MULTIPLE SCLEROSIS PATHOPHYSIOLOGY

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Pathogenesis
Anatomy

The lesions of MS (plaques)

1 or 2 mm to several cm

Acute MS lesions
perivenular cuffing with inflammatory mononuclear cells
T cells and macrophages, which also infiltrate the surrounding white matter

Sites of inflammation
the blood-brain barrier is disrupted, but vessel wall is preserved.

Pathogenesis
Anatomy

In many lesions,
MYELIN-SPECIFIC AUTOANTIBODIES
promoting demyelination directly stimulating macrophages and microglial cells (bone marrowderived CNS phagocytes) that scavenge the myelin debris

As lesions evolve,
astrocytic proliferation (gliosis).

Pathogenesis
Anatomy

Surviving oligodendrocytes or those that differentiate from precursor cells

may partially remyelinate the surviving naked axons shadow plaques

In many lesions
oligodendrocyte precursors are present but fail to remyelinate.

Pathogenesis
Anatomy

Ultrastructural studies of MS lesions

different underlying pathologies may exist in different patients.
1. whether the inflammatory cell infiltrate is assoc. with antibody deposition and activation of complement 2. whether the target of the immunopathologic process is the myelin sheath itself or the cell body of the oligodendrocyte.

Pathogenesis
Anatomy

Relative sparing of axons is typical of MS

partial or total axonal destruction can also occur, esp. within highly inflammatory lesions. AXONAL LOSS
major contributor to irreversible neurologic disability in MS

Pathogenesis Physiology

Nerve conduction in MYELINATED AXON

saltatory manner
nerve impulse jumping from one node of Ranvier to the next without depolarization of the axonal membrane underlying the myelin sheath between nodes.

Pathogenesis Physiology
MYELINATED AXON
faster conduction velocities (~70 m/s) than the slow velocities

UNMYELINATED
1 m/s by continuous propagation in nerves. Conduction block occurs when the nerve impulse is unable to traverse the demyelinated segment.

Pathogenesis Physiology

CONDUCTION BLOCK
when the nerve impulse is unable to traverse the demyelinated segment. the resting axon membrane becomes hyperpolarized due to the exposure of voltage-dependent K channels that are normally buried underneath the myelin sheath.

Pathogenesis Physiology

TEMPORARY CONDUCTION BLOCK

often follows a demyelinating event before sodium channels (originally concentrated at the nodes) redistribute along the naked axon

Pathogenesis Physiology

Pathogenesis Physiology

REDISTRIBUTION
ultimately allows continuous propagation of nerve AP through the demyelinated segment. On occasion, conduction block is incomplete
e.g., high- but not low-frequency volleys of impulses

Pathogenesis Physiology

VARIABLE CONDUCTION BLOCK

can occur with raised body temp. or metabolic alterations
explain clinical fluctuations that vary from hour to hour or appear with fever or exercise.

CONDUCTION SLOWING
when the demyelinated segments support only (slow) continuous nerve impulse propagation.

Immunology Autoreactive T Lymphocytes

MYELIN BASIC PROTEIN

T cell antigen in EAE and probably also in human MS.

Activated MBP-reactive T cells

blood, CSF and within MS lesions. DR2 may influence the autoimmune response
it binds with high affinity to a fragment of MBP (spanning amino acids 8996), stimulating T cell responses to this self-protein.

Immunology Humoral Autoimmunity

B cell activation and antibody responses

necessary for the full development of demyelinating lesions to occur, both in experimental models and in human MS. Increased numbers of clonally expanded B cells with properties of postgerminal center memory or antibody-producing lymphocytes
MS lesions, CSF

Immunology Humoral Autoimmunity

MYELIN SPECIFIC AUTOANTIBODIES

some directed against MYELIN OLIGODENDROCYTE GYCOPROTEIN detected bound to vesiculated myelin debris in MS plaques.

In the CSF, elevated levels of locally synthesized immunoglobulins and oligoclonal antibodies derived from expansion of clonally restricted plasma cells are also characteristic of MS.

Immunology Cytokines

PATTERN OF OLIGOCLONAL BANDING

unique to each individual one recent report indicated that some bands recognized EBV antigens

Immunology Triggers

CYTOKINES AND CHEMOKINES

regulate many of the cellular interactions that operate in MS.

Proinflammatory TH1 cytokines

IL- 2 TNF IFN
directly injure oligodendrocytes or the myelin membrane.

play key roles in activating and maintaining autoimmune responses

Immunology Triggers

EARLY IN MS
most disease activity is clinically silent. triggers are unknown relapses after nonspecific upper respiratory infections
suggests that either molecular mimicry between viruses and myelin antigens or viral superantigens activating pathogenic T cells may play a role in MS pathogenesis

Neurodegeneration

AXONAL DAMAGE
occurs in every newly formed MS lesion,

CUMULATIVE AXONAL LOSS

the major cause of progressive and irreversible neurological disability in MS. As many as 70% of axons are lost from the lateral corticospinal tracts in pts with advanced paraparesis from MS longitudinal MRI studies
progressive axonal loss over time within established, inactive, lesions.

Neurodegeneration

Knowledge of the mechanisms responsible for axonal injury

incomplete

Unclear whether demyelination

is a prerequisite for axonal injury in MS.

Demyelination can result in :

reduced trophic support for axons redistribution of ion channels destabilization of AP membrane potentials.

Neurodegeneration

AXONS can initially adapt, but eventually distal and retrograde degeneration occurs. EARYL PROMOTION OF REMYELINATION and PRESERVATION OF OLIGODENDROCYTES
important therapeutic goals in MS.

Neurodegeneration

Some evidence suggests that: AXONAL DAMAGE is mediated directly

by resident and invading inflammatory cells and their toxic products
microglia, macrophages, CD8 T lymphocytes

Activated microglia
likely to cause axonal injury through the release of NO and oxygen radicals and via glutamate,
toxic to oligodendrocytes and neurons.

Genetic Consideration

Caucasians at higher risk than Africans or Asians

Risk of Developing MS 1 in 3 1 in 15 1 in 25 1 in 50 1 in 100 1 in 1000 1 in 1000 If an identical twin has MS If a fraternal twin has MS If a sibling has MS If a parent or half-sibling has MS If a first cousin has MS If a spouse has MS If no one in the family has MS