Multiple Sclerosis

Question 1

What is Multiple Sclerosis?

Answer 1

is an immune mediated DEmyelination disease of the central nervous system.

Question 2

What is affected in MS?

Answer 2

myelin sheath (which is a protective membrane that wraps around the axon of a nerve cell) is destroyed with inflammation
- therefore, OLIGODENDROCYTES which are making myelin are affected too

Question 3

When does MS occur?

Answer 3

when activated immune cells INFILTRATE the CNS and ATTACK myelin.
- suggests MS is not a single disease but rather a SPECTRUM (immune mediated disease)

Question 4

What is the Epidemiology of MS?

Answer 4

• Canada’s disease (highest prevalence)
• majority b/t 15-40 yoa

Question 5

What is a reason why MS is called a spectrum disease?

Answer 5

b/c see a spectrum of symptoms b/c MS can happen ANYWHERE in CNS
- like brain, visual area etc.
- therefore, we see a spectrum of symptoms

Question 6

What are the main symptoms?

Answer 6

• Fatigue
• Numbness, tingling
• Walking difficulty
• Pain
• Muscle spasms

Question 7

What are the identifies predisposing factors (triggers) of MS?

Answer 7

GENETIC: 200 genes have been associated
- identical twins show 30% chance
- siblings show 2-5% chance

• FEMALES>males (but males seem to have worse symptoms)
• Viruses (EBV*, VZV)
• Pollutants
• VITAMIN D DEFICIENCY!
• Smoking
• Excessive salt intake

regardless, causes immune mediated attack

Question 8

How do you diagnose for MS?

Answer 8

• BLOOD TESTS
• SPINAL TAP (lumbar puncture) - to check abnormalities in antibodies
• NEUROLOGICAL & EVOKED POTENTIAL TESTS
• MRI - check for lesions in brain/SC (MS inflammatory lesions around BV’s & demyelinated MS plaques)

Question 9

What are the clinical classification of MS?

Answer 9

1. Progressive Relapsing (PRMS)
2. Secondary Progressive (SPMS)
3. Primary Progressive (PPMS)
4. Relapsing Remitting (RRMS)

Question 10

Progressive Relapsing (PRMS):

Answer 10

Steady progression since onset with super-imposed attacks.

Question 11

Secondary progressive (SPMS):

Answer 11

Initial RRMS that suddenly begins to decline without periods of remission and relapses.

(like RRMS, but overtime the immune attack becomes constant which causes a steady progression of disability)

Question 12

Primary Progressive (PPMS)

Answer 12

Gradual progression of the disease from its onset with no relapses or remissions

(constant attack, but with bouts superimposed, which means this disability happens even faster)

Question 13

Relapsing Remitting (RRMS):

Answer 13

Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission (the MOST COMMON)

Question 14

What does MS involve?

Answer 14

BOTH innate & adaptive immune response peripherally & in the CNS

Question 15

Immune response in the pathogenesis of MS

MS pathogenesis starts from periphery:

Answer 15

1. Antigen presentation & T-cell activation
2. B-cell activation & antibody formation
3. Chemotaxins, adhesion & migration
4. Macrophage activation & demyelination
5. Axonal degredation & loss of trophic support
6. Apoptosis

Question 16

What is the role of T cells in pathogenesis of MS?

Answer 16

1. Activated Th cells leave the lymph nodes & migrate into the CNS across the BBB
2. In the CNS, Th cells interact with resident microglia, are reactivated upon recognition of myelin antigens & produce cytokines & chemokines & chemokines that promote (Th1 & Th17) or suppress (Treg) the inflammatory cascade & damage in the CNS

Question 17

What are the pathological consequences of immune mediated attacks in MS?

Answer 17

demyelination & neurodegeneration
- recurrent autoimmune attacks destroy myelin & lead to oligodendrocyte cell death via NECROSIS & APOPTOSIS

Question 18

Summarize the neurological events in the course of MS

Answer 18

1. @ beginning, immune attacks are freq. & active (then decrease or disappear throughout)
2. Brain volume reduces sign. throughout the course
3. Axons begin to be lost as inflammation decreases/disappears

Question 19

How does MS start & then progress?

Answer 19

starts as inflammatory immune mediated (inflammation plays a big role), but with the course of the disease, neurodegeneration becomes predominate
- when neurodegeneration is occurring we have progression NOT relapses

Question 20

What is the difference b/t RIS & CIS?

Answer 20

RIS = radiologically isolated syndrome (came in for something & has NO MS symptoms, but MS is detected)

CIS = clinically isolated syndrome (clinical presentation of MS symptoms - has to be followed up to see if they have it or not –> many become mS)

Question 21

What is PROGRESSIVE MS associated with?

Answer 21

with axon degeneration causing irreversible & permanent deficits
- WITHOUT myelin & oligodendrocyte support systems, axons degenerate permanently resulting in permanent neurological impairments (brain shrinks)

Question 22

How is MS treated?

Answer 22

• NO CURE
• disease modifying treatments that typ. REDUCE immune attacks, slowing disease progression & managing MS symptoms

Question 23

What are examples of disease modifying treatments to reduce immune attacks in MS?

Answer 23

• CORTICOSTEROIDS (reduce inflammation)
• PLASMA EXCHANGE (if symptoms are new, severe & haven’t responded to steroids; this will remove harmful proteins)
• IMMUNOSUPPRESSANTS

Question 24

For relapsing-remitting MS, there are several drugs that results in:

Answer 24

o Fewer relapses

o Lower severity of MS

o Interferon beta has been the earliest approved medication for MS

o MS attacks often recur when these medicines are stopped

(use anti-inflammatory drugs - there are many)

Question 25

For primary-progressive MS,

Answer 25

ocrelizumab (Ocrevus) is the only approved drug in Canada (neuroprotective therapies used for progression - less drugs avail)

Question 26

We also need to therapies to promote remyelination. What is the importance of this?

Answer 26

Myelin repair is essential for: - RESTORATION of structure - CONDUCTION of neural signals along axons - & PROTECTION of axons from degeneration Effective tx to promote remyelination will protect axons from permanent degeneration in progressive MS

Question 27

When does remyelination decline?

Answer 27

in PROGRESSIVE MS - initially in the course of MS, remyelination happens sucessfully resulting in remission - but as MS progresses, relapses are LONGER as remyelination becomes challenging - generation of oligodendrocytes & myelin is a complex process that requires proper differentiation & maturation of OPCs to myelinating cells

Question 28

What are the animal models of MS for research?

Answer 28

- EAE - Toxic-mediated demyelination - TMEV-IDD

Question 29

Explain the Experimental autoimmune encephalomyelitis (EAE) mouse model

Answer 29

Day 1: Myelin peptide vaccination Day 1-2: Administration of pertussis toxin Day 9-14: Onset of disease Day 16: Peak of disease Day 14-21: Partial recovery

Question 30

What are the recent advances in MS research?

Answer 30

- MESENCHYMAL STEM CELLS (reduce harmful inflammation in brain) - DIET (reducing saturated fats, excluding dairy, reducing salt) - VITAMIN D3 - EXERCISE & PHYSICAL ACTIVITY

Question 31

How is Vitamin D related?

Answer 31

- Deficiency in VitD3 is a risk factor - VitD3 promotes the differentiation of immunosuppressive Treg cells - promotes Treg (anti-inflammatory Tcell) therefore Th1 cells can't overactivate - need VitD for balance in our immune response, so we'll be able to resolve inflammation quicker

Question 32

Explain how LINGO-1 is an ex of how medications are targeted towards a specific mech in MS

Answer 32

LINGO-1 suppresses oligodendrocyte precursor cell maturation and myelination and its inhibition by opicinumab is being tested in clinical trials (if inhibited, it cannot suppress oligodendrocytes) therefore, Anti-Lingo is being studied to help