1. MULTIPLE SCLEROSIS

2. Multiple Sclerosis
A chronic, progressive neurologic disease characterized by scattered demyelination of nerve fibers in the brain and spinal cord.

3. Multiple Sclerosis Most common disabling condition in young adults
Most common demyelinating disorder
Progresses to disability in majority of cases
Unpredictable course & variety of signs and symptoms; sometimes mistaken for psychiatric disorder

4. MS- Incidence Peak onset 20-40 years of age 70% between ages 21-40
Rarely prior to age 10 or after age 60
F > M (approx. 2:1)
White > non-white (2:1)

6. 6 6

8. Risk factors Autoimmune process Viral infection
Allergic reactions to infection
Familial tendencies.
Cool, temperature climates.

9. Etiology Autoimmune Viral T-cells activate against myelin
Specific viral protein not yet identified
Suspected “molecular mimicry”
Roseola (HHV6) associated with demyelination in MS patients
Viral infections known to provoke relapses

10. 1. Research into the Causes of MS
Genetic
factors
Environmental
factors
Immunological
factors MS 10

11. Pathological Hallmarks
Described in late 1800s by Dr. Charcot
Inflammation and demyelination
Plaques occur anywhere in the CNS
Most frequent: optic nerve, brainstem, cerebellum, spinal cord
Axon sparing within the plaques

12. Structure Of Plaques Outer layers of myelin sheath separate
Degenerative changes in myelin
Infiltration with macrophages
Preservation of axons

13. Normal Conduction

14. Abnormal Conduction

15. Results Of Demyelination
Conduction block at site of lesion
Slower conduction time along affected nerve
Increased subjective feeling of fatigue secondary to compensation for neurologic deficits

16. Initial Presentation of MS
Incidence (%)
Optic nerve inflammation
14–29
Poor balance (ataxia)
2–18
Dizziness (vertigo)
2–9
Weakness
10–40
Double visions (diplopia)
8–18
Bladder, bowel dysfunction
0–14
Pain
21–40
Sensory loss
13–39

17. Initial Symptoms Double vision / blurred vision Numbness
Heat intolerance
Motor weakness
Fatigue
Problems with bladder control
Facial Palsy

18. Signs and Symptoms. Instability while walking Poor coordination
Dizziness
Tremors
Spasticity of extremities
**All symptoms can be precipitated by heat**

19. Signs and Symptoms Slurred speech Difficulty in chewing and swallowing
Mental changes
cognitive dysfunction
Fecal or urinary incontinence or retention.
Impotence

21. Classification Benign Multiple Sclerosis
Mild infrequent sensory exacerbations with full recovery.
Relapsing Remitting Multiple Sclerosis
Episodes of exacerbations and remissions during which not all symptoms resolve completely.

22. Classification Secondary Chronic Progressive
Relapses become more severe while remissions are less complete, shorter in duration, and eventually non-existent. The course of MS becomes steadily progressive.
Primary Progressive
No relapse. Disease begins with a slow progression of neurologic deficits.

23. Diagnostic tests CSF Analysis Magnetic resonance imaging
Positron Emission Tomography
Evoked Potential Studies

24. Dissemination in space and time
MS Diagnosis
Dissemination in space and time

25. Summarized Diagnostic Criteria
1. Dissemination in space: Objective evidence of neurological deficits localized to two separate parts of the CNS
2. Dissemination in Time:
Onset of neurological deficits separated by at least one month
3. Rule out other explanations!
August
November 26 26 26

26. New Diagnostic Criteria
Incorporate use of MRI
Clinically Isolated Syndrom + MRI Dissemination in space + MRI Dissemination on time =
Earlier MS Diagnosis
DIS
August
November
DIT 27 27 27

27. MRI - Dissemination in Space
3 of the following:
9 T2 or 1 Gd+
3 Periventricular
1 Infratentorial
1 Juxtacortical lesion 28 28 28

28. MRI - Dissemination in TimeGd Gd
> 3 months T2 T2
> 1 month
> 1 month
CIS
Polman, 2005 29 29 29

29. DIAGNOSTIC WORK UP History & Physical Exam Brain and Spinal Cord MRI
Labs: rule out mimics of MS
Connective tissue diseases, infections, metabolic disorders
Cerebrospinal Fluid (when clinical and MRI evidence inconclusive)
Evoked Potentials:
Identify damage to visual, auditory, & touch perception systems
Less sensitive than MRI or cerebrospinal fluid 30 30 30

30. CSF Increased immunoglobulin concentration Elevated IgG index
Oligoclonal bands
Elevated protein

31. o

32. Evoked Potentials VER (visual evoked response)—75% abnormal
BAER (brainstem auditory evoked response)—30% abnormal
SSER (somatosensory evoked response) – 80% abnormal

33. MRI- Cerebellum

34. MRI- Spine

35. MRI- Spine

36. MRI- Optic Nerve

38. MRI- Cerebral Hemisphere

39. JUXTACORTICAL

40. MRI- Cerebral Hemisphere

46. T1 nn „black holes“

48. Differential Diagnosis
Encephalomyelitis
CNS Vasculitis
Lyme Disease
Lupus Erythematosus
Spastic Paraparesis
Behçet Syndrome
Vitamin B-12 Deficiency and Syphilis
Hereditary Degenerative Disorders

51. Standard Therapy Treatment of Relapses Corticosteroids-
Methyl Prednisolone

52. Disease Modifying Therapies: 1993-2002
Glatiramer Acetate
(Copaxone®)
1997
IFN -1b
(Betaseron®)
1993
IFN -1a
(Rebif®)
2002
IFN -1a
(Avonex®)
1996
Type Polypeptide Recombinant Recombinant Recombinant
mixture protein protein protein
Indication Reduce freq. Reduce freq. Reduce freq. Slow prog.
of relapses of relapses of relapses in relapsing
in RRMS Slow Delay forms
disability in disability in Prevent 2nd
relapsing forms relapsing forms attack in CIS
Injection SC SC SC IM
Administration Daily Every other day 3x/week Weekly
decrease relapses of MS by 33%
Immunomodulatory Treatments
The long-term data that was published on glatiramer acetate1 involves a 6-year interim analysis of the ongoing 10-year open-label study. Some 8-year data are available.
An extension of the pivotal North American study of IFN -1b (Betaseron®) provided placebo-controlled data for up to 5 years (median treatment period, 48.0 months).2 More recently, data from the 4-year extension of the PRISMS trial suggest that IFN -1a SC (Rebif®) may be efficacious for up to 4 years.3 No long-term studies (>2 years) have been published describing neurologic outcomes following the long-term use of IFN -1a IM (Avonex®).
1. Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Mult Scler. 2000;6:
2. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45:
3. The PRISMS (Prevention of Relapses and Disability by Interferon-- 1a Subcutaneously in Multiple Sclerosis) Study Group. PRISMS-4: long-term efficacy of interferon--1a in relapsing MS. Neurology ;56: 54 54

53. Natalizumab-Tysabri
Humanized monoclonal Antibody against 41 integrin
Selective adhesion-molecule inhibitor (SAM)
Prevents transendothelial migration of activated leukocytes from small venules into CNS

54. “68% relative reduction in the annualized
rate of relapse produced by natalizumab
was maintained at two years (P<0.001)” 56 56

55. Newer treatments for RRMS: the return of immunosuppression!
Mitoxantrone
Natalizumab
Oral Treatments (Fingolimod)

56. Fingolimod (Gilenya)
Sphingosine-1-phosphate receptor blocker; traps lymphocytes in lymph nodes
Licenced for rapidly evolving MS (second line)
60% reduction in relapse rate
Side effects include bradycardia, macula oedema, infections (esp herpes virus), skin cancers

57. Existing Therapies and Emerging Therapies for MS
2005
2006
2007
2010
2011
2012
2013
Orals
Injectables
BG 12 Oral Fumarate
Oral Cladribine
Rebif
Teriflunomide
Betaseron
FTY 720
Laquinimod
Copaxone
Fampridine
ambulation indication?
SB683699
Avonex IV
Novantrone IV
Campath
Tysabri
Rituximab
II - RRMS; III - PPMS
Generic Mitoxantrone
(oncology) (MS)
Daclizumab
MBP 8298
MLN1202
Filed
approved
In phase II
In phase III

58. Complications Respiratory failure Pneumonia
Neurologic deficits: paralysis.
UTI
Sexual dysfunction
Contractures

59. Factors that influence prognosis
Females
Low rate of relapses per year
Complete recovery from the first attack
Long interval between first and second attack
Low disability at 2 to 5 years from the disease onset

60. Factors that influence prognosis
Symptoms predominantly from afferent systems (i.e.,. sensory symptoms)
Younger age of onset
Later cerebellar involvement
Involvement of only one CNS system at the time of onset

61. What Happens?
50% of MS patients will need help walking within 15 years of disease onset
Life Expectancy:
82.5% of normal
58 years old

62. Expanded Disability Status Scale

63. Thank you