Influence of CNS T2-focal lesions on cervical cord atrophy and disability in multiple sclerosis

Abstract

Background:

Mechanisms associated with cervical spinal cord (CSC) and upper thoracic spinal cord (TSC) atrophy in multiple sclerosis (MS) are poorly understood.

Objective:

To assess the influence of brain, CSC and TSC T2-hyperintense lesions on cord atrophy and disability in MS.

Methods:

Thirty-four MS patients underwent 3T brain, cervical and thoracic cord magnetic resonance imaging (MRI) and Expanded Disability Status Scale (EDSS) score assessment. CSC/TSC lesion number and volume (LV), whole-brain and cortico-spinal tract (CST) LVs were obtained. Normalized whole CSC and upper TSC cross-sectional areas (CSAn) were also derived. Age- and sex-adjusted regression models assessed associations of brain/cord lesions with CSAn and EDSS and identified variables independently associated with CSAn and EDSS with a stepwise variable selection.

Results:

CSC CSAn (β = −0.36, p = 0.03) and TSC CSAn (β = −0.60, p < 0.001) were associated with CSC T2 LV. EDSS (median = 3.0) was correlated with CSC T2 LV (β = 0.42, p = 0.01), brain (β = 0.34, p = 0.04) and CST LV (β = 0.35, p = 0.03). The multivariate analysis retained CSC LV as significant predictor of CSC CSAn (R² = 0.20, p = 0.023) and TSC CSAn (R² = 0.51, p < 0.001) and retained CSC and CST LVs as significant predictors of EDSS (R² = 0.55, p = 0.001).

Conclusions:

CSC LV is an independent predictor of cord atrophy. When neurological impairment is relatively mild, central nervous system (CNS) lesion burden is a better correlate of disability than atrophy.

Keywords

Multiple sclerosis magnetic resonance imaging cervical spinal cord thoracic spinal cord

Introduction

The spinal cord (SC) is frequently involved in multiple sclerosis (MS), with 90% of patients presenting with focal and/or diffuse T2-hyperintense signal abnormalities in both the cervical spinal cord (CSC) and thoracic cervical spinal cord (TSC) segments.^1–3 SC lesions are often symptomatic and contribute to the prediction of subsequent disease course.⁴ Despite this, the correlation between the number of SC focal lesions, which represents a gross measure of demyelination, and patients’ disability status is generally modest.^1,2,5 The majority of previous investigations, however, were mainly focused on the CSC segment, while the relationship between TSC lesions and clinical impairment has been rarely investigated.^6,7 Furthermore, most studies employed simple lesion count methodologies which largely approximated the impact of lesion size variability.^3,8 On the contrary, obtaining accurate SC lesion volume (LV) estimates from standard T2-weighted images may be difficult, due to the presence of cerebrospinal fluid (CSF) partial volume effect, magnetic field inhomogeneity – particularly occurring at high magnetic field strength⁶ – as well as truncation and pulsation artefacts.⁹

In addition to demyelination, atrophy frequently develops in the CSC of MS patients as a consequence of axonal loss and shrinkage.^1,2 Tissue loss seems also to occur in the TSC, as reported by preliminary studies.¹⁰ While seminal post-mortem investigations have suggested that atrophy severity may be unrelated to demyelination,¹¹ a recent study has described an association between focal demyelination and decreased axonal density, although this latter was not correlated with SC atrophy.¹⁰ An association between CSC atrophy and neurological disability in MS has been proven by several studies,^2,3 especially in patients with the progressive MS forms.^12,13 Conversely, findings on the clinical relevance of SC atrophy in patients with low levels of disability are still controversial.^2,13–15

In this study, we hypothesized that SC LV may influence CSC and/or TSC atrophy, as well as neurological status, in patients with relatively low disability. To improve SC LV estimation, we employed proton density (PD)-weighted images, which previously demonstrated superior reliability than standard T2-weighted images for lesion assessment.¹⁶ Associations of SC atrophy and disability with damage of brain structures involved in the motor pathway were also evaluated.

Methods

Subjects

Approval was received from the local ethical standards committee on human experimentation and written informed consent was obtained from all subjects prior to study participation. Inclusion criteria were as follows: stable treatment during the past 6 months and no corticosteroids administration during the last month. Exclusion criteria were as follows: history of cervical cord/brain trauma; SC compression and/or other MS-unrelated abnormalities on previous magnetic resonance imaging (MRI); major comorbidities; history of drug/alcohol abuse; inability to undergo MRI (claustrophobia, metal implants, pacemakers, etc.); and pregnancy or breastfeeding.

We recruited 28 relapsing remitting, six progressive MS patients and 15 healthy controls (HC) at the Neurocenter of Southern Switzerland (Lugano, Switzerland). In patients, neurological disability was evaluated using the Expanded Disability Status Scale (EDSS) score within 48 hours from MRI acquisition. The clinical assessment was performed by an experienced neurologist, unaware of the MRI results.

MRI acquisition

Using a 3.0T Siemens Skyra scanner (Erlangen, Germany), the following images were acquired during a single session:

SC: (a) sagittal PD-weighted turbo-spin-echo (TSE) of the CSC and TSC (repetition time (TR) = 2000 ms, echo time (TE) = 9 ms, flip angle (FA) = 145°, echo train length (ETL) = 6, matrix = 384 × 269, parallel imaging acceleration factor = 2, number of averages = 2, slice thickness = 3 mm, slice gap = 0.3 mm, slice number = 18, voxel size = 0.42 × 0.42 × 3.3 mm³); (b) axial T2-weighted multi-echo recombined gradient-echo (MERGE) in the CSC (TR = 510 ms, TE = 14 ms, FA = 30°, ETL = 4, matrix = 256 × 256, slice thickness = 3 mm, slice gap = 0.3 mm, slice number = 30, voxel size = 0.4 × 0.4 × 3.3 mm³); and (c) axial T2-weighted TSE in the TSC (TR = 3500 ms, TE = 103 ms, FA = 145°, ETL = 23, matrix = 448 × 336, slice thickness = 3 mm, slice gap = 0.3 mm, slice number = 20, voxel size = 0.31 × 0.31 × 3.3 mm³). Axial MERGE sequences were employed for the CSC because they previously demonstrated optimal lesion detection accuracy in this segment.¹⁷ However, T2-weighted TSE images were preferred in the TSC due to better resilience to magnetic field artefacts at this level. Finally, (d) a sagittal three-dimensional (3D) T1-weighted magnetization-prepared rapid acquisition gradient-echo (MPRAGE), which covered the whole CSC segment and the upper portion of the TSC until Th4 (TR = 2300 ms, TE = 5 ms, FA = 8°, inversion time (TI) = 1140 ms, matrix = 256 × 256, parallel imaging acceleration factor = 2, slice thickness = 1 mm, slice number = 104, voxel size = 0.98 × 0.98 × 1 mm³), was employed for atrophy assessment.

Brain: (a) axial dual-echo TSE (TR = 2670 ms, TE = 24–120 ms, FA = 145°, ETL = 12, matrix = 256 × 192, slice thickness = 3 mm, slice number = 44, parallel to the AC-PC plane, voxel size = 0.98 × 0.98 × 3.3 mm³) and (b) sagittal 3D T1-weighted MPRAGE (TR = 2300 ms, TE = 2.81 ms, FA = 9°, TI = 900 ms, matrix = 256 × 256, slice thickness = 0.9 mm, slice number = 192, voxel size = 0.93 × 0.93 × 0.9 mm³).

MRI analysis

Lesion analysis

Lesion assessment was performed by an expert neuroradiologist (E.P., 11 years of experience) supervised by one senior observer. In order to improve detection accuracy,⁷ the number of lesions was counted using both sagittal PD-weighted and axial T2-weighted images, both in the cervical and thoracic segments. After lesion detection, LV was contoured on the sagittal PD-weighted scans (Jim 7; Xinapse Systems, Colchester, UK) (Figure 1). Brain T2-hyperintense LV was quantified from dual-echo TSE scans. T2-weighted images were co-registered to the MNI space using SPM12. The inverse transformation was used to warp the mask of the cortico-spinal tract (CST) included in the ICBM-DTI-81 white matter atlas¹⁸ to the single subject space. This mask was superimposed to binarized T2 lesion masks and used to calculate CST LV for each patient.

Figure 1.

T2-hyperintense lesions in the spinal cord of MS patients and measurements of the cervical and thoracic spinal cord atrophy. (a) Sagittal proton density (PD)-weighted scan of the right lateral cervical cord column of a patient with multiple sclerosis (male, 45 years old), which shows four hyperintense lesions. Lesion boundaries were segmented (red outlines) based on their relatively good contrast with cerebrospinal fluid and cord parenchyma. (b) Similar findings in the left lateral thoracic cord column in another patient with multiple sclerosis (female, 53 years old). The thin arrows in panel (b) indicate the linear hyperintensity coursing through the whole cord anterior to the midline, a normal finding in PD-weighted sagittal images that corresponds to the central grey matter.[9] Dashed lines in (a) and (b) indicate the corresponding axial planes supporting lesion detection (black arrows in a₁ and b₁, respectively). (c)–(f) Illustrative examples of (c, d) cervical, (e, f) and thoracic cord outlines estimated on the 3D T1-weighted MPRAGE scan using the active surface method, in a healthy control (female, 40 years old). Segmentations boundaries, corresponding to the C2–C7 and Th1–Th3 vertebral levels respectively, are indicated.

Atrophy analysis

A method based on active surfaces was applied on SC MPRAGE to estimate the mean CSC cross-sectional area (CSA) between C1/C2 and C7.¹⁹ The same method was applied on the upper (Th1–Th3) TSC segment, which was covered by our CSC MPRAGE scan in all study subjects (Figure 1). The centre of the cord was manually identified by placing landmarks at the extremes of the cord region to be studied and approximately every 10 mm between these landmarks. The cord centre line and cord outlines were then automatically estimated for each slice.¹⁹ The mean CSC and upper TSC CSA were obtained as the total cord volume divided by the cord length. After T1-hypointense lesion refilling,²⁰ normalized brain volume was calculated on brain MPRAGE using FSL SIENAx software.²¹ Automatic segmentation of the bilateral thalamus was performed using FSL FIRST software.²² The SIENAx brain scaling factor to the standard space, which is inversely proportional to the intracranial volume, was used to produce normalized CSC and TSC CSA (CSAn),¹⁹ as well as average normalized thalamic volume. Average cortical thickness (CTh) of the bilateral precentral gyrus was obtained with Freesurfer²³ (version 6.0; http://surfer.nmr.mgh.harvard.edu ) from brain MPRAGE scans. In detail, after registration to Talairach space and intensity normalization, automated removal of non-cerebral structures was performed using a previously described technique.²⁴ Then images were segmented into grey matter, white matter and CSF, and the white–grey matter boundary was outlined. The resulting segmentations were carefully reviewed and control points added, as needed. Then, registration to a spherical atlas was performed, and the cerebral cortex was parcellated according to the Desikan atlas.²⁵ Average CTh of the bilateral precentral gyrus, included as label in this atlas, was measured as the average shortest distance between the white matter boundary and the pial surface.

Statistical analysis

All analyses were performed using the SPSS software (version 23.0). Between-group differences of demographic and clinical variables were investigated using chi-square and Mann–Whitney U tests, as appropriate. Age- and sex-adjusted linear regression models were used to find associations of cord and brain lesion/atrophy measures, with CSC and TSC CSAn, as well as with the EDSS score. The same modelling strategy was used to identify the set of variables independently associated with CSAn and EDSS, using a stepwise variable selection (p = 0.10 for entry and p = 0.05 to remain in the multivariate model). The proportion of variance explained by each model was expressed by the R² index. Standardized beta coefficients (β) were reported to compare the relative strengths of association of each predictor with the dependent variable.

Results

Table 1 summarizes the main demographic, clinical and MRI findings of study participants. Compared to HC, MS patients had significant brain (p < 0.001), thalamic (p < 0.001), TSC (p = 0.01) and CSC (p = 0.01) atrophy, while average CTh of the precentral gyrus did not differ significantly between groups (Table 1).

Table 1.

Main demographic, clinical and MRI characteristics of study subjects.

	MS patients	HC	p value
Sex (M/F)	16/18	4/11	0.2^a
Mean age (SD) (years)	47.0 (12.9)	40.0 (10.4)	0.001^b
Median EDSS (IQR)	3.0 (2.0–3.5)	–	–
Mean disease duration (SD) (years)	13.2 (7.9)
Mean brain T2 LV (SD) (mL)	5.5 (7.4)	–	–
Mean CST T2 LV (SD) (mL)	0.1 (0.2)	–	–
NBV (SD) (mL)	1434 (69)	1525 (71)	<0.001^b
Normalized thalamic volume (SD) (mL)	10.1 (0.9)	11.1 (0.7)	<0.001^b
Average CTh of the precentral gyrus (SD) (mm)	2.5 (0.1)	2.6 (0.2)	0.6^b
Mean CSC CSAn (SD) (mm²)	71.5 (7.8)	76.9 (4.8)	0.01^b
Mean TSC CSAn (SD) (mm²)	40.9 (10.6)	47.4 (4.3)	0.01^b
Whole cord
Median lesion number (IQR)	4 (1–8)
Mean T2 LV (SD) (ml)	0.72 (0.87)
CSC
Median lesion number (IQR)	2 (1–5)	–	–
Mean T2 LV (SD) (mL)	0.45 (0.48)	–	–
TSC
Median lesion number (IQR)	1 (0–3)	–	–
Mean T2 LV (SD) (mL)	0.27 (0.53)	–	–

EDSS: Expanded Disability Status Scale; LV: lesion volume; CST: cortico-spinal tract; NBV: normalized brain volume; CTh: cortical thickness; CSC: cervical spinal cord; TSC: thoracic spinal cord; CSAn: normalized cervical cord cross-sectional area; HC: healthy controls; MS: multiple sclerosis; IQR: interquartile range; SD: standard deviation; MRI: magnetic resonance imaging.

Chi-square test.

Mann–Withney U test.

Correlations with cervical and thoracic CSAn

CSC T2 LV (β = −0.36, p = 0.03, 95% confidence interval (CI) = −0.69 to −0.03) and TSC CSAn (β = 0.45, p = 0.002, 95% CI = 0.05 to 0.74) were significantly associated with CSC CSAn. CSC T2 LV (β = −0.60, p < 0.001, 95% CI = −0.85 to −0.34), together with CSC CSAn (β = 0.42, p = 0.002, 95% CI = 0.004 to 0.68), was also linked to TSC CSAn. Trends towards a correlation between CSC CSAn and CSC lesion number (β = −0.28, p = 0.09, 95% CI = −0.62 to 0.05), as well as between TSC CSAn and TSC lesion number (β = −0.29, p = 0.07, 95% CI = −0.62 to 0.03), were also found. Conversely, brain T2 LV was not correlated with CSC (p = 0.24) or TSC CSAn (p = 0.46). Similarly, no correlations were found between CSC/TSC atrophy and NBV, normalized thalamic volume and precentral gyrus CTh (p = 0.18–0.98). The age- and sex-adjusted multivariable regression model retained CSC T2 LV as significant independent predictor of CSC CSAn (R² = 0.20, p = 0.023) and TSC CSAn (R² = 0.51, p < 0.001) (Table 2).

Table 2.

Results of age- and sex-adjusted univariate and multivariate regression models explaining normalized cervical cord cross-sectional area (CSAn) and Expanded Disability Status Scale (EDSS) scores.

Dependent variable	Independent variable	Univariate analysis		Multivariate analysis
Dependent variable	Independent variable	Standardized β	p value	Standardized β	p value
CSC CSAn	TSC lesion number	−0.006	0.97	–	–
	TSC T2 LV	0.11	0.50	–	–
	TSC CSAn	0.45	0.002*	–	–
	CSC lesion number	−0.28	0.09	–	–
	CSC T2 LV	−0.36	0.03*	−0.36	0.03*
	Whole-cord T2 LV	−0.12	0.48	–	–
	Brain T2 LV	0.20	0.24	–	–
	CST T2 LV	0.33	0.06	–	–
	NBV	0.28	0.19	–	–
	Normalized thalamic volume	0.12	0.58	–	–
	Average CTh of the precentral gyrus	−0.30	0.24	–	–
TSC CSAn	TSC lesion number	−0.29	0.07	–	–
	TSC T2 LV	−0.17	0.30	–	–
	CSC lesion number	−0.22	0.17	–	–
	CSC T2 LV	−0.60	<0.001*	−0.60	<0.001*
	CSC CSAn	0.42	0.002*	–	–
	Whole-cord T2 LV	−0.42	0.007*	–	–
	Brain T2 LV	0.12	0.46	–	–
	CST T2 LV	0.22	0.18	–	–
	NBV	−0.003	0.98	–	–
	Normalized thalamic volume	0.004	0.98	–	–
	Average CTh of the precentral gyrus	−0.26	0.24	–	–
EDSS score	TSC lesion number	0.30	0.07	–	–
	TSC T2 LV	0.22	0.18	–	–
	TSC CSAn	−0.16	0.39	–	–
	CSC lesion number	0.13	0.45	–	–
	CSC T2 LV	0.42	0.01*	0.42	0.01*
	CSC CSAn	−0.19	0.29	–	–
	Whole-cord T2 LV	0.36	0.03*	–	–
	Brain T2 LV	0.34	0.04*	–	–
	CST T2 LV	0.35	0.03*	0.35	0.03*
	NBV	0.10	0.70	–	–
	Normalized thalamic volume	−0.15	0.49	–	–
	Average CTh of the precentral gyrus	−0.029	0.91	–	–

TSC: thoracic spinal cord; CSC: cervical spinal cord; LV: lesion volume; CST: cortico-spinal tract; NBV: normalized brain volume; CTh: cortical thickness.

Effect size of correlations is reported by using standardized regression coefficients. Significant associations are marked with an asterisk.

Correlations with the EDSS score

Significant associations between whole-cord LV (β = 0.36, p = 0.03, 95% CI = 0.03 to 0.68), CSC LV (β = 0.42, p = 0.01, 95% CI = 0.10 to 0.74), brain T2 LV (β = 0.34, p = 0.04, 95% CI = 0.007 to 0.70) and CST T2 LV (β = 0.35, p = 0.03, 95% CI = 0.02 to 0.67) and EDSS score were detected. Trends towards an association with TSC lesion number were also found (β = 0.30, p = 0.07, 95% CI = −0.03 to 0.64). Conversely, we found no association between brain atrophy (p = 0.70), thalamic atrophy (p = 0.49), precentral gyrus CTh (p = 0.91), CSC CSAn (p = 0.29) or TSC CSAn (p = 0.39) and EDSS score. The age- and sex-adjusted multivariable regression analysis retained CSC and CST T2 LVs as significant independent predictors of the EDSS score (R² = 0.55, p = 0.001) (Table 2).

Discussion

In this study, we showed that the CSC LV was the best independent predictor of cervical and upper thoracic SC atrophy, as well as of the EDSS score (together with CST LV), in MS patients with relatively mild neurological disability. By contrast, no significant associations between the TSC LV and these variables were detected. To the best of our knowledge, no previous study has assessed the relationship between putative measures of whole SC demyelination and whole SC atrophy using in vivo MRI. Information about TSC atrophy contribution to MS patients’ disability is also limited.¹⁰ Post-mortem investigations suggested a negligible impact of focal spinal lesions on SC atrophy.^10,11 However, such findings were mostly based on data from MS patients with progressive disease phenotypes and/or high disability. In addition, information from volume measurements obtained from specimens may not directly apply to MRI-based assessments.²⁶ Using MRI, we found that the CSC LV was the only variable having a significant association with both CSC and upper TSC atrophy, whereas TSC and brain T2 LV appeared to play only a marginal relation with CSC atrophy in our patients. Taken together, these results suggest that the effect of focal demyelination may be mainly region-specific, especially for the CSC. At the same time, the strong relationship between CSC LV and upper TSC tissue loss suggests that secondary neurodegenerative processes may also play some role for TSC atrophy. Future non-conventional MRI investigations may help to further clarify the relative contribution of focal tissue destruction within lesions or Wallerian degeneration caused by remote lesions on SC atrophy development.²

Our second important finding was that CSC LV and brain T2 LV (in particular, the fraction of lesions located in the CST) were independently associated with patients’ disability. Interestingly, CSC and CST LVs, taken together, helped to explain about 50% of variance of patients’ disability. This suggests that a multiparametric evaluation of cord and brain damage is the most appropriate strategy to accurately monitor MS patients. Even if the correlation between cord LV and EDSS was mainly driven by CSC LV, a trend towards a contribution of the TSC was also detected. Conversely, despite patients being significantly atro-phic compared with HC, measures of atrophy of the brain and SC were not associated with the EDSS score. Previous studies have failed to demonstrate an association between cord lesions and patients’ disability.^1,7 However, they did not estimate cord LV⁷ and were performed at lower field strengths.¹ Advancements of MRI technology have allowed significant improvements in SC image quality. In this regard, the use of PD-weighted scans provided us a better lesion conspicuity and a more accurate lesion representation compared to standard T2-weighted scans.⁷ This has likely improved results of cord LV estimate and, as a consequence, correlations with clinical impairment. Of note, our findings are in line with a recent study that has assessed upper CSC LV using a 3D phase-sensitive inversion-recovery sequence.²⁷ CSC, upper TSC and various measures of brain atrophy were not associated with disability in our patients, who had a relatively low EDSS score (median = 3.0). This is in agreement with previous investigations conducted on patients with relatively mild disability^14,15,28 and corroborates the potential contribution of lesion burden in explaining disability in MS patients with mild neurological impairment. Such an association is usually lost in progressive MS phenotypes, probably because of the well-known plateauing effect between T2 LV and EDSS score.²⁹ We speculate that in more advanced disease stages, other processes, including atrophy, may become more prominent to explain clinical impairment. In this regard, future studies should assess systematically the relationships between brain grey and white matter and SC atrophy, and their relative influence on patients with different degrees of disability.

Our study is not without limitations. First, HC were younger than MS patients. However, age was always included as covariate in our statistical analysis, and CSAn was found to have only a modest correlation with subjects’ age.³⁰ Second, the limited sample size did not allow us to stratify MS patients by disease phenotype or disability severity. Third, this was a cross-sectional study. Future longitudinal studies may investigate the predictive role of whole SC lesions and atrophy on subsequent disability worsening. Fourth, our data did not include ad hoc MPRAGE scans covering the whole TSC, so atrophy estimation in this segment was limited to the upper TSC.³¹ Finally, our data did not allow for a compartmental assessment of SC grey and white matter atrophy, which may be conducted in future studies employing dedicated volume sequences providing appropriate tissue contrast.

In conclusion, we showed that the volume of the cervical, but not thoracic, SC lesions is linked to SC atrophy in MS patients. CNS lesion burden was a better correlate of neurological status than atrophy, in MS patients with relatively mild disability.

Supplemental Material

MSJ865989_supplementary_appendix – Supplemental material for Influence of CNS T2-focal lesions on cervical cord atrophy and disability in multiple sclerosis

Supplemental material, MSJ865989_supplementary_appendix for Influence of CNS T2-focal lesions on cervical cord atrophy and disability in multiple sclerosis by Emanuele Pravatà, Paola Valsasina, Claudio Gobbi, Chiara Zecca, Gianna C Riccitelli, Massimo Filippi and Maria A Rocca in Multiple Sclerosis Journal

Supplemental Material

MSJ865989__STROBE_checklist – Supplemental material for Influence of CNS T2-focal lesions on cervical cord atrophy and disability in multiple sclerosis

Supplemental material, MSJ865989__STROBE_checklist for Influence of CNS T2-focal lesions on cervical cord atrophy and disability in multiple sclerosis by Emanuele Pravatà, Paola Valsasina, Claudio Gobbi, Chiara Zecca, Gianna C Riccitelli, Massimo Filippi and Maria A Rocca in Multiple Sclerosis Journal

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: The authors declare that they have no competing interests in relation to this work. Potential conflicts of interest outside the submitted work are as follows: E.P. and G.C.R. have no disclosures. P.V. received speaker honoraria from ExceMED. C.G. and C.Z., from The Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland, received financial support from Teva, Merck Serono, Biogen, Genzyme, Roche, Celgene, Bayer and Novartis. M.F. is the Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck Serono, Novartis, Teva Pharmaceutical Industries; and received research support from Biogen Idec, Merck Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and ARiSLA (Fondazione Italiana di Ricerca per la SLA). M.A.R. received speakers honoraria from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono and Roche and received research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

ORCID iDs

Chiara Zecca

Massimo Filippi

Maria A Rocca

Supplemental Material

Supplemental material for this article is available online.

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