Ms diagnosis mc donald’s criteria giovannoni ens june 2013

L1: MS diagnosis

McDonald’s criteria

Gavin Giovannoni

Institute of Cell and Molecular Science

Barts and The London School of Medicine and Dentistry

BLT 24th July 2008.

What is multiple sclerosis?

What is a disease?

Jean-Martin Charcot (1825-1893)

1. Definite links between the symptomatology, now known to be MS, and the pathological changes seen in post-mortem samples.

2. Charcot's developed diagnostic criteria, which included the now famous Charcot's triad, diplopia, ataxia and dysarthria, which he observed in his own housekeeper.

3. Charcot gave the first complete histological account of MS lesions, describing many important features including loss of myelin and proliferation of glial fibres and nuclei.

Ludwig Wittgenstein

1889-1951

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).

What is multiple sclerosis?

Multiple sclerosis definition

Pathological Definition: Inflammatory disease of the CNS

characterised by demyelination and variable degrees of axonal

loss and gliosis; relative axonal sparing in relation to

demyelination.

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

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

with no other aetiology.

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.

Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria

Polman et al. ANN NEUROL 2011;69:292–302.

Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria

Polman et al. ANN NEUROL 2011;69:292–302.

Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria

Polman et al. ANN NEUROL 2011;69:292–302.

Diagnostic Tautology!

Conventional Definition:

Pathology

Pretheoretical definition:

Clinical

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.

• Neuropathological examination of 518 consecutive patients with clinically definite MS revealed a correct diagnosis in 485 cases (94%).

• Clinical diagnosis had been established by a neurologist in all cases.

• Erroneous diagnosis included a variety of other neurological disorders.

• Also investigated was a randomly selected series of 33 patients with a clinical diagnosis of probable MS:

• post mortem confirmation of MS was obtained in circa 66%.

• The remainder the error pattern was similar to the above.

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

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. .

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.”

Inactive CIS Active CIS RRMS

MS diagnosed according the old Poser Criteria

Inactive CIS

Less active RRMS

More Active RRMS

MS diagnosed according the New McDonald Criteria

Will Rogers Phenomenon in Multiple Sclerosis

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

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 3 Years

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n P

rogr

essi

ng

Positive Negative

CSF

Slide courtesy of Jerry Wolinsky

P =0.03

Whiting et al. BMJ. 2006 Apr 15;332(7546):875-84.

Accuracy of MRI for the diagnosis of MS: systematic review

Whiting et al. BMJ. 2006 Apr 15;332(7546):875-84.

“Many evaluations of the accuracy of magnetic resonance imaging for the early detection of multiple sclerosis have produced inflated estimates of test performance owing to methodological weaknesses. Use of magnetic resonance imaging to confirm multiple sclerosis on the basis of a single attack of neurological dysfunction may lead to over-diagnosis and over- treatment.”

Whiting et al. BMJ. 2006 Apr 15;332(7546):875-84.

Whiting et al. BMJ. 2006 Apr 15;332(7546):875-84.

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)

Diagnostic criteria for neuromyelitis optica (Devic’s syndrome)

Wingerchuk et al. Neurology 1999; 53: 1107–14.

Lennon et al. Lancet 2004;364:2106-12.

Lennon et al. Lancet 2004;364:2106-12.

Lennon et al. Lancet 2004;364:2106-12.

Lennon et al. J Exp Med 2005;202:473-477.

Aquaporin-4

Jarius et al. Nat Clin Pract Neurol. 2008 Apr;4(4):202-14.

Wingerchuk et al. Neurology 2006;66:1485-1489.

Phenotypic spread

Phenotypic spread

Pittock et al. Arch Neurol. 2006;63:390-396.

MS mimics

Multiple sclerosis definition

Pathological Definition: Inflammatory disease of the CNS

characterised by demyelination and variable degrees of axonal

loss and gliosis; relative axonal sparing in relation to

demyelination.

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

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

with no other aetiology.

Miller et al. Multiple Sclerosis 2008; 14: 1157–1174.

Red Flags

Miller et al. Multiple Sclerosis 2008; 14: 1157–1174.

Developing Diagnostic Criteria

Diagnostic tautology ? disease

Described the disease

Level 1: Descriptive study

Level 2: Diagnostic criteria

Developing polythetic diagnostic criteria

? Disease x

Disease X

Level 1: Diagnostic criteria

Disease Xy

Level 2: Diagnostic criteria

Not Xy vs. Xy

Level 3: Comparison

Clinical, paraclinical, pathology, etc.

Level 4: Validate on different cohorts

Multiple Sclerosis PPMS

NMO OSMS

CIS TSP

? SS

ASYMP

AT RISK

NOT MS

MS

The evolving definition of MS

LHON

APL

SLE CVD

NS

Etc.

AMN ADEM

“What is a disease?”

“What is a disease?”

Biological definition of MS

At risk individual

•Ethnicity

•Sex

•Family history

•Genetics (HLA-DRB1*1501, IL7RA, etc.)

•Environmental risk factor exposure

•Auto-antibodies (~Type 1 diabetes)

Asymptomatic MS

•White matter lesions (dissemination in time and space)

•CSF - +ve OCBs

•EP’s +ve

Symptomatic disease

•CIS

•Chronic fatigue

•Seizure

•Dementia

Multiple sclerosis

•MS

•Relapse-onset

•Primary progressive

•Possible MS

“What is a disease?” A patient’s perspective

A definitive diagnosis is important for several reasons:

• Treatment

• Prognosis

• Knowledge

• Stigmatising

• Family counselling

• Disability Allowances

• Financial planning

• Insurance

• Etc.

Weak points in MS diagnosis

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

• Doesn’t define MS as a biological disease.

• Current diagnostic criteria are a moving target

• 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 ?

• Current diagnostic criteria difficult to implement clinically

• We can’t diagnosis pre-symptomatic disease

• Potentially important for treatments that may prevent or cure the disease

• We can’t identify people at-risk of MS

• Important for preventative strategies

• EBV vaccination trials

• vD supplementation trials