Clinical Course

The clinical course of MS has four basic patterns: Relapsing remitting, secondary progressive, primary progressive, and progressive relapsing (Fig. 29-3). Relapsing remitting MS develops into secondary progressive MS in 50% of patients within 10

years and in 75% within 25 years of diagnosis.1 Rating scales are used clinically

(Table 29-2). MS reduces overall life expectancy 6 to 7 years. Suicide is disproportionately high in MS patients, accounting for about 15% of MS-related deaths. r

TREATMENT

Desired Outcomes and General Approach to Treatment

The overall goal of treatment is preventing permanent neurologic damage. There are three general approaches to treatment. First, acute relapses are treated with corticosteroids to speed recovery. Second, disease-modifying therapies decrease the number of relapses, prevent permanent neurologic damage, and prevent disability.

Third, symptomatic treatments minimize the impact of MS on quality of life. Pharmacologic Treatment Treatment of Acute Relapses

The mechanism of action of corticosteroids is unclear, but may involve:

• Prevention of inflammatory cytokine activation

• Inhibition of T-cell activation

• Prevention of immune cells from entering the CNS

• Increased death of activated immune cells

Systemic immune

Blood-Oram

compartment

barrier

Central nervous system

Central nervous system

1: Antigen presentation Ä T-celi activation

2: B-celi activation & antibody formaton

3: Chemotaxis, adhesion & migration

1: Antigen presentation Ä T-celi activation

Antigen presenting cell

2: B-celi activation & antibody formaton

Antigen presenting cell

T lymphocyte

Ag VCD40L CD40

CD5-

CD5-

3: Chemotaxis, adhesion & migration

CCRs CXCRs

T lymphocyte

CCRs CXCRs

MMPS

4: Macrophage activation 4 demyelination

4: Macrophage activation 4 demyelination

5: Axonal degeneration & loss ot trophic Support

6. Programmed eel death-apoptosis

Na4 channel upreguiafon Mrtochondr«!

dysluncton

Ca2,mflux

Ca2,mflux

Ca2'

Cytoskeleton disintegration

FIGURE 29-1. Synoptic view of the immune response in the pathogenesis of MS. Autoreactive T cells recognize with their TCR a specific autoantigen presented by MHC class II molecules and the simultaneous delivery of costimulatory signals (CD 28, B7, CD40, CD 40L) on the cell surface of APCs, such as macrophages, in the systemic immune compartment (panel 1). Activated T lymphocytes can cross the blood-brain barrier in order to enter the CNS. The mechanisms of transendothelial migration is mediated by the complex interplay of CAMs, chemokines, and their receptors (CCRs, CXCRs) and MMPs (panel 3). Within the CNS, T cells activate microglia cells/macrophages (M9) to enhanced phagocytic activity; production of cytokines, such as TNF-a and LT; and the release of toxic mediators, such as NO, propagating demyelination and axonal loss. Abs crossing the blood-brain barrier or locally produced by B cells or mast cells (B*) contribute to this process. Autoantibodies activate the complement cascade resulting in the formation of the membrane-attack complex (C5b-9)

and its subsequent lysis of the target structure (panels 2 and 4). The upregulation of Na and Ca channels on the axon as well as mitochondrial dysfunction and loss of trophic support contribute to axonal disintegration and degeneration (panel 5). The inflammatory response is regulated by antiinflammatory cytokines, such as IL-10 or TGF-ß, as well as IL-2, inducing programmed cell death (apoptosis) in immunoreactive T lymphocytes (panel 6). (Abs, autoantibodies; Ag, antigen; APC, antigen-presenting cells; CAM, cellular adhesion molecule; CNS, central nervous system; IL, inter-leukin; LT, lymphotoxin; MHC, major histocompatibility complex; MMP, matrix metalloproteinases; NO, nitric oxide; T, T cell; TCR, T-cell receptor; TGF, transforming growth factor; TNF, tumor necrosis factor.) (From Ref. 7.)

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