Multiple Sclerosis

Dr. Ronan Walsh

Learning objectives:

Pathophysiology of multiple sclerosis

Know the clinical features of MS

Basic principles of management of MS

Outline of Talk

Pathophysiology of demyelination
Epidemiology
Clinical features of MS
Diagnosis
Therapy
Remissions / progressive disease
Complications
Multidisciplary
Pathology and
Pathogenesis of
Multiple Sclerosis
MS: A DISORDER OF THE
IMMUNE SYSTEM
Pathogenesis
Activation of autoreactive CD4+ T cells in peripheral
immune system
Migration of autoreactive Th1 cells into CNS
In situ reactivation by myelin
autoantigens/astrocytes (reactivity against MBP or
PLP)
Activation of macrophages, B cells (oligoclonal
bands!)
Secretion of proinflammatory cytokines (e.g. TNF),
antibodies
Inflammation -> demyelination -> axonal damage -
> neurodegeneration
H&E low power
H&E high power
Luxol Fast Blue / H&E
 MS Pathology in Spinal Cord

Courtesy of Peter Ostrow, MD, PhD, State University of New York, Buffalo, NY.
Multiple Sclerosis

Demyelinating and
degenerative disease of the
central nervous system
predominantly involving white
matter

Hallmark: dissemination of
lesions in time and space
 Epidemiology

Affects 120-180/100,000 persons in Ireland

1.7:1.0 female: male ratio

Earlier in females than males

Sibling risk 3-5%

Monozygotic twins exhibit 25% concordance
rate

McGuigan et al. JNNP

McGuigan et al. JNNP
Stages of Multiple Sclerosis
Benign
Relapsing
Remitting
Secondary
progressive
Primary
progressive
Progressive
Relapsing
Acute Tumoral
 85% - Relapsing remitting MS (RRMS)
45% of these progress to SPMS within 10
years;
85% within 25 years
15% benign MS - no further attacks for 15
years
15% - Primary progressive MS (PPMS)
 Symptoms and Signs of
Multiple Sclerosis

Commonly involves:
optic nerves
spinal cord
brainstem

Visual disturbance
Sensory abnormalities
Bladder dysfunction
Spasticity and paresis
Incoordination
 Multiple Sclerosis

Eye Brain
Blurred vision Emotional lability /
Unilateral eye pain pseudobulbar affect
Diplopia Cognitive impairment

Cerebellar Brainstem
Vertigo INO
Nystagmus Trigeminal neuralgia
Ataxia
Spinal cord
Also LHermittes phenomenon
Numbness Bladder: urgency
Pins/needles Incontinence
Spastic paraparesis
Optic oedema (neuritis) in
right eye
PRESENTING COMPLAINTS
EYES
Optic neuritis - loss of central vision, relative
afferent pupillary defect, pale optic disc, colour
desaturation
90% regain vision within 6 months

BRAINSTEM
Double vision - Ophthalmoplegia
Internuclear ophthalmoplegia - lesion in MLF
Vertigo
Trigeminal neuralgia (tic douloreux)
PRESENTING COMPLAINTS

Sensory symptoms -
Sensory level on abdomen, sensory loss in limb
Lhermittes sign - indicates lesion in posterior column

Motor symptoms -
Due to corticospinal tract dysfunction
Weakness, hemiplegia, paraplegia, quadriplegia
Extensor/flexor spasms of legs
Increased tone - stiffness
Increased deep tendon reflexes with clonus
Extensor Plantar Response (Positive Babinski sign)
PRESENTING COMPLAINTS
Cerebellar symptoms
Slurred speech dysarthria
Hand incoordination dysmetria, dysdiadokinesia
Low tone - hypotonia
Gait imbalance - truncal ataxia
oscillopsia

General
Fatigue
Uhtoffs phenomenon - increases in body temperature worsen
symptoms
Episodic phenomena e.g. tonic spasms
PRESENTING COMPLAINTS
Cognitive disturbance -
poor memory and attention deficits 60%
depression 13-34%
epilepsy 3%

Impairment of bladder, bowel, sexual function

Bladder - uninhibited detrusor contraction
Urgency, urinary incontinence, incomplete emptying, atonic
bladder
Bowel - constipation most common
Sexual dysfunction
50% patients become sexually inactive due to multiple
problems, sensory and motor lesions, psychological factors,
mechanical problems.
Relapsing Remitting MS

Acute Relapse
 Diagnosis of Multiple Sclerosis

Clinical Examination
MRI scan
Lumbar puncture
Evoked potential

Exclusion of other conditions generated

by differential diagnosis
 Diagnostic criteria for MS
Clinical evidence for
lesions of white matter
dysfunction
disseminated in space
and time in the
expected age group

Objective
abnormalities on
neurologic exam
 Differential Diagnosis of MS

Inflammatory diseases Granulomatous diseases

Granulomatous angiitis Sarcoidosis
SLE Wegeners
Sjogrens disease granulomatosis
Behcets disease Lymphomatoid
Polyarteritis nodosa granulomatosis
ADEM Diseases of myelin
Neuromyelitis optica Metachromatic
leukodystrophy
Infectious diseases Adrenomyelodystrophy
Lyme neuroborreliosis
Miscellaneous
HTLV-1
Spinocerebellar disorders
HIV
Arnold-Chiari
PML malformation
Neurosyphilis Vitamin B12 deficiency
Olek and Dawson, MS and other Inflammatory Demyelinating
Diseases of the CNS - in Neurology in Clinical Practice
MRI in Multiple Sclerosis
Noseworty et al. NEJM, September 2000
 Common MRI Lesions in MS

The exact relationship between MRI findings and the clinical status of patients is unknown
Courtesy of Douglas Jeffery, MD, PhD
MRI basics

T1-weighted scan
Shows hypointense lesions (black holes)
T2-weighted scan
Indicates total burden of disease
May show new lesions
FLAIR image
Suppresses CSF
Gadolinium enhancement
Highlights new or active lesions
 MS Lesions on MRI
A B

T2 T2-FLAIR

C D
T1 T1/Gd
precontrast postcontrast
black holes disease activity
More MRI lesions

Gd-enhancing T2-hyperintense Brainstem

Juxtacortical Periventricular Spinal Cord

 Neuroimaging

T2

T1 Gd
MRI in Optic Neuritis
 Brain Atrophy in MS

None Mild Moderate Severe

Non-contrast T1-weighted images.

Courtesy of Rohit Bakshi, MD, State University of New York, Buffalo, NY.
 T1 Black Holes
Chronic T1 hypointensity correlates with
axonal loss

1: strongly hypointense

2: mildly hypointense

3: slightly hypointense
Brueck et al., Ann Neurol 1997; van Waesberghe et al., Ann
Neurol 1999
MS Disease Course

Brain volume

T2

Disability

GD enhancement

Time in years
Oligoclonal Bands
Reflect an
inflammatory
process

Not diagnostic

Differential dx
must be
considered
EVOKED POTENTIALS
Neuromyelitis optica
Demyelinating lesions in spinal cord and optic nerves
predominantly (Devics)

Some cerebral lesions seen but generally

asymptomatic & not seen initially

Spinal lesions extend over 3 or more vertebral

segments

More common in Asians

Anti-aquaporin 4 antibody test

Treated differently to MS
Axonal damage reflects
disability in MS

Axonal loss over time

Particularly in progressive phase of
disease
Neurodegeneration in MS
Relationship to neurological disability

Trapp 1999 Neuroscientist

MS Disease Course

Brain volume

T2

Disability

GD enhancement

Time in years
Treatment of MS
 Goals of MS Therapy
Slow the accumulation of permanent
physical disabilities
Reduce inflammation
Clinical: relapse rate
MRI: lesion load (enhancing and nonenhancing)
Reduce progression of brain atrophy
Slow down the accumulation of cognitive
dysfunction
Maximize quality of life
Relapse

Episode of neurological dysfunction

lasting >24 hours in the absence of
fever
Often lasts weeks to months
May gradually improve (remission)
May be residual disability following
relapse
Treatment of Acute
Exacerbations
Distinguish between mild, moderate and
severe exacerbations
High dose Steroids I/V for severe
exacerbations
Short term sequelae: Behavioural, Infection

No evidence that steroids affect long-term

outcome of MS.
POTENTIAL TREATMENTS
Inflammation
 Cytokine Imbalance in MS
Normal MS

Th2
Th1 Th2 Anti-
Th1 inflammatory
Inflammatory Anti- IL-4
IFN- inflammatory IL-10
IL-12 IL-4 Inflammatory TGF-
TNF IL-10 IFN-
TGF- IL-12
TNF
The dual nature of MS Inflammation
and neurodegeneration

Relapsing Non-relapsing

TIME
DISEASE MODIFYING
THERAPIES
 Disease Modification

Of Proven Effect
Beta-interferon (1 alpha: Rebif,Avonex
1 beta Betaferon)
Glatiramer-acetate ( Copaxone)
Natralizumab (Tysabri)

Second Line Therapy

Intravenous gamma-globulin
Mitoxantrone, Azathioprine
Who Should Be Treated?

Clinical Attack &

1: Evidence of
dissemination in time
History
MRI
2: Evidence of
dissemination in space
Lesion load
Clinical exam

Relapsing Remitting
Course
 Natural Course of MS
Disease Course
Relapses and Disability Total MRI-Lesion load MRI-Activity

Relapsing Remitting Secondary Progressive

First Clinical MS
exacerbation
Adapted from McFarland et al., 52nd Annual Meeting American Academy of Neurology, May 2000, San Diego, USA
Clinically isolated syndromes -
risk of developing MS

Followup: 5 year 10 year 14 year

ONTT ORiordan Brex

Normal MRI 16% 11% 19%

Abnormal MRI 51% 85% 88%

 Natural Course of MS
Disease Course
Relapses and Disability Total MRI-Lesion load MRI-Activity

Relapsing Remitting Secondary Progressive

First Clinical MS
exacerbation
Adapted from McFarland et al., 52nd Annual Meeting American Academy of Neurology, May 2000, San Diego, USA
 Potential Mechanisms of
Action of IFN- in MS
Antiproliferative effect
Blocking T-cell activation
Apoptosis of autoreactive T cells
IFN- antagonism
Cytokine shifts
Antiviral effect
Does not cross blood-brain barrier
Indirect effects on CNS
Interferons:
Summary
All are effective

Route of administration probably do not

significantly affect efficacy

Effects are dose related

Optimal treatment for a patient with

relapsing remitting MS not known: evidence
in favour of the highest tolerated dose
Interferons: Side Effects

Injection site reactions

Pain and erythema
Flu-like symptoms
Lymphopenia
LFT abnormality
Depression
Neutralising antibodies
Interferons: Side Effects

Major side effects are self-limiting, and

usually disappear within 3 months

Factors that influence treatments

include convenience of formulation
and dose-scheduling
 Glatiramer Acetate:
Possible Mechanisms of
Action
Blocking autoimmune T cells
Induction of anergy
Induction of anti-inflammatory Th2 cells
Bystander suppression
Neuroprotection
 Phase III Results:
Annual Relapse Rates
% Reduction in relapse rates

35 32% 34%
32%
P=0.0001 29%
30 P<0.005 29%
P=0.002
P<0.005 P=0.007
25
20
15 18%
P=0.04*
10 8%
5 P=0.01

0
Avonex Betaseron Betaseron Rebif Rebif Copaxone
(30 mcg qw) (1.6 MIU (8 MIU (22 mcg (44 mcg (20 mg qd)
qod) qod) tiw) tiw)

Note: These studies were not designed to make direct comparisons across studies.
*Intent to treat; For patients who had been in the study for 2 years.
Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; PRISMS Study Group.
Lancet. 1998;352:1498; Johnson et al. Neurology. 1995;45:1268.
 Interferon -1a IM:
Annual Relapse Rate
1.0
Mean Number of Relapses
32% Placebo
0.9 18%* Interferon -1a
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
All Patients Patients Treated
2 Years
*P < 0.04; P < 0.002.
Adapted from Jacobs LD et al. Ann Neurol. 1996;39:285-294.
 Glatiramer Acetate: Mean
Relapse Rate
Placebo
Glatiramer Acetate
32%
Mean Number of Relapses

2.0
1.8 29%*
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
24 Months 24 Months
+ Extension
*P < 0.007; P < 0.002.
Adapted from Johnson KP et al. Neurology. 1998;50:701-708.
 Phase III Results:
Sustained Disability*
40
% Reduction in sustained

P=NS
disability progression

37%
P=0.02
30 29% 30%
P=0.043
22% P<0.05
20
P<0.05
12%
10
P=NS
0%
0
Avonex Betaseron Betaseron Rebif Rebif Copaxone
(30 mcg qw) (1.6 MIU (8 MIU (22 mcg (44 mcg (20 mg qd)
qod) qod) tiw) tiw)

Note: These studies were not designed to make direct comparison across studies.
*1 EDSS point sustained for 6 mo in Avonex phase III trial, and for 3 mo in Betaseron,
Rebif, and Copaxone phase III trials.
3-year data; Betaseron disability progression data not available at the end of 2 years.

Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; PRISMS Study Group.
Lancet. 1998;352:1498; Johnson et al. Neurology. 1995;45:1268.
 Glatiramer Acetate: 8-Year Data
Yearly EDSS Change From Baseline

0.8 Glatiramer Acetate

Placebo/Active
Change in EDSS Score

0.7
P = 0.0279 (RMA)
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.1
Entry 1 2 3 4 5 6 7 8
*P < 0.05. * * *
Year
Johnson KP et al. Neurology. 2002;58(suppl 3):A458.
IMMUNOMODULATION
Natalizumab in MS

Phase II study showed promising results in

suppression of new MRI lesions, and in
number of relapses

Phase III trial confirmed findings of 66%

reduction in relapse rate

Drug withdrawn in Feb 2005 following report

of 2 cases of PML: 2 Further cases identified

Qualified approval for re-introduction

following preliminary FDA announcement
 Progressive Multifocal
Leukoencephalopathy

JC virus
Affects oligodendrocytes
Immunosuppressed at
risk
Fatal
Natalizumab Treatment

Monthly infusion of product

Will require infusion centres in
hospitals & close monitoring of
patients: May require yearly MRIs
Likely that first cohort to be offered
treatment will be interferon failures.
 Mitoxantrone

10 times as toxic as cyclophosphamide

Small phase III trials confirm efficacy
Limited by side effects
Cardiotoxicity
Amenorrhoea (loss of periods)
Teratogenicity
Risk of cancer
Criteria for Mitoxantrone Therapy
(Cochrane Collaboration, Oct 2005)

Poorly defined
Best evidence in favour of brittle
RRMS & relapsing progressive MS
No definitive protocols
No evidence in favour of PPMS
Long term sequelae unclear
WHY DONT STEM CELLS WORK
IN MS?
We dont know enough about how
demyelination / remyelination occurs
Axons are also damaged
Brain already contains stem cells: Why arent
they present in plaques?
Treatment of MS with stem cells would
require hundred/thousands of injections
throughout the nervous system
NEW DEVELOPMENTS IN
SYMPTOMATIC THERAPY
 Spasticity

Spasticity may limit mobility, induce and

abnormal posture, and lead to painful
muscle spasms

Treatment targeted to most

incapacitating symptoms
Spasticity: Treatment

Physiotherapy
Oral Drugs : Altering spinal cord
circuitry
Bacofen
Tizanidine : Less weakness in lower
extremities. Can be used with baclofen
Gabapentin
Clonazepam /diazepam: May be more
effective for cerebral-mediated spasticity
Spasticity: Treatment
Intrathecal Baclofen
(Pump)
(may be used in
combination with
oral tizanidine)
Botulinum toxin
(max dose 6 iu/kg)
Surgery
Chronic epidural
stimulation
Fatigue

Common in MS
Multifactorial
Difficult to treat:
Amantidine
4 Aminopyridine
Antidepressnants
Modafinil
Non-Pharmacological
Therapy in MS
Multidisciplinary Clinic
Specialist Team for
Conditions like MS
Hospital based Community based
Neurologist Voluntary organisation
Specialist MS nurse Public health nurse
Physiotherapist Occupational therapist
Occupational therapist Physiotherapist
Speech & language Palliative care team
Nutritionist
Psychologist
Social worker
Palliative care team
Multidisciplinary
Management
Neurologist
Social MS
Worker Nurse

SLT GP
Patient
/Carer
Psychologist OT

Dietitian PT
MS
Society