Multiple Sclerosis

Question 1

What is multiple sclerosis (MS)

Answer 1

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

Question 2

What is Myelin?

Answer 2

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

Question 3

What does demyelination do to neuronal function>

Answer 3

Loss of function or hyper-excitable

Question 4

What causes MS

Answer 4

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

Question 5

What is required for a diagnosis of MS?

Answer 5

Magnetic Resonance Imaging (MRI ) can be used to support diagnosis and monitor disease

Question 6

What are some MS symptoms and systems?

Answer 6

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

Question 7

What are MS risk factors?

Answer 7

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

Question 8

What are some enviromental risks for MS?

Answer 8

Virus/Bacteria (Epstein-Barr virus)

Smoking

Latitude

Vitamin D/Sunlight

Timing of Exposure

Question 9

What is the development of MS (step to step)?

Answer 9

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

Question 10

What are the different types of MS

Answer 10

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)

Question 11

what is a relapse period?

Answer 11

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

Question 12

What does the physical location of the plaques influence?

Answer 12

The physical location of the plaques will influence the type of motor, sensory, autonomic or cognitive symptoms of MS

Question 13

What is a remission period?

Answer 13

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

Question 14

What does Relapse mean?

Answer 14

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

Question 15

What does exacerbation mean?

Answer 15

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

Question 16

What does fluctuations mean?

Answer 16

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

Question 17

What does Disease progression mean?

Answer 17

Disease progression—An accumulation of disability, which can be continuously progressive or stepwise (after acute deteriorations which do not fully recover)

Question 18

How is MS diagnosed?

Answer 18

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

Question 19

What is the treatment of acute relapse?

Answer 19

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

Question 20

What are the side effects of MS treatments?

Answer 20

Side effects: anxiety, insomnia, restlessness, depression, psychosis or euphoria

Question 21

What are DMT ( disease modifying therapies)?

Answer 21

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

Question 22

Older drug therapies

Answer 22

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

Question 23

An example for DMT?

Answer 23

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

Question 24

What is the treatment for highly active RRMS?

Answer 24

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%.

Question 25

State DMT’s in MS

Answer 25

DMTs
Dimethyl fumarate (DMF)

Fingolimod

Natalizumab

(MMF: Monomethyl fumarate)

Alemtuzumab

Teriflunomide

Others undergoing further evaluation and/or further clinical trial

Question 26

What are the disadvantages of DMT’s

Answer 26

Not established if long term ( >5 years) time course of MS is significantly altered

Antibody based treatments have a problem with long-term use through the bodies production of antibodies to the drugs themselves that inhibits effectiveness

Fingolimod: encephalitis, hypertension, bradycardia, AV block,…….

Anti-CD28 caused a catastrophic ‘cytokine storm’ in six healthy volunteers participating in a Phase I trial

Range of Serious Side Effects: fever, myalgia, fatigue, pain or swelling at injection site, depression and suicidal thoughts

Question 27

What are the 1st, 2nd and 3rd line for management of symptoms of MS? For spasticity

Answer 27

Muscle relaxants for Spasticity in MS

1st line
Baclofen or Gabapentin: centrally acting on spinal cord-mechanisms

2nd line
Tizanidine or Dantrolene

3rd line
Benzodiazepines

Question 28

What is spasticity and why does it occur?

Answer 28

Spasticity is a condition in which there is an abnormal increase in muscle tone or stiffness of muscle, which might interfere with movement, speech, or be associated with discomfort or pain. Spasticity is usually caused by damage to nerve pathways within the brain or spinal cord that control muscle movement

Spasticity due to changes in the CNS NOT due to demyelination of peripheral motor nerve

Question 29

What medication is used to treat pain for MS patients?

Answer 29

Pain

Musculoskeletal: secondary to postural or mobility issues

Neuropathic: Offer a choice of amitriptyline, duloxetine (SNRI), gabapentin or pregabalin as initial treatment
(see NICE guidance on pain management)

Pain
Anticonvulsants (carbamazepine, phenytoin) or tricyclic antidepressants (imipramine, amitriptyline)

Question 30

What medication would be supplied for bladder dysfunction?

Answer 30

Bladder dysfunction:
Anticholinergic drugs eg oxybutinin, tolterodine.
ADH analogue (desmopressin) - tablet or nasal spray Side-effects: fluid retention, Na+ ,headache
Catheterisation, urinary diversion procedures, suprapubic bladder neck vibration systems.

Question 31

What are treatments to avoid for MS patients?

Answer 31

Vitamin D for MS alone
Omega-3 or Omega-6 fatty acid compounds
Sativex (cannabinoids) for spasticity
Fampridine (sustained release form of potassium channel blocker) for mobility

“The guidance does not recommend the use of the cannabinoid drug Sativex or fampridine as they provide only a modest benefit at a significant cost to the NHS. Sativex costs £50,000 per quality-adjusted life year (QALY), while fampridine costs in the region of £160,000 per QALY. Both are well above NICE’s threshold of £30,000 per QALY.”

Question 32

How does ALEMTUZUMAB work?

Answer 32

ALEMTUZUMAB
A monoclonal antibody also approved for leukaemia, alemtuzumab binds
to CD52, a protein on the surface of mature B cells and T cells, which are
then targeted for destruction by the immune system. Widespread B-cell
depletion from alemtuzumab treatment may promote the growth of T cells
that are less autoreactive and do not cause inflammation.

Question 33

How does Fingolimod work?

Answer 33

FINGOLIMOD
T cells in the lymph nodes develop
into central memory T cells, which
predominate in the cerebrospinal uid of
people with multiple sclerosis. Fingolimod
binds to the S1P receptor on T cells,
trapping them in the lymph nodes so they
cannot reach neurological tissues