Multiple Sclerosis:
Physician’s Overview
Defining Multiple Sclerosis
• An immune-mediated disease of the
central nervous system
– Immune cells are made throughout the body
except in the brain and spinal cord
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Tonsils
Thymus
Bone Marrow
Spleen
Lymphoid tissue of the gut
The Body’s Immune System
Balancing the Mediators
of the Immune System
Proinflammatory and
Neurotoxic Factors
TH1 and TH17 cytokines
TNF
IL-1
osteopontin
leukotrienes
MMP
plasminogen activators
nitric oxide
reactive oxygen species
glutamate
antibody + complement
cell-mediated cytotoxicity
neurotrophins via p75NTR?
Destruction
The balance between the protective and
destructive response determines the net
effect of the inflammatory response
Kerschsteiner M et al. Ann Neurol 2003;53:292-304
Anti-inflammatory and
Neuroprotective Factors
TH2 cytokines
TGF-beta
soluble TNF receptor
soluble IL-1 receptor
IL-1 receptor antagonist
some prostaglandins
lipoxins
TIMP
antithrombin
BDNF
NGF
NT3
neurotrophic
NT4/5
factors
GDNF
LIF
Protection
Defining Multiple Sclerosis
• An immune-mediated disease of the
central nervous system
• A disease of myelin and axons
Active Inflammatory Demyelination
and Axonal Transection
• It has been shown that
active inflammation
results in both
demyelination and
axonal transection
Arrowheads = areas of active demyelination; Arrow = terminal axon ovoid; Human brain;
Red = immunostained for myelin basic protein; Green = immunostained for nonphosphorylated neurofilament;
Bar = 45 m.
Trapp BD et al. N Engl J Med. 1998;338:278-285.
Peterson JW et al. Neurol Clin. 2005;23:107-129.
Multiple Sclerosis
• An immune-mediated disease of the
central nervous system
• A disease of myelin and axons
• A disease of people
Who gets MS?
• Usually diagnosed between 20 and 50
– Occasionally diagnosed in young children and older
adults
• More common in women than men (>2-3:1)
• Most common in those of Northern European ancestry
– More common in Caucasians than Hispanics or African
Americans; rare among Asians
• More common in temperate areas of the world
– Environmental factor(s)?
– Genetic factor?
– Lower vitamin D exposure?
– Combination?
The genetic factor in MS
• The risk of getting MS is approximately:
– 1/750 for the general population (0.1%)
– 1/40 for those with first-degree relative with MS (3%)
– 1/4 for an identical twin (25%)
• 20% of people with MS have a blood relative with MS
The risk is higher in any family in which there are several
family members with the disease (multiplex families)
Diagnosing MS
• MS is a clinical diagnosis
– Signs and symptoms
– Medical history
• Paraclinical tests provide support
– Magnetic resonance imaging
– Spinal fluid
– Evoked potentials
• Diagnostic criteria:
– Dissemination in time and space: evidence that
damage has occurred in at least two separate areas
of the CNS at different points in time
– There must be no other explanation
Conventional MRI in MS Clinical Practice
FLAIR
T2
BOD*
T1 precontrast
T1 Gd
postcontrast
Disease Activity†
Black Holes†
The strongest
correlation with
progression of
disability
*Reprinted with permission from Miller DH et al. Magnetic Resonance in Multiple Sclerosis. Cambridge: Cambridge
University Press; 1997. †Reprinted with permission from Noseworthy JH et al. N Engl J Med. 2000;343:938-952. Copyright
© 2003 Massachusetts Medical Society. All rights reserved.
Clinically Isolated Syndrome (CIS)
• A first neurologic event suggestive of demyelination
• Individuals with CIS are at high risk for developing
clinically definite MS if the neurologic event is
accompanied by multiple, clinically silent
(asymptomatic) lesions on MRI typical of MS
Clinical Patterns of MS
Relapsing-remitting
Secondary progressive
Primary progressive
Progressive relapsing
Time
Adapted from Lublin et al. Neurology. 1996;46:907-911.
Disease Courses in MS:
Demographics
(N=3019)
Primaryprogressive
10%
Progressiverelapsing
5%
Secondary-progressive
30%
Jacobs et al. Mult Scler. 1999;5:369-376
Relapsing-remitting
55%
FDA-Approved Disease-Modifying Drugs
Drug
Origin
Dosage
Freq
Route
IFNb-1b
Recombinant protein
0.25 mg
Every other day
SC
IFNb-1a IM
Recombinant protein
30 mcg
1x/wk
IM
Glatiramer acetate
Random polypeptides
20 mg
Every day
SC
IFNb-1a SC
Recombinant protein
22 mcg
44 mcg
125 mg
3x/wk
IFNb-1a SC
SC
2x/mo
Fingolimod
Sphingosine 1-phosphate
receptor modulator
0.5 mg
Every day
Oral
Teriflunomide
De novo pyrimidine
synthesis inhibitor of the
DHO-DH enzyme
7 mg or 14 mg
Daily
Oral
Dimethyl fumarate
Oral formulation of
dimethyl fumarate rapidly
hydrolyzed to monomethyl
fumarate
24o mg
Twice daily
Oral
Mitoxantrone
Chemotherapy
12 mg/m2
(cumulative
lifetime dose <
140 mg/m2)
Every 3 months
IV infusion
Deciding Which Disease-Modifying
Agent Should Be Used—and When
•A medical decision taking into account several factors:
– Patient’s disease course and prognostic
indicators
– Benefits vs. risks of each medication
– Co-morbidities
– Cost vs. benefits for each patient
– Patient’s lifestyle and preferences
– Patient readiness
Lifestyle and Personal Preferences
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Patient readiness to treat their MS
Preconceptions/attitudes about medications
Comfort with needles and self-injection
Medication side effects
Lifestyle
Depression, anxiety
Cognitive status
Negative Prognostic Indicators
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Frequent, multifocal attacks
Heavy MRI burden on initial scans
Pyramidal involvement
Ataxia
Cognitive difficulties
5 year accumulation of disability
Spinal progression (primary progressive MS)
The Concept of “Benign” MS
Maybe it should be called:
“Mild MS”
Relapse Management
• Relapse = new symptom or sudden worsening of old
symptom lasting at least 24 hours, and usually
accompanied by an objective change in neurologi findings
• Treatment with corticosteroids recommended if relapse
significantly interferes with everyday functioning
– 3-5 day course of high-dose intravenous methylprednisolone with
or without oral taper
– High-dose oral steroids may also be used
• Rehabilitation can help restore function following a
relapse
MS Symptom Management
• MS symptoms are variable and unpredictable
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Fatigue (most common)
Loss of sensation
Decreased visual acuity,
diplopia
Bladder and/or bowel
dysfunction
Pain
Sexual dysfunction
Paresthesias (tingling,
(numbness, burning)
Emotional disturbances
(depression, mood
swings)
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Cognitive difficulties
(memory, attention,
processing)
Heat sensitivity
Spasticity
Gait, balance, and
coordination problems
Speech/swallowing
problems
Tremor
Weakness
Managing Weakness
• Exercise
– The role of progressive resistive exercise
• Pharmacological treatment
– Dalfampridine
• Mobility aids
Mobility vs. Ambulation
• The goal of treatment is to promote function, comfort,
and independence
• Mobility aids conserve energy, enhance safety, and
allow people to remain active and involved
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Cane
Crutches
Walker
Ankle foot orthosis
Manual wheelchairs
Motorized scooters
Electric wheelchairs
• Dalfampridine (Ampyra™) was approved in 2010 to
improve walking speed in MS.
A Word about Temperature Sensitivity
• Heat sensitivity is common in MS
• Sensitivity to cold can also occur
• Even a slight elevation in core body temperature
can cause temporary worsening of symptoms
(called a pseudoexacerbation)
• Cooling strategies are beneficial during:
– Hot, humid weather
– Exercise
– Cooking
Treating Bladder Dysfunction
• The small (failure to store) bladder
– Oxybutynin in various forms
– Tolteridine
– Trospium chloride
– Others
• The large (failure to empty) bladder
– Stimulating medication
– Intermittent self-catheterization
Treating Bladder Dysfunction, cont’d
• Dysynergic bladder
– Alpha adrenergic agonists
• dibenzyline, terazosin (Hytrin), Cardura
– Intermittent self-catheterization
• Nocturia
– DDAVP-desmopressin
Managing Bowel Dysfunction
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Regular bowel regimen
High fiber diet; sufficient liquids
Bulk formers
Stool softeners
Mini enemas
Suppositories
Enemas
Managing Pain
• Dysesthesia, paresthesia
– Pharmacological: gabapentin (Neurontin), lamotrigine
(Lamictal), carbamazepine (Tegretol), amitriptyline
(Elavil), pregabalin (Lyrica), others
– Mechanical: gloves, counter-irritant
– Other: accupuncture, biofeedback
• Orthopedic, mechanical
Depression in MS:
Diagnosis and Treatment
• Symptoms of depression can be confused with
symptoms of MS  difficult to diagnose.
• Depression is under-diagnosed and under-treated
in MS.
• Best treatment for depression:
Psychotherapy + Medication (+ Exercise)
Depression in MS: What Do We Know?
• Depression differs from normal grieving.
• People with MS are at increased risk.
• 50+% of people will experience a major depressive
episode at some point over the course of the
disease.
• Suicide is 7.5x more common in MS than in
general population (Sadovnick et al., 1991).
• Depression in MS is under diagnosed and under
treated.
Feinstein, A. (2007). The clinical neuropsychiatry of multiple sclerosis (2nd ed.). Cambridge
and New York: Cambridge University Press.
Depression: The Implications
People who are depressed:
• Carry an additional, painful burden
• Can’t participate actively in their
own care
• Can’t plan/problem-solve effectively
• Are difficult to live with
Note: Depression is one of the most
treatable symptoms of MS
Common Misconceptions about
MS and Cognition
• Cognitive impairment (CI) is rare in MS.
• CI only occurs in late stage MS or severe MS.
• MS is a white-matter disease and does not affect:
1) brain volume, 2) gray matter, 3) the cerebral
cortex.
• If an MS patient can pass a brief mental status
exam, everything is OK.
• Memory problems reported by MS patients are
usually caused by stress, anxiety, and/or
depression.
• Discussing CI will upset MS patients/families.
Cognition and Other Disease Characteristics
• Cognitive function correlates with lesion load and
brain atrophy.
• Cognitive dysfunction can occur at any time (even
as a first symptom) but is more common later on.
• Cognitive dysfunction can occur with any disease
course, but is more likely in progressive MS.
• Being in an exacerbation is a risk factor for
cognitive dysfunction.
• Depression can worsen cognition, particularly
executive functions (Arnett et al., 1999).
LaRocca N, Kalb R. Multiple Sclerosis: Understanding the Cognitive Challenges.
New York: Demos Medical Publishing, 2006.
Cognitive Functions Affected in MS
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Attention & concentration - working memory
Memory - acquisition and retrieval
Speed of information processing
Executive Functioning
Visual/spatial organization
Verbal fluency - word finding
DeLuca, J. What we know about cognitive changes in multiple sclerosis. In LaRocca, N &
Kalb, R (eds.) Multiple sclerosis: understanding the cognitive challenges. New York: Demos
Medical Publishing, 2006.
Current Treatment Priorities
• Better understanding of MS pathogenesis and
heterogeneity to guide development of better therapies
and monitoring methods
• Additional treatment options for relapsing-remitting
MS(RRMS) that are more effective, convenient, and/or
tolerable
• Effective therapies for purely progressive MS
• Neuroprotective and repair strategies
• More effective treatments for common symptoms such
as fatigue, pain, tremor, and cognitive impairment
• More effective psychosocial support
Cohen J. Arch Neurol. 2009;66(7):821-828
National MS Society
Resources for Your Patients
• 48 chapters around the country
• Newly-designed Web site
(www.nationalMSsociety.org)
• Access to reliable information and referrals
(1-800-344-4867)
• Educational programs (in-person, online)
• Support programs (self-help groups, peer and
professional counseling, friendly visitors)
• Consultation (legal, employment, insurance,
long-term care)
• Financial assistance
National MS Society
Resources for You
•
Professional Resource Center –
www.nationalMSsociety.org/PRC;
healthprof_info@nmss.org
– Free Multiple Sclerosis Diagnosis, Disease & Symptom
Management app for smart phones
– The Use of Disease-Modifying Therapies in Multiple
Sclerosis: Principles and Current Evidence – a
consensus paper by the Multiple Sclerosis Coalition
(http://ntl.MS/coalitionDMTconsensus)
– Literature search services
– Clinical consultations with MS specialist physicians
– Professional publications
– Insurance Appeal template letters
– Consultation on insurance and long-term care issues