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36 Cards in this Set
- Front
- Back
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What is MS? |
It is a disease of the CNS characterised by inflammation, demyelination and gliosis. |
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What is the difference between primary and secondary demyelination? |
In primary, the myelin is damaged or destroyed however axons remain intact. In secondary, the myelin sheath is damaged as a result of primary axonal damage. |
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What is the result of damage to myelin sheaths? |
Impaired signal conduction resulting in deficiency in sensation, movement and cognition. |
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Where are lesions commonly found in MS? |
White matter of CNS |
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What are the underlying mechanisms behind MS? |
Destruction of myelin Failure of myelin production |
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What are the risk factors for MS? |
Genes - 2% chance child will get MS, 3% chance if sibling has MS Mutation in human leukocyte antigen increases risk by 20 - 60% Women more common Age of onset 20 - 40yrs Environment - less common in sunny tropical countries near equator. Common in UK, Canada,US, Scandinavia, Southern Australia and New Zealand. - link with low vit D Infection - Epsteinn Barr virus (causes glandular fever) Smoking - likely to affect immune system Obesity - link with low vit D, and it increases activity of immune system -> inflammation |
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What are the tests for MS? |
Neurological examination MRI Evoked Potentials Lumbar Puncture Other tests |
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What happens in a neurological examination? |
History + current symptoms Physical examination to check weaknesses in eye movements, leg and hand co-ordination, balance, sensation, speech or reflexes. |
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What do they look for in MRI? |
Increase in vascular permeability due to breakdown of BBB - detected by leakage of intravenous gadolinium (Gd) into parenchyma (tissue). - Early market Gd is a large molecule - normally cannot cross BBB Lesions in brain, brain stem or spinal cord |
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What indicates a lesion? |
Myelin is fat - it repels water. In areas of myelin damage, fat is stripped away so there is more water in the area, this shows up on MRI as a bright white spot or darkened area depending on scan used. |
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What is a evoked potentials test? |
Involves taking the time it takes your brain to receive messages by placing electrodes on head to monitor brain waves responding to what you see or hear. If myelin is damaged, this will be slower. Sensory pathways are stimulated. Electrical activity as a response in the brain is measured. Slowing of electrical conduction indicates demyelination along pathway. |
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What is a visual evoked potentials test? |
Patient sits before a screen where an alternating checkboard pattern is displayed. Their brain activity is measured. |
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What is a lumbar puncture? |
A needle is inserted into space around spinal cord under local anaesthetic and sample of CSF is obtained. CSF is then tested for abnormalities e.g. - elevated IgG - Oligoclonal bands - Proteins that are breakdown products of myelin |
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How is MS diagnosed? |
2+ episodes of symptoms & 2+signs reflecting pathology in anatomically non-contiguous (not touching) white matter tracts of CNS. Symptoms must have lasted 24+hrs and episodes must be distinct and separated by a month or more. |
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What are the signs and symptoms for MS? |
Motor, visual, autonomic and sensory symptoms: Paresis (muscular weakness), plegia (paralysis), dysarthria, dysphagia, urogenital changes, in coordination, tiredness or pain, depression |
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What are the different types of MS? |
Relapsing-remitting - 85% Primary progressive - follows relapsing remitting Secondary progressive - 15% - continued deterioration + plateaus Progressive-relapsing - 5% - continued deterioration interrupted with relapses |
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What are the 3 common stages in the pathophysiology of MS? |
1) inflammation 2) demyelination 3) lesions |
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What happens during the inflammation phase? |
Normally the BBB prevents entry of T-cells however it can be damaged and become permeable due to infection. This allows T cells to cross. Chemokines can activate adhesion molecules on lymphocytes allowing them to bind to the BBB and express MMP (matrix metalloproteinase) which degrades it allowing macrophages and lymphocytes to enter and attack myelin sheaths in the CNS. |
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Summary of MS Pathophysiology |
BBB disrupted T cells enter and attack myelin Initiates inflammatory process where cytokines and antibodies are recruited Causing swelling, macrophage activation and further recruitment of cytokines |
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What happens during relapse? |
T lymphocytes Th1 & Th17 are involved IL12 is responsible for the differentiation of naive Th cells into inflammatory T cells. Overproduction of IL12 causes overproduction of inflammatory T cells causing inflammation. These cells recognise myelin as foreign and attack it causing further inflammation. |
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What happens during remission? |
Oligodendrocytes cannot completely remyelinate or repair a destroyed myelin sheath and the new myelin produced is thinner and less effective. Multiple attacks cause a scar-like plaque (sclerosis) to form around damaged axons. |
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What type of cell is commonly found in active plaques? |
Macrophages |
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Where are active lesions often found? |
Small veins |
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What do you see in inactive plaques? |
Decreased oligodendrocyte nuclei Astrocytic proliferation Gliosis |
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What do Th1 cells secrete and what effect does this have? |
IFNy which activates macrophages |
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What do Th17 cells promote? |
Recruitment of leukocytes |
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Name the treatments for MS. |
Vitamin D3 supplements Methylprednisolone (1g/day for 3days) Beta interferons, glatiramer acetate, fingolimod or natalizumab |
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What treatment is given for acute relapses? |
Methylprednisolone 1g/day for 3 days Prednisolone 500mg for 5 days |
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Effects of beta interferon |
Inhibits T cell activation, proliferation and migration into BBB |
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What is glatiramer acetate? |
An immune modulator which reduces relapse frequency |
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What is it's mechanism of action? |
Binds to MHC Class 2 molecules and prevents other antigens from binding. Competes with myelin basic protein (important for myelination) for binding to T cell receptor Shifts Th1 (proinflammatory) cells to Th2 cells which suppress inflammation |
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Mechanism of action of fingolimod or gilenya? |
Binds to sphingosine 1 phosphate receptor 1 This blocks capacity of autoreactive lymphocytes to leave lymph nodes and decreases the number of lymphocytes in peripheral blood. This reduces lymphocyte migration into CNS. |
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What does natalizumab do? |
Stops leukocytes micgrating into CNS |
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What do immunosuppressants do? |
Decrease T cell function |
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What does teriflunomide (aubagio) do? |
Inhibits mitochondrial enzyme dihydroorate dehydrogenase (DHODH) which decreases T cell function. |
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What does dimethyl fumarate do? |
Activates Nrf 2 transcriptional pathway to decrease inflammation. |
