Multiple Sclerosis: Pathogenesis and Characteristics

• Demyelinating Disorders affect the Central Nervous System (CNS).

Learning Objectives

• Understand myelin damage mechanisms in the CNS.
• Define multiple sclerosis with its disease characteristics.
• Identify common risk groups for multiple sclerosis.
• Describe the common and natural disease course of multiple sclerosis.
• Recognize common reasons causing CNS demyelination.

Myelin Function

• Increases the conduction of impulses.
• Protects axons from injury.
• Contains growth factors for axonal survival.

Content of Myelin

• Water comprises 40%.
• Lipids make up 70-85% of dry mass.
• Proteins account for 15-30% of dry mass.
• Key myelin proteins include:
• Myelin/Oligodendrocyte Glycoprotein (MOG).
• Myelin Basic Protein (MBP).
• Myelin Associated Glycoprotein (MAG).
• Proteolipid Proteins (PLP).
• These proteins can be antigenic targets.

What is Multiple Sclerosis?

• Involves central nervous system.
• It is a chronic, immune-mediated demyelinating disease, impacting mainly young age groups.

Pathogenesis

• Autoimmune involvement.
• The immune system's organization is altered.
• The immune system fights against someone's own body.
• Genetics and environmental factors, such as HHV6, EBV and Vitamin D, alongside other genetic components, play a role.

Immun Myelin Damage Mechanism in Multiple Sclerosis

• Genetic and environmental factors can facilitate autoreactive T cells in the blood system that may cause direct myelin damage when they enter to the CNS.
• The expression of endothelial adhesion molecules is up-regulated.
• Intercellular adhesion molecule 1 (ICAM-1), vascular-cell adhesion molecule 1 (VCAM-1), and E-selectin play roles.
• MMP's help penetration of T cells into The Central Nervous System.
• Proinflammatory cytokines like Interferon gamma and tumor necrosis factor 6 (TNF 6), which are released by activated T cells, up-regulate cell-surface molecules on neighboring lymphocytes and antigen-presenting cells.
• Antigen-presenting cells form complexes with myelin antigens like MOG, MBP, MAG, and T cell receptors.
• Enhanced cytokine response results in cytokine-mediated injury.
• Cytokines from T cells activate the B cell response and antibody synthesis.
• Antibody-mediated injury occurs through the digestion of surface, myelin antigens by macrophages, including antibody binding against myelin and oligodendrocytes.
• Direct injury of oligodendrocytes is caused by CD4+ and CD8+ T cells.

Multiple Sclerosis Pathology

• Multiple sclerosis includes inflammation and deydemination.
• Axonal loss and neurodegeneration are included in the pathology

Epidemiology

• The common age group for multiple sclerosis spans 15-45 years old.
• Symptom onset: 70% occurs between 20-40 years old.
  • 10% before 20 years.
  • 20% after 40 years.
• Sex ratio of females to males is 2:1.
• Prevalence varies considerably around the world; it is common in Northern countries.
• Environmental and genetic factors, along with winter seasons, low vitamin levels, and common immune problems, contribute to its spread.

Immune System and the CNS

• Gates to the CNS include the blood (via BBB) and the choroid plexus producing CSF.
• Initial lesions arise around small veins, showing a perivenous orientation in demyelinated lesions.
• Lesion locations usually include:
  • The lateral ventricles.
  • The corpus callosum.
  • The Optic nerve.
  • The Corticomedullary junction.
  • The Brain stem.
  • The Subpial part.
  • The Spinal cord dorsal column.
• The brain MS lesions appear as Dawson's Fingers.

Symptoms and Clinical Findings

• Visual disturbances.
• Cranial nerve involvement.
• Cerebellar problems.
• Weakness/Sensory symptoms.
• Spinal cord issues.
• Urinary/Bowel problems.

Disease Course

• Includes Relapsing-Remitting, Secondary Progressive, Primary Progressive and Progressive-Relapsing types where the acute immune attacks can lead to nearly total recovery.

Relapsing-Remitting MS

• 80-85% of patients initially have this course.
• Progression to SPMS occurs in 25% in 10 years and 90% in 25 years, spanning several years.

Evaluation

• First-order MRI with contrast is vital for active region evaluation.

2010 Revised McDonald Diagnostic Criteria for MS

• Requires eliminating more likely diagnoses and demonstrating dissemination of lesions in space and time.
• Diagnostic uses Chronic, immune mediated demyelinating disease of the cental nervous system.
• Chronic must be seen, or you have to prove chronicity by adding new lesions in MRI, or new attacks.

Treatment

• Acute attacks are treated with intravenous steroids on a daily basis for 3-5 days at 1 g.
• Includes disease-modifying treatments
• Immunomodulatory treatments
• Immunosuppressive treatments
• Targets included are: Blood-Brain Barrier, adhesion molecules, myelin proteins, inflammatory cytokines, T and B cells.

Natural Progression of MS

• In time, if the symptoms show, and the disease become clinical MS, the frequency of new lesions and brain volume will decrease after the second attack.

Other Demyelinating Disorders

• Can include: -Acute Disseminated Encephalomyelitis (ADEM) -Neuromyelitis optica (Devic's Disease) -Demyelinisation in Connective Tissue Diseases (SLE, Sjogren Disease, Neurobehcet Disease) -Marchiafava-Bignami Disease -Central Pontine (Myelinolysis) -Progressive multifocal leukoencephalopathy PML) -Leukodystrophies if a the symptoms appear. If the disease progresses without new lesions or attacks, a different diagnosis is needed.

Acute Disseminated Encephalomyelitis (ADEM)

• It typically follows viral infection or vaccination, within 6 days-6 weeks.
• There is typically a monophasic spread.
• Multiple inflammatory lesions in the brain and spinal cord exist, especially in the white matter.
• Results from infectious antigens and myelin antigens.

Diagnosis of Acute Disseminated Encephalomyelitis (ADEM)

• The onset is typically in under 10 years.
• Use Astrainly for diagnosis.
• Encephalopathy is present, with polysymptomatic manifestations and bilateral optic neuritis alongside the presence of cortical and deep grey matter lesions.
• Lymphocytosis is also indicated.
• No new lesions are present.

Neuromyelitis Optica (Devic's Disease)

• Antibody-mediated inflammation of optic nerves and spinal cord
• AQP4 antibodies occur.

Marchiafava-Bignami Disease

• Central focal demyelination of corpus callosum.
• This is typically observed in vitamin B complex deficiencies.
• The common mechanism is the fast correction of hyponatremia or hypernatremia.

Progressive Multifocal Leukoencephalopathy (PML)

• Human papilloma virus: JC virus infects oligodendrocytes and causes demyelination.