Multiple Sclerosis Flashcards
What is Multiple Sclerosis?
is an immune mediated DEmyelination disease of the central nervous system.
What is affected in MS?
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
When does MS occur?
when activated immune cells INFILTRATE the CNS and ATTACK myelin.
- suggests MS is not a single disease but rather a SPECTRUM (immune mediated disease)
What is the Epidemiology of MS?
- Canada’s disease (highest prevalence)
- majority b/t 15-40 yoa
What is a reason why MS is called a spectrum disease?
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
What are the main symptoms?
- Fatigue
- Numbness, tingling
- Walking difficulty
- Pain
- Muscle spasms
What are the identifies predisposing factors (triggers) of MS?
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
How do you diagnose for MS?
- 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)
What are the clinical classification of MS?
- Progressive Relapsing (PRMS)
- Secondary Progressive (SPMS)
- Primary Progressive (PPMS)
- Relapsing Remitting (RRMS)
Progressive Relapsing (PRMS):
Steady progression since onset with super-imposed attacks.
Secondary progressive (SPMS):
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)
Primary Progressive (PPMS)
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)
Relapsing Remitting (RRMS):
Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission (the MOST COMMON)
What does MS involve?
BOTH innate & adaptive immune response peripherally & in the CNS
Immune response in the pathogenesis of MS
MS pathogenesis starts from periphery:
- Antigen presentation & T-cell activation
- B-cell activation & antibody formation
- Chemotaxins, adhesion & migration
- Macrophage activation & demyelination
- Axonal degredation & loss of trophic support
- Apoptosis
What is the role of T cells in pathogenesis of MS?
- Activated Th cells leave the lymph nodes & migrate into the CNS across the BBB
- 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
What are the pathological consequences of immune mediated attacks in MS?
demyelination & neurodegeneration
- recurrent autoimmune attacks destroy myelin & lead to oligodendrocyte cell death via NECROSIS & APOPTOSIS
Summarize the neurological events in the course of MS
- @ beginning, immune attacks are freq. & active (then decrease or disappear throughout)
- Brain volume reduces sign. throughout the course
- Axons begin to be lost as inflammation decreases/disappears
How does MS start & then progress?
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
What is the difference b/t RIS & CIS?
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)
What is PROGRESSIVE MS associated with?
with axon degeneration causing irreversible & permanent deficits
- WITHOUT myelin & oligodendrocyte support systems, axons degenerate permanently resulting in permanent neurological impairments (brain shrinks)
How is MS treated?
- NO CURE
- disease modifying treatments that typ. REDUCE immune attacks, slowing disease progression & managing MS symptoms
What are examples of disease modifying treatments to reduce immune attacks in MS?
- CORTICOSTEROIDS (reduce inflammation)
- PLASMA EXCHANGE (if symptoms are new, severe & haven’t responded to steroids; this will remove harmful proteins)
- IMMUNOSUPPRESSANTS
For relapsing-remitting MS, there are several drugs that results in:
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)
For primary-progressive MS,
ocrelizumab (Ocrevus) is the only approved drug in Canada
(neuroprotective therapies used for progression - less drugs avail)
We also need to therapies to promote remyelination. What is the importance of this?
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
When does remyelination decline?
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
What are the animal models of MS for research?
- EAE
- Toxic-mediated demyelination
- TMEV-IDD
Explain the Experimental autoimmune encephalomyelitis (EAE) mouse model
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
What are the recent advances in MS research?
- MESENCHYMAL STEM CELLS (reduce harmful inflammation in brain)
- DIET (reducing saturated fats, excluding dairy, reducing salt)
- VITAMIN D3
- EXERCISE & PHYSICAL ACTIVITY
How is Vitamin D related?
- 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
Explain how LINGO-1 is an ex of how medications are targeted towards a specific mech in MS
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
