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Multiple Sclerosis:
Overview for
Physician Assistants
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
•
•
•
•
•
Tonsils
Thymus
Bone Marrow
Spleen
Lymphoid tissue of the gut
The Body’s Immune System
Trafficking Is a Multistep Process
Requiring Many Molecules
Resting
State
Inflammatory
Stimulus
Leukocyte
Inactive
Integrin
Selection
Counterceptor
Vessel Lumen
Rolling
Adhesion
Activated
Integrin
Firm
Adhesion
Transendothelial
Migration
Selectin
Selectin
Expression
Endothelial
Cell
Subendothelial Matrix
Papadaki HA. Haema 1992;2:180-191
Vascular cell adhesion molecule
Chemokines
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
Nerve Damage and Myelin Loss
A
B
C
D
E
A. Normally, axons have a protective myelin coating that is necessary
for normal conduction of electrical impulses
B. In MS, the immune system destroys myelin, resulting in slowed
conduction and exposure of axons
C. Exposed axons may then be severed…
D. …leading to permanent loss of the axon
E. The result is permanent loss of nerve function
Adapted from Trapp BD, et al. The Neuroscientist. 1999;5:48-57.
Myelin in Chronic
Multiple Sclerosis Lesions
• In a demyelinated
area, a remyelinating
oligodendrocyte
extends its
processes to
myelin internodes
Arrowheads = oligodendrocyte processes; White arrow = oligodendrocyte; Yellow arrows = myelin
internodes; Human brain; Green = immunostained for nonphosphorylated neurofilament;
Red = immunostained for proteolipid protein; Bar = 20 m.
Chang A et al. N Engl J Med. 2002;346:165-173.
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.
Evoked Potential Testing
Lumbar Puncture
Oligoclonal Banding
Disease Types
• Clinically isolated syndrome (CIS)
• Relapsing-remitting MS (RRMS)
– About 85% of people are diagnosed with RRMS
• Primary progressive MS (PPMS)
– About 15% of people experience this course
• Secondary progressive
– Most people diagnosed with RRMS will eventually
transition to SPMS
Lublin et al, 2014
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
Lublin et al, 2014
Lublin et al, 2014
Lublin et al, 2014
Lublin et al, 2014
Managing Multiple Sclerosis
•A complex disease requiring a multi-pronged approach
that involves many clinical disciplines:
– Disease Management
– Relapse Management
– Symptom Management
– Rehabilitation
– Psychosocial Support
Patient-Physician Communication:
Autonomy preferences among 168 MS patients
Active roles
“I prefer to make the
decision” (Pure
autonomy)
“I prefer to make the
final decision after
consideration my
doctor’s opinion”
(informed choice)
“I prefer that my doctor
and I share
responsibility” (shared
decision making)
Passive roles
– “I prefer that my doctor makes the
final decision” (Professional-asagents)
– “I prefer to leave all decisions to
my doctor” (paternalistic)
Heesen C et al. Multiple Sclerosis 2004
Proposed MS Health-Care Standards
Key
issues
- Certain, clear diagnosis
- Appropriate support at diagnosis
- Access to information
- Continuing education
Key
issues
- Continuity in service provision
- Access to support and informed advice
- Access to appropriate treatment/management
options aimed at keeping people with MS healthy
3. Moderate disability
Key
issues
- Responsiveness of services
- Access/location
- Expertise
- Communication/co-ordination
- Empowerment
4. Severe disability
Key
issues
1. Diagnostic phase
2. Experiencing
minimal impairment
Freeman et al. 2002, www.mssociety.org.uk
- Provision of respite care
- Appropriate long-term care
- Access to information
- Expertise
- Communication/co-ordination
- Adequate community care
- Community mobility
Management of Multiple Sclerosis
The MS “Treatment Team”:
•
•
•
•
•
•
•
•
Neurologist
Urologist
Nurse
Primary care physician
Physiatrist
Physical therapist
Occupational therapist
Speech/language
pathologist
•
•
•
•
Psychiatrist
Psychotherapist
Neuropsychologist
Social worker/Care
manager
• Pharmacist
FDA-Approved Disease-Modifying Drugs
Drug
Origin
Dosage
Freq
Route
Glatiramer acetate
Random polypeptides
20 mg
Every day
SC
IFNb-1b
Recombinant protein
0.25 mg
Every other day
SC
IFNb-1a IM
Recombinant protein
30 mcg
1x/wk
IM
IFNb-1a SC
Recombinant protein
22 mcg
44 mcg
125 mg
3x/wk
IFNb-1a SC
SC
2x/mo
Dimethyl fumarate
Oral formulation of dimethyl
fumarate rapidly hydrolyzed to
monomethyl fumarate
24o mg
Twice daily
Oral
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
Alemtuzumab
CD52-directed cytolytic Mab
12 mg/day
5 consecutive days
3 consecutive days
12 mos. later
IV infusion
Mitoxantrone
Chemotherapy
12 mg/m2
(cumulative
lifetime dose <
140 mg/m2)
Every 3 months
IV infusion
Deciding Which Immunomodulating
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
– Cost vs. benefits for each patient
– Patient’s lifestyle and preferences
– Patient readiness
Lifestyle and Personal Preferences
•
•
•
•
•
•
•
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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•
•
•
•
•
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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”
Managing Progressive MS
• Azathiorpine (Imuran)
• Methotrexate
• Mitoxantrone (Novantrone)
• Monthly administration of methylprednisolone
• IVIg
• Cladribine
• Cytoxan
• Bone marrow transplantation
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
-
-
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)
-
-
Cognitive difficulties
(memory, attention,
processing)
Heat sensitivity
Spasticity
Gait, balance, and
coordination problems
Speech/swallowing
problems
Tremor
Weakness
Treating MS Fatigue
• Deconditioning
– Exercise
• Impaired mobility requiring extra exertion
– Mobility aids; dalfampridine
• Depression
– Diagnosis and treatment
• Sleep disruption
– Symptom management
• Medication side effects
– Adjustment of dosage/timing
• MS Lassitude
– Amantidine, SSRI, modafinil,armodafinil
Treating Spasticity
Step 1: Eliminate sources of pain in the body
Step 2: Reduce the spasticity if it interferes with
comfort or function
Treating Spasticity, cont’d
• Exercises and Therapy
– Stretching
– Range of motion
– Weight bearing
– Cryotherapy
– Inhibitory casting
– Pool therapy
– Aerobic exercise
– EMG biofeedback
– Electrical stimulation
Treating Spasticity, cont’d
• Medications
– Baclofen (Lioresal) – oral; intrathecal
– Tizanidine (Zanaflex)
– Clonazapam (Klonopin)
– Gabapentin (Neurontin)
– Cyproheptidine (Periactin)
– Dantrolene (Dantrium)
– Dopaminergic agonists
Treating Spasticity, cont’d
• Procedures
– Botulinum toxin (Botox)
– Baclofen pump
– Cryotherapy (cooling and stretching)
– Tendonotomy
– Rhizotomy
– Myelotomy
– Motor point blocks
Baclofen Injection: Intrathecal Delivery
Adjusting the Baclofen Dose
Before Treatment with ITB
After Treatment with ITB
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
–
–
–
–
–
–
–
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
A Word about Stress and MS
• Stress worsens the symptoms of any neurological
disease.
• Data concerning the role of stress in the onset or
progression of MS is conflicting.
• Patients need effective strategies to manage the
unavoidable stresses of everyday life
Mohr D. Talking about Stress. National MS Society, 2009.
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.
Cognitive Symptoms
Severity of Cognitive Changes
in Multiple Sclerosis
None
50%
Mild
40%
Moderate to
severe
10%
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.
The Impact of Cognitive Dysfunction
in Daily Life
Work status
P<0.01
Social activity
P<0.05
Personal assistance
P<0.01
Community services
Financial status
Cognitively intact (n=52)
Transportation
Cognitively impaired (n=48)
Personal residence
0
1
2
Mean scale score
Rao et al. Neurology. 1991;41:692.
Worsening
3
Cognitive Functions Affected in MS
•
•
•
•
•
•
Memory - acquisition and retrieval
Attention & concentration - working memory
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.
When Cognitive Evaluation is Appropriate
•
•
•
•
•
To establish a baseline
There are reported changes in ability
There is a potentially treatable condition
Person is being started on a new treatment
When considering an application for SSDI or
vocational rehabilitation
• When there is a need to know
Note: The standard mental status examination used in
the neurologic exam will miss 50% of cognitively
impaired patients (Peyser J., 1980)
Cognitive Dysfunction:
Guidelines for Treatment
• Symptomatic Treatments – slow progress
- Not much of real value has emerged—donepezil
and methylphenidate seem to hold promise
• Disease Modifying Agents – may be most important
- Modest results so far, but if they can slow or halt
accumulation of cerebral lesions . . .
• Cognitive Rehabilitation – common-sense help
- Disappointing thus far but common-sense points to
compensatory measures as best strategy
MS-Related Stresses
for Patients and Families
• MS is a chronic disease that many will live with for
decades.
• The unpredictability from day to day and year to
year is difficult for patients and families to handle
• MS is a disease characterized by change and loss.
• Treatment costs and loss of income threaten
patient and family well-being.
• With more options available and choices to make,
patients and families worry about making “wrong”
choices.
Where do we go from
here?
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
On the Horizon - Parenteral Medications
• Alemtuzumab—In phase II trial, significantly reduced the rate of
sustained disability progression vs. IFN beta-1a. Also reduced
relapse rate and improved EDSS score.1 Phase III trials underway
• Daclizumab—In phase II trial, pts., adding daclizumab to IFN
beta experienced a significant reduction in cumulative # of new,
enhancing lesions.2
• Rituximab—In phase II trial, reduction in GdE lesions vs. placebo
and smaller proportion of pts. experiencing relapses.3
• Dirucotide—In SPMS, Phase II trial showed trend toward slower
rate of progression—favoring HLA-DR2-positive and/or DR4-positive
pts.4
• BHT-3008—In phase II trial, GdE lesions significantly reduced vs.
placebo.5
(Cohen J. Arch Neurol 2009; 66(7):821-828)
National MS Society
Resources for Your Patients
• Nationwide network of chapters around the country
• Web site (www.nationalMSsociety.org)
• Access to information, referrals, support
(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;
[email protected]
– Clinical consultations with MS specialists
– Literature search services
– Professional publications (Clinical Bulletins; Expert
Opinion Papers; Talking with Your MS Patients about
Difficult Topics; Pamela Cavallo Education Series for
nurses, rehab professionals, mental health
professionals, and pharmacists
– Professional Education Programs (Nursing, Rehab,
Mental Health)
– Consultation on insurance and long-term care issues