Regina Schlaeger

Prediction of long-term disability in multiple sclerosis.

Background: Little is known about the predictive value of neurophysiological measures for the long-term course of multiple sclerosis (MS). Objective: To prospectively investigate whether combined visual (VEP) and motor evoked potentials (MEP) allow prediction of disability over 14 years. Methods: A total of 30 patients with relapsing–remitting and secondary progressive MS were prospectively investigated with VEPs, MEPs and the Expanded Disability Status Scale (EDSS) at entry (T0) and after 6, 12 and 24 months, and with cranial MRI scans at entry (T2-weighted and gadolinium-enhanced T1-weighted images). EDSS was again assessed at year 14 (T4). The association between evoked potential (EP), magnetic resonance (MR) data and EDSS was measured using Spearman’s rank correlation. Multivariable linear regression was performed to predict EDSST4 as a function of z-transformed EP-latenciesT0. The model was validated using a jack-knife procedure and the potential for improving it by inclusion of additional baseline variables was examined. Results: EDSS valuesT4 correlated with the sum of z-transformed EP-latenciesT0 (rhou2009=u20090.68, pu2009<u20090.0001), but not with MR-parametersT0. EDSST4 as predicted by the formula EDSST4u2009=u20094.194u2009+u20090.088 * z-score P100T0u2009+u20090.071 * z-score CMCTUE, T0 correlated with the observed values (rhou2009=u20090.69, pu2009<u20090.0001). Conclusion: Combined EPs allow prediction of long-term disability in small groups of patients with MS. This may have implications for the choice of monitoring methods in clinical trials and for daily practice decisions.

Combined evoked potentials as markers and predictors of disability in early multiple sclerosis

OBJECTIVEnTo prospectively assess combined evoked potentials (EP) as markers and predictors of the disease course of early MS over 3 years.nnnMETHODSnFifty patients in the early phase of relapsing remitting MS prospectively received visual, somatosensory and motor EP and EDSS assessments at baseline (T1) and at 6 months intervals during 3 years. Spearman rank correlation was used to determine the relationship between z-transformed EP-latencies (z-EPL) and EDSS. Multivariable linear regression was performed to predict EDSS at year 3 (T7) in function of z-EPL(T1). Validity of the models was assessed using group cross-validation.nnnRESULTSnAt each of the seven points in time, EDSS correlated with the sum of z-EPL (0.64 ≤ rho ≤ 0.79, p<0.001). The change of the sum of z-EPL(T7-T1) correlated with the change of EDSS(T7-T1) (rho=0.51, p=0.001). EDSS(T7) as predicted by the sum of z-scores of EP latencies or by the number of pathological EP results at baseline correlated with the observed clinical values after 3 years (rho>0.70, p<0.001, for both measures).nnnCONCLUSIONSnMultimodal EPs correlate well with clinical disability in cross-sectional and longitudinal comparison in early MS and allow prediction of disease evolution over 3 years.nnnSIGNIFICANCEnEPs seem well suited as markers of the disease course in early MS in clinical trials and bear potential for supporting decision-finding in individual patients.

Combined visual and motor evoked potentials predict multiple sclerosis disability after 20 years

Background: The development of predictors of multiple sclerosis (MS) disability is difficult due to the complex interplay of pathophysiological and adaptive processes. Objective: The purpose of this study was to investigate whether combined evoked potential (EP)-measures allow prediction of MS disability after 20 years. Methods: We examined 28 patients with clinically definite MS according to Poser’s criteria with Expanded Disability Status Scale (EDSS) scores, combined visual and motor EPs at entry (T0), 6 (T1), 12 (T2) and 24 (T3) months, and a cranial magnetic resonance imaging (MRI) scan at T0 and T2. EDSS testing was repeated at year 14 (T4) and year 20 (T5). Spearman rank correlation was used. We performed a multivariable regression analysis to examine predictive relationships of the sum of z-transformed EP latencies (s-EPT0) and other baseline variables with EDSST5. Results: We found that s-EPT0 correlated with EDSST5 (rho=0.72, p<0.0001) and ΔEDSST5-T0 (rho=0.50, p=0.006). Backward selection resulted in the prediction model: E (EDSST5)=3.91–2.22×therapy+0.079×age+0.057×s-EPT0 (Model 1, R2=0.58) with therapy as binary variable (1=any disease-modifying therapy between T3 and T5, 0=no therapy). Neither EDSST0 nor T2-lesion or gadolinium (Gd)-enhancing lesion quantities at T0 improved prediction of EDSST5. The area under the receiver operating characteristic (ROC) curve was 0.89 for model 1. Conclusions: These results further support a role for combined EP-measures as predictors of long-term disability in MS.

Electrophysiological markers and predictors of the disease course in primary progressive multiple sclerosis

Background: Currently no valid surrogate marker exists for primary progressive multiple sclerosis (PPMS). Objective: Our aim was to prospectively investigate multimodal evoked potentials (EPs) as markers and predictors of the disease course in PPMS. Methods: Twenty-two PPMS patients were prospectively examined with visual, somatosensory and motor EPs and Expanded Disability Status Scale (EDSS) assessments at baseline (T0) and at six-month intervals over three years. Spearman rank correlation was used to determine the relationship between EP measures and EDSS. The relationship between disease evolution and a numerical score derived from z-transformed EP-latencies (s-EP-Q) and baseline characteristics was further assessed using multivariable linear regression analysis. Results: s-EP-Q correlated with EDSS score at all points in time in cross-sectional comparison (0.53≤rs ≤0.68; 0.0007≤p≤0.0232) and also longitudinally by trend (rs=0.46, p=0.0740). The s-EP-QT0 correlated with the EDSS score at year 3 (T6) (rs=0.77, p<0.0001). The s-EP-Q changes became statistically significant six months before corresponding changes were seen in the EDSS score. EDSST6 as predicted by EDSST6= −1.027+0.037* age+0.217* s-EP-QT0 + 0.695* EDSST0 correlated with the observed values (rs=0.92, p<0.0001). Conclusions: Multimodal EPs correlate well with disability in PPMS, and allow some prediction of the disease course over three years. These findings support a role of EPs as surrogate markers in clinical trials in PPMS.

Monitoring multiple sclerosis by multimodal evoked potentials: Numerically versus ordinally scaled scoring systems

OBJECTIVEnTo compare the ability of different evoked potential scores (EPS) to monitor and predict the disease course in multiple sclerosis (MS).nnnMETHODSnSeventy-two patients with MS or clinically isolated syndrome were investigated by visual, motor, and somatosensory EP and expanded disability status scale (EDSS) at baseline (T0) and months 6, 12, 24, 36 (T4). EP results were rated according to ordinal (o), semi-quantitative (sq), and quantitative (q) EPS. Spearman rank correlation and multivariable linear regression were used to investigate the associations between EPS and clinical disability.nnnRESULTSnAll EPS correlated with EDSS cross-sectionally (0.72⩽rho⩽0.87, all p<0.001) and longitudinally (0.39⩽rho⩽0.47, all p⩽0.004). EPS(T0) and EDSS(T0) together explained 85-86% of EDSS(T4) variance. A posteriori power calculation showed that the sample sizes needed to detect significant changes over 6 months in q-EPS, sq-EPS and o-EPS with 90% certainty would be 50, 129 and 222, respectively. q-EPS change(T1-T0) correlated with EDSS change(T4-T0) (rho=0.56, p<0.001), while sq-EPS and o-EPS changes(T1-T0) did not.nnnCONCLUSIONnAll three EPS allow disease course monitoring in MS. However, the quantitative EPS detects clinically relevant short-term changes with a smaller sample size than semi-quantitative or ordinal EPS.nnnSIGNIFICANCEnThese results underscore the potential of EPS to characterize MS disease evolution.

Prediction of MS disability by multimodal evoked potentials: Investigation during relapse or in the relapse-free interval?

OBJECTIVEnLittle is known about optimal timing of multimodal evoked potential (EP)-investigations regarding prediction of MS disability. The aim of this study was to investigate whether timing of EP-investigations during a relapse or in the relapse-free interval influences prediction of MS disability.nnnMETHODSnTwo groups of MS patients with similar age and gender distributions received visual, motor and somatosensory EPs either during a relapse (Group 1) or in the relapse-free interval (Group 2). Expanded Disability Status Score (EDSS) was obtained at baseline (T0) and year 3 (T2). Linear regression analysis was performed to examine the association between EDSS(T2) and a baseline EP compound measure (s-EP-Q(T0)) for each group.nnnRESULTSnMedian EDSS(T0) was 3.0 for Group 1 and 1.5 for Group 2. Mean disease durations were 2.0 and 2.8 years, respectively. Median EDSS(T2) was 2.0 for both groups. The s-EP-Q(T0) significantly predicted EDSS(T2) (R(2)=0.47) for patients in Group 2, but not for patients in Group 1 (R(2)=0.07).nnnCONCLUSIONnIn early MS the functional remnants of relapses are a better predictor for development of medium-term disability than is the extent of impulse propagation impairment measured during relapse.nnnSIGNIFICANCEnThis suggests a role of multimodal EPs in prediction of MS disability if performed in the relapse-free interval.

Future Brain and Spinal Cord Volumetric Imaging in the Clinic for Monitoring Treatment Response in MS

Purpose of reviewVolumetric analysis of brain imaging has emerged as a standard approach used in clinical research, e.g., in the field of multiple sclerosis (MS), but its application in individual disease course monitoring is still hampered by biological and technical limitations. This review summarizes novel developments in volumetric imaging on the road towards clinical application to eventually monitor treatment response in patients with MS.Recent findingsIn addition to the assessment of whole-brain volume changes, recent work was focused on the volumetry of specific compartments and substructures of the central nervous system (CNS) in MS. This included volumetric imaging of the deep brain structures and of the spinal cord white and gray matter. Volume changes of the latter indeed independently correlate with clinical outcome measures especially in progressive MS. Ultrahigh field MRI and quantitative MRI added to this trend by providing a better visualization of small compartments on highly resolving MR images as well as microstructural information.SummaryNew developments in volumetric imaging have the potential to improve sensitivity as well as specificity in detecting and hence monitoring disease-related CNS volume changes in MS.

Superficial brain stimulation in multiple sclerosis

Central motor conduction time (CMCT) is the most frequently studied measure derived from transcranial magnetic stimulation (TMS) in multiple sclerosis (MS); it is abnormal in 57-93% of patients. Addition of the triple stimulation technique and combining motor with other evoked potentials (EPs) increases sensitivity. Cross-sectional correlations of TMS measures with clinical assessments of motor dysfunction or global disability are high. Longitudinally, CMCT is sensitive to both worsening and improvement of motor function, showing its potential to detect therapeutic responses. Moreover, combined multimodal EPs are valid quantitative predictors of the clinical course over periods ranging from 2 to 14 years. Measures of transcallosal connectivity (ipsilateral silent period and interhemispheric inhibition) are altered even in early MS, and yield complementary information on subclinical changes. Pathological brain plasticity in MS has been demonstrated by paired associative stimulation studies revealing a compensatory role of the ipsilateral motor and premotor areas. Central motor fatigue is associated with reduced motor EP amplitudes and increased cortical silent periods in normal controls, whereas patients with MS suffering from subjective fatigue show various abnormalities in cortical modulation of the motor system.

Electrophysiological surrogate markers for primary progressive multiple sclerosis (PPMS) – cross-sectional analysis of 23 patients

leads to diagnostic difficulties, unnecessary, invasive exams, in particular muscle biopsy, and most of all to treatment delay. We describe two cases of proximal autoimmune myasthenia: A young 12-year-old girl who developed progressive difficulties of ambulation followed by appearance of mild, proximal shoulder girdle palsy. Only at the age of 16 the diagnostic of proximal autoimmune myasthenia was made and treatment began. The second case is of 58-year-old female with progressive, proximal muscle weakness, whom’’ limb girdle’’ myasthenia was diagnosed and thymoma disclosed. These two cases confirm that the diagnosis of myasthenia should be considered in both young and elderly patients with proximal muscular deficit and without a history of fluctuations because of important therapeutic and prognostic consequences. The clinical history of these two cases and the revue of literature are discussed.