The Natural History of Multiple Sclerosis

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry

London, UK

Disclosures

Over the last 15 years Professor Giovannoni has received personal compensation forparticipating on Advisory Boards in relation to clinical trial design, trial steeringcommittees and data and safety monitoring committees from: Abbvie, Bayer-ScheringHealthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK,GW Pharma, Ironwood, Merck, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis,Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec for makingavailable data slides on daclizumab for this presentation. He would also like to thanknumerous colleagues for providing him with data and/or slides for this, and other,presentations.

This presentation has been designed and prepared by Professor Giovannoni with noinput from any other parties.

The natural history of MS

Epidemiology

• Worldwide incidence and prevalence

• Age of onset

• Changing sex ratio

• Clinical subtypes – Relapse onset

– Single-attack progressive

– Secondary progressive

– Primary progressive

• Disease course

• Mortality

• Suicide risk

• Etc.

What is multiple sclerosis?

.

Jean-Martin Charcot (1825-1893)

• Link between symptomatology, now known to be MS, and the pathological changes seen in post-mortem samples.

• Charcot's triad– diplopia (double vision)– ataxia (disturbances of balance or

co-ordination)– dysarthria (difficulties with, or

slurred speech)

• Histological of MS lesions– loss of myelin – proliferation of glial fibers and

nuclei.

Multiple Sclerosis is a clinico-pathological correlate

Pathological Definition: Inflammatory disease of the CNS

characterised by demyelination and variable degrees of axonal

loss and gliosis.

Clinical Definition: Objective CNS dysfunction, i.e. involvement of

two or more white matter structures (space) separated by time,

with no other aetiology.

Diagnostic Tautology!

Conventional Definition:

Pathology

Pretheoretical definition:

Clinical

What is a disease?

What is a disease/what is MS?

A. Conventional definition

• E.g. “hepatitis is inflammation of the liver”

B. Pre-theoretical definition

• “SLE is characterised by the ARA criteria”

• Indirect definition

• Usually “polythetic”

• Inclusive definition using multiple characteristics

• According to Wittgenstein's model of a "long rope twisted together out of

many shorter fibres.“*

C. Theoretical definition

• E.g. “Down’s syndrome is trisomy 21”.

• Usually “monothetic”.

*Ludwig Wittgenstein a controversial 20th-century analytical philosopher (1889-1951).

Medical Philosophy

Ludwig Wittgenstein1889-1951

Long rope twisted together out of many shorter fibres

Diagnostic & pathogenic markers

The evolving clinical definition of MS

1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis:

Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple

Sclerosis. Ann N Y Acad Sci 1965;122:552-68.

2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research

protocols. Ann Neurol 1983;13:227-31.

3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from

the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.

4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald

Criteria". Ann Neurol 2005;58:840-6.

5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald

criteria. Ann Neurol. 2011;69:292-302.

Will Rogers Phenomenon in Multiple Sclerosis

1879 - 1935

“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”

Will Rogers Phenomenon in Multiple Sclerosis

Sormani et al. Ann Neurol 2008;64:428–433.

Poser

McDonald

Less activeCIS

More activeCIS

Less activeRRMS

ActiveRRMS

Will Rogers Phenomenon in RRMS

ActiveRRMS

Less activeCIS

CIS CDMS

MSCIS

Poser, et al. Ann Neurol 1983;13:227-31.

McDonald, et al. Ann Neurol 2001;50:121-7.

Intrathecal synthesis of IgG

Images courtesy of Alastair Compston and Ed Thompson.

Kabat et al. J Clin Invest. 1942 Sep;21(5):571-7.

Carl Lange – Colloidal Gold Curve

Isoelectric focusing with immunfixation

Diagnostic criteria for Primary Progressive MS

Polman et al. Ann Neurol 2005;58:840-6.

Accumulation of disability in PPMS:stratified by intrathecal IgG abnormalities

Proportion Progressing as Percent

Epoch CSF- CSF+

6 mo 7.3 9.8

12 mo 15.0 20.4

18 mo 22.8 28.1

24 mo 25.4 34.3

Years to Progression

2.43 2.26

Based on data from a second meeting of the DSMB and assume no therapeutic effect

0 1 2 3Years

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n P

rog

ress

ing

PositiveNegative

CSF

Slide courtesy of Jerry Wolinsky

P =0.03

NotPPMS

PossiblePPMS

OCB-ve

PPMSOCB-ve

PPMSOCB+ve

Will Rogers Phenomenon in PPMS

PPMSOCB+ve

Not PPMS

? PPMS PPMS

PPMS? PPMS

McDonald, et al. Ann Neurol 2001;50:121-7.

Polman, et al. Ann Neurol 2005;58:840-6.

What constitutes a useful diagnostic test or set of criteria?

TARGET DISORDER

PRESENT ABSENT

DIAGNOSTIC TEST RESULT

+ a b a + b

- c d c + d

a + c b + d a + b + c + d

From these we determine the sensitivity and specificity as follows:

SENSITIVITY = a/(a+c) > 80%SPECIFICITY = d/(b+d) > 80%

Neurobiol Aging 1998; 19:109-116.

A clinico-pathoanatomical study of multiple sclerosis diagnosis

SENSITIVITY = True+ve /(True+ve + False-ve)

Eye Department, Hvidovre Hospital, Denmark.

• Clinical diagnosis had been established by a neurologist in all cases. • Erroneous diagnosis included a variety of other neurological disorders.

Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.

518 CDMS(Schumacher & Poser)

418 (94%) MS

33 (6%) not-MS

Post-mortem

33 Probable MS(Poser)

22 (66%) MS

11 (33%) not-MS

Post-mortem

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

PML complicating treatment with natalizumab and IFNb-1a for MS

A clinico-pathoanatomical study of multiple sclerosis diagnosis

SPECIFICITY = True-ve /(True-ve + False+ve) ?

~25% of cases of MS are undiagnosed in life (asymptomatic or benign cases)

Engell T. Acta Neurol Scand. 1989 May;79(5):428-30.

Diagnosed MS

not diagnosed MS

Multiple Sclerosis

Other diagnoses - MRI white matter changes

• ADEM

• Ageing

• Behcet’s syndrome

• Cerebrovascular disease

• Decompression sickness

• Fat embolism

• HIV encephalitis

• HTLV1-associated myelopathy

• Hydrocephalus

• irradiation

• Leukodystrophies

• Migraine

• Mitochondrial encephalopathy

• MND

• Neurosarcoidosis

• Phenylketonuria

• PML

• SSPE

• SLE/APL

• Trauma

Miller DH. (1997)

Secondary progressive MS

Onset of SPMS

a Utility score <0 indicates MSers felt their health status was worse than death. 1. Orme M et al. Value Health 2007;10:54-602. Zwibel HL, Smrtka J. Am J Manag Care 2011;17( Suppl 5):S139-45.Figure adapted from Naci H et al. J Med Econ 2010;13:78-89.

Relationship between EDSS and health status1,2

1.0

0.8

0.6

0.4

0.2

0

–0.2

–0.4

0 1 2 3 4 5 6 6.5 7 8 9

He

alt

h S

tatu

s (U

tili

ty)

EDSS

Essentially restricted to bed, chair, or wheelchair

AustriaBelgiumGermany Italy The NetherlandsSpainSwedenSwitzerlandUK UKa

Perfect health

Death

SPMS

Onset of SPMS

a Utility score <0 indicates MSers felt their health status was worse than death. 1. Orme M et al. Value Health 2007;10:54-602. Zwibel HL, Smrtka J. Am J Manag Care 2011;17( Suppl 5):S139-45.Figure adapted from Naci H et al. J Med Econ 2010;13:78-89.

Relationship between EDSS and health status1,2

1.0

0.8

0.6

0.4

0.2

0

–0.2

–0.4

0 1 2 3 4 5 6 6.5 7 8 9

He

alt

h S

tatu

s (U

tili

ty)

EDSS

Essentially restricted to bed, chair, or wheelchair

AustriaBelgiumGermany Italy The NetherlandsSpainSwedenSwitzerlandUK UKa

Perfect health

Death

SPMS

Median 11.4yrs (10.5–12.3)

Disability progression in two phases

In RRMS, gender, age at onset, residual deficit after the first relapse, and relapses during the first 2 years are independent predictors of disability progression only in phase 1

DS

S S

core

Years from clinical onset of MS

6

5

4

3

2

1

0

0 5 10 15 20 25 30

7

Phase 2

Phase 1

Natural History

Leray E et al. Brain 2010;133:1-14.

TOP: Natalizumab stabilises EDSS scores in patients with either a high or low starting EDSS score at baseline

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 6 12 18 24 30 36 42 48

Med

ian

ED

SS

Sco

re

Time (months)

Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic. O261.

Baseline EDSS Score ≤3.0 (n=1591)

Baseline EDSS Score >3.0 (n=1840)

EDSS: Expanded disability status scale

Tuohy O, et al. J Neurol Neurosurg Psychiatry. 2015;86(2):208-15.

Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy

Tuohy O, et al. J Neurol Neurosurg Psychiatry. 2015;86(2):208-15.

Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy

“Four alemtuzumab-treated patients (5%) fulfilled the definition of secondary progression of two consecutive SAD events.”

Untreated MS Patients Convert From RRMS to SPMS Sooner Than Treated Patients

Trojano et al. Ann Neurol. 2007;61:300–306.

Cu

mu

lati

ve

Pro

ba

bil

ity

Probability of Reaching SPMS

HR = 0.38, P<0.0001

Follow-up Years

Untreated group (n=401)

Treatment group (n=1103)

0.00

0.05

0.10

0.15

0.20

0.25

1 2 3 4 5 6 7

Window of therapeutic efficacy

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

Therapeutic lag

Yr -1 Yr -2 Yr +1 Yr +2 Yr +3 Yr +4 Yr +5 Yr +6 Yr +7

IFN-beta-1b

Placebo

Notreatment

No treatment

9HP

T, c

og

nit

ion

, bra

in a

tro

ph

y

Progression from inflammation in years -2 and -1

Progression from inflammation in years +1 and +2

Progression from inflammation in

years +3 to +5

Note the slopes are now parallel

because IFN-beta was stopped after

year +2

Delayed effect on disability progression from IFN-beta

treatment in years 1 & 2

TimeTur et al. Arch Neurol. 2011 Nov;68(11):1421-7.

Primary Progressive MS

Therapeutic window 5

Asynchronous progressive MS hypothesis

Motor system to legs

Lower limb sensory

BladderTherapeutic window 1

Therapeutic window 2

Therapeutic window 4

Upper limb sensory

Upper limb motor

Cognition

Vision

Etc.

Therapeutic window 6

Therapeutic window 7

Therapeutic window 8

Therapeutic window 9

Therapeutic window 10, etc….

Diagnosis of clinically-apparent progressive MS

Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological systems despite some systems have

entered the clinically-apparent progressive phase of the disease

Cerebellar or balance systems

MS Endophenotype

MS Endophenotype

Ramagopalan SV, Dobson R, et al. Lancet Neurol. 2010.

The evolving clinical definition of MS

1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by

the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y

Acad Sci 1965;122:552-68.

2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.

Ann Neurol 1983;13:227-31.

3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the

International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.

4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald

Criteria". Ann Neurol 2005;58:840-6.

5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.

Ann Neurol. 2011;69:292-302.

6. ??, et al. Diagnostic criteria for multiple sclerosis: 2016 revisions to the McDonald criteria. Ann

Neurol. 2016; In Press. ASYMPTOMATIC MS OR RIS

Conclusion

• The natural history of MS is changing

– Increasing incidence and prevalence and sex ratio

– Secondary to ascertainment bias, better care and environmental factors

• The diagnosis of MS relies on a pre-theoretical definition

– This doesn’t define MS as a biological disease

– Current diagnostic criteria are a moving target

• Earlier diagnosis and the Will Rodger’s effect

– Not everybody who fulfils the current diagnostic criteria for MS has MS

• Specificity ~95%.

– People almost certainly have MS who don’t fulfil the current diagnostic criteria

• Sensitivity ?

• Diagnosis of SPMS is also a moving target

– Changing natural history

– Changing prevalence of co-morbidtiies are confounding the natural history

• We can’t diagnosis pre-symptomatic disease

– Important for preventative and curative strategies

• There is a philosophy and a science behind defining a disease