B.M.J. Uitdehaag

MR spectroscopic evidence for glial increase but not for neuro-axonal damage in MS normal-appearing white matter

Quantitative single‐voxel, short echo‐time (TE) MR spectroscopy (MRS) was used to determine metabolite concentrations in the cerebral normal‐appearing white matter (NAWM) of 76 patients with multiple sclerosis (MS), and the WM of 25 controls. In NAWM of all MS disease types (primary progressive, relapsing‐remitting, and secondary progressive), the concentration ratio of total N‐acetyl‐aspartate (tNAA)/total creatine (tCr) was decreased compared to controls. Remarkably, this was entirely due to an increase of tCr in MS patients, whereas there was no difference in tNAA. Separate quantification of the two tNAA components yielded no significant difference in NAA (N‐acetyl‐aspartate), while the concentration of NAAG (N‐acetyl‐aspartyl‐glutamate) was slightly—but significantly—elevated in MS patients. Myo‐inositol (Ins) was strongly increased in MS patients, and choline‐containing compounds (Cho) were mildly increased. There were no metabolite differences between disease types, and no correlations with disability scores. The results are supported by measures of spectral quality, which were identical for patients and controls. In conclusion, MS NAWM containing very little perilesional tissue is characterized by increased glial cell numbers (increase of Ins and tCr) without evidence of axonal dysfunction (normal NAA). Further studies should elucidate the mechanism underlying increased NAAG in MS NAWM. Magn Reson Med 53:256–266, 2005.

POSTWITHDRAWAL REBOUND INCREASE IN T2 LESIONAL ACTIVITY IN NATALIZUMAB-TREATED MS PATIENTS

Natalizumab significantly reduces relapse rate, disability progression, and lesion development in relapsing multiple sclerosis (MS).1,2 Dosing was suspended when cases of progressive multifocal leukoencephalopathy were reported and reintroduced after a safety analysis of all patients being treated with natalizumab had been completed.3 Our center participated with 23 patients in the phase III program (13 in AFFIRM [Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis], 10 in SENTINEL [Safety and Efficacy of Natalizumab in Combination with Interferon β-1a in Patients with Relapsing Remitting Multiple Sclerosis]). All patients underwent safety MRI shortly after dose suspension and unenhanced MRI as part of the baseline assessments before reintroduction of natalizumab. The neuroradiologist who reviewed these images noticed that in some patients a considerable number of new lesions had developed in this 15-month interval. As for these patients longitudinal MRI data were available from the period before natalizumab treatment, we performed a formal analysis comparing the annualized number of new MRI lesions in the period before patients started with natalizumab vs the 15-month interval after withdrawal of natalizumab. ### Methods. Patients randomized to natalizumab had active treatment during the double-blind and extension phases of the study (30 to 37 infusions, median 36). Patients randomized to …

Concurrent validity of the MS Functional Composite using MRI as a biological disease marker

Introduction: The MS Functional Composite (MSFC), a recently developed outcome measure for MS clinical trials measuring three dimensions (ambulation/leg function, arm/hand function, and cognition), was applied to 134 patients with MS to study the concurrent validity, using MRI measurements as a biological disease marker. The results were compared to correlations between the traditionally applied Expanded Disability Status Scale (EDSS) and MRI measurements in the same patients. Methods: The assessments of MSFC and EDSS were performed in combination with brain MRI. MRI consisted of T1- and T2-weighted images, from which the hypointense and hyperintense lesion loads were quantified. Results: The MSFC score ranged from −2.54 to 0.99. The median EDSS was 3.0 (interquartile range [IQR] 1.5 to 6.0). The median T2-weighted lesion load was 8.4 cm3 (IQR 3.4 to 19.8) and the median T1-weighted lesion load was 1.1 cm3 (IQR 0.3 to 3.2). Correlations between the MSFC and both T1 (−0.24) and T2 (−0.25) lesion loads were demonstrated, but not between the EDSS and both MRI parameters. Significant correlations between MSFC components and T1 and T2 lesion loads existed for cognitive function and arm/hand function, but not for ambulation. If relapse-onset patients (relapsing-remitting and secondary progressive) were combined, the correlation between MSFC and MRI parameters became stronger for both T1 (−0.37) and T2 lesion loads (−0.35). Conclusions: The authors present the concurrent validity of the MSFC with a biological disease marker by showing correlations with MRI. Specifically, they demonstrate significant correlations with cognition and arm/hand function assessments, domains that are not well represented in the EDSS.

Outcome measures for multiple sclerosis clinical trials: relative measurement precision of the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite.

We compared the relative measurement precision (RMP) of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functio nal C omposite (MSFC) for discriminating between groups of patients known to differ in their extent of multiple sclerosis (MS). A total of 133 patients were rated with the EDSS and MSFC and had magnetic resonance imaging (MRI) scans. Patients were grouped on the basis of MRI appearances (T1- and T2-weighted lesion loads, parenchymal and ventricular fractions - T1LL, T2LL, PF, VF, respectively) and RMP was determined using the method of group differences. For each MRI parameter, the total sample was arranged in ascending order of magnitude and divided into two, three, four and five similar sized groups. For each division (two, three, four or five groups), EDSS and MSFC scores for the groups were compared using parametric (paired samples t-tests, one-way A NOVA) and nonparametric (Wilcoxon’s rank-sum test, Kruskal -Wallis analysis of variance) statistical methods and RMP was estimated. The EDSS and MSFC were correlated substantially (r = -0.64). Relative to the MSFC, the EDSS had inferior measurement precision regardless of the number of groups into which the total sample was divided, or the statistical method. However, the RMP of the EDSS compared with the MSFC varied from 2% to 86%. Results suggest the MSC F is better than the EDSS for detecting differences between groups of patients, defined by these MRI markers of MS. However, the finding that both scales correlated weakly with MRI markers, indicated that they are limited as predicto rs of MS patho logy as defined by MRI. A n explanatio n for this well-established clinical -MRI paradox is that rating scales and MRI measure fundamentally different manifestations of MS.

Value of health-related quality of life to predict disability course in multiple sclerosis

Objective: To determine the value of health-related quality of life (HRQoL) to predict change in disability status in patients with multiple sclerosis (MS). Methods: Over a 5-year period, data were collected on HRQoL (Medical Outcomes Study Short Form-36 Health Survey) and disability status (Expanded Disability Status Scale) from a heterogeneous group of 81 Dutch-speaking patients with MS. Results: Multivariate logistic regression analysis showed that HRQoL in the domains of Physical Functioning and Role-Physical Functioning is a significant predictor of change in disability status. Conclusions: A patient’s subjectively perceived health-related quality of life may not be only a clinically and psychosocially meaningful outcome per se but may also be a predictor of objective outcomes such as change in disability status over a substantial period of time.

Psychometric evaluation of the multiple sclerosis impact scale (MSIS-29) for proxy use

Background: There may be difficulties in the use of self report measurements in patients with cognitive impairment or serious mood disturbances which interfere with reliable self assessment, as may be the case in multiple sclerosis (MS). In such cases proxies may provide valuable information. However, before using any questionnaires in a proxy sample, the questionnaire should be evaluated for proxy use. Objective: To evaluate the psychometric properties of the 29 item Multiple Sclerosis Impact Scale (MSIS-29) when used by proxies of MS patients. Methods: A sample of 62 partners of MS patients completed the MSIS-29. The data were evaluated for the psychometric criteria of the MSIS-29, including data quality, scaling assumptions, acceptability, reliability, validity, and responsiveness. Results: Psychometric evaluation was satisfactory; data quality was high, and scaling assumptions and acceptability were good. Reliability was high (α>0.80). Findings were consistent with results of a psychometric evaluation in a patient sample. Conclusions: The MSIS-29 can be used reliably in proxies of patients with MS. As a next step the relation between data obtained from patients and proxies needs to be studied, focusing on factors that may affect agreement and discrepancies.

Brain atrophy in multiple sclerosis: impact of lesions and of damage of whole brain tissue

Introduction: In multiple sclerosis (MS), brain atrophy measurement on magnetic resonance imaging (MRI) reflects overall tissue loss, especially demyelination and axonal loss. We studied which factor contributes most to the development of brain atrophy: extent and severity of lesions or damage of whole brain tissue (WBT). Methods: Eighty-six patients with MS [32 primary progressive (PP), 32 secondary progressive (SP)] and 22 relapsing-remitting (RR) were studied. MRI included T1- and T2-weighted imaging to obtain hypointense T1 lesion volume (T1LV) and two brain volume measurements: 1) the parenchymal fraction (PF; whole brain parenchymal volume/intracranial volume) as a marker of overall brain volume, and 2) the ventricular fraction (VF; ventricular volume/intracranial volume) as a marker of central atrophy. From magnetization transfer ratio (MTR) histograms, the relative peak height (rHp) was derived as an index of damage of WBT (a lower peak height reflects damage of WBT). Results: Multiple linear regression analysis revealed that damage of WBT explains most of the variance of PF (standardized coefficient b=0.59, p <0.001 for WBT and b= −0.19, p <0.05 for T1LV). These findings are independent of disease phase; even in RR patients, damage of WBT plays a dominant role in explaining the variance in overall brain volume. By contrast, the variance in VF is explained by both T1LV and damage of WBT (standardized coefficient b =0.43, p<0.001 for T1LV and b = −0.38, p <0.001 for WBT). Conclusion: This study shows that overall brain volume (PF) is best explained by damage of WBT, supporting the significance of nonfocal pathology in MS in producing tissue loss. Central atrophy (VF) is determined by both lesion volume and damage of WBT. Our results underline the importance of nonfocal pathology even in the early (RR) phase of the disease.

Patterns of enhancing lesion evolution in multiple sclerosis are uniform within patients.

Background: Histopathologic studies suggest that lesion development differs between patients with multiple sclerosis (MS), but that all lesions appear similar within patients. It is unclear whether the same applies to the evolution of lesions on T1-weighted MRI. Objective: To evaluate lesion evolution on MRI, comparing variance within and between patients, as well as the relationship between MRI lesion development and clinical characteristics. Methods: In 48 patients, signal intensity at baseline and at follow-up on T1-weighted MRI of 789 newly enhancing lesions was studied in relationship with clinical data. Patients were included on the basis of showing at least five enhancing lesions that could be followed on monthly scans for 6 months. Variance component analysis and multilevel analysis were used to compare within-patient and between-patient variability. Results: Although various types of lesion evolution could be observed within a single patient, between-patient variance was considerably larger than within-patient variance for MRI parameters used to describe lesion evolution, indicating that lesion evolution is a patient-specific phenomenon. Evolution of lesions in patients with secondary progressive disease more frequently followed a hypointense–hypointense pattern than in patients with relapsing–remitting disease (odds ratio 4.2). Patients with a benign disease course had more persistent isointense lesions at follow-up, whereas patients with aggressive disease had more hypointense lesions. Conclusion: Lesion evolution on MRI appears to be a patient-specific phenomenon, although the outcome seems to vary according to the phase and severity of the disease.

Predicting short-term disability progression in early multiple sclerosis: added value of MRI parameters

Objective: Magnetic resonance imaging (MRI) and clinical parameters are associated with disease progression in multiple sclerosis (MS). The aim of this study was to investigate whether adding MRI parameters to a model with only clinical parameters could improve these associations. Methods: 89 patients (55 women) with recently diagnosed MS had clinical and MRI evaluation at baseline (time of diagnosis) and at follow-up after 2.2 years. Detailed clinical data were available, including disease type (relapse-onset or progressive-onset) and disability, as measured by the Expanded Disability Status Scale (EDSS). MRI parameters included Normalised Brain Volume (NBV) at baseline, percentage brain volume change (PBVC/year), T2- and T1-lesion loads and spinal cord abnormalities. Progression of disability (increase in EDSS of at least 1 point at follow-up) was the main outcome measure. For a model containing only clinical parameters, the added value of MRI parameters was tested using logistic regression. Results: PBVC/year and lesion loads at follow-up were significantly higher in the group with progression. Adding PBVC/year to a clinical model improved the model, indicating that MRI parameters added independent information (p<0.001). Conclusion: The rate of cerebral atrophy conveys added information for the progression of disability in patients with early MS, suggesting that clinical disability is determined by neurodegenerative changes as depicted by MRI.

Gender differences in multiple sclerosis: Cytokines and vitamin D

The disproportional increase of the female:male ratio in relapse-onset (relapsing remitting (RR) and secondary progressive (SP)) multiple sclerosis (MS) patients in the last 20 years has further raised scientific interest in gender difference in MS. It has been suggested that the immune system, especially cytokines, plays an important role in the gender issue, as can also be seen in other autoimmune diseases. The immune system is influenced by different factors including hormones and seasonal fluctuations (vitamin D). This overview will highlight the gender differences in MS, with emphasis on the cytokines and vitamin D.