Case 4 - Multiple Sclerosis

Question 1

epidemiology

Answer 1

• MS typically begins between the ages of 20 and 40 years and it is the leading cause of non-traumatic disability in young adults
• More prevalent in women (2times)
• Caused by Epstein Barr virus (mononucleosis)

Question 2

types

Answer 2

1. Relapsing–remitting MS: the most common form, affecting about 85% of MS patients.
    It is marked by flare-ups (relapses or exacerbations) of symptoms followed by periods of remission, when symptoms improve or disappear.
2. Secondary progressive MS: may develop in some patients with relapsing–remitting disease.
    For many patients, treatment with disease-modifying agents helps delay such progression.
    The disease course continues to worsen with or without periods of remission or levelling off of symptom severity (plateaus).
3. Primary progressive MS: affects approximately 10% of MS patients.
    Symptoms continue to worsen gradually from the beginning.
    There are no relapses or remissions, but there may be occasional plateaus.
    This form of MS is more resistant to the drugs typically used to treat the disease.
4. Clinically and radiologically syndromes: when lesions are first found

Question 3

pathophysiology

Answer 3

• Multiple sclerosis (MS) is a chronic complex neurodegenerative disease, targeting the central nervous system (CNS) – myelin - and widely believed to be autoimmune in nature.
• It is mediated by autoreactive lymphocytes and macrophages that cross the blood-brain barrier (BBB) and enter the CNS where they cause local inflammation that results in demyelination, gliotic scarring, and axonal loss (areas in which these cells are present and this happens are referred to as plaques)

Question 4

myelin targetting

Answer 4

• Myelin sheaths are particularly vulnerable to non-specific products, such as cytotoxic cytokines, excitotoxins, reactive oxygen or nitric oxide species, which are released by activated macrophages and microglia.
• However, the most commonly observed patterns of demyelination are antibody and complement-associated changes, as well as hypoxia-like tissue injury, in which the initiation of demyelination is attributed to the degeneration of distal oligodendrocyte processes and apoptosis of oligocytes –> loss of mature oligodendrocytes

Question 5

lymphocyte involvement

Answer 5

• It is believed that this disease begins in inflammatory-induced lesions consisting mainly of CD8+ T cells (cytotoxic), and CD4+ T cells (helper1= inflammatory), and activate microglia/macrophages
• MS is likely influenced by B cells through a variety of mechanisms, including the establishment of ectopic lymphoid follicles within the CNS, antigen presentation, cytokine production and antibody production

Question 6

BBB involvement

Answer 6

• The disruption of blood–brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for the CNS self-sustained ‘inside-out’ demyelination and neurodegeneration processes
• Centrally activated lymphocytes against self-myelin return in the peripheral compartment to recruit more proinflammatory lymphocytes
• Antigen presenting to B-cells  anti-myelin antibodies
• Leukocyte-derived proinflammatory cytokines activate the endothelial cells in the BBB and induce the expression of additional adhesion molecules, leading to a self-sustained CNS infiltration of more immune cells

Question 7

symptoms

Answer 7

• fatigue.
• vision problems.
• numbness and tingling.
• muscle spasms, stiffness and weakness.
• mobility problems.
• pain.
• problems with thinking, learning and planning.
• depression and anxiety

Question 8

risk factors

Answer 8

• smoking
• vitamin D deficiency
• family history of MS
• female sex

Question 9

genetics

Answer 9

• The human leukocyte antigen (HLA) gene cluster on chromosome 6p21 had been mostly consistently identified as the strongest genetic locus for MS
• HLA genes encode polymorphic cell surface glycoproteins that are involved in immune regulation via recognition of either intracellular nonself (class I) or extracellular proteins (class II)
• HLA is found within the MHC class 2 region which is known to play a large role in MS pathogenesis
• Evidence suggests that the HLA locus has a moderate effect on disease development and many loci have small effects

Question 10

biomarkers

Answer 10

• Oligoclonal bands are bands of immunoglobulins that are seen when patient’s blood serum and CSF are analyzed in parallel. They are created by immunoglobulin G (IgG) and M (IgM) produced by plasma cells in the CNS
• The immunoglobulin (Ig) G index describes the ratio of the CSF/serum quotient of IgG to the CSF/serum quotient of the reference protein albumin –> used as a measure of blood-CSF barrier dysfunction in MS
• MRI to detect white matter lesions
• Gadolinium T1 weighted –> sight of inflammation
• Physical examination
• Visual response
• EEG

Question 11

treatment

Answer 11

no curative only disease altering agents

• It is common practice to treat acute relapses of MS with a short course of a corticosteroid such as intravenous (IV) methylprednisolone or dexamethasone
• Four beta interferon drugs
  o Although the mechanisms of action of interferons beta-1a and beta-1b in MS are unknown, these cytokines perform regulatory functions in the immune system, and their anti-inflammatory properties are thought to be beneficial.
• Glatiramer acetate is a synthesized copolymer polypeptide mixture consisting of l-glutamic acid, l-lysine, l-alanine, and l-tyrosine.
  o The drug was designed to mimic and compete with myelin basic protein
• Mitoxantrone was used to treat certain forms of cancer.
  o Mitoxantrone suppresses the activity of T cells, B cells, and macrophages that are thought to lead the attack on the myelin sheath
• Natalizumab is a recombinant humanized immunoglobulin (IgG4) monoclonal antibody.
  o Natalizumab binds to the alpha 4-subunit of integrins expressed on the surface of leukocytes (except neutrophils), and it inhibits the adhesion of leukocytes to their counterreceptors
• Fingolimod is a sphingosine-1-phosphate receptor modulator that is metabolized by sphingosine kinase to the active metabolite fingolimod phosphate, which in turn blocks the migration of lymphocytes from lymph nodes, thereby reducing the number of lymphocytes in peripheral blood.
• Teriflunomide  stop lymphocyte proliferation
• Anti-CD20 stops b-cell proliferation