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Multiple Sclerosis (MS) Program
 Epidemiology/Demographics
 Pathophysiology
 Clinical course
 Symptoms
 Diagnosis
 Treatment options
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Multiple Sclerosis
Overview
 Chronic, inflammatory, demyelinating disease
 Affects the myelin sheath and axons of the Central
Nervous System (CNS)
 Progressive clinical course
 Common cause of disability
in young adults
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Epidemiology
• Prevalence varies around the world
• Greater frequency in higher latitudes (above
40° latitude) than in lower latitudes
•
•
•
Two to three times more common in women
350,000 to 500,000 people in U.S.
The average person in the United States has about
one chance in 750 of developing MS
Sources: http://www.msfacts.org/info/info_faq.html and http://www.nationalmssociety.org/Sourcebook-Epidemiology.asp. Accessed May 9, 2006.
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Demographic Factors
 Age
 Onset: 15 to 50 years of age
 Peak onset: between 20 and 30 years of age
 Onset rare before age 10 or after age 60
 Gender
 More common in females
- 3:1 female versus male
 Race
 Incidence higher in Caucasians
Sources: http://www.msfacts.org/info/info_faq.html, http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm#54263215 and
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http://www.nationalmssociety.org/Sourcebook-Epidemiology.asp. Accessed May 17, 2006.
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Is MS a Hereditary Disease?
 Genetic factors
 First- and second-degree relatives are at
increased risk
 Risk is higher in siblings
- Nontwin siblings (2%)
- Monozygotic twins (30%)
- Dizygotic twins (2.3%)
 Susceptibility gene
 Major histocompatibility
complex (MHC) on
chromosome 6
Source: http://www.msfacts.org/info/info_faq.html, http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm#54263215 and
http://www.nationalmssociety.org/Sourcebook-Epidemiology.asp. Accessed May 17, 2006
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Effects of Demyelination and
Axonal Damage
 Loss of myelin and axonal damage may lead to:
 Conduction block at the site of myelin/axonal loss
 Slowed motor and sensory impulses in areas of
disease activity, resulting in compromised sensation
or movement
 Increased subjective fatigue (greater energy
consumption)
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Signs and Symptoms
 Depend on clinical course and disease progression
 Vary based on lesion location
 Exacerbated by heat and stress
 Secondary complications due to underlining
neurological dysfunction
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Signs and Symptoms of MS
by Lesion Location
 Optic nerve
 Monocular visual loss
 Scotoma
 Spinal cord
 Limb weakness
 Spasticity and
hyper-reflexia
 Lhermitte’s sign
 Urinary urgency and
incontinence
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Signs and Symptoms of MS
by Lesion Location
 Brainstem
 Diplopia (double vision)
 Pain (acute versus chronic)
- Trigeminal neuralgia, tic-like
extremity pain
- Aching back pain, burning
sensation, leg spasms
 Numbness of face and
tongue
 Vertigo (sensation of moving
around in space)
 Nystagmus (involuntary eye
movements)
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Signs and Symptoms of MS
by Lesion Location
 Cerebrum
 Impairment of
concentration or memory
 Hemiparesis (unilateral
paralysis)
 Hemisensory loss
 Visual field defect
 Cerebellum
 Incoordination of limbs
 Ataxic gate
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Signs and Symptoms of MS
 Severe fatigue
 Experienced by 75% to 95% of MS sufferers
 Depression
 Etiology can be a:
- Symptom
- Secondary complication
- Side effect of medications
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Secondary Complications
 Depression
 Urinary tract infection
 Accelerated lumbar spondylosis
 Aspiration pneumonia
 Pulmonary thromboembolism
 Pressure sores
 Limb contractures
 Gastroparesis
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What is an Exacerbation?
 Neurological attacks or aggravation of symptoms
 Indicative of a new immune attack on myelin
 Should last at least 24 hours
 Untreated attacks, can last from weeks to months
(resulting in slow recovery/residual effects)
 Precipitating factors can be identified
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Precipitating Factors
for Exacerbations
 Fever (most common), infections – especially
urinary tract infections – without fever
 Heat sensitivity
 Emotional stress
 Physical exertion
 Fatigue
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Diagnosis
 Clinical findings
 History
 Neurologic exam
 Clinical picture
 Laboratory evaluations
 Magnetic resonance
imaging (MRI)
 Evoked potentials
 Cerebrospinal fluid
(CSF) analysis
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Diagnosis
 Lesions disseminated in time and space
 Time: More than one attack separated by
at least one or two months
 Space: CNS involvement of more than
one area
 Exclusion of other possible causes
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Diagnosis:
History
 Signs and symptoms
 Frequency of occurrence
 Relapsing/remitting pattern
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Diagnosis:
Neurological Exam
 Cerebral (mental)
 Pyramidal (motor)
 Sensory
 Bowel and bladder
 Brain stem
 Visual/Optic
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Diagnosis:
MRI
 Highly sensitive in detecting MS lesions of the
brain and spinal cord
 Evidence of dissemination of lesions in time
and space
 Helpful in excluding other causes, such as tumors
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Diagnosis:
Evoked Potentials
 Measure nerve conduction velocity
 Visual
 Brainstem auditory
 Somatosensory
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Diagnosis Cerebrospinal
Fluid Analysis
 Immune abnormalities
 Increased intrathecal Immunoglobulin G (IgG)
synthesis with oligoclonal bands present
 Increased inflammatory cytokines -- such as,
interferon gamma (IFN-y) -- TNF and interleukin 2
(IL-2)
 Increased activated CD4+ T cells
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Clinical Course:
Relapsing-Remitting (RRMS)
 Most common type of MS
 Signs and symptoms evolve over several days
 Spontaneous improvement or in response to
corticosteroids
 Full recovery or some residual deficit upon
recovery
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Clinical Course:
Secondary Progressive (SPMS)
 Initially begins as relapsing-remitting MS
 Progressive deterioration with or without relapses
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Clinical Course:
Primary-Progressive (PPMS)
 Progressive deterioration without relapses
and remissions
 Occasional plateaus and temporary
minor improvements
 Tends to occur in older people
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Clinical Course:
Progressive-Relapsing (PRMS)
 Rare
 Progressive course from the onset
 Acute relapses that may or may not result in
complete recovery
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Progression
 Relapsing-remitting to secondary progressive
 30% to 40% within six years to 10 years of onset
 58% within 11 years to 15 years
 90% after 25 years
 Disability progression
 8 years to moderate disability
 15 years to severe disability
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Factors Affecting Prognosis
 Favorable
 Low attack rate
 Long interval to second
attack
 Complete recovery from
first attack
 Younger age at onset
 Female sex
 Low disability at 2 and 5
years
 Unfavorable
 High attack rate
 Short interval to second
attack
 Lack of recovery from
first attack
 Older age at onset
 Early cerebellar
involvement
 Insidious motor onset
 Early development of
mild disability
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Evaluating Disability in MS
 Functional systems (FS):
 Pyramidal, cerebellar, brain stem, sensory, bowel
and bladder, visual, cerebral, and other
 Each FS is independent of each other
 Grading:
- Pyramidal, sensory, bowel and bladder, visual (0-6)
- Cerebellar, brain stem, cerebral (0-5)
- Other (0 or 1)
 Scores are not additive
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Evaluating Disability in MS (cont.)
 Expanded disability status scale (EDSS)
 Consists of 20 steps from 0 (normal) to 10 (death due
to MS). Half-steps are included.
 Gain/loss of 0.5 steps defines disease
improvement/worsening
 Ordinal (rank scale)
 Relies on standard neurologic examination
(FS assessment)
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Treatment Goals
 Reduce (control) relapses
 Delay disease progression
 Delay disability
 Alleviate symptoms
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Early Treatment
The National MS Society recommends:
“Initiation of therapy with an immunomodulator is
advised as soon as possible following a definite
diagnosis of MS with a relapsing course, and may be
considered for selected patients with a first attack
who are at high risk for MS.”
Source: Recommendation of the Executive Committee of the Medical Advisory Board of the Nat’l MS Society
www.nationalmssociety.org/Sourcebook-Early.asp. Accessed May 17, 2006.
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Current Therapies:
Immunosuppressants and Immunomodulators
 Corticosteroids
 Interferons :
 Betaseron (interferon -1b)
 Avonex (interferon -1a)
 Rebif (interferon -1a)
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Current Therapies: (cont.)
Immunosuppressants and Immunomodulators
 Immunosuppressants and immunomodulators:
cornerstone of therapy (cont.)
 Copaxone (glatiramer acetate)
 Novantrone (mitoxantrone)
 Symptomatic management
33
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Corticosteroids
 Symptomatic management
 Used in moderate-to-severe exacerbations
 IV methylprednisolone 500 mg/day for five days
followed by oral prednisone (optional)
 Hasten clinical recovery
 Delay recurrence of neurologic events
 Does not alter the course of MS
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Interferon Beta
Mechanism of Action
 Reduce the production of the TNFa (tumor
necrosis factor alpha) and T-cells, known to induce
damage to myelin
 Reduce inflammation by:
 Switching cytokine production from type 1 (proinflammatory) to type 2 (anti-inflammatory) cells
 Increasing levels of interleuken 10 (IL-10)
 Decrease antigen presentation, to reduce the
attack on myelin
 Reduce the ability of immune cells to cross the
blood-brain barrier, by affecting adhesion
molecules, chemokines, and proteases
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Interferons :
Avonex (Interferon -1a)
 Indication: relapsing





Avonex-lyo-vial
forms of MS
Dose: 30 mcg IM
once weekly
Reduces rate of
clinical relapse
Reduces the development
of new lesions
Delays the increase in
the volume of lesions
May delay progression
of disability
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36
Interferons :
Rebif
 Interferon -1a
 Indication: relapsing/remitting forms of MS
 Dose: 22 or 44 mcg SC 3 times per week
 Decreases frequency of relapse
 Delays the increase in the
volume of lesions
 May delay progression
of disability
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Caremark proprietary and confidential information. Not for distribution.
37
Interferons :
Betaseron (interferon beta-1b)
 Indication: Relapsing forms of MS
 Dose: 8 million IU SC every other day
 Reduces rate of clinical relapse
 Reduces the development of
new lesions
 Delays the increase in the
volume of lesions
This page contains prescription brand drugs that are registered or registered trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.
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38
Side Effects of Interferons
 Common:






Flu-like symptoms
Chills
Fever
Muscle aches
Asthenia (weakness)
Betaseron and Rebif
have injection site
reactions
 Uncommon:






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Severe depression
Suicide
Seizures
Cardiac effects
Anemia
Elevated liver enzymes
Severe hepatic injury,
including cases of
hepatic failure, has been
reported in patients
taking Avonex
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39
Noninterferons:
Copaxone (glatiramer acetate) PFS
 Indication: Reduction of frequency of relapses in
patients with RRMS
 Dose: 20 mcg SC once daily
 Reduces the frequency of exacerbations
 Moderately reduces the
development of new lesions
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40
Copaxone Mechanism of Action
 Synthetic chain of four amino acids
 Structurally resembles the myelin basic protein
molecule
 Believed to block the immune system from
attacking myelin
 Switches the immune response from TH-1 cells
(pro-inflammatory) to TH-2 cells (anti-inflammatory)
which could reduce myelin damage
This page contains prescription brand drugs that are registered or registered trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.
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41
Copaxone:
Side Effects
 Common
 Injection site reactions
 Chest pain (transient –
20 to 30 minutes – not
life threatening but very
scary)
 Uncommon
 Nausea
 Vomiting
 Dizziness
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42
Auto Injectors
autoject® 2 for glass syringe
Dispenses Copaxone
Rebiject®
Dispenses Rebif
autoject® 2.25
Dispenses Betaseron
All provided free from manufacturer.
Rebiject and Copaxone need a prescription.
This page contains prescription brand drugs that are registered or registered trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.
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43
Antineoplastics:
Novantrone (mitoxantrone)
 Indication: Reduction of

relapse rate and clinical
disability in patients with
SPMS, PRMS or
worsening RRMS
Dose: 12 mg/m2 as short
IV infusion (five minutes
to 15 minutes every three
months)
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44
Antineoplastics:
Novantrone (cont.)
 Reduces exacerbation rate
 Prolongs time to first treated relapse
 Improves EDSS scores versus baseline
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45
Novantrone
Mechanism of Action
 Inhibits or prevents the development of any
uncontrolled new or abnormal growth, such as a
neoplasm or tumor
 Suppresses B-cell and T-cell immunity
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46
Novantrone
Side Effects
 Moderate to severe
 Bone marrow suppression
- Neutropenia (decreased WBC and ANC)
- Thrombocytopenia (decreased platelets)
- Acute myelogenous leukemia
 Cardiac toxicity
- Congestive heart failure (CHF)
- Decreased left ventricular ejection fraction (LVEF)
- Maximum cumulative dose 140 mg/m2
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47
Novantrone
Side Effects
 Moderate to severe
 Teratogenic effects
- Fetal growth retardation in rats
- Shortened gestation period
- Excreted in breast milk
 Mild to moderate
 Increased liver enzymes
 Nausea
 Alopecia (hair loss - transient)
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48
Novantrone
Contraindications
 LVEF < 50%
 CHF
 Baseline neutrophil count < 1500 cells/mm3
 Pre-existing myelosuppression
 Abnormal LFT
 Pregnancy, breastfeeding
 Cumulative lifetime dose  140 mg/m2
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49
Immunosuppressants
 Show only slight evidence of benefit in MS
 Used only for progressive MS
 Associated with serious side effects




Thiopurines (Imuran)
Methotrexate
Alkylating agents (Cytoxan)
Cyclosporine
This page contains prescription brand drugs that are registered or trademarks of pharmaceutical manufacturers that are not affiliated with Caremark.
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50
Symptomatic Treatments
Problem
Symptoms
Management
Spasticity
Painful spasms in the
lower and upper limbs
Remove irritating factors
Physical therapy,
baclofen, diazepam,
dantrolene
Paroxysmal phenomena
Trigeminal neuralgia,
pain, tonic seizures
carbamazepine,
Neurontin, phenytoin
Fatigue
Feeling tired (morning or
early afternoon)
Energy conservation,
amantidine
Depression
Common, occurs in high
percentage of patients
Anti-depressants
Sexual dysfunction
Inability to produce/
sustain an erection
Behavioral therapy
Viagra, Muse
Urinary dysfunction
Urgency, frequency and
retention
Detrol, Ditropan, Botox
Note, some of the drugs listed are shown for off-label use.
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51
Conclusion
 Early treatment may delay disability and enhance
recovery from relapses
 Treatment must be a cooperative effort between
multidisciplinary team of healthcare providers
 Medications are not a cure for MS
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Challenges
 Challenges for the person with MS




Physical difficulties
Financial concerns
Social issues
Emotional issues
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Resources and Links
 Support/Information




National MS Society (NMSS) 1-800-FIGHT-MS
Consortium of MS Centers 1-201-837-0727
MS Foundation 1-800-441-7055
MS Association of America 1-800-833-4MSA
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Resources and Links
 Copaxone - Shared Solutions®, 1-800-887-8100
 www.copaxone.com
 www.mswatch.com
 www.MSuniversity.com
 Rebif – MS LifeLines™, 1-877-44-REBIF
 www.rebif.com
 www.mslifelines.com
 Avonex – MS Active SourceSM, 1-800-456-2255
 www.avonex.com
 www.MSactivesource.com
Caremark does not operate the Web sites/organizations listed here, nor is it responsible for the availability or reliability of their content. These
listings do not imply or constitute an endorsement, sponsorship or recommendation by Caremark.
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55
Resources and Links
 Betaseron - MS PathwaysSM, 1-800-788-1467
 www.betaseron.com
 www.MSpathways.com
 Novantrone, 1-877-447-3243
 www.novantrone.com
 www.MSlifelines.com
Caremark does not operate the Web sites/organizations listed here, nor is it responsible for the availability or reliability of their content. These
listings do not imply or constitute an endorsement, sponsorship or recommendation by Caremark.
Caremark proprietary and confidential information. Not for distribution.
56