Mutliple Sclerosis

Question 1

What is MS?

Answer 1

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.

Question 2

Common age of diagnosis?

Answer 2

15-60yrs

Most common cause of disability in younger adults.
Highest prevalence for MS 60-69yrs

Question 3

Outline gender differences in MS

Answer 3

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.

Question 4

What are the 4 types of MS

Answer 4

1) relapse-remit
2) Secondary
3) Primary
4) Progressive-relapsing

Characterised by pathophysiology.

Question 5

Treatment of MS?

Answer 5

No cure but symptoms are controllable.

Question 6

Main MS symptoms?

Answer 6

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

Question 7

Prevalence of MS?

Answer 7

190 per 100,000

Question 8

Outline optic neuritis

Answer 8

Inflammation of the optic nerve

Question 9

Outline Uhthoff’s phenomenon

Answer 9

Transient fluctuation/worsening of MS symptoms with rise in body temp.

Question 10

Lhermitte’s phenomenon

Answer 10

Abnormal electric shock like sensation down spine or limbs upon moving neck.

Question 11

What is clinically isolated syndrome?

Answer 11

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

Question 12

What is relapsing remitting MS?

Answer 12

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.

Question 13

What is secondary progressive MS?

Answer 13

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.

Question 14

Primary progressive MS

Answer 14

20% of initial MS cases
* gradual worsening of symptoms following initial onset.
* increased disability over time
* no remission
* condition stabilises

Question 15

Progressive relapsing MS

Answer 15

Type of primary progressive MS
* Gradual worsening of symptoms with intermittent periods of remission

Question 16

What cells in the immune system are implicated in MS?

Answer 16

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

Question 17

Theory of MS pathogenesis.

Answer 17

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

Question 18

Role of macrophages

Answer 18

promote the pro-inflammatory response of the T- and B-cells and execute tissue damage

Question 19

How may microglia play role in MS pathology?

Answer 19

Activated and secret pro-inflamm, free-radicals and increase the release of glutamate.

Free radicals (ROS and NO) - cause neuronal mitochondrial dysfunction.

Question 20

Mitochondria in MS

Answer 20

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

Question 21

What techniques can be used to observe MS?

Answer 21

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

Question 22

Environmental risk factors

Answer 22

• 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

Question 23

Genetic factors

Answer 23

30% genetic twin
* HLA (human leukocyte antigen): associated with most autoimmune.
30% genetic susceptibility in MS

Question 24

Outline Fingolimod

Answer 24

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

Question 25

Ocrelizumab

Answer 25

Ocrelizumab: anti-CD20 antibody that depletes circulating immature and mature B-cells through complement-dependent and antibody-dependent cytotoxicity.

Question 26

Cladribine

Answer 26

Cladribine: selectively disrupts T-cell and B-cell immunity. Once within the cell, it increases deoxycytidine kinase (DCK), leading to lymphocyte apoptosis.

Question 27

Natalizumab

Answer 27

Natalizumab: an antibody that binds a4B1-integrins and blocks its interaction with VCAM-1. leukocyte migration into brain tissue is inhibited, reducing inflammation and preventing formation of lesions in the CNS

Question 28

Study on MS drugs

Answer 28

Ocrelizumab and Natalizumab more effective than fingolimod

• relapse reduced or controlled
• symptoms stabilised or improved

Question 29

Stem cells for MS

Answer 29

Adults with aggressive MS
* stem cells taken before treatment
* chemo to destroy immune system inclu T cells
* stem cell inplant

After T cells created with no autoimmune reactivity, 80% disease free long term.

Question 30

Interferon beta

Answer 30

Endogenous cytokine released in response to foreign antigens/invaders – it is one of the most common immunotherapies used in treatment of MS.
* reduces relapse and slows decline of motor function.

MOA not understood..
* binds to zinc: reduces pro-inflam and increases anti production.
* RBS increase NO by release and stimulated production in lining of blood vessels.
* zinc/peptideC/albumin latch onto RBCs and stimulate NO production.
* binds to zinc and prohibits complex binding to RBC therefore reduces hypermetabolic state of RBC down to healthy control

Question 31

Gut microbiome

Answer 31

31 bacteria enriched in MS: caudovirales
* group 1 viruses that interact with surface features of host bacterium
* associated with improved executive function

Disease active: cytokines in abundance
* associated with high relapse rate

Non-disease active: anti-inflam metabolites

Faecalibacterium prausnitzii: decreased

Question 32

Diet and MS

Answer 32

Mouse model (can u extrapolate to humans)fed different diets
* guar gum: delayed disease and neuroinflammation.
* limited gut micro alterations.

CD4+T cells are key cells of the adaptive immune system that use T cell antigen receptors to recognize peptides that are generated in endosomes or phagosomes and that are displayed on the host cell surface bound to major histocompatibility complex molecules.
CD4+ T-cells - encephalitogenic: less prone to inflammation
Reduced Th1 differentiation * thought to be a key player in the pathogenesis of MS
And altered migratory potential.

Guar gum causes deficits of CD4+ activation (Fettig et al., 2022)
Western diet (high fats, salts, sugars) promotes inflammation but high fibre diets reduce disability scores, relapses and circulating CD4+ cells.

Question 33

ADEM

Answer 33

Acute disseminated encephalomyelitis: occurs once (NOT MS but can be first sign of MS), occurs in children
* MOG antibodies present in 40%.
* inflam in CNS = damaged myelin

Anti-inflam used.
* usually recover in 2 weeks.

Question 34

Childhood MS

Answer 34

2+ clinical events separated in time and space.
* white blobs on MRI with more blobs in follow up MRIs.

Question 35

What makes diagnosis of childhood MS hard?

Answer 35

Variable presentation, other diseases present similarly
* trauma
*PVL
* infection
* v12 deficiency

Important correct diagnosis for correct treatment.

Question 36

Siblings and childhood MS

Answer 36

siblings decrease risk: thought to be due to exposure to more bacteria at younger age.