precoce della Sclerosi multipla Luisa Pastò SODc Riabilitazione Neurologica AOU CAREGGI Viareggio 57 Aprile 2019 There is no single pathognomonic clinical feature or diagnostic test ID: 1033341
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1. Controversie sulla diagnosi precoce della Sclerosi multiplaLuisa PastòSODc Riabilitazione NeurologicaAOU CAREGGI Viareggio 5-7 Aprile 2019
2. There is no single pathognomonic clinical feature or diagnostic testClinical, biological, MRI, cerebrospinal fluid (CSF) examination and electrophysiological data, taken together, are the basis of the different diagnostic classificationsCompston A et al. McAlpine's Multiple Sclerosis, 4th Edition. London 2005; Solomon, Neurology 2019 Multiple sclerosis (MS): a probabilistic diagnosis
3. 1868clinical diagnosis/autopsy gold standard McDonald 2017 revisionsClinical diagnosisSchumacher Ann NY Acad Sci 1965; Poser, Ann Neurol 1983; McDonald Ann Neurol 2001; Polman Ann Neurol 2005; Polman Ann Neurol 2011EVOLVING DIAGNOSTIC CRITERIA OF MULTIPLE SCLEROSIS
4. Thompson, Lancet Neurol 2018Rationale for the 2017 revisions
5. Thompson, Lancet Neurol 2018Key ConceptsKey concept (from Schumacher) dissemination in space and time (DIS & DIT)NO BETTER EXPLANATION!!!
6. Key ConceptsPolman et al., Ann Neurol 2011“In applying the McDonald Criteria, it remains imperative that alternative diagnoses are considered and excluded.”
7. Key ConceptsPolman et al., Ann Neurol 2011, Thompson Lancet Neurol 2018“…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.”
8. 2017 McDonald criteria for demonstration of DIS by MRI in CIS DIS: ≥1 T2 lesions in ≥2 locationsChanges from the 2010 McDonald Criteria:No distinction between symptomatic and asymptomatic lesionsBoth cortical and juxtacortical lesions can be utilizedperiventricularcortical/juxtacorticalinfratentorialspinal cordThompson AJ, et al Lancet Neurol. 2018 Feb;17(2):162-173.
9. INTRACORTICAL LESIONSFilippi et al., Neurology 2010Demonstration of DIS by MRI
10. INTRACORTICAL LESIONSThis 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 misdiagnosisIncreased consistency in acquisition protocols may improve scoring agreementDemonstration of DIS by MRIPreziosa et al., JNNP 2017; Geurst, Neurology, 2011
11. Brownlee, Neurology 2016; Demonstration of DIS by MRIAsymptomatic vs Symptomatic lesionspatients with single symptomatic lesion a similar risk compared to patients with 1 asymptomatic lesion954 CISIncluding lesions in the symptomatic region in DIS increases the sensitivity of MRI without compromising specificityTintorè, Neurology 2016
12. Brownlee, Neurology. 2016; Demonstration of DIS by MRIAsymptomatic vs Symptomatic lesions954 CISTintorè, Neurology 2016inclusion of symptomatic lesions in theMRI determination of DIS or DIT increases diagnostic sensitivity with no reduction in specificity
13. Periventricular: 1 vs 3 (McDonald 2001, 2005) lesions Demonstration of DIS by MRIThe 1PV cut-off shows good specificity and sensitivity to predict a second attackDIS specificity with ≥ 1 PV lesionswas slightly lower than with ≥ 3 PVArrambide et al, Neurology 2017
14. Periventricular: 1 vs 3 lesions thresholdDemonstration of DIS by MRIHowever, drops in specificity using the 1 PV cut-off in older age populationsArrambide et al, Neurology 2017
15. Periventricular: 1 vs 3 lesions thresholdDemonstration of DIS by MRIwhen assessing DIS plus DIT no found differences in specificityArrambide et al, Neurology 2017
16. Periventricular: 1 vs 3 lesions thresholdDemonstration of DIS by MRINeurology 2017the 2017 McDonald criteria maintain the requirement for one periventricular lesionThompson, Lancet Neurol 2018For 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
17. 2017 McDonald Criteria for Demonstration of DIT by MRI in CISSimultaneous presence of gadolinium-enhancing and non-enhancing lesions at any timeORA new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI with reference to a baseline scan, irrespective of the timing of the baseline MRIThompson AJ, et al. Lancet Neurol. 2018Changes from the 2010 McDonald Criteria:No distinction between symptomatic and asymptomatic lesionsThe presence of CSF-specific oligoclonal bands does not demonstrate DIT per se but can substitute for the requirement for demonstration of this measure
18. Role of oligoclonal bandsObjective: to explore the value of oligoclonal bands in the context of the 2010 McDonald criteria, in patients fulfilling dissemination in space at baseline566 patients CIS with IgG oligoclonal bands and sufficient data on baseline brain MRI to assess dissemination in space and time
19. Arrambide, Brain 2018aHR for fulfilling 2010 McDonald MS over time
20. 2017 Diagnostic AlgorithmCIS: clinical isolated syndromeCIS + clinical or MRI evidence of DIS and DITCIS but no clinical or MRI evidence of DIS and DITCIS + clinical or MRI evidence of DIS but not DIT2nd event or new MRI with DIS and DIT2nd event ornew MRI with DITMultiple sclerosis* Similar to Poser laboratory-supported definite MSCSF: OCBs *Thompson AJ, et al. Lancet Neurol. 2018.If no better explanation
21. The 2017 McDonald criteriaThompson, Lancet Neurol 2018If criteria are applied roboticallyPatients with MSmay not fulfill diagnostic criteria but stillthe underlying disease is MSPatients with other conditionsmay fulfill diagnostic criteriabutthe underlying condition is not MS
22. CADASILMigraineHyperhomocysteinemiaCerebrotendinous Xanthomatosis FabryLeberVit B12 DeficiencyCopper DeficiencyKrabbeHypertensionChronic Progressive External OphtalmoplegiaBehcetAntiphospholipidantibodiesSteinertAdrenoleukodystrophyCourtesy of Nicola De Stefano
23. Thompson, Lancet Neurol 2018 Warning about the risk of misdiagnosis
24. Clinical syndromes typical and atypical for MSSolomon, Neurology 2019; Thompson Lancet Neurol 2018
25. Thompson, Lancet Neurol 2018 Warning about the risk of misdiagnosisEach 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
26. Diagnoses and syndromes mistaken for MSSolomon, Neurology 2016
27. Thompson, Lancet Neurol 2018 Warning about the risk of misdiagnosis
28. Siva Neurol Clin 36 (2018); Thompson Lancet Neurol 2018Validation studies for the 2017 McDonald criteria were conductedlargely in “patients under 50 within Europe, United States, and Canada”ageethnicity< 11 years(ADEM/ antiMOG-spectrum)African> 50 yearsLatin American MS Red flags“think a twice”
29. Siva, Neurol Clin 36 (2018) 69–117BloodSystemic inflammationAntinuclear antibodies (ANA)positive in 20-30%, low titers (≤1:320). No specificity Might reflect only dysregulation in the immune response Paraclinical MS Red flagsBiological presentation
30. Paraclinical MS Red flagsBiological presentationalthough not specific for multiple sclerosisCSF supports the diagnosis and to rule out differential diagnosesCerebro-spinal fluid examinationpleiocytosis > 50 WBC/mm3; Polymorphonuclear cellsCSF Proteins > 1g/LIsoelectrofocusing 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 MS92% 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
31. MS Red flagsMRI presentationGeraldes R, et al. Nat Rev Neurol. 2018
32. 32Geraldes R, et al. Nat Rev Neurol. 2018iMIMICs mnemonicMRI Red flags
33. 33iMIMICs mnemonicIf the criteria for DIS are not met, other diagnoses should be considered according to the imaging featuresMRI Red flagsGeraldes R, et al. Nat Rev Neurol. 2018
34. central vein is thought to be characteristic of MS lesions central veins can detect in ~80% of MS lesions at 3T Sati, NATURE REVIEWS | NEUROLOGY 2016
35.
36. Sati, Nature Reviews Neurology 2016; Maggi et al, Ann Neurol 2018a cut-off of 50% is highly predictive in distinguishing MS from other diseases that mimic this condition
37.
38. Lesioni definite perivenulari qualora:contengano una sottile linea ipointensa (d <2 mm) o una puntiforme ipointensità visibile in almeno 2 piani perpendicolari di RMe la vena che attraversa parzialmente o interamente la lesione appaia posizionata approssimativamente al centro della lesioneMaggi et al, Ann Neurol 2018
39. Maggi et al, Ann Neurol 2018
40. central vein sign lower in migraine 22% than in MS 84%MRI Red flags Sati, NATURE REVIEWS | NEUROLOGY 2016MSMigraineFLAIRSWI
41. migraine vs MS the median percentage of WMLs with the central vein sign was lower in migraine (22%) than in MS (84%)Migrainelesion without central vein signMRI Red flags Sati, NATURE REVIEWS | NEUROLOGY 2016
42.
43. Susceptibility-weighted MRICentral vein visibility Three or more periventricular lesions?One or more optic nerve lesionThe MAGNIMS proposed modifications
44. when the MRI in Multiple Sclerosis MAGNIMS 2016 or the 2017 revised criteria are applied84 patients with migraine with aura (MA) and 79 patients with CISpresence at least 3 periventricular lesions (MAGNIMS criteria) increases the specificity in distinguishing MA from CIS (100% vs 87%)PVLs were the best factor separating CIS from MA (odds ratio 0.156, 95% CI 0.076, 0.319; p < 0.001)The MAGNIMS proposed modifications
45. 130 with optic neuritis CISThe 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%)
46. ControversyConclusionDiagnosis of MS: ART and SCIENCE
47. GRAZIE PER L’ATTENZIONE!!