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dNP
Multiple SclerosisFor Non Neurologists
Naraporn Prayoonwiwat, M.D.Neurology Division, Department of Medicine
Siriraj Hospital
[email protected] 02 419 7101-2
September 24, 2009; Khonkaen
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Multiple Sclerosis
MS is a rare disease, it is unlikely tobe seen in my general practice.
d NP
Do you think so?
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Diagnosis: optic neuritis
Rx: high dose steroids
Case Presentation
A young woman had dimmed
vision of the left eye for 2 days. Eyedrop tried without improvement.
d NP
Eye:
Vision got worse. Pain on eye
movement was noted.
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Case Presentation
A young woman felt spinning for
a few days, getting worse withmotion. There was no hearing lossor visual blurring.
d NP
Diagnosis: vertigo
Rx: antivertigo drug
ENT:
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Case Presentation
A young woman difficulty in
voiding for 3 days.Urinalysis: WBC 3-5, RBC 5-10, fewbacteria
d NP
Diagnosis: acute urinary retention
Rx: Foley’s catherization, quinolone
Urology:
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Case Presentation
A middle age woman had
nausea and vomiting for 5 days. Shehad very frequent hiccoughs for 1day.
EGD: showed mild gastritis
d NP
Diagnosis: acute gastritis
Rx: intravenous PPI
GI:
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Case Presentation
A middle age woman had gait
difficulty 2-3 weeks. She could notproperly lift her feet above theground. There was some numbness
at the lower legs.
d NP
Diagnosis: lumbar spondylosis
Inx: CT myelogram
Orthopedics:
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Case Presentation
A middle age man experienced
itching at the anterior chest left sidefor 1 week. No rash was noted.
d NP
Diagnosis: dermatitis
Rx: topical steriods
Skin:
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Case Presentation
A middle age woman had
headache for 1-2 months. She couldnot do her routine work, was slow inresponse. Mild weakness was noted.
d NP
Inx: CT brain with contrast -mass
Diagnosis: brain tumor
Surgery:
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Multiple Sclerosis
The neurological deficits inthese patients were caused by
demyelinating disease of the CNS. All of had MS.
d NP
Do you agree?
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Demyelinating Disease
• What is a demyelinating
disease of the CNS?
• What is the significance of
myelin?
d NP
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Demyelinating Disease
• Myelin wraps around thenerve axon and contributes to
the conduction velocity of thenerve.
d NP
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Demyelinating Disease
• Oligodendrocytes areresponsible for myelin
production in the CNS; whileSchwann cells are responsiblein the PNS.
d NP
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Demyelinating Disease
• Diseases affecting the CNSmyelin cause white matter
lesions in the CNS, whereasdiseases affecting the PNScause demyelinating type of
peripheral neuropathy.
d NP
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Immunopathogenesis
Myelinated neuron
Demyelinated neuron
Autoimmune attack
Degenerated neuron
Information flow
Partial Information flow
No Information flow
Disabilities Neurological symptoms
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Demyelinated fiber
Node of Ranvier
axon
Myelinated fiber
Nerve Conductions
d NP
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Demyelinating Disease
• What is MS?
d NP
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Multiple Sclerosis
An immune-mediated disorderinvolving mainly the white matter
(myelin) of the CNS which affectssusceptible individuals of both sexesafter exposure to certain
environmental factors.
d NP
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Multiple Sclerosis
- Immune-mediated disorderof the CNS
- White matter (myelin)involvement
- Response to environmentalfactors in susceptible persons
- Affect both sexes
d NP
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Multiple Sclerosis
Scope:
Clinical manifestations
Pathology
Pathogenesis
DiagnosisTreatment in MS
d NP
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dNP
Clinical Presentation
Multiple Sclerosis
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Multiple SclerosisClinical Presentation
Cerebrum
Optic nerve
Cerebellum/cerebellar pathway
Brainstem
Spinal cordBladder & Bowel function
Other
d NP
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Multiple SclerosisClinical Presentation
Cerebrum
Cognitive impairment
: deficits in attention, reasoning,
executive function (early)
dementia (late)Hemiparesis: UMN
Hemisensory loss
NP
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Multiple SclerosisClinical Presentation
Cerebrum (2)
Affects (mainly depression)
Epilespy (rare)
Focal cortical deficits (rare)
Psychiatric symptoms (rare)
NP
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Multiple SclerosisClinical Presentation
Optic nerve
Unilateral painful loss of vision
: scotoma
: reduced visual acuity
: impaired color vision: relative afferent pupillary
defect (RAPD)
NP
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Multiple SclerosisClinical Presentation
Cerebellum/cerebellar pathway
Tremor
: postural tremor
: intention tremor
Clumsiness and poor balance: limb in-coordination
: gait ataxia
NP
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Multiple SclerosisClinical Presentation
Brainstem
Diplopia (double vision)
Internuclear ophthalmoplegia: INO
Nystagmus
Vertigo
d NP
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Multiple SclerosisClinical Presentation
Brainstem (2)
Dysarthria (slurred speech)
Dysphagia (swallowing difficulty)
Pseudobulbar palsy
d NP
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Multiple SclerosisClinical Presentation
Spinal cord
Weakness
: upper motor neuron signs
Stiffness
: spasticityPainful spasms
d NP
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Multiple SclerosisClinical Presentation
Spinal cord (2)
Bladder dysfunction
Erectile dysfunction (impotence)
Constipation
d NP
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Multiple SclerosisClinical Presentation
Other
Pain
Fatigue
Paroxysmal symptoms
Temperature sensitivityExercise intolerance
d NP
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Multiple SclerosisCommon Presentations
Optic neuritis acute visual loss,
intraorbital pain on eye movement
Acute myelitis limb weakness,
numbness, urinary retention
Brainstem diplopia, INO, facialnumbness, hemiparesis,
hemisensory loss, ataxia
d NP
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Multiple SclerosisFunctional Status System
Cerebrum
Optic nerve
Cerebellum/cerebellar pathway
Brainstem
Spinal cordBladder & Bowel function
Other
d NP
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Clinical Course
d NP
Primary-progressive: PPSecondary–progressive: SP
Progressive-relapsing: PR Relapsing-remitting: RR
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Clinical Course
d NP
Clinical threshold
Inflammation
Axonal loss
Brain
volume
Relapses
PR RR
PPSP
PR
RR
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E xpanded D isability S tatus S cale
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Multiple Sclerosis
Scope:
Clinical manifestations
Pathology
Pathogenesis
DiagnosisTreatment in MS
d NP
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dNP
Pathology
Multiple Sclerosis
MS: Pathology
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MS: Pathology Active Lesion
d NP
Gross Luxol fast blue
Frohman EM, et al NEJM 2006;354:942-55
MRI
MS: Pathology
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d NP Frohman EM, et al NEJM 2006;354:942-55
LFB stain
Perivascular infiltratesMRP14
(Macrophage)
Numerousmacrophage
PLP mRNA in situ hybridization
Toluidine
blue
Electron
Micrograph
Loss of myelin
Demyelination
MS: Pathology
MS Plaque: Acute
MS Patholog
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MS: Pathology
MS Plaque: Chronic
d NP Frohman EM, et al NEJM 2006;354:942-55
LFB stainNumerousmacrophage
Demyelinated area Chronic gliotic lesion
Toluidine blue
Astrocyte
No Oligodendrocyte
EM
Astrocyte
Demyelinated axon
Macrophage
Remyelinated axon
Microglia nuclei
MS: Pathology
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MS: Pathology
Demyelination-Remyelination
d NP Frohman EM, et al NEJM 2006;354:942-55
EM
Demyelinated axon
Remyelinated axon
RemyelinationDemyelination
MS: Pathology
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MS: Pathology
Active Lesion
Werkle H and Lassmann H in McAlpine’s MS 4th Ed. 2005
LossofOPC OPCpreserved
Demyelina5on
OPC: oligodendrocyte progenitor cell
MS: Pathology
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MS: Pathology
Active Lesion
Werkle H and Lassmann H in McAlpine’s MS 4th Ed. 2005
Early Completed
Remyelina5on
OPC: oligodendrocyte progenitor cell
MS: Pathology
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MS: Pathology
Active Lesion
Werkle H and Lassmann H in McAlpine’s MS 4th Ed. 2005
R e m y e l i n a 5 o n
D e m
y e l i n a 5 o n
MS: Pathology
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MS: Pathology
Chronic Lesion
Werkle H and Lassmann H in McAlpine’s MS 4th Ed. 2005
R e m y e l i n a 5 o n
D e m
y e l i n a 5 o n
Arrestofremyelina5ngprocess
l
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Template SR
[email protected] March 26, 2009 02 419 7101-2d NP
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Multiple Sclerosis
Scope:
Clinical manifestations
PathologyPathogenesis
DiagnosisTreatment in MS
d NP
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dNP
Pathogenesis
Multiple Sclerosis
Pathogenesis
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T
Periphery
Demyelination and axon loss
BBB
Transmigration
Activation via APC,Differentiation,
Proliferation
Trigger
Local reactivation
APC
Adhesion/attraction
Release of cytokinesRecruitment of MΦ
Antibodies
B
Mφ Nitric Oxide
IFN-γ
TNF-α
TNF-α Adapted with kind permission from Prof. R. Hohlfeld
Pathogenesis
Autoreactive T-cells
TT
T
T
T
T
T
CNS
T APC
T
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Multiple Sclerosis
Scope:
Pathology
PathogenesisClinical manifestations
Diagnosis Treatment in MS
d NP
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dNP
Diagnosis
Multiple Sclerosis
Multiple Sclerosis
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Multiple SclerosisDiagnosis
Schumacher 1965Poser 1983
McDonald 2001Revised 2005*
d NP
Recommended Diagnostic Criteria for MS:Guidelines from International Panel.McDonald et al. Ann Neurol 2001;50:121-7*Diagnostic Criteria for Multiple Sclerosis:
2005 Revisions to the “McDonald Criteria”.
Polman, et al. Ann Neurol 2005;58:840-6.
Multiple Sclerosis
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Multiple SclerosisDiagnosis
Schumacher 1965Poser 1983
McDonald 2001Revised 2005*
d NP
Recommended Diagnostic Criteria for MS:Guidelines from International Panel.McDonald et al. Ann Neurol 2001;50:121-7*Diagnostic Criteria for Multiple Sclerosis:
2005 Revisions to the “McDonald Criteria”.
Polman, et al. Ann Neurol 2005;58:840-6.
Multiple Sclerosis
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Multiple SclerosisDiagnostic Consideration
• Objective evidence of
dissemination in time and space
d NP
• Clinical evidence:
presence of clinical signs
history of symptoms:
Ann Neurol 2001;50:121-7
insufficient
Multiple Sclerosis
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Multiple SclerosisInvestigations
• Magnetic resonance imaging
• Evoked potentials:
visual auditorysomatosensory motor
• CSF analysis
cell count IgG index
oligoclonal band
d NP
Multiple Sclerosis
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Multiple SclerosisMRI Criteria
MRI criteria:• Dissemination in space
brain MRIspinal cord MRI
• Dissemination in time
Barkhof F. Brain 1997;120:2059-69Tintore M. Am J Neuroradiol 2000;21:702-6 NP
Multiple Sclerosis
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Multiple SclerosisMRI Criteria
MRI criteria:• Dissemination in space
brain MRI spinal cord MRI
• Dissemination in time
Barkhof F. Brain 1997;120:2059-69Tintore M. Am J Neuroradiol 2000;21:702-6 NP
Multiple Sclerosis
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Multiple SclerosisDissemination in Space
Brain MRI criteria:• 9 T2 hyperintense lesions or
1 Gd-enhancing lesion• > 1 infratentorial lesion
• > 1 juxtacortical lesion
(subcortical U-fiber)• > 3 periventricular lesions
Barkhof F. Brain 1997;120:2059-69Tintore M. Am J Neuroradiol 2000;21:702-6
Lesion > 3 mm in cross section
3 i n 4
Spinal cord
d NP
MRI Criteria for
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T2W lesions > 9
MRI Criteria for Dissemination in Space
or
Gd+ lesion
3 in 4 1)
2) 3) 4)
>1 Infra-tentorial
>1 Juxta-cortical
> 3 peri-ventricular
> 1
Barkhof F. Brain 1997;120:2059-69Tintore M. Am J Neuroradiol 2000;21:702-6 NP
MRI Criteria for
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MRI Criteria forDissemination in Space
or
Gd+ lesion
3 in 4
T2W lesion
1)
2) 3) 4)
>1 Infra-tentorial
>1 Juxta-cortical
> 3 peri-ventricular
> 1 > 9
Barkhof F. Brain 1997;120:2059-69Tintore M. Am J Neuroradiol 2000;21:702-6 NP
Nine or more hyperintense
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Nine or more hyperintense
lesions in T2 (or FLAIR)
FLAIR T2Wd NP Ann Neurol 2001;50:121-7
One Gd enhancing lesion
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One Gd enhancing lesionin T1
T1W T1W c Gdd NP Ann Neurol 2001;50:121-7
At least one
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At least one infratentorial lesion
d NP Ann Neurol 2001;50:121-7
At least one
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At least one juxtacortical lesion
FLAIR d NP Ann Neurol 2001;50:121-7
At least three
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At least three periventricular lesions
FLAIR d NP Ann Neurol 2001;50:121-7
Multiple Sclerosis
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Multiple SclerosisMRI Criteria
MRI criteria:• Dissemination in space
brain MRIspinal cord MRI
• Dissemination in time
Barkhof F. Brain 1997;120:2059-69Tintore M. Am J Neuroradiol 2000;21:702-6 NP
Multiple Sclerosis
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Multiple SclerosisDissemination in Space
Spinal MRI criteria:• Little or no swelling of cord• T2 hyperintense lesions
- size > 3 mm- length < 2 vertebral segments- partial involvement of cord
(cross section)
d NP Ann Neurol 2001;50:121-7
MRI Criteria for
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MRI Criteria for Dissemination in Space
or
3 in 4
2)
>1 Infra-tentorial
3)
>1 Juxta-cortical
4)
> 3 peri-ventricular
Gd+ lesion
1)
> 1 T2W lesions > 9 =
Note
Barkhof F. Brain 1997;120:2059-69Tintore M. Am J Neuroradiol 2000;21:702-6 NP
Little or no cord swelling
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Little or no cord swelling
d NP
T1W w GdT2W
Ann Neurol 2001;50:121-7
T2W lesion > 3 mm
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T2W lesion > 3 mm
d NP Ann Neurol 2001;50:121-7
T2W
Cervical cord
T2W T2W
Cervical cord
Length <2 vertebral
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Length <2 vertebralbody segments
d NP Ann Neurol 2001;50:121-7
T1W w GdT2W
Partial involvement of cord
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Partial involvement of cord
d NP Ann Neurol 2001;50:121-7
T2W T2W
Cervical cord
Multiple Sclerosis
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Multiple SclerosisDissemination in Space
Spinal MRI criteria (revised):• A spinal lesion is equivalent to
a brain infratentorial lesion• An enhancing spinal lesion equals
to an enhancing brain lesion• Individual spinal lesions count
together with individual brain
lesions
d NP Ann Neurol 2005;58:840-6
MRI Criteria for
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MRI Criteria for Dissemination in Space (spinal)
1)
3)
2)
count each spinaltogether with eachbrain lesion
Gd +lesion
1 = =
Infra-tentoriallesion
1
Ann Neurol 2005;58:840-6
+ =
d NP
Brainstem and spinal lesion
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d NP
T2W
One spinal lesion can besubstituted for one
infratentorium brain
lesion.
A n n
N e u r o l
2 0 0 5 ; 5 8 : 8 4 0 - 6
Brainstem and spinal lesion
Spinal Gd-enhanced lesion
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d NP
T1W w Gd T2WT2W
Cervical cordOne spinal Gd lesion can
be substituted for oneGd brain lesion.
Ann Neurol 2005;58:840-6
Spinal Gd enhanced lesion
Multiple Sclerosis
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Multiple SclerosisMRI Criteria
MRI criteria:• Dissemination in space
brain MRIspinal cord MRI
• Dissemination in time
Barkhof F. Brain 1997;120:2059-69Tintore M. Am J Neuroradiol 2000;21:702-6 NP
Multiple Sclerosis
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Multiple SclerosisDissemination in Time
a. 1st scan >3 mo of clinical onset:
d NP
• Gd positive lesions; not at the site
implicated in the original clinicalevent
Follow-up scan ~ 3 mo
• New T2 lesion• New Gd positive lesion
2001
Ann Neurol 2001;50:121-7
Multiple Sclerosis
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Multiple SclerosisDissemination in Time
b. 1st scan <3 mo of clinical onset:
d NP
2001
Ann Neurol 2001;50:121-7
• No Gd positive lesion
Follow-up scan > 3 mo of onset• New Gd positive lesion If not
Follow-up scan > 3 mo of 1st scan
• New T2 lesion• New Gd positive lesion
MRI Criteria for
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Dissemination in Time Clinical
event
Category 1 yes
yes
yesGd +veNew T2
3 months3 months
Ann Neurol 2001;50:121-7
2001
d NP
Multiple Sclerosis
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p oDissemination in Time
a. 1st scan >3 mo of clinical onset:
d NP
• Gd positive lesions; not at the siteimplicated in the original clinicalevent
b. 1st scan >1 mo of clinical onset;
Follow-up any time after 1st scan• New T2 lesion
Polman et al. Ann Neurol 2005;58:840-6
Revised2005
MRI Criteria for
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Dissemination in Time Clinical
event
Category 2
yes yes
yesGd +veNew T2
3 months
3 months
Ann Neurol 2001;50:121-7
2001
MRI Criteria for
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Dissemination in Time clinicalevent 3 months 3 months
3 months
Category 1
Category 2
yes yes
yes
yes yes yes
Gd +veNew T2
Ann Neurol 2001;50:121-7
2001
d NP
MRI Criteria for
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Dissemination in Time clinicalevent 3 months
1 monthCategory 1
Category 2
yes
yes
Gd +ve
New T2
Any timePolman et al. Ann Neurol 2005;58:840-6
Revised2005
d NP
Multiple Sclerosis
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pInvestigation
• Magnetic resonance imaging
• Evoked potentials:
visual auditorysomatosensory motor
• CSF analysis
cell count IgG index
oligoclonal band
d NP
Multiple Sclerosis
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pInvestigation
d NP Visual Evoked Potentials
Multiple Sclerosis
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pInvestigations
• Magnetic resonance imaging
• Evoked potentials:
visual auditorysomatosensory motor
• CSF analysis
cell count IgG index
oligoclonal band
d NP
Multiple Sclerosis
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pInvestigation
d NP CSF oligoclonal bands
Serum
CSF
Serum: +CSF : ++
Serum: -
CSF : ++
Multiple SclerosisDi i C i i Revised
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dNP
Diagnostic Criteria
Primary Progressive Multiple SclerosisClinical Data Additional Data
Brain MRI positive1 year of diseaseprogression
(prospective- retrospective)
9 T2 lesions
Spinal MRI positive
> 4 T2 lesions + VEP
2 focal T2 lesionsCSF positive
Ann Neurol 2005;58:840-6
OCB or IgG indexPlus 2/3 of
Revised2005
Criteria: Primary Progressive MS
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dNP
y g
Progressive course 1 y
T2W
9 2 >4 Ann Neurol 2005;58:840-6
Revised2005
Brain Spinal CSF
- Oligoclonal
bands
- IgG index
Plus 2/3 of
or + VEP
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dNP
Differential Diagnosis
Multiple Sclerosis
Multiple Sclerosis
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pDifferential Diagnosis
ADEM APL syndrome
SLE CNS vasculitis
Behcet’s disease 1o Sjogren syndrome
CADASIL Sarcoidosis
CNS infection: HIV, PML, SSPE, Lyme’s disease,
meningovascular syphilis, Whipple’s disease
Mitochondrial 1o CNS lymphomaencephalopathy
d NP
ADEM: acute demyelinating encephalomyelitis, APL: antiphospholipid, SLE: systemic lupuserythematosus, CNS: central nervous system, CADASIL: cerebral autosomal dominant arteriopathy
with subcortical infarcts and leucoencephalopathy, HIV: human immune deficiency virus, PML:
progressive multifocal leucoencephalopathy, SSPE: subacute sclerosing panencephalitis
Multiple Sclerosis
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pDifferential Diagnosis
Tabes dorsalis
Familial ataxia
Subacute combined degeneration
(B12 deficiency)
Spinal cord tumor
Cervical spondylosis
d NP
Neuromyelitis Optica
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Diagnosis
Absolute criteria: Optic neuritis + acute myelitisNo clinical disease outside optic-spinalSupportive criteria:
Major: negative brain MRI at onsetabnormal spinal cord MRI > 3 vertebraCSF > 50 WBC/mm3 or > 5 PMN/mm3
Minor:
bilateral optic neuritissevere ON, VA < 20/200 in 1 or 2 eyesevere fixed weakness (MRC < 2 in 1 or morelimbs
d NP Wingerchuck et al. Neurology 1999;53:1107-14.
Neuromyelitis Optica
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Diagnosis
Absolute criteria: Optic neuritis + acute myelitisNo clinical disease outside optic-spinalSupportive criteria:
Major: negative brain MRI at onsetabnormal spinal cord MRI > 3 vertebraCSF > 50 WBC/mm3 or > 5 PMN/mm3
Minor:
bilateral optic neuritissevere ON, VA < 20/200 in 1 or 2 eyesevere fixed weakness (MRC < 2 in 1 or morelimbs
d NP
Absolute criteria: Optic neuritis + acute myelitisNo clinical disease outside
optic-spinal
Supportive criteria: Major: negative brain MRI at onsetabnormal spinal MRI > 3 vertebra
CSF >50 WBC or >5 PMN per mm3
Supportive criteria: Minor: bilateral optic neuritis
severe ON, VA< 20/200 in 1 or 2 eyesevere fixed weakness (MRC < 2
in 1 or more limbs
Wingerchuck et al. Neurology 1999;53:1107-14.
Neuromyelitis Optica
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Diagnosis
Definite NMO:
Optic neuritis
acute myelitis
Supportive criteria: 2 in 3Brain MRI not compatible with Barkhof’s criteria
Spinal MRI > 3 vertebral body segments
NMO IgG antibody positive
d NP Wingerchuck et al. Neurology 2006;66:1485-9.
Definite NMO: • Optic neuritis• acute myelitis
Supportive criteria: 2 in 3• Brain MRI not compatible with
Barkhof’s criteria
• Spinal MRI > 3 vertebral bodysegments
• NMO IgG antibody positive
Multiple Sclerosis
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Multiple Sclerosis
Scope:
Clinical manifestations
PathologyPathogenesis
Diagnosis
Treatment
d NP
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dNP
Treatment
Multiple Sclerosis
Multiple Sclerosis
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Treatment
Acute relapses
Disease modifying therapies (DMT)
Symptom control
d NP
Multiple Sclerosis
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Treatment
Acute relapses
Disease modifying therapies (DMT)
Symptom control
d NP
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Multiple Sclerosis
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Acute Relapses Rx
2. Plasma exchange
Rational: To remove circulating
autoantibodies, complimentsIndication: Severe steroid-resistant
relapses, neuromyelitis optica (NMO),
acute disseminated encephalomyelitis(ADEM) within 1 month of onset of
symptom
d NP Kieseier BC, et al. Curr Opion Neurol 2007;20:286-93
Multiple Sclerosis
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Acute Relapses Rx
2. Plasma exchange
Rx: 1 plasma volume
7 exchanges alternate day
d NP Kieseier BC, et al. Curr Opion Neurol 2007;20:286-93
Multiple Sclerosis
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Treatment
Acute relapses
Disease modifying therapies (DMT)
Symptom control
d NP
Multiple Sclerosis
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Disease Modifying Therapy
Disease modifying therapies DMT
1. Interferon beta
2. Glatiramer acetate
3. Mitoxantrone
4. Monoclonal antibodies
5. Oral therapies
De Angelis T, Lublin F. Curr Opion Neurol 2007;20:261-71
Costello FC, Stuve O, Weber M, et al. Curr Opion Neurol 2007;20:281-5
Kieseier BC, Weindl H, Hemmer B, et al. Curr Opion Neurol 2007;20:286-93dNP
Multiple Sclerosis
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Disease Modifying Therapy
1. Interferon beta IFN β
Mechanism: Anti-inflammatory effect by
- inhibit cytokine production- limit access of immune cell infiltration
to CNS
De Angelis T, Lublin F. Curr Opion Neurol 2007;20:261-71
Costello FC, Stuve O, Weber M, et al. Curr Opion Neurol 2007;20:281-5
Kieseier BC, Weindl H, Hemmer B, et al. Curr Opion Neurol 2007;20:286-93dNP
Multiple Sclerosis
f
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Disease Modifying Therapy
De Angelis T, Lublin F. Curr Opion Neurol 2007;20:261-71
Costello FC, Stuve O, Weber M, et al. Curr Opion Neurol 2007;20:281-5
Kieseier BC, Weindl H, Hemmer B, et al. Curr Opion Neurol 2007;20:286-93dNP
IM: intramuscular, Sc: subcutaneous, wk: week, AD: alternate day
Type Drug Company µg Route Dose
IFN β 1a AvonexR Biogen Idec 30 IM 1/wk Rebif R Merck Serono 22, 44 Sc 3/wk
IFN β 1b BetaseronR Bayer Schering
Pharma
250 Sc AD
1. IFN β 1
Multiple Sclerosis
i dif i h
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Disease Modifying Therapy
2. Glatiramer acetate (Copolymer-1)
Mechanism: Anti-inflammatory effect by
- induce changes in phenotypicexpression of T helper cell
- modify central effects of inflammation
De Angelis T, Lublin F. Curr Opion Neurol 2007;20:261-71
Costello FC, Stuve O, Weber M, et al. Curr Opion Neurol 2007;20:281-5
Kieseier BC, Weindl H, Hemmer B, et al. Curr Opion Neurol 2007;20:286-93dNP
Multiple Sclerosis
Di M dif i Th
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Disease Modifying Therapy
3. Mitoxantrone
Mechanism:
- reduce Th1 cytokines- eliminate lymphocytes
Indication: SP MS, PR MS,
refractory RR MS
De Angelis T, Lublin F. Curr Opion Neurol 2007;20:261-71
Costello FC, Stuve O, Weber M, et al. Curr Opion Neurol 2007;20:281-5
Kieseier BC, Weindl H, Hemmer B, et al. Curr Opion Neurol 2007;20:286-93dNP
Multiple Sclerosis
Di M dif i Th
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Disease Modifying Therapy
4. Monoclonal antibodies
Mechanism: Targeted therapies of
molecules involved in pathogenesis
De Angelis T, Lublin F. Curr Opion Neurol 2007;20:261-71
Costello FC, Stuve O, Weber M, et al. Curr Opion Neurol 2007;20:281-5
Kieseier BC, Weindl H, Hemmer B, et al. Curr Opion Neurol 2007;20:286-93dNP
Multiple Sclerosis
DMT M l l A tib d
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DMT: Monoclonal Antibody
dNP
Type Drug Company Target
Natalizumab TysabriR Biogen Idec α-4 integrins
Alemtuzumab CampathR Bayer Schering
Pharma
CD52 NK, B cell
Rituximab MabTheraR Roche CD20 B cell
Daclizumab ZenapaxR Biogen Idec CD25, IL 2
De Angelis T, Lublin F. Curr Opion Neurol 2007;20:261-71
Costello FC, Stuve O, Weber M, et al. Curr Opion Neurol 2007;20:281-5
Kieseier BC, Weindl H, Hemmer B, et al. Curr Opion Neurol 2007;20:286-93
Multiple Sclerosis
Di M dif i Th
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Disease Modifying Therapy
Disease modifying therapies DMT
1. Interferon beta
2. Glatiramer acetate
3. Mitoxantrone
4. Monoclonal antibodies
5. Oral therapies
De Angelis T, Lublin F. Curr Opion Neurol 2007;20:261-71
Costello FC, Stuve O, Weber M, et al. Curr Opion Neurol 2007;20:281-5
Kieseier BC, Weindl H, Hemmer B, et al. Curr Opion Neurol 2007;20:286-93dNP
Multiple Sclerosis
O l Th
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Oral Therapy
5.1 Cladribine (Merck Serono)
5.2 Fingolimod (Novartis)
5.3 Fumaric acid ester (Biogen Idec)
5.4 Laquinimod (Teva Neurosci.)
5.5 Teriflunamide (Sanofi Aventis)
5.6 Glatiramer acetate (Teva Neurosci.)5.7 statin
De Angelis T, Lublin F. Curr Opion Neurol 2007;20:261-71
Costello FC, Stuve O, Weber M, et al. Curr Opion Neurol 2007;20:281-5
Kieseier BC, Weindl H, Hemmer B, et al. Curr Opion Neurol 2007;20:286-93dNP
Multiple SclerosisT t t
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Treatment
Acute relapses
Disease modifying therapies (DMT)
Symptom control
d NP
Multiple SclerosisS t C t l
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Symptom Control
Weakness
Spasticity
PainFatigue
Psychological disorders
d NP
Multiple SclerosisS t C t l
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Symptom Control
Weakness
Rehabilitation:
increase strengthincrease endurance
d NP
Multiple SclerosisS t C t l
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Symptom Control
Spasticity
Exercise
MassageCentral muscle relaxant:
baclofen, tizanidine
Botulinum toxin injection
d NP
Multiple SclerosisS t C t l
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Symptom Control
Pain
neuropathic pain
- antidepressant: TCAs, SSRIs- anticonvulsant: carbamazepine,
gabapentin, oxcarbazepine,
pregabalin
NP
Multiple SclerosisS mptom Cont ol
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Symptom Control
Pain
tonic spasm: spontaneous, action
- behavior adjustment: slow, steadymovement
- antidepressant: TCAs, SSRIs
- central muscle relaxant:
baclofen, tizanidine
NP
Multiple SclerosisSymptom Control
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Symptom Control
Fatigue: feeling lack of ‘energy’
- not weakness or depressive mood
- improve with exercise- balance between rest and exercise
- keep cool while exercise
d NP
Multiple SclerosisSymptom Control
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Symptom Control
Psychological disorders:
Depressive mood
- psychological support- antidepressant: TCAs, SSRI
Anxiety
- psychological support
- anxiolytic
NP
Multiple SclerosisTreatment
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Treatment
Acute relapses
Disease modifying therapies (DMT)
Symptom control
d NP
Multiple Sclerosis
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p
Scope:
Clinical manifestations
PathologyPathogenesis
Diagnosis
Treatment in MS
d NP
Case Presentation
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Diagnosis: optic neuritisRx: high dose steroids
A young woman had dimmed
vision of the left eye for 2 days. Eyedrop tried without improvement.
d NP
Eye:
Vision got worse. Pain on eye
movement was noted.
Case Presentation
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A young woman felt spinning for
a few days, getting worse withmotion. There was no hearing lossor visual blurring.
d NP
ENT:
Few days later she had double
vision, nystagmus and ataxia.MRI: brainstem lesion
Diagnosis: clinically isolated synd.Rx: high dose steroids
Case Presentation
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A young woman difficulty in
voiding for 3 days.Urinalysis: WBC 3-5, RBC 5-10, fewbacteria
d NP
Urology:
One day later she developed
numbness and weakness of bothlegs.
LP: h WBC
MRI: intrinsic cord lesion T level
Diagnosis: acute myelitis
Case Presentation
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A young woman had nausea and
vomiting for 5 days. He had veryfrequent hiccoughs for 1 day.
EGD: showed mild gastritis
d NP
Rx: iv methylprednisolone (MP)
GI:
Past history: visual loss (optic
neuritis) left eye
Case Presentation
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A middle age woman had gait
difficulty 2-3 weeks. She could notproperly lift her feet above theground. There was some numbness
at the lower legs.
d NP
Diagnosis: lumbar spondylosisCT myelogram: disc herniation
Orthopedics:
Rx: laminectomy
Few months later she had bilateralvisual loss.
Dx: RR MS
Case Presentation
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A middle age man experienced
itching at the anterior chest left sidefor 1 week. No rash was noted.
d NP
Diagnosis: dermatitisRx: topical steriods
Skin:
Few weeks later he had numbness
at the left chest down to the leftleg and weakness of both legs.
MRI: intrinsic cord lesionRx: IV MP
Case Presentation
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A middle age woman had
headache for 1-2 months. She couldnot do her routine work, was slow inresponse. Mild weakness was noted.
d NP
Inx: CT brain with contrast -massDiagnosis: brain tumor
Surgery:
Brain biopsy: chronic demyelination
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dNP
MS
Q&A
Acute Optic NeuritisInvestigations
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Investigations
1. Demonstrate the lesion
2. Look for other site involved
3. Look for other causes
d NP
Optic nerve MRI, VEPs Brain, whole cord MRI,
CSF oligoclonal bands Immune profile, (anti HIV)
Acute MyelitisInvestigations