Multiple Sclerosis Flashcards
What is multiple sclerosis (MS)
Multiple sclerosis is an incurable illness in which the body’s own immune system destroys tissues in the
central nervous system. T cells and B cells are thought to remove a protective coating called myelin that
wraps around nerve fibres in the brain, spinal column and optic nerve. Exposed fibres are degraded,
producing symptoms that vary depending on where the damage occurs
Slow, progressive, immunologically mediated disease of the central nervous system (CNS)
Characterised by inflammation & plaques of de-myelination and axonal loss in the white matter of the brain & spinal cord
What is Myelin?
Several layers of cytoplasmic membrane wrapped around axons: OLIGODENDROCYTES (central) or SCHWANN CELL (motor/peripheral)
Insulation due to structure, high lipid and low water content
A series of shwann cells. Sheath blocks ion movements therefore action potential must ‘jump’ from node to node
What does demyelination do to neuronal function>
Loss of function or hyper-excitable
What causes MS
Plaques are areas of scarring (sclerosis)
due to demyelination, with associated
inflammation, axonal loss and oedema
Plaques can be multiple in that they occur in a number of different places in the CNS and may occur at different times
Common locations for plaques are in: the optic tract; spinal cord; brain stem; and basal ganglia
What is required for a diagnosis of MS?
Magnetic Resonance Imaging (MRI ) can be used to support diagnosis and monitor disease
What are some MS symptoms and systems?
Fatigue
Vision: optic neuritis
Motor symptoms: weakness and spasticity in limbs
Cerebellar symptoms: intention tremor and ataxia
Sensory: altered sensation including burning, tearing & numbness, pain
Bladder and bowel dysfunction: incontinence and constipation
Sexual dysfunction: impotence
Cognitive: memory, euphoria, dementia
(note: ~50% of MS suffers describe some cognitive impairment)
Depression, anxiety and mood swings
What are MS risk factors?
Age - 25-40
Obesity - can alter inflammatory response
Genetic risk - : human leukocyte antigen system (HLA) on chromosome 6 forms major histo-compatibility complex (MHC); weaker associations with CD58, CD6 and interleukin receptor genes; ethnic and parent-of-origin effects
Sex- Higher risk in females but not associated with X chromosome – potential epigenetic or hormonal signals
Sphingosine-1-phosphate receptor 2 (S1PR2) higher levels in women
What are some enviromental risks for MS?
Virus/Bacteria (Epstein-Barr virus)
Smoking
Latitude
Vitamin D/Sunlight
Timing of Exposure
What is the development of MS (step to step)?
Peripheral immune response with
activation and proliferation of self-reactive T-cells
Interaction with adhesion molecules on brain endothelial cells leads to crossing of the blood brain barrier (BBB)
Reactivation within the CNS leading to pro-inflammatory environment recruitment of more B cells, macrophages, microglia resulting in autoimmune demyelination
What are the different types of MS
Relapsing/remitting (RR-MS) ~ 80%
Periods of disability (relapse) with a stable periods of recovery (remission)
Often (~50%) followed by slowly progressive clinical course known as Secondary Progressive (SP-MS)
A minority of patients will have a benign form of MS where their disease follows a relapsing/remitting pattern but will make a full recovery from each episode
Around 10% of patients will have steady progress over time Primary Progressive multiple sclerosis (PP-MS)
what is a relapse period?
Relapse periods: symptoms arise from the
effects of cytokines and signalling cascade on neuronal function and because myelin and oligodendrocytes are destroyed resulting in nerve transmission being slowed or blocked
What does the physical location of the plaques influence?
The physical location of the plaques will influence the type of motor, sensory, autonomic or cognitive symptoms of MS
What is a remission period?
Remission periods: the limited ability of the CNS to repair or replace damage but more a reflection of the CNS redirecting signals through alternate routes
What does Relapse mean?
Relapse—New signs and symptoms caused by a new focal demyelinating lesion in the central nervous system that usually resolves, partially or completely, within days to weeks
What does exacerbation mean?
Exacerbation—A worsening of existing signs and symptoms because of a focal demyelinating lesion in the central nervous system that usually resolves, partially or completely, within days to weeks
What does fluctuations mean?
Fluctuations—Transient changes in symptoms that do not represent a relapse or progression of disease. A common cause of fluctuations is increased heat, such as that encountered in a hot bath
What does Disease progression mean?
Disease progression—An accumulation of disability, which can be continuously progressive or stepwise (after acute deteriorations which do not fully recover)
How is MS diagnosed?
No specific test
Neurologist
2 or more relapses in previous 2 years (dissemination of lesions with time)
2 or more clinically defined lesions
(dissemination of lesions in space)
MRI to locate and identify lesions
Evoked Potentials to stimulate neuronal pathways, usually visual or sensory to test transmission velocity and strength
Lumbar Puncture to measure oligo-clonal bands of IgG in cerebral spinal fluid (CSF)- an inflammatory marker found in ~70-80% of MS patients
Differential diagnosis
What is the treatment of acute relapse?
Oral or intravenous corticosteroids are used to shorten the duration of a relapse. Glucocorticoids part of natural feedback system to regulate immune response
Oral Methylprednisolone 0.5g for 5 days as close to start of relapse as possible – do not offer a dose less than 0.5g
Intravenous methylprednisolone 1 g daily for 3–5 days as an alternative for MS patient in whom oral steroids have failed or not been tolerated or needs admitting to hospital for a severe relapse or monitoring of medical or psychological conditions such as diabetes or depression
NOT supplied to MS patients to self administer at home for future relapses
What are the side effects of MS treatments?
Side effects: anxiety, insomnia, restlessness, depression, psychosis or euphoria
What are DMT ( disease modifying therapies)?
Drugs that will affect or modify the course of multiple sclerosis
Suppress the inflammatory responses and immune response against myelin at a range of sites
Not a cure, but they can reduce the number and severity of attacks
Reduce relapse and prolong remission
Older drug therapies
Interferon beta and Glatiramer acetate
These can no longer recommended but should be maintained until an appropriate alternative can be initiated for those who have already been started on these drugs
An example for DMT?
Dimethyl Fumerate: for RRMS but not active or rapidly progressing
Dimethyl Fumarate : Broad spectrum of actions-suppresses T cell activation, modifies dendritic cells, neuro-protective and immuno-suppressant
Significantly reduced the annualized relapse rate (ARR) by up to 53% and Gd enhanced lesions by
up to 90%
Alemtuzumab for treating adults with active RRMS (Relapsing remitting MS is a type of MS where you have relapses (symptoms getting worse) followed by recovery (that’s when it’s “remitting”). mAb against the pan-leukocyte
surface marker CD52.
Up to 78% of patients were relapse-free over 2 years
Natalizumab: for the treatment only of rapidly evolving severe (RES) multiple sclerosis.
mAb against α4 subunit of α4β1 integrin that blocks T lymphocyte entry into CNS
Reduces ARR by ~60% and Gd lesions by ~80%
Cladribine: purine analogue that targets lymphocytes and suppresses the immune system
Ocrelizumab: anti-CD20 monoclonal antibody targets B lymphocytes and acts as an immunosuppressive drug
What is the treatment for highly active RRMS?
Fingolimod: used in treatment of highly active RRMS in adults if an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon
Binds to S1PR1 (G-protein coupled) reduces lymphocytes movement out from some lymph tissues and prevents lymphocytes interaction with antigens. Promotes oligodendrocyte survival and thus myelination.
ARR reduced by ~50%.
