Multiple SclerosisPresentation by Jacqueline Godin

What is MS?

Pathophysiologic condition where nerve fibers in CNS lose their myelin Causes slow transmission of impulses

Autoimmune disease Body’s own immune system attacks the myelin sheath

Arises from combination of genetic and environmental factors Genetic predisposition causes increased susceptibility to

environmental factors that may cause the disease Some possible environmental factors: viral infections,

environmental toxins, and vitamin D deficiency Not generally fatal, but chronic and disabling for some Currently no cure

Symptoms Common

Fatigue Numbness Balance & Coordination

Problems Depression Vision Problems Dizziness and Vertigo Spasticity Pain Gradual Paralysis

Less Common Respiration/Breathing

Problems Swallowing Problems Headache Speech Disorders Tremors Hearing Loss Seizures

• The disruption of nerve signals produces the primary symptoms of MS, which vary depending on where the damage has occurred

Four Courses Relapsing-Remitting

Clearly defined attacks (exacerbations) of worsening neurologic function followed by partial or complete remissions (85%)

Primary-Progressive Slowly worsening neurologic function from the start with no

distinct relapses or remissions (10%) Secondary-Progressive

Following an initial period of Relapsing-Remitting in which the disease worsens more steadily, with or without occasional remissions or flare-ups

Progressive-Relapsing Steadily worsening disease from the start with clear attacks of

worsening neurologic function along the way; disease continues to progress without remissions (5%)

http://www.youtube.com/watch?v=KGzsriXqg6U

The Process

Characterized by local infiltration of T cells and macrophages into the nerve tissue, local multiple areas of inflammation in this tissue, activation of the glia (astrocytes and microglia), damage to oligodendrocytes, demyelination of nerve fibers, and injury of axons

A hardened scar (sclerosis) forms at the sites of myelin damage These scars interfere with and can eventually block the

propagation of action potentials in these axons

Mechanism

Mechanism Normally blood-brain barrier (BBB) is impermeable to blood

cells, but infiltration by T cells causes the appearance of inflammation and development of demyelination This can be initiated by the penetration of viral and bacterial

factors in the nerve tissue, which results in the appearance of their proteins on the membranes of oligodendrocytes and myelin sheaths

A subsequent autoimmune response is then directed against myelin antigens, which leads to disorders of recognition of these antigens

The viral/bacterial proteins exposed on the surface cause antigen-presenting cells to induce primary activation of autoreactive T cells circulating in the vascular system

T lymphocytes proliferate and express cell adhesion molecules (CAMs) and cytokines, intensifying damage to the BBB and causing an abnormal increase in its permeability

Mechanism Then the endothelial leukocyte-connected CAMs with the

participation of metalloproteinases of the external matrix (MEMs) promote passing of T cells, B cells, plasmocytes, and activated microphages via the basal membrane of the BBB in the CNS

Then T cells in the presence of local autoantigens induce the development of scattered foci of inflammation in the CNS

T cell-synthesized proinflammatory cytokines (interleukin 2, lymphotoxin, γ-interferon, and tumor necrosis factor (TNF-α)) promote the continued intensification of the BBB permeability

Under these conditions, B cells and antibodies present in the blood migrate in the CNS much more intensely and, via activation of the complement system, form membrane-attacking complexes that damage myelin and oligodendrocytes

Mechanism In addition, cytokines trigger the processes of activation of

microglial cells, macrophages, and astrocytes As a result, microglial cells begin to secrete inflammatory

cytokines, MEMs, and increased amounts of free radicals Also, microglia frequently play the role of antigen-presenting cells

in the CNS, which intensify the development of a pathological immune response in MS

Astrocytes also acquire the properties typical of immune effector cells, producing a few cytokines, antigens, CAMs, and immunomodulators

Therefore, microglia together with astrocytes form the abnormal immune response in the cerebral tissue

Mechanism

As a result of the previously stated local auto-immune response and local vascular inflammation, the myelin sheaths are subjected to destruction, while oligodendrocytes are injured This leads to demyelination and degeneration of the axons with

subsequent formation of sclerotic plaques The damaged myelin is then phagocytized and destroyed by

microglia-activated astrocytes and macrophages penetrating the CNS

Mechanism

Secretion of chemokines is activated by proinflammatory cytokines In MS, endothelial cells synthesize MCP-3; activated perivascular

T cells synthesize RANTES; macrophages synthesize MIP-1β; astrocytes synthesize RANTES, MCP-1,2,3, and MIP-1β; microglial units synthesize MIP-1β

Chemokines mediate humoral and cellular immune reactions and can contribute to the intensification and distribution of the inflammatory reaction and process of demyelination

Mechanism MEMs synthesized by activated T cells, monocytes,

astrocytes, and microglia in MS promote invasion of inflammatory cells in the CNS after damage to the basal membrane of the BBB and extracellular matrix They are also directly involved in the process of destruction of

myelin With the development of MS, the impairment of the process

of lipid peroxidation results in the production of increased amounts of free radicals, which promote extensive injury to the myelin and oligodendrocytes

Mechanism Summary

The autoimmune response and the vascular inflammation causes demyelination and degeneration of axons, formation of sclerotic plaques (lesions), and injury of oligodendrocytes

The damaged myelin on the axons is then phagocytized by astrocytes and macrophages

Treatments

*As neural inflammation resolves, some remyelination can occur along with some recovery of function, however this may be due to neural plasticity

No cure, but some effective strategies include modifying the disease course, treating exacerbations, managing symptoms, improving functioning and safety, and providing emotional support

Treatment: Modifying Disease Course

Some modifying agents include Copaxone, Gilenya, and Rebif

The drug Gilenya, for example, acts by retaining certain lymphocytes in the lymph nodes, thereby preventing those cells from crossing the BBB into the CNS This reduces inflammatory

damage to nerve cells

Treating Exacerbations Managing Symptoms

Treatments

Exacerbation is caused by inflammation in the CNS that causes damage to the myelin and slows or blocks the transmission of nerve impulses Most commonly treated with

high-dose corticosteroids to reduce the inflammation

Symptoms are highly variable from person to person and from time to time, but most can be managed through medication, self-care techniques, rehabilitation, or use of assistive devices

Promoting Function Through Rehabilitation

Role of Complementary and Alternative Medicine

Treatments

Rehab programs focus on helping improve or maintain ability to perform effectively and safely at home and work

Focus on overall fitness and energy management, while addressing problems with accessibility and mobility, speech and swallowing, and memory

Important at all stages of the disease

Includes everything from exercise and diet to food supplements, stress management strategies, and lifestyle changes

Examples: Yoga, hypnosis, relaxation techniques, etc.

Complementary = used in conjunction with conventional medical treatments

Alternative = instead of

Questions?