Transcript Treatment of MS - McGill University

Treatment
of MS
Alina Webber
Neurology R3
Outline
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Overview of MS
Acute treatment (relapse)
Long term management
MS and Lifestyle
MS (A brief overvveiw)
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Figure. A: RRMS is characterized by acute attacks with full recovery or with partial
recovery. B: SPMS starts with a RR course followed by a progressive phase. C:
PPMS is characterized by progression from onset of disease without acute
relapses. D: PRMS is characterized by progression from onset of disease with acute
relapses. Data from Lublin F, et al.[2]
Pathogenesis of MS
T cells, B cells and antigen-presenting
cells (APCs), including macrophages,
enter the central nervous system (CNS),
where they secrete certain chemicals
known as cytokines that damage the
oligodendroglial cells. Lymphocytes
diapedese into the CNS through use of a
surface receptor known as alpha4integrin. This step is impeded by
antibodies specific for alpha4-integrin
or by interferon-beta (IFN-beta). Once
the blood–brain barrier is breached,
other inflammatory cells accumulate in
the white matter. Inside the brain, T cells
and accompanying macrophages and
microglial cells release osteopontin
(OPN), interleukin-23 (IL-23), IFNgamma and tumour-necrosis factor
(TNF), all of which damage the myelin
sheath. Also, the presence of OPN might
lead to the attraction of T helper 1 (TH1)
cells. T-cell activation can be blocked by
altered peptide ligands (APLs), such as
copaxone, or by statins. Concomitantly,
B cells (plasma cells) produce myelinspecific antibodies, which interact with
the terminal complex in the
complement cascade to produce
membrane-attack complexes that
further damage oligodendroglial cells.
DNA vaccination can be used to tolerize
T- and B-cell responses to myelin.
Lawrence Steinman & Scott Zamvil. Nature 2003
Good to know when talking
about MS trials…
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EDSS
McDonald Criteria
Poser Criteria
Dinner tomorrow?
EDSS (Expanded
Disability Status
Scale)
EDSS steps 1.0 to 4.5 refer to people with MS who are fully ambulatory. EDSS steps 5.0 to 9.5 are
defined by the impairment to ambulation. (FS = functional systems: cerebellar, bladder,
brainstem, sensory, motor… )
0.0: Normal Neurological Exam
1.0: No disability, minimal signs on 1 FS
2.0: Minimal disability in 1 of 7 FS
3.0: Moderate disability in 1 FS; or mild disability in 3 - 4 FS, though fully ambulatory
4.0: Fully ambulatory without aid, up and about 12hrs a day despite relatively severe disability.
Able to walk without aid 500 meters
5.0: Ambulatory without aid for about 200 meters. Disability impairs full daily activities
6.0: Intermittent or unilateral constant assistance (cane, crutch or brace) required to walk 100
meters with or without resting7.0: Unable to walk beyond 5 meters even with aid, essentially
restricted to wheelchair, wheels self, transfers alone; active in wheelchair about 12 hours a day
8.0: Essentially restricted to bed, chair, or wheelchair, but may be out of bed much of day; retains
self care functions, generally effective use of arms
9.0: Helpless bed patient, can communicate and eat
10.0: Death due to MS
Kurtzke JF. Neurology. 1983; 33: 1444-52.
McDonald Criteria
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Origianlly devised in
2001 by Dr. Ian
McDonald.
They made use of
MRI, and were
intended to replace
old Poser and
Schumacher criteria.
Recent update and
change to criteria in
2010 (out of criticism
that non-caucasion
pts did not fit the
origincal criteria
A Historical note: Poser Criteria
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Replaced Shumaker criteria for diagnosis of MS.
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Clinically definite MS
– 2 attacks and clinical evidence of 2 separate lesions
– 2 attacks, clinical evidence of one and paraclinical evidence of another separate lesion
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Laboratory supported Definite MS
– 2 attacks, either clinical or paraclinical evidence of 1 lesion, and cerebrospinal fluid (CSF)
immunologic abnormalities
– 1 attack, clinical evidence of 2 separate lesions & CSF abnormalities
– 1 attack, clinical evidence of 1 and paraclinical evidence of another separate lesion, and CSF
abnormalities
•
Clinically probable MS
– 2 attacks and clinical evidence of 1 lesion
– 1 attack and clinical evidence of 2 separate lesions
– 1 attack, clinical evidence of 1 lesion, and paraclinical evidence of another separate lesion
•
Laboratory supported probable MS
– 2 attacks and CSF abnormalities
SCHUMACKER et al. Ann N Y Acad Sci. 1965 Mar 31;122:552–568
Poser CM, Paty DW, Scheinberg L, et al. (March 1983). Annals of Neurology 13 (3): 227–
31
Steroids, and acute MS
Treatment of the acute attack
• History:
• First RCT in 1970’s: adrenocorticotropic hormone (ACTH) was given
IM. (Rose et al, 1970)
• n~200
• Shortened recovery time, but 4 weeks post treatment there
was no clinical difference.
• Prominent SE’s (Na retention, hyperglycemia, Psych disorders)
was what prompted trials of synthetic corticosteroids with a
short half life.
• 1992: Several RCTs emerged with methylprednisolone (but the
duration and dose of treatment varied from 500mg IV QD x 3days
to 1000mg IV QD x 10 days. Some trials showed benefit of PO
methylprednisolone (500mg PO QD x 5d) (Meyers 1992, medlink)
Current Protocol?
• MOST COMMON CURRENT PROTOCOL: 3-7day course of IV
methylprednisolone (500-100mg IV QD) with OR without a short taper
• Methyprednisolone reduced the risk of worsening or not improving within
5 weeks. No long term benefits, however, just a quicker recovery.
• Why not PO glucocorticoids?
• Barnes, Lancet 1997: RCT, n~80 acute MS relapses:
• Methlprednisolone 48 mg PO x 7d, then 24mg PO x 7d, then 12mg
PO x 7d.
• Vs. 1000mg IV methylpred x 3days.
• No statistical difference in EDSS at 4 weeks.
• The authors concluded that oral steroids was a better regime in
terms of cost, pt preference….
So, why not PO steroids?
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The Optic Neuritis Treatment Trial (ONTT)
314 patients. Random assignment to:
• PO prednisone 1mg/kg/d x 14 days, with a 4 day taper
• IV methyprednisolone 250 QID x 3days, PO pred 1mg/kg/d x 11 days, four
day taper.
• PO placebo x 14 days
• Primary outcome: visual acuity, contrast sensitivity
• IV methylpred accelerated recovery, but 1 year outcomes were the same.
• IV methypred reduced the risk of conversion to MS (7.5% vs. 14.7 and
16.7%
• Oral pred arm had a significantly higher 2 year risk of recurrent optic
neuritis in both eyes (30% vs 13 and 16%). At 10 years this risk remained.
Beck et al. Am J Ophthalmol. 2004
Steroids continued
• Oral regimes are often used for MS exacerbations without optic neuritis.
• No good theoretical evidence as to why PO glucocorticoids would do this.
• SE’s of short term IV methyprednisolone:
• Relatively few
• Mental status changes
• Unmasking of infection
• GI disturbances
• Decreased bone density if repeated Tx: yearly bone density scans
recommended in pts with repeated treatments.
Other options for acute MS?
• PLEX: plasma exchange vs. plasmapheresis? The difference?
• Plasma exchange: removal of plasma and replacement with fluids
• Plasmapheresis: the removal of plasma (aphaeresis is removal in
greek)
• The two are often used synonymously in medical literature.
• Up to date uses them synonymously: (“Complications of
therapeutic plasma exchange” article)
Buskard, Can Med Assoc J. 1978
PLEX
• May be beneficial in acute severe MS attacks that do
not respond to glucocorticoids.
• One trial: 22 pts with CNS demyelinating disease (12
MS pts total) assigned to PLEX vs sham.
– Moderate to greater improvements (42% PLEX, 6% sham).
• A later trial: 116 MS pts: results were that PLEX led to
faster improvement in exacerbations that sham. (Note:
no long term benefits)
• This let the AAN to include PLEX into the guidelines for
a possible adjunctive treatment of relapsing MS.
Weiner, Neurology. 1989
Disease Modifying Treatment
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Avonex (interferon beta 1a)
Betaseron (interferon beta 1b)
Extavia (Interferon beta-1b)
Rebif (interferon beta 1a)
Copaxone (Glatiramer acetate)
Tysabri (natalizumab)
Mitoxantrone
Interferons
• Pharmacology: Cytokines that mediate antiviral,
antiproliferative and immunomodulatory
activities in response to viral infections and other
biological inducers.
• Interferon beta binds to human cells, leads to ifn
gene product production… exact mechanism not
understood, but there are some ideas:
• Modulates plasma cell IgG synthesis
• Decreases antigen presentation in microglia
• Anti inflammatory effects via T cells (regulates
migration, downregulates adhesion molecules…
The Interferons
• History
• Landmark paper in the 1980’s (Jacobs et al, 1986)
showed for the first time that interferon beta, when
intrathecally administered, could improve MS
exacerbations.
• In 1987 a trial of IV interferon gamma was performed
(n=18). (Panitch et al).
– The results? A dramatic increase in the relapse rate
of patients treated with interferon gamma!
– Yet the important discovery that activating the
peripheral immune system with peripheral drug
administration can change the course of a CNS
disease.
History continued
• The first approved med by the FDA was interferon beta 1b in
1993.
• In double blind placebo studies, interferon beta 1b:
– Decreases relapses by 34% at 2 years
– Decreased T2 lesion burden at 5 years
– Slowed disease progression
The IFNB Multiple Sclerosis Study Group. Neurology. Apr
1993;43(4):655-61
Interferon beta-1a
• Interferon beta 1a had similar efficacy:
• 301 patients initially
– Exacerbation rate decreased 29%
– Disease progression was slowed (progression in 29% of patients
on interferon vs 34% in the placebo group).
– Decrease in the mean MRI lesion volume and number of
enhancing lesions.
– The Multiple Sclerosis Collaborative Research Group (MSCRG).
Ann Neurol. Mar 1996;39(3):285-94
• Dosing? Evidence of Interferon Dose-response: European North
American Comparative Efficacy (EVIDENCE) trial
– Relapses occurs less frequently with higher doses, and MRI
lesions were reduced with higher doses
– Neutralizing antibodies occurred more with higher doses, and
this did affect the outcome in pts with neutralizing Abs.
Options for interferons:
Brand
(Generic Name)
Frequency
Route of Delivery
Once a week
Intramuscular (into
the muscle)
30 mcg
injection
Every other day
Subcutaneous
(under the skin)
injection
250 mcg
Extavia
(interferon beta1b)
Every other day
Subcutaneous
(under the skin)
injection
250 mcg
Rebif
(interferon beta1a)
Subcutaneous
Three times a week (under the skin)
injection
Avonex
(interferon beta1a)
Betaseron
(interferon beta1b)
Usual Dose
44 mcg
Side Effects of Interferons
SE
Beta-1b
every
other
day
Once
weekly
beta-1a
3x/week
beta 1a
management
tolerability
Local Skin
reactions
85%
15%
46%
Transient 50% dose
reduction, or improve
injection technique
Good
Fever
49%
23%
35%
Tylenol, NSAIDS,
pentoxyphilline
Good
Flulike Sx.
52%
61%
56%
Tylenol, NSAIDS,
pentoxyphilline
Good
Leuko or
thrombocyt
openia
40%
8%
20%
Transient 50% dose
reduction
Good
Increased
liver
enzymes
19%
10%
20%
Transient 50% dose
reduction
Good
(disappear
within
months.
Interferon Beta SE’s continued…
SE
Beta-1b
every
other
day
Once
weekly
beta-1a
3x/week
beta 1a
management
tolerability
Depression
16%
10%
24%
Anti-depressants
Poor
Skin
Necrosis
5%
0%
2%
Improve injection
technique, stop
treatment
Poor
Thyroid
alterations
1-2%
1-2%
1-2%
Transient 50% dose
reduction
Good
Other SE’s worth mentioning (that
didn’t fit neatly into my table):
• Neutralizing antibodies to interferon beta (NAbs)
• May effect clinical and MRI efficacy.
• Whether or not NAbs are detrimental to initial treatment response is
unclear (studies yield mixed results)
• NAbs have been more consistantly shown to have a detrimental effect
in the long term (3-4 years)
• NAbs occur with a lower frequency in IM interferon 1A (2-6%).
• SubQ interferon beta 1a (12-25%)
• Interferon beta 1b (22-38%)
Monitoring guidelines:
– CBC, Chem7, LFTS at 1,3, and 6 months. TSH
should be checked every 6 months if Hx. Thyroid
dysfunction
– Psych sx (depression, SI)
– Pregnancy test
– CXR
– EKG
Glatiramer acetate
Copaxone is a random polymer of four amino acids found in
myelin basic protein, namely glutamic acid, lysine, alanine, and
tyrosine. The mixture is antigenically similar to myelin basic
protein, a component of the myelin sheath of nerves
Glatiramer acetate (copolymer 1)
• Mechanism of action – unclear of the exact mechanism, but:
– Experimental models: binds to MCH molecules and
competes with myelin antigens for their presentation to T
cells.
– Induces T helper 2 type suppressor cells to the CNS, these
cells express anti-inflammatory granules.
History:
• Benefits of Glatiramer acetate first established in a double
blind trial of RRMS pts (n=251) (Johnson et al 1995)
– At two years, significantly lower relapse rate (29%)
– Slowed EDSS progression
– No MRI outcome in initial trial.
– Other studies, including a 2007 trial which showed similar
results and a reduction of MRI activity –
• two doses were tested as well (20 and 40mg). The
higher dose was more effective
• (Cohen et al, 2007)
SE’s of Copaxone:
Local skin reactions
Frequency
Management
Tolerability
90%
Transient, no
treatment
Good
Transient, no
treatment
Good
Pain
64%
Erythema
57%
Pruritis
38%
Necrosis
0%
Lipoatrophy
45%
Systemic reactions
15%
Dyspnea
13%
Flushing
8%
Chest Pain
10%
Palpitations
5%
Side effects
• Generally well tolerated
• Short lived skin reactions are most common
• Localized lipoatrophy has been reported in up to 45% of pts in some
studies, mainly women.
• May occur within months of therapy.
• Disfiguring, permanent
Monitoring:
No routine tests recommended
Fingolimod
Before I talk about Fingolimod, the
following was stolen shamelessly from
Medscape’s latest CME quiz on Oral
MS treatment (An okay video, but
sponsored by Novartis):
What factor(s) go into selecting the optimal therapy, both
injectable and oral, for patients with RRMS?
a) Efficacy, cost, convenience, monitoring, tolerability,
and safety
b) Burden of therapy
c) Safety and efficacy
d) Cost, convenience, monitoring, tolerability, and safety
Answer:
• Efficacy, cost, convenience, monitoring,
tolerability, and safety
Which of the following treatment approaches is best
supported by a currently available evidence base in a patient
with highly active RRMS who shows breakthrough disease
after taking interferon-beta for 6 months?
a) Switching to natalizumab
b) Switching to fingolimod
c) Continuing with interferon-beta for another 6 months and
then switching to fingolimod
d) Continuing with interferon-beta until steroids can no
longer control motor symptoms and then switching to
either fingolimod or natalizumab
Answer:
A wide body of evidence supports an early switch
in RRMS to fingolimod in pt’s with highly active
disease and show signs of disease progression
while on interferon beta therapy.
Little data is available on the benefits of
switching to tysabri
For patients with no history of cardiovascular disease and
who are considering starting fingolimod, guidelines from
the European Medicines Agency (EMA) recommend that
they should have their heart activity monitored:
a) Before the first dose of fingolimod and continuously
overnight after the first dose
b) Periodically during the first 6 weeks of therapy
c) Never, only patients with a history of cardiovascular
disease are at risk of cardiac side effects
d) Before the first dose and continuously for at least the
first 6 hours thereafter
Answer:
The EMA (European Medicines Agency)
recommends all patients starting fingolimod should
have their heart activity monitored BEFORE the 1st
dose, and continuously for 6 hours.
EXTEND monitoring by 2 hours in pts whose HR is
lowest 6h post first dose, or overnight if cardiac
problems are clinically significant.
Fingolimod
• An Sphingosine 1-Phosphate
(S1P)-receptor modulator,
derived from a fungal
metabolite
• Reduces circulating WBCs by
sequestering lymphocytes in
lymph nodes, preventing
them from becoming active.
• Originally developed as an
antirejection drug, not
marketed for this. Now
under investigation as a
potential CHF/antiarrythmic
med.
History:
• FREEDOMS trial
– N-1272, RRMS patients (0.5 or 1.25 mg PO QD)
• 24 months:
– The annual relapse rate was 0.18, 0.16, and 0.4 (0.4 was placebo).
– Incidence of serious infections was similar.
– Macular edema occurred in 7 pts on the high dose group.
• TRANSFORMS trial
– N = 1200, RRMS pts (0.5mg or 1.25mg PO QD vs interferon beta-1a
• Relapse rate lower in fingolimod group ( 0.2, 0.16 and 0.33)
• MRI favored fingolimod
• No change in disease progression
• More serious adverse effects in fingolimod groups: (2 serious
disseminated infection: 1 herpes, 1 VSV. 12 patients developed skin or
breast ca, 19 developed bradycardia or AV block)
SE’s
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Risk of Herpes virus infections
Macular edema
Fatal tumor development
Headache (25%)
Diarrhea (12%)
Elevated LFTs (14%)
Flu like sx (13%)
Cardio: HTN, bradycardia
Heme: Lymphopenia, leukopenia
Monitoring:
• Before initiation:
– CBC, LFTs,
– EKG
– Optho exam
– Varicella serology and vaccination Hx. (Fingolimod
should not be started one month after vaccination
– Derm exam – r/o precancerous lesions
Monitoring:
• First dose;
– BP, cardiac monitor x 6hr (exxtend for 2 more hours if
lowest HR at 6hr post dose), and overnight if cardiac
sx.
• During Tx:
– Avoid live vaccines
– Optho exam at 3 mo, and routinely if diabetic or hx
uveitis
– LFT follow up
– Pulmonary Function tests if clinically indicated
Tysabri
(Natalizumab)
• Tysabri is a monoclonal antibody directed against alpha 4 integrins,
specifically the very late antigen 4 (VLA-4) and vascular-cell
adhesion molecule 1 (VCAM-1) and lymphocyte functionassociated antigen 1 (LFA-1) and intercellular adhesion molecule 1
(ICAM-1) interactions, respectively
• Alpha-4 integrin is expressed on the surface of inflammatory
lymphocytes and monocytes and may play a critical role in
adhesion to the vascular endothelium.
• Mechanism of action and significance?
– Rituximab, Natalizumab, and Efalizamab all inhibit
the lyphocytes from binding to the endothelium in
a similar manner, and all three are associated with
rare cases of PML.
Tysabri:
• Two key trials: AFFIRM and SENTINEL – results
pooled in a 2011 review:
– Significantly reduced the risk of having a relapse
during two years of Tx (57%)
– Reduced the risk of progression of sx (RR = 0.74)
– NNT to prevents one exacerbation in 2 years was
4.
– 83% reduction in MRI plaques
– Increased proportion of relapse free patients
(32%)
Side effects: Tysabri
AFFIRM study
ENTINEL study
Flu-like syndrome
22%
24%
Infections
13%
15%
Allergic reactions
7%
--
GI disorders
8%
12%
Menstrual disorders
5%
18%
Chest discomfort
4.5%
<1%
Vertigo
6%
--
Anxiety
--
12%
Tremor
1%
5%
Depression
19%
21%
Local Bleeding
3%
--
Insomnia
--
17%
PML
--
<1%
Clinical use
• AAN guidelines recommend Tysabri be reserved for selected
RRMS pts who have failed therapies because of:
– Continued disease activity
– Medication intolerance (should try both interferons AND
copaxone before determining treatment
failure/intolerance)
– Aggressive initial disease course (debatable*)
• Not to be used with beta interferon or other
immunosuppresants b/c of PML risk.
• Drug Holiday?
– NOT recommended (gr 2C evidence), but a reasonable
option for pts who are more concerned about PML.
Monitoring on Tysabri
• Before initiating: Leukocyte counts, initial brain MRI, JC
serology for risk stratification
• Clinical evaluations every 6 months
• Monitor for:
– hepatotoxicity
– hypersensitivity reactions 1hr post infusion
– Consider antibody testing to tysabri if drug holiday (higher
risk of allergic rxn)
• US: tysabri can only be given in select centers. Manditory
patient registry (US) with checklist that asks about PML
symptoms.
Mitoxantrone
• An antineoplastic drug with long lasting
immunosuppressive effects.
• Approved for both RRMS and progressive
forms of MS (Note: in progressive MS other
meds are otherwise used off label)
• AAN 2003 Guidelines: because of cardiac
toxicity, and limited benefits in small trials,
mitoxantrone should be limited to patients
who have failed other therapies.
SideManagement
Effects:
Nausea
Frequency
76%
Alopecia
61%
Transient, no treatment
Good
Menstrual
disorders
60%
Transient, no treatment
Good
(10%)
(hormonal replacement)
(may be
irreversible)
32%
Antibiotics (check white
blood cell count)
Good
Leukopenia
19%
Good
(granulocytop
enia)
(6%)
White blood cell count 3
to 6 days before and
every 10 days after
infusions (50% dose
reduction in neutrophil
count less than 1500
mm3
(secondary
amenorrhea)
Urinary tract
infection
Give always
intravenous antiemetics
before infusions
Tolerability
Good
SE
Frequency
Management
Tolerability
Increased liver
enzymes
15%
Usually transient, 50%
dose reduction if
greater than 5-fold
baseline
Good
Cardiac toxicity
2%
Echocardiogram every
6 months or above 100
mg cumulative dose;
stop if left ventricular
ejection fraction drops
by 10% or below 50%
May progress
even after
stopping
treatment
Acute leukemia
Exceptiona
l
May occur even
after stopping
treatment
Multiple other trials for disease
modifying drugs with no evidence, or
further evidence needed:
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Alemtuzumab
Azathioprine
CCSVI treatment
Cladribine
Cyclophosphamide
Daclizumab
Dalfampridine
Fumarate
Glucocorticoids in combination therapy
Intravenous immune globulin
Laquinimod
Ocrelizumab
Rituximab
Statins
Stem cell transplantation
Teriflunomide
Since the first disease modifying treatment came out in 1993, there are now 7
drugs that are FDA approved for use in MS
Brand
(Generic Name)
Frequency
Route of Delivery
Usual Dose
Avonex®
(interferon beta-1a)
Once a week
Intramuscular (into the
muscle) injection
30 mcg
Betaseron® (interferon
beta-1b)
Every other day
Subcutaneous (under the
250 mcg
skin) injection
Copaxone® (glatiramer
acetate)
Every day
Subcutaneous (under the
20 mg (20,000 mcg)
skin) injection
Extavia®
(interferon beta-1b)
Every other day
Subcutaneous (under the
250 mcg
skin) injection
Gilenya™
(fingolimod)
Every day
Capsule taken orally
Rebif®
(interferon beta-1a)
Three times a week
Subcutaneous (under the
44 mcg
skin) injection
Tysabri® (natalizumab)
Every four weeks
IV infusion in a registered
300 mg
infusion facility
0.5 mg
Manufacturer/Distributor & Year of Health Canada
Approval
• Avonex® Biogen Idec Canada — 1998
Betaseron® Bayer HealthCare Pharmaceuticals, Inc. —
1995
Copaxone® Teva Neuroscience — 1997
Extavia® Novartis Pharmaceuticals Canada Inc. — 2009
Gilenya® Novartis Pharmaceuticals Canada Inc. — 2011
Rebif® EMD Serono Canada Inc. — 1998
Tysabri® Biogen Idec Canada Inc. — 2006
For interest’s sake:
How much would you guess MS drug
treatment costs per year, in Canada?
From MS Society Canada:
• Cost of disease modifying therapy: $20,000$40,000 (dependant on the drug, the
pharmacy, etc)
• The amount of reimbursement varies between
provinces.
A few small points on complementary tx
MS and Lifestyle
• Diet – no recommendations
• Vitamin D:
• ? Linked to decreased incidence of MS
• 1000-2000IU vitamin D/day for people who may be vit D
deficient.
• Exercise
• Reduces fatigue, improved bladder and bowel function,
strength and mood.
• Acupuncture
• Studies suggesting benefit, not cosidered to be a CAM to
avoid
MS Society Canada (2012)
Controversy and new directions
Surgeons look over a balloon at the end of the wire, which is put through
with a surgical catheter into the patient as part of MS treatment.
(JOHN LEHMANN/THE GLOBE AND MAIL)
Commonly use CAM methods to avoid:
• Removal of amalgam fillings
• Some suggestions that mercury in dental fillings can
cause or trigger MS – No evidence
• Bee sting therapy
• 24 week RCT showed no change in activity, disability or
fatigue. No change in quality of life.
MS Society Canada (2012)
Thanks!