Transcript Slide 1

1
Purpose of this Slide Kit
• The MS Forum is a group of approximately 70
distinguished neurologists and clinicians
• The aim of the MS Forum is to increase awareness
and improve understanding in multiple sclerosis
(MS) through a variety of educational materials
• This slide kit is based on the Annual Modern
Management Workshop, held in San Francisco, on
28 March 2003, entitled Early Management of
Multiple Sclerosis
• The slide kit has been distributed to MS clinicians
around the world
2
Early Management
of Multiple Sclerosis
3
Contents
• Scientific Aspects of Early Multiple Sclerosis
• Predicting Multiple Sclerosis using Clinically
Isolated Syndromes
• Diagnosis of Early Multiple Sclerosis
• Giving the Diagnosis of Multiple Sclerosis
• The Action, Communication and Treatment (ACT)
in Multiple Sclerosis Programme
• Early Disease Management: Lessons from Type 1
Diabetes Mellitus
• Early Treatment of Multiple Sclerosis
• In Conclusion
4
Scientific Aspects of
Early Multiple Sclerosis
5
Introduction
Advances in the management of MS in the last
decade include
• Improved understanding of the disease pathology
and its course
• Increased patient awareness
• Better treatments
• Superior support services
• Better diagnosis
6
Early Management of MS:
the Questions
• How early and how accurately can MS be
diagnosed?
• Can we predict clinically definite (CD) MS from the
early signs and symptoms?
• How should a person with early MS be managed?
• How should a person with early MS be treated?
7
Early Signs: What is a Clinically
Isolated Syndrome?
• A clinically isolated syndrome (CIS) is an acute
or subacute neurological syndrome
• A CIS is usually the first clinical event in an
MS patient
BUT
• Differential diagnosis is necessary because:
– CIS covers a broad spectrum of syndromes
– It is important to rule out other pathologies
– MS is not the only recurrent demyelinating
disease
8
Early Signs: CIS Subtypes
•
•
•
•
•
•
•
•
•
•
•
Optic neuritis
Brainstem syndrome
Spinal cord syndrome
Transverse myelitis
Polyfocal lesions
Cerebral lesions
Lhermitte’s symptom
Sensory useless hand
Paroxysmal tonic spasms
Other sensory symptoms (e.g. numbness, itching)
Bladder dysfunction
9
A CIS can be Indicative of
Conditions Other than MS
• Haemangiomata
• Arteriovenous malformation
• Tumour
• Thrombotic thrombocytopenic purpura
• Thoracic disk protrusion
• Idiopathic thrombocytopenic purpura
• Cervical spondylosis
• Mitochondrial encephalomyopathies
• Recurrent neuropathy
• Acute disseminated encephalomyelitis
• Leber’s optic atrophy
• Mycoplasma pneumonia encephalopathy
• Multiple cerebral emboli
• Adult-onset leukodystrophy
• Cerebral vasculitis
• Arnold-Chiari malformation
• Glioblastoma
• Foramen magnum lesions
• Sarcoidosis
• Periodic cerebellar ataxia
• Behçet’s disease
• Familial spastic paraplegia
• Lyme disease
• Adult-onset leukodystrophies
10
The CIS Challenge
• CIS needs to be confirmed as suggestive of MS:
– Other possible pathologies must be excluded
– That the CIS has the characteristics of an MS relapse must
be confirmed
• This is important in early diagnosis of MS
• And may define early management of MS
11
Which CIS Symptoms are
Characteristic of MS?
• Painful optic neuritis
• Partial acute transverse myelitis
• Lhermitte’s symptom
• Bilateral internuclear ophthalmoparesis (INO)
• Paroxysmal dysarthria\ataxia
• Tonic seizures
12
CIS Characteristics in MS only
• Onset: over hours to days
• Magnetic resonance imaging (MRI) findings
compatible with demyelination:
– No or minimal oedema/mass effect
– Contrast enhancing
– Other lesions
• Spontaneous or steroid responsive remissions
• Evolution of lesion in MRI, compatible with
demyelination
13
The Importance of CIS
• Early axonal loss leads to CNS damage and lesions
• The CIS subtype can predict MS course
• Patient with a CIS already has MS and early
treatment is now recognised as important1,2,3
1. Beck RW et al. Ann Neurol 2002;51(4):481–90
2. Comi G et al. Lancet 2001;357:1576–82
3. Brex PA et al. N Engl J Med 2002;346:158–64
14
MS is Not a Purely Inflammatory
Demyelinating Disease
• Axonal loss occurs even at the early stages of MS
• Transected axons are common in MS lesions1
• Axonal loss may remain clinically silent for years2
• Irreversible neurological disability will develop:3
– Confirmed in experimental allergic encephalomyelitis (EAE)
animal model. 15–30% of spinal cord axons can be lost
before ambulatory impairment2
1. Trapp BD et al. N Engl J Med 1998;338:232–325
2. Bjartmar C et al. J Neurol Sci 2003;15:165–71
3. Ferguson B et al. Brain 1997;120:393–9
15
Inflammation and Axonal
Degeneration in MS
Axonal damage
+
-
Clinical symptoms
THERAPY
Subclinical degeneration
Time (years)
16
Do Axonal Loss and Atrophy Correlate
with Long-Term Neurological Disability?
Yes, there is a correlation
• In chronic MS patients (EDSS 7.5):
– N-acetyl aspartate levels in spinal cords containing
MS lesions, MRI and Expanded Disability Status
Scale (EDSS) score1 show correlation
• In chronic EAE:2
– Fixed neurological impairment, axonal loss, number
of symptomatic attacks, are all present
Furthermore
• N-acetyl aspartate levels abnormally low in early stages
of MS3
1. Bjartmar C et al. Ann Neurol 2000;48:893–901
2. Wujek JR et al. J Neuropathol Exp Neurol 2002;61:23–32
3. De Stefano N et al. Arch Neurol 2001;58:65-70
17
Courtesy of Professor Ioannis Milonas
Axonal Injury (Dystrophic Axon) and
Loss in Chronic EAE in C57B/6 Mice
Grigoriadis N et al. Inflammation, demyelination and axonal injury interrelationship
in chronic EAE. Unpublished observations
18
Courtesy of Professor Ioannis Milonas
Axonal Injury (Dystrophic Axons, Ovoids)
and Loss in Chronic EAE in C57B/6 Mice
Grigoriadis N et al. Inflammation, demyelination and axonal injury interrelationship
in chronic EAE. Unpublished observations
19
Courtesy of Professor Ioannis Milonas
Coexistence of Axonal Injury
Demyelination and Inflammation in
Chronic EAE in C57B/6 Mice
Grigoriadis N et al. Inflammation, demyelination and axonal injury interrelationship
in chronic EAE. Unpublished observations
20
In Summary: Why Should a CIS
be Taken Seriously?
• A CIS can be the first indicator of MS
• A CIS can indicate that MS is already active
• Early MS therapy could slow progression
• Therefore, clinicians need to know which CIS are
indicative of MS
21
Predicting Multiple
Sclerosis using
Clinically Isolated
Syndromes
22
What Tools can We use to
Predict MS?
• MRI
• Oligoclonal bands (OBs)
• Genetics
• Biological markers
• Natural history studies
23
MRI as a Predictor of MS
MRI can be used to predict CDMS in patients with a
CIS suggestive of MS
• In patients without enhancement in MRI, 9 T2 lesions is
a strong indicator for CDMS1
• Other MRI criteria:1
– Gadolinium (Gd) enhancement
– Infratentorial lesions
– Juxtracortical lesions
– Periventricular lesions
• If all 4 MRI criteria observed, risk of confirmation of
CDMS is 87% (in 3 years). Of those with confirmed
CDMS, 50% occurred by 9 months and 90% by
30 months1
1. Barkhof F et al. Brain 1997;120:2059–69
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Patients with CDMS (%)
Baseline Lesion Burden versus Confirmed
MS at 3 Years: Optic Neuritis
45
40
35
30
25
20
15
10
5
0
0 lesions
1–2 lesions
Beck RW et al. N Engl J Med 1992;326:581–88
3 lesions
25
MRI and CSF Studies give Clinically
Important Information on the Risk for
Future MS
5-year follow-up study of patients presenting with CIS
(optic nerves, brainstem, spinal cord)1
•
•
•
•
65% had abnormal MRI at presentation confirmed with CDMS
3% had normal MRI at presentation confirmed with CDMS
4 lesions associated with CDMS
CSF OBs associated with increased risk of progression to MS
5-year follow-up study of patients presenting with optic neuritis2
• Brain MRI investigation revealed:
– 55% had 3 lesions
– 9% had 1–2 lesions
– 35% had normal MRI
• 72% of patients had CSF OBs
• 36% of patients developed CDMS
• Presence of 3 or more MRI lesions (P<0.001) and OBs (P<0.001) strongly
associated with CDMS
1. Morrissey SP et al. Brain 1993;116:135–46
2. Söderstrom M et al. Neurology 1998;50:708–14
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Natural History of MS:
Prognosis of Disability
• 50% of all patients will need assistance in walking,
within 15 years of the onset of MS1–3
• The exacerbation rate early in the disease course
predicts the future progression rate and disability
status: according to Weinshenker et al.1 the median
time to reach EDSS 6.0 is:
– <7 years in patients who had 5 attacks in the first year
– 13 years in those who had 2–4 attacks in the first year
– 18 years in those who had <2 attacks in the first year
1. Weinshenker BG et al. Brain 1989;112:133–46
2. Weinshenker BG et al. Brain 1989;112:1419–28
3. Weinshenker BG et al. Brain 1991;114:1045–56
27
Median Time to EDSS 6 versus
Attacks in the First 2 Years
Time (years)
25
20
15
10
5
0
0 or 1
attack
2–4
attacks
1. Weinshenker BG et al. Brain 1989;112:133–46
5
attacks
28
Genetic Markers as Predictors
in MS
• Genetic control in MS is likely to be very complex
• Processes that are candidates for gene regulation
include:
–
–
–
–
–
–
–
–
Disease initiation
Disease severity
T-cell regulation
MHC expression
Vascular permeability
Macrophage presentation
Control of inflammatory mediators
Repair mechanisms
29
Problems of Reporting Genetic
Associations with Complex Outcomes
• It is difficult to replicate published reports of significant
associations between genetic variation and disease-related
outcome:
– Publication bias
– Failure to attribute results to chance
– Inadequate sample sizes
‘Ratio of published true-positive association to
false-positive association should be about 20:1’1
• Currently, therefore, genetic markers are of limited use
1. Colhoun HM et al. Lancet 2003;361:865–72
30
Biological Markers in MS
Biological markers are being analysed to assist in:
• Diagnostic testing
• Pathogenesis:
– Immunology
– Disease progression
– Disease heterogeneity
• Monitoring the disease:
– Prognosis
– Monitoring effect of therapeutic interventions
31
Problems with Biological Markers for
Predicting or Monitoring Disease Activity
• None of the currently available inflammatory
markers are good enough to be used as surrogate
markers of MS disease activity
• Neurodegenerative markers (e.g. neurofilament and
glial fibrillary acidic protein) appear to be more
promising and may prove to be reasonable
surrogate markers of MS disease activity
• Further research is needed to identify a valid and
reliable marker to monitor MS
Giovannoni G. 15th MS Forum Modern Management Workshop, 2003
32
In Summary: Predicting MS
using CIS
• A CIS is an important indicator of ongoing MS
• Defining which CISs are indicative of MS is
difficult
• A CIS can predict disease progression in MS
• All CISs should be examined with the possibility
of MS in mind:
– Early diagnosis
– Early management
– Early treatment
33
Diagnosis of Early
Multiple Sclerosis
34
What are We Aiming for in the
Diagnostic Process?
• To establish a diagnosis of MS:
– Exclusion of other diseases
– Exclusion of other treatments
• To give a sub-classification
With implications for:
– Prognosis
– Treatment choice
• To inform patients
35
Key Steps in the Diagnostic
Process
• History:
– Previous episodes
– Other diseases
– Family history
– ‘Credibility’
• Comprehensive physical examination:
– ‘Objective evidence’
– Other lesions
• Additional tests:
– MRI
– OBs
– Computed tomography
36
Fundamentals of MS Diagnosis
• Having two or more attacks in different parts of
the brain (separated in space) at different times
(separated in time) define MS
• An attack is a set of neurological symptoms that
occur together, usually fairly abruptly
• The neurological symptoms have to be objectively
verified by a neurologist
MS remains a clinical diagnosis requiring an
expert neurologist
37
Diagnostic Criteria
Several different diagnostic criteria have evolved:
• Allison RS, Millar JHD. Prevalance and familial incidence of
disseminated sclerosis. Ulster Med J 1954;23:5–27
• Schumacher GA, Beebe G, Kibler RF et al. Problems of experimental
trials of therapy in multiple sclerosis. Ann NY Acad Sci
1965;122:552–68
• McAlpine D, Lumsden CE, Acheson ED. Multiple Sclerosis: A
reappraisal. Churchill Livingstone, Edinburgh, 1972
• Rose AS, Ellison GW, Myers LW et al. Criteria for the clinical diagnosis
of MS. Neurology 1976;26:20–22
• Poser CM, Paty DW, Scheinber L et al. New Diagnostic Criteria For
Multiple Sclerosis; Guidelines For Research Protocols. Ann Neurol
1983;13:227–31
• McDonald WR, Compston A, Edan G et al. Recommended diagnostic
criteria for multiple sclerosis: guidelines from the international panel
on diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7
38
Poser Diagnostic Criteria
Category
Attacks
A. Clinically definite
CDMS A1
CDMS A2
B. Laboratory-supported definite
LSDMS B1
LSDMS B2
LSDMS B3
C. Clinically probable
CPMS C1
CPMS C2
CPMS C3
D. Laboratory-supported
probable
LSPMS D1
Poser CM et al. Ann Neurol 1983;13:227–31
Clinical
Evidence
Paraclinical
Evidence
2
2
2
1 and
1
2
1
1
1 or
2
1 and
2
1
1
1
2
1 and
2
1
1
CSF
OB/IgG
+
+
+
1
+
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McDonald Diagnostic Criteria
• 2 or more lesions within the CNS
• 2 or more episodes of CNS dysfunction (relapses)
• Or chronic progression for defined observation
time (>6 or 12 months)
• Exclusion of other diagnoses:
— In many cases, additional tests are valuable in excluding other
diagnoses, rather than positively establishing the diagnostic
criteria of multiplicity in space and time
McDonald WI et al. Ann Neurol 2001;50:121–7
40
McDonald Criteria:
Dissemination in Space and Time
Dissemination in space
•
Definition of positive MRI: 3 out of 4 of the following:
– 1 Gd enhancing lesion OR 9 T2 hyperintense lesions
– 1 or more infratentorial lesion
– 1 or more juxtacortical lesion
– 3 or more periventricular lesions
•
1 cord lesion can substitute for 1 brain lesion
Dissemination in time
EITHER
•
1 or more Gd lesions demonstrated in a scan carried out at least 3 months following
onset of clinical attack
OR
•
In absence of Gd enhancing lesion, a follow up scan after an additional
3 months shows Gd or new T2 lesion
McDonald WI et al. Ann Neurol 2001;50:121–7
41
McDonald Criteria:
Laboratory Tests
• Positive CSF
Oligoclonal IgG bands in CSF (not matched in
serum)
OR
elevated IgG index
• Positive VEP
Delayed and well-preserved wave form
McDonald WI et al. Ann Neurol 2001;50:121–127
42
McDonald MS Diagnostic
Criteria: What‘s New?
• No single diagnostic test is definitive proof – always
need a synthesis of history, neurological findings and
results of additional investigations
• The focus remains on the objective demonstration of
dissemination of lesions in both time and space
• MRI is integrated with clinical and other paraclinical
diagnostic methods
• Three diagnostic groups:
- MS
- Possible MS
- No MS
McDonald WI et al. Ann Neurol 2001;50:121–7
43
McDonald New Diagnostic Criteria for
Primary Progressive MS
• Positive CSF
AND
• Dissemination in space
AND
– MRI evidence of 9 T2 brain lesions
OR
– 2 or more cord lesions
OR
– 4–8 brain and 1 cord lesions
OR
– positive VEP and 4–8 MRI lesions
OR
– positive VEP and <4 brain and 1 cord lesions
• Dissemination in time
– by MRI
OR
clinical continued progression for 1 year
McDonald WI et al. Ann Neurol 2001;50:121–7
44
New MS Diagnostic Criteria:
What are the Effects?
• With McDonald Criteria, after 1-year follow-up, more patients
presenting with CIS suggestive of MS were confirmed with MS
compared with Poser criteria (37% versus 11%)1
• McDonald criteria had 74% sensitivity, 86% specificity, and
80% accuracy in predicting confirmation of CDMS1
• After 3 years 58% of CIS-presenting patients had MS
according to the McDonald criteria, whereas 38% had CDMS2
• More long-term prospective studies are needed to define real
accuracy and prognostic value
• Therefore, fulfilment of the McDonald Criteria serves as a
background for therapeutic decisions, but does not
automatically imply indication for treatment. Individualised
decisions are still required
1. Tintoré M et al. Neurol 2003;60:27–30
2. Dalton CM et al. Ann Neurol 2002;52:47–53
45
In Summary:
Diagnosis of Early MS
• MS remains a clinical diagnosis requiring an
expert neurologist
• Useful diagnostic criteria exist to assist clinicians
in carrying out a diagnosis
• Fulfilment of criteria can assist in therapeutic
decisions
• BUT individualised decisions are needed
46
Giving the Diagnosis
of Multiple Sclerosis
47
Patient Responses to Diagnosis of
MS: ‘The Day that Changed my Life’
‘(nothing) would have prepared me for the two
words the neurologist bludgeoned me with that day’
‘the air sucked out of my lungs … my only clear
memory is of wondering why he was doing this to
me, and what I was going to tell (my wife)’
‘I looked at the doctor and stared; he was so composed’
‘As I stepped out of the door of his office … it was as
if I were entering a whole new world’
48
Receiving the Diagnosis of MS
• Initial contacts can shape the patient’s attitude
about their disease
• A pivotal, life-altering moment, which is severely
stressful
• Memories can be filled with anger about how the
diagnosis was delivered
• Long uncertainty about a confirmed diagnosis is
also stressful
Therefore, a diagnosis of MS needs to be
delivered with due care and attention
49
Psychological Aspects
• Listening to the diagnosis is a shocking event
inducing fear, vulnerability and powerlessness
• Progressive recovery through each of the successive
emotional phases depends on the individual’s
personality and affective environment:
– Denial
– Despair
– Anger
– Fear
– Bargaining
– Acceptance
• Means of delivery of MS diagnosis can affect a
patient’s progress through these emotional phases
50
What to Tell: Effective
Communication Strategies
• Communication is most effective when targeted to
the individual:
– Identify the patient’s knowledge and misconceptions
– Use understandable explanations in everyday terms
– Apply appropriate form of communication from those
available
51
Guidance for Delivering the
Diagnosis of MS
• People with MS expect a clear explanation of their
symptoms, which almost always involves
communicating the specific diagnosis to the patient
• Many people prefer a relative or friend to be with
them
• The doctor giving the diagnosis must provide
appropriate guidance about the disease at the
appropriate time
• A timely follow-up appointment with the doctor who
has discussed the diagnosis should be offered
• Information should be given about the local MS
society supplemented by appropriate written
information about MS1
1. Ford and Johnson. British MS Society, 1995
52
Psychosocial Assessment
• What are the primary stresses the patient is
currently coping with?
– Work
– Finances
– Family (nuclear/extended)
– Internal distress, anxiety, disequilibrium
• What worries him or her most?
• What assistance is needed?
• What specialist advice does he or she need?
• What needs to be referred to another specialist?
53
Psychosocial Assessment
(Continued)
• What is the patient’s previous experience of illness,
disability, loss, personal crisis?
• How has he or she coped previously?
– Making sense of reality
– Coping styles and mechanisms
– Coping techniques
• What does the patient know about MS and what is
his or her previous exposure to it?
– Correcting myths and misconceptions
54
Newly Diagnosed Programme
Multi-disciplinary presentation:
• Neurologist:
– The disease: aetiology and mechanism, symptom
management, prognosis, treatments, research
and Q & A
• Managing Team:
– Nurse Practitioner, Social Worker, Psychologist,
Physiotherapist, Occupational Therapist and others
55
Information Sources
• Patient societies
• Books and libraries
• Research journals
• Friends and family
• Support groups
• Health service brochures
• The Internet
56
The Internet
• A source of endless information
• Gives access to a vast amount of MS information–
over 1.75 million sites on MS
• Internet sites may include information that is not
verifiable
• Giving patients selected sites is preferable to
them searching themselves
• MSIF site is a good place to start
57
MSIF Website: World of MS
www.msif.org
World of MS aims to provide:
• Online information about MS and its effects and
implications
• Research news about new drugs and therapies
• Access to a community that supports those
affected by MS
• Access to the US National MS Society and its
services
• Links to almost 1200 other MS Internet sites
58
In Summary:
Giving the Diagnosis of MS
• A diagnosis of MS needs to be delivered with
sensitivity, care and attention
• Individualised communication is effective
communication
• The role of the managing team is crucial
• A wealth of patient information is available, and
the Internet, although particularly useful, needs
to be used selectively
59
The Action,
Communication and
Treatment (ACT) in
Multiple Sclerosis
Programme
60
What is the Goal of the ACT
Programme?
Today, people with MS are looking for:
Reliable and valid
information on MS
A better understanding of MS
and treatments
A more active role in coping
with the disease
Better communication with
their healthcare providers
and friends
61
Introduction to the ACT
Programme
ACT is a psychological support programme designed to
help people with MS to understand and cope with their
condition, adhere to a treatment plan, and communicate
more effectively with their healthcare providers
Using questionnaires and information sheets, ACT
guides people with MS towards a better perception of
their illness and helps to manage their expectations of
treatment options and their effects
62
The ACT Material Consists of
Three Main Sections
The Mental Representation Model
The Treatment Options Guide
The Self-Assessment Questionnaires
63
Mental Representation Model
The Mental Representation Model has been developed to
look at how internal pictures, memories and thoughts of
having an illness affect outcome, coping and the
relationship between the health professional and
patient
It is based on the concept that:
“Individuals respond to the world as they view it, not
necessarily as it is.”
Skelton and Croyle, 1991
64
Treatment Options Guide
Goal: To provide people with complete information on MS
and its treatments
A consensus review of MS and current approved treatments
Endorsed by an independent expert panel
Helps to improve understanding of MS and the effects of treatments
Can be used as a basis of discussion between people with
MS and their healthcare providers
Can help to improve communication and lead to more
constructive consultations
65
Self-Assessment Questionnaires
Prompt patients to explore how they feel about MS
To think about how they can manage their condition
Identify actions they can take to cope better
Helps to review the effectiveness of coping actions
Helps people to prepare for their meetings and consultations with
the healthcare professionals
66
Learning and Reassessment
Representation
Actions and
choices in living
Correction & clarification
of patient’s perceptions
of MS
Choices a patient makes
to cope with MS
e.g. wheelchair bound within
5 years
e.g. part- time work, consider
therapy, redesign living
Evaluation
Review of attempts at
coping and outcome
e.g. altered perception of MS
better coping strategies &
outcomes, rehabilitation
67
In Summary: ACT
A novel &
innovative programme
Better outcome
Valid source of
Information on MS
ACT
Better coping actions in MS
Better understanding
of MS
Better communication
in MS
Shorter and more
efficient consultations
68
Early Disease
Management:
Lessons from Type 1
Diabetes Mellitus
69
MS and Type 1 Diabetes Mellitus:
Genetics and Prevalence
Lifetime Risk (%)
T1DM
MS
General population
0.4
0.1–0.2
Mother with T1DM/MS
1.5–3
41
Father with T1DM/MS
3–6
31
Sibling with T1DM/MS
6–8
3–5
HLA-identical sibling with T1DM/MS
12–19
6–102
Identical twin with T1DM/MS
20–30
25–30
T1DM: Type 1 diabetes mellitus
Similar genetics and prevalence mean Type 1 diabetes mellitus
may be a good model for MS
1. Ebers G et al. Canadian Collaborative Study on genetic susceptibility. Unpublished data.
2. Willer CJ Proc Natl Acad Sci 2003;100:12877–82
70
Type 1 Diabetes Mellitus:
Disease Risk
• Multiple autoantibodies confer greater risk, especially in
a first degree relative (FDR)
• 5-year risk of developing Type 1 diabetes mellitus in
FDR:
– 1 autoantibody = 15% risk
– 2 autoantibodies
= 44% risk
– 3 autoantibodies
= 100% risk
• The younger the age at first appearance of
autoantibodies, the greater the risk of Type 1 diabetes
mellitus
• Genetic risk increased with HLA-DQB1*02 and/or
DQB1*0302 allele, without protective alleles
(DQB1*0301, *0602 and *0603)
Verge CF et al. Diabetes 1996;45:926-933
71
MS: Disease Risk
• Compelling evidence that autoantibodies cause
peripheral neurological disorders
• Autoantibodies to myelin antigens have been
investigated in MS but none have proved to be a
reliable marker to date:
– But: Recent data suggest that antibodies against
myelin OG and myelin basic protein may be a predictor
for early conversion to CDMS1
• Autoantibodies currently have little predictive
value in MS, so not as useful as in Type 1 diabetes
mellitus
Berger T et al. N Engl J Med 2003;349:139–45
72
Type 1 Diabetes Mellitus:
Therapeutic Approaches
Genetic
predisposition
Environmental factors
1o Intervention
-cell autoimmunity
Dietary
Intervention
-cell loss
2o Intervention
Insulin deficiency
Insulin,
Nicotinamide
Asymptomatic
hyperglycaemia
T1DM
3o Intervention
Symptomatic
hyperglycaemia
Insulin,
Immunotherapy
73
Type 1 Diabetes Mellitus:
Evidence for 3o Immune Therapy
Percent Remission
40
Cyclosporin
30
20
Placebo
10
0
1
2
3
4
5
6
7
8
9
10
11
12
Months of Therapy
The Canadian-European Randomized Control Trial Group. Diabetes 1988;37:1574–82
74
Insulin for High-Risk Individuals:
2o Prophylaxis against Type 1
Diabetes Mellitus
Beta Cell Rest Therapy
Percent without DM
100
Treated
80
60
40
Historical Controls
Declined Treatment
20
0
0
1
2
3
4
Time (years)
Keller RJ et al. Lancet 1993;341:927–8
75
Relative T1DM Risk
Type 1 Diabetes Mellitus:
1o Dietary Intervention
14
12
10
Genes and weaning diet
Patients with high risk genes
Patients with moderate risk
genes
versus
8
Healthy controls with
similar risk genes
6
4
2
0
Less than 3 months
More than 3 months
Age at first cow milk exposure
Perez-Bravo F et al. J Mol Med 1996;74:105–9
76
MS: Therapeutic Approaches
Genetic
predisposition
Environmental factors
1o Intervention
Oligodendrocyte
autoimmunity
Oligodendrocyte
cell loss
CNS demyelination
None known
2o Intervention
None known
Asymptomatic
white matter lesions
MS
3o Intervention
Symptomatic MS
e.g. diseasemodifying therapy
77
MS: 3o Disease-Modifying
Therapy
Disease Modifying Therapy
RRMS
Interferon beta-1b sc

Interferon beta-1a sc

Interferon beta-1a im

Glatiramer acetate

Mitoxantrone*
* Only used in rapidly progressing individuals

SPMS


78
In Summary:
MS and Type 1 Diabetes
• There are similarities between MS and Type 1
diabetes that may help evaluate early treatment
BUT
• Limitations in comparison with MS due to lack of
primary and secondary interventions
• Currently, only tertiary intervention with diseasemodifying therapy is possible in MS
79
Early Treatment of
Multiple Sclerosis:
Considerations
80
Early Treatment of MS:
Arguments Against
• Disease-modifying therapy in CIS has not been
shown to have a long-term effect on disability
• Progression of MRI Gd-enhancing and T2 lesions
predicts relapses but provide no information on the
risks of cumulative disability
• Some patients will have benign disease so why not
wait
• When considered in the context of 15–20 years of
therapy using a partially effective treatment with
known side-effects, why not wait to be sure that
disease is active
81
Early Treatment of MS:
Arguments For
• Damage occurs early in MS
• Early treatment is successful in MS
• Relevant outcomes are improved
82
Natural History of MS:
Damage Occurs Early
Preclinical
Relapsing
Progressive
Time
Relapses and impairment
MRI activity
MRI Total T2 lesion area
Measures of brain volume
83
Terminal Axonal Bulbs:
Evidence of Transected Axons
Doinikow, 1915
Doinikow B. D Zeitschr Nervenheilkunde 1915;26:233–47
Trapp BD. NEJM 1998;338:278–85
Trapp, 1998
84
Transected Axons: MS Lesions
11236
Number of transected
axons/mm3
12000
10000
8000
6000
4000
2000
3138
875
17
0
Active
Chronic active/core
Chronic active/edge
Normal appearing white matter
• Incidence of axonal transection is related to degree of inflammation1
• Early treatment reduces inflammation and therefore axonal transection
1. Trapp BD et al. NEJM 1998;338:278–85
85
Change in burden
of disease (%)
MRI (median) Change in Burden
of Disease: ETOMS Trial
10
Placebo
5
Interferon
beta-1a
0
-5
-10
-15
P=0.032
Year 1
P=0.009
Year 2
• Effect of interferon beta-1a in patients after first presentation
with neurological event
• Conclusion: Increase in lesion burden in non-treated patients,
even in earliest phases of the illness1
1. Comi G et al. Lancet 2001;357:1576–82
86
Therapy in MS:
Early Treatment Works
CIS
Relapsing-remitting (RR)
trials more successful than
secondary progressive (SP)
trials
Clinical trial
RR to SP
Axonal loss
RR
Betaseron
Avonex
Rebif
Disability
threshold
EU-SP
Betaferon
Rebif SP
Avonex SP
RRMS
Betaferon, interferon beta-1b sc every other day
Avonex, interferon beta-1a im once weekly
Rebif, interferon beta-1a sc three times a week
Disease stage
NA-SP
Betaseron
SPMS
time
87
Interferon Beta Delays Time to
CDMS: CHAMPS Trial
Placebo
50
CDMS (%)
40
30
Interferon
beta-1a
20
10
Logrank: P=0.002
0
1
4
7
10
13
16
19
22
25
28
31
34
37
Time (months)
Jacobs LD et al. NEJM 2000;343:898–904
88
Proportion with confirmed CDMS
Interferon Beta Delays Time
to CDMS: ETOMS Trial
1.0
0.9
0.8
Interferon
beta-1a
0.7
0.6
Placebo
0.5
0.4
Logrank: P=0.034
0.3
0.2
0.1
0
0
50
100
150
200
250
300
Comi G et al. Lancet 2001;357:1576–82
350
400
450
500
550
600
650
700
750
Time (days)
89
Relevant Outcomes are
Improved
Effect of Early Clinical Characteristics on Long-Term Disability
Clinical Characteristic
Significance*
Number of attacks, first 2 years
P< 0.001
Interval between first 2 attacks
P< 0.001
EDSS score at 2 years
P < 0.001
EDSS score at 5 years
P < 0.001
* Controlled for age at onset, remitting at onset, cerebellar, cerebral
Weinshenker BG et al. Brain 1991;114:1045–56
90
Long-term Disability:
Effect of Early Relapses
Patients EDSS <6 (%)
100
Low (0–1 attacks in 2 years)
Intermediate (2–4 attacks in 2 years)
High ( 5 in 2 years)
80
60
40
P<0.0001
20
0
0
10
20
30
40
50
Time from onset of MS (years)
Weinshenker BG et al. Brain 1989;112:1422
91
Long-term Disability: Time from
Onset of MS to EDSS 4
1 = 0–19 years old
2 = 20–29 years old
3 = 30–39 years old
4 = 40–49 years old
5 = 40 years old
Confavreux C et al. Brain 2003;126:770–82
92
Relationship of MRI: Disease
Evolution
Patients with EDSS >3
after 10 years (%)
Patients with EDSS 6
after 10 years (%)
80
80
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
>10 Lesions
O’Riordan JI et al. Brain 1998;121:495–503
10 Lesions
93
Predictors of Disability: MRI T2
Disease Burden in CIS Patients
5
years1
Lesion load
(normal)
(<1.23cm3)
(>1.23cm3)
Conversion to CDMS
6%
55%
90%
EDSS >3
0%
23%
52%
10
years2
Lesion load
(normal)
(<3.0 cm3)
(>3.0 cm3)
Conversion to CDMS
19%
78%
100%
EDSS >3
19%
27%
90%
EDSS >6
4%
18%
45%
1. Filippi M et al. Neurology 1994;44:635-41
2. Sailer M et al. Neurology 1999;52:599–606
94
Predictors of Disability: MRI T2
Lesion Volume in CIS Patients
The EDSS score at 14 years correlated with lesion
volumes on MRI at all time points:
r
P
0–5 years
0.58
< 0.001
5–10 years
0.41
0.002
10–14 years
0.35
0.02
Lesion volume at any time contributes to the development
of later disability1
1. Brex PA et al. NEJM 2002;346:158–64
95
In Summary: Early Treatment
of MS
• Early treatment is effective and may be more
successful than therapy later in the illness
• Early relapse rate and early disease severity are
associated with long-term disability
• As a result, therapy should be started early in the
course of illness
• It may not, however, be necessary to begin therapy
at the first clinical sign of disease in all patients
96
In Conclusion: Early
Management of MS
97
Early-Onset Immunotherapy
in MS
• Treat as early as possible in order to prevent
accumulation of disability
• Confirm diagnosis to ensure correct treatment
• Ideally treat the patients who have a bad
prognosis:
– Can we, based on the initial course/symptoms,
identify the patient with benign MS?
98