John M. Bertoni, M.D., Ph.D.

Creighton University

Multiple Sclerosis Multiple Sclerosis

Diagnosis of MS

MS is a clinical diagnosis

Supported by

–Imaging

–Spinal fluid analysis

Multiple Sclerosis – A to Z1. MS Pathology

• Inflammation• Neurodegeneration

2. Immunomodulatory Therapies (IMTs)• Glatiramer Acetate (Copaxone®)• Beta Interferons (Avonex®, Betaseron®, Rebif®)• Natalizumab (Tysabri®) – NOT CURRENTLY AVAILABLE

3. Magnetic Resonance Imaging (MRI)• Conventional MRI (T1, T2)• Non-conventional MRI (MRS, MTI, Brain Atrophy)

4. Clinical Data• Pivotal Trials• Open-Label Comparative Trial

5. Safety & Tolerability of the IMTs

Adapted with permission from Elsevier (The Lancet. 2002;359:1221-1231).

Repairing-Remitting Secondary Progression

Clinical Disability

Clinical Threshold

Brain Volume

Inflammation

Axonal Loss

Frequent inflammation,demyelination, axonaltransection, plasticity,and remyelination

Continuing inflammation,persistent demyelination

Infrequent inflammation,chronic axonal degeneration, gliosis

Inflammation and Axonal Loss in MS

Progression of DisabilityMS Courses as Redefined by MRI

EnhancementsEarlyRRMS

LateRRMS

SPMS

Time

Occ

urr

ence

, E

xten

t o

f S

ever

ity

MRI-Defined Plaque Burden

Clinical Impairment

Adapted with kind permission from Dr. J.S. Wolinsky.

MS Is More Than a Demyelinating Disease

Adapted with permission from Waxman SG. N Engl J Med. 1998;338:323-325. Copyright © 2003 Massachusetts Medical Society. All rights reserved.

NormalMyelinated

Axon

AcutelyDemyelinated

Axon

ChronicallyDemyelinated

Axon

DegeneratedAxon

Conduction restored byIncrease in density of

sodium channels

Postsynapticneuron

Sodiumchannels

Action potential

End oftransected

axon

Myelinsheath

Postsynapticneuron

Action potential

DemyelinationAxon

A

B

C

D

Axonal Transection in MS Lesions

Reprinted with permission from Trapp BD et al. N Engl J Med. 1998;338:278-285.Copyright © 2003 Massachusetts Medical Society. All rights reserved.

64m 45m

MS Pathogenesis

CNS

Autoreactive T Cells

T

Periphery

Demyelination and Axon Loss

BBB

Transmigration

T

Danger Signal or Trigger

Activation, Differentiation,Clonal Expansion T

T

T

T

Local ReactivationT

T

APC

APC

Adhesion/Attraction

T

Release of Cytokines;Recruitment of M

Antibodies

B

MNO

IFN-

TNF-

TNF-

Adapted with kind permission from Prof. R. Hohlfeld.

Adapted with kind permission from Dr. W. Brück.

MS: A Disease of Severe Myelin, Axonal, and Neuronal Losses

Normal White Matter Plaque

Myelin

Axons

Astrocytes

NeuronsLymphocytes

Macrophages

TISSUE DAMAGE TISSUE PROTECTION

Pro-inflammatory and Neurotoxic Factors Th1 cytokines TNF- IL-2 Nitric oxide Reactive oxygen species Glutamate Antibodies and complement Cell-mediated neurotoxicity

Anti-inflammatory and Neuroprotective Factors Th2 cytokines TGF- IL-10 Neurotrophic factors

– BDNF– NGF– NT-3– CNTF– GDNF

The Dual Nature of Inflammation in MS

Detrimental Inflammation in MS

Evidence from animal models implicates activated T cells in initiating MS pathology

Subsequent injury to CNS is mediated by T cells, B cells, and macrophages/microglia

Inflammatory components destroy myelin and oligodendrocytes

Inflammation is associated with axonal damage

Neuhaus O et al. Trends Pharmcol Sci. 2003;24:131-138.

Inflammatory Cells May Downregulate Detrimental Inflammation

Inflammatory cells produce growth factors

Inflammatory cells remove myelin-associated inhibitory molecules

Inflammatory cells may adapt a protective suppressor phenotype

Martino G et al. Lancet Neurology. 2002;1:499-509.

Multiple Sclerosis – A to Z1. MS Pathology

• Inflammation• Neurodegeneration

2. Immunomodulatory Therapies (IMTs)• Glatiramer Acetate (Copaxone®)• Beta Interferons (Avonex®, Betaseron®, Rebif®)• Natalizumab (Tysabri®) – NOT CURRENTLY AVAILABLE

3. Magnetic Resonance Imaging (MRI)• Conventional MRI (T1, T2)• Non-conventional MRI (MRS, MTI, Brain Atrophy)

4. Clinical Data• Pivotal Trials• Open-Label Comparative Trial

5. Safety & Tolerability of the IMTs

Type Polypeptide mixture

Recombinant protein

Recombinant protein

Recombinant protein

Recombinant monoclonal

antibody

FDA Indication

Reduction of the

frequency of relapse

Reduce the frequency

of clinical exacerbation

Decrease the frequency

of clinical exacerbation

Slow accumulation

of disability

Decrease the frequency

of clinical exacerbation

Slow accumulation

of disability

Reduce the frequency

of clinical exacerbation

Dosage and Administration

SC

Daily

20 mg

SC

Q O D

250 µg (8 MIU)

SC

3 X Wk

22 µg

44 µg

IM

Weekly

30 µg

IV infusion

Q 4 Weeks

300 mg

IFN -1a(Avonex®)

IFN -1a(Rebif®)

IFN -1b(Betaseron®)

Glatiramer Acetate

(Copaxone®)

Natalizumab(Tysabri®)

Immunomodulatory Therapies

Mode of Action of Glatiramer Acetate:Bystander Suppression and Neuroprotection

Adapted with permission from Neuhaus O et al. Neurology. 2001;56:702-708. Ziemssen T et al. Brain. 2002;125:2381-2391.

Th1 Th2 Th2

Macrophage MicrogliaAntigen-PresentingCell

GlatiramerAcetate-SpecificT Cell

GA

Th

erap

y

Blo

od

-Bra

in B

arri

er

Anti-inflammatoryCytokines

Neuroprotection

Glatiramer Acetate Bystander

Suppression

Periphery CNS

TCR TCR

MHCCNS Ag

MHC

BDNFNeurotrophins

TCR

Progression to Disability—EDSS Steps

8.0 - 8.5 = Confined to bed or chair

7.0 - 7.5 = Confined to wheelchair

6.0 - 6.5 = Walking assistance is needed

5.0 - 5.5 = Increasing limitation in ability to walk

4.0 - 4.5 = Disability is moderate

3.0 - 3.5 = Disability is mild to moderate

2.0 - 2.5 = Disability is minimal

1.0 - 1.5 = No disability

0 = Normal neurologic exam

10.0 = Death due to MS

9.0 - 9.5 = Completely dependent

Walking ability

Confined to a

wheelchair or bed

Walks with aid(< 5 yards)

Walks with assistance

(22 - 110 yards or more)

Walks unaided (110 - 220

yards or more)

Walks unaided (330 - 550

yards or more)

Fully ambulatory

Long-term Disability: Time from Onset of MS to EDSS 4

Confavreux C et al. Brain 2003;126:770–82

1 = 0–19 years old1 = 0–19 years old

2 = 20–29 years old2 = 20–29 years old

3 = 30–39 years old3 = 30–39 years old

4 = 40–49 years old4 = 40–49 years old

5 = 5 = 40 years old40 years old

Imaging in Multiple Sclerosis

Examples of Atrophy in MS

36 y/o womanRR MS (2 y)

43 y/o womanSP MS (19 y)

31 y/o maleHealthy control

Rudick et al. Neurology. 1999;53:1698-1704.Rudick et al. Neurology. 1999;53:1698-1704.

Diagnosis and Monitoring MS

Subjective:

– detects minor sensory, visual, vestibuloauditory lesions

Clinical exam:

– Motor and sensory tracts, brainstem tegmentum

– Sensitive to multifocal, microscopic disease

Electrophysiology:

– Characterizes, localizes, detects silent disease in sensory tracts, sensitive to microscopic disease

CSF Exam:

– Detects chronic immune system activity in meninges

Neuropsychometric testing:

– Cognition and mood

MRI detects ‘silent activity’

There are approximately 7-10+ brain lesions for every clinical event

The symptomatic lesion is seen only 20% of time

Spinal cord MRI is insensitive for lesions

– Unless special techniques used and carefully inspected by reader

Typical callosal lesions

Brainstem lesion – Facial MyokymiaBrainstem lesion – Facial Myokymia

Proton density T2 FLAIR (adjusted) T1 post GAD

21 year old, mother with MS, presents with facial myokymia

Positive oligoclonal bands and elevated IgG index

Negative otherwise MRI

Lesion is subtle and requires anatomical knowledge to appreciate

Typical subpial position, equivocal enhancement

Optic nerve lesion – asymptomatic prior optic Optic nerve lesion – asymptomatic prior optic neuritisneuritis

Proton density T2 FLAIR

Optic neuritis 8 years before, complete recovery

Proton density usually sees better than T2

MRI spinal cord – Acute lesions, low contrast

T2 PD STIR T1 post GAD

These are very edematous (mass, STIR)

PD is more extensive than T2 (also old gliosis)

Minimal contrast extravasation

Heterogeneous Pathology of T2 hyperintense lesions Evolution of MS Lesions

Adopted from Paty and Ebers

BBB DisruptionBBB Disruption

InflammationInflammation

Increased InflammationIncreased Inflammation

DemyelinationDemyelination

Reactivated LesionsReactivated Lesions

GliosisGliosis

AxonalAxonal Loss Loss

Axo

nal

Lo

ssA

xon

al L

oss

Dawson’s fingers,Black holes

Seeing the brain as never before

INSULAR FIBRES

TEMPORAL FIBRES

BROCA‘S AREAWERNICKE’S

AREA

LONG FIBRES

SHORT FIBRES

SHORT FIBRES

LONG FIBRES

Superior Longitudinal Fasciculus

Diffusion TractographyImages Courtesy of:

Dr. Derek Jones, Institute of Psychiatry, London UK

THE END