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Neuroscience 2 > Pathology of Multiple Sclerosis > Flashcards

Pathology of Multiple Sclerosis Flashcards

Describe the main features of the gross and microscopic pathology of MS Understand how the different cellular pathologies might give rise to clinical symptoms Discuss the nature of the inflammatory changes in the MS brain Correlate the various main pathological features with the clinical course of MS

1
Q

What is the pathological correlate of fatigue in MS?

A

Diffuse white matter changes

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2
Q

State the McDonald criteria for diagnosis of MS

A

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

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3
Q

What do MRI scans look for in MS?

A

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.

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4
Q

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

A

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

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5
Q

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

A

Extensive lesions, often following the lateral ventricles

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6
Q

Describe the appearance of the brain on immunohistochyemistry in MS

A

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

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7
Q

Why do spinal cord lesions often appear shrunken?

A

Due to axonal loss as well as loss of myelin

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8
Q

Describe the pathological changes during the early relapsing stage

A

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

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9
Q

What are CD8 cells?

A

Cytotoxic T cells which can directly degrade cells or tissues

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10
Q

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

A

Macrophages

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11
Q

Which cells are abundant in demyelinated areas?

A

Macrophages

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12
Q

What are foamy macrophages?

A

Macrophages which have taken up lots of lipid from myelin breakdown

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13
Q

Name the four stages of MS lesions

A

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

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14
Q

Describe the appearance of an acute active lesion

A

Macrophages throughout the lesion with synchronous myelin destruction

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15
Q

Describe the appearance of a chronic active lesion

A

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

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16
Q

Describe the appearance of a chronic inactive lesion

A

Hypocellular plaques with no macrophages and no ongoing demyelination

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17
Q

Describe the appearance of a shadow plaque

A

Remyelinated lesion with thin myelin sheaths

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18
Q

In which type of MS is a destructive plaque seen?

A

Marburg-type MS

19
Q

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

A

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

20
Q

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

A

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

21
Q

Why can demyelination lead to chronic symptoms?

A

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

22
Q

Name the two mechanisms of demyelination

A

The bystander effect (inflammation) and autoimmune-mediated degradation

23
Q

Briefly state the consequences of demyelination

A

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

24
Q

Describe the effect of demyelination on sodium ions

A

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

25
Q

Describe the effect of demyelination on calcium ions

A

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

26
Q

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

A

Grey matter lesions

27
Q

Describe typical cortical grey matter pathology

A

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

28
Q

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

A

20-30%

29
Q

Why do tertiary lymphoid structures tend to retain inflammatory cells?

A

They have reduced cerebrospinal fluid flow and a protected microenvironment

30
Q

Describe the relationship between the meninges and grey matter pathology

A

Increased meningeal inflammation correlates with increased grey matter pathology

31
Q

Describe the location and function of tertiary lymphoid organs

A

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

32
Q

Why do tertiary lymphoid organs increase the rate of inflammation?

A

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

33
Q

State at least three over diseases which feature tertiary lymphoid organs

A

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

34
Q

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

A

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

35
Q

Name 3 things which can stop remyelination

A

Ongoing inflammation, accumulating axon damage, loss of oligodendrocytes

36
Q

Can complete remyelination of MS lesions occur?

A

Yes - but not at the same density

37
Q

Where are glial progenitors that can theoretically become oligodendrocytes located?

A

Cerebral cortex, hippocampus, corpus callosum

38
Q

What do glial progenitors that can theoretically become oligodendrocytes express?

A

NG2

39
Q

State 4 possible mechanisms of repair failure

A

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

40
Q

Name a mouse model used to study myelination

A

Cuprizone-induced MS or lysolecithin-induced MS

41
Q

Why are EAE mice bad models of MS?

A

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

42
Q

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

A

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

43
Q

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

A

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

44
Q

What is the TMEV mouse model good for studying?

A

Grey matter lesions and CD8

Neuroscience 2 (30 decks)

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