Mutliple Sclerosis Flashcards
(36 cards)
What is MS?
Autoimmune, demyelinating disease where myelin sheath that insulated nerve fibres is attacked and breaks down leading to nerve damage.
* Region of damage determines physical symptoms.
Common age of diagnosis?
15-60yrs
Most common cause of disability in younger adults.
Highest prevalence for MS 60-69yrs
Outline gender differences in MS
Sex differences? Voskuhl et al., 2020
Females: up to 3x more likely to get MS with female to male ratio increasing in past few decades.
Females have more robust immune responses to self and foreign antigens and therefore have higher risk of all autoimmune diseases.
Animals with XX genotypes have a greater proinflammatory response than XY genotypes.
NB: men have greater risk of worse disability and show greater Grey Matter loss compared to age-matched controls.
What are the 4 types of MS
1) relapse-remit
2) Secondary
3) Primary
4) Progressive-relapsing
Characterised by pathophysiology.
Treatment of MS?
No cure but symptoms are controllable.
Main MS symptoms?
fatigue
difficulty walking
vision problems, such as blurred vision
problems controlling the bladder
numbness or tingling in different parts of the body
muscle stiffness and spasms
problems with balance and co-ordination
problems with thinking, learning and planning
Prevalence of MS?
190 per 100,000
Outline optic neuritis
Inflammation of the optic nerve
Outline Uhthoff’s phenomenon
Transient fluctuation/worsening of MS symptoms with rise in body temp.
Lhermitte’s phenomenon
Abnormal electric shock like sensation down spine or limbs upon moving neck.
What is clinically isolated syndrome?
a term that describes the first clinical onset of potential multiple sclerosis (MS): 80% of initial MS cases.
* acute and affects one or more sites of CNS
What is relapsing remitting MS?
Episodes of new or worse relapses that typically last for days/weeks and then slowly improve.
* thought to be due to increased level of inflammation that leads to further demyelination in CNS.
* sporadic and associated with stress and illness.
* remission can last years.
usually occurs for 10-15 years.
What is secondary progressive MS?
Follows relapsing remitting MS
* gradual worsening of condition even when further attacks are absent.
* inflammation is reduced but demyelination of axons and atrophy of white and grey matter is thought to underlie neurodegeneration in the CNS.
Primary progressive MS
20% of initial MS cases
* gradual worsening of symptoms following initial onset.
* increased disability over time
* no remission
* condition stabilises
Progressive relapsing MS
Type of primary progressive MS
* Gradual worsening of symptoms with intermittent periods of remission
What cells in the immune system are implicated in MS?
T and B cells of adaptive immune system (delayed but specific).
T: balance between two types usually regulated.
T1) increase inflam
T2) suppress inflam
b: produce antibodies when active that destroy foreign.
- NORMALLY ALL PREVENTED FROM CROSSING BBB
Theory of MS pathogenesis.
only CNS affected in MS: specific antigens expressed.
* bacteria/virus shares structural similarities with key proteins in myelin and infection causes T-cell activation which cross-reacts with myelin.
*MOG, PLP, MAG: myelin molecules that share peptides with pathogens.
* T cells activated in peripheral blood = proinflam cytokine release.
* Ligands and integrins on T-cell surface and VCAM1 adhesion molecules of BBB.
* This facilitates T-cell-BBB binding and BBB breakdown via matrix metalloproteases secreted by Tcells.
* triggers other autoimmune cells.
* Tcells in CNS secrete pro-inflam and activate microglia and macrophages.
* myelin specific T cells activated by antigen presenting cells in CNS by HLAII molecule recognition, further activated as myelin degrades.
Evidence: t-cells responding to myelin proteins are at higher levels in peripheral blood of individuals with MS
Role of macrophages
promote the pro-inflammatory response of the T- and B-cells and execute tissue damage
How may microglia play role in MS pathology?
Activated and secret pro-inflamm, free-radicals and increase the release of glutamate.
Free radicals (ROS and NO) - cause neuronal mitochondrial dysfunction.
Mitochondria in MS
Free radicals cause mitochondrial dys - impaired mito activity and further increase in free radicals.
* less ATP - demyelination, apoptosis of oligodendrocytes, degen of axons, increased ca levels that can lead to cell death.
Evidence: mito DNA deletions and iron accumulation in oligo contribute to neuronal oxidative stress induced by inflammation and mitochondrial dysfunction
What techniques can be used to observe MS?
we can observe what is happening within the CNS through MRI, PET scans, marker bioavailability in individuals with MS, and cellular response in dish and in vivo models of MS, and from this, suggest possible mechanisms and pathways, we don’t actually know or understand yet what the initial trigger for BBB breakdown is
Environmental risk factors
- low vit D (increased incidence in temperate regions bar japan) and obesity increases rise due to low vit D
- smoking
- Epstein Barr virus exposure increases risk
Genetic factors
30% genetic twin
* HLA (human leukocyte antigen): associated with most autoimmune.
30% genetic susceptibility in MS
Outline Fingolimod
Fingolimod-phosphate activates lymphocyte S1P1 inducing S1P1 down-regulation that prevents its escape from lymphoid tissues, thus reducing auto-aggressive lymphocyte infiltration into the CNS; common drug for MS, 19K person p.a.
- side effects: increased relapse incidence, disease progression.
- lack of alternatives
