Correlation of clinical findings and brain volume data in multiple sclerosis

Journal of Clinical Neuroscience xxx (2017) xxx–xxx

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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn

Case report

Correlation of clinical findings and brain volume data in multiple sclerosis Yara Dadalti Fragoso a,⇑, Paulo Roberto Wille b,c, Marcelo Abreu d, Joseph Bruno B. Brooks a, Ronaldo Maciel Dias e, Juliana Avila Duarte f,g, Luciano Farage h, Alessandro Finkelsztejn f,g, Alan Christmann Frohlich i,j, Marcus Vinicius Magno Goncalves b,c, Bruno V. Sobreira Guedes k, Leonardo Medeiros l, Rodrigo Andre Oliveira m, Flavio Diniz Ribas n, Fernando Coronetti Gomes da Rocha l, Gutemberg Augusto C. Santos o, Claudio Scorcine a, Guilherme Lopes da Silveira m, Carina Tellaroli Spedo p, Carlos Bernardo Tauil h, Juliana Santos Varela f,g, Vera Lucia Ferreira Vieira q, on behalf of theBrazilian Brain Volume Studies (B-BRAVOS) group a

Department of Neurology, Universidade Metropolitana de Santos, Santos, SP, Brazil Department of Neurology, Universidade Regional de Joinville, Joinville, SC, Brazil Department of Radiology, Universidade Regional de Joinville, Joinville, SC, Brazil d Department of Radiology, Clinoson Image, Porto Alegre, RS, Brazil e Department of Neurology, Hospital de Base do Distrito Federal, Brasilia, DF, Brazil f Department of Neurology, Hospital de Clinicas de Porto Alegre, RS, Brazil g Department of Radiology, Hospital de Clinicas de Porto Alegre, RS, Brazil h Faculty of Health Sciences, Universidade de Brasilia, Brasilia, DF, Brazil i Department of Neurology, Passo Fundo, RS, Brazil j Department of Neurosurgery of Passo Fundo, Passo Fundo, RS, Brazil k Department of Radiology, Multscan Image, Vitoria, ES, Brazil l Department of Neurology, Universidade Estadual de São Paulo, Botucatu, SP, Brazil m Department of Radiology, Megaimagem, Santos, SP, Brazil n Department of Neurology, Hospital Dona Helena, Joinville, SC, Brazil o Department of Neurology, Universidade Estácio de Sa, Rio de Janeiro, RJ, Brazil p Department of Neurosciences and Behavioral Sciences, Universidade de São Paulo Campus Ribeirao Preto, Ribeirao Preto, SP, Brazil q Department of Neurology, Universidade Federal do Espirito Santo, Vitoria, ES, Brazil b c

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Article history: Received 24 February 2017 Accepted 9 June 2017 Available online xxxx Keywords: Multiple sclerosis Brain volume Brain atrophy Disability Magnetic resonance image

a b s t r a c t Brain volume measurements are becoming an important tool for assessing success in controlling multiple sclerosis (MS) activity. MSmetrix (icometrix) is an easy-to-use platform, specific for MS magnetic resonance imaging (MRI) of the brain. It provides data on total brain volume, grey matter volume and lesion load volume. The objective of the present study was to assess whether disability and the number of relapses during the previous year correlated with brain volume measurements from MSmetrix. Data on 185 icometrix reports from patients with MS were used to evaluate the potential correlation between brain volume measurements and clinical parameters. There was a significant correlation between higher disability and decreased brain volume (total and grey matter). Increased lesion load in the brain and higher number of relapses in the previous year were also independently correlated with decreased brain tissue volume and with increased disability. This is the first study with real-world data to show that icometrix is a relevant tool for the study of brain volume loss in MS. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction

⇑ Corresponding author at: Department of Neurology, Medical School, UNIMES, Avenida Conselheiro Nebias 518, CEP 11015-001 Santos, SP, Brazil. E-mail address: [email protected] (Y.D. Fragoso).

Clinical trials and daily medical practice in multiple sclerosis (MS) now include more parameters associated with long-term disease control than they did previously. While in the past control over clinical relapses and new lesions seen on magnetic resonance

http://dx.doi.org/10.1016/j.jocn.2017.06.006 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Fragoso YD et al. Correlation of clinical findings and brain volume data in multiple sclerosis. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.006

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Case report / Journal of Clinical Neuroscience xxx (2017) xxx–xxx

imaging (MRI) were the most important outcomes, nowadays avoidance of disability and reduced brain atrophy have taken center stage in disease control [1]. Among the software for measuring brain volume, MSmetrix (https://msmetrix.icometrix.com) has an easy-to-use interface and the results come in the format of a report individually quantifying volumes for the whole brain, grey matter and lesion load. MSmetrix has recently been approved by the United States Food and Drug Administration and has been used by several research groups. The program uses three-dimensional T1weighted and FLAIR images in a probabilistic model, plotted in relation to a previously established curve of normality for a given gender, age and head size [2]. The aim of the present study was to assess whether MSmetrix volumetric data from MS patients correlated with clinical findings. 2. Methods The present cross-sectional study was approved by the Ethics Committee at Universidade Metropolitana de Santos, SP, Brazil, under registration number CAAE 59870516.3.0000.5509, in September 2016. Members of the Brazilian Brain Volume Studies (B-BRAVOS) group collected demographic, clinical and imaging data on patients with MS whose MRI had been assessed using MSmetrix. Only cases with complete data (n = 185) were included in the study, and only one scan from each patient was considered. The degree of disability was assessed using the Expanded Disability Scale Score (EDSS) [3]. Whole brain volume and grey matter volume were measured in grams. The volume of lesions was considered as a whole number in milliliters. Zero lesions are considered to be the normal finding in healthy subjects. The volumetric data for each patient was corrected using the ratio ‘‘patient’s volume/minimum expected volume for that patient”, considering age, gender and head size. Thus, the data were calculated for each patient as a ratio expressing the minimum volume that might have been considered normal for that particular patient. The sample size was calculated as 125 subjects, which enabled detection of a 5% error in the confidence interval, with 95% confidence level. The Kolmogorov-Smirnov test was used to confirm whether the data presented normal distribution. Comparisons and ratios were assessed using the Wilcoxon test. The MannWhitney U test was used for comparison of all variables between the groups with and without relapses over the previous three months. The same test was used for comparison between patients who had used corticosteroids during the previous 30 days and those who had not used this drug. The Spearman model was used to make correlations between disability assessed using EDSS and the other variables. Data were considered statistically significant when p  0.05. 3. Results The group consisted of 124 women and 61 men, with a median age of 36 years. There were 173 patients with the diagnosis of relapsing-remitting MS (93.5%), 11 cases of progressive MS (5.9%) and one case of clinically isolated syndrome (CIS) (0.6%). The median disease duration was five years (range: 1– 40 years) and the median EDSS was 2.0 (range: 0 – 8.5). The average whole brain volume for this sample of patients (1475.05 ± 57.45 g) was not significantly different from the minimum expected volume for matched healthy controls (1488.83 ± 57.45 g; p = 0.075). On the other hand, grey matter volume was significantly different (p = 0.01) between this sample of patients (875.5 ± 55.93 g), and the minimum expected volume for matched healthy controls (887.44 ± 32.18 g).

A significant correlation was observed between disability and brain volume. The higher the disability was, the lower the whole brain volume (p < 0.001) and grey matter volume (p < 0.001) were. Likewise, a higher number of clinical relapses during the previous year was correlated with lower brain volume (p < 0.001). Higher lesion load volume was correlated with lower brain volume (p < 0.001). The average volume of lesions in patients with MS was 15.62 ml (range: 1– 43.1 ml). Higher volumes of lesions correlated with the number of relapses during the previous year (p < 0.001), higher disability (p < 0.001) and lower whole brain volume (p < 0.001) and grey matter volume (p < 0.001). The use of corticosteroids within 30 days of the MRI was registered in 13 patients. Results from this group did not show significant changes in volumetric data. 4. Discussion Accelerated tissue loss from the central nervous system is a sign of neurodegeneration in MS. Cross-sectional and longitudinal studies have shown a correlation between clinical disability and brain atrophy in MS [4]. Overall, grey matter loss seems to show better correlation with clinical disability [5] and lesion load [6]. Diffuse damage to brain tissue (rather than specific demyelinating lesions in the white matter) seems to be relevant in assessing neurodegeneration [7]. More recent studies have also shown that grey matter volume does not seem to be affected by volume changes relating to pseudoatrophy and acute inflammation, which typically affect white matter volume [8]. Caution is required in interpreting brain volume measurements, even though the methods have been shown to be sensitive and reproducible [9]. MSmetrix, which was specifically developed for volumetric studies on the brain in MS, has been found to be superior to other methods for reliability and sensitivity [10] and has shown good correlation with disability in MS [2]. While disability and MSmetrix data have been reported, other information with this very recent platform is still required. The present study shows that MSmetrix data not only correlate brain tissue loss with disability, but also disability to the lesion load and number of relapses during the previous year. Both whole brain volume and grey matter volume seem to be relevant parameters for assessment of clinical data. Lesion load volume was shown here to correlate with clinical and volumetric data from patients with MS. Therefore, whole brain volume, grey matter volume and lesion load volume assessed using MSmetrix could prove helpful in clinical trials and, hopefully in the near future, in daily practice as well. 5. Conclusion Brain volume data and lesion load assessed using MSmetrix showed a clear and significant correlation with the clinical parameters of MS. Funding No funding was provided to any of the participants by Novartis or any other private or public institution. Conflicts of interest Novartis has provided the means for the initial meeting of the Brazilian Brain Volume Study Group (B-BRAVOS) with transportation, one meal for participants and a room for the meeting. Novartis has paid for MSmetrix (icometrix) analyses to all Brazilian

Please cite this article in press as: Fragoso YD et al. Correlation of clinical findings and brain volume data in multiple sclerosis. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.006

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Please cite this article in press as: Fragoso YD et al. Correlation of clinical findings and brain volume data in multiple sclerosis. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.006