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
What is the pathological correlate of fatigue in MS?
Diffuse white matter changes
State the McDonald criteria for diagnosis of MS
Two events (lesions causing relapses) disseminated in time and space
What do MRI scans look for in MS?
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.
Describe the surface appearance of the brain post-mortem in MS
Grossly normal, as demyelination of white matter tracts is hard to make out
Describe the appearance of the brain on cross-section post-mortem in MS
Extensive lesions, often following the lateral ventricles
Describe the appearance of the brain on immunohistochyemistry in MS
Brain atrophy, ventricular enlargement, white matter lesions (especially periventricular and perivascular), grey matter lesions (sub-meningeal), remyelinating areas
Why do spinal cord lesions often appear shrunken?
Due to axonal loss as well as loss of myelin
Describe the pathological changes during the early relapsing stage
Perivascular immune cell infiltration of CD4 and CD8 T cells and CD20 B cells. This can occur in both the white and grey matter
What are CD8 cells?
Cytotoxic T cells which can directly degrade cells or tissues
Which are the main cells involved in degrading the myelin sheath?
Macrophages
Which cells are abundant in demyelinated areas?
Macrophages
What are foamy macrophages?
Macrophages which have taken up lots of lipid from myelin breakdown
Name the four stages of MS lesions
Acute active, chronic active, chronic inactive, and shadow plaque
Describe the appearance of an acute active lesion
Macrophages throughout the lesion with synchronous myelin destruction
Describe the appearance of a chronic active lesion
Numerous macrophages at the expanding plaque edge, with the centre containing few cells
Describe the appearance of a chronic inactive lesion
Hypocellular plaques with no macrophages and no ongoing demyelination
Describe the appearance of a shadow plaque
Remyelinated lesion with thin myelin sheaths
In which type of MS is a destructive plaque seen?
Marburg-type MS
State at least 3 inflammatory mechanisms of neuronal damage (the bystander effect)
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
Describe the difference in the borders of active lesions and chronic silent lesions
Active lesions have ragged borders, whereas chronic lesions are usually well-defined
Why can demyelination lead to chronic symptoms?
Without myelin, ions producing electrical signals leak out and fade away, making axons more vulnerable to damage
Name the two mechanisms of demyelination
The bystander effect (inflammation) and autoimmune-mediated degradation
Briefly state the consequences of demyelination
Channel dysfunction, ionic imbalance, decreased action potential conductivity ATP exhaustion, and mitochondrial damage
Describe the effect of demyelination on sodium ions
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
Describe the effect of demyelination on calcium ions
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
Do grey or white matter lesions correlate more strongly with clinical symptoms
Grey matter lesions
Describe typical cortical grey matter pathology
Demyelination of cortical layers, axon and neurite damage, neuronal and synaptic loss, microglial activation
How much of the total cortical grey matter is demyelinated in progressive MS?
20-30%
Why do tertiary lymphoid structures tend to retain inflammatory cells?
They have reduced cerebrospinal fluid flow and a protected microenvironment
Describe the relationship between the meninges and grey matter pathology
Increased meningeal inflammation correlates with increased grey matter pathology
Describe the location and function of tertiary lymphoid organs
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
Why do tertiary lymphoid organs increase the rate of inflammation?
They are closer to the site of inflamamtion - cells do not have to be recruited from the periphery
State at least three over diseases which feature tertiary lymphoid organs
Rheumatoid arthritis, autoimmune thyroiditis, Graves disease, ulcerative colitis, Crohns disease, Lyme disease, hepatitis C
Describe the effect of lymphoid-like tissue formation on MS prognosis, as stated by Howell et al in 2011
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
Name 3 things which can stop remyelination
Ongoing inflammation, accumulating axon damage, loss of oligodendrocytes
Can complete remyelination of MS lesions occur?
Yes - but not at the same density
Where are glial progenitors that can theoretically become oligodendrocytes located?
Cerebral cortex, hippocampus, corpus callosum
What do glial progenitors that can theoretically become oligodendrocytes express?
NG2
State 4 possible mechanisms of repair failure
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
Name a mouse model used to study myelination
Cuprizone-induced MS or lysolecithin-induced MS
Why are EAE mice bad models of MS?
Disease process short with no remyelination, no relapses, mainly spinal cord white matter affected
Why was the Theiler’s murine encephalomyelitis virus (TMEV) mouse model developed?
Due to the epidemiological correlation between early life viral infections (e.g. EBV) and incidence of MS
How does Theiler’s virus affect mice in TMEV mouse models?
It infects neurons and causes an inflammatory demyelinating disease, mostly of the grey matter with axonal damage preceding demyelination
What is the TMEV mouse model good for studying?
Grey matter lesions and CD8
