DIS - Glaucoma Histopathology I - Week 2 Flashcards
List 6 causes of optic neuropathy and note which is the primary genetic link. Also note which of the 6 neuritis falls under.
Inherited ON - primary genetic link Inflammatory/infectious ON - neuritis Demyelinating ON Toxic ON Compressive ON Ischaemic ON
Give two general appearances of optic neuropathy.
Swollen (oedema)
Pale (pallid)
List the two conditions associated with neuritis and note which of them apply to imflammatory/infectious ON and demyelinating ON.
Papillitis
Retrobulbar neuritis
Inflammatory/infectious ON - both
Demyelinating ON - retrobulbar neuritis
Distinguish what is meant by primary and secondary glaucoma.
Primary - other cause of the glaucoma
Secondary - due to other eye disease
Lis the two kinds of primary glaucoma.
Primary open angle glaucoma
Primary closed angle glaucoma
True or false
Primary closed angle glaucoma always has a high IOP
True
True or false
Primary open angle glaucoma always has a high IOP
False, it may or may not have high IOP
What is the normal rate of RGC loss due to ageing per year? What percentage of neurons are lost by age 80?
5,000 cells per eye per year due to apoptosis
Normally will lose ~30% by 80 years of age
What happens to the rate of RGC loss with glaucoma and by what process? What happens with an ischaemic trigger?
glaucomatous optic neuropathy gives accelerated loss of neurons by apoptosis
An ischaemic trigger results in sudden/complete loss
How long can you expect a normal NFL layer to last before all RGCs are dead naturally due to ageing?
~200 years
What is the mitochondria count like in the prelamina region and what does this signify?
Very dense in this region, signifying a high energy demand for axons here
Given the amount of mitochondria in the prelamina region, describe what mitochondrial abnormalities would promote (4).
Oxidative damage and inflammation
Energy depletion leading to axoplasmic stasis
Both promote apoptosis
What is the density of the capillary plexus in the lamina and about the optic nerve like? Descibe why and why it is this so important in neuropathy ().
Its very dense, so it can deliver oxygen and metabolites to axons/mitochondria to regionsof hgih energy demand
If compromised, it leads to hypoxia/ischaemia
What three pressure gradients are important in the health of the optic nerve and what can an imbalance between these two cause (2)?
Blood pressure and IOP vs post lamina tissue pressure
Imbalance can cause lamina bowing and/or scleral stretch
List 4 consequences of lamina bowing and scleral stretch, specifying which apply to each one.
Both can distort lamina pores to crink capillaries, reducing capillary perfusion to the lamina and peripapillary choroidal region
Collectively, what can a pressure gradient imbalance at the optic nerve head promote (3)?
Promotes neuroinflammatory processes as well as axonal and RGC apoptosis
What three structures at the optic nerve head are particularly susceptible to high IOP that contributes to neuropathy?
Axons
RGC soma
Microglia
Describe what happens when IOP increases, including what happens to the RGC (2) and glial cells and what it produces as a result.
Increased IOP activates RGC pressure receptors, which become stressed and have difficulty sustaining axoplasmic flows through the lamina cribrosa
Glial cells become reactive, increasing the production of TNFα
Consider the response of the glial cells to increased IOP. What does this activate and what does it result in?
TNFα activates inflammatory cascades which damage axons at the lamina
This stops retro-grade flows of neurotrophins
Explain how the glial response to increased IOP ultimately results in damage to the ONH, specifying where the damage occurs and how. Describe how this damage can result in optic disc cupping.
RGC soma and axons cannot survive without neurotrophins, and undergoes apoptosis
This leads to a thinning of the RNFL
The loss of axons weakens the lamina integrity, allowing it to bow backwards and the cup to deepen at the surface
Describe a consequence of optic disc cupping on local blood vessels.
It will crink local small vessels, compromising blood delivery to this and the peripapillary region
List and describe the two main mechanisms behind optic neuropathy in glaucoma.
Acute cell death subsequent to trauma/ischaemia, causing disruption of membranes and neuronal necrosis
Programmed cell death causing neuron apoptosis and autophagy
Does histology of glaucomatous optic neuropathy show that the disease is a clean loss of RGCs and axons or are other layers involved?
It is a clean loss
Describe how the loss of two specific structures (name them) contribute to the loss of the neural rim. Describe what this is called clinically.
Loss of ganglion cells and the loss of axons (or NFL) gives a loss of neural rim
This leads to cupping of the ONH
Define ONH cupping (not just mechanism).
The enlargement of the central depression in the nerve due to a loss of NFL/axons
Is the cup-disc ratio a good indicator of glaucomatous optic neuropathy? Explain.
Poor indicator due to large variation in normal disc size
At what pole is the neuroretinal rim generally most pale (in normal people)?
Palest temporally
What effect does glaucoma generally have on the neuroretinal rim proportions (2)?
Generalised (at the poles mostly) or localised losses (called notches)
Is the ISNT rule a good or poor indicator for glaucoma?
Moderate
What does a loss at poles (in the neuroretinal rim) indicate loss in NFL?
Loss in arcuate regions
Do more superficial or deeper lesions contribute to loss further from the ONH?
Deeper lesions result in loss further from the ONH
Explain the enface view of an OCT scan for the RNFL, including the two types of summary graphs provided and how many areas for each should not be red.
A colour thickness map summarised in quadrants and clockface
A single quadrant or 2x clockfaces should not be red
Describe the pointwise analysis of the enface view for OCT scans of the RNFL and whether or not it should be red.
It is a deviation map comparing to age norms that should not be red
What is meant by symmetry in an enface view of OCT RNFL scans?
Symmetry between the two eyes, red indicating abnormality
What is the TSNIT plot and what kind of curve does it have?
A thickness graph showing thickness of the NFL at each pole, and has a double hump curve
Compare the spatial detail and diagnostic benefit of neuroretinal rim scans vs ganglion cell complex paramacula scans vs NFL (TSNIT) scans. Which is better, and which of the three would be needed to make a diagnosis?
For which kind of glaucoma does it have the best sensitivity? Order them by their value.
GCC gives better spatial detail but has little diagnostic benefit over RNFL scans
Need all three for a diagnosis
In general:
NFL (TNSIT) > GCC > NRR (ONH)
What is the usual cause of cell death in RGCs (2)?
Necrosis or apoptosis due to some trigger
List three necrotic triggers for RGCs.
Very high IOP
Low sBP
Loss of blood (shock)
List 5 apoptotic triggers for RGCs.
Prolonged IOP elevation (above limit)
Loss of mitochondrial capacity (ageing)
Reduced perfusion (chronic hypoxia - moderate IOP)
Neuroinflammatory induction
List three apoptotic mechanisms of RGCs.
Pressure dependent (mechanical) Neuroinflammatory (FAS, TNFα) Mechanisms secondary to mitochondrial ageing
Describe the stretch and tension components of the pressure dependent mechanism for apoptosis in RGCs and what they both ultimately result in.
Stretch - modulates K+ influx causing hyperpolarisation, dislodging Mg ions from NMDA channels
Tension on the lipid membrane dislodges Mg ions from NMDA channels
Collectively, these increase Ca+ levels, causing apoptosis
Explain why high Ca+ levels cause apoptosis (2).
It activates caspases and endonucleases
What effect does Glu have on NMDA channels?
Activates it, resulting in high Ca+ levels
What happens to Glu levels with necrosis to tissue?
Free Glu in the extracellular space
In what two ways does mitochondrial ageing cause neuronal apoptosis?
Produce osixative stress
Reduced ATP
What do axons need to survive and what does it need for axonal transport?
Axons need neurotrophins to survive
Neurotrophins need ATP for axonal transport
From what two sources can neurotrophins come from? Name the neurotrophins.
Brain (LGN/SC) (bDNF) Lamina region (LDNF) brain delivered or lamina delivered neurotrophic factor
List two mechanisms related to neurotrophins that promote apoptosis. Which of these gets worse with increasing IOP?
Lack of bDNF to axoplasmic stasis (ageing)
Lack of LDNF due to elevated IOP
Both get worse with increasing IOP
Can IOP independently affect the lamina?
Yes
Which pores of the lamina are the weakest (2)?
Largest pores and those away from the central retinal artery
Where can the largest pores of the lamina be found? What appearance does this give it?
Superior and inferiorly
Gives an hourglass shape
Which regions of the ONH are sites for early glaucoma loss?
Superior and inferior regions
Does carotid stenosis give glaucoma?
No
Does hypertension give glaucoma?
No
What 7 factors can promote reduced perfusion, leading to glaucomatous optic neuropathy?
Decreased cardiac output Decreased BP at night (nocturnal hypotension) Large IOP variation (spikes) Vasospasm - poor circulation Acute loss of blood (shock) Sleep apnoea (poor oxygenation) Chronic vascular obstruction (tumour)
Are migraines associated with reduced perfusion?
Yes, due to vasospasm
Consider diurnal cycles and the effect on BP. What do small imbalanes promote vs large imbalances?
Keeping this in mind, is BP lowering detrimental?
Small imbalances promote apoptosis
Large imbalanes promote necrosis
If BP lowering is too vigourous, it is detrimental
