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M Filippi

Publications and source records attributed to M Filippi.

At least 19 recordsLinked to original sources
PubMed1998

Correlations between monthly enhanced MRI lesion rate and changes in T2 lesion volume in multiple sclerosis.

Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established. The most commonly used MRI parameters in treatment trials are (1) monthly gadolinium-enhanced MRI, with the number of active lesions serving as the outcome measure, and (2) annual lesion load quantification, in which change in MS lesion volume provides the MRI endpoint. We evaluated clinical/MRI correlations and the relationship between these two markers of disease activity in 73 patients with clinically definite MS. Quantification of T2 lesion load was performed at study entry and exit, with a median study duration of 11 months (range, 9 to 14 months). Monthly postgadolinium T1-weighted images were acquired between these time points. Lesion load at study entry was significantly correlated with the baseline Expanded Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated. The number of enhancing lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated with the subsequent enhancing lesion activity over the study period. A significant correlation was found between change in lesion load and disease activity on the monthly scans. Our results suggest that annual lesion load quantification provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of disease evolution in phase III treatment trials.

Adolescent↗
PubMed1998

Proinflammatory cytokines regulate antigen-independent T-cell activation by two separate calcium-signaling pathways in multiple sclerosis patients.

Central nervous system (CNS) lesions typical of multiple sclerosis (MS) are characterized by demyelinating inflammatory infiltrates that contain few CNS antigen-specific autoreactive T cells and a multitude of pathogenic non-antigen-specific mononuclear cells. Here, we report that in patients with MS the combined action of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-2, and IL-6 leads to the activation of most peripheral T cells (mainly CD4 memory) by promoting a persistent intracellular calcium increase via two independent signaling pathways. The activation of these pathways, one activated by IFNgamma and the other by the combination TNFalpha/IL-2/IL-6, is independent from myelin antigens and precedes by 2 weeks phases of disease activity (eg, clinical relapses and/or appearance of gadolinium-enhancing lesions on brain magnetic resonance imaging scans during 1 year of follow-up). Our results indicate that an appropriate combination of the four cytokines, three with a proinflammatory profile and one necessary for T-cell growth and differentiation, can activate in an antigen-independent fashion most peripheral T cells from MS patients. This mechanism is likely to contribute to the recruitment of nonspecific lymphocytes into the cellular activation processes leading to CNS demyelination and may represent a major target for immune intervention in MS.

Antigens↗
PubMed1998

Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis.

The change of brain lesion load, measured on T2-weighted magnetic resonance imaging (MRI) using computer-assisted techniques, is a widely used secondary endpoint for phase III clinical trials in multiple sclerosis (MS). Collection, transfer, and analysis of the electronic data across multiple centers have all proved challenging and give rise to potential errors. However, many new acquisition schemes and postprocessing techniques have been developed; these may reduce scan times and result in better lesion conspicuity or lessen the human interaction needed for data analysis. This review considers many aspects of the use of MRI in clinical trials for MS and provides international consensus guidelines, derived from a task force of the European Magnetic Resonance Networks in Multiple Sclerosis (MAGNIMS) together with a group of North American experts. The main points considered are the organization of correctly powered trials and selection of participating sites; the appropriate choice of pulse sequences and image acquisition protocol given the current state of technology; quality assurance for data acquisition and analysis; accuracy and reproducibility of lesion load assessments; and the potential for the application of quantitative methods to other MRI-derived measures of disease burden.

Brain↗
PubMed1998

A preliminary study comparing the sensitivity of serial monthly enhanced MRI after standard and triple dose gadolinium-DTPA for monitoring disease activity in primary progressive multiple sclerosis.

We performed this study to evaluate and compare the numbers of total and new enhancing lesions detected on serial monthly brain magnetic resonance imaging (MRI) after the injection of a standard dose (SD) and a triple dose (TD) of gadolinium-DTPA (Gd) in patients with primary progressive multiple sclerosis (PPMS). Every 4 weeks for 3 months and in two separate sessions, MRI scans were obtained from 5 patients with PPMS, 5 (early) and 20 minutes (delayed) after SD (0.1 mmol/kg) or TD (0.3 mmol/kg) Gd injection. In 2 patients, T1-weighted scans with a magnetization transfer pulse (MT) after SD and TD injection were also obtained. There were 13 enhancing lesions (5 of which were new) on the early SD scans, 15 (5 new) on the delayed SD scans, 17 (6 new) on the early TD scans and 18 (7 new) on the delayed TD scans. TD MRI scans detected more enhancing lesions than SD scans in 3 patients (two of them were those with the lowest disability). The application of the MT pulse did not change the numbers of enhancing lesions seen after the injection of SD and TD of Gd in the remaining two patients. No side effects were reported and no significant changes in blood test parameters were found throughout the study. Our results suggest that serial monthly TD MRI, delayed scanning, MT T1-weighted scans or their combination, although safe, have a limited role for monitoring disease evolution in patients with PPMS.

Adult↗
PubMed1998

Effect of training and different measurement strategies on the reproducibility of brain MRI lesion load measurements in multiple sclerosis.

In this study, we evaluated the intra- and interobserver variabilities in measuring lesion load of brain MRI abnormalities present on proton-density scans from patients with MS, using using both manual outlining or a semiautomated local thresholding technique (LTT). We also evaluated how these variabilities were affected by the use of standard rules for lesion load measurements, training, and different measurement strategies. The intraobserver variabilities obtained after establishing rules for lesion load measurements and training were not significantly different from those obtained before any consensus among the observers, both for manual outlining and for the LTT. On the contrary, the interobserver variabilities obtained with manual outlining or the LTT were significantly reduced when rules for lesion load measurements were used. For manual outlining, the intraobserver variability did not significantly change when the measurements were performed after an experienced radiologist identified lesions or when using adjacent slices and the corresponding T2-weighted images as reference for lesion identification. On the contrary, for the LTT, the intraobserver variability was significantly reduced by the use of the radiologic marking. The interobserver variabilities for both manual outlining and the LTT were reduced compared with the free condition when these measurement strategies were used. Our findings demonstrate that both lesion identification and outlining are important sources of variation for MRI lesion load measurements in MS and that there are simple strategies to reduce such variation that might be useful when planning clinical trials.

Brain↗
PubMed1998

Characteristics of chronic MS lesions in the cerebrum, brainstem, spinal cord, and optic nerve on T1-weighted MRI.

We analyzed the prevalence of severely hypointense lesions on T1-weighted MRI in the brainstem, spinal cord, and optic nerve from 65 patients with MS. About half of 1,274 supratentorial lesions were classified as severely hypointense. Severe hypointensity was not seen in the optic nerve and spinal cord, and in only one of 168 chronic brainstem lesions. Tissue destruction in the brainstem, spinal cord, and optic nerve of MS patients does not usually result in severely hypointense lesions.

Adolescent↗
PubMed1998

Benign versus secondary-progressive multiple sclerosis: the potential role of proton MR spectroscopy in defining the nature of disability.

PURPOSE: We determined the clinical utility of proton MR spectroscopy in defining the extent of disability in benign versus secondary-progressive multiple sclerosis (MS). METHODS: Thirty patients with clinically definite MS, including 16 patients with benign MS and 14 with secondary-progressive MS, and a group of 13 healthy volunteers were studied with combined stimulated-echo acquisition mode proton MR spectroscopy and MR imaging (all patients received contrast material). RESULTS: Acute enhancing lesions of benign and secondary-progressive MS were characterized by a reduction in N-acetylaspartate (NAA)/choline and NAA/creatine and an increase in inositol compounds/creatine as compared with normal white matter. Such variations were also detected in chronic unenhancing lesions in patients with secondary-progressive MS, although they were not found in chronic unenhancing lesions in patients with benign MS. Chronic lesions of the two forms of the disease have significative differences in NAA and inositol signals. CONCLUSION: Proton MR spectroscopy is able to show metabolic changes occurring in the white matter of patients with MS. Such changes differ according to the phase (acute versus chronic) and the clinical form (benign versus secondary-progressive) of the disease.

Adult↗
PubMed1998

Increased spatial resolution using a three-dimensional T1-weighted gradient-echo MR sequence results in greater hypointense lesion volumes in multiple sclerosis.

PURPOSE: Our goal was to evaluate whether improved spatial resolution of MR images results in the detection of higher volumes of hypointense lesions in patients with multiple sclerosis (MS). METHODS: A magnetization-prepared rapid acquisition gradient-echo (MP-RAGE) sequence with subsequent reconstruction of axial sections with 5-, 3-, and 1-mm thickness and a dual-echo sequence were obtained in 16 patients with relapsing-remitting or secondary-progressive MS. The volumes of MR imaging abnormalities present on each of these studies were measured using a semiautomated segmentation technique based on local thresholding. The hypointense lesion volumes seen on the three reconstructed MP-RAGE sets of images were compared using the Friedman test and correlated with the hyperintense lesion volume on proton density-weighted images and with scores on the Expanded Disability Status Scale using Spearman's rank correlation coefficient. RESULTS: The median volume of hypointense lesions increased from 1.2 mL (range, 0 to 14.9 mL) on the 5-mm-thick MP-RAGE images to 1.7 mL (range, 0 to 15.8 mL) on the 3-mm-thick images, and to 1.9 mL (range, 0 to 16.2 mL) on the 1-mm-thick images. The hypointense lesion volumes measured on the three MP-RAGE images correlated significantly with the degree of disability, whereas this correlation was not significant with the T2-weighted lesion load. CONCLUSION: Our findings indicate that a significant increase in the volume of potentially disabling MS lesions is observed when obtaining MR images with thin sections.

Adult↗
PubMed1998

Intraobserver and interobserver variability in schemes for estimating volume of brain lesions on MR images in multiple sclerosis.

PURPOSE: Our goal was to evaluate the intraobserver and interobserver reproducibility of measurements of brain lesion load in multiple sclerosis (MS) by using two proposed acquisition schemes. METHODS: Three-millimeter-thick conventional spin-echo (CSE) and fast fluid-attenuated inversion-recovery (FLAIR) sequences were obtained and the lesions segmented using a semiautomated technique based on local thresholding to calculate intraobserver and interobserver reproducibility. These were compared with images obtained from two separate MR units in which 5-mm CSE sequences were obtained and segmented by using the local thresholding technique and also by manual outlining. RESULTS: The intraobserver coefficient of variation was 4.0% (95% confidence interval [CI], 3.0% to 4.5%) for the 5-mm CSE sequence measured with manual outlining, 3.1% (95% CI, 2.5% to 3.2%) and 5.1% (95% CI, 4.1% to 5.6%) for the two sets of 5-mm CSE sequences measured using the local thresholding technique, 5.7% (95% CI, 3.9% to 6.6%) for the 3-mm CSE sequence, and 2.6% (95% CI, 2.1% to 2.7%) for the fast FLAIR sequence. The interobserver coefficient of variation was 7.1% (95% CI, 4.9% to 8.7%) and 8.3% (95% CI, 6.4% to 9.6%) for the two sets of 5-mm CSE sequences, 7.3% (95% CI, 4.7% to 9.1%) for the 3-mm CSE sequence, and 2.9% (95% CI, 2.3% to 3.3%) for the fast FLAIR sequence. The intraobserver and interobserver reproducibility of measurements obtained with the fast FLAIR technique was significantly better than those obtained with the other techniques. CONCLUSIONS: Our data indicate that the intraobserver and interobserver variability in quantifying MS lesions can be reduced significantly with the use of fast FLAIR sequences, while no significant improvement is gained by reducing the section thickness from 5 mm to 3 mm.

Adult↗
PubMed1998

Intraobserver and interobserver variability in measuring changes in lesion volume on serial brain MR images in multiple sclerosis.

PURPOSE: We evaluated the intraobserver and interobserver variability in measuring long-term changes in the volume of brain lesions on 5- and 3-mm-thick MR sections in patients with multiple sclerosis. METHODS: Eighteen 18 patients were scanned on two separate occasions with a mean interval of 16.4 months between the two examinations. In each session, a scan with 24 contiguous 5-mm-thick axial sections and another with 40 contiguous 3-mm-thick axial sections was acquired consecutively without moving the patient. We assessed MR lesion load by using a semiautomated local thresholding technique. RESULTS: Lesion volume was significantly higher on images with 3-mm-thick sections than on those with 5-mm-thick sections both at baseline and at follow up. Significant increases in total lesion volume were observed during the follow-up period on images obtained with both 5- and 3-mm-thick sections. The intra- and interobserver variability in measurements of changes in lesion volume was significantly higher on images with 5-mm-thick sections than on those with 3-mm-thick sections. CONCLUSION: Our data indicate that the acquisition of thinner sections increases the reliability of the assessment of changes in brain lesion load on MR images in patients with multiple sclerosis.

Adult↗
PubMed1998

Recurrent acute transverse myelopathy associated with anticardiolipin antibodies.

In three patients with recurrent episodes of acute transverse myelopathy, spinal MR imaging during each episode showed areas of hyperintensity on proton density- and T2-weighted images with inconsistent contrast enhancement. Cranial MR imaging, laboratory screenings, and CSF analysis showed only increased titers of anticardiolipin antibodies. Although a causative role in neurologic conditions has not been established conclusively, an association between these antibodies and acute transverse myelopathy and its recurrences cannot be ignored.

Acute Disease↗
PubMed1997

Tumor necrosis factor alpha and its receptors in relapsing-remitting multiple sclerosis.

In the attempt to further characterize the extent and timing of tumor necrosis factor (TNF)alpha-system activation during multiple sclerosis (MS), we performed a cross-sectional and a longitudinal study in a total of 73 relapsing-remitting MS patients. We assessed serum levels of soluble TNFalpha, soluble TNFalpha receptor 1 (R1) and soluble TNFalpha receptor 2 (R2) in 65 relapsing-remitting MS patients in different phases of disease. TNFalpha, R1 and R2 serum levels measured in MS patients did not differ from those measured in healthy individuals and did not correlate with (a) clinical relapses, (b) presence of gadolinium-enhancing brain-magnetic resonance imaging (MRI) lesions, and (c) bioactivity of TNFalpha. We also measured in 8 additional relapsing-remitting MS patients peripheral blood mononuclear cells (PBMC) mRNA levels of TNFalpha, R1 and R2 every 15 days for one year. In 4 of these patients we also measured levels of soluble TNFalpha, R1 and R2 every 15 days for 5 months across a clinical exacerbation. PBMC TNFalpha, R1 and R2 mRNA levels and serum levels of soluble R1 and R2, but not TNFalpha, fluctuated concordantly (P<0.05) and peaked a mean of 6 weeks before clinical and MRI evidence of disease activity. Moreover, we found a significant positive correlation between cumulative TNFalpha and R2 mRNA levels (measured during the follow-up period in the 8 MS patients studied serially) and the number of clinical attacks recorded in these patients during the study. Our data show that serum levels of soluble TNFalpha, R1, and R2 in MS patients do not differ from those of healthy individuals. However, although within normal values, the transcription and production rate of all these molecules fluctuate concordantly in the peripheral blood during the course of the disease (with the exception of soluble TNFalpha) and their maximal elevation significantly precedes the occurrence of clinical exacerbations. It is not clear whether soluble TNFalpha escapes recognition by commonly used assays or is simply not released in its soluble form in MS patients. In any case, measurement of TNFalpha mRNA levels and R1 and R2 mRNA and protein levels appears to be a better indicator of disease fluctuations during the course of MS than assessments of soluble TNFalpha protein.

Adult↗
PubMed1997

Magnetization transfer ratio changes in a symptomatic lesion of a patient at presentation with possible multiple sclerosis.

Short-term changes of magnetization transfer ratio (MTR) of a symptomatic lesion in a patient at presentation with clinically isolated syndrome suggestive of multiple sclerosis (MS) are presented. These changes strictly correlated with the evolution of the corresponding clinical symptomatology. This suggests that following changes of individual strategically located lesions might be useful to monitor evolution of demyelinating white matter diseases.

Adult↗
PubMed1997

A magnetization transfer study of white matter in siblings of multiple sclerosis patients.

In this study, we evaluated magnetization transfer ratio values in the brain white matter of siblings of multiple sclerosis (MS) patients and compared them to those obtained in sex- and age-matched normal controls. No statistically significant difference was found between the two groups for all the white matter areas studied (frontal and occipital lobes, centrum semiovale, periventricular white matter, internal capsule, genu and splenium of the corpus callosum).

Adult↗
PubMed1997

Strategies for optimizing MRI techniques aimed at monitoring disease activity in multiple sclerosis treatment trials.

Serial magnetic resonance imaging (MRI) detects substantial subclinical disease activity in multiple sclerosis (MS) and is presently included in most treatment trials as an objective outcome measure. Our current knowledge of the role of MRI in MS treatment trials is derived from very limited patient studies, and the aim of this paper is to identify strategies to optimize the use of MRI in monitoring disease activity in treatment trials. The number of active lesions revealed by MRI can be used as the primary outcome measure in exploratory treatment trials. With monthly scanning, the majority of active lesions will be seen by virtue of a limited number of new areas of gadolinium enhancement. The contrast between enhancing lesions and background could be increased by: (1) using higher doses of gadolinium, (2) suppressing the background signal with magnetization transfer, (3) delayed scanning, or (4) a combination of these. Following a systematic comparison of those approaches, the effect on the sensitivity in detecting active lesions should be analysed with reference to the power of treatment trials. We present preliminary results showing marked agreement between observers in reporting enhancing lesions; however, with new acquisition strategies, the observer variation should be re-established in a multicentre fashion. In definitive trials, the increase in total lesion load serves as a secondary outcome measure. Since the majority of lesions making up the total lesion load are inactive during the study, spatial resolution should be maximized in order to preclude any artificial changes in lesion load to be superimposed (noise) upon the relatively small actual change (information). Reduction in measurement error can be attempted by improved acquisition techniques with increased lesion to background contrast. More importantly, improvement in quantitation techniques is warranted. With a 6% coefficient of variation in measuring a baseline lesion load, we calculate the standard error of the mean yearly increase in T2 lesion load (typically 10% in untreated patients) in a treatment arm of 124 patients to be 7.5%. A comparison of several quantitation techniques should be performed in a multicentre longitudinal fashion in order to include variation caused by both scanner and segmentation technique, in addition to biological activity.

Clinical Trials as Topic↗
PubMed1997

Intra-observer reproducibility in measuring new putative MR markers of demyelination and axonal loss in multiple sclerosis: a comparison with conventional T2-weighted images.

New magnetic resonance (MR) measures considered to be putative workers of demyelination and axonal loss were found to be more closely related to clinical disability than T2-weighted MR imaging (MRI) findings in patients with multiple sclerosis (MS). In this study, we evaluated the reproducibility of such measurements in order to assess their reliability for longitudinal studies in MS. The intra-observer coefficients of variation for repeated measurements did not significantly differ among the MR techniques studied [2.6% for T2-weighted MR, 4.38% for unenhanced T1-weighted MRI, 3.65% for magnetisation transfer imaging (MTI) and 2.28% for spinal cord cross-sectional area at C5]. Our findings suggest that non-conventional MR techniques may be reliable outcome measures for clinical trials in MS.

Adult↗
PubMed1997

An oblique cylinder contrast-adjusted (OCCA) phantom to measure the accuracy of MRI brain lesion volume estimation schemes in multiple sclerosis.

A new OCCA phantom using Oblique Cylinders and Contrast Adjustment for measuring the accuracy of brain lesion volume estimation schemes is described. It uses obliquely oriented cylinders made from acrylic rod, mounted in a water bath, to give realistic partial volume errors. Image intensities are inverted, scaled, and shifted, and noise is added, to form images that have realistic values of lesion-white matter contrast (5-30%) and contrast-to-noise ratio (3-20%). Artificial gray matter, CSF (cerebrospinal fluid), and scalp lipid are added because these bright areas may determine how the gray level display window is set. The performance of manual and contouring methods for estimating lesion volume was measured for three observers and nine lesions with individual volumes from 0.3 to 6.2 ml. There was a large variation, depending on the choice of method, the observer, and the lesion contrast. Volumes were usually overestimated, with the error increasing at high contrasts. The average error in estimating total lesion volume was 17% (range -16% to +30%). The OCCA phantom may have a role in training observers to improve their accuracy (and hence inter- and intraobserver reproducibility).

Brain↗