Neurophysiology in diagnosis and monitoring of MS
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1 ISTITUTO SCIENTIFICO UNIVERSITARIO SAN RAFFAELE MS Academia Amsterdam - October 18, 2011 Neurophysiology in diagnosis and monitoring of MS Letizia Leocani Dep.t of Neurology, Clin. Neurophysiol. and Neurorehabilitation INSPE- Scientific Institute Hospital San Raffaele, Milan
2 Evoked Potentials Expanded Neurological Examination Visual-VEP optic nerve Somatosensory-SEP, Motor-MEP brain - spinal cord Auditory-BAEP brainstem
3 MS functional deficits: Pathological substrates Segmental demyelination Axonal degeneration MS pathology: functional effects (on EPs) Conduction slowing (10 mm=15-25 msec) (Latency) Temporal dispersion (Morphology) Increased refractoy period (Amplitude) Conduction block (>5mm) (Amplitude) Axonal degeneration (Amplitude)
4 Delayed latency EPs abnormalities Demyelination most often asymptomatic detection of subclinical lesions may be predictive of future axonal loss Reduced amplitude Good correlation with clinical impairment Transient Conduction block (demyelination/inflammation) Permanent Axonal loss
5 Visual EPs patterns Normal 2- Amplitude asymmetry 3- Latency prolongation 4- Amplitude asymmetry and latency prolongation Anderson et al 1987
6 Relationship between clinical findings and EPs abnormalities % 80.00% Symptomatic patients Asymptomatic patients 60.00% 40.00% 20.00% 0.00% Abnormal VEP Abnormal SEP Abnormal BAEP Comi G. et al. Multiple Sclerosis 1999; 5:
7 115 CIS patients followed for 5 years VEP SEP MEP BAEP N. of patients Abnormal Eps (n) Abnormal Eps (%) 47.0% 67.5% 50.6% 17.5% Sensitivity (symptomatic) 83.3% 67.7% 58.5% 27.0% Sensitivity (asymptomatic) 34.1% 67.3% 35.7% 12.5% Di Maggio et al. ECTRIMS 2011
8 Predictive value of paraclinical tests in CIS to early evolution to CDMS test Predictive value (%) POS NEG brainmri CSF VEP SEP-UL SEP-LL BAEP pts avg follow-up 3 yrs Filippini et al 1994
9 Proportion of disease-free pts CIS EPs and conversion to CDMS over 2 years n: 115 (all MRI+) EPs <5 EPs >5 MRI < 9 EPs <5 EPs >5 MRI > 9 months Di Maggio et al. ECTRIMS 2011
10 Multifocal VEPs in ON: predictive value of fellow eye abnormalities of conversion to MS after 1 year (McDonald criteria) 48 ON pts Klistorner et al Mult Scler 2009
11 Optical Coherence Tomography Frohman 2008
12 OCT in chronic ON RNFL thickness correlates with VEP amplitude (axonal loss) unaffected affected Trip et al. 2005
13 65 pts 6 months after ON Clinical ON VEPs 81% OCT 60% Subclinical ON VEPs 75% OCT <20% Residual contrast sensitivity Naismith et al, JNNP 2009
14 VEPs after high doses of steroids in MS - Optic Neuritis basal 1 week 1 month Smith et al 1986
15 VEPs in MS anti-aquaporin positive (17) and negative (84) pts Watanabe et al Mult Scler 2009
16 VEPs after ON in NMO spectrum disorder (19) and MS (18) pts 73% 27% 35% 65% ms Straffi et al ECTRIMS 2011
17 FREQUENCY OF EP ABNORMALITIES (%) in clinically definite MS (n. 116: 50 RR, 48 SP, 18 PP) SEP (upper) SEP (lower) PP vs RR: p<0.02 SP vs RR: * p<0.02; ** p<0.001 * ** * * MEP (upper) MEP (lower) BAEP VEP RR PP SP
18 SPMS: > absent VEPs vs PPMS even excluding previous ON Bianco et al in prep.
19 EPs and longitudinal monitoring of MS
20 Longitudinal changes of P100 latency after acute ON Affected eye Unaffected eye 6 months 3 years 6 months 3 years Brusa et al. 1999
21 Longitudinal MEPs changes (2 yrs) worsened stable Jung et al 2008
22 MEPs after high doses of steroids (24 pts) 5 days Central Motor Conduction Time 1 g/day 2 g/day EDSS MRC Fierro et al 2002
23 Somatosensory EPs abnormalities Normal > N20 latency N13 absent N13 and N20 absent 3 Progression no longer detectable! from Anderson et al modified
24 EP SCORES 0 = normal 1 = abnormal latency or amplitude 2 = abnormal latency and amplitude 3 = absence
25 % EPs abnormalities: basal vs final (4 yrs) Leocani et al, JNNP 2006
26 EPs score: basal vs final Baseline Final p SEP < MEP VEP BAEP Global EP Leocani et al, JNNP 2006
27 global basal EP score Global basal EP* score vs EDSS *VEP, MEP, SEP, BAEP N=84 EDSS R=0.6 p< (Spearmann rank correlation) Leocani et al, JNNP 2006
28 global basal EP score Basal EPs and changes in disability at follow-up (4 yrs) * N=84 12 * * 0 BAEP MEP t. SEP global EDSS - EDSS + * p< 0.04, Signed ranks EDSS + 1 if basal EDSS <5 0.5 if basal EDSS > 5 Leocani et al, JNNP 2006
29 EPs score - time to EDSS 4.0 and MS patients (62 RR, 14 PP, 4 SP) EPs <8 EPs <8 EPs >8 EPs >8 SEP VEP BAEP MEP yrs yrs Invernizzi J Neurol 2011
30 Predicted vs observed EDSS using linear models 50 patients (47 RR, 3 CIS) SEP VEP BAEP MEP Schlaeger 2011
31 CIS: n. abnormal EPs - time to EDSS 3.0 n: 247 (out of 335) SEPs VEPs BAEPs no MEPs Pelayo, Montalban et al. Multiple Sclerosis 2010
32 Predictive value of subclinical Eps abnormalities on future clinical involvement of the same FS (5 yrs) VEPs: PPV=15.8% BAEPs: PPV=55.6% SEPs: PPV=38.8% MEPs: PPV=90.0% (p=0.03) Di Maggio et al. ECTRIMS 2011
33 Clinical usefulness of EPs in MS DIAGNOSIS Detection of clinically silent lesions SCARCE Indication on underlying pathology (demyelination, axonal damage/block) VERY GOOD MONITORING (e.g. assessing treatment efficacy) Detection of disease activity SCARCE Objectivation of involvement of sensory/motor pathways in patients with vague symptoms (e.g.relapse confirmation) GOOD Detection of disease progression GOOD Prediction of future disability (?)
34 Experimental Neurophysiology Unit (INSPE) Supervisor Letizia Leocani Thanks to: Giancarlo Comi Gianvito Martino Mauro Comola Vittorio Martinelli PhD Students (INSPE): Federica Alemanno Ninfa Amato Marco Cambiaghi Alberto Inuggi (ex) Kara Sinem Svetla Velikova Visiting Professors: Javier Gonzalez-Rosa (Marie-Curie Fellowship) Luis Teneud, PhD (FISM Fellowship) Residents (Neurology Dep.t) Raffaella Chieffo Elisabetta Coppi Francesca Spagnolo Laura Straffi
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