MULTIPLE SCLEROSIS SYMPTOM MANAGEMENT & EMERGING THERAPIES, Bertha C. Fonseca, MD

Bertha C. Fonseca, MD
NSC Multiple Sclerosis Center, Coral Gables, FL

Multiple Sclerosis
 Is an autoimmune chronic neurological condition
where the myelin (protective covering) surrounding
nerve fibers in the brain, optic nerves, and spinal cord
is damaged or destroyed.
 These lesions can cause interruption in the electrical
impulses which are transmitted to and from the brain
resulting in the symptoms of MS.

Multiple Sclerosis
 The exact cause is unknown, but it is believe to be
multi-factorial.
 Usually develops between the 20-40.
 There are approximately 400,000 patients diagnosed
with MS.
 There are different types of MS: RRMS, PPMS, SPMS,
and PRMS.

Common Symptoms in MS
 Loss of function/sensation in limbs
 Disturbance of walking/balance
 Disturbance of vision
 Bowel/bladder dysfunction *
 Fatigue *
 Pain
 Cognitive changes *
 Sexual dysfunction

Cognitive Impairment
 Cognition is the process of thought
 It can be seen in 45-65% of MS patients, usually mild
to moderate
 Only 5-10% have severe dysfunction
 Disability and disease duration are not good predictors
of cognitive dysfunction

Cognitive Impairment
 There are certain areas of cognition that are more
affected in MS
 Recent memory (short term memory)
 Verbal fluency
 Abstract reasoning
 Sustained attention (specifically with multiple tasks)
 Concentration

Etiology of Cognitive Impairment
 Extent and location of lesions
 Greater burden of disease T2 lesions
 Locations such as the frontal lobe
 Degree or extent of brain atrophy
 T1 “Black holes” lesion volume

Etiology of Cognitive Impairment
 Other causes which need to be evaluated:
 Depression (common cause of pseudodementia)
 Stress
 Fatigue (affects concentration and performance of
intellectual tasks)
 Medications (Baclofen, Neurontin, Clonazepam, etc)
 Sleep disturbances

Assessment of Cognitive
Impairment
 Screening Neuropsychological test batteries have been
developed specifically for MS patients
 Performed by Neuropsychologists mainly.

Treatment of Cognitive Impairment
 Multiple medications have been studied and they
have failed to show benefit in the treatment of MS
related cognitive impairment.
 The most important factor is to be on an approved
treatment for MS
 Like in the case of RRMS one of the many FDA approved
options that we have now (9).

 Cognitive Rehab
 Restorative – to restore and strengthen impaired
functions through drills and exercises
 Compensatory – to train the patient to function and
use strategies that can be helpful (ex., organizers,
notes, etc)

 Cognitive strategies:
 Write everything down
 Have a designated space for everything
 Repeat things that need to be remembered
 Take your time
 If you find cognitive problems happen at a particular
time reorganize activities so you have the more
demanding things done before that time.
 Focus on thing at a time.

 Most importantly, discuss all your symptoms,
including cognitive impairment or memory loss, with
you physician immediately so that he or she can
evaluate you and treat you accordingly.

Fatigue
 One of the most disabling and common symptoms in
MS patients (80%).
 Consists of lack of energy, tiredness and/or
generalized weakness.
 Could be more pronounced in patients with atrophy in
certain parts of the brain (parietal lobes).
 Other causes must be excluded including: depression,
insomnia, OSA, thyroid dysfunction, medications,
vitamin deficiencies, anemia, etc.
16

Treatment of Fatigue
 Depending on cause it would need specific treatment.
 If fatigue is caused my MS, there are several un-
approved treatments for it:
 Amantadine
 Provigil
 Nuvigil
17

Treatment of Fatigue
 Non-pharmacological treatments of fatigue:
 Conserve energy.
 Take naps during the day.
 Arrange activities to be done in the part of the day with
most energy.
 Stay away from the heat.
 Stay hydrated and eat healthy.
 Exercise regularly, if your physician approves.
18

Bowel and Bladder
Dysfunction
19

Bladder dysfunction
 Some patients with MS might experience problems
with their bladder. There are several types of bladder
problems:
 Bladder with failure to store (spastic)
 Bladder with failure to empty
 Conflicting bladder
20

Bladder dysfunction
 There are several symptoms that can be seen:
 Frequency and/or urgency of urination.
 Hesitancy of urination.
 Inability to completely empty bladder.
 Inability to hold urine.
 Frequent nighttime urination.
 Discuss with your HCP if you are experiencing these
symptoms, so that further tests such as post-voidal
residual, urodynamics, ultrasound, and Urology
evaluation can be ordered.
21

Bladder dysfunction
 Some tips that can help with bladder issues:
 Stay hydrated.
 Avoid caffeine.
 Don’t sip water and liquids all day long.
 Take bathroom breaks.
 Also, there are approved medications for the treatment
of overactive bladder that can be of help for those that
can take them.
22

Bowel dysfunction
 Some patients with MS might experience two
problems with bowel:
 Accidental loss of stool (incontinence)
 Constipation which might be caused by lack of proper
hydration, lack of physical exercise or by medication.
23

Bowel dysfunction
 Some tips that could help some patients with bowel
dysfunction would be:
 Stay well hydrated.
 Changes in diet, by increasing fiber intake.
 Stool softeners.
 Bowel program.
 In some cases, medication.
24

Vitamin D
 Vitamin D is a fat soluble vitamin that is responsible
for the absorption of calcium and phosphate.
 It is mainly obtained from our diet and also
synthesized by exposure to sunlight.
 Low vitamin D levels are associated to cardiovascular
disease, osteoporosis, and certain cancers (ex. colon).
 It is also believed to have a positive effect on our
immune system.
26

Vitamin D
 Low levels of vitamin D are associated with Multiple
Sclerosis.
 Several studies have shown that maintaining adequate
levels of Vit D have protective effect and lower the risk
of developing MS.
 Another study from the Netherlands suggest that for
MS patients, vitamin D may lessen the frequency and
the severity of their symptoms.
27

Vitamin D
 The connection between MS and vitamin D is linked
to the association of sunlight and the risk of MS.
 The father away a person lives from the Equator, the
higher the risk of MS.
 Your HCP needs to check the level of Vitamin D-25
with a simple blood test and based on that give specific
recommendations on dosing to prevent toxicity.
28

Smoking
 In a study in Norway, published in Neurology, the risk
of MS was significantly higher among smokers when
compared to those who had never smoked.
 Another paper published in Brain supported the link
between smoking and the risk of developing MS, and
also suggested that smoking may be a risk factor for
transforming a relapsing-remitting clinical course into
a secondary-progressive course. (NMSS)
29

Smoking
 Another study in Buffalo demonstrated that
individuals that smoked had lower brain volumes.
 Also, another study suggested that MS patients that
smoked had accumulated disability faster than non-
smokers.
 Discuss with your HCP your desire to stop smoking so
that he/she can provide recommendations that can
help you quit smoking.
30

Salt
 Recently, studies evaluated a possible link of high salt
diets and the increment in the cases of autoimmune
disease, such as MS.
 A study published in the journal Nature, showed that
high salt diets increased levels of a type of immune
cells , Th17 (that promote inflammation), linked with
autoimmune diseases.
 In this study, mice that were genetically engineered to
develop MS got much worse when they ate high salt
diets when compared to those that ate a more
moderate salt intake.
31

Salt
 These studies could suggest that high salt intake could
play a role in triggering autoimmune disease, such as
MS and DM, in individuals who are genetically
predisposed.
 The effect of high salt intake on MS now needs to be
studies in humans.
 Reducing the dietary salt might be a good idea for
those that can, since it has also been linked for many
years to hypertension and cardiovascular disease.
32

Treatments for MS
 There are several FDA approved treatments for Relapsing
Remitting Multiple Sclerosis:
 Betaseron
 Avonex
 Copaxone
 Novantrone
 Rebif
 Tysabri
 Extavia
 Gilenya
 Aubagio
 Tecfidera

The changing treatment landscape1-18
1. Multiple Sclerosis Treatments. Avonex Web site. 2. Company news; F.D.A. approves a multiple sclerosis drug. 3. Biotechnology medications move closer to the market.
4. Serono's rebif(R) receives FDA approval. 5. Immunex gets FDA OK. 6. Multiple sclerosis (relapsing-remitting): emerging therapies that offer improved convenience will not unseat
current drugs. Decision Base 2009. 7. Novartis media release. 8. Merck Serono news release. 9. Giovannoni G, et al. N Engl J Med. 2010; 362(5):416-426. 10. Cohen JA, et al.
N Engl J Med. 2010;362(5):402-415. 11. Kappos L, et al. N Engl J Med. 2010;362(5):387-401. 12. Study results: multiple sclerosis patients have significant and sustained reduction
in disability and risk of relapse on alemtuzumab versus approved therapy. 13. ALLEGRO study. Clinicaltrials.gov Web site. 14. BRAVO study. Clinicaltrials.gov Web site.
15. Biogen Idec showcases more than 70 data presentations at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis [news release].
16. Study of teriflunomide in reducing the frequency of relapses and accumulation of disability in patients with multiple sclerosis (TEMSO). 17. Novantrone®. National Multiple
Sclerosis Society Web site. 18. Tysabri® prescribing information. Biogen Idec Inc.
Under FDA review Currently not submittedFDA-approved therapies
1995 2000 2005 2009 2010 2011
Cladribine
Fingolimod
Alemtuzumab
Fumarate
(BG-12)
Teriflunomide
Extavia®
(IFNβ-1b)
Tysabri® (natalizumab)
Betaseron®
(IFNβ-1b)
COPAXONE®
(glatiramer acetate injection)
Avonex®
(IFNβ-1a)
Rebif®
(IFNβ-1a)
Novantrone®
(mitoxantrone)
Laquinimod
Approval date Estimated launch date
35

Emerging therapies for MS
 Copaxone
 Approved for the treatment of RRMS since 1996.
 Believed to cause a shift from Th1 cells (inflammatory)
to Th2 (anti-inflammatory cells).
 GALA Study
 Copaxone was given to patients at 40 milligrams three times
a week, rather than 20 mg daily sub cut.
 Awaiting for approval currently.
36

 Tecfidera (formerly known as BG-12)
 Dimethyl fumarate
 Approved by FDA on March 2013 for RRMS.
 Exact mechanism not understood, but it is believed have
an antiinflammatory effect and also inhibits an enzyme
that accumulates leukocytes at sites of inflammation.
 It is believed to reduce the oxidative stress, which
releases free radicals.
 Similar component has been used for treatment of
Psoriasis for 30 years in Europe.

 Tecfidera
 In the DEFINE (Determination of the Efficacy and safety
of oral Fumarate IN Relapsing Remitting MS) showed
53% reduction in ARR and 90% reduction in the mean
number of new or enlarging lesions at 2 years when
compared to placebo (NEJM, Fox et al)
 Most common side effects: Flushing, headache, nausea,
diarrhea, and abdominal pain.

 Tecfidera
 It is started 120 mg po bid with food for 1 week and then
increased to 240 mg po bid, unless recommended
otherwise by the HCP.
 It has been shown that when taken with food it reduces
the risks of the side effects.
 It is recommended to monitor liver enzymes and WBC
and lymphocytes. Labs must be done before starting
medication and followed up according to the HCP.
39

 Teriflunomide
 Oral agent
 Approved as Aubagio
 Inhibits rapidly dividing cells. Suppresses proinflammatory
factors and limits proliferation of T and B cells
 Used for Rheumatoid Arthritis
 In the studies it has shown decreased ARR by 30%
 Patients also showed fewer gadolinium-enhancing lesions per
T1-weighted scan than those in the placebo group .
 Most common side effects: hair loss, nausea, and diarrhea.
Infections have been reported. It is teratogenic (for men and
women) and hepatotoxic, therefore it has two black box
warnings.

 Teriflunomide (Aubagio)
 Other warnings and precautions:
 May decrease WBC count (TB testing and not recommended
for patients with immunodeficiencies).
 Acute renal failure.
 Skin reactions
 Peripheral neuropathy
 Increase in blood pressure
 Could interact with other medications (propanolol,
acetaminophen, diazepam, etc)
41

 Alemtuzumab
 Intravenous infusion
 Monoclonal antibody
 Currently used for treatment of chronic lymphocytic
leukemia and T-cell lymphoma
 Causes lymphocyte depletion
 Within an hour of receiving dose, lymphocytes and
monocytes are no longer detectable in circulation.

 Alemtuzumab
 The cumulative number of relapses over time was reduced by
74%, and the time to sustained accumulation of disability
(SAD) was reduced by 71% with alemtuzumab, compared
with interferon.
 Side effects: autoimmune thyroid dysfunction, mild to
moderate infections (respiratory, UTI, herpes), infusion
reactions, etc.
 In the CAMMS223 trial there were 3 cases of cancer, 3 cases of
serious infusion reactions and 1 death related to cardiac
disease
 Needs monitoring with monthly CBC, quarterly TSH,
Acyclovir for 1 month as prevention, and needs monitoring
for 4 years after last dose.

 Rituximab
 Approved for non-Hodgkin lymphoma and refractory
RA.
 Causes rapid depletion of B cells for 4-12 months
 Reduction of contrast enhancing lesions in MRI and
relapse rate
 Side effects: infusion reactions, nausea, infections, and
there have been cases of PML described.

 Ocrelizumab
 Phase II trial
 Targets mature B lymphocytes, hence it has an
immunosuppressive effect.
 Trials have shown significant MRI activity decrease and
decrease ARR by 80%
 Deaths have been reported in the RA trial and was
suspended for SLE as well due to opportunistic
infections.

 Laquinimod
 Induces anti-inflammatory cytokines and reduces
proinflammatory cytokines production by monocytes.
 Targets cells in the CNS and peripheral immune cells
that then lead to demyelination and neuronal loss.
 It penetrates the blood-brain barrier.
 Probably will be available, if approved by the FDA, in the
year 2017.
46

 Laquinimod
 In the ALLEGRO study, Laquinimod showed:
 23% reduction in the annualized relapse rate.
 36% decrease in the risk of disability progression when
compared to placebo.
 33% reduction in progression of brain volume loss vs. placebo
 The most common side effects seen in the study were:
 Abdominal pain, elevated liver enzymes, back pain, and
cough. Also a higher rate of appendicitis was reported in the
Laquinimod group.
47

Other medications for MS
 Ampyra
 “The walking pill”
 Only approved for use by MS patients
 Believed to send the nerve impulses faster towards the
legs, therefore could give patient the ability to walk
faster.
 Contraindicated in patients with seizures or kidney
dysfunction
 Some of the side effects are: UTI, dizziness, imbalance,
gastrointestinal issues, etc.
49

Other medications for MS
 ACTHAR gel
 ACTH which is a hormone that helps the body produce
natural steroid hormones to reduce inflammation.
 Recommended to treat MS exacerbations for patients
that have developed side effects to Solumedrol, have
poor venous access or have not responded well to
Solumedrol treatment during a flare-up.
 Given daily in subcutaneous form for the amount of days
necessary to treat relapse (average of 5 days).
50

Conclusions
 There are currently several trials in the process to
provide us with treatment options, oral and
intravenous, for MS patients.
 Many of them show promising results, proving to be
not only effective but also safe.

MULTIPLE SCLEROSIS SYMPTOM MANAGEMENT & EMERGING THERAPIES, Bertha C. Fonseca, MD

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