Exploring the predictive value of the evoked potentials score in MS within an appropriate patient population: a hint for an early identification of benign MS?

Margaritella et al. BMC Neurology 2012, 12:80 http://www.biomedcentral.com/1471-2377/12/80 RESEARCH ARTICLE Open Access Exploring the predictive value of the evoked potentials score in MS within an appropriate patient population: a hint for an early identification of benign MS? Nicolò Margaritella1, Laura Mendozzi2, Massimo Garegnani1, Raffaello Nemni3, Elena Colicino4, Elisabetta Gilardi1 and Luigi Pugnetti1* Abstract Background: The prognostic value of evoked potentials (EPs) in multiple sclerosis (MS) has not been fully established. The correlations between the Expanded Disability Status Scale (EDSS) at First Neurological Evaluation (FNE) and the duration of the disease, as well as between EDSS and EPs, have influenced the outcome of most previous studies. To overcome this confounding relations, we propose to test the prognostic value of EPs within an appropriate patient population which should be based on patients with low EDSS at FNE and short disease duration. Methods: We retrospectively selected a sample of 143 early relapsing remitting MS (RRMS) patients with an EDSS < 3.5 from a larger database spanning 20 years. By means of bivariate logistic regressions, the best predictors of worsening were selected among several demographic and clinical variables. The best multivariate logistic model was statistically validated and prospectively applied to 50 patients examined during 2009–2011. Results: The Evoked Potentials score (EP score) and the Time to EDSS 2.0 (TT2) were the best predictors of worsening in our sample (Odds Ratio 1.10 and 0.82 respectively, p=0.001). Low EP score (below 15–20 points), short TT2 (lower than 3–5 years) and their interaction resulted to be the most useful for the identification of worsening patterns. Moreover, in patients with an EP score at FNE below 6 points and a TT2 greater than 3 years the probability of worsening was 10% after 4–5 years and rapidly decreased thereafter. Conclusions: In an appropriate population of early RRMS patients, the EP score at FNE is a good predictor of disability at low values as well as in combination with a rapid buildup of disability. Interestingly, an EP score at FNE under the median together with a clinical stability lasting more than 3 years turned out to be a protective pattern. This finding may contribute to an early identification of benign patients, well before the term required to diagnose Benign MS (BMS). Keywords: Multiple Sclerosis, EP score, Disability prediction, Multivariate analysis, ROC analysis, Benign MS, Evoked potentials * Correspondence: 1 Laboratory of Clinical Neurophysiology, Scientific Institute (IRCCS) S. Maria Nascente, don C. Gnocchi Foundation, Via Capecelatro 66, Milan 20148, Italy Full list of author information is available at the end of the article © 2012 Margaritella et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Margaritella et al. BMC Neurology 2012, 12:80 http://www.biomedcentral.com/1471-2377/12/80 Background In the neuroimaging era the role of evoked potentials as diagnostic tools has been greatly diminished. This led many authors to explore how Evoked Potentials (EPs) could still be useful as predictors of clinical disability in multiple sclerosis (MS) [1-11]. Part of the recent literature addressed this problem from a multivariate parametric perspective by looking at the absolute latencies of multimodal EPs [6,7,10,11], whereas in another group of studies individual EPs measures were first transformed into an ordinal summary score (the EP score) [2-5,8,9]. Given that different EP scores as well as different statistical approaches have been proposed, it is perhaps not surprising that a general consensus over both methodology and results is still to be found. A question strictly confined to the choice of the best EP score or the best statistical model is for whom the prediction is most appropriate. Some studies have assessed the predictive value of the EP score by selecting patients with long disease duration and a moderate to severe clinical disability at First Neurological Evaluation (FNE) [2,3,5], while others have enrolled patients with short disease duration and low clinical disability at FNE [2,4]. The definition of the appropriate patient population is decisive for the relation between clinical and subclinical variables, e.g. high values of EP score are more likely to be correlated with high values of EDSS, thus the prediction of disability could be automatically improved in a patient population with a large percentage of secondary progressive MS courses; however, the clinical utility of this choice is questionable because the interest in predicting worsening in patients who are already significantly impaired is low. Our aim was to evaluate the predictive value of the EP score first by determining how an appropriate patient population should be defined, and then by assessing the performance of the EP score in a multivariate logistic regression analysis. As the EP score summarizes the quantitative information of different EP modalities, it is an optimal tool to evaluate the overall subclinical impairment of MS patients. By analyzing its performance within an appropriate patient population it should be possible to better evaluate the unbiased ability of this score to predict worsening in MS. In particular, the identification of a group with a low risk of worsening may contribute to an early identification of putative benign MS patients [12]. Methods Patients A total of 143 MS patients, who were referred to our centre (Scientific Institute S. Maria Nascente, don Gnocchi Foundation, Milan, Italy) during the period 1989– 2009 for clinical, neuroimaging and neurophysiological Page 2 of 11 assessments, were retrospectively selected from our clinical database. Inclusion criteria for this study were: (1) a diagnosis of Relapsing Remitting MS (RRMS) using Poser [13] and McDonald criteria [14]; (2) at least one complete EPs evaluation performed at FNE (F_EP score) including Visual (VEP 30’ and 15’), auditory (BAER) and somatosensory (SEP lower limbs LL and upper limbs UL) evoked potentials; (3) EDSS at FNE (F_EDSS) lower than 3.5 points assessed by the same trained neurologist using the pre-neurostatus version; (4) at least 2 EDSS follow-ups before the last assessment (5) last EDSS (L_EDSS) and last EPs (L_EP score) assessments for all patients during 2008–2009. Additionally, it has been possible to measure the time between FNE and EDSS 2.0 (TT2) in 65% of the patient population with F_EDSS below 2.0. Thirty-one patients were defined as benign MS according to the last accepted criteria, i.e. EDSS ≤ 2.0 for at least 10 years [12]. At FNE, 10 patients (7%) were receiving immunomodulatory treatments an (...truncated)