MS Pathophysiology and Animal Models

Question 1

Popescu, B. F. , Pirko, I. & Lucchinetti, C. (2013). Pathology of Multiple Sclerosis. CONTINUUM: Lifelong Learning in Neurology, 19 (4, Multiple Sclerosis), 901-921. doi: 10.1212/01.CON.0000433291.23091.65.

Answer 1

• The pathologic hallmark of MS consists of focal demyelinated plaques within the CNS, with variable degrees of inflammation, gliosis, and neurodegeneration.
• Active MS lesions show pathologic heterogeneity with four major patterns of immunopathology, suggesting that the targets of injury and mechanisms of demyelination in MS may be different in different disease subgroups.
• Subarachnoid space and cortex may be initial sites and targets of the MS disease process, inflammatory cortical demyelination is present early in MS, and meningeal inflammation may drive cortical and white matter injury in some patients.
• The presence of major myelin protein (10 day breakdown) but not minor myelin protein (1-3 day breakdown) degradation products within macrophages indicates a late active lesion. Presence of minor indicates an early lesion.
• Inflammation together with the demyelination and vasogenic edema present in early MS lesions are responsible for their pinkish-yellow, soft, and poorly demarcated appearance on fresh slices of brain and spinal cord.
• Astrocytes become gemistocytes in active lesions
• Pattern I lesions are sharply demarcated perivascular lesions with active demyelination with equal loss of all myelin components, lack of immunoglobulin deposition, and lack of complement activation on a T lymphocyte and activated macrophage/microglia inflammatory background.
• Pattern II lesions are sharply demarcated lesions characterized by active demyelination with equal loss of all myelin components associated with immunoglobulin and complement deposition on myelin, as well as phagocytosis of complement-opsonized myelin debris by macrophages, on an inflammatory background. Variable loss of oligodendrocytes at the active border, with their reappearance in the inactive plaque center and a high incidence of remyelinated shadow plaques.
• Pattern III lesions - ill-defined lesions that show active demyelination with oligodendrocyte apoptosis and preferential loss of the periaxonal myelin components (MAG and CNPase) on an inflammatory background. Loss of oligodendrocytes is pronounced at the active plaque border and extends into the apparently normal periplaque white matter. The inactive center is devoid of oligodendrocytes, and remyelinated shadow plaques are absent. No immunoglobulin deposition/ complement activation.
• Pattern IV lesions are extremely rare and show a profound nonapoptotic death of oligodendrocytes in the periplaque white matter
• Chronic plaques are more frequently seen than active plaques in patients with progressive MS.
• Chronic active plaques are sharply demarcated demyelinated lesions where numerous myelin-laden macrophages are concentrated at the centrifugally expanding edges of the plaque and diminish toward its hypocellular inactive center, while smoldering plaques may contribute to progression and are characterized by a slowly expanding rim of activated microglia (few of which contain myelin degradation products) surrounding their inactive center.
• Chronic inactive plaques are completely demyelinated, sharply circumscribed hypocellular lesions characterized by substantial loss of axons and oligodendrocytes, astrogliosis, and minor infiltration by macrophages/microglia and lymphocytes

Question 2

List the main clinical phenotypes of MS

Answer 2

• Relapsing-remitting MS (RRMS), characterized by periods of neurological worsening following by remissions
• Secondary-progressive MS (SPMS), in which there is gradual progression of neurological dysfunction with fewer or no relapses
• Primary-progressive MS (MS), in which neurological deterioration is observed from onset.

Question 3

List the 5 characteristics in the CNS in MS

Answer 3

• Inflammation beyond classical white matter lesions
• Intrathecal Ig production with oligoclonal bands
• An environment fostering immune cell persistence
• A disruption of the blood–brain barrier outside of active lesions.
• The scars that give the name to the condition are produced by astrocytes healing old lesions. MS is active even during remission periods

Question 4

Describe immunology of MS

Answer 4

• Autoreactive lymphocytes trigger attack of the myelin sheath and ODC
• Demyelination results in axon death
• Affects only the CNS

Question 5

Describe McDonald Criteria

Answer 5

• Two events separated in time or space

Question 6

Describe diagnosis of MS on imaging

Answer 6

MRI:

• Fluid (axial flair)
• BBB breakdown (gallodium enhanced)

Question 7

Describe MS diagnosis via post mortem

Answer 7

• Samples from the brain and spinal cord

- Allows molecular/ hisological investigation

Question 8

Describe appearance on post mortem

Answer 8

• Atrophy
• Enlargement of ventricles
• Demyelination (white matter lesions are perivascular, perventricular, disseminated. Grey matter lesions are Sub Meningeal)
• Remyelinating lesions

Question 9

Describe macrophages in CNS lesions

Answer 9

• The main culprit in MS

- Engulf myelin and become foamy macrophages with lipid vesicles inside

Question 10

Compare white vs grey matter pathology and prognosis

Answer 10

• White matter pathology does not correlate with disease severity
• Grey matter pathology is a predictor for disease severity