1. Controversie sulla diagnosi precoce della Sclerosi multipla
Viareggio 5-7 Aprile 2019
Controversie sulla diagnosi precoce della Sclerosi multipla
Luisa Pastò
SODc Riabilitazione Neurologica
AOU CAREGGI

2. Multiple sclerosis (MS): a probabilistic diagnosis
There is no single pathognomonic clinical feature or diagnostic test
Clinical, biological, MRI, cerebrospinal fluid (CSF) examination and electrophysiological data, taken together, are the basis of the different diagnostic classifications
Compston A et al. McAlpine's Multiple Sclerosis, 4th Edition. London 2005; Solomon, Neurology 2019

3. EVOLVING DIAGNOSTIC CRITERIA OF MULTIPLE SCLEROSIS
1965 Schumacher criteria
‘80 Poser
Clinical & Paraclinical
MRI
McDonald 2001
McDonald 2005
McDonald 2010
McDonald 2017 revisions .
1868
clinical
diagnosis/autopsy
gold standard
Clinical
diagnosis
Schumacher Ann NY Acad Sci 1965; Poser, Ann Neurol 1983; McDonald Ann Neurol 2001; Polman Ann Neurol 2005; Polman Ann Neurol 2011

4. To talk a «common language»
Rationale for the 2017 revisions
to simplify or clarify components of
the 2010 McDonald criteria
to facilitate earlier diagnosis with earlier fulfillment of the 2010 diagnostic criteria
To preserve the specificity of the 2010 McDonald criteria
To minimize errors
To talk a «common language»
For clinical research
Thompson, Lancet Neurol 2018

5. Key concept (from Schumacher) dissemination in space and time
Key Concepts
Key concept (from Schumacher)
dissemination in space and time
(DIS & DIT)
NO BETTER EXPLANATION!!!
Thompson, Lancet Neurol 2018

6. Key Concepts “…the Panel stressed that the McDonald Criteria should
only be applied in those patients who present with a
TYPICAL CLINICALLY ISOLATED SYNDROME (CIS)
suggestive of MS or symptoms consistent
with a CNS inflammatory demyelinating disease…”
Correct interpretation of symptoms and signs is a fundamental prerequisite for diagnosis.”
Polman et al., Ann Neurol 2011, Thompson Lancet Neurol 2018

7. 2017 McDonald criteria for demonstration of DIS by MRI in CIS
DIS: ≥1 T2 lesions in ≥2 locations
cortical/
juxtacortical
periventricular
infratentorial
spinal cord
Changes from the 2010 McDonald Criteria:
No distinction between symptomatic and asymptomatic lesions
Both cortical and juxtacortical lesions can be utilized
Thompson AJ, et al Lancet Neurol Feb;17(2):

8. INTRACORTICAL LESIONS
Demonstration of DIS by MRI
INTRACORTICAL LESIONS
Filippi et al., Neurology 2010

9. INTRACORTICAL LESIONS
Demonstration of DIS by MRI
INTRACORTICAL LESIONS
This has been reassessed in a MAGNIMS multicentre cohort (n=86) with CIS
adding the evaluation of ICLs improves specificity of the diagnostic criteria preserving sensitivity and accuracy
The assessment of ICLs is likely to reduce current MS misdiagnosis
Increased consistency in acquisition protocols may improve scoring agreement
Preziosa et al., JNNP 2017; Geurst, Neurology, 2011

10. increases the sensitivity of MRI without compromising specificity
Demonstration of DIS by MRI
Asymptomatic vs Symptomatic lesions
patients with single symptomatic lesion a similar risk compared to patients with 1 asymptomatic lesion
954 CIS
Including lesions in the symptomatic region in DIS
increases the sensitivity of MRI without compromising specificity
Tintorè, Neurology 2016
Brownlee, Neurology 2016 ;

11. Demonstration of DIS by MRI
Periventricular: 1 vs 3 (McDonald 2001, 2005) lesions
The 1PV cut-off shows good specificity and sensitivity to predict a second attack
DIS specificity with ≥ 1 PV lesions
was slightly lower than with ≥ 3 PV
Arrambide et al, Neurology 2017

12. Demonstration of DIS by MRI
Periventricular: 1 vs 3 lesions threshold
However, drops in specificity using the 1 PV cut-off in older age populations
Arrambide et al, Neurology 2017

13. Demonstration of DIS by MRI
Periventricular: 1 vs 3 lesions threshold
when assessing DIS plus DIT
no found differences in specificity
Arrambide et al, Neurology 2017

14. one periventricular lesion a higher number of periventricular lesions
Demonstration of DIS by MRI
Periventricular: 1 vs 3 lesions threshold
Neurology 2017
the 2017 McDonald criteria maintain the requirement for
one periventricular lesion
For some patients—eg, older individuals or those with vascular risk factors including migraine—
it might be prudent for the clinician to seek
a higher number of periventricular lesions
Thompson, Lancet Neurol 2018

15. Changes from the 2010 McDonald Criteria:
2017 McDonald Criteria for Demonstration of DIT by MRI in CIS
Simultaneous presence of gadolinium-enhancing and non-enhancing lesions at any time OR
A new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI with reference to a baseline scan, irrespective of the timing of the baseline MRI
Changes from the 2010 McDonald Criteria:
No distinction between symptomatic and asymptomatic lesions
The presence of CSF-specific oligoclonal bands does not demonstrate DIT per se but can substitute for the requirement for demonstration of this measure
Thompson AJ, et al. Lancet Neurol. 2018

16. Role of oligoclonal bands
Objective:
to explore the value of oligoclonal bands in the context of the 2010 McDonald criteria, in patients fulfilling dissemination in space at baseline
566 patients CIS with IgG oligoclonal bands and sufficient data on baseline brain MRI to assess dissemination in space and time

17. aHR for fulfilling 2010 McDonald MS over time
Arrambide, Brain 2018

18. If no better explanation
2017 Diagnostic Algorithm
If no better explanation
CIS + clinical or MRI evidence of DIS and DIT
CIS but no clinical or MRI evidence of DIS and DIT
CIS + clinical or MRI evidence of DIS
but not DIT
2nd event or new MRI with
DIS and DIT
2nd event or
new MRI with DIT
Multiple sclerosis
* Similar to Poser laboratory-supported definite MS
CSF:
OCBs *
Thompson AJ, et al. Lancet Neurol
CIS: clinical isolated syndrome

19. The 2017 McDonald criteria If criteria are applied robotically
Patients with MS
may not fulfill diagnostic criteria
but still
the underlying disease is MS
Patients with other conditions
may fulfill diagnostic criteria
but
the underlying condition is not MS
Thompson, Lancet Neurol 2018

20. Hyperhomocysteinemia
CADASIL
Migraine
Hyperhomocysteinemia
Cerebrotendinous
Xanthomatosis
Fabry
Leber
Vit B12 Deficiency
Copper Deficiency
Krabbe
Hypertension
Chronic Progressive
External Ophtalmoplegia
Behcet
Antiphospholipid
antibodies
Steinert
Adrenoleukodystrophy
Courtesy of Nicola De Stefano

21. Warning about the risk of misdiagnosis
Thompson, Lancet Neurol 2018

22. Clinical syndromes typical and atypical for MS
Solomon, Neurology 2019; Thompson Lancet Neurol 2018

23. Warning about the risk of misdiagnosis
Each one can raise red flags and lead to consider alternate diagnoses
Much worse to overdiagnose patients with MS rather than waiting to have enough confidence in the diagnosis
Thompson, Lancet Neurol 2018

24. Diagnoses and syndromes mistaken for MS
Solomon, Neurology 2016

25. Warning about the risk of misdiagnosis
Thompson, Lancet Neurol 2018

26. MS Red flags “think a twice” age ethnicity < 11 years African
(ADEM/ antiMOG-spectrum)
African
> 50 years
Latin American
Validation studies for the 2017 McDonald criteria were conducted
largely in “patients under 50 within Europe, United States, and Canada”
Siva Neurol Clin 36 (2018); Thompson Lancet Neurol 2018 28

27. Paraclinical MS Red flags
Biological presentation
Blood
Systemic inflammation
Antinuclear antibodies (ANA)
positive in 20-30%, low titers (≤1:320). No specificity
Might reflect only dysregulation in the immune response .
Siva, Neurol Clin 36 (2018) 69–117 29

28. Paraclinical MS Red flags
Biological presentation
although not specific for multiple sclerosis
CSF supports the diagnosis and to rule out differential diagnoses
Cerebro-spinal fluid examination
pleiocytosis > 50 WBC/mm3; Polymorphonuclear cells
CSF Proteins > 1g/L
Isoelectrofocusing and immunofixation IgG (the most sensitive approach)
No IgG oligoclonal bands
< 5-10% in MS
30% in CIS  presence of OCBs is associated with a markedly increased risk of conversion to MS
92% in Behcet, 75% in Lupus, 50% in sarcoidosis
Siva, Neurol Clin 36 (2018) 69–117; Link et Huang, 2006; Dobson, J Neurol Neurosurg Psychiatry 2013; Mc Lean et al. 1995 30

29. MS Red flags MRI presentation 31
Geraldes R, et al. Nat Rev Neurol. 2018 31

30. MRI Red flags iMIMICs mnemonic 32
Geraldes R, et al. Nat Rev Neurol. 2018 32

31. MRI Red flags
iMIMICs mnemonic
If the criteria for DIS are not met, other diagnoses should be considered according to the imaging features
Geraldes R, et al. Nat Rev Neurol. 2018 33

32. central vein is thought to be characteristic of MS lesions
Sati, NATURE REVIEWS | NEUROLOGY 2016
central vein is thought to be characteristic of MS lesions
central veins can detect in ~80% of MS lesions at 3T

34. Sati, Nature Reviews Neurology 2016; Maggi et al, Ann Neurol 2018
a cut-off of 50% is highly predictive in distinguishing MS from other diseases that mimic this condition

35. central vein sign lower in migraine 22%
MRI Red flags MS
Migraine
FLAIR
SWI
central vein sign lower in migraine 22%
than in MS 84%
Sati, NATURE REVIEWS | NEUROLOGY 2016

37. The MAGNIMS proposed modifications
Susceptibility-weighted MRI
Central vein visibility
Three or more periventricular lesions?
One or more optic nerve lesion

38. 130 with optic neuritis CIS
The DIS criteria that included optic nerve involvement were more sensitive (95% vs 83%) than the McDonald 2017 DIS criteria but less specific (57% vs 68%).
In combination with DIT criteria, the modified DIS criteria remained
more sensitive (83% vs 74%); the specificity was the same (77%)

39. GRAZIE PER L’ATTENZIONE!!