Pitfalls in MS diagnosis

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry

What is multiple sclerosis?

What is a disease?

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).

“A disease is a clinicopathological entity.”

Phrenology

“A disease is a clinicopathological entity.”

.

Robert Carswell (1793-1857)

1. The first important step toward a recognition of the pathology of MS came with a discovery by Robert Carswell, a pathologist of the mid 19th century. During a postmortem, Carswell found strange lesions in the spinal cord of an unfortunate subject. Unaware of their cause, he meticulously recorded their gross appearance.

2. Carswell's handpainted illustration of the lesions is seen here in the slide. It appeared, together with descriptive text, in his Atlas of Pathology, published in 1838.

3. Within the text, Carswell described the pathology as: 4. "a peculiar diseased state of the chord and pons

Varolii, accompanied with atrophy of the discoloured portions".

5. Despite his major contribution in describing the pathology of MS lesions, Carswell did not record any clinical associations with his observations. The clinical symptoms of MS were not linked to the 'diseased' state Carswell described until much later.

.

Jean Cruveilhier (1791 – 1874)

1. Jean Cruveilhier was an eminent Parisian anatomist who also lived through the mid 19th century. Cruveilhier, like Robert Carswell, described the pathology of the lesions seen in MS and although the two men worked independently, their illustrations appeared almost simultaneously. Much debate exists as to which illustration was made first. However, Cruveilhier's version, seen in this slide, was not published until 1842.

2. Cruveilhier's contribution to our understanding of MS goes beyond his description of its pathology as he was the first to record the clinical history of a patient later found to have neuronal lesions. His notes recall that the woman:

3. "had been ill six years without cause … she noticed that the left leg resisted her will to such a degree that she fell in the street" .

4. Cruveilhier described how over several years, the patient developed weakness of both legs and arms, spasms, difficulty in swallowing and visual disturbances. From this he diagnosed 'a lesion of the upper portion of the spinal cord'.

.

Jean-Martin Charcot (1825-1893)

1. Jean-Martin Charcot was an eminent 19th century French neurologist who worked at the SalpÃtriÀre hospital, Paris. Without doubt, Charcot was one of the most important characters in the history of MS, his findings representing a huge breakthrough for the clinical understanding of the disease.

2. Charcot was the first to make definite links between the hitherto mysterious symptomatology, now known to be MS, and the pathological changes seen in post-mortem samples. For the first time, almost forty years after the discovery of the lesions, the clinical condition was described by Charcot as 'sclr¾rose en plaques' and MS as recognised as a distinct disease entity.

3. Charcot's contribution extended to the development of diagnostic criteria, which included the now famous Charcot's triad, diplopia (double vision), ataxia (disturbances of balance or co-ordination) and dysarthria (difficulties with, or slurred speech) which he observed in his own housekeeper.

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

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.

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.

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

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

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 Tautology

Conventional Definition: Pathology

Pretheoretical definition: Clinical

McDonald vs. Poser

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..

Phenotypic spread

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. J Exp Med 2005;202:473-477.

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

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

Not MS Not MS OCB-ve

OCB+ PPMS

PPMS diagnosed according the original McDonald criteria

Not MS

OCB-ve PPMS

OCB+ PPMS

PPMS diagnosed according the New Polman-McDonald Criteria

Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.

Misrepresentation

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

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

Accuracy of MRI for the diagnosis of MS: systematic review

Whiting, et al. BMJ 2006;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.”

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)

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 / RIS

•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

MS mimics

“What is a disease?”

Multiple Sclerosis PPMS

NMO OSMS

CIS TSP

? SS

ASYMP

AT RISK

NOT MS

MS

The evolving definition of MS

LHON

Flags

My flags

• The 3 best investigation neurologists have are

• Repeating the history and examination

• Always step back and ask the question ‘can it be something else?’

• Flags

• Normal CSF: OCB-ve

• Abnormal CSF: raised protein, pleocytosis

• Systemic symptoms & signs; e.g. uveitis

• Age (>50)

• Ethnicity

• Comorbidities (vascular risk factors and headache)

• Neuropsychiatry (undoing the diagnosis)

• Peripheral nerve involvement

• Clinical Vigilance

• Clinical blindspots

• ‘Go for the money’

• Dual pathology (MND, CNS lymphoma, migraine, vascular disease)

Mistry et al. JAMA Neurol. 2013;70(5):623-628.

“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.

• Misdiagnosis may have serious consequences

Weak points in MS diagnosis

• The diagnosis of MS relies on a pretheoretical 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 • Important for clinical trials

• We can’t diagnosis pre-symptomatic disease • Important for treatments that potentially cure the disease

• We can’t identify people at-risk of MS • Important for preventative strategies

• Medicine remains and art and is very alive and kicking

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