defining a disease
DESCRIPTION
A talk about defining a disease. I gave this talk on my recent lecture tour of Canada.TRANSCRIPT
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Defining a disease: the effect of incorporating biomarkers into clinical practice
Gavin Giovannoni Blizard Institute, Barts and The London School of Medicine
December 2014
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Disclosures
Over the last 15 years Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, 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 making available data slides on daclizumab for this presentation. He would also like to thank numerous colleagues for providing him with data and/or slides for this, and other, presentations.
Professor Giovannoni’s tour to Canada has been kindly sponsored by Biogen-Idec, therefore please interpret anything he says about Biogen-Idec’s products in this context.
This presentation has been designed and prepared by Professor Giovannoni with no input from any other parties.
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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
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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
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What is multiple sclerosis?
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.
Jean-Martin Charcot (1825-1893)
• Link between the hitherto mysterious 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 fibres and
nuclei.
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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.
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Diagnostic Tautology!
Conventional Definition:
Pathology
Pretheoretical definition:
Clinical
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What is a disease?
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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).
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Medical Philosophy
Ludwig Wittgenstein 1889-1951
Long rope twisted together out of many shorter fibres
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Neurologists vs. Psychiatrists
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Diagnostic & pathogenic markers
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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.
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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.”
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Will Rogers Phenomenon in Multiple Sclerosis
Sormani et al. Ann Neurol 2008;64:428–433.
Poser
McDonald
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Less active CIS
More active CIS
Less active RRMS
Active RRMS
Will Rogers Phenomenon in RRMS
Active RRMS
Less active CIS
CIS CDMS
MS CIS
Poser, et al. Ann Neurol 1983;13:227-31.
McDonald, et al. Ann Neurol 2001;50:121-7.
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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
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Diagnostic criteria for Primary Progressive MS
Polman et al. Ann Neurol 2005;58:840-6.
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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
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Not PPMS
Possible PPMS
OCB-ve
PPMS OCB-ve
PPMS OCB+ve
Will Rogers Phenomenon in PPMS
PPMS OCB+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.
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Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.
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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.
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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
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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
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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
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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)
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Lennon et al. Lancet 2004;364:2106-12.
NMO
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Diagnostic criteria for neuromyelitis optica (Devic’s syndrome)
Wingerchuk et al. Neurology 1999; 53: 1107–14.
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Wingerchuk et al. Neurology 2006;66:1485-1489.
Phenotypic spread
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Phenotypic spread
Pittock et al. Arch Neurol. 2006;63:390-396.
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Whiting et al. BMJ. 2006 Apr 15;332(7546):875-84.
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Accuracy of MRI for the diagnosis of MS: systematic review
Whiting et al. BMJ. 2006 Apr 15;332(7546):875-84.
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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.
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20/170 (12%) patients (12 minimal non-specific & 8 zero MRI lesions)
Abnormal spinal MRI Spinal MRI
12 CDMS / LSDMS 1 clinically -probable MS
7 possible MS
Normal brain MRI
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Differential diagnosis of suspected MS: a consensus approach
Miller et al. MSJ 2008; 14: 1157–1174
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MS mimics
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Neurosarcoidosis
• “Sarcoidosis is an inflammatroy multisystem
disorder of unknown cause.”
• “Neurosarcoidosis is a serious and commonly
devastating
complication of sarcoidosis.”
• “Solitary nervous system sarcoidosis is difficult
to diagnose.”
Hoitsma E, et al. Neurosarcoidosis: a clinical dilemma. Lancet Neurol. 2004 Jul;3(7):397-407. Review.
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Zajicek et al. QJ Med 1999;92:103-117.
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Zajicek et al. QJ Med 1999;92:103-117.
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Diagnostic tautology
? disease
Describe the disease
Level 1: Descriptive study
Level 2: Diagnostic criteria
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Developing polythetic diagnostic criteria
? Disease x
Disease X
Level 1: Diagnostic criteria
Disease Xy
Level 2: Diagnostic criteria
Level 4: Validate on different cohorts
Not Xy vs. Xy
Level 3: Comparison
Clinical, paraclinical, pathology, etc.
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Neurosarcoidosis
Q: Was the diagnosis
neurosarcoidosis?
Study Eligibility Criterion (n = 531)
• A diagnosis of neurosarcoidosis in the differential diagnosis.
Inclusion Criterion A (n=85)
• A final diagnosis of neurosarcoidosis by a consultant neurologist.
Q: Was there histological
confirmation of non-
caseating granulomas?
Q: Was it a multisystem
disease?
Q: Was there no occupational or
surgical exposure to
inorganic foreign bodies?
Q: Was there no
alternative diagnoses?
yes yes yes
no
yes
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Inclusion Criterion B (n=53)
• Histological evidence of sarcoid granulomas on an organ biopsy or Kveim test.
• Multisystem disease.
• No occupational or surgical exposure to inorganic foreign bodies.
• No alternative diagnoses
Inclusion Criterion C (n=25)
• Histological evidence of sarcoid granulomas on an organ biopsy.
Q: Was the histological confirmation of non-caseating granulomas based on
organ biopsy, i.e. sarcoid granulomas, vs. a Kveim test only?
Q: Was the onset of the neurological problems
more than 5 years since the tissue biopsy?
Q: Was there additional evidence of systemic sarcoid activity within 5 years of the
onset of the neurological problems?
no
yes
yes
yes
no
no
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Inclusion Criterion D (n=22)
• If onset of neurological problems is more than 5 years after sarcoid granulomas were identified on organ biopsy, there must be additional evidence of systemic sarcoid activity within 5-years of the onset of the neurological problems.
Q: Was the histological
confirmation of sarcoid granulomas
obtained from neurological tissue?
Q: Was there histological or
additional evidence of sarcoid
granulomas outside the nervous system?
Inclusion Criterion E (n=4)
• Histological evidence of sarcoid granulomas within brain, spinal cord, meninges or nerves on biopsy. • Sarcoid granulomas outside brain, spinal cord, meninges and nerves are likely to be present on the basis of histological or other findings.
no
yes yes
no
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Neurosarcoidosis
Diagnostic Category
No. patients
A
85
B
53
C
25
D
22
E 4
% intrathecal synthesis oligoclonal IgG
26% 13% 14% 5% 0%
Chamoun et al. To be resubmitted for publication.
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New polythetic diagnostic criteria for neurosarcoidosis
Chamoun et al. Cambridge Thesis 1998.
Essential criteria to be fulfilled by all cases
a. Multisystem disease with neurological involvement compatible with sarcoidosis.
b. Neurological and systemic involvement must be temporally related with evidence of disease activity occurring within 5 years of each other.
c. No occupational or surgical exposure to inorganic foreign bodies.
d. No alternative diagnoses.
1. Possible neurosarcoidosis – clinically supported 1a - Clinically supported without Kveim testing
Clinical picture compatible with sarcoidosis.
1b – Clinically supported with Kveim testing
Clinical picture compatible with sarcoidosis and histological evidence of granulomatous reaction on Kveim testing.
2. Probable neurosarcoidosis - histologically supported by non-nervous tissue biopsy
Histological evidence of sarcoid granulomas on a non-nervous tissue biopsy.
3. Definite neurosarcoidosis - histologically supported by nervous tissue biopsy
Histological evidence of sarcoid granulomas on nervous tissue biopsy.
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De Seze et al. Neurology 2001;57:1359-63.
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• Tended to be female • Fewer brain MRI
abnormalities • Less likely to fulfill
criteria for definite PPMS
PPMS
n=10 (17%) SS / PPMS
n=60 PPMS
PPMS - SS
n=50 PPMS
n=10 (17%) SS / PPMS vs.
Conclusion: Sjögren’s myelopathy is not a disease yet; there is no clinicopathological correlate
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Multiple Sclerosis PPMS
NMO OSMS
CIS TSP
? SS
ASYMP
AT RISK
NOT MS
MS
The evolving definition of MS
LHON
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Important points
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“What is a disease?”
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“What is a disease?”
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“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.
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Conclusion
• The diagnosis of MS relies on a pretheoretical definition – This 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 – Important for preventative and curative strategies
• We can’t identify people at-risk of MS – Important for preventative strategies
• There is a philosophy and a science behind defining a disease
• Inaccurate and accurate diagnosis have major implications
• Undiagnosing MS is hard
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