G

1. Multiple Sclerosis

2. 2010/07/06
Natural History of MS
Relapsing
Preclinical Progressive
Relapses and impairment MRI Total T2 lesion area
Time
MRI activity Measures of brain volume

3. 2010/07/06
Documented Benefits of DMTs
Clinical benefits
–  relapse rate and relapse severity
–  time to next relapse
–  proportion of relapse free patients
–  time to sustained disability worsening
–  in development of disability
MRI benefits
–  in lesion (new, active) number and size
–  stable burden of disease

4. 2010/07/06
Inflammation and Axonal
Degeneration in MS
Clinical
symptoms
Subclinical degeneration
Time (years)
+
-
THERAPY
Axonal
damage

5. 2010/07/06
FDA-approved DMTs in MS
Immunomodulators
– Interferon-1
1a: Avonex, Rebif
1b: Betaferon
– Glatiramer acetate
Immunosuppressants
– Mitoxantrone
Monoclonal antibodies
– Natalizumab

6. Classification
 Relapsing-remitting MS
 Primary progressive MS
 Secondary progressive MS
 Optic-spinal MS
 Devic disease (neuromyelitis optica)
 Anti-aquaporin-4 water channel
 Marburg
 Schilder/Balo
 Tumefactive MS

7. Symptoms and Signs
 Motor (most common):
 Muscle weakness
 Spasticity, hyperreflexia, Babinski
 Sensory:
 Impairment of vibratory/position sense
 Impairment of pain, temperature, or touch
 Pain
 Lhermitte sign

8. Symptoms and Signs
 Cerebellar:
 Charcot triad: Ataxia, tremor, scanning
speech
 CN:
 Retrobulbar neuritis (central scotoma)
 Internuclear ophthalmoplegia (MLF)
 Trigeminal neuralgia
 Hemifacial spasm, true vertigo

9. Symptoms and Signs
 Automatic
 Bladder dysfunction
 Bowel dysfunction
 Sexual dysfunction
 Psychiatric
 Depression, euphoria
 Cognitive abnormalities
 Fatigue (a prodromal symptom)

10. Multiple Sclerosis, 12: 501-506, 2006
S/S %
Weakness 55.67
Sensory loss 42.67
Paresthesia 38.67
Blurred vision 36.00
Nystagmus 21.33
Ataxia 18.67
Sphincter
dysfunction
18.67
Diplopia 14.67
Dysarthria 2.67
Global (from Merritts’)
S/S
Motor
Sensory
Cerebellar
CN
Autonomic
Psychiatric

11. Symptoms and Signs
 Uhtoff phenomenon
 Transient dysesthesias, visual blurring, or
diplopia or weakness following hot showers or
exercise.
 Derangements of the neurologic signal
through previously damaged pathways.
 Lhermitte sign

13. Laboratory Data
 MRI: T2-weighted and FLAIR images
 CSF:
 IgG increase in 70% of patient with MS
 IgG index: (CSF IgG/serum IgG)/(CSF
alb/serum alb)
 Oligoclonal IgG bands electrophoresis in more
than 90% of patient with MS

14. Evoked Potentials
 VEP: Very sensitive
 BEP: For pontine lesions
 SEP: For sensor abnormalities

15. Porser criteria of MS
1983
Category Criteria
Clinical definite 2 attacks and clinical evidence of 2 separate lesions
2 attacks, clinical evidence of one and paraclinical evidence of
another separate lesion
Laboratory
supported definite
2 attacks, either clinical or paraclinical evidence of 1 lesion, and
cerebrospinal fluid (CSF) immunologic abnormalities
1 attack, clinical evidence of 2 separate lesions & CSF
abnormalities
1 attack, clinical evidence of 1 and paraclinical evidence of
another separate lesion, and CSF abnormalities
Clinically probable 2 attacks and clinical evidence of 1 lesion
1 attack and clinical evidence of 2 separate lesions
1 attack, clinical evidence of 1 lesion, and paraclinical evidence of
another separate lesion
Laboratory
supported probable
2 attacks and CSF abnormalities

16. McDonald criteria of MS
Ann. Neurol. 2001; 50: 121-127

17. Diagnostic criteria for multiple sclerosis:
2005 revisions to the 'McDonald Criteria'.
Ann Neurol. 2005 Dec;58(6):840-6.

18. Paraclinical evidence in MS
diagnosis
• What is a positive MRI? (Barkhof criteria)
3 out of 4 of the following:
• 1 Gd-enhancing lesion,
or 9 T2 hyperintense lesions if no Gd-enhancing lesion
• 1 or more infratentorial lesion(s)
• 1 or more juxtacortical lesion(s)
• 3 or more periventricular lesions
Note: 1 cord lesion can substitute for 1 brain lesion.

19. • What provides MRI evidence of
dissemination in time?
One of the following:
• A Gd-enhancing lesion demonstrated in a scan
done at least 3 months following onset of
clinical attack at a site different from attack
• In absence of Gd-enhancing lesions at 3 month
scan, follow-up scan after an additional 3
months showing Gd-lesion or new T2 lesion
Ann. Neurol. 2001; 50: 121-127

21. • What is positive CSF?
One of the following:
• Oligoclonal IgG bands in CSF (and not serum)
• Elevated IgG index
• What is positive VEP?
Delayed but well-preserved wave form

22. Diagnosis
Definite MS:
 Two or more attacks
 Objective clinical evidence of 2 or more
lesions

23. Diagnosis
If two or more attacks, objective clinical
evidence of 1 lesion:
 Dissemination in space, demonstrated by MRI,
or
 Two or more MRI-detected lesions consistent
with MS plus positive CSF, or
 Await further clinical attack implicating a
different site

24. Diagnosis
One attack; objective clinical evidence of 2
or more lesions:
 Dissemination in time, demonstrated by MRI,
or
 Second clinical attack

25. Diagnosis
One attack; objective clinical evidence of 1
lesion:
 Dissemination in space by MRI, or
 Two or more MRI-detected lesions consistent
with MS plus positive CSF
AND
 Dissemination in time by MRI, or
 Second clinical attack

26. Insidious Neurologic Progression
 Positive CSF (oligoclonal bands)
And
 ≧9 brain lesions
 ≧2 spinal lesions
 4-8 brain lesions + 1 spinal lesion
 Abnormal VEP associated with 4-8 brain lesions, or
with fewer than 4 brain lesions plus 1 spinal cord
lesion
And
 Dissemination in time by MRI, or
 Continued progression for 1 yr

27. MRI Criteria for Brain Abnormality
Three of the four following:
 One gadolinium-enhancing lesion ( >3 mm)
or nine T2-hyperintense lesions if no
gadolinium-enhancing lesion
 At least one infratentorial lesion
 At least one juxtacortical lesion
 At least three periventricular lesions

28. MRI Criteria for Dissemination of
Lesions in Time
 If a first scan occur 3 months or more
after the onset of the clinical event, the
presence of a gadolinium-enhancing lesion
or new T2 lesion is sufficient.
 If the first scan is performed <3 mos after
the onset of the clinical event, a 2nd scan
done 3 mos or more after the clinical
event showing a new lesion is sufficient.

29. DDX
 Vascular
 Stroke
 AVM
 Arachnoid cysts
 Arnold-chiari malformations

30. DDX
 Infection
 Lyme disease
 HIV
 HTLV
 Neurosyphilis
 Progressive multifocal leukoencephalopathy
(PML)

31. DDX
 Neoplasm
 Lymphoma
 Paraneoplastic syndrome
 Acute disseminated encephalomyelitis
(ADEM)

32. DDX
 Autoimmune
 SLE
 Polyarteritis nodosa
 Sjogrene
 Behcet
 Sarcoidosis
 Cervical spondylosis
 Endocrine
 Subacute combined degeneration

33. DDX
 Hereditary or degenerative
 Adrenomyeloneuropathy (AMN/ALD)
 Spinocerebellar syndromes (SCA)
 Hereditary spastic paraparesis
 Primary lateral sclerosis

34. Management
 1 g of methylprednisolone by IVF qd for 7
to 10 days, for acute attack

35. Immunomodulator
 β-interferon-1b (Betaseron, SC, qod)
 β-interferon-1a (Avonex, IM, once a week)
 β-interferon-1a (Rebif, SC, 3 times a week)
 Neutralizing antibody
 Glatiramer Acetate (Copaxone)
 Natalizumab (Tysabri, monthly infusion)
 Ab against α4β1-integrin receptor on Lφ, blocking
Lφ binding to VCAM-1 on BBB
 PML