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Original Contribution |

Rate of Brain Atrophy in Benign vs Early Multiple Sclerosis FREE

Susan A. Gauthier, DO, MPH; Annika M. Berger, MD; Zsuzsanna Liptak, MD; Yang Duan, MD; Svetlana Egorova, MD, PhD; Guy J. Buckle, MD; Bonnie I. Glanz, PhD; Samia J. Khoury, MD; Rohit Bakshi, MD; Howard L. Weiner, MD; Charles R. G. Guttmann, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, Partners Multiple Sclerosis Center (Drs Gauthier, Buckle, Glanz, Khoury, and Weiner), and Department of Radiology (Drs Berger, Liptak, Duan, Egorova, Bakshi, and Guttmann), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Dr Gauthier is now with the Judith Jaffe Multiple Sclerosis Center, Weill Cornell Medical College, New York, New York.


Arch Neurol. 2009;66(2):234-237. doi:10.1001/archneurol.2008.567.
Text Size: A A A
Published online

Background  Benign multiple sclerosis (MS) is defined by minimal or no disability after many years of observation, therefore a less degenerative disease process is suspected to be present in this subset of patients.

Objective  To compare brain atrophy rates in patients with long-standing benign MS vs typical early MS.

Design  A longitudinal prospective cohort study and a retrospective database review.

Setting  An academic MS center.

Patients  Thirty-nine patients with clinically defined benign MS and an age-matched group of 40 patients with early relapsing-remitting MS.

Main Outcome Measures  Baseline demographic, treatment, brain magnetic resonance imaging measures, and annualized atrophy rates, derived from serial brain parenchymal fraction measurements across 2 years, were compared.

Results  In the baseline analysis, patients with benign MS were matched to the early MS group on age, sex, treatment with immunomodulatory therapy, T2 lesion volume, and brain parenchymal fraction. The mean (SD) annualized brain atrophy rate in patients with benign MS (−0.16% [0.51%]) was lower than that in patients with early MS (−0.46% [0.72%]) (P = .02). The difference remained significant after controlling for age, sex, and treatment (P = .04).

Conclusions  Serial magnetic resonance imaging revealed a low 2-year rate of brain atrophy in patients with clinically benign MS, suggesting a less prominent degenerative component in its pathogenesis than in patients with typical early MS. Identification of patients with a low rate of brain atrophy may indicate a benign course.

Benign multiple sclerosis (MS) has been recognized and defined as engendering minimal or no disability after many years of observation.1 Longitudinal studies have identified cohorts of patients with benign MS, but a method for early identification of these patients is still lacking, and benign MS remains a retrospective diagnosis. Early and accurate identification of patients with benign MS could help limit patient anxiety, prevent the need to initiate immunomodulatory therapy, and avoid the associated adverse effects and expense of treatment.

The pathogenesis of benign MS has been postulated to relate to differences in the mechanism of irreversible disability or the ability for remyelination compared with the standard course of MS, although a clear understanding as to why these patients have a milder disease course is lacking.1 The brain parenchymal fraction (BPF) has been used to measure brain atrophy in MS25; more importantly, early measurements of BPF change were predictive of long-term irreversible disability.6 The aim of this study is to determine whether the rate of brain atrophy, as measured by the change in the BPF in 2 years, differs in a cohort of patients with benign MS compared with an age-matched cohort with early MS. This study addresses the need to identify magnetic resonance imaging (MRI) markers that predict benign MS and to provide further insight into the pathologic differences between this cohort and other patients with MS.

Data were collected as part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study7 and the research database at the Partners Multiple Sclerosis Center. A computerized research database approved by the institutional review board of Brigham and Women's Hospital is used to store data regarding individuals enrolled in the CLIMB study and regarding all patients observed in the MS clinic. Clinical history regarding the first MS symptom was collected retrospectively at the initial evaluation if the patient was not seen at the time of his or her initial symptom, and data were collected prospectively thereafter.

Patients were classified as having benign MS if they met 1 of 2 definitions: (1) disease duration of 10 to 14 years from the initial symptom and an Expanded Disability Status Scale (EDSS) score of 1.5 or less or (2) disease duration of 15 years or longer and an EDSS score of 2.0 or less. The EDSS score had to be sustained throughout clinical follow-up. An age-matched cohort of patients with relapsing-remitting MS and a disease duration of 5 years or less from the initial symptom was selected as the early MS comparison group.

MRI ACQUISITION AND ANALYSIS

Participants underwent MRI using a 1.5-T scanner (Signa; General Electric Healthcare Technologies, Waukesha, Wisconsin), and imaging sequences included dual-echo (proton density and T2-weighted) axial images (3-mm-thick sections). The image analysis laboratory previously developed and validated a 2-channel pipeline for the fully automated segmentation of white matter signal abnormalities/lesions and the derivation of BPF8, which is defined as the ratio of brain parenchymal tissue volume to intracranial cavity volume.

The annualized atrophy rate was derived from BPF measurements in patients who had at least 2 serial brain MRIs and had not received corticosteroids within 30 days of an MRI. The mean (SD) interval between serial MRI examinations in the benign group was 2.0 (0.1) years and in the early group was 2.0 (0.2) years. This was an observational analysis with MRIs obtained within 3 months from yearly clinical visits. Four patients were excluded owing to errors found in segmentation during the quality control review.

STATISTICAL ANALYSIS

Comparisons of mean values and proportions in patients with benign vs early MS for different demographic and clinical characteristics were performed using either a Mann-Whitney or a χ2 test, depending on whether the variables were continuous or categorical. Multivariable logistic regression analysis was used to evaluate the association of atrophy rate in benign vs early MS controlling for age, sex, and treatment with immunomodulatory agents. Linear regression was applied to evaluate the association of the baseline variables and the brain atrophy rate in the combined cohorts. Statistical analyses were performed using statistical software packages (GraphPad Prism 4; GraphPad Software Inc, La Jolla, California, and SAS 9.1; SAS Institute Inc, Cary, North Carolina).

We identified 39 patients with benign disease and 40 with early MS, according to the criteria set forth. The baseline comparison between the 2 groups is outlined in Table 1. Both groups included treated and untreated patients, and the proportion of patients treated with different MS therapies, such as interferon β-1b, high- or low-dose interferon β-1a, glatiramer acetate, pulse monthly methylprednisolone, and combination therapy, was similar (P = .19). In addition, the interval between treatment initiation and baseline MRI was similar between cohorts.

Table Graphic Jump LocationTable 1. Baseline Characteristics of Patients With Benign and Early MS

The annualized brain atrophy rate calculated across 2 years was significantly slower in patients with benign MS compared with patients with early MS (P = .02) (Table 2). The association of a lower atrophy rate with benign disease remained significant in the multivariable analysis after controlling for age, sex, and treatment with immunomodulatory therapy (odds ratio, 0.39; P = .04). For every 1% increase in yearly atrophy rate, the odds of being categorized as having benign MS decreased by a factor of 0.39. After separating treated vs untreated patients, atrophy rates in patients with benign MS remained lower compared with those in patients with early MS (Table 2), although these groups were no longer age matched and the association did not remain significant in the multivariable analysis.

Table Graphic Jump LocationTable 2. Annualized Brain Atrophy Ratesa

The association between annualized BPF change and baseline demographic, clinical, and MRI characteristics was evaluated in the combined cohort of patients with benign and early MS (Table 3). Neither the baseline BPF nor T2 lesion volume was associated with the annualized atrophy rate; however, patients receiving immunomodulatory therapy had a higher rate of brain atrophy compared with untreated patients. This relationship remained significant in the multivariable analysis (P = .03).

Table Graphic Jump LocationTable 3. Association of Baseline Variables and the Annualized 2-Year Atrophy Rate in the Combined Cohort

Loss of brain volume is affected by factors such as inflammation, edema, and gliosis, although it is thought to predominantly reflect axonal loss and demyelination.4,5 In this study, serial MRI revealed a lower 2-year rate of brain atrophy, as measured by the BPF, in patients with clinically defined benign MS compared with an age-matched cohort of patients with early MS. These results suggest that benign MS may have a less destructive pathologic process and, thus, a less prominent or slower degenerative component. Studies using magnetization transfer imaging and magnetic resonance spectroscopy in benign MS have also suggested that a less destructive pathologic process may underlie benign MS,911 although others, including those using a global measure such as the BPF, have not found differences between benign and other subgroups of MS.1216 A direct comparison of these studies is challenging due to technical MRI differences that exist among them. As had other researchers, we found that the cross-sectional BPF was similar between benign and relapsing-remitting MS, but unique to the present study was the slower rate of longitudinal cerebral atrophy in patients with benign disease. Taken together, these results suggest that a degenerative process still remains but may occur at a slower rate in some patients with clinically defined benign disease. Furthermore, the rate of atrophy in patients with early MS in the present study corresponds to the expected annualized rate for relapsing-remitting MS5 and validates this BPF method to previously published methods.

The decision to use the early MS group as a comparative one in the present study was an attempt to compare benign MS with minimally disabled relapsing-remitting MS, as opposed to comparing patients with a similar disease duration, for whom differences would be expected. However, the rate of cerebral atrophy cannot be assumed to be a linear process, and differences in atrophy rates could be a reflection of disease duration. Therefore, an additional comparative nonbenign group with a long disease duration would have strengthened the study. Ideally, early cerebral atrophy rates of benign and nonbenign MS of similar durations should be compared; however, these data are not available and will eventually be studied in the context of the CLIMB study. A less active disease process in benign MS is further supported in the present study by the finding that patients with benign MS and those with early MS have similar T2-hyperintense lesion loads, although the benign group had a disease duration 7 times longer. Similarly, recent studies have demonstrated that higher T2 lesion volume early in the disease is associated with higher subsequent irreversible disability17,18 and that baseline T2 lesions correlated with the BPF 13 years later.19 The present selection criterion for benign MS was based on clinical criteria alone to minimize the effect of a potential MRI selection bias regarding either lesion volume or BPF.

Specific definitions of benign disease have varied among studies and, recently, an EDSS score of 2 or less and a disease duration of 10 years have been proposed to redefine benign MS20; however, other researchers21,22 have found that a low EDSS score at 10 years could not accurately predict patients whose disease would remain benign at 20 years. In an attempt to identify patients with truly benign MS, we used a conservative definition of benign disease. In this study, patients at 10 years of disease lacked noticeable disability (EDSS score ≤1.5) and at 15 years had only minimal disability in 1 functional system (EDSS score ≤2). In addition, it was required that these EDSS levels were sustained throughout multiple semiannual visits to ensure the accuracy of patients' disease status. Although this definition is conservative, it has yet to be validated. A unified validated definition of benign MS would allow for a more accurate comparison between studies.

Because benign disease is mainly a retrospective diagnosis, it is possible that a small percentage of patients in the early MS group would ultimately witness their disease following a benign course and contribute to the observed variability. In addition, to not include a measure of cognitive function in the analysis could also affect the variability of the results. A measure of cognitive function is lacking in all definitions of benign disease; however, cognitive dysfunction has been found in a cohort of patients with clinically defined benign MS.23 Inclusion of cognitive function would be of interest because brain atrophy has been shown to be related to cognitive impairment in patients with MS.2,24,25

Apparent acceleration in brain volume loss, known as pseudoatrophy, has been shown to occur in the first few months after the initiation of immunomodulatory therapy and is likely to be related to the anti-inflammatory effect of therapy.5 Because this was an open-label observational study, there were several untreated patients and patients who initiated treatment at various time points. Although the cohorts were matched regarding these treatment variables, we further attempted to address pseudoatrophy as a possible effect on the results and analyzed treated and untreated patients separately. The benign group was consistently found to have lower atrophy rates, although the groups were no longer age matched; therefore, this finding should be interpreted with caution. With both cohorts combined, we found that treatment had an effect on brain atrophy rate such that patients undergoing treatment had a higher atrophy rate than untreated patients. A possible explanation for this observation is that patients with more active disease have a higher likelihood of being treated with an immunomodulatory agent; however, pseudoatrophy may also be a contributing factor. These results reinforce the need to control for treatment in any analysis of brain atrophy.

The present results do not show an association between the baseline BPF or T2-hyperintense lesion load and the subsequent annualized brain atrophy rate in the combined cohorts, indicating that a cross-sectional MRI measurement may not accurately reflect the ongoing biological process compared with the measurement the longitudinal rate of change. Because clinical characteristics of MS have not accurately predicted a benign disease course,26 the quest for biological markers is of particular importance. These results indicate that the rate of BPF change may provide an indication of subsequent disease course and should be further evaluated for its predictive potential.

Correspondence: Susan A. Gauthier, DO, MPH, Judith Jaffe Multiple Sclerosis Center, Weill Cornell Medical College, 1305 York Ave, New York, NY 10021 (sag2015@med.cornell.edu).

Accepted for Publication: August 8, 2008.

Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Gauthier, Berger, Buckle, Glanz, Khoury, Bakshi, Weiner, and Guttmann. Acquisition of data: Gauthier, Berger, Liptak, Duan, Egorova, Buckle, Glanz, Khoury, Bakshi, Weiner, and Guttmann. Analysis and interpretation of data: Gauthier and Guttmann. Drafting of the manuscript: Gauthier and Guttmann. Critical revision of the manuscript for important intellectual content: Gauthier, Berger, Liptak, Duan, Egorova, Buckle, Glanz, Khoury, Bakshi, Weiner, and Guttmann. Statistical analysis: Gauthier. Administrative, technical, and material support: Berger, Liptak, Duan, Egorova, Buckle, and Glanz. Study supervision: Khoury, Bakshi, Weiner, and Guttmann.

Financial Disclosure: None reported.

Ramsaransing  GSDe Keyser  J Benign course in multiple sclerosis: a review. Acta Neurol Scand 2006;113 (6) 359- 369
PubMed
Hohol  MJGuttmann  CROrav  J  et al.  Serial neuropsychological assessment and magnetic resonance imaging analysis in multiple sclerosis. Arch Neurol 1997;54 (8) 1018- 1025
PubMed
Rudick  RAFisher  ELee  JCSimon  JJacobs  LMultiple Sclerosis Collaborative Research Group, Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 1999;53 (8) 1698- 1704
PubMed
Miller  DHBarkhof  FFrank  JAParker  GJMThompson  AJ Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002;125 (pt 8) 1676- 1695
PubMed
Bermel  RABakshi  R The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol 2006;5 (2) 158- 170
PubMed
Fisher  ERudick  RASimon  JH  et al.  Eight-year follow-up study of brain atrophy in patients with MS. Neurology 2002;59 (9) 1412- 1420
PubMed
Gauthier  SAGlanz  BIMandel  MWeiner  HL A model for the comprehensive investigation of a chronic autoimmune disease: the multiple sclerosis CLIMB study. Autoimmun Rev 2006;5 (8) 532- 536
PubMed
Wei  XWarfield  SKZou  KH  et al.  Quantitative analysis of MRI signal abnormalities of brain white matter with high reproducibility and accuracy. J Magn Reson Imaging 2002;15 (2) 203- 209
PubMed
De Stefano  NBattaglini  MStromillo  ML  et al.  Brain damage as detected by magnetization transfer imaging is less pronounced in benign than in early relapsing multiple sclerosis. Brain 2006;129 (pt 8) 2008- 2016
PubMed
Filippi  MIannucci  GTortorella  C  et al.  Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI. Neurology 1999;52 (3) 588- 594
PubMed
Davie  CABarker  GJThompson  AJTofts  PS McDonald  WIMiller  DH 1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis. J Neurol Neurosurg Psychiatry 1997;63 (6) 736- 742
PubMed
Brass  SDNarayanan  SAntel  JPLapierre  YCollins  LArnold  DL Axonal damage in multiple sclerosis patients with high versus low expanded disability status scale score. Can J Neurol Sci 2004;31 (2) 225- 228
PubMed
Horsfield  MALai  MWebb  SL  et al.  Apparent diffusion coefficients in benign and secondary progressive multiple sclerosis by nuclear magnetic resonance. Magn Reson Med 1996;36 (3) 393- 400
PubMed
Droogan  AGClark  CAWerring  DJBarker  GJ McDonald  WIMiller  DH Comparison of multiple sclerosis clinical subgroups using navigated spin echo diffusion-weighted imaging. Magn Reson Imaging 1999;17 (5) 653- 661
PubMed
Ceccarelli  ARocca  MAPagani  E  et al.  The topographical distribution of tissue injury in benign MS: a 3T multiparametric MRI study. Neuroimage 2008;39 (4) 1499- 1509
PubMed
Strasser-Fuchs  SEnzinger  CRopele  SWallner  MFazekas  F Clinically benign multiple sclerosis despite large T2 lesion load: can we explain this paradox? Mult Scler 2008;14 (2) 205- 211
PubMed
Brex  PACiccarelli  OO'Riordan  JISailer  MThompson  AJMiller  DH A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002;346 (3) 158- 163
PubMed
Tintoré  MRovira  ARío  J  et al.  Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 2006;67 (6) 968- 972
PubMed
Rudick  RALee  JCSimon  JFisher  E Significance of T2 lesions in multiple sclerosis: a 13-year longitudinal study. Ann Neurol 2006;60 (2) 236- 242
PubMed
Pittock  SJ McClelland  RLMayr  WT  et al.  Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 2004;56 (2) 303- 306
PubMed
Hawkins  SA McDonnell  GV Benign multiple sclerosis? clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry 1999;67 (2) 148- 152
PubMed
Sayao  ALDevonshire  VTremlett  H Longitudinal follow-up of “benign” multiple sclerosis at 20 years. Neurology 2007;68 (7) 496- 500
PubMed
Amato  MPZipoli  VGoretti  B  et al.  Benign multiple sclerosis: cognitive, psychological and social aspects in a clinical cohort. J Neurol 2006;253 (8) 1054- 1059
PubMed
Christodoulou  CKrupp  LBLiang  Z  et al.  Cognitive performance and MR markers of cerebral injury in cognitively impaired MS patients. Neurology 2003;60 (11) 1793- 1798
PubMed
Lazeron  RHde Sonneville  LMScheltens  PPolman  CHBarkhof  F Cognitive slowing in multiple sclerosis is strongly associated with brain volume reduction. Mult Scler 2006;12 (6) 760- 768
PubMed
Ramsaransing  GSDe Keyser  J Predictive value of clinical characteristics for “benign” multiple sclerosis. Eur J Neurol 2007;14 (8) 885- 889
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of Patients With Benign and Early MS
Table Graphic Jump LocationTable 2. Annualized Brain Atrophy Ratesa
Table Graphic Jump LocationTable 3. Association of Baseline Variables and the Annualized 2-Year Atrophy Rate in the Combined Cohort

References

Ramsaransing  GSDe Keyser  J Benign course in multiple sclerosis: a review. Acta Neurol Scand 2006;113 (6) 359- 369
PubMed
Hohol  MJGuttmann  CROrav  J  et al.  Serial neuropsychological assessment and magnetic resonance imaging analysis in multiple sclerosis. Arch Neurol 1997;54 (8) 1018- 1025
PubMed
Rudick  RAFisher  ELee  JCSimon  JJacobs  LMultiple Sclerosis Collaborative Research Group, Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 1999;53 (8) 1698- 1704
PubMed
Miller  DHBarkhof  FFrank  JAParker  GJMThompson  AJ Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002;125 (pt 8) 1676- 1695
PubMed
Bermel  RABakshi  R The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol 2006;5 (2) 158- 170
PubMed
Fisher  ERudick  RASimon  JH  et al.  Eight-year follow-up study of brain atrophy in patients with MS. Neurology 2002;59 (9) 1412- 1420
PubMed
Gauthier  SAGlanz  BIMandel  MWeiner  HL A model for the comprehensive investigation of a chronic autoimmune disease: the multiple sclerosis CLIMB study. Autoimmun Rev 2006;5 (8) 532- 536
PubMed
Wei  XWarfield  SKZou  KH  et al.  Quantitative analysis of MRI signal abnormalities of brain white matter with high reproducibility and accuracy. J Magn Reson Imaging 2002;15 (2) 203- 209
PubMed
De Stefano  NBattaglini  MStromillo  ML  et al.  Brain damage as detected by magnetization transfer imaging is less pronounced in benign than in early relapsing multiple sclerosis. Brain 2006;129 (pt 8) 2008- 2016
PubMed
Filippi  MIannucci  GTortorella  C  et al.  Comparison of MS clinical phenotypes using conventional and magnetization transfer MRI. Neurology 1999;52 (3) 588- 594
PubMed
Davie  CABarker  GJThompson  AJTofts  PS McDonald  WIMiller  DH 1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis. J Neurol Neurosurg Psychiatry 1997;63 (6) 736- 742
PubMed
Brass  SDNarayanan  SAntel  JPLapierre  YCollins  LArnold  DL Axonal damage in multiple sclerosis patients with high versus low expanded disability status scale score. Can J Neurol Sci 2004;31 (2) 225- 228
PubMed
Horsfield  MALai  MWebb  SL  et al.  Apparent diffusion coefficients in benign and secondary progressive multiple sclerosis by nuclear magnetic resonance. Magn Reson Med 1996;36 (3) 393- 400
PubMed
Droogan  AGClark  CAWerring  DJBarker  GJ McDonald  WIMiller  DH Comparison of multiple sclerosis clinical subgroups using navigated spin echo diffusion-weighted imaging. Magn Reson Imaging 1999;17 (5) 653- 661
PubMed
Ceccarelli  ARocca  MAPagani  E  et al.  The topographical distribution of tissue injury in benign MS: a 3T multiparametric MRI study. Neuroimage 2008;39 (4) 1499- 1509
PubMed
Strasser-Fuchs  SEnzinger  CRopele  SWallner  MFazekas  F Clinically benign multiple sclerosis despite large T2 lesion load: can we explain this paradox? Mult Scler 2008;14 (2) 205- 211
PubMed
Brex  PACiccarelli  OO'Riordan  JISailer  MThompson  AJMiller  DH A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002;346 (3) 158- 163
PubMed
Tintoré  MRovira  ARío  J  et al.  Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 2006;67 (6) 968- 972
PubMed
Rudick  RALee  JCSimon  JFisher  E Significance of T2 lesions in multiple sclerosis: a 13-year longitudinal study. Ann Neurol 2006;60 (2) 236- 242
PubMed
Pittock  SJ McClelland  RLMayr  WT  et al.  Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 2004;56 (2) 303- 306
PubMed
Hawkins  SA McDonnell  GV Benign multiple sclerosis? clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry 1999;67 (2) 148- 152
PubMed
Sayao  ALDevonshire  VTremlett  H Longitudinal follow-up of “benign” multiple sclerosis at 20 years. Neurology 2007;68 (7) 496- 500
PubMed
Amato  MPZipoli  VGoretti  B  et al.  Benign multiple sclerosis: cognitive, psychological and social aspects in a clinical cohort. J Neurol 2006;253 (8) 1054- 1059
PubMed
Christodoulou  CKrupp  LBLiang  Z  et al.  Cognitive performance and MR markers of cerebral injury in cognitively impaired MS patients. Neurology 2003;60 (11) 1793- 1798
PubMed
Lazeron  RHde Sonneville  LMScheltens  PPolman  CHBarkhof  F Cognitive slowing in multiple sclerosis is strongly associated with brain volume reduction. Mult Scler 2006;12 (6) 760- 768
PubMed
Ramsaransing  GSDe Keyser  J Predictive value of clinical characteristics for “benign” multiple sclerosis. Eur J Neurol 2007;14 (8) 885- 889
PubMed

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