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M Rovaris

Publications and source records attributed to M Rovaris.

At least 55 records · Page 3Linked to original sources
PubMed2001

Intra-observer, inter-observer and inter-scanner variations in brain MRI volume measurements in multiple sclerosis.

INTRODUCTION: Measurement of brain volume on magnetic resonance imaging (MRI) scans is regarded as an objective marker of multiple sclerosis (MS) severity with the potential to monitor treatment efficacy accurately. This study was performed to assess the variability of brain MRI volume measurements. PATIENTS AND METHODS: We studied nine patients with relapsing-remitting MS, who were imaged on two occasions (separated by an interval of 24 h) using two different MR scanners and fast fluid-attenuated inversion recovery (fast-FLAIR) sequences. The whole brain volume computed from each image was measured three times by three observers using a seed-growing technique based on signal intensity thresholding. Intra-observer, inter-observer and inter-scanner variabilities were expressed as coefficients of variations (COVs). The inter-scanner variability included not only the intra-observer variation but also the repositioning variability and the variation in observed brain volume caused by different scanner hardware and sequence implementations. RESULTS: There was no statistically significant difference in patients' brain volume values between observers (P=0.82) or between scanners (P=0.30). The mean intra-observer COV was 1.2% (s.e.=0.4%), the mean inter-observer COV was 1.8% (s.e.=0.8%) and the mean inter-scanner COV was 2.4% (s.e.=1.2%). The intra-observer variance was not statistically different from those found between observers (P=0.83) or scanners (P=0.44). CONCLUSION: The intra-observer variability in brain volume measurements found in this study was within the range of intra-observer variability found in previous studies. This study shows that the use of different observers and MR scanners has only a small influence on the measured brain volume and does not affect the reproducibility of this measurement greatly.

Adult↗
PubMed2001

Modelling new enhancing MRI lesion counts in multiple sclerosis.

Magnetic resonance imaging (MRI) has been established as the most relevant paraclinical tool for diagnosing and monitoring multiple sclerosis (MS). In this context, counting the number of new enhancing lesions on monthly MRI scans is widely used as a surrogate marker of MS activity when evaluating the effect of treatments. In this study, we investigated whether parametric models based on mixed Poisson distributions (the Negative Binomial (NB) and the Poisson-Inverse Gaussian (P-IG) distributions) were able to provide adequate fitting of new enhancing lesion counts in MS. We found that the NB model gave good approximations in relapsing-remitting and secondary progressive MS patients not selected for baseline MRI activity, whereas the P-IG distribution modelled better new enhancing lesion counts in relapsing-remitting MS patients selected for baseline activity. This study shows that parametric modelling for MS new enhancing lesion counts is feasible. This approach should provide more targeted tools for the design and the analysis of MRI monitored clinical trials in MS.

Humans↗
PubMed2001

Correlation of multiple sclerosis measures derived from T2-weighted, T1-weighted, magnetization transfer, and diffusion tensor MR imaging.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), the severity of tissue damage can vary from edema and inflammation to irreversible demyelination and axonal loss. Compared with conventional T2-weighted MR imaging, magnetization transfer (MT) and diffusion tensor (DT) MR imaging provide quantitative indices with increased specificity to the most destructive aspects of MS. To increase our understanding of the pathophysiologic processes of MS, we assessed the correlations between MT and DT MR imaging-derived metrics and the correlations between these quantities and measures derived from conventional MR in patients with MS. METHODS: T2-weighted, T1-weighted, MT, and DT MR images of the brain were obtained from 34 patients with relapsing-remitting MS (RRMS) and 15 age-matched control subjects. T2 and T1 lesion volumes (LV) and brain volume were measured. MT ratio (MTR), mean diffusivity (D macro), and fractional anisotropy (FA) histograms from the overall brain tissue (BT) and the normal-appearing brain tissue (NABT) were obtained. Average lesion MTR, D macro, and FA were also calculated. The correlations between T2 and T1 LV, brain volume, MT-, and DT-derived metrics were assessed with the Spearman rank correlation coefficient. RESULTS: No significant correlations were found between MT and FA histogram-derived metrics and quantities derived from conventional MR scans (T2 and T1 LV and brain volume). On the contrary, T2 and T1 LV (but not brain volume) were significantly correlated with the average D macro values of BT and NABT (r values ranging from 0.52 to 0.78). No significant correlation was found between MT- and DT-derived metrics. CONCLUSION: These results suggest that MT and DT MR imaging provide, at least partially, independent measures of lesion burden in patients with RRMS. This suggests that a multiparametric MR approach has the potential for increasing our ability to monitor MS evolution.

Adult↗
PubMed2001

Cladribine. Ortho Biotech Inc.

Cladribine, an adenosine deaminase inhibitor, has been developed and launched by Ortho Biotech in collaboration with The Scripps Research Institute for the treatment of several neoplasms, including acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneos T-cell lymphoma, hairy-cell leukemia and non-Hodgkin's lymphoma. It was first launched in the US in February 1993. Ortho Biotech and The Scripps Research Institute have since been developing the compound for its potential use in multiple sclerosis (MS). In 1997, Ortho filed air NDA in the US for the use of cladribine in the treatment of relapsing-remitting and secondary progressive MS. An FDA drug advisory committee was planning to meet in January 1999 to discuss the NDA. However, Ortho cancelled the meeting. Following an FDA inspection during December 1998 and January 1999, the Scripps Clinic received a warning letter from the FDA in April 1999 regarding violations in the clinical studies of cladribine for MS, and Ortho withdrew the NDA after concluding that further clinical studies would be necessary. Cladribine has been known since the 1960s as an intermediate for the synthesis of 2-deoxynucleotides and its potential for the treatment of leukemia was disclosed in 1984. The Scripps Research Institute and the Johnson & Johnson group hold several patents claiming preparation methods (US 05208327), and additional indications, such as multiple sclerosis (WO-09316706) and rheumatoid arthritis (US-05310732). The associated patent, WO-09323508, is the only one among those patents that claims the use of unmodified cladribine for the treatment of leukemia, but it focuses particularly on a specific form of the disease, chronic myelogenous leukemia. Analysts at UBS Warburg predicted in October 2001, that the product would make US sales of $50 million in 2004 for its MS indication.

Adenosine Deaminase Inhibitors↗
PubMed2000

Whole brain volume changes in patients with progressive MS treated with cladribine.

OBJECTIVE: To compare changes in whole brain volume measured using MRI scans in patients with progressive MS enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two doses of cladribine (0.7 and 2.1 mg/kg) and to assess the correlations between change in whole brain volume and change in other conventional MRI measures. BACKGROUND: Measuring brain parenchymal volumes is an objective and reliable surrogate for the destructive pathologic process in MS. The dynamics and the mechanisms of tissue loss in progressive MS are unclear. METHODS: Whole brain volumes were measured using postcontrast T1-weighted scans with 3 mm slice thickness from 159 patients with progressive MS (70% secondary progressive and 30% primary progressive) enrolled in a double-blind, placebo-controlled trial of 12-month duration. RESULTS: Whole brain volumes were similar in the placebo and cladribine-treated patients on the baseline scans. A significant decrease of brain volume over time was observed both in the entire population of patients (p = 0.001) and in the placebo patients in isolation (p = 0.04). No significant treatment effect of either dose of cladribine on brain volume changes over time was found. In the 54 patients who received placebo, the change in brain volume was not significantly correlated with other MRI measures at baseline (enhancing lesion number and volume and T2-hyperintense and T1-hypointense lesion volumes) or at follow-up (cumulative number of enhancing lesions and absolute and percentage changes of enhancing T2- and T1-hypointense lesion volumes). CONCLUSIONS: This study shows in a large cohort of patients that brain parenchymal loss occurs, even over a short period of time, in progressive MS and that cladribine is not able to alter this process significantly. It also suggests that MRI-visible inflammation and new lesion formation has a marginal role in the development of brain atrophy in patients with progressive MS.

Brain↗
PubMed2000

Magnetization transfer imaging to monitor the evolution of MS: a 1-year follow-up study.

OBJECTIVES: To assess the sensitivities of magnetization transfer imaging (MTI)-derived measures in detecting changes over time of macro- and microscopic lesion burdens in different MS phenotypes and to compare them with those of T2-weighted and T1-weighted lesion volumes. METHODS: A total of 96 patients were studied: 39 with relapsing-remitting MS (RRMS), 19 with secondary progressive MS (SPMS), nine with primary progressive MS, and nine with benign MS; 20 with clinically isolated syndromes suggestive of MS at presentation; and 20 healthy subjects. Brain T2-weighted, T1-weighted, and MTI scans were obtained at baseline and after 12 months. The authors measured T2-weighted and T1-weighted lesion volumes and average lesion MT ratio (MTR). The authors also derived MTR histograms from whole brain tissue (WBT) and normal-appearing brain tissue (NABT). RESULTS: In healthy control subjects, there was no significant change of any of the MTR histogram parameters. At follow-up, in the entire patient group, T2-weighted lesion volume significantly increased and average lesion MTR, WBT-MTR, NABT-MTR, and histogram peak positions significantly decreased. Patients with RRMS and SPMS had significantly higher changes in T2-weighted lesion volume and all the MTI-derived metrics compared with the other subgroups. MTI changes were more prominent (and significantly different) in patients with SPMS than in those with RRMS. Compared with patients with benign MS, patients with RRMS had significantly greater changes in T2-weighted lesion volume and WBT- and NABT-MTR metrics. Compared with patients with SPMS, patients with primary progressive MS had similar changes of T1-weighted and T2-weighted lesion volumes, but significantly lower changes of MTI-derived measures. CONCLUSIONS: MTI-derived measures are sensitive for detecting MS-related changes and might provide valuable outcome measures when assessing treatment effects in clinical trials of patients with MS.

Adult↗
PubMed2000

Cervical cord magnetic resonance imaging findings in systemic immune-mediated diseases.

Brain magnetic resonance imaging (MRI) findings in patients with systemic immune-mediated diseases (SID) affecting the central nervous system (CNS) are heterogeneous and lack diagnostic specificity. In the present study, we evaluated the potential role of cervical cord MRI for increasing confidence when making a diagnosis of SID. Sagittal, T2-weighted images of the cervical cord were obtained in patients affected by systemic lupus erythematosus (SLE) with (NSLE, n=9) and without clinical CNS involvement (n=15), Behçet disease (BD, n=5), Wegener granulomatosis (WG, n=9), antiphospholipid antibody syndrome (APLAS, n=6) and multiple sclerosis (MS, n=10). Spinal cord hyperintense lesions were found in 9/10 MS patients, while no lesions were visible in the cervical cord of any patient with SID, regardless of the presence or absence of brain abnormalities. Cervical cord MRI can be useful in diagnosing patients suspected of having a SID.

Adult↗
PubMed2000

The effect of cladribine on T(1) 'black hole' changes in progressive MS.

We compared the changes of the volumes of T(1)-hypointense lesions seen on the magnetic resonance imaging scans of the brain from 159 progressive multiple sclerosis (MS) patients who were enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two doses of cladribine. Although in patients treated with cladribine there was a tendency to have a lower increase of T(1)-hypointense lesion volumes than those treated with placebo, no statistically significant effect of cladribine on T(1)-hypointense lesion accumulation was found over the one-year double-blind phase. Furthermore, no significant treatment effect was also detected in a subset of 22 patients who received placebo during the double-blind phase of the study and cladribine during the subsequent one-year open-label phase. We conclude that cladribine does not have a major impact on the mechanisms leading to severe tissue destruction in progressive MS.

Analysis of Variance↗
PubMed2000

The role of magnetic resonance in the assessment of multiple sclerosis.

Although the correlations between magnetic resonance imaging (MRI) findings and long-term disease evolution range from poor to moderate, conventional pre- and post-contrast MRI provides sensitive and reliable measures to monitor multiple sclerosis (MS) activity over time. MRI pulse sequences that have been recently introduced have shorter acquisition times and their use in large-scale studies can significantly decrease their costs in terms of both working load and patients' discomfort. The application of non-conventional techniques can increase the pathological specificity of MRI findings and, as a consequence, improve the relationship with the clinical evolution of the disease. These techniques also enable us to quantify the subtle abnormalities occuring in the so-called normal-appearing white matter, thus allowing a more accurate assessment of MS burden to be achieved. Some of these techniques have already shown their value for assessing MS dynamics, whereas other still need to go through a more complete validation process prior to any extensive clinical application in MS.

Brain Diseases↗
PubMed2000

Assessment of the damage of the cerebral hemispheres in MS using neuroimaging techniques.

The pattern of mental dysfunction in multiple sclerosis (MS) is characteristic of the so-called subcortical dementia. Cognitive dysfunction results predominantly by the disruption of communication among cortical and subcortical areas, as a consequence of the white matter damage. As expected, studies with conventional magnetic resonance imaging (MRI) demonstrated that cognitive impairment in MS patients is related to the lesion burden, although the strength of this correlation is weak. This can be partially explained by the poor pathological specificity of conventional MRI techniques and by the invisible damage in the normal-appearing white matter (NAWM). Recent studies using non-conventional MRI techniques with a higher specificity for the heterogeneous substrates of MS pathology, such as the assessment of hypointense lesion load on T1-weighted scans and the measurement of the magnetization transfer ratio (MTR) of whole brain, MS lesions and NAWM, support this interpretation. Other factors, such as the site of MS lesions and the presence of active inflammation, also seem to play an important role.

Brain Diseases↗
PubMed2000

The contribution of fast-FLAIR MRI for lesion detection in the brain of patients with systemic autoimmune diseases.

Fast fluid-attenuated inversion recovery (fFLAIR) is more sensitive that conventional or fast spin echo T2-weighted magnetic resonance imaging (MRI) for detecting lesions in the brain of patients with ischemic, inflammatory, or demyelinating diseases of the CNS. We investigated whether the use of fFLAIR also increases the sensitivity of brain MRI assessment in patients with systemic autoimmune disorders. Turbo spin echo (TSE) dual-echo and fFLAIR scans of the brain were obtained from patients affected by systemic lupus erythematosus (SLE) with (NSLE, n = 9) and without clinical CNS involvement (n = 15), Behçet disease (n = 5), Wegener granulomatosis (n = 9), and antiphospholipid antibody syndrome (n = 6). Brain hyperintense lesions were counted and classified according to their size and their location by two observers by consensual agreement. The total lesion volume was measured using a semiautomated technique for lesion segmentation on both TSE and fFLAIR scans. The imaging modalities showed brain hyperintense lesions in all 9 SLE patients with CNS involvement, 5 of 15 SLE patients without CNS involvement, 5 of 9 patients with Wegener granulomatosis, 1 of 5 with Behçet disease, and 3 of 6 with antiphospholipid antibody syndrome. A total of 342 lesions were seen on both sequences; 88 were seen only on TSE and 54 only on fFLAIR scans. The average number of brain lesions per scan was higher on TSE than on fFLAIR, since significantly more discrete (P<0.002) and small (P = 0.004) lesions were seen on TSE than on fFLAIR. The median total lesion volume, however, was similar on TSE and fFLAIR. Our study indicates that the use of fFLAIR does not improve the sensitivity of fast dual-echo MRI for detecting brain abnormalities in patients with systemic autoimmune disorders.

Adult↗
PubMed2000

Sensitivity and reproducibility of volume change measurements of different brain portions on magnetic resonance imaging in patients with multiple sclerosis.

The course of multiple sclerosis (MS) can be monitored by measuring changes in brain volume, but consensus is still lacking on the best strategy to be adopted. We compared the reproducibility and sensitivity of volume measurements from different brain portions for detecting changes on magnetic resonance imaging (MRI) in patients with MS. T1-weighted MRI of the brain was performed in 50 patients with relapsing-remitting MS at study entry and after an average follow-up of 18.4 months. Using a semiautomated technique for brain parenchyma segmentation, the volumes of the following brain portions were measured: (a) the whole brain (whole-brain volume, WBV), (b) the seven slices rostral to the velum interpositum (seven-slice volume, SSV), (c) the central slice of the image set (central-slice volume, CSV) and (d) the infratentorial regions (infratentorial-brain volume, IBV). All these measurements were carried out by a single observer and were repeated twice on ten randomly selected scans to test the intra-observer reproducibility using the four strategies. At follow-up there was a significant decrease in all the measures of brain volume (P ranged from 0.002 to < 0.001). The univariate correlations between changes in WBV, SSV, CSV and IBV were all statistically significant, with the exception of that between changes in CSV and IBV; r values ranged from 0.34 (for the WBV/IBV correlation) to 0.80 (for the WBV/SSV correlation). The mean intra-observer coefficient of variations were 1.9% for WBV, 1.5% for SSV, 2.9% for CSV and 2.2% for IBV measurements. The measurement of volume on a portion of brain selectively including the regions in which MS pathology is more diffuse is as reliable and sensitive to disease-related changes as that on the whole brain, with significant time saving for processing.

Adult↗
PubMed2000

MRI and motor evoked potential findings in nondisabled multiple sclerosis patients with and without symptoms of fatigue.

Fatigue is a common symptom of multiple sclerosis (MS) even in the early phases of the disease, when neurological disability is usually still not present. To investigate the pathophysiology of fatigue we compared neurophysiological (motor evoked potentials of the four limbs, MEPs) and brain magnetic resonance imaging (MRI) findings in two groups of nondisabled MS patients, those with (n=15) and those without (n=15) fatigue. Fatigue was assessed by an interview and scored by the Fatigue Severity Scale. The two groups were matched for sex, age, disease duration, Expanded Disability Status Scale score, pyramidal Functional System (FS) score, and depression score. MEPs were abnormal in five patients with fatigue and in one patient without fatigue. A significant association was found between the patient scores on the Fatigue Severity Scale, and the burden of MRI lesions (r=0.5; P< 0.005). Significantly higher parietal lobe (P< 0.05), internal capsule (P< 0.05), and periventricular trigone (P< 0.05) lesion loads were found in patients with fatigue than in those without. Our results agree with a central nervous system origin of fatigue in MS patients. This symptom might be a consequence either of a functional deafferentation of the cortex due to cortico-subcortical interconnection damage or of a demyelination in critical sites of the CNS, such as the cortico-spinal tract.

Adolescent↗
PubMed2000

A comparison of the sensitivity of MRI after double- and triple-dose Gd-DTPA for detecting enhancing lesions in multiple sclerosis.

We compared the number and volume of enhancing lesions detected in patients with multiple sclerosis (MS) seen on post-contrast T(1)-weighted scans obtained after the injection of different gadolinium-DTPA (Gd) doses. Enhanced magnetic resonance imaging (MRI) scans were obtained from 16 patients with relapsing remitting or secondary progressive MS on two different occasions separated by an interval of approximately 24 h. On the first occasion, enhanced scans were obtained 15 min after the injection of a double dose of Gd (0.2 mmol/Kg), on the second 15 min after the injection of a triple dose (0.3 mmol/Kg) of Gd. Scans were assessed by consensus in a random order by two observers unaware of the dose of Gd used. We counted the same 30 enhancing lesions on both double dose and triple dose scans from 9 patients. The mean (SD) volumes of enhancing lesions were 1.7 (2.7) mL on double dose and 1.9 (3.4) mL on triple-dose scans. This difference was not statistically significant. This study demonstrated that double dose of Gd has a sensitivity for detecting MS activity similar to that of a triple dose, with the advantage of a significant cost saving.

Adult↗
PubMed2000

Detection of multiple sclerosis lesions using EPI-FLAIR images.

Fast fluid-attenuated inversion recovery (fast-FLAIR) sequences are very sensitive for detecting lesions of patients with multiple sclerosis (MS). Echo planar imaging allows to obtain FLAIR images (EPI-FLAIR) with significantly shorter scanning times. EPI-FLAIR images obtained with 10 measurements are as sensitive as fast-FLAIR for the detection of large MS lesions. Aim of this study was to compare the numbers of MS lesions seen on EPI-FLAIR images with fewer measurements (and, as a consequence, very short scanning times) with those seen on EPI-FLAIR images with 10 measurements. EPI-FLAIR scans with 2 (EPI-2), 4 (EPI-4), 6 (EPI-6), 8 (EPI-8) and 10 (EPI-10) measurements were obtained from 29 MS patients. Lesions seen using each of the five approaches were counted by agreement by two observers. EPI-10 images were used as the "gold standard" for pairwise comparisons. EPI-FLAIR scans with fewer measurements (EPI-2, -4, -6, -8) were all significantly less sensitive than EPI-10 for the detection of small, intermediate and large MS lesions. All the EPI-FLAIR scans, however, fulfilled MR diagnostic criteria for definite MS. When rapid MR scanning of uncooperative MS patients is needed, EPI-FLAIR images covering the entire brain in less than one minute may be considered.

Adult↗