Introduction
What Is Multiple Sclerosis?
• Chronic progressive autoimmune disease
• Immune system attacks the myelin sheath on nerve fibers in the
brain and spinal cord (CNS)
• May lead to focal areas of damage, axon injury, axon
transection, neurodegeneration, and subsequent scar or plaque
formation
Myelin Sheath
(With Axon
Through It)
Nucleus
Schwann Cell
Soma
Node of
Ranvier
Axon Terminal
Dendrite
Graphic by Quasar Jarosz at en.Wikipedia.org
What the Primary Care Clinician
Needs to Know About MS
• Common presenting symptoms of demyelinating
disease
– For example, what is CIS, optic neuritis, brain stem
syndrome, etc
• How the diagnosis of MS is made
• Early symptoms that trigger need to refer patient to
neurologist
• How to classify MS
• How to manage treatment of MS/monitor MS patients
(and what to monitor for)
• How to manage treatment side effects
PIK NW Regional Survey (N = 50)
Barriers to Diagnosis and Treatment
• Lack of clinician knowledge about MS, its diagnosis,
and treatments
• Infrequency of MS in primary care populations
• Lack of time, especially since patients have other
complaints to address
• Absence of screening tools
• Financial/insurance-related obstacles
• Side effects of treatment
• Patients’ psychosocial status and lack of support
• Poor adherence to treatment
Addressing Local Needs
• To address the needs identified in the local survey,
this activity provides education regarding the
following MS topics:
–
–
–
–
–
–
–
Risk factors
Pathogenesis
Diagnostic criteria
Role of imaging
Efficacy, safety, and initiation of current therapies
Efficacy and safety of emerging therapies
Monitoring for response, adherence, and tolerability of
therapy
– Management of MS symptoms
What Factors Contribute to the
Risk for MS?
MS Epidemiology
Prevalence
~350,000 persons in the United
States
Sex distribution
~75% female
Age at onset
Ethnic origin
Typically 20−40 years,
but can present at any age
Predominantly Caucasian
Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston; 2006. Hauser
SL, et al. Multiple Sclerosis. In: Fauci AS, et al. Harrison’s Principles of Internal Medicine. Available at:
http://www.accessmedicine.com/content.aspx?aID=2906448. Accessed on: February 19, 2010.
Multiple Sclerosis
An Immunogenetic Disease
Environmental Factors
Genetic Predisposition
Immune Dysregulation
MS
Graphic courtesy of Suhayl Dhib-Jalbut, MD.
Approximate Probability of
Developing MS
Evidence for Genetic Basis of
MS
50
45
40
35
30
25
20
15
10
5
0
25%
5%
3%
2%
1%
0.1%
0.1%
Identical Fraternal Sibling Parent or First
Spouse
No
Twin
Twin
HalfCousin
Family
Sibling
Member
Hauser SL, et al. Multiple Sclerosis. In: Fauci AS, et al, eds. Harrison's Principles of Internal Medicine.
Available at: http://www.accessmedicine.com/content.aspx?aID=2906445. Accessed on: February 19,
2010. Willer CJ, et al. Proc Natl Acad Sci U S A. 2003;100:12877-12882.
Evidence for Environmental
Basis of MS
• No evidence of MS prior to 1822 (~ onset of industrial revolution
in Europe)
• Change in the gender ratio over time
• These changes (eg, gender ratio, increasing incidence) took
place over ~ 30 years (1–2 generations)—too fast for a genetics
cause
• Increased incidence of MS in many regions (especially in
women)
– When individuals migrate before age 15 from a region of high MS
prevalence to one of low prevalence (or vice versa), they seem to
adopt a prevalence similar to that of the region to which they moved
– When they make the same move after age 15, they seem to retain
the risk of the region from which they moved
Multiple Sclerosis
What Are the Environmental Factors?
• Many environmental factors have been
proposed
• Two currently popular candidates for
involvement in MS pathogenesis are:
– Epstein-Barr virus (EBV) infection
– Vitamin D deficiency (sunlight exposure)
– Cigarette smoking
• These are hypotheses—not proven facts!
– Either, neither, or both may be correct
Evidence for EBV
• Indirect evidence
– Late EBV infection is associated with MS
– Symptomatic mononucleosis is associated with MS
• Direct evidence
– 10 out of 12 studies found a significantly higher rate of EBV
positivity in MS patients than in controls1-12
– When data from these 12 trials are combined
(N = 4155), EBV positivity is found in 99.5% of MS patients
vs 94.2% of controls (P <10-23)
1. Sumaya, 1980. 2. Bray, 1983. 3. Larson, 1984. 4. Sumaya, 1985. 5. Shirodaria, 1987. 6. Munch, 1998. 7.
Myhr, 1998. 8. Wagner, 2000. 9. Ascherio, 2001. 10. Sundström, 2004. 11. Haahr, 2004. 12. Ponsonby, 2005.
Direct Evidence for Vitamin D
• >185,000 women interviewed about their diet: Those in
highest quintile of vitamin D consumption had significantly
less new-onset MS compared with lowest quintile1
• Study of MS patients and controls from Tasmania found
significant negative association between total sun
exposure during childhood (especially in those 6–10 years
old) and adolescence and the subsequent development of
MS2,3
• Evaluation of stored serum samples from 257 MS patients
and 514 matched controls (US Military) showed the risk of
MS was significantly decreased in those with increased
serum vitamin D3 levels4
1. Munger KL, et al. Neurology. 2004;62:60-65. 2. Van der Mei IA, et al. J Neurol. 2007;254:581-590. 3. Van
der Mei IA, et al. BJM. 2003;327:316. 4. Munger KL, et al. JAMA. 2006;296:2832-2838.
Cigarette Smoking and MS
• Several cohort and case-control studies have suggested
that cigarette smoking nearly doubles the risk of MS1-3
– Risk increases with cumulative smoking “dose”2
• Parental smoking also doubles the risk of MS in children
who are passively exposed to the smoke4
• Smokeless tobacco has not been found to increase MS
risk1,2
– Implies that non-nicotinic components of cigarette
smoke are responsible
1. Carlens C, et al. Am J Respir Crit Care Med. 2010;Mar 4:epub ahead of print. 2. Hedström AK, et al.
Neurology. 2009;73:696-701. 3. Riise T, et al. Neurology. 2003;61:1122-1124. 4. Mikaeloff Y, et al. Brain.
2007;130(pt 10):2589-2595.
Risk Factors for MS
Summary
• MS is caused by a complex interaction of genetic and
environmental factors
– In someone with an affected identical twin, risk of MS is
25%, suggesting that genetics play a role in susceptibility but
are not the complete story
• Vitamin D insufficiency, EBV infection, and cigarette
smoking have shown possible links to MS
– This research is thought-provoking, but these factors have
not been definitely proven as causes of MS
Pathophysiology of MS
Pathophysiology of MS
• Acute Inflammation
• Neuronal Degeneration
Relapses
Disability
Immune Dysregulation in MS
T Cells
• T cells normally recognize specific antigens
– CD8+ T cells destroy infected cells
– CD4+ T cells release cytokines that mediate inflammatory
and anti-inflammatory responses
• T cells reactive to myelin are found in MS lesions,
blood, and cerebrospinal fluid
– CD8+ T cells transect axons, induce oligodendrocyte death,
promote vascular permeability1
– There is a cytokine imbalance in MS, favoring secretion of
inflammatory (Th1) cytokines
– T cells that normally regulate immune function have reduced
activity in MS2
1. Dhib-Jalbut S. Neurology. 2007;68:S13-S21. 2. Viglietta V, et al. J Exp Med. 2004;199:971-979.
Cytokine Imbalance in MS
TH1
Normal
Inflammatory
TH2
Anti-inflammatory
IFN-g, IL-12, TNF
IL-4, IL-10, TGFß
TH2
MS
Anti-inflammatory
TH1
Inflammatory
IFN-g, IL-12, TNF
Graphic courtesy of Suhayl Dhib-Jalbut, MD.
IL-4, IL-10,TGFß
Immune Dysregulation in MS
B Cells
• In some MS patients, ectopic lymphoid
follicles have been found in the meninges1
• Mechanisms of B cells in MS may include:
– Antimyelin antibody production
– Antigen presentation to autoreactive T cells
– Proinflammatory cytokine production
1. Uccelli A, et al. Trends Immunol. 2005;26:254-259.
Immune Dysregulation in MS
Other Involved Cells
• Natural killer (NK) cells
– May play opposing roles as both regulators and inducers of disease
relative to cytokine environment and cell:cell contact
– NK cell function may be lost during clinical relapse
• Monocytes
– Secrete IL-6 (promotes B cell growth) and IL-2 (aids differentiation
of Th1 cells)
• Macrophages
– Phagocytic activity may contribute to demyelination
• Microglia
– Specialized macrophages in the CNS, also may contribute to T cell
activation
Neurodegeneration
• Loss of axons is the main cause of permanent disability in MS
• Axonal damage has been shown to occur in acute inflammatory
plaques1 and can lead to brain atrophy
– Occurs in white and gray matter
– May also produce cognitive impairment
• Axonal damage could be the result of
– Cumulative inflammatory damage over time
– A parallel degenerative process related to loss of trophic support or
an independent axonal degeneration2
• Can effective immune therapy early in MS prevent worsening
disability?
1. Trapp BD, et al. N Engl J Med. 1998;338:278-285. 2. Trapp BD. Neuroscientist. 1999;5:48-57.
Conclusions
• Pathogenesis of MS involves complex interactions between
genetic and environmental factors
– Multiple genes are involved
– Vitamin D deficiency, EBV infection, and cigarette smoking are
environmental candidates
• MS incidence has increased over the past 30 years due to a
change in environmental exposure
• MS pathogenesis involves multiple immune cell types (T cells,
B cells, NK cells, others)
• Along with chronic inflammation, MS pathogenesis involves
axonal loss
– Neurodegeneration is the major source of disability in MS
Challenges in Diagnosing MS
What Is an MS “Attack”?
• Neurologic symptoms lasting ≥24 hours but
generally longer
– Not explained by other conditions
– Do not represent recurrent symptoms in
association with increased body temperature or
infection (pseudoexacerbations)
• To be considered separate attacks, the
interval between episodes must be ≥30 days
McDonald WI, et al. Ann Neurol. 2001;50:121-127.
Clinical Presentation
• MS symptoms vary widely among individual patients
• Numbness, tingling, or weakness in the limbs
– Usually unilateral or only lower half of body
• Tremor, spasticity, incoordination, unsteady gait, imbalance
• Vision loss (usually unilateral), pain with eye movement, double
vision
• Fatigue, dizziness, cognitive impairment, unstable mood
• Urinary and bowel incontinence or frequency
• Increased body temperature may trigger or worsen symptoms
Four Clinical Subtypes of MS
PPMS
Disability
Disability
RRMS
Time
Time
RPMS
Disability
Disability
SPMS
Time
Time
Fauci AS, et al. In: Harrison's Manual of Medicine, 17th ed. McGraw-Hill Medical; 2009.
Reprinted with permission from McGraw-Hill.
Disease Course
• After initial episode, MS patients typically follow a
chronic pattern of acute neurologic symptoms
(relapses) followed by periods of stability (remission)
• Timing, progression, duration, severity, and specific
symptoms are variable and unpredictable
• Typically 2 to 3 relapses per year in untreated
patients; treated patients have significantly fewer
relapses
• Some symptoms may be ongoing/chronic; these do
not represent relapse
• Long-term deficits range from mild to severe
Diagnosis of MS
• Clinically definite MS must meet criteria for1
– Dissemination in space
– Dissemination in time
• A single episode of MS-like symptoms (clinically
isolated syndrome [CIS]) will not meet these criteria
– But if MS is likely based on MRI, it still should be treated like
MS
• Delaying treatment may be missing an important window of
opportunity to delay the onset of irreversible disability
– Requires close monitoring over time to confirm diagnosis
1. Polman CH, et al. Ann Neurol. 2005;58:840-846.
Natural History of MS
Clinical and MRI Measures
Relapses/Disability
MRI Activity
Disability
MRI T2 Burden of Disease
Axonal Loss
Preclinical
*
Secondary Progressive
MS
Relapsing-Remitting
MS
CIS
Time
Trapp BD, et al. Neuroscientist. 1999;5:48-57. Reprinted with permission from Sage Publications.
Natural History of CIS (Queen
Square)
Risk of Conversion Based on Lesion
Count at Presentation
100
92%
87%
90
80%
% Converting to CDMS
80
89% 87% 88%
85%
79%
0 lesions
1-3 lesions
70
4-10 lesions
60
>10 lesions
54%
50
40
30
19%
20
11%
10
6%
0
5 (N = 89)
10 (N = 81)
14 (N = 71)
Years Post CIS Diagnosis
Morrissey S, et al. Brain. 1993;116:135-146. O’Riordan J, et al. Brain. 1998;121:495-503. Brex PA, et al. N
Engl J Med. 2002;346:158-164.
Revised McDonald Criteria
• At least 3 of the following on MRIa:
– ≥1 Gd-enhancing brain or spinal cord lesion or ≥9
T2 hyperintense brain and/or spinal cord lesions of
≥3 mm in size if none of the lesions are Gdenhancing
– ≥1 brain infratentorial lesion or spinal cord lesion
≥3 mm in size
– ≥1 juxtacortical lesion ≥3 mm in size
– ≥3 periventricular lesions ≥3 mm in size
aTo
meet criteria for dissemination in space
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Revised McDonald Criteria
• At least 1 of the followinga
– A 2nd clinical episode
– A Gd-enhancing lesion detected ≥3 months after onset of
initial clinical event
• Located at a site different from the one corresponding to the
initial event
– A new T2 lesion detected any time after a reference scan
that was performed at least 30 days after the onset of an
initial clinical event
• Thus, it is not always necessary to wait for 2 attacks
to diagnose MS. A first attack plus changes on MRI
may be enough
aTo
meet criteria for dissemination in time
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Typical MRI Lesions in MS
Gd-enhancing
A and B: Courtesy of Tracy M. DeAngelis, MD.
Corpus Callosum
Typical MRI Lesions in MS
Infratentorial
C and D: Courtesy of Daniel Pelletier, MD.
Juxtacortical
Typical MRI Lesions in MS
Periventricular
E: Courtesy of Daniel Pelletier, MD.
F: Courtesy of Tracy M. DeAngelis, MD.
Spinal Cord
CMSC MRI Protocol 2009
• Obtain brain MRI at baseline, with contrast
• Obtain spinal cord MRI if symptoms pertaining to
spinal cord lesions or no evidence of disease activity
in brain
• Repeat scan if:
– Unexpected clinical worsening
– Need to re-evaluate diagnosis
– Starting or modifying treatment
• Consider serial MRI every 1-2 years to evaluate
subclinical activity
Consortium of Multiple Sclerosis Centers.
http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf
Performing Serial MRIs
for Follow-up
• A standardized protocol using consistent technology
and protocols is essential to serial MRI interpretation
–
–
–
–
–
Same magnet strength and slice thickness
Same sequence acquisition
Same patient positioning
Same plane
Section selection should match prior MRIs as closely as
possible
• Radiologists should follow the updated CMSC
protocol1 for standardizing MRIs in clinical MS
applications
1. Consortium of Multiple Sclerosis Centers.
http://www.mscare.org/cmsc/images/pdf/mriprotocol2009.pdf
MRI Correlates Poorly With
Clinical Outcomes
• T2 lesion volume at a single point in time correlates
weakly with clinical disability and is a measure of past
attack frequency1
– Change in lesion volume over time may be a better
correlate2
• T1-weighted black holes are a better but still
imperfect correlate of disability3
• Brain atrophy is a measure of neurodegeneration that
may predict disability4
1. Bar-Zohar D, et al. Mult Scler. 2008;14:719-727. 2. Brex PA, et al. N Engl J Med.
2002;346:158-164. 3. Truyen L, et al. Neurology. 1996;47:1469-1476. 4. Miller DH, et al.
Brain. 2002;125:1676-1695.
Why MRI Correlates Poorly
with MS Disability
• MRI cannot determine extent/nature of tissue
damage
• Location of lesion influences its clinical manifestation
• MRI cannot distinguish between demyelinated and
remyelinated lesions
• MRI cannot detect gray matter lesions or diffuse
damage in normal-appearing white matter
• Plasticity of CNS may lead to compensatory use of
alternative neural circuit to circumvent damaged
areas
Emerging MRI Technologies
•
•
•
•
•
Measures of CNS atrophy
Magnetization transfer imaging
Proton magnetic resonance spectroscopy
Diffusion tensor imaging
Susceptibility weighted imaging
Other Diagnostic Tools for MS
CSF Analysis
• Positive if oligoclonal IgG bands present but absent
from corresponding serum sample or IgG index is
elevated
– Sensitive but not specific: other causes of CNS inflammation
can yield similar findings
• Lymphocytic pleocytosis is rarely >50/mm3
• Protein levels rarely exceed 100 mg/dL
• Elevated myelin basic protein is not pathognomonic
for MS
Other Diagnostic Tools for MS
Visual Evoked Potentials (VEPs)
• Provides evidence of a lesion associated with
visual pathways
• Positive if shows delayed but well-preserved
wave forms
– Abnormal VEP is not specific for MS
• Can help establish dissemination in space
EDSS1
Bedridden
Death
Restricted to
wheelchair
Need for walking
assistance
Normal
neurologic
exam
Some limitation
in walking ability
Minimal
disability
3.5 4.0
3.0
2.0 2.5
1.5
0 1.0
10.0
9.0
4.5 5.0
5.5
6.0
6.5
7.0
7.5
8.0
9.5
8.5
Time to EDSS score of 4.0 strongly influenced
by relapses in the first 5 years and time to
CDMS.2
1. Kurtzke JF. Neurology. 1983;33:1444-1452. 2. Confavreux C, et al. Brain. 2003;126:770-782.
Residual Disability Sustained
After a Relapsea
Patients with Residual Disability (%)
Days Since Exacerbation
30−59 Days
60−89 Days
90+
Days
≥0.5 EDSS points
42%
44%
41%
≥1 EDSS points
27%
29%
30%
aIn
224 placebo patients from the NMSS task force on clinical outcome assessment.
Lublin FD, et al. Neurology. 2003;61:1528-1532.
Neuromyelitis Optica (NMO)
• Syndrome of aggressive inflammatory demyelination afflicting
the optic nerves and spinal cord1, often associated with severe
disability
• Associated with infections and collagen vascular diseases1
– Idiopathic form is considered a variant of MS
• Modern case series indicate that NMO is characterized by1
– Recurrent attacks of optic neuritis and acute transverse myelitis
– Multisegmental spinal cord lesion >3 vertebral segments
– Initial brain MRI that is often (but not always) normal
• The NMO-IgG antibody recognizes aquaporin-4 (AQP4),2 a
water channel expressed on astrocytes
– Anti-AQP4 antibody is 73% sensitive and 91% specific for NMO3
– Blood testing is available at Mayo Medical Laboratories4
1. Cree B. Curr Neurol Neurosci Rep. 2008;8:427-433. 2. Lennon VA, et al. J Exp Med. 2005;202:473477. 3. Lennon V, et al. Lancet. 2004;364:2106-2112. 4. Mayo Medical Laboratories.
http://www.mayomedicallaboratories.com/test-catalog/Overview/83185.
Distinguishing NMO from MS
NMO
Courtesy of Bruce A.C. Cree, MD, PhD, MCR
MS
Courtesy of Tracy M. DeAngelis, MD
Conclusions
• Diagnosis of MS is based on a combination of clinical
and radiologic factors
– MRI should be performed according to CMSC standardized
protocol
• Revised McDonald criteria are the gold standard for
diagnosis
• High-risk CIS should be treated the same as clinically
definite MS
• Clinical variants and red flags should be taken into
account in formulating differential diagnosis
Achieving Therapeutic Goals
with Current Treatments
Therapeutic Goals in MS
• In the absence of a cure for MS, current goals of
disease modifying therapy are to
– Prevent disability
– Prevent relapses
– Prevent development of new or enhancing lesions on MRI
• Additional goals in the management of MS are to
– Relieve symptoms
– Maintain well-being
– Optimize quality of life
Treating Acute Relapse
• IV corticosteroids = standard of care
– Methylprednisolone 500 to 1000 mg/d IV for 3 to
5 days
• May be followed by oral steroid taper
• High-dose oral steroids may be acceptable
alternative
– Phase III randomized OMEGA trial currently
comparing oral and IV steroids
• Plasmapheresis and IVIG for refractory
relapse
Therapeutic Targets in MS
FDA-Approved
Disease-Modifying Agents
First line:
• Interferon beta
– Interferon beta-1b 250 mcg SC QOD (two brands)
– Interferon beta-1a 44 mcg SC TIW
– Interferon beta-1a 30 mcg IM weekly
• Glatiramer acetate
– 20 mg SC QD
Second line:
• Mitoxantrone
– 12 mg/m2 over 5 to 15 min q3mo; lifetime max, 144 mg/m2
• Natalizumab
– 300 mg IV monthly infusion
Current First-Line MS
Therapies
• Interferon beta-1a, interferon beta-1b,
glatiramer acetate
– Interferons are FDA approved for relapsing forms
of MS
– Glatiramer acetate is FDA approved for RRMS
• Similar efficacy for relapse rate reduction
~ 30%
• Generally very safe and well tolerated
• All require self-injection
Mechanisms of Action for
Interferons
• Reduction of proinflammatory cytokine
secretion
• Promotion of anti-inflammatory cytokine
secretion
• Stabilization of blood-brain barrier
• Enhancement of regulatory T cell activity
• Downregulation of antigen presentation to
T cells
Mechanisms of Action for
Glatiramer Acetate
• Competitive inhibition of antigen presentation
(myelin basic protein) to autoreactive T cells
• Activates regulatory T cells
• Promotes Th1 to Th2 cytokine shift
Head-to-Head Study
EVIDENCE (IFN beta-1a) Trial,
48 Weeks
Patients
Relapse-Free
IFN beta-1a 30
mcg IM QW
IFN beta-1a 44
mcg SC TIW
Difference
P Value
19% in favor of
IFN beta-1a 44
mcg SC TIW
<.009
52%
62%
Abbreviations: IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously; TIW, 3 times
per week.
Pantich H, et al. Neurology. 2002;59:1496-1506.
Head-to-Head Study
INCOMIN (IFN beta-1b vs beta-1a)
Trial, 104 Weeks
Patients
Relapse-Free
IFN beta-1b 250
mcg SC EOD
IFN beta-1a 30
mcg IM QW
Difference
P Value
42% in favor of
IFN beta-1b
<.036
51%
36%
Abbreviations: EOD, every other day; IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously.
Durelli L, et al. Lancet. 2002;359:1453-1460.
Head-to-Head Study
REGARD (Glatiramer Acetate vs
IFN beta-1a), 96 weeks
Patients
Relapse-Free
Glatiramer
acetate 20 mg
QD
62%
IFN beta-1a 44
mcg SC TIW
62%
Difference
P Value
No difference
<.96
Abbreviations: IFN, interferon; SC, subcutaneously; QD, once daily; TIW, 3 times per week.
Mikol DD, et al. Lancet Neurol. 2008;7:903-914.
Head-to-Head Studies
BECOME and BEYOND
(Glatiramer Acetate vs IFN beta-1b)
Patients
RelapseFree
BECOME1
(18 mo)
GA 20 mg QD
70%
IFN beta-1b 250
mcg SC QOD
62%
BEYOND2
(2 years)
GA 20 mg QD
59%
IFN beta-1b 250
mcg SC QOD
58%
IFN beta-1b 500
mcg SC QOD
60%
Difference
P Value
8% in favor
of GA
NS
1% in favor
of IFN 500
mcg
NS
Abbreviations: GA, glatiramer acetate; QD, once daily; IFN, interferon; SC, subcutaneously; QOD, every other
day; NS, not significant.
1. Cadavid D, et al. Neurology. 2009;72:1976-1983. 2. O’Connor P, et al. Lancet Neurol. 2009;8:889-897.
Head-to-Head Studies
Bottom Line
• Higher-dose subcutaneous interferons are
more effective than lower-dose intramuscular
interferon
• High-dose subcutaneous interferon
formulations and glatiramer acetate probably
all offer comparable efficacy
Side Effects of Interferons
• Side effects include flu-like symptoms, injection site
reactions/necrosis (SC), liver enzyme elevations,
lymphopenia, depression
• Pregnancy category C
• Warnings: depression/suicide, decreased peripheral
blood counts, hepatic injury, seizures,
cardiomyopathy/CHF, autoimmune disease
• Laboratory tests: periodic CBC with differential, liver
function profile, thyroid function
Avonex [package insert]. Cambridge, MA: Biogen Idec; 2006. Betaseron [package insert] Montville, NJ:
Bayer HealthCare Pharmaceuticals; 2009. Extavia [package insert]. Montville, NJ: Bayer HealthCare
Pharmaceuticals; 2009. Rebif [package insert]. Rockland, MA: EMD Serono; 2009.
•
Interferon therapies are associated
with production of neutralizing
antibodies (NAbs) to the interferon
beta molecule1
–
•
NAbs may reduce radiographic and
clinical effectiveness of interferon
treatment
NAb testing
–
–
Sometimes used when deciding
whether to switch from one
interferon to another (usually IM to
SC) in a patient with suboptimal
response
There are no guidelines on when to
test, which test to use, how many
tests are needed, or which cutoff
titer to apply1
1. Goodin DS, et al. Neurology. 2007;68:977-984.
Probability of NAbs (%)
Neutralizing Antibodies
100
80
60
45
40
31
24
20
5
0
IFN beta-1b 250 mcg SC QOD
IFN beta-1a 22 mcg SC TIW
IFN beta-1a 44 mcg SC TIW
IFN beta-1a 30 mcg IM QW
Data from prescribing information.
Side Effects of Glatiramer
Acetate
• Injection-site reactions, vasodilation, rash,
dyspnea, chest pain
• Pregnancy category B
• Warnings: Immediate postinjection reaction,
chest pain, lipoatrophy, skin necrosis
– Postinjection reaction (flushing, chest pain,
palpitations, anxiety, dyspnea, constriction of
throat, urticaria) is self-limited; no treatment
required
• No lab testing required
Copaxone [package insert]. Kansas City, MO: Teva Neuroscience; 2009.
Side Effect Management Tips
Side Effect
Management
Flu-like symptoms
NSAIDs (eg, naproxen 500 mg 1 h before injection + 12 h
later); IFN administration before bedtime; for patients on
IFN beta-1a IM, prednisone 10 mg on day of injection;
switch to glatiramer acetate
Injection-site
reactions and
injection-site pain
Rotate injection sites; administer injection without the
autoinjector; topical anesthetics; application of ice before
injecting; ensure proper product preparation including
warming to room temperature
Difficulty selfinjecting
Have partner administer injection; if “click” of autoinjector
induces anxiety, administer without the autoinjector; call
company nurse for retraining; home health agency might
administer IFN beta-1a IM; switch to a therapy with less
frequent injections
Timing of Therapy May Be Key
to Preventing Disability
First
Pre- Demyelinating
Relapsing-Remitting
Event
clinical
Transitional
Secondary
Progressive
First Clinical Attack
Time
window for
early
treatment
Axonal loss
Clinical threshold
Demyelination
Inflammation
Time (years)
Rationale for Early Treatment
• Time is ticking…
• What is lost by delaying early therapy is
not regained by starting later
Treating CIS
• Treating CIS vs waiting until patient has
clinically definite MS (CDMS)
–
–
–
–
–
Decrease progression to CDMS
Decrease rate of disability progression
Reduced lesion load on MRI
Fewer and less severe relapses
Most clinicians advocate early treatment BUT not
all CIS will develop MS
Placebo-Controlled Trials of
Disease-Modifying Therapy in
CIS
Study
Treatment
N
Conversion to CDMS
Followup
On
Tx
Placebo
P
CHAMPS1
Interferon beta-1a
30 μg IM qwk
383
3y
35%
50%
.002
ETOMS2
Interferon beta-1a
22 μg SC once
weekly
309
2y
34%
45%
.047
BENEFIT3
Interferon beta-1b
250 μg SC q48h
468
2y
28%
45%
<.0001
PreCISe4
Glatiramer acetate
20 mg/d
481
3y
61%
77%
.0005
1. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 2. Comi G, et al. Lancet. 2001;357:1576-1582. 3.
Kappos L, et al. Neurology. 2006;67:1242-1249. 4. Comi G, et al. Lancet. 2009;374:1503-1511.
FDA Approved for CIS
•
•
•
•
Interferon beta-1a 30 mcg IM QW
Interferon beta-1b 250 mcg SC QOD
Glatiramer acetate 20 mg SC daily
Interferon beta-1a 44 mcg SC TIW is
sometimes used off-label
Second-Line MS Therapies
Natalizumab
• Inhibits cell adhesion and leukocyte migration across BBB
• AFFIRM trial1 of natalizumab vs placebo in RRMS
– 42% reduction in risk of sustained progression of disability in 2
years (P <.001)
– 68% reduction in clinical relapse at 1 year (P <.001)
– 83% reduction in new or enlarging T2 lesions over 2 years (P
<.001)
– 92% reduction in Gd-enhancing lesions at 1 and 2 years
(P <.001)
1. Polman CH, et al. N Engl J Med. 2006;354:899-910.
Second-Line Therapies
Natalizumab
• FDA approved for relapsing MS
• Due to risk of PML, natalizumab is generally reserved for
patients who have not responded to or tolerated alternate
therapies
– PML (JC virus of brain) leads to severe disability or death; no
known treatment
– Available only through very restricted distribution program (TOUCH
Prescribing Program)
• Other warnings: hepatotoxicity, hypersensitivity reactions,
immunosuppression
Tysabri [package insert]. Cambridge, MA: Biogen Idec; 2009.
Mitoxantrone
• Antineoplastic in anthracenedione class
• FDA approved for SPMS, PRMS, worsening RRMS
• Causes cross-links and strand breaks in DNA; inhibits B cell,
T cell, and macrophage proliferation
• Due to serious side effects, reserve for patients with rapidly
advancing MS despite other disease-modifying therapies
–
–
–
–
Cardiomyopathy (LVEF decreased in up to 18%; CHF)
Secondary acute myelogenous leukemia (0.25%)
Elevated liver enzyme and glucose levels
Requires frequent monitoring (CBC, liver function tests, LVEF,
ECG)
• Administration should be performed by an oncologist
Novantrone [package insert]. Rockland, MA: EMD Serono, and Melville, NY: OSI Pharmaceuticals; 2009.
Starting an MS Patient on a
Disease-Modifying Agent
• Obtain starter kit from local representative
• Complete physician portion of Enrollment Form and have
patient complete the patient portion
• Upon receipt of form, company will verify patient’s
insurance benefits
• Company will supply medication and send nurse to the
patient’s home for training on self-injection and proper
needle disposal
• Titrate interferon dose as indicated on the Enrollment
Form
Monitoring
• Follow up 4−6 weeks after initiating therapy
– Assess injection technique and tolerability
• If stable on therapy, re-evaluate every 3−6 months
• Laboratory testing for interferon
– CBC and liver enzyme levels 4–6 weeks after starting
treatment,
3 months later, then every 6 months
• No laboratory testing needed for glatiramer acetate
• Continue on therapy indefinitely unless clear lack of
benefit, intolerable side effects, or better treatment
becomes available
Assess Adherence!
Most Patients Who Discontinue
Do So in First 2 Years
Cohort of patients who stopped therapy
Year 7Year 8
Year 6 3% 3%
5%
Year 1
22%
Year 5
8%
Year 4
13%
Year 2
27%
Year 3
20%
Rio J, et al. Mult Scler. 2005;11:306-309.
Assess Adherence by Asking
• Patients typically will not tell you they have been
nonadherent if you do not ask
• Ask in nonjudgmental manner that assumes they
have missed some doses
– For example: How many injections do you think you have
missed in the past 2 months?
• Being asked helps motivate patients to adhere
• Assess barriers by asking: What prevents you from
taking your medication?
– NOT: Why aren’t you taking it? (Avoid casting blame)
Address Barriers to Adherence
•
•
•
•
•
•
•
•
•
•
Difficulty self injecting
Adverse events
Unrealistic expectations of therapy (symptom relief)
Lack of acceptance of MS diagnosis and need for treatment
Financial considerations
“Treatment fatigue”
Depression
Cognitive deficits
Impairment in fine motor skills
Changes to family and support circumstances
Suboptimal Treatment
Response
• Worsening clinical status
• Radiologic changes (MRI)
– New Gd enhancement and/or new or enlarging T2 lesions
are signs of disease activity
• No consensus as to when such findings warrant change in
treatment
• Interpret in context of whole clinical picture
• If found on repeat scans, even if patient is clinically stable,
probably warrants change in therapy
– Remember: comparison of serial MRI scans requires
consistent use of standardized MRI protocol (CMSC
protocol)
Suboptimal Response
Potential Causes
• Nonadherence
• Pharmacogenomics: responsiveness to IFN β
related to genetics1
• Variable pathologies with differing responses to
immune therapies
• NAbs
• MS subtype (disease modifying agents do not
work in PPMS)
1. Byun E, et al. Arch Neurol. 2008;65:337-344.
Refer or Consult a Neurologist
• When diagnosis is in doubt
• If a consult is desired regarding selection of
initial therapy
• For patients with poor response or toleration
of first-line therapies
• When considering use of natalizumab or
mitoxantrone
Conclusions
• Current MS therapies can reduce relapse rates and
disability progression
– Interferon beta or glatiramer acetate is first line
• It is best to start treatment as early as possible
• Patient education is essential when starting treatment
– Rationale for treatment, injection technique, side effect
management, importance of adherence
• After starting treatment, monitor for response,
tolerability, and adherence
Emerging MS Therapies
Limitations of Current
Therapies
• All are only partially effective
• All are injectable or IV and have side effects
• Risks vs benefits
– Existing therapies have advantage of long-term
safety data
• Difficulty predicting therapeutic response
• Goal: Individualized, more effective, safe
medication(s) that are easier to administer
Two Oral Therapies Have
Completed Phase III Studies
• Fingolimod
• Cladribine
• 3 important questions to ask1
– How do they compare with current therapies?
– Are all of the long-term safety issues known?
– What do they tell us about MS and our treatment
goals?
1. Carroll WM. N Engl J Med. 2010;362:456-458.
Fingolimod
• Modulates sphingosine-1-phosphate receptors
– Receptors play a role in egress of lymphocytes out of lymph
nodes
• Fingolimod sequesters lymphocytes in lymph nodes
• Fingolimod crosses blood-brain barrier and may have
neuroprotective properties
• Dosing: once-daily pill
• Status: 2 phase III trials completed; pending FDA
review
Brinkmann V, et al. J Biol Chem. 2002;277:21453-21457. Pinschewer DD, et al. J Immunol. 2000;164:57615770. Chiba K, et al. J Immunol. 1998;160:5037-5044.
Fingolimod
FREEDOMS, 24-Month Study
N = 1272 RRMS
Fingolimod 0.5 mg QD
n = 425
Fingolimod 1.25 mg QD
n = 429
Placebo
n = 418
Annualized relapse rate
0.18
P < .001 vs placebo
Annualized relapse rate
0.16
P < .001 vs placebo
Annualized relapse rate
0.40
No disability progression
at 3 months: 82.3%
P = .03 vs placebo
No disability progression
at 3 months: 83.4%
P = .01 vs placebo
No disability progression
at 3 months: 75.9%
Fingolimod reduced relapse rate by 54% to 60% vs placebo
and reduced risk of disability progression
Placebo-controlled FREEDOMS II study is ongoing.
Kappos L, et al. N Engl J Med. 2010;362:387-401.
Fingolimod
TRANSFORMS, 12-Month Study
N = 1292 RRMS randomized
Fingolimod 0.5 mg QD
n = 429
Fingolimod 1.25 mg QD
n = 420
IFN beta-1a 30 mcg IM Q
n = 431
Annualized relapse rate
0.16
P <.001 vs IFN
Annualized relapse rate
0.20
P < .001 vs IFN
Annualized relapse rate
0.33
No disability progression
94.1%
P = .25 vs IFN
No disability progression
93.3%
P = .50 vs IFN
No disability progression
92.1%
Fingolimod reduced relapse rate by 38% to 52% versus IFN beta-1a
but was not significantly different with regards to effect on disability
Cohen JA, et al. N Engl J Med. 2010;362:402-415.
Fingolimod
Safety
•
•
•
Common: nasopharyngitis, infections, cough/dyspnea, fatigue,
headache, back pain, diarrhea, nausea, and elevated ALT levels
Malignancies (skin cancer, breast cancer)
Bradycardia/atrioventricular block
– Requires 6-hour first-dose monitoring with hourly ECGs
– Bradycardia persisting >6 hours requires continued monitoring
– Break in therapy >2 days requires repeat first-dose monitoring; therefore,
not good choice for nonadherent patients
•
•
•
•
•
Severe herpes infections (some fatal)
Disseminated Varicella Zoster (fatal)
Macular edema requiring ophthalmology screening
Reduction in FEV1 —PFTs and HRCT required in phase III studies
Lower dose has fewer side effects
Cohen JA, et al. N Engl J Med. 2010;362:402-415. Kappos L, et al. N Engl J Med. 2010;362:387-401.
Cladribine
• Results in selective long-term depletion of CD4+ and
CD8+ T cells
• FDA approved for treatment of hairy-cell leukemia
• Dosing: given orally for 5 consecutive days for
2 cycles, 1 month apart
• Status in MS
–
–
–
–
Fast-tracked by the FDA
Phase III study completed
FDA issued “refuse to file” letter Nov. 30, 2009
NDA will be resubmitted as soon as FDA’s concerns can be
addressed
Sipe JC. Expert Rev Neurother. 2005;5:721-727.
Oral Cladribine
CLARITY
N = 1326 RRMS
Cladribine 3.5 mg/kg
n = 433
Cladribine 5.25 mg/kg
n = 456
Placebo
n = 437
Annualized relapse rate
0.14
P<.001 vs placebo
Annualized relapse rate
0.15
P<.001 vs placebo
Annualized relapse rate
0.33
No disability progression
at 3 months: 85.7%
P=.02 vs placebo
No disability progression
at 3 months: 84.9%
P=.03
No disability progression
at 3 months: 79.4%
Oral cladribine reduced the relapse rate by 54.5% to 57.6%
and the risk of sustained disability progression at 3 months
by about one third compared with placebo.
Giovanni G, et al. N Engl J Med. 2010;362:416-426.
Cladribine
Safety
• Common adverse effects: headache, nasopharyngitis, upper
respiratory tract infection, nausea
• Infections/infestations
– Herpes zoster
– Primary varicella
•
•
•
•
Benign uterine leiomyomas
Malignancies (melanoma, pancreatic, ovarian, cervical)
Decreased lymphocyte counts/severe aplastic anemia
Exacerbation of latent tuberculosis
Giovanni G, et al. N Engl J Med. 2010;362:416-426.
Do We Have the Answers to
the
Three Questions?
• Fingolimod and cladribine are likely to be at least as effective as
available treatments
– Fingolimod > IFN beta-1a IM in TRANSFORMS
– IFN beta-1a IM was the least effective of available therapies in prior
head-to-head trials
• Fingolimod and cladribine may have greater safety issues
– Severe herpes infections, malignancies, lymphocytopenia (both
fingolimod and cladribine)
– Macular edema, bradycardia/AV block (fingolimod)
– Higher discontinuation rates than available therapies
• It is not yet clear whether these therapies can prevent immunemediated injury
Carroll WM. N Engl J Med. 2010;362:456-458.
Additional Oral Small-Molecule
MS Therapies in Late-Stage
Development
• Fumarate (BG00012)
• Teriflunomide
• Laquinimod
Emerging Monoclonal
Antibodies
•
•
•
•
Rituximab
Ocrelizumab
Alemtuzumab
Daclizumab
Conclusions
• Oral therapies for MS may soon be available
• Phase III studies have been completed for fingolimod and
oral cladribine
– Possibly more effective at reducing relapse rates
compared with current therapies, but not clear that they
are any better at preventing disability
– Some serious adverse events have been observed
 Requires patient understanding of risks and need
for close monitoring
• Other small molecules and monoclonal antibodies are in
late-stage development for MS
Symptom Management
MS Symptoms vs Relapses
MS symptoms
• Chronic or ongoing indicators of MS lesion damage
to certain areas of the brain or spinal cord
MS relapses
• Flare-ups or attacks of new or previously resolved
symptoms that typically evolve over at least 48 hours
and last several days to weeks
Common MS Symptoms
•
•
•
•
•
•
•
•
Fatigue
Bladder dysfunction
Spasticity
Gait difficulties
Pain
Cognitive impairment
Mood instability
Sexual dysfunction
MS Fatigue
• One of the most common (80%) symptoms
• One of the most disabling symptoms
– Primary reason to stop working
– More likely than other types of fatigue to interfere with daily
responsibilities
• Occurs daily, starts suddenly
– Can start early in the morning, even after restful sleep
• Worsens as day progresses, with heat and humidity
• Cause unknown
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/whatwe-know-about-ms/symptoms/fatigue/index.aspx
Managing MS Fatigue
Lifestyle Changes
• Physical therapy/exercise
• Good nutrition
• Enough sleep
– Going to bed on time
– Management of other symptoms that interfere with sleep
•
•
•
•
•
Rest breaks
Weight management
Prioritization of tasks; maintaining realistic expectations
Letting others help
Avoidance of excessive caffeine, multitasking, overheating
Managing MS Fatigue
Pharmacologic Strategies
(Off-Label Uses)
• Amantadine hydrochloride 100-200 mg/d
early in day
– May need additional 100 mg around noon
• Modafanil 100-200 mg/d early in day
• Amphetamine-type therapies
– Methylphenidate, can start at 5 mg PO in AM and
titrate to effect; 10 mg in AM and around noon or
early afternoon is common
– Can use long-acting formulations
Bladder Dysfunction
•
•
•
•
•
•
•
Affects 80% of MS patients
Frequency and/or urgency
Hesitancy in starting urination
Nocturia
Incontinence and/or dribbling
Urinary retention, which can lead to UTIs
May interfere with normal activities and cause social
embarrassment
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-weknow-about-ms/symptoms/bladder-dysfunction/index.aspx and http://www.nationalmssociety.org/aboutmultiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/download.aspx?id=64
Managing Bladder Dysfunction
Management
• Assessment
– Urinalysis/dipstick, culture (UTI)
– Postvoid residual urine
– Urodynamic studies
• Dietary and fluid management
– Do not restrict fluids! 6-8 glasses daily, spread over course of day,
but fewer before bed
• Exception: restrict intake ~ 2 hours before activities where no bathroom
will be available
– Limit caffeine, alcohol, citrus juice
• Intermittent self-catheterization
• Absorbent pads
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-weknow-about-ms/symptoms/bladder-dysfunction/index.aspx and http://www.nationalmssociety.org/aboutmultiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/download.aspx?id=64
Managing Bladder Dysfunction
Pharmacologic Strategies
• Antibiotics if positive for UTI
• Anticholinergic agents
– Oxybutynin, propantheline, imipramine, tolterodine,
solifenacin succinate, darefenacin, trospium chloride
• Desmopressin acetate nasal spray or tablets (for
nocturia)
– Need to monitor serum sodium
• Antispasticity agents (to relax sphincter muscle)
– Baclofen, tizanidine hydrochloride
• Alpha-adrenergic blockers
– Prazosin, terazosin, tamsulosin
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-weknow-about-ms/symptoms/bladder-dysfunction/download.aspx?id=64
Spasticity
• Velocity-dependent increase in muscle tone, with hyperactive
deep tendon reflexes
–
–
–
–
–
–
Clonus: repetitive rhythmic beating of foot or wrist
Difficulty initiating movement
Impaired voluntary muscle control
Difficulty relaxing muscles after movement cessation
Sensation of muscle tightness or pain
Decreased range of motion
• Potential triggers: sudden movements or position changes,
fatigue, stress, cold, humidity, tight clothes, tight shoes,
constipation, poor posture, infection
• Can be worsened by interferons
• Can add to MS fatigue
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-weknow-about-ms/symptoms/spasticity/index.aspx. Kushner S, et al. Spasticity. NMSS Clinical Bulletin.
http://www.nationalmssociety.org/download.aspx?id=147
Managing Spasticity
Nonpharmacologic Strategies
• Daily stretching and exercise (cool environment)
– Balance and coordination, strengthening, timing, range of
motion, posture
•
•
•
•
•
Transcutaneous electrical nerve stimulation (TENS)
Thermal (hot and cold)
Biofeedback
Relaxation (yoga, Tai Chi)
Bracing/splinting
Kushner S, et al. Spasticity. NMSS Clinical Bulletin.
http://www.nationalmssociety.org/download.aspx?id=147
Managing Spasticity
Pharmacologic Strategies
•
•
•
•
•
Baclofen - oral or intrathecal; start low and titrate
Tizanidine
Dantrolene sodium
Diazepam
Other off-label agents sometimes used
– Clonazepam, gabapentin
– Botulinum injections for focal spasticity
• Phenol nerve blocks
Kushner S, et al. Spasticity. NMSS Clinical Bulletin.
http://www.nationalmssociety.org/download.aspx?id=147.
Managing Spasticity
Surgery for Intractable Symptoms
• Tenotomy
• Neurectomy
• Rhizotomy
Kushner S, et al. Spasticity. NMSS Clinical Bulletin.
http://www.nationalmssociety.org/download.aspx?id=147
Managing Gait Difficulties
• Dalfampridine—previously known as fampridine SR
or 4-aminopyridine SR
• FDA approved January 2010
• Indication: improve walking speed in patients with MS
– This is not a disease-modifying therapy
• Mechanism: K+ channel blockade
– Enhances axonal conduction
• Dose-dependent side effect: seizures
Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics; 2010.
Dalfampridine Phase III Studies
43
45
40
35
Responders (%)
• Dalfampridine
10 mg BID (n = 229)
or placebo (n = 72) x
14 weeks
• Response =
consistent
improvement on
timed 25-foot walk
• Walking speed
improved by 25%
among fampridine
responders vs 5%
with placebo (Trial 1)
Fampridine
P <.001
35
Placebo
30
25
20
15
10
5
8
9
0
Trial 1
Trial 2
Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics; 2010. Goodman AD, et al. Lancet.
2009;373:732-738.
Botulinum Toxin for MS
Spasticity
• N = 74 MS patients with disabling spasticity of the hip adductor
muscles of both legs
• Randomized to botulinum toxin 500, 1000, or 1500 U IM
injections into hip adductor muscles or placebo
• Botulinum was associated with improved passive hip abduction
and distance between the knees
• Botulinum reduced muscle tone, and all groups (including
placebo) had reduced frequency of spasms and leg pain
• Nonsignificant trend toward greater efficacy with higher doses
but there were twice as many side effects with 1500 U
Hyman N, et al. J Neurol Neurosurg Psychiatry. 2000;68:707-712.
Managing Other MS Symptoms
Symptom
Management
Pain
Carbamazepine, phenytoin, gabapentin, amitriptyline, duloxetine hydrochloride,
pregabalin, baclofen, tizanidine, acetaminophen, NSAIDs, pressure
stocking/glove, warm compresses, massage
Cognitive
impairment
Referral for cognitive rehabilitation and psychotherapy, memory aids (recordings,
lists, mnemonics, etc), assistive technologies (computers, electronic calendars),
minimization of distractions, donepezil (if dementia present)
Depression
Referral for counseling/psychotherapy, TCAs, SSRIs, SSRNIs, bupropion,
mirtazapine
Sexual
dysfunction
Consider medication side effects (eg, SSRIs, beta blockers), sildenafil, vardenafil,
tadalafil, papaverine, OTC lubricants, alternative means of stimulation, counseling
to address relationship issues
National Multiple Sclerosis Society. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-knowabout-ms/symptoms/pain/index.aspx, http://www.nationalmssociety.org/download.aspx?id=127,
http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-aboutms/treatments/medications/antidepressants/index.aspx, http://www.nationalmssociety.org/about-multiplesclerosis/what-we-know-about-ms/symptoms/sexual-dysfunction/index.aspx
Conclusions
• Managing MS means thinking about more than just preventing
relapse and new lesions
• It is important to address other symptoms that interfere with
QOL
• Symptoms need to be recognized in order to treat
• Address 1 or 2 symptoms per visit—prioritize
• Through counseling and treatment, most symptoms can at least
be reduced
• Refer to specialists as needed for optimized symptom control
• Expect that many symptoms will never be fully controlled
The Dialogue of MS
in Primary Care
Communicating with Patients
and Peers
• There are many resources for clinicians and patients
available online
• Social media sites offer resources as well as an
opportunity to connect with others
• Some of the information your patients receive over
the Internet and via social media sites is more
accurate than others
– Know what is available
– Recommend reputable sites
– Ask what they are using
What Your Patients May Be
Doing
You Tube
What Your Patients May Be
Doing
Facebook
What Your Patients May Be
Doing
Twitter
What Your Patients May Be
Doing
Blogging
Other Projects In Knowledge
MS Enduring Materials
• The Advanced Certificate Program: Multiple
Sclerosis Management II
www.projectsinknowledge.com/cp/1877
• Living Medical Textbook: Multiple Sclerosis
Edition
www.livingmedicaltextbook.org/1876