2. Introduction

3. 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
Nucleus
Soma
Dendrite
Myelin Sheath (With Axon Through It)
Schwann Cell
Node of Ranvier
Axon Terminal
Graphic by Quasar Jarosz at en.Wikipedia.org

4. 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

5. 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

6. 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

8. What Factors Contribute to the Risk for MS?8

9. MS Epidemiology Prevalence ~350,000 persons in the United States
Sex distribution
~75% female
Age at onset
Typically 20−40 years,
but can present at any age
Ethnic origin
Predominantly Caucasian
Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston; Hauser SL, et al. Multiple Sclerosis. In: Fauci AS, et al. Harrison’s Principles of Internal Medicine. Available at: Accessed on: February 19, 2010. 9

10. Multiple Sclerosis An Immunogenetic Disease
Environmental Factors
Genetic Predisposition
Immune Dysregulation MS
Graphic courtesy of Suhayl Dhib-Jalbut, MD. 10

11. Evidence for Genetic Basis of MS50 45 40 35
Approximate Probability of Developing MS 30
25% 25 20 15 10 5% 2% 3% 5 1%
0.1%
0.1%
Identical
Fraternal
Sibling
Parent or
First
Spouse No
Twin
Twin
Half-
Cousin
Family
Sibling
Member
Hauser SL, et al. Multiple Sclerosis. In: Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. Available at: Accessed on: February 19, Willer CJ, et al. Proc Natl Acad Sci U S A. 2003;100: 11

12. 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 12

13. 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 13

14. Evidence for EBV Indirect evidence Direct 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, Bray, Larson, Sumaya, Shirodaria, Munch, Myhr, Wagner, Ascherio, Sundström, Haahr, Ponsonby, 2005. 14

15. 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: Van der Mei IA, et al. J Neurol. 2007;254: Van der Mei IA, et al. BJM. 2003;327: Munger KL, et al. JAMA. 2006;296: 15

16. 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: Riise T, et al. Neurology. 2003;61: Mikaeloff Y, et al. Brain. 2007;130(pt 10):

17. 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

18. Pathophysiology of MS 18

19. Pathophysiology of MS Acute Inflammation Relapses
Neuronal Degeneration Disability 19 19

20. 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-S Viglietta V, et al. J Exp Med. 2004;199: 20

21. Cytokine Imbalance in MS
IFN-g, IL-12, TNF
IL-4, IL-10, TGFß
Inflammatory
Anti-inflammatory
IL-4, IL-10,TGFß
Normal MS
TH1
TH2
Graphic courtesy of Suhayl Dhib-Jalbut, MD. 21 21

22. 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: 22

23. 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 23

24. 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: Trapp BD. Neuroscientist. 1999;5:48-57. 24

25. 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 25

27. Challenges in Diagnosing MS

28. 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: 28

29. 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 29

30. Four Clinical Subtypes of MS
RRMS
Disability
Time
Disability
Time
PPMS
Time
Disability
SPMS
RPMS
Disability
Time
Fauci AS, et al. In: Harrison's Manual of Medicine, 17th ed. McGraw-Hill Medical; Reprinted with permission from McGraw-Hill. 30

31. 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 31 31

32. 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: 32

33. Natural History of MS Clinical and MRI Measures
Relapses/Disability
MRI Activity
MRI T2 Burden of Disease
Axonal Loss
Secondary Progressive MS
Preclinical
Relapsing-Remitting MS
CIS *
Disability
Time
Trapp BD, et al. Neuroscientist. 1999;5: Reprinted with permission from Sage Publications. 33

34. Natural History of CIS (Queen Square) Risk of Conversion Based on Lesion Count at Presentation
11%
79%
87%
85%
19%
89%
88% 6%
54%
92%
80%
Morrissey S, et al. Brain. 1993;116: O’Riordan J, et al. Brain. 1998;121: Brex PA, et al. N Engl J Med. 2002;346: 34 34

35. 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 Gd-enhancing
≥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: 35

36. 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: 36

37. Typical MRI Lesions in MS
Gd-enhancing
Corpus Callosum
A and B: Courtesy of Tracy M. DeAngelis, MD. 37

38. Typical MRI Lesions in MS
Infratentorial
Juxtacortical
C and D: Courtesy of Daniel Pelletier, MD.

39. Typical MRI Lesions in MS
Periventricular
Spinal Cord
E: Courtesy of Daniel Pelletier, MD. F: Courtesy of Tracy M. DeAngelis, MD.

40. 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. 40

41. 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. 41

42. 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: Brex PA, et al. N Engl J Med. 2002;346: Truyen L, et al. Neurology. 1996;47: Miller DH, et al. Brain. 2002;125: 42

43. 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 43

44. Emerging MRI Technologies
Measures of CNS atrophy
Magnetization transfer imaging
Proton magnetic resonance spectroscopy
Diffusion tensor imaging
Susceptibility weighted imaging 44

45. 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 45

46. 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 46

47. EDSS1 Bedridden Restricted to wheelchair Death
Need for walking assistance
Some limitation
in walking ability
10.0
9.5
Minimal
disability
9.0
Normal
neurologic exam
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
Time to EDSS score of 4.0 strongly influenced by relapses in the first 5 years and time to CDMS.2
3.0
2.5
2.0
1.0
1.5
1. Kurtzke JF. Neurology. 1983;33: Confavreux C, et al. Brain. 2003;126: 47 47

48. 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: 48 48

49. 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: Lennon VA, et al. J Exp Med. 2005;202: Lennon V, et al. Lancet. 2004;364: Mayo Medical Laboratories. 49 49

50. Distinguishing NMO from MS
Courtesy of Bruce A.C. Cree, MD, PhD, MCR
Courtesy of Tracy M. DeAngelis, MD

51. 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 51

53. Achieving Therapeutic Goals with Current Treatments53

54. 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 54

55. 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 55

56. Therapeutic Targets in MS56

57. 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 57

58. 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 58

59. 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 59

60. 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 60

61. Head-to-Head Study EVIDENCE (IFN beta-1a) Trial, 48 Weeks
Patients Relapse-Free
Difference
P Value
IFN beta-1a 30 mcg IM QW
52%
19% in favor of IFN beta-1a 44 mcg SC TIW
<.009
IFN beta-1a 44 mcg SC TIW
62%
Abbreviations: IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously; TIW, 3 times per week.
Pantich H, et al. Neurology. 2002;59: 61

62. Head-to-Head Study INCOMIN (IFN beta-1b vs beta-1a) Trial, 104 Weeks
Patients Relapse-Free
Difference
P Value
IFN beta-1b 250 mcg SC EOD
51%
42% in favor of IFN beta-1b
<.036
IFN beta-1a 30 mcg IM QW
36%
Abbreviations: EOD, every other day; IFN, interferon; IM, intramuscular; QW, once weekly; SC, subcutaneously.
Durelli L, et al. Lancet. 2002;359: 62

63. Patients Relapse-Free
Head-to-Head Study REGARD (Glatiramer Acetate vs IFN beta-1a), 96 weeks
Patients Relapse-Free
Difference
P Value
Glatiramer acetate 20 mg QD
62%
No difference
<.96
IFN beta-1a 44 mcg SC TIW
Abbreviations: IFN, interferon; SC, subcutaneously; QD, once daily; TIW, 3 times per week.
Mikol DD, et al. Lancet Neurol. 2008;7: 63

64. Patients Relapse-Free
Head-to-Head Studies BECOME and BEYOND (Glatiramer Acetate vs IFN beta-1b)
Patients Relapse-Free
Difference
P Value
BECOME1
(18 mo)
GA 20 mg QD
70%
8% in favor of GA NS
IFN beta-1b 250 mcg SC QOD
62%
BEYOND2
(2 years)
59%
1% in favor of IFN 500 mcg
58%
IFN beta-1b 500 mcg SC QOD
60%
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: O’Connor P, et al. Lancet Neurol. 2009;8: 64

65. 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 65

66. 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; Betaseron [package insert] Montville, NJ: Bayer HealthCare Pharmaceuticals; Extavia [package insert]. Montville, NJ: Bayer HealthCare Pharmaceuticals; Rebif [package insert]. Rockland, MA: EMD Serono; 2009. 66

67. Neutralizing Antibodies
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
Probability of NAbs (%)
Data from prescribing information.
1. Goodin DS, et al. Neurology. 2007;68: 67

68. 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. 68

69. Side Effect Management Tips
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 self-injecting
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 69

70. Timing of Therapy May Be Key to Preventing Disability
First Demyelinating Event
Secondary
Progressive
Pre- clinical
Relapsing-Remitting
Transitional
Time window for early treatment
First Clinical Attack
Axonal loss
Clinical threshold
1841 CMSC Slide
Demyelination
Inflammation
Time (years) 70

71. Rationale for Early Treatment
Time is ticking…
What is lost by delaying early therapy is not regained by starting later
1841 CMSC Slide 71

72. 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 72 72

73. Placebo-Controlled Trials of Disease-Modifying Therapy in CIS
Study
Treatment N
Conversion to CDMS
Follow- up
On Tx
Placebo P
CHAMPS1
Interferon beta-1a 30 μg IM qwk
383
3 y
35%
50%
.002
ETOMS2
Interferon beta-1a 22 μg SC once weekly
309
2 y
34%
45%
.047
BENEFIT3
Interferon beta-1b 250 μg SC q48h
468
28%
<.0001
PreCISe4
Glatiramer acetate 20 mg/d
481
61%
77%
.0005
1. Jacobs LD, et al. N Engl J Med. 2000;343: Comi G, et al. Lancet. 2001;357: Kappos L, et al. Neurology. 2006;67: Comi G, et al. Lancet. 2009;374: 73

74. 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 74

75. 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: 75

76. 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.

77. 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. 77

78. 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 78

79. 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 79

80. Assess Adherence! Most Patients Who Discontinue Do So in First 2 Years
Cohort of patients who stopped therapy
Rio J, et al. Mult Scler. 2005;11: 80

81. 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)

82. 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 82

83. 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) 83

84. 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: 84

85. 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

86. 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 86

88. Emerging MS Therapies 88

89. 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 89

90. 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: 90

91. 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: Pinschewer DD, et al. J Immunol. 2000;164: Chiba K, et al. J Immunol. 1998;160: 91

92. Fingolimod FREEDOMS, 24-Month Study
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: 92

93. Fingolimod TRANSFORMS, 12-Month Study
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: 93

94. 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: Kappos L, et al. N Engl J Med. 2010;362: 94

95. 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: 95

96. Oral Cladribine CLARITY
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: 96

97. 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: 97

98. 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 immune-mediated injury
Carroll WM. N Engl J Med. 2010;362: 98

99. Additional Oral Small-Molecule MS Therapies in Late-Stage Development
Fumarate (BG00012)
Teriflunomide
Laquinimod 99

100. Emerging Monoclonal Antibodies
Rituximab
Ocrelizumab
Alemtuzumab
Daclizumab
100

101. 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
101

103. Symptom Management
103

104. MS Symptoms vs Relapses
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

105. Common MS Symptoms Fatigue Bladder dysfunction Spasticity
Gait difficulties
Pain
Cognitive impairment
Mood instability
Sexual dysfunction
105

106. 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.
106

107. 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
107

108. Managing MS Fatigue Pharmacologic Strategies (Off-Label Uses)
Amantadine hydrochloride mg/d early in day
May need additional 100 mg around noon
Modafanil 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
108

109. 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. and
109

110. 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. and
110

111. 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.
111

112. 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. Kushner S, et al. Spasticity. NMSS Clinical Bulletin.
112

113. 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.
113

114. 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.
114

115. Managing Spasticity Surgery for Intractable Symptoms
Tenotomy
Neurectomy
Rhizotomy
Kushner S, et al. Spasticity. NMSS Clinical Bulletin.
115

116. 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.
116

117. Dalfampridine Phase III Studies
Responders (%)
P <.001
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)
Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics; Goodman AD, et al. Lancet. 2009;373:
117

118. 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:
118

119. Managing Other MS Symptoms
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
119

120. 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
120

122. The Dialogue of MS in Primary Care

123. 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

124. What Your Patients May Be Doing You Tube

125. What Your Patients May Be Doing Facebook

126. What Your Patients May Be Doing Twitter

127. What Your Patients May Be Doing Blogging

128. Other Projects In Knowledge MS Enduring Materials
The Advanced Certificate Program: Multiple Sclerosis Management II
Living Medical Textbook: Multiple Sclerosis Edition