Histopathology of Diabetic retinopathy

Question 1

where in the retina are Arterioles and venules (and some capillaries) found

Answer 1

found within the nerve fibre layer/ganglion cell layer

Question 2

where in the retina are Capillaries only found

Answer 2

at the level of the inner nuclear layer

Question 3

what is the capillary wall made up of and how are adjacent capillaries linked

Answer 3

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

Question 4

what do capillary pericytes:
form
provide and
inhibit

Answer 4

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

Question 5

what to capillary pericytes and endothelial cells both share

Answer 5

the same basement membrane

Question 6

what do capillary pericytes and endothelial cells both share

Answer 6

the same basement membrane

Question 7

what 2 things is the capillary basement membrane composed of

Answer 7

collagen glycoproteins and proteoglycans

Question 8

what is the capillary basement membrane a determinant of

Answer 8

vascular permeability and also plays a role in the angiogenesis process

Question 9

what is the homeostasis of the blood-retinal barrier maintained by

Answer 9

the selective permeability of retinal vessels and tight junctions between RPE cells = outer blood retinal barrier

Question 10

which type of examining method is the clinical integrity of the blood-retinal barrier assessed by

Answer 10

fluorescein angiography

Question 11

what is there a causal link of with diabetic retinopathy

Answer 11

between hyperglycaemia and diabetic retinopathy

high HBA1C levels

Question 12

list the 3 classifications of DR

Answer 12

Non-proliferative
– Background
– Pre-proliferative

Proliferative

Maculopathy

Question 13

list 3 clinical features of background retinopathy

Answer 13

Microaneuryms • Haemorrhages • Hard exudates

Question 14

list 3 structural microscopic changes in micro vessels

Answer 14

Basement membrane thickening
Selective pericyte loss
Endothelial damage

Question 15

what is an early histological feature of the disease

Answer 15

Basement membrane thickening

Question 16

how much change in thickness and what is the 2 possible causes of basement membrane thickening

Answer 16

3-5X increase in thickness

caused by increased production or reduced degradation

Question 17

what may a thickened basement membrane impede

Answer 17

may impede endothelial:pericyte and endothelial:glial interaction

Question 18

what is a unique feature of diabetic retinopathy that is not seen in any other retinopathy

Answer 18

Selective pericyte loss

Question 19

what is the endothelial cell:pericyte ratio in a normal and in a diabetic person

Answer 19

normal = 1:1

diabetic = 4:1

Question 20

what may capillary pericyte loss influence

Answer 20

local blood-flow control

Question 21

what does the endothelial changes in diabetes result in and what does endothelial damage result in

Answer 21

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)

Question 22

what is the first ophthalmoscopic sign of diabetic retinopathy

Answer 22

Microaneurysms

Question 23

how do Microaneurysms appear and of what size

Answer 23

Dark red dots (10-100 microns in diameter)

Question 24

name 2 possible theories of microaneurysm pathogenesis

Answer 24

abortive neovascular response or vascular occlusion/dilatation

Question 25

name 2 clinical features which shows ophthalmoscopic evidence of a compromised BRB

Answer 25

the presence of haemorrhages and hard exudates

Question 26

how in particular does hard exudates show evidence of a compromised BRB which retinal layer are they found in

Answer 26

represent leakage of plasma lipoproteinaceous material at the level of the retinal outer plexiform layer

Question 27

how do superficial haemorrhages appear in comparison to deeper ones

Answer 27

Superficial haemorrhages are “flame” shaped e.g. in the NFL - spread laterally Deeper haemorrhages are of the “blot” type = darker and more circular

Question 28

what sign of DR indicates chronic retinal vascular leakage

Answer 28

Macula Oedema Diabetic maculopathy with exudates centred around the fovea which are cystoid in nature

Question 29

list 4 features of Pre-proliferative retinopathy

Answer 29

• Venous changes (beading, loops) • Multiple cotton wool spots • Intra-retinal microvascular abnormalities (IRMA) • Multiple haemorrhages

Question 30

what is venous changes/loops associated with in pre proliferative DR

Answer 30

associated with partitions of the larger retinal venules, which allows blood flow around the loop

Question 31

what are Cotton wool spots associated with

Answer 31

capillary non- perfusion

Question 32

what is Capillary non-perfusion preceded by and what has been recently implicated

Answer 32

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)

Question 33

where in the retinal do cotton wool spots aggregate and what does electron microscopy show

Answer 33

In the nerve fibre layer Electron microscopy shows swollen axons containing accumulated debris of degenerated axoplasm

Question 34

what are cotton wool spots thought to be caused by

Answer 34

an interruption of axoplasmic transport

Question 35

how does IRMA appear and in which areas of the retina mostly

Answer 35

Retinal vessels showing abnormal branching patterns and irregular focal dilations Lie within the retina at margins of areas of capillary non-perfusion

Question 36

what is IRMA a significant risk factor for

Answer 36

neovascularisation

Question 37

what is Proliferative retinopathy characterised by

Answer 37

active growth of new vessels - within the retina due to ischaemia

Question 38

which 2 places can active new vessels occur and which part of the circulation do new vessels arise from

Answer 38

on the disc or elsewhere in the retina typically arise from the venous side of the circulation - where oxygen tension is lowest

Question 39

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 ________ ___________

Answer 39

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

Question 40

where do new vessels proliferate

Answer 40

in the retro hyaloid space

Question 41

list the 5 steps of the pathogenic mechanisms of diabetic retinopathy

Answer 41

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

Question 42

what is the name of the enzyme associated with the pathogenic mechanism of diabetic retinopathy

Answer 42

PKC - protein kinase C

Question 43

what is vascularisation of the retina controlled by

Answer 43

vasoformative growth factors

Question 44

what have several angiogenic growth factors been implicated in and name 5 examples

Answer 44

implicated in retinal neovascularisation VEGF IGF-1 bFGF PDGF PIGF

Question 45

what is an early and potent angiogenic signal

Answer 45

VEGF (vascular endothelial growth factor)

Question 46

what does VEGF cause an increase in

Answer 46

vascular permeability

Question 47

list 5 cells that produce VEGF

Answer 47

RPE ganglion cells Muller cells pericytes smooth muscle cells

Question 48

what consequence does VEGF produced by the RPE lead to with diabetic retinopathy

Answer 48

VEGF acting on the other blood retinal barrier at level of RPE leads to macula oedema

Question 49

what 2 things does VEGF act synergistically with

Answer 49

other growth factors (e.g. IGF-1 and bFGF) and prostaglandins

Question 50

Both Ranibizumab (Lucentis)) and Alfibercept (Eylea) have been approved by NICE for the treatment of DMO in eyes with a central retinal thickness of?

Answer 50

400 micrometres or more at the start of treatment