Multiple Sclerosis

Question 0

What is ms

Answer 0

Chornic inflammatory disease of brain and spinal cord

100.000 cases in UK

Question 1

What mediates MS

Answer 1

Seen as a t- cell mediated disorder

Mostly Th1 and Th17

Question 2

Epidemiology of MS

Answer 2

Illness of WESTERN european countries
2nd gen non caucasians affected the same
Twice as common in women
Risk of familial inheritance is 15%- polygenic inheritance. HLA region, IL-7R, IL-2R

Question 3

Vitamin D and MS

Answer 3

Increased Vitamin D decreased risk of MS

Give either alone or with beta interferon

Question 4

Types of MS

Answer 4

Relapse remitting
Secondary progressive
Primary progressive
Progressive relapsing

Question 5

Relapse remitting

Answer 5

Most common 85-90%
Attacks with complete or partial recovery between.
No progression
Relapses spontaneous or triggered by infection

Question 6

Secondsry progressive

Answer 6

Initial relapse remitting
Followed by progrssion
Can be with or without attacks
After 5 yrs 50% will move from RR to SP

Question 7

Primary progressive

Answer 7

10-15%

Progresses gradually with NO ATTACKS

Question 8

Progressive relapsing

Answer 8

<5%

Started off with progression then sudden attack

Question 9

Demyelination

Answer 9

No myelin around the axon
No saltatory conduction as usually there is an aggregation of Na+ channels at node of ranvier
But in MS there is less aggregation, as the channels are more randomly spread. And different phenotypes of Na+ channels

Question 10

Diagnosis of MS

Answer 10

TIME: lesions at least 3 months apart

SPACE: different parts of the CNS involved

Any 2 NEW Lesions have to be ovoid at least 3mm in diameter

Question 11

Common sites of MS demyelination

Answer 11

Corpus callosum
Periventricular regions of brain
Optic nerve
Cerebellum
Brainstem
Spinal cord

Question 12

Process of demyelination

Answer 12

T cells become autoreactive in the periphery
Cross the blood brain barrier
Recognise myelin derived antigens on surface of microglia (NS antigen presenting cell) and undergo clonal proliferation
Inflammatory cascade, releasing cytokines (IL-12)
Initiates destruction of oligodendrocyte-myelin unit by macrophages

Question 13

Lesion

Answer 13

Plaque of inflammatory demyelination
Fried egg appearance on MRI T1
- centre is inflammation and lumphocytes etc
- outside is oedema

Gandalinium (contrast) seeps through holes

Question 14

Types of plaque

Answer 14

Enhancing: 6-8 weeks. Acute fried egg appearance

Non enhancing: older than 8 weeks. Undergone gliosis leaving shrunken grey scar

Question 15

Treatment for RR CONVENTIONAL MS

Answer 15

If had 2 or more relapses in previous 2 years then can give
Avonex
Betaferon
Extavia
Copaxone
Rebif
All reduce relapses by a third. Long term effects on disability unkown

Question 16

Treatment for RR RAPIDLY EVOLVING MS

Answer 16

If had 2 or more relapses in previous year
And 1 or more GAD lesion on MRI or increased T2 lesion load
Then can give TYSABRI

Question 17

How do lymphocytes get to the brain parenchyma

Answer 17

Adhere to vascular endothelial cells via gycoprotein integrin (VLA4) expressed on their surface

Question 18

How are beta interferons though to work?

Answer 18

Inhibits t cell activation
Prevents t cell proliferation
Blocks t cell migration across BBB
Reduces CNS inflammation

Question 19

Copaxone

Answer 19

Daily injection
Synthetic polypeptides containing 4 amino acids: L-glutamatic acid, lysine, alanine, tyrosine
Bind to MHC 2 molecules preventing binding of other antigens
Competes with MBP for binding to t cell receptor
Inhibit activation of MBP reactive t cells

Question 20

Fingolimod

Answer 20

Given if beta interferon proved unhelpful
Blocks S1P receptors, reversibly trapping autoreactive lymphocytes in lymph nodes
Stop circulating lymphocytes
52% reduction in relapse

Question 21

Tysabri/ natalizumab

Answer 21

Monoclonal antibody to integrin
Prevents binding of lymphocytes to vascular endothelium, preventing them from crossing BBB

81% reduction of relapse
But bad side effects

Question 22

Risk factors for Progressive Multifocal Leukoencephalopathy PML

Answer 22

Duration of treatment with tysabri (over 2 years)
Previous immunosupressive drugs
JC virus positive

PML and its treatment can be fatal

Question 23

Treatments on the horizon

Answer 23

Teriflumonide
BG12
Laquinimod (low effect on relapse rates but good at reducing brain atrophy)

Question 24

Teriflunomide

Answer 24

Reduce no of autoreactive T cells
Targets DHODH
Side effects: diarrhoea, nausea and hair thinning

Question 25

BG-12

Answer 25

Activates Nrf2 transcriptional pathway
- Increases cell protection by inducing expression of proteins involved in reducing metabolic and oxidative stress
- Decreases inflammation by reducing pro inflam cytokines and lymphocyte activation
2 times daily tablet
Reduce relapse by 50%

Question 26

Alemtuzumab

Answer 26

Anti CD52 monoclonal antibody ONCE YEARLY
Depletes T and B cells and modulates activity
Treat early or in illness when inflam is high
Major adverse effects (thyroid disorders, ITP)
59% reduction in relapse

Question 27

Genetics for MS

Answer 27

Not herditory
But Human Leukocyte Antigen (HLA) group of genes on chpromosome 6 that serves as Major Histocompatability Complex (MHC)
20-60% of genetic predisposition

Question 28

Viral cause evidence

Answer 28

Presence of oligoclonal IgG bands in brain and csf (present in 80% of cases act as inflamm markers)
Human herpes virus is risk and those previously effected by epstein barr virus at greater risk

Question 29

Acute relapse medication

Answer 29

Short course of methylprednislone
Glucocorticoid. Cross cell membranes and bind w high aff to cytoplasmic receptors, modifying transcription and protein synth
So inhibits leukocyte infiltration at inflam site, interfere w inflam mediators, suppress immune responses
1g a day for 3 days