Pathology of Multiple Sclerosis

Question 1

What is the pathological correlate of fatigue in MS?

Answer 1

Diffuse white matter changes

Question 2

State the McDonald criteria for diagnosis of MS

Answer 2

Two events (lesions causing relapses) disseminated in time and space

Question 3

What do MRI scans look for in MS?

Answer 3

An increase in fluid due to brain atrophy and the brain becoming more porous, with greater fluid movement and blood-brain barrier breakdown - as well as focal lesions. Two modalities used are axial FLAIR and gadolinium enhancement.

Question 4

Describe the surface appearance of the brain post-mortem in MS

Answer 4

Grossly normal, as demyelination of white matter tracts is hard to make out

Question 5

Describe the appearance of the brain on cross-section post-mortem in MS

Answer 5

Extensive lesions, often following the lateral ventricles

Question 6

Describe the appearance of the brain on immunohistochyemistry in MS

Answer 6

Brain atrophy, ventricular enlargement, white matter lesions (especially periventricular and perivascular), grey matter lesions (sub-meningeal), remyelinating areas

Question 7

Why do spinal cord lesions often appear shrunken?

Answer 7

Due to axonal loss as well as loss of myelin

Question 8

Describe the pathological changes during the early relapsing stage

Answer 8

Perivascular immune cell infiltration of CD4 and CD8 T cells and CD20 B cells. This can occur in both the white and grey matter

Question 9

What are CD8 cells?

Answer 9

Cytotoxic T cells which can directly degrade cells or tissues

Question 10

Which are the main cells involved in degrading the myelin sheath?

Answer 10

Macrophages

Question 11

Which cells are abundant in demyelinated areas?

Answer 11

Macrophages

Question 12

What are foamy macrophages?

Answer 12

Macrophages which have taken up lots of lipid from myelin breakdown

Question 13

Name the four stages of MS lesions

Answer 13

Acute active, chronic active, chronic inactive, and shadow plaque

Question 14

Describe the appearance of an acute active lesion

Answer 14

Macrophages throughout the lesion with synchronous myelin destruction

Question 15

Describe the appearance of a chronic active lesion

Answer 15

Numerous macrophages at the expanding plaque edge, with the centre containing few cells

Question 16

Describe the appearance of a chronic inactive lesion

Answer 16

Hypocellular plaques with no macrophages and no ongoing demyelination

Question 17

Describe the appearance of a shadow plaque

Answer 17

Remyelinated lesion with thin myelin sheaths

Question 18

In which type of MS is a destructive plaque seen?

Answer 18

Marburg-type MS

Question 19

State at least 3 inflammatory mechanisms of neuronal damage (the bystander effect)

Answer 19

1) Release of free radicals by peripheral immune cells and activated microglia
2) Glutamate release by activated microglia, resulting in excitotoxicity
3) Hypoxia-like events due to large number of cells and oxygen demand
4) Mitochondrial dysfunction
5) Cytotoxic cytokine (TNF, lymphotoxin, IL-1beta, IFN-gamma) release by immune cells and microglia

Question 20

Describe the difference in the borders of active lesions and chronic silent lesions

Answer 20

Active lesions have ragged borders, whereas chronic lesions are usually well-defined

Question 21

Why can demyelination lead to chronic symptoms?

Answer 21

Without myelin, ions producing electrical signals leak out and fade away, making axons more vulnerable to damage

Question 22

Name the two mechanisms of demyelination

Answer 22

The bystander effect (inflammation) and autoimmune-mediated degradation

Question 23

Briefly state the consequences of demyelination

Answer 23

Channel dysfunction, ionic imbalance, decreased action potential conductivity ATP exhaustion, and mitochondrial damage

Question 24

Describe the effect of demyelination on sodium ions

Answer 24

Demyelination results in the overexpression of sodium channels on the axon surface, allowing more sodium to enter the axon. This increases the activity of the sodium-potassium pump so ATP demand increases, resulting in metabolic problems and mitochondrial damage

Question 25

Describe the effect of demyelination on calcium ions

Answer 25

Due to excess sodium concentration in the axon, the activity of the sodium-calcium pump increases to try and remove it. This results in more calcium entering, triggering caspases and neuronal death by apoptosis and necrosis

Question 26

Do grey or white matter lesions correlate more strongly with clinical symptoms

Answer 26

Grey matter lesions

Question 27

Describe typical cortical grey matter pathology

Answer 27

Demyelination of cortical layers, axon and neurite damage, neuronal and synaptic loss, microglial activation

Question 28

How much of the total cortical grey matter is demyelinated in progressive MS?

Answer 28

20-30%

Question 29

Why do tertiary lymphoid structures tend to retain inflammatory cells?

Answer 29

They have reduced cerebrospinal fluid flow and a protected microenvironment

Question 30

Describe the relationship between the meninges and grey matter pathology

Answer 30

Increased meningeal inflammation correlates with increased grey matter pathology

Question 31

Describe the location and function of tertiary lymphoid organs

Answer 31

Located in the depths of cerebral sulci, tertiary lymphoid organs contain germinal centres important for the maturation of B cells and increasing the efficiency of antibodies

Question 32

Why do tertiary lymphoid organs increase the rate of inflammation?

Answer 32

They are closer to the site of inflamamtion - cells do not have to be recruited from the periphery

Question 33

State at least three over diseases which feature tertiary lymphoid organs

Answer 33

Rheumatoid arthritis, autoimmune thyroiditis, Graves disease, ulcerative colitis, Crohns disease, Lyme disease, hepatitis C

Question 34

Describe the effect of lymphoid-like tissue formation on MS prognosis, as stated by Howell et al in 2011

Answer 34

It causes an earlier age of disease onset, more rapid progression, earlier age at secondary progression, earlier age at wheelchair use, and earlier age of death

Question 35

Name 3 things which can stop remyelination

Answer 35

Ongoing inflammation, accumulating axon damage, loss of oligodendrocytes

Question 36

Can complete remyelination of MS lesions occur?

Answer 36

Yes - but not at the same density

Question 37

Where are glial progenitors that can theoretically become oligodendrocytes located?

Answer 37

Cerebral cortex, hippocampus, corpus callosum

Question 38

What do glial progenitors that can theoretically become oligodendrocytes express?

Answer 38

NG2

Question 39

State 4 possible mechanisms of repair failure

Answer 39

1) No migration of precursor cells into lesion 2) No differentiation of glial precursor cells into oligodendrocytes 3) Differentiation but not maturation so no myelin formation 4) Axons not reactive to myelin so no sheath formation

Question 40

Name a mouse model used to study myelination

Answer 40

Cuprizone-induced MS or lysolecithin-induced MS

Question 41

Why are EAE mice bad models of MS?

Answer 41

Disease process short with no remyelination, no relapses, mainly spinal cord white matter affected

Question 42

Why was the Theiler's murine encephalomyelitis virus (TMEV) mouse model developed?

Answer 42

Due to the epidemiological correlation between early life viral infections (e.g. EBV) and incidence of MS

Question 43

How does Theiler's virus affect mice in TMEV mouse models?

Answer 43

It infects neurons and causes an inflammatory demyelinating disease, mostly of the grey matter with axonal damage preceding demyelination

Question 44

What is the TMEV mouse model good for studying?

Answer 44

Grey matter lesions and CD8