Neurology Lecture Series

Multiple Sclerosis

Dr. Yelly Oktavia Sari, M.Pharm, Apt

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Background
⚫ Recurrent or chronically progressive
neurological dysfunction
⚫ Repeated episodes of inflammation resulting in
widespread plaques throughout brain, optic
nerve and spinal cord
• Axonal transection and neuronal loss contribute to
irreversible nature
⚫ There is an immune medicated component
⚫ Causes and triggers are a complex mix of
genetic, environmental and infectious factors

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Epidemiology
⚫ 2.5M worldwide (0.04%)
⚫ 16,500 in Aust (0.075%)
⚫ 350,000 in USA (0.1%%
⚫ Curious geographical distribution
⚫ Women 3x as likely as men
⚫ Onset 20 – 40 years (peaks at 30)
• 10% are less than 20 years
⚫ 2nd only to trauma as a neurological disability

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Geographical distribution

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Classification
⚫ Relapsing remitting (85% of patients)
• (a) relapses with return to normal neurological function
• (b) relapsing disease with stepwise, accumulated
disability

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Classification
⚫ Secondary progressive disease (risk of
conversion from RRMS about 2.5% per year)
• (a) continues to have relapses
• (b) doesn’t continue to have relapses

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Classification
⚫ (a) Primary progressive disease (15%)
⚫ (b) Progressive relapsing disease (5%)
• An overlap of PPMS and SPMS

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Symptoms (early/RRMS)
⚫ Limb weakness/heaviness
• Common presenting feature, often exercise induced
⚫ Loss of vision
• Acute optic neuritis
⚫ Parasthesias
• Commences in the periphery of one or more limbs and spreads to the
trunk
⚫ Diplopia
⚫ Vertigo
⚫ Altered micturation
⚫ Paroxysmal symptoms
• Trigeminal neuralgia, ataxia, tonic seizures, pain, itching
⚫ Other symptoms (rare in early disease)
• Altered intellectual function, mood disturbance, epilepsy

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Impact of RRMS
⚫ Physical disability
• Median time to requiring cane/crutch: 15 years
• Median time to wheelchair confinement: 25 years
⚫ Cognitive function
• Prevalence 42 to 65%
• Affects employment, normal daily functioning, social impact
⚫ Life shortening
• 5 to 7 year decrease in life expectancy
• 2 to 7 times increase in suicide risk
• 50% (approx) die of MS related causes
• 25 year survival is only 85% expected

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Symptoms (established)
⚫ Mental function
• Altered mental function
• Depression
⚫ Eye movements
• Internuclear ophthalmoplegia
⚫ Motor function
• Spastic paraparesis
⚫ Cerebellar function
• Gait disturbances due to ataxia
⚫ Sphincter function
• Usually urinary frequency/urgency
⚫ Sexual function
• Erectile dysfunction in up to 40% males

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Diagnosis
⚫ MRI
• To detect MS lesions
⚫ Neurophysiological tests
• Conduction studies
⚫ Cerebrospinal fluid
• Total protein conc elevated
• Elevated IgG
⚫ Clinical staging
• EDSS (Expanded disability status score)
• Neurological examination
• Formalised assessment of symptoms
• Evaluation of patient’s ability to walk/transfer etc
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Treatment ACUTE attack
⚫ Corticosteroids
• Choice of agent?
• Severe attack
• Methylprednisolone 500mg to 1g od for 3-5 days
• Give over >60 minutes as rapid infusion can cause a
drop in vascular resistance and BP
• Moderate attack
• Prednisolone 60mg od one week (and wean?)
• Mild attack
• Treatment probably unnecessary

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Treatment of symptoms
⚫ Fatigue
• Amantadine, modafinil
⚫ Motor function
• Fampridine – modest benefit – rarely used
⚫ Depression
• Avoid TCAs where possible
⚫ Sexual problems
• Phosphodiesterase inhibitors if not CI (not always effective)
⚫ Pain
• trigeminal neuralgia
• Carmbamazepine
• Chronic pain (burning sensation in lower limbs)
• Amitriptyline (if tolerated) or gabapentin
⚫ Other paroxysmal symptoms
• Tonic seizures, dysarthria and itching
• Carbamazepine, or mexilitine

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Treatment of symptoms
⚫ Spasticity
• Oral antispastic agents
• Baclofen (Stelax, Clofen)
• 15-100mg d in divided doses
• GABA agonist at spinal level
• Sedation, nausea, dizziness, ataxia, depression, tremor
• Diazepam (Valium, Valpam, Antenex)
• 2-15mg d divided doses
• GABA mediated inhibitory circuits
• Sedation, confusion, ataxia, dependency, paradoxical aggression
• Dantrolene (Dantrium)
• 25-400mg d divided doses
• Acts peripherally on inhibitory circuits
• Sedation, nausea, diarrhoea, headache, hepatotoxicity
• Gabapentin (Neurontin)
• Tizanidine
• Alpha2-adrenoreceptor agonist at spinal level
• Not available in Australia

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Treatment of symptoms
⚫ Spasticity
• Intrathecal agents
• Baclofen
• Via pump
• Substantially more effective than oral
• Relieves spasticity, spasms and pain
• Adverse effects
• Wound/pump site infections
• Pump malfunctions
• Low pressure headaches
• Intramuscular agents
• Botulium toxin (Botox)
• Effective relief of spasticity
• Large amounts required for large muscles (eg legs)
• Cost
• Needs repeated every three months
• Nonpharmacological treatment
• Physiotherapy
• Stretching exercises together with baclofen shown to be beneficial
• Cannabinoids
• No evidence of improvement in spasticity, but evidence in improvement of patients
perception of effects on spasticity.

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Treatment of symptoms
⚫ Bladder problems
• Urge incontinence
• Due to detrusor hyperreflexia
• Anticholinergics
• Oxybutinin (Ditropan) 5-15mg d divided doses
• Propantheline (Pro-banthine) 30-90mg d divided doses
• Tolterodine (Detrusitol) 1-2mg bd
• Amitriptyline 10-50mg nocte
• Usual anticholinergic adverse effects
• Discontinue if transfers to urinary retention
• Incomplete emptying
• Residual volume >100mL
• Alpha adrenergic blocker
• Relaxes smooth muscle, including internal sphincter
• Prazosin (Pressin, Minipress) 0.5-2mg bd
• Tamsulosin (Flomaxtra) 400mcg daily
• Indoramin (Doralese) not available in Aust
• Eventually (self) catheterisation required

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Treatment of symptoms
⚫ Bladder problems
• Urinary tract infections
• Frequent, despite best care taken
• Take culture before starting treatment, usually
responsive to the usual antibiotics
• If frequent, prophylactic therapy may be required
• Nitrofurantoin 50-100mg nocte
• Trimethoprim 150mg nocte
• Bowel problems
• Faecal incontinence uncommon
• Constipation more common
• Compounded by anticholinergic drugs
• Treat with dietary fibre or isoosmotic laxatives (Movicol)

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Treatment with immunomodulators
(disease modifying drugs)

⚫ Reduce the frequency of future attacks

⚫ Reduce the probability of accumulating
neurological disability over time
• Interferons
• Glatiramer
• Natalizumab
• Fingolimod
⚫ Also considered for steroid failure
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Treatment with immunomodulators
(disease modifying drugs)
⚫ Interferons
• Reduce attacks by 30% in relapsing forms of MS
• Efficacy in chronic MS not established
• Improves quality of life and cognitive function
• Interferon B most widely studied
• IFNB1b (Betaferon)
• 250mcg s/c alt days
• Decreases frequency of relapses in relapsing MS
• IFNB1a (Rebif)
• 44mcg s/c 3 x weekly
• IFNB1a (Avonex)
• 30mcg i/m weekly
• Adverse effects
• Injection site reactions, flu-like symptoms, raised LFTs, rash, anaemia,
thrombocytopenia
• Uhthoff effect
• First doses result in transient worsening of neurological function (improves
rapidly with subsequent injections

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Treatment with immunomodulators
(disease modifying drugs)
⚫ Glatiramer (Copaxone)
• For relapsing remitting MS
• Reduces number of clinical attacks
• May slow accumulated disability
• Well tolerated
• Transient pain/swelling at injection site
• No flu like symptoms
• Occasional systemic reactions (one off events)
• Flushing, sweating, palpitations, anxiety
• Last minutes to hours
• Benign, no correlation to first or subsequent doses

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Treatment with immunomodulators
(disease modifying drugs)
⚫ Natalizumab (Tysabri)
• Recombinant humanised monoclonal antibody to a4-integrin
• Reduces the frequency of clinical attacks in relapsing MS
• Introduced then withdrawn in 2005
• Associated with progressive multifocal encephalopathy (PML) – 3
cases
• Re-released 2007
• Also used for Chron’s +/- MTX
• Section 100 PBS (was compassionate use previously)
• Evidence
• AFFIRM (68% reduction in attacks vs placebo, maintained at 2 years),
therefore about twice as effective as IFNB
• SENTINEL (in combination with IFNB, this combination not currently used)
• Adverse effects
• Hepatotoxicity, fatigue, anxiety, peripheral oedema, allergic reactions

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Treatment with immunomodulators
(disease modifying drugs)
⚫ Natalizumab (Tysabri)
• 300mg in normal saline every 4 weeks infused over
one hour
• Patient recieves in day centre, and is monitored for
anaphylaxis
• Long half life (11days) means it stays in the blood for
a long time
• Can be removed by PLEX
• Increases circulating leukocytes
• Pre-infusion questionnaire
• Screening for PML
• 13 doses per year, around $2000 per dose

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Treatment with immunomodulators
(disease modifying drugs)

⚫ Natalizumab
• Risk of PML
• Rare, risk 1-1000 (3 initial cases)
• Usually associated with immune suppression
• Associated with JC virus
• Risk management program
• Much higher usage now, but risk still 1-1000
• Some success with primaquine in vitro

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Treatment with immunomodulators
(disease modifying drugs)
⚫ Mitoxantrone
• Antineoplastic agent useful in MS
• Can reduce relapses by 65%
• Can be used for progressive MS
• Adverse effects
• Nausea, vomiting, stomatitis, alopecia
• Blue/green urine and sclera may occur
• Myelosuppresion
• Cardiotoxicity
• Cumulative and limits dosing to 2-3 years
• Decreased LVEF
• ECG changes

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Treatment with immunomodulators
(disease modifying drugs)
⚫ Fingolimod
• Sphingosine 1-phosphate (S1P) receptor modulator
• Blocks acpacity of lymphocytes to egress from lymph nodes, causing
a redistribution (rather than depletion) of lymphocytes
• This reduces the infiltration of pathogenic lymphocyte cells into CNS where
they cause damage
• For RRMS and 2PMS (with relapses)
• 0.5mg daily, currently available only on patient familiarisation program
• Screening pre first dose
• FBC, LFTs, U&E, Hep B&C serology, varicella zoster and HIV serology,
CXR (exclude active TB), ECG (>50yo), ophthalmic exam, adequate
contraception
• First dose monitoring
• Observe patient for 6 hours for bradyarrythmia
• Repeat ophthal exam in 3-4 months
• LFT and FBC at 1,3,6,9,12 months, then annually

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Treatment with immunomodulators
(disease modifying drugs)
⚫ Fingolimod
• Precautions
• Infections
• Reduction in WCC by 20-30%
• Continue monitoring for infections for 2 months after therapy
• Vaccinations
• May be less effective during and up to 2 months after therpay
• Avoid live attenuated vaccines
• VZV vaccination should be considered for negative patient prior to therapy
• Macular oedema
• Diabetic patients at increased risk
• Regular ophthal tests and compare to baseline
• Bradyarrythmia
• Usually first degree AV block
• Occurs 4-5 hours after dose, usually transient and assymptomatic
• Do not use in patients on Class Ia or III anti-arrythmic drugs due to risk iof
Torsades
• Liver function
• Discontinue if LFTs significantly elevated or patient jaundiced
• CI in Childs-Pugh C

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Hospitalised patients
⚫ Not very many
⚫ For acute exacerbations
⚫ For chemotherapy (or neutropenia)
⚫ New diagnosis and assessment
⚫ “social problems”
⚫ Natalizumab patients
⚫ First dose fingolimod patients
⚫ BMT for secondary progressive patients

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MS in pregnancy
• Important consideration due to prevalence in
young women, consider...
• (in the 60s/70s MS women were warned
against becoming pregnant)
1. Implications of MS on pregnancy foetal risk
2. Implications of pregnancy on MS exacerbations
3. Genetic implications, passed on?
4. Use of medications in pregnancy
5. Use of medications in breastfeeding

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MS in pregnancy cont...
1. Implications of MS on pregnancy foetal risk
• Little or no effect on pregnancy, fertility, delivery (although
assisted delivery may be required if patient in relapse)
• No increase in spontaneous abortion
• MS may cause sexual dysfunction or decrease in libido
however
2. Implications of pregnancy on MS exacerbations
• Relapse during pregnancy uncommon
• Long term prognosis favourable in patient that become
pregnant
• Patients with progressive disease likely to fare worse than
those with relapsing disease
3. Genetic implications, passed on?
• No gene that passes on MS, although risk with a first degree
relative (0.2% vs 2-4%)

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MS in pregnancy cont...
4. Use of medications in pregnancy
• No disease modifying therapies are cat A, and are advised
against in those trying to become pregnant, usally advised to
cease one month prior
• Interferons (cat C) are abortofacient
• Fingolimod (cat C) developmental toxicity in animal models
• Natalizumab (cat C) associated with miscarriages in animal
models
• Glatiramer (cat B) occasioanlly used if necessary, and is the
safest
• Epidural safe to use in MS
5. Use of medications in breastfeeding
• Breastfeeding is considered a contraindication to treatment
• Breastfeeding may reduce the occurrence of postpartum
relapse

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Emerging therapies
⚫ Other MAB’s
• Alemtuzemab (in late phase III development for MS,
currently used for CLL)
• Reduces rate of accumulation of disability, increases
infection occurrence, cytokine reactions (pyrexia, malaise,
rash), autoimmune thyroid disease in 30%
• Rituximab (associated with PML), Ocrelizumab
(testing suspended due to serious oppurtunistic
infections), Ofatumumab
• At various phases of testing
• Daclizumab (anti-CD25)
• Shows most promise in trials, further efficacy and safety
profiles underway

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Emerging therapies cont...
⚫ Cladribine
• Reduces levels of proinflammatory cytokines in CSF
• Taken as short course 8-20 days per year
• Good efficacy against placebo
• Low side effect profile (some herpes zoster infections, ?increase
malignancy)
⚫ Laquinimod
• Thought to release transforming growth factor
• Currently being trialled against IFN and placebo
⚫ Teriflunomide
• Active metabolite of leflunomide
• Anti-inflammatory by interfering with B and T cell proliferation
• Currently in phase III trials as single and add on therapy
• Teratogenic

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Complementary/alternative
therapy
⚫ Vitamin D
• Rationale is geographic link, evidence for supplementation not strong
• Generally well tolerated, supplement if levels are low or if low bone density risk factors
⚫ Bee Venom Therapy (BVT)
• Generally well tolerated, occasional anaphlyaxis
• Not shown to be effective
⚫ Cooling therapy
• Well tolerated, may alleviate symptoms in some
⚫ Dental amalgam removal
• Anecdotal evidence, likely of little benefit
⚫ Cranberry
• May prevent UTI recurrence
⚫ Marijuana
• May relieve symptoms and modify disease course. Many side effects. Obvious legal
issues.
⚫ Other
• Antioxidants, Echinacea, Vitamin B12, Ginkgo, St John’s Wort, Hyperbaric Oxygen,
• All mooted, but no evidence for their use

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Case Study
⚫ 31 year old woman
⚫ First symptoms 2000
• Developed vomiting then bilateral arm parathesias
⚫ New lesions on MRI 4 weeks ago, initial ones
in the medulla
⚫ Today hospitalised as has lost use of legs
⚫ MRI showed new lesions
1. Is it MS?
2. What treatment would you expect?
3. What prognosis would you expect?

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Case Study
⚫ Is it MS?
• Yes, two lesions on the different part of the brain
• Yes, two or more episodes affecting different sites
within the myelinated regions of the CNS have
occurred at different times
• Do we need any further test to confirm diagnosis?
• No
• What type of MS is it?
• Probably relapsing-remitting MS
• First symptoms in 2000, no episodes until 4 weeks ago

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Case Study
⚫ Expected treatment
• Initially
• Beta-interferon 1a
• Pulse methylpred (and a tapering course oral pred)
• Consider later
• Gatiramir
• Mitoxantrone
• Natalizumab
• Fingolimod
• Symptom management
• Bladder and bowel dysfunction, spasticity, sexual
dysfunction, fatigue, pain etc

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Case Study
⚫ Expected prognosis?
• Good at this stage
• As long as the disease stays as relapsing-remitting
• May be relapsing-remitting with slow progression
• Ultimately
• May progress more rapidly
• May require walking aids, or wheelchair eventually

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