PubMed Health⌕ Search

Biomedical subjects

M Rovaris

Publications and source records attributed to M Rovaris.

At least 19 recordsLinked to original sources
PubMed2001

Sample size estimations for MRI-monitored trials of MS comparing new vs standard treatments.

The authors estimated the sample sizes needed for exploratory trials of MS assessing the efficacy of new treatments in reducing the number of new enhancing lesions vs those of interferon-beta or glatiramer acetate. The sample sizes per arm ranged from 868 (effect: 20%) to 94 (effect: 50%) for patients with relapsing-remitting MS and from 2,484 (effect: 20%) to 361 (effect: 50%) for patients with secondary progressive MS. In MS, exploratory trials of new vs available therapies require large numbers of patients, even when MR end-points are used.

Adjuvants, Immunologic↗
PubMed2001

Glatiramer acetate reduces the proportion of new MS lesions evolving into "black holes".

The authors evaluated whether glatiramer acetate (GA) modifies the severity of tissue damage in 1,722 new lesions from 239 patients with MS enrolled in a placebo-controlled trial monitored with monthly cerebral MRI. The percentage of new lesions that evolved into "black holes" was lower in GA-treated than in placebo patients on scans at 7 (18.9 and 26.3%; p = 0.04) and 8 (15.6 and 31.4%; p = 0.002) months after lesion appearance. GA has a favorable effect on tissue disruption in MS lesions once they are formed.

Adolescent↗
PubMed2001

Magnetization transfer and diffusion tensor MR imaging of the optic radiations and calcarine cortex from patients with Leber's hereditary optic neuropathy.

Optic nerve abnormalities are easily detectable in patients with Leber's hereditary optic neuropathy (LHON), using magnetic resonance imaging (MRI). However, the presence of structural changes in the optic radiations and calcarine cortex of these patients is still an unresolved issue. In this study, we obtained magnetization transfer (MT) and diffusion tensor (DT) MRI to investigate the integrity of these structures in patients with LHON. Dual echo, MT- and DT-MRI scans of the brain were obtained from 10 men with LHON and 10 healthy sex- and age-matched controls. After image co-registration, we obtained MT ratio (MTR), average diffusivity (D) and fractional anisotropy (FA) maps. MTR, D and FA values for the white matter of the optic radiations and MTR and D values for the calcarine cortex were obtained using a region of interest (ROI) analysis. No macroscopic abnormalities were detected in any of the scans from LHON patients and controls. No statistically significant differences of MTR, D or FA values were found for any of the regions studied in LHON patients and healthy controls. Our results suggest that, in patients with LHON, the optic radiations and the calcarine cortex are spared from structural damage, both at a macroscopic and a microscopic level.

Adult↗
PubMed2001

Delivery to the central nervous system of a nonreplicative herpes simplex type 1 vector engineered with the interleukin 4 gene protects rhesus monkeys from hyperacute autoimmune encephalomyelitis.

Systemic administration of antiinflammatory molecules to patients affected by immune-mediated inflammatory demyelinating diseases of the central nervous system (CNS) has limited therapeutic efficacy due to the presence of the blood-brain barrier (BBB). We found that three of five rhesus monkeys injected intrathecally with a replication-defective herpes simplex virus (HSV) type 1-derived vector engineered with the human interleukin 4 (IL-4) gene were protected from an hyperacute and lethal form of experimental autoimmune encephalomyelitis induced by whole myelin. The intrathecally injected vector consistently diffused within the CNS via the cerebrospinal fluid and infected ependymal cells, which in turn sustained in situ production of IL-4 without overt immunological or toxic side effects. In EAE-protected monkeys, IL-4-gene therapy significantly decreased the number of brain as well as spinal cord inflammatory perivenular infiltrates and the extent of demyelination, necrosis, and axonal loss. The protective effect was associated with in situ downregulation of inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein 1 (MCP-1), upregulation of transforming growth factor beta (TGF-beta), and preservation of BBB integrity. Our results indicate that intrathecal delivery of HSV-1-derived vectors containing antiinflammatory cytokine genes may play a major role in the future therapeutic armamentarium of inflammatory CNS-confined demyelinating diseases and, in particular, in the most fulminant forms where conventional therapeutic approaches have, so far, failed to achieve a satisfactory control of the disease evolution.

Animals↗
PubMed2001

Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.

BACKGROUND: Interferon beta reduces activity in multiple sclerosis as measured clinically and by magnetic resonance imaging (MRI). We assessed the effect of interferon beta-1a on the occurrence of relapses in patients after first presentation with neurological events, who are at high risk of conversion to clinically definite multiple sclerosis. METHODS: Eligible patients had had a first episode of neurological dysfunction suggesting multiple sclerosis within the previous 3 months and had strongly suggestive brain MRI findings. Patients were randomly assigned interferon beta-1a 22 microg or placebo subcutaneously once weekly for 2 years. Neurological and clinical assessments were done every 6 months and brain MRI every 12 months. Analyses excluded one patient assigned placebo who received no study injections. FINDINGS: 241 (78%) of 308 randomised patients received study treatment for 2 years; 278 (90%) remained in the study until termination. 57 (85%) of 67 who stopped therapy did so after conversion to clinically definite multiple sclerosis. Fewer patients developed clinically definite multiple sclerosis in the interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047). The time at which 30% of patients had converted to clinically definite multiple sclerosis was 569 days in the interferon group and 252 in the placebo group (p=0.034). The annual relapse rates were 0.33 and 0.43 (p=0.045). The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment. INTERPRETATION: Interferon beta-1a treatment at an early stage of multiple sclerosis had significant positive effects on clinical and MRI outcomes.

Adolescent↗
PubMed2001

The role of non-conventional MR techniques to study multiple sclerosis patients.

Conventional magnetic resonance imaging (MRI) lacks pathological specificity to the heterogeneous substrates of multiple sclerosis (MS) lesions and is not able to detect subtle, disease-related changes in the normal-appearing white matter (NAWM). As a consequence, the correlation between MRI findings and the long-term evolution of MS is moderate at best. To overcome the limitations of conventional MRI, new quantitative magnetic resonance (MR) techniques, such as cell-specific imaging, magnetization transfer imaging (MTI), proton magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI) and functional MR imaging (fMRI) have all been recently applied to the study of MS. These techniques should provide more accurate and pathologically specific estimates of the MS lesion burden than conventional MR and should improve our understanding of the mechanisms leading to MS-related irreversible disability.

Humans↗
PubMed2001

An MR study of tissue damage in the cervical cord of patients with migraine.

Hyperintense abnormalities on T2-weighted magnetic resonance (MR) scans of the brain from patients with migraine are a relatively frequent finding and may represent a diagnostic challenge. We studied the cervical cord of patients with migraine using T2-weighted and magnetization transfer (MT) scans to assess whether the study of macro- and microscopic tissue damage in the cervical cord of these patients may have some diagnostic utility. T2-weighted and MT scans of the cervical cord and dual-echo scans of the brain were acquired from 16 patients with migraine and 17 sex- and age-matched healthy volunteers. Cervical cord MT ratio (MTR) histograms were obtained from all subjects and the relative peak height, the peak position, and the average MTR measured. Five migraine patients (31%) had hyperintense lesions in the brain. Neither healthy controls nor patients with migraine had any abnormalities on cervical cord MR scans. There was no difference for any of the cord MTR histogram-derived metrics between patients with migraine and healthy controls. No MTR histogram-derived measures from migraine patients were 2 standard deviations below the mean values from controls. Patients with migraine do not have MR or MT abnormalities in the cervical cord. MR scanning of the cervical cord in patients with migraine and hyperintense brain lesions of unknown etiology may be a useful investigation to facilitate the diagnostic workout.

Adolescent↗
PubMed2001

Neuroimaging techniques in the diagnostic work-up of patients with the antiphospholipid syndrome.

The detection of multisystemic involvement often leads to a correct diagnosis of the antiphospholipid syndrome (APS), even in cases with predominant neurologic manifestations. However, when central nervous system deficits are isolated and have a relapsing-remitting or a progressive course, other conditions must be carefully considered. In this context, the diagnostic accuracy of conventional magnetic resonance imaging (MRI) is hampered by its limited pathologic specificity, which is one of the reasons why no or only modest correlations have been found between the burden of MRI-visible lesions and other clinical or laboratory measures of disease severity in patients with APS. Neuroimaging techniques with a higher pathologic specificity than conventional MRI show promise in achieving diagnostic confidence earlier in the course of APS and in better monitoring the efficacy of therapeutic interventions.

Antibodies, Antiphospholipid↗
PubMed2001

In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis.

In patients with primary progressive (PP) multiple sclerosis, brain MRI lesion activity and burden are low, despite the presence of severe neurological impairment. On the contrary, the degree of cord atrophy and diffuse tissue damage in the brain and cervical cord have been found to be associated with clinical disability. Against this background, this study aimed at providing an in vivo indirect assessment of brain and cervical cord pathology in a large cohort of PP multiple sclerosis patients, using conventional MRI and magnetization transfer imaging (MTI). Ninety-one PP multiple sclerosis patients, 36 secondary progressive (SP) multiple sclerosis patients and 30 healthy controls underwent brain and cervical cord MRI scans, using dual echo (brain) or fast short-tau inversion recovery (cervical cord) MTI and T(1)-weighted sequences. For the brain, T(2) hyperintense and T(1) hypointense lesion volumes were calculated and the volume of the whole of the brain tissue measured. For the cervical cord, the number and burden of lesions and the cross-sectional area were assessed. MTI scans were post-processed and analysed to obtain magnetization transfer ratio (MTR) histograms from the whole of the brain and cervical cord tissue and from the normal-appearing brain tissue in isolation. In PP multiple sclerosis patients, brain, normal-appearing brain tissue and cervical cord MTR histogram-derived metrics revealed the presence of diffuse tissue damage whose characteristics did not significantly differ from those of SP multiple sclerosis patients, even though SP multiple sclerosis patients had higher MRI-visible lesion burdens. None of the correlations between MRI or MTI measures obtained from the brain and the cord were significant. PP multiple sclerosis patients' disability was significantly, albeit weakly associated with a composite MR model including measures of loss and intrinsic damage of cervical cord tissue. Our data indicate the presence of a diffuse tissue damage undetectable by conventional MRI in PP multiple sclerosis patients, whose extent seems to match that of SP multiple sclerosis patients with similar levels of disability. They also suggest that the severity of multiple sclerosis pathology in the cervical cord is one of the factors contributing to neurological impairment in PP multiple sclerosis.

Adult↗
PubMed2001

Short-term brain volume change in relapsing-remitting multiple sclerosis: effect of glatiramer acetate and implications.

The assessment of brain volume change with serial MRI provides an objective measure of an important component of the pathology of multiple sclerosis. Glatiramer acetate (GA) has a beneficial effect on clinical and MRI measures of disease activity and burden in patients with relapsing-remitting (RR) multiple sclerosis. This study investigated the impact of GA treatment on the development of brain atrophy in RR multiple sclerosis patients. The study consisted of a 9-month, double-blind, placebo-controlled phase followed by a 9-month open-label phase. Patients were randomized to receive either 20 mg GA or placebo by daily subcutaneous injections and underwent brain MRI scans every month during the first phase, and every 3 months during the second phase of the study. Using a semi-automated segmentation technique based on local thresholding, brain volume was measured from seven contiguous periventricular slices from the scans obtained at baseline, the end of the double-blind phase and the end of the study. From the original trial cohort, image sets from 113 out of 119 patients randomized to GA, and 114 out of 120 randomized to placebo treatment were evaluated. Brain volume was significantly correlated with patients' disability at each time-point. No significant differences between placebo- and GA-treated patients were found for baseline brain volume and rate of brain volume change over the study, even though a possible late trend for treatment with GA to retard the loss of brain volume was observed. There was a significant, but modest, correlation between MRI activity during the double-blind phase, and brain volume change over the entire study among patients originally treated with placebo. The modest correlation between enhancement frequency and brain atrophy loss indicates that the suppression of inflammatory activity in RR multiple sclerosis patients is not fully and rapidly associated with a similar effect on the global neurodegenerative processes. This study also suggests that any effect of GA in preventing brain volume decrease is not evident early following institution of treatment.

Adult↗
PubMed2001

Magnetic resonance imaging, magnetisation transfer imaging, and diffusion weighted imaging correlates of optic nerve, brain, and cervical cord damage in Leber's hereditary optic neuropathy.

OBJECTIVES: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease leading to bilateral loss of central vision and severe optic nerve atrophy. A subtype of LHON presents additional clinical and MRI aspects indistinguishable from those of multiple sclerosis (MS) (LHON-MS). In patients with LHON or LHON-MS, an assessment was made of (a) the severity of optic nerve damage, using MRI and magnetisation transfer imaging (MTI), and (b) the presence and extent of macroscopic and microscopic pathology in the brain and cervical cord, using MRI and MT ratio (MTR) and mean diffusivity (D) histogram analysis. METHODS: Ten patients with LHON, four with LHON-MS, and 20 age and sex matched healthy controls were studied. For the optic nerve and the brain, dual-echo turbo spin echo (TSE), T1 weighted spin echo, and MT images were obtained. For the brain, fast fluid attenuated inversion recovery (fast FLAIR) and diffusion weighted images were also obtained. For the cervical cord, fast short tau inversion recovery (STIR) and MT images were obtained. The volume and the average MTR value of both the optic nerves were measured. MTR and histograms of the normal appearing brain tissue (NABT) and MTR histograms of the whole cervical cord tissue were created. RESULTS: The mean values of optic nerve volumes and MTR were significantly lower in patients with LHON than in healthy controls. Mean NABT-MTR histogram peak height was significantly lower in patients with LHON than in controls, whereas no significant difference was found for any of the cervical cord MTR histogram derived measures. Average diffusivity (D) was higher in patients with LHON than in controls. Optic nerve volume and MTR value and mean NABT-MTR were lower in patients with LHON-MS than in those with LHON. CONCLUSIONS: The severity of optic nerve pathology in LHON is measurable in vivo using MRI and MTI. MTR and histogram analysis suggests that microscopic brain damage occurs in LHON and that it is more severe in the MS-like form of the disease.

Adult↗
PubMed2001

Clinical trials of multiple sclerosis monitored with enhanced MRI: new sample size calculations based on large data sets.

OBJECTIVE: A new parametric simulation procedure based on the negative binomial (NB) model was used to evaluate the sample sizes needed to achieve optimal statistical powers for parallel groups (with (PGB) and without (PG) a baseline correction scan). It was also used for baseline versus treatment (BVT) design clinical trials in relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS), when using the number of new enhancing lesions seen on monthly MRI of the brain as the measure of outcome. METHODS: MRI data obtained from 120 untreated patients with RRMS selected for the presence of MRI activity at baseline, 66 untreated and unselected patients with RRMS, and 81 untreated and unselected patients with SPMS were fitted using an NB distribution. All these patients were scanned monthly for at least 6 months and were all from the placebo arms of three large scale clinical trials and one natural history study. The statistical powers were calculated for durations of follow up of 3 and 6 months. RESULTS: The frequency of new enhancing lesions in patients with SPMS was lower, but not significantly different, from that seen in unselected patients with RRMS. As expected, enhancement was more frequent in patients with RRMS selected for MRI activity at baseline than in the other two patient groups. As a consequence, the estimated sample sizes needed to detect treatment efficacy in selected patients with RRMS were smaller than those of unselected patients with RRMS and those with SPMS. Baseline correction was also seen to reduce the sample sizes of PG design trials. An increased number of scans reduced the sample sizes needed to perform BVT trials, whereas the gain in power was less evident in PG and PGB trials. CONCLUSION: This study provides reliable estimates of the sample sizes needed to perform MRI monitored clinical trials in the major MS clinical phenotypes, which should be useful for planning future studies.

Adult↗
PubMed2001

Correlations between clinical findings and magnetization transfer imaging metrics of tissue damage in individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

BACKGROUND AND PURPOSE: We obtained magnetization transfer imaging (MTI) scans from individuals with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1) to investigate the presence, extent, and nature of pathology in white and gray matter outside proton density (PD)-visible lesions; (2) to quantify the degree of tissue damage occurring in lesions seen on PD-weighted scans; and (3) to correlate MTI-derived measures of disease burden with age, physical disability, and cognitive performance. METHODS: Dual-echo, T1-weighted, and MTI scans of the brain were obtained from 33 individuals with CADASIL and 12 control subjects. Magnetization transfer ratio (MTR) values from PD-visible lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM) were measured. Histograms of MTR from the whole brain and normal-appearing brain tissue were also produced. RESULTS: All MTR values from NAWM and NAGM regions studied were significantly lower for individuals with CADASIL than for control subjects, with the exception of those obtained from the NAWM of the infratentorial structures and the NAGM of the occipital cortex. The average MTR from PD lesions in individuals with CADASIL was significantly lower than that from all the NAWM regions. Average MTR and peak location from whole-brain and normal-appearing brain tissue histograms were significantly lower for individuals with CADASIL than for control subjects. MTR values from NAWM were strongly correlated with the extent of macroscopic lesions and their average MTR. Apart from NAGM, average MTR from all other tissues studied significantly decreased with increasing age, physical disability, and cognitive impairment. CONCLUSIONS: PD lesions of individuals with CADASIL have variable degrees of tissue damage. Brain tissue outside PD abnormalities is also damaged. This study suggests that the extent and the severity of the brain tissue damage are critical factors in determining clinical status in CADASIL.

Age Factors↗
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↗