Novità diagnostiche nella Sclerosi Multipla

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1 Novità diagnostiche nella Sclerosi Multipla Pietro Maggi MD, PhD ECTRIMS Fellowship Florence, April

2 MS diagnostic criteria On neurologic examination there must be evidence of involvement of 2 or more separate parts of the CNS Schumacher et al. Annals New York Academy of Sciences 1965 The involvement of neuraxis must have occurred temporally in two or more episodes of worsening Magnetic McDonald et Resonance al. Annals of Neurology Imaging 2001 can substitute for clinical findings in the determination of DIS and DIT in patient with a typical CIS. Polman et al. Annals of Neurology 2011 Thompson et al. Lancet Neurology 2018 Reich D.S. et al. NEJM 2018

3 MRI red flags: features atypical for MS but instead suggestive of an alternative diagnosis

4 Solomon A.J et al. Neurology 2016; 87:

5 FLAIR* MRI T2* in a Mag patient with MS and systemic Phase@CHUV sarcoidosis

6 Imaging parenchymal veins in MS The presence of a central vein within the lesion is a pathological hallmark of MS LFB-PAS 100um Image courtesy of Martina Absinta (NIH)

7 Imaging parenchymal veins in MS The perivenular topography of MS lesions has been recently visualized in vivo using susceptibility based MRI at high field strength 1 : Magnitude T2* and Phase T2* relaxation: combination of true T2 relaxation and relaxation caused by magnetic field inhomogeneities 2 Due to the deoxyhemoglobin (paramagnetic molecule), central veins appear prominent within MS lesions. The susceptibility effect is more important at higher field strength (3T & 7T) 1. Absinta M. et al. Nature Review Neurology 2. Cavhan GB et al. Radiographics, RSNA 2009 Image courtesy of Dr Pascal Sati NINDS, NIH

8 Imaging parenchymal veins in MS Recently, the combination of FLAIR and T2*, so called FLAIR* image, allows to achieve an excellent lesion/wm contrast (FLAIR) and vein detection (T2*) Images courtesy of Dr. Daniel Reich and Pascal Sati Translational Neuroradiology Unit, NIB, NINDS, NIH Bethesda US Sati et al. Radiology, 265 (2012)

9 University Hospital

10 Consensus criteria of the NAIMS cooperative Published 11 Nov 2016

11 Consensus criteria of the NAIMS cooperative The central vein in other diseases: Individuals with cerebral small vessel disease, migraine, AQP4-IgG-positive NMOSD, Susac syndrome have a significantly lower proportion of brain lesions with a central vein compared to MS. Mistry et al. MS Journal 2016 Tallantyre et al. Neurology 2011 Sati et al. Nature Review Neurology 2016 Mistry et al. JAMA Neurology 2013 Other MRI mimics of MS, such as SAD, neurosarcoidosis and Sjo gren syndrome, should also be investigated.

12 Accepted for publication in the Annals of Neurology on January 8, 2018

13 Background Multiple Sclerosis: Recurrent focal neurological symptoms associated to focal CNS lesions Sagittal Coronal FLAIR* Image courtesy of Dr. Martina Absinta (NIH, 2016) CNS vasculitis: Neurological presentation variable & non-specific Possible recurrent focal neurological symptoms Possible association to focal CNS lesions FLAIR* Giannini et Al. Acta Neuropathologica 2012

14 Background The differential diagnosis between MS and CNS vasculitis can be difficult because: Clinical course Radiological presentation PACNS MS flare-like clinical course CNS vasculitis context of SADs MS flare-like clinical course MRI abnormalities can be undistinguishable from those observed in MS (DIS criteria) Limited specificity of current MRI diagnostic techniques Focal neurological symptom can be the first clinical manifestation in SADs Sometimes MS and a SADs can coexist in the same pt. is there a place for the central vein sign? PACNS: primary angiitis of the CNS SADs: systemic inflammatory or autoimmune disorder Published online on November Nature Review Neurology

15 Patients and Methods 83 patients were included in this study: Patients where recruited from: the Careggi Hospital (Florence) the Erasme Hospital (Brussels) the San Raffaele Hospital (Milan) MRI acquisition and image post-processing: MRI scanners: 3T Philips Intera MRI scanners (Brussels and Milan) 1.5T Philips Achieva MRI scanner in Florence. 52 patients with RRMS according to McDonald s criteria 31 patients with systemic autoimmune disease and clinical/mri evidence of brain involvement or with PACNS ( inflammatory vasculopathies ) vasculitis patients: 9 patients with SLE 7 patients with APS 10 patients with Behçet disease 2 patients with Sjögren Disease 3 patients with PACNS T2*w EPI Post processing: FLAIR* FLAIR MRI acquisition protocol : 3D T2*-w EPI images acquired during Gd injection and 3D T2-FLAIR images acquired after Gd injection Sati P et al. Nature reviews Neurology. 2016;12(12): Sati P et al. Radiology. 2012;265(3):

16 central vein assessment on FLAIR* images: MS vs. SADs with CNS involvment Axial Multiple Sclerosis Sjögren disease Axial Sagittal Sagittal Coronal Coronal Axial APS SLE Axial Sagittal Sagittal Coronal Coronal

17 Results: central vein assessment Central vein sign assessment % perivenular lesions % 14% % perivenular lesions % 40% 0 Vasculitis MS 0 APS SLE Sjögr en Behçet PACNS MS Topographical distribution of brain lesions The percentage of perivenular lesions was significantly higher in MS vs. vasculitis (p<0.0001) 13% 20% Among vasculitides, Behçet disease showed the highest percentage of perivenular lesions 69% 32% Juxtacortical/ leukocortical lesions * Subcortical/deep white matter lesions * Periventricular lesions * Infratentorial lesions * The separation between the two groups was complete when 50% rule is applied. The frequency of perivenular lesions did not differ significantly between 1.5T and 3T MRI 41% Tallantyre EC et al. Neurology. 2011;76(6):534-9.

18 Results: Fulfillment of different MRI diagnostic criteria for MS

19 Ongoing projects: The central vein sign in challenging diagnostic cases We have recently shown that the central vein sign can accurately distinguish patients known to have MS from patients known to have central nervous system vasculitis Accepted for publication in the Annals of Neurology on January 8, 2018 Now, we would like to test the usefulness of this diagnostic biomarker on its accuracy at the time of the patient s initial diagnosis Aim of the study is to prospectively assess the value of a single 3T FLAIR* MRI scan for: clinical 1. predicting imaging an eventual laboratory diagnosis of MS in patients with possible MS but atypical clinical, biological and/or radiological presentation Diagnostic decision: 2. Predict or confirm an MS diagnosis in patients neuroimmunology with both a possible or established MS diagnosis and a concomitant systemic autoimmune grand rounds disorder (potentially affecting the central nervous system) FLAIR*?

20 The central vein sign in challenging diagnostic cases Male, 52 years old patient Clinical neurological features : 1. (age 48): hemi-face numbness/hypoesthesia 2. (age 50): visual deficit (no better specified) 3. (age 51): right sup limb hypoesthesia with ataxia 4. (age 52) right inferior limb weakness with abnormal gait EDSS: 2.5 (pyramidal 2; sensitive 2; cerebellar 1) Other, systemic symptoms : Bilateral hands pain (joints?) improved after steroid therapy No other systemic symptoms Imaging work-up : Brain MRI: several infratentorial and supratentorial WM lesions suggestive of MS Spinal cord MRI: multiple discrete (<3 segm.) cervical and thoracic cord lesions; one lesion showing contrast enhancement (Gd+) Laboratory work-up : LP: Absence of OCB; elevated protein concentration 1000mg/dl; leuco count<5 cells Infectious and autoab work-up is negative; serologic AQP4 Ab is negative

21 The central vein sign in challenging diagnostic cases Male, 52 years old patient Sagittal FLAIR* Imaging work-up n2: Brain MRI: one new Gd enhancing periventricular lesion Spinal cord MRI: multiple discrete (<3 segm.) cervical and thoracic cord lesions (3 cervical lesion showed mild Gd enhancement) Laboratory work-up n2: LP: Absence of OCB; elevated protein concentration 1300mg/dl Coronal FLAIR* Axial FLAIR* 100% lesions are perivenular on FLAIR* T2w T1w Gd T1w Gd FLAIR Considering the clinical and imaging features highly suggestive of MS and the exclusion of alternative diagnosis (NMOS, Sarcoidosis, Sjogren..) The neuroimmunology round (blinded to FLAIR* results) decided for an MS diagnosis

22 The central vein sign in challenging diagnostic cases Female, 68 years old patient Neurological symptoms : Progressive walking impairment since 8 years Constant bilateral assistance required to walk since 1 year Neurological examination: moderate paraparesis with tetrapiramidal syndrome (pronunced jaw-jerk reflex) and spastic gait Imaging work-up : Brain MRI: several supratentorial periventricular and center semi-ovale WM lesions without Gd enhancement Spinal cord MRI: absence of spinal cord lesions FLAIR images

23 The central vein sign in challenging diagnostic cases Female, 68 years old patient Laboratory work-up : LP: Absence of OCB; normal IgG index; leuco count<1 cells Differential diagnosis: Primary Progressive MS: but negative OCB and spinal cord MRI Inflammatory, metabolic, degenerative, genetic disease Diagnostic work-up: Immune, infectious, metabolic and genetic work-up showed an SPG4 mutation Hereditary spastic paraplegia (autosomal dominant and incomplete penetrance.. ) Sagittal FLAIR* Axial FLAIR* 13% lesions are perivenular on FLAIR* Coronal FLAIR*

24 Acknowledgment National Institutes of Health (NIH) Translational Neuroradiology Section, NINDS Martina Absinta Pascal Sati Daniel Reich University of Florence Department of Neurology, Careggi Hospital Luca Massacesi Matteo Grammatico Luisa Vuolo Vita-Salute San Raffaele University Neuroimaging Research Unit Massimo Filippi Martina Absinta Department of Neuroradiology Roberta Scotti Department of Neurology Vittorio Martinelli Lausanne University Hospital (CHUV) Department Neurology CHUV Renaud Du Pasquier Marie Theaudin Team NIS Department of Radiology Merixtell Bach Cuadra Hagmann Patric Ecole Polytechnique de Lausanne (EPFL) Siemens Healthineers Tobias Kober Jonas Richiardi Mario Fartaria de Oliveira Université Libre de Bruxelles (ULB) Department of Radiology, Hopital Erasme Niloufar Sadeghi Department of Neurology, Hopital Erasme Gaetano Perrotta Department of Neurology, CHU Brugmann Bernard Dachy