Module 4.2.2 (Management of Multiple Sclerosis)

Question 1

How to diagnose MS?

Answer 1

Presence of typical lesions throughout the CNS, shown clinically and on MRI (McDonald criteria)

• If initial MRI shows two or more white matter lesions, the patient has about an 80% risk of developing MS, if the MRI is normal –> risk falls to about 11%

> MS can be diagnosed after a single clinical event if the MRI shows lesions of different ages

Question 2

No preventative therapies in primary and seconday progressive MS. True or False

Answer 2

True

Question 3

What is a clinically isolated syndrome?

Answer 3

Some patients have a single demyelinating event without evidence of changes over time (no new lesions on MRI or no new clinical events)

Question 4

Types of MS?

Answer 4

Relapse remitting MS (RRMS): unpredictable attacks which may or may not leave permanent deficits followed by periods of remission

Primary progressive MS (PPMS): steady increase in disability without attacks

> average onset is approx 10 years later in PPMS than in relapsing MS

> those with PPMS tend to experience more problems with walking and more difficulty remaining in the workforce

> those with PPMs require more assistance with their everyday activities

Secondary progressive MS (SPMS): initial relapsing-remitting multiple sclerosis that begins to have decline without periods of remission

Progressive-relapsing MS (PRMS): steady decline onset with super-imposed attacks

Question 5

What to do in relapsing forms?

Answer 5

Introduce immunotherapy early, to slow or minimise disability

AIM: no evidence of disease activity (NEDA), clinically stable, no relapses, no new lesions on MRI

Question 6

What is used to acute inflammatory clinical events (relapses)?

Answer 6

Corticosteroids

Question 7

What is the focus of MS therapy?

Answer 7

Ease symptoms caused by neurological damage (QOL)

Adherence to a healthy lifestyle

Question 8

When to use immunotherapy in MS? What drugs are used?

Answer 8

Indicated for patients with relapsing forms of MS and active disease

> required expert management = risks vs benefits

Monoclonal antibodies (alemtuzumab, natalizumab, ocrelizumab)

• more potent but higher risk therapies
• started early in high risk patients

modern approach: use highly effective treatment early, to achieve NEDA (no evidence of disease activity)

Question 9

What potency are oral immunotherapies such as dimethyl fumarate, fingolimod, teriflunomide, cladribine

Answer 9

Moderate potency

Question 10

Why older drugs like interferon beta and glatiramer not used anymore?

Answer 10

Relapses more common than with other drugs

Question 11

These drugs are rarely used, but when they may be used?

Answer 11

Rapidly progressive MS

When patient does not meet criteria for other therapies or C/Is

Question 12

What are the three monoclonal antibodies used? What are their ADRs?

Answer 12

1. Alemtuzumab

ADR: infusion reactions, thyroid dysfunction, blood dyscriasis, anti-GBM, kidney disease (rare), listeriosis (rare)

>licensed for RRMS

2. Natalizumab

ADR: infusion reactions, hypersensitivity reactions, infection (UTI,RTI), hepatotoxicity, progressive multifocal leukoencephalopathy (PML)

> monitor for PML and for JCV

> Progressive multifocal encephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by JC virus

> PML occurs when the protective myelin coating on nerve cells in the brain breaks down, which leads to tissue damage. PML is incurable and can have severe physical effects. Complications include dementia, blindness, paralysis, and seizures.

3. Ocrelizumab

> License for RRMS (relapse remitting MS) and PPMS (primary progressive MS); only PBS subsidised for RRMS

ADR: hypersensitivity and infusion-related reactions, infection, transient neutropenia

Question 13

What are the four main oral immunotherapies used? ADRs?

Answer 13

1. Dimethyl fumarate

ADR: NVD, flushing, leucopaenia, lymphopaenia, rash, itch, increased ALT/AST, proteinuria, PML

2. Fingolimod

ADR: bradycardia, transient 1st degree AV block, increased LFTs, blood dyscriasis, cough, dyspnoea, infection (e.g. shingles), mascular oedema, oppurtunistic CNS infections, PML

> may increase risk of major congenital malformations

>licensed for RRMR

3. Teriflunomide

ADR: N/D, alopecia, rash, infeciton, blood dyscriasis, neuropsychiatric effects, increased ALT/AST - hepatitis, hypersensitivity reactions, SJS, interstitial lung disease

> Washout procedures (activated charcoal or cholysteramine) in cases of toxicity (as for leflunonomide)

4. Cladribine

2 treatment courses, 12 months apart

Safety concerns: severe lymphopenia, infection, possible malignancy

Question 14

ADR of interferon beta and glatiramer? What is license for?

Glatiramer acetate is indicated in treating relapsing-remitting type MS via a subcutaneous injection

Answer 14

Licensed for 1st demyelinating event suggestive of MS

interferon beta (interferon beta-1a and 1b; also peginterferon beta 1-b = similar efficacy)

ADR: injection site reaction, flu-like symptoms (use at night and use paracetamol to manage before), depression, elevated LFTs, blood dyscriasis, neutralising antibodies (reduced efficacy and loss of effect after 2 years)

glatiramer

ADR: injection site reactions, post-injection reaction, nausea, arthralgia, oedema, hypertonia, tremor, anti-glatiramer Abs

Question 15

Symptoms of mild and moderate/severe relapse of MS?

Answer 15

Mild Relapses (tingling in extremities)

• No disability
• No signs of neurological symptoms
• May include pain, fatigue, bladder and bowel symptoms, spasticity, psychiatric symptoms, sexual dysfunction

> reassure the patient and monitor to ensure resolution

Moderate to severe relapses

• Are disabling
• Typically occur over hours to days
• Usually objective - you can see that the patient has deteriorated; neurological signs are consistent & progressive and can be localised to part of the brain

Neurological signs include:

Ataxia

Facial and limb numbness

Limb weakness

Diplopia/double vision

Optic neuritis

Neuralgia

Loss of vision

Loss of bladder control

> high-dose corticosteroids— intravenous therapy is preferred. Oral formulations have slightly more adverse effects (eg insomnia) but are convenient when intravenous therapy is not available

> Intravenous formulations can be given as a day-patient, but severe relapses warrant admission for multidisciplinary care

Question 16

How to manage acute relapses if they are:

A) mild relapses

B) moderate to severe relapses. What medication to use?

Answer 16

A)

• If no signs of disability, reassure and monitor

B)

• Develop over hours to days
• Objective neurological signs, consistent progressive sx that can be localised to part of the CNS
• Corticosteroid therapy hastens recovery and improves short-term clinical outcome –> also prevent neuronal loss and improve longer-term outcomes

> methylprednisolone sodium succinate IV once daily for 3 days

• oral therapy when IV is unavailble
• plasma exchange in severe cases
• review for precipitating factors: fever, URTI, UTI

Question 17

What are some of the complex symptoms that has to be managed in MS?

Answer 17

Question 18

How to manage spasticity in MS which occurs due to corticospinal tract damage?

Answer 18

Management to reduce pain, improve mobility and prevent contractures

• Baclofen –> Baclofen is a GABA agonist, and its primary site of action is the spinal cord, where it reduces the release of excitatory neurotransmitters and substance P by binding to the GABA-B receptor. Inhibits mono- and polysynaptic spinal reflexes. may cause drowsiness in elderly.
• Add BDZ at night to help spasms (clonazepam, diazepam)
• Gabapentin if neuropathic pain and spasms
• Medicinal cannabis –> nabiximols, other cannabis products

Question 19

How to manage reduced mobility in MS?

Answer 19

Fampridine MR

• Improves walking speed; modest effect on cognitive function

ADR: insomnia, anxiety, tremor, constipation, dyspnoea

> renally cleared

> Review in 8 weeks: if there is no improvement then cease it

Question 20

What type of pain in MS?

Answer 20

Pain

• often trigeminal neuralgia, neuropathic pain

Question 21

What to do for fatigue in MS? What drugs might help?

Answer 21

Common, causes complex and management difficult

• Seek contributing factors
• Drugs have poor efficacy; amantadine and modafinil sometimes used

Question 22

What to do for bladder symptoms in MS?

Answer 22

• Urgency (due to detrusor overactivity) most common
• Mild symptoms: anticholinergic drug –> such as oxybutynin, darifenacin, solifenacin, tolterodine
• Expert treatments: intradetrusor injections of botulinum toxin, sacral neuromodulation; catheter may be required

> tamsulosin can be used in men only (alpha-1 adrenoreceptor blocker)

> trimethoprim (anti-folate antibiotic)

> desmopressin (hormonal treatment mimicking endogenous vasopressin)

> mirabegron (beta-3 adrenoreceptor agonist)

Question 23

What is most common bowel symptoms in MS?

Answer 23

Constipation most common, also faecal urgency and incontinence

Question 24

Why does psychiatric symptoms occur in MS?

Answer 24

Depression common, causes:

• reaction to diagnosis, physical effects and its effects on patient’s life
• drug of ADR
• attack of demyelination

Question 25

How to manage sexual difficulties in MS? Why does it occur?

Answer 25

Due to spinal plaques, psychological factors, relationship difficulties, fatigue or medication

• Specialist counselling +/- sildenafil in men (viagra)

Question 26

General health advice for MS?

Answer 26

• Healthy, low fat diet –> improve BMI, lipid profile, possibly fatigue
• Low serum vitamin D level associated with increase relapse frequency and MRI activity in early MS

> check vitamin D at diagnosis and supplement if < 50 nmol/L

> benefits of higher doses unclear

• Stop smoking –> increases risk of MS, and disease progression
• Increased exercise and moderate alcohol intake –> associated with lower disability
• Screening for HIV, TB (immunotherapy reactivates latent TB), hepatitis B and C required prior to immunotherapy initiation
• Vaccination –> influenza vaccine safe; live vaccines dangerous with some immunotherapies

Question 27

Discuss general health advice in relation to womens health. What type of MS medication is safest in pregnancy e.g.?

Answer 27

Hormonal contraception and HRT safe

• Risk of MS relapse decreased in pregnancy but increased in 3 months after delivery

> pregnancy should be planned

• Glatiramer and dimethyl fumarate safest in pregnancy

> immunotherapy can usually be stopped before attempting conception –> restart 2 weeks post-partum

> evidence lacking for safety of breastfeeding during immnotheapy

Question 28

How to monitor for efficacy of treatment in MS?

Answer 28

• Clinical monitoring + MRI (every 3-12 months) –> for lesions
• Further disease activity requires escalation of therapy or switch to an alternative agent
• Discontinue therapy in severe diasability or disease progression
• S and S requiring symptomatic relief

Question 29

How to monitor for safety factors in MS?

Answer 29

• Infection suh as UTI or URTI
• FBP –> monitor for blood dyscriasis
• LFT –> >3 times ULN = monitor patient
• Drug specific toxicities

> U and Es, TFTs (atalizumab), PML (6-monthly JC virus Ab testing for seronegative patients), cardiac (fingolimod), opthalmological

Question 30

Carbamazepine is sometimes recommended for patients with MS. What is the usual indication for this drug in a patient with MS

Answer 30

Paroxysmal symptoms

Paroxysmal is a term that describes the way that some symptoms of multiple sclerosis come on very suddenly, last only a few seconds or minutes and then disappear just as quickly. Sometimes this cycle repeats a few times or, perhaps, many times in a day. Some people call them attacks, clusters, surges, episodes or intermittent symptoms. They may also be called episodic symptoms.

Many symptoms of MS can come and go in a paroxysmal way including pain, spasms and difficulties with vision.

Paroxysmal symptoms (eg dystonic posturing, tonic spasms) in patients with multiple sclerosis usually respond to carbamazepine.