Multiple Sclerosis Flashcards
What is ms
Chornic inflammatory disease of brain and spinal cord
100.000 cases in UK
What mediates MS
Seen as a t- cell mediated disorder
Mostly Th1 and Th17
Epidemiology of MS
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
Vitamin D and MS
Increased Vitamin D decreased risk of MS
Give either alone or with beta interferon
Types of MS
Relapse remitting
Secondary progressive
Primary progressive
Progressive relapsing
Relapse remitting
Most common 85-90%
Attacks with complete or partial recovery between.
No progression
Relapses spontaneous or triggered by infection
Secondsry progressive
Initial relapse remitting
Followed by progrssion
Can be with or without attacks
After 5 yrs 50% will move from RR to SP
Primary progressive
10-15%
Progresses gradually with NO ATTACKS
Progressive relapsing
<5%
Started off with progression then sudden attack
Demyelination
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
Diagnosis of MS
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
Common sites of MS demyelination
Corpus callosum Periventricular regions of brain Optic nerve Cerebellum Brainstem Spinal cord
Process of demyelination
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
Lesion
Plaque of inflammatory demyelination
Fried egg appearance on MRI T1
- centre is inflammation and lumphocytes etc
- outside is oedema
Gandalinium (contrast) seeps through holes
Types of plaque
Enhancing: 6-8 weeks. Acute fried egg appearance
Non enhancing: older than 8 weeks. Undergone gliosis leaving shrunken grey scar
Treatment for RR CONVENTIONAL MS
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
Treatment for RR RAPIDLY EVOLVING MS
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
How do lymphocytes get to the brain parenchyma
Adhere to vascular endothelial cells via gycoprotein integrin (VLA4) expressed on their surface
How are beta interferons though to work?
Inhibits t cell activation
Prevents t cell proliferation
Blocks t cell migration across BBB
Reduces CNS inflammation
Copaxone
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
Fingolimod
Given if beta interferon proved unhelpful
Blocks S1P receptors, reversibly trapping autoreactive lymphocytes in lymph nodes
Stop circulating lymphocytes
52% reduction in relapse
Tysabri/ natalizumab
Monoclonal antibody to integrin
Prevents binding of lymphocytes to vascular endothelium, preventing them from crossing BBB
81% reduction of relapse
But bad side effects
Risk factors for Progressive Multifocal Leukoencephalopathy PML
Duration of treatment with tysabri (over 2 years)
Previous immunosupressive drugs
JC virus positive
PML and its treatment can be fatal
Treatments on the horizon
Teriflumonide
BG12
Laquinimod (low effect on relapse rates but good at reducing brain atrophy)
Teriflunomide
Reduce no of autoreactive T cells
Targets DHODH
Side effects: diarrhoea, nausea and hair thinning
BG-12
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%
Alemtuzumab
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
Genetics for MS
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
Viral cause evidence
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
Acute relapse medication
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
