associated with a breakdown of the blood-retinal barrier (BRB)
what is the first ophthalmoscopic sign of diabetic retinopathy
Microaneurysms
how do Microaneurysms appear and of what size
Dark red dots (10-100 microns in diameter)
name 2 possible theories of microaneurysm pathogenesis
abortive neovascular response or vascular occlusion/dilatation
name 2 clinical features which shows ophthalmoscopic evidence of a compromised BRB
the presence of haemorrhages and hard exudates
how in particular does hard exudates show evidence of a compromised BRB
which retinal layer are they found in
represent leakage of plasma lipoproteinaceous material at the level of the retinal outer plexiform layer
how do superficial haemorrhages appear in comparison to deeper ones
Superficial haemorrhages are “flame” shaped e.g. in the NFL - spread laterally
Deeper haemorrhages are of the “blot” type = darker and more circular
what sign of DR indicates chronic retinal vascular leakage
Macula Oedema
Diabetic maculopathy with exudates centred around the fovea which are cystoid in nature
list 4 features of Pre-proliferative retinopathy
• Venous changes (beading, loops)
• Multiple cotton wool spots
• Intra-retinal microvascular abnormalities (IRMA)
• Multiple haemorrhages
what is venous changes/loops associated with in pre proliferative DR
associated with partitions of the larger retinal venules, which allows blood flow around the loop
what are Cotton wool spots associated with
capillary non- perfusion
what is Capillary non-perfusion preceded by
and what has been recently implicated
vascular occlusion / occurs as a result of capillary plugging
Leukocyte plugging of microvessels has recently been implicated
(vessels become plugged by WBCs which become sticky and attach themselves to the capillary wall and to each other to impede blood flow)
where in the retinal do cotton wool spots aggregate and what does electron microscopy show
In the nerve fibre layer
Electron microscopy shows swollen axons containing accumulated debris of degenerated axoplasm
what are cotton wool spots thought to be caused by
an interruption of axoplasmic transport
how does IRMA appear and in which areas of the retina mostly
Retinal vessels showing abnormal branching patterns and irregular focal dilations
Lie within the retina at margins of areas of capillary non-perfusion
what is IRMA a significant risk factor for
neovascularisation
what is Proliferative retinopathy characterised by
active growth of new vessels - within the retina due to ischaemia
which 2 places can active new vessels occur and which part of the circulation do new vessels arise from
on the disc or elsewhere in the retina
typically arise from the venous side of the circulation - where oxygen tension is lowest
Stages of neovascularisation
Proliferating endothelial cells breach the __________ membrane and form a capillary ______
_______ extends by further endothelial ___________
Sprout becomes ________ forming a capillary _____
Capillary tube becomes invested with __________ cells
New vessels cross the _______ _________ ________ into the retro-hyaloid space
New vessels prone to _________ and ___________
New vessel formation associated with _________ __________ (_______)
Fibrosis causes abnormal attachments to the _______
Contraction of fibrotic tissue leads to _________ traction and _______ _____ formation
__________ _________ formation carries a high risk of ________ ___________
Proliferating endothelial cells breach the basement membrane and form a capillary sprout
Sprout extends by further endothelial proliferation
Sprout becomes canalised forming a capillary tube
Capillary tube becomes invested with perivascular cells
New vessels cross the inner limiting membrane into the retro-hyaloid space
New vessels prone to leakage and haemhorrage
New vessel formation associated with fibroblast proliferation (fibrosis)
Fibrosis causes abnormal attachments to the vitreous
Contraction of fibrotic tissue leads to vitroretinal traction and retinal tear formation
Retinal tear formation carries a high risk of retinal detachment
where do new vessels proliferate
in the retro hyaloid space
list the 5 steps of the pathogenic mechanisms of diabetic retinopathy
Hyperglycaemia
leads to
Biochemical Changes - such as in Polyol pathway PKC activation AGE
leads to
Vessel Damage
leads to
Vessel occlusion - causing Vascular growth factors
leads to
New vessel formation
what is the name of the enzyme associated with the pathogenic mechanism of diabetic retinopathy
PKC - protein kinase C
what is vascularisation of the retina controlled by
vasoformative growth factors
what have several angiogenic growth factors been implicated in and name 5 examples
implicated in retinal neovascularisation
VEGF
IGF-1
bFGF
PDGF
PIGF
what is an early and potent angiogenic signal
VEGF (vascular endothelial growth factor)
what does VEGF cause an increase in
vascular permeability
list 5 cells that produce VEGF
RPE
ganglion cells
Muller cells
pericytes
smooth muscle cells
what consequence does VEGF produced by the RPE lead to with diabetic retinopathy
VEGF acting on the other blood retinal barrier at level of RPE leads to macula oedema
what 2 things does VEGF act synergistically with
other growth factors (e.g. IGF-1 and bFGF) and prostaglandins
Both Ranibizumab (Lucentis)) and Alfibercept (Eylea) have been approved by NICE for the treatment of DMO in eyes with a central retinal thickness of?
400 micrometres or more at the start of treatment
