Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system. There are four main types of MS based on disease progression: relapsing-remitting, primary progressive, secondary progressive, and progressive relapsing. Disease-modifying therapies (DMTs) have been shown to reduce relapse rates, delay disability progression, and decrease lesion activity on MRI scans. While inflammation drives early disease, axonal damage and neurodegeneration contribute to long-term disability. The McDonald criteria are now used to diagnose MS based on clinical symptoms, MRI findings, and cerebrospinal fluid analysis demonstrating dissemination in space and time. Management involves immunomodulators like interferon beta or glatiramer acetate

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