D - Glaucoma Histopath 1 - Week 2

Question 1

Define ocular perfusion

Answer 1

amount of blood getting to the nerve

Question 2

Define papilloedema

Answer 2

oedema in the discs of BOTH eyes. (so has to be bilateral. If unilateral oedema, it’s not papilloedema)

Question 3

How does papilloedema occur?

Answer 3

only occurs from brain/neural causes (e.g. brain tumour)

Question 4

Does the disc in a patient with only glaucoma (glaucoma optic neuropathy) present with swelling or palor?

Answer 4

NO

Question 5

What is the major cause of demyelination of nerves in the eye?

Answer 5

Multiple sclerosis

Question 6

List 6 causes of optic neuropathy that present with swelling/pale/vision afected

Answer 6

Inherited ON
Inflammatory/infectious ON
Demyelinating ON
Toxic ON
Compressive ON
Ischemic ON

Question 7

Is vision normal in glaucoma optic neuropathy?

Answer 7

yes

Question 8

Describe how the nerve appearance typically changes as optic neuropathy progresses

Answer 8

Starts with oedema at 1 week. By 2 months, the oedema gets paler, and by 3 months, oedema goes away and is replaced with just palor.

Question 9

Why can diagnosing optic neuropathy be difficult if a patient has had it for 6 months?

Answer 9

By 6 months, you can’t tell the cause of the disc palor in fundus examination. You would need contact from GP or something from previous appointment to help determine the cause of the pallor

Question 10

What are the 2 main types of glaucoma? Describe typical IOP levels for each

Answer 10

POAG: may or may not have high IOP
PCAG: always has high IOP (>30mmHg at some stage)

Question 11

List two mechanisms for angle closure glaucoma. Can they be seen with VH?

Answer 11

1. Pupil block/iris impeding angle - can be identified with VH
2. Gunk in eye causing TM blockage - need gonio to see this

Question 12

What is the normal number of RGCs lost per eye per year with normal ageing?

Answer 12

~5000 cells/eye/year (due to apoptosis)

Question 13

How does GON impact the number of RGCs lost over time?

Answer 13

accelerates loss of neurons by apoptosis.

Question 14

How does ischemia impact the number of RGCs lost over time? Explain what happens to the RGCs.

Answer 14

Ischemia triggers a sudden/massive loss of RGCs. This results in creating so much gunk etc. that the remaining neurones can no longer survive, causing them to undergo autophagy (a slower loss).

(So a fast big loss, followed by a smaller slower loss)

Question 15

What aspects of the optic nerve makes it susceptible to neuropathy?

Answer 15

1. High mitochondrial density
2. Dense capillary plexus in lamina & about the nerve
3. Complex pressure gradients on tissues/axons
4. Axons, RGC soma & microglia susceptible to increase in IOP

Question 16

Where is high mitochondrial density found in the optic nerve? Why?

Answer 16

Very dense mitochondria in prelamina region due to the high energy demand of axons going through the lamina to the brain.

Question 17

What does mitochondrial abnormality promote? (2)

Answer 17

Oxidative damage + inflammation
Energy depletion

Both promote apoptosis

Question 18

What does “axoplasmic stasis” refer to?

Answer 18

A cease in axonal transport due to energy depletion/mitochondrial abnormality

Question 19

What is the role of the capillary plexus? What happens if it’s compromised?

Answer 19

delivers oxygen & metabolites to axons + mitochondria. If compromised, you can get hypoxia/ischaemia

Question 20

What pressure gradient exists for the optic nerve?

Answer 20

Translaminar Pressure Gradient. (TLPG)
This gradient is created at the lamina cribrosa and is a gradient between the IOP and intracranial pressure (ICP). Can be defined as the difference between IOP and ICP per unit thickness of the lamina cribrosa

TLPG = (IOP/ICP) /thickness of LC

i.e. it’s IOP vs ICP

(or alternatively, you could say IOP + BP vs TP, where TP = the post lamina tissue pressure, which is equivalent to ICP)

Question 21

How can an imbalance of the translaminar pressure gradient affect the optic nerve?

Answer 21

Imbalance can cause lamina bowing &/or scleral stretch

i.e. the lamina starts stretching out as the pressure increases. “It’s like putting too much air in a soccer ball”

Question 22

How can lamina bowing & scleral stretch affect the appearance and function of the optic nerve?

Answer 22

Distorts lamina pores which breaks capillaries, thus reducing capillary perfusion to the lamina and peripapillary choroid (scleral) region (hypoxia)

Question 23

What does an imbalance of the translaminar pressure gradient ultimately lead to?

Answer 23

promotes neuroinflammatory processes and axonal and RGC apoptosis

Question 24

Where in the optic nerve do nerve fibres become myelinated?

Answer 24

in the post-laminar region

Question 25

How can an increase in IOP affect axons, RGC soma and microglia of the optic nerve? (6)

Answer 25

Increased IOP activates RGC pressure receptors RGCs get stressed - can't sustain axoplasmic flow through LC Glial cells become reactive - increase production of TNFalpha Inflammatory cascades activate - damage lamina axons Damage stops neurotrophins (FOOD) flowing to axons Axons get sick.

Question 26

What does axonal damage at the lamina lead to? (4)

Answer 26

``` RGC apoptosis (b/c no neurotrophins/food) Leads to thinning in RNFL Loss of axons weakens lamina integrity causing lamina to bow backwards (cup deepens) Capillaries break etc. ```

Question 27

What happens to the optic nerve in advanced stages of IOP damage? (3)

Answer 27

Apoptosis + neuroinflammation ==> soma/axon death Lamina weakens further (b/c large loss of axons) + remodels Lamina bows even further backward

Question 28

Which kind of glaucoma is likely responsible for acute cell death? What about programmed cell death?

Answer 28

Acute cell death: PACG | Programmed cell death: POAG

Question 29

Describe the histological changes in: A: Early GON (glaucomatous optic neuropathy) B: Advanced GON [NB: the images from this slide are practically guaranteed on exam!]

Answer 29

A: Clean loss of NFL and GCL = apoptosis. INL is ok B: increased thickness of NFL due to gliosis. INL thins (*gliosis = activation of glia cells. e.g. astrocytes)

Question 30

How does RGC loss manifest clinically? (2) Explain

Answer 30

Loss of neural rim. Via 1. loss of ganglion cell and 2. loss of axons or NFL This expresses as increased CDR

Question 31

Is CDR a good indicator of GON? What do we consider a normal CDR?

Answer 31

Poor indicator of GON due to large variation in disc size. Normal CDR = 0.7

Question 32

What aspect of the optic nerve appearance is a good indicator of GON?

Answer 32

NRR thickness! | ---ISNT rule is a moderate indicator for GON

Question 33

Briefly describe how visual field defects progress with glaucoma in 4 steps

Answer 33

1. Little blind spots in arcuate regions (b/w 10 and 20 deg) 2. Blind spots join up to form arcuate scotoma 3. Inferior seidel scotoma formation 4. Central Ronne's step (a nasal step) formation

Question 34

What are the 3 tests for counting RGC numbers? And which is better in general?

Answer 34

O.N (NRR photos) NFL (TSNIT) Macula GCC In general, NFL > GCC > NRR

Question 35

Which test for counting RGCs is good for myopes? Why not use NFL for myopes?

Answer 35

ON is good for myopes. | NFL not as good b/c NFL is thinner in myopes

Question 36

How many of the 3 tests for counting RGCs are needed to make a diagnosis?

Answer 36

all of them

Question 37

List 4 apoptotic triggers for GON induced RGC death

Answer 37

prolonged IOP elevation loss of mitochondrial capacity reduced perfusion neuroinflammatory induction (technically this has been covered earlier in lecture)

Question 38

List 3 necrotic triggers for GON induced RGC death

Answer 38

very high IOP low sBP loss of blood (shock) (causing acute trauma/ischemia)

Question 39

What apoptotic mechanisms are there? (3)

Answer 39

``` Pressure dependent mechanisms (mechanical) Neuroinflammatory mechanisms (FAS, TNFalpha) Mechanisms secondary to mitochondrial aging ```

Question 40

What are the 2 pressure dependent mechanisms of apoptosis? Explain them

Answer 40

Stretch mechanism: Potassium influx via TRAAK/TRASK alters NMDA channel causing Ca+ influx Tension mechanism: Tension on the membrane alters NMDA causing Ca+ influx Too much calcium = apoptosis

Question 41

How do the 2 pressure dependent mechanisms alter the NMDA channel?

Answer 41

By dislodging the Mg-ion

Question 42

What inflammatory responses can cause apoptosis? (2)

Answer 42

Direct pressure effect on microglia or Reduced perfusion (BP-IOP) --- i.e. chronic imbalance of IOP and blood supply at optic nerve

Question 43

What does a chronic imbalance of IOP and blood supply at the optic nerve lead to? (3)

Answer 43

Reduced mitochondrial function Increased inflammatory cytokines Reduced axoplasmic flow (leading to reduced bDNF)

Question 44

What does mitochondrial aging generally do? (2)

Answer 44

``` Produces oxidative stress Reduced ATP (energy) (therefore harder to do axonal transport, therefore reduced neurotrophic/food support) ```

Question 45

What 2 mechanisms from mitochondrial aging promote apoptosis

Answer 45

1. Lack of bDNF due to axoplasmic stasis 2. Lack of lamina derived neurotrophic factors (LDNF) due to elevated IOP *bDNF = brain derived neurotrophic factor

Question 46

How can IOP independently affect the lamina?

Answer 46

the actual lamina pores get larger and move further away from each other