MS & Treatment

Question 1

What is MS?

Answer 1

Multiple episodes of the same or different neurological symptoms separated by periods of remission.

MS follows a very unpredictable and variable disease course
from relatively benign forms to rapidly progressive forms.

Although neurological recovery does occur during the early
stages, the majority of MS cases develop chronic
progressive symptoms eventually.

Question 2

What is the incidence & prevalence of MS?

Answer 2

3-7 new cases per year per 100,000 population

100-120 per 100,000 are living with MS

= 50 - 60,000 people in England and Wales

Question 3

Disease course

Answer 3

• Relapsing/remitting MS
  – 80% of people at onset
• Secondary progressive MS
  – about 50% of those with relapsing/remitting MS develop secondary
  progressive MS during the first 10 years of their illness
• Primary progressive MS
  – 10–15% of people at onset

Question 4

What are the diverse symptoms of MS?

Answer 4

Blind areas in L eye
Weakness / paralysis in legs
Numbness in L hand
Loss of senses of balance and taste

Hot baths: “a nightmare, everything goes haywire”

Constant tingling / fizzing in feet
With eyes shut, sees dots / sparks of light

Eye movement: brighter, bigger flashes
Bending neck causes electric shock from waist to toes

“I used to have a relapse and get back to normal, but
now I don’t get back to normal”

Question 5

What causes symptoms of MS?

Answer 5

1. Demyelination
   
   • Loss of myelin sheaths (‘demyelination’)
2. Inflammation
   
   • Inflammation in the brain and spinal cord
3. Degeneration
   
   • Axonal damage and neuronal loss

Consequences:
a) acute loss of function
b) repairable damage
c) chronic damage

Question 6

Demyelination

Answer 6

Most characteristic feature of MS pathology is the demyelinated plaque.

Sharply demarcated lesions are suggestive of chronic MS.

Usually centred around one or more blood vessels.
Myelin sheaths are completely lost in the plaques.

CNS lesion in MS is the demyelinated plaque which can be identified at post-mortem & can occur at any site where myelin sheaths are
present.

Question 7

How does demyelination cause MS?

Answer 7

A conduction block meaning that nerve impulses cannot propagate along the axon of the nerve cell

Question 8

What is remyelination?

Answer 8

Restoration of the conduction (remylination= can take days to occur)

In the early stages of MS, rapid and extensive remyelination occurs, to the point complete remyelination of lesions can occur.

In MS remyelination is relatively common but eventually fails.

If remyelination is effective during the early stages of MS why then
does it fail as the disease progresses?

Repair strategies could try to repopulate the CNS with cells that can
produce myelin (oligodendrocytes).

Restoration of conduction= AKA remission

Question 9

What is remission?

Answer 9

Restoration of conduction

This can take days usually to occur. As sodium channel expression also needs to occur

Question 10

Clinical feature, primary cause, pathology

Answer 10

Clinical Feature: Relapse, Remission, Positive Phenomena (Uhtoff’s Lhermitte’s), Progression.

Causes & Pathology:

Relapse-> Conduction block -> Demyelination & inflammation

Remission-> Restoration of conduction -> Remylination & Inflammation

Positive phenomena -> Hyperexcitability (ectopic impulses/ mochanosensitivity)-> Demyelination

Progression -> Persistent loss of conduction -> Demyelination & Axonal loss

Question 11

How does inflammation cause acute MS?

Answer 11

• Initial lesion induces release of cytokines & chemokines (2,3) which attract:
  – T cells (myelin antigen specific)
  – B cells
  – Macrophages (4)
• Cells can’t leave the site of lesion (adhere)

Question 12

Inflammation & MS

Answer 12

Inflammatory infiltrates mainly consist of lymphocytes & macrophages

Active MS plaques characterised by lymphocyte infiltration.

Active plaques also contain numerous macrophages containing myelin at various stages of degradation.

myelin whorls
myelin proteins
neutral lipids

inflammation alone may be sufficient to cause significant clinical deficits without demyelination

Question 13

How does Axonal degeneration cause acute MS?

Answer 13

• In primary progressive MS, 5% of the spinal cord cross sectional area can be lost annually
• Chronic lesions in paralysed MS patients show an average loss of 68% (45-84%) of axons
• Axonal degeneration is a major cause of irreversible deficit with no
  effective therapy

MS probably has a silent stage of axonal degeneration, which lasts for 10-12 years in relapsing-remitting patients. Because inflammatory attacks occur during this period it should be possible to start neuroprotective therapies early enough

Question 14

Therapeutic opportunities in MS

Answer 14

1. Inflammation in the brain and spinal cord - STOPPABLE
2. Loss of myelin sheaths (‘demyelination’)- REPAIRABLE
3. Axonal damage & neuronal loss- IRREPAIRABLE BUT PREVENTABLE

Question 15

MS symptoms

Answer 15

• Spasticity/spasms
• Bladder/bowel symptoms (incontinence)
• Pain
• Cognitive symptoms
• Emotionalism
• Depression
• Anxiety
• Fatigue
• Walking

Question 16

MS symptoms

Answer 16

• Spasticity/spasms
• Bladder/bowel symptoms (incontinence)
• Pain
• Cognitive symptoms
• Emotionalism
• Depression
• Anxiety
• Fatigue
• Walking

Question 17

Management of MS

Answer 17

• Recommended
  – Exercise
  – Offer amantadine to treat fatigue, mindfulness
  – Consider baclofen or gabapentin as first line treatment to treat spasticity
  – Consider amitriptyline to treat emotional lability
  – Neuropathic pain management

Question 18

Current treatments for MS

Answer 18

• Acute episode:
  – First choice: high dose corticosteroid
• Oral methylprednisolone, 500 mg daily, 5 days
  – Risks with steroids?
  – If considering iv steroid, then some of the DMARDs may be used
  instead.

Question 19

Past treatments for MS (No longer recommended)

Answer 19

Relapsing-remitting and secondary progressive MS:
– linoleic acid 17-23g/day (sunflower, corn, soya, safflower oils)
– azathioprine (immunosuppressant)
– mitoxantrone (antineoplastic agent), may extend the time between
relapses
– intravenous immunoglobulin
– plasma exchange
– intermittent (4-monthly) short (1–9 days) courses of high dose
methylprednisolone.

Question 20

Disease-modifying treatments

Answer 20

1. Alemtuzamab
2. Beta interferons & glatiramer acetate
3. Cladribine
4. Dimethyl fumarate
5. Fingolimod
6. Natalizumab
7. Ocrelizumab
8. Teriflunomide
9. Back to management if they don’t work

Question 21

Alemtuzumab (Lemtrada)

Answer 21

– Monoclonal antibody, binds CD52, a protein found on lymphocytes
– Approved in Sept 2013 as a first line treatment
– 12 mg/day by iv infusion for 2 treatment courses
* 5 consecutive days
* 12 months later 2nd course of 3 consecutive days

– £7045 per 12 mg vial (£56,360 over 2 years)
– Significant complications possible, include susceptibility to viral, bacterial & fungal infections due to immunosuppressant properties.

Question 22

Interferons

Answer 22

• normally produced by fibroblasts as part of the immunological
  response to viral and non-viral antigens
• pro-inflammatory factor, activating cytokine and chemokine
  production, by activating macrophages and natural killer
  lymphocytes. Enhancing MHC classes I and II.
• however acts as an anti-inflammatory and immunosuppressant
  agent in some circumstances, e.g. MS, where it Induces the
  production of anti-inflammatory factors
• mechanism of action poorly understood but considered to reduce
  inflammation (& possibly promote remyelination)
• reduces the rate of relapse of MS.
• Clinically effective

Question 23

Glatiramer acetate

Answer 23

• Synthetic amino acid/peptide mixture
  – Glutamate, Alanine, Lysine, Tyrosine
• unknown mechanism of action
  – myelin decoy?
• Proposed to be an immunomodulatory drug.
  – Shifts T-cell population from pro-inflammatory Th1 to regulatory
  Th2 that suppresses inflammatory response
• Clinically effective

Question 24

NICE TA527 covers interferons and glatiramer

Answer 24

– interferon beta-1a (Avonex and Rebif) – recommended
– Interferon beta-1b (Extavia) – recommended option for severe MS
– interferon beta-1b (Betaferon) –not recommended (too expensive
for benefits)
– Glatiramer acetate (Copaxone) – recommended

– Licensed in UK under commercial arrangements of the companies
with NHS, i.e. discount.
– Patients originally on betaferon are not prevented from staying on
this medication

Question 25

Cladribrine

Answer 25

Purine (nucleoside) analogue

– Accumulates in cells which actively take up adenosine, e.g. actively
dividing cells
– Prevents DNA synthesis
– Immunosuppressant

• 1 treatment course of 1.75 mg/kg per year.
• 2 treatment weeks
  
  • 1 at the beginning of the first month
  • and 1 at the beginning of the second month of the respective
    treatment year.
  • Each treatment week consists of 4 or 5 days on which a patient
    takes 10 mg or 20 mg (1 or 2 tablets) as a single daily dose.
• Following completion of the 2 treatment courses, no further
  cladribine treatment is required in years 3 and 4.

– £2,047 per 10 mg tablet e.g. ca. £10,000 - £20,000 per year for two
years

• NICE TA493

Question 26

Dimethylfumarate (Tecfidera)

Answer 26

• Originally used in industrial chemistry (<£20 per ton), licensed for psoriasis in Germany in the 1950s
• Immunosuppressant
  – Proposed to act by activating the Nrf2 pathway in cells, inhibiting release of pro-inflammatory cytokines from immune cells
  – Can produce allergic reactions e.g. rash as well as other potential side effects caused by immunosuppression
• 120 mg twice daily for first week, 240 mg twice daily thereafter.
  – £1373 per month (56 x 240 mg tablets)
• NICE TA320

Question 27

Fingolimod (Gileyna)

Answer 27

– Sphingosine analogue
– Sequesters lymphocytes in lymph nodes
– Reduces rate of relapse
– 0.5mg oral, once daily
* £19,168 pa

– NICE recommends for people who have had beta interferon treatment but still have had severe or frequent relapses

Question 28

Natalizumab (Tysabri)

Answer 28

• Immune modulator
  – monoclonal antibody which inhibits leukocyte migration into CNS
  – binds to a4 subunit of a4b1 and a4b7 integrins which are expressed
  on the surface of activated T-cells
  – prevents binding of cells to receptors on the endothelium
  – anti-inflammatory effects
• Natalizumab licensed by NICE for the treatment of adults
  with highly active relapsing-remitting multiple sclerosis

Question 29

Ocrelizumab (Ocrevus)

Answer 29

• Humanised anti CD20 monoclonal andibody
  – Targets CD20 on B-lymphocytes
  – Immunosuppressant
• Approved in March 2017 in US
• 2 x 300 mg infusions 2 weeks apart, then 600 mg every 6 months
  – £4,790 per 300 mg vial.
• No proven benefit (yet) over other treatments, more costly than
  alemtuzumab. Therefore currently recommended only where
  alemtuzumab is unsuitable.

Question 30

Daclizumab

Answer 30

• Bind to CD25, T-lymphocyte IL-2 receptor
• Phase 3 Clinical trials have shown positive results
• Was promising a year ago, however Biogen withdrew its marketing
  authorisation (encephalitis)

Question 31

Terifunomide (Aubagio)

Answer 31

• Immunomodulator
  – Inhibits pyrimidine synthesis
  – Inhibits cell division in rapidly dividing cells including activated T-
  cells
  – Proposed to reduce number of activated lymphocytes
• Oral, 14 mg daily
  – £1037 per month

Question 32

Cannabinoids in MS

Answer 32

• Many MS patients self-medicate by smoking cannabis
• Cannabinoids ameliorate many of the symptoms of MS
  – tremor and spasticity
  – pain associated with MS
  – Bladder function
• Sativex not recommended by NICE due to cost-effectiveness

Question 33

Licensed Cannabinoids that may be useful in MS

Answer 33

1. Sativex- Pain & Spasticity (THC/ CBD- 50:50)
2. Marinol/ dronabinol- N&V, pain, appetite stimulation (THC)
3. Nabilone- Pain, nausea & vomiting (N&V)