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Massimo Filippi

Publications and source records attributed to Massimo Filippi.

At least 91 records · Page 5Linked to original sources
PubMed2003

Spinal-cord MRI in multiple sclerosis.

The potential of MRI of the spinal cord as a diagnostic tool in MS has recently gained much interest. Dual echo spin echo MRI is most sensitive for the detection of spinal-cord abnormalities, which range from multiple focal lesions to confluent areas of high signal intensity. In some patients, commonly those with primary progressive disease, diffuse areas of slightly increased signal intensity are found. Disappointingly, the relation between MRI findings and clinical disability is weak. Studies relating MRI findings with histopathology have revealed substantial axonal loss in the spinal cords of patients with MS, whether focal lesions are present of not. Further, diffuse cord atrophy is found in advanced MS, which may reflect axonal loss. In the diagnostic setting, spinal-cord imaging is valuable. First, asymptomatic spinal-cord lesions are very rare in disorders other than MS. For example, in a patient with equivocal brain findings such as an elderly patient with vascular-ischaemic lesions, a normal spinal-cord examination can help rule out MS. Second, presence of asymptomatic spinal lesions may help confirm a diagnosis of MS when few or no brain lesions are present.

Adult↗
PubMed2003

Magnetic resonance-based techniques for the study and management of multiple sclerosis.

Conventional magnetic resonance imaging (cMRI) is widely used for diagnosing multiple sclerosis (MS) and for monitoring its activity and evolution. However, the correlation between cMRI and clinical findings of MS is limited, possibly due to the low pathological specificity of the abnormalities seen on cMRI scans and to the inability of cMRI to quantify the extent of the damage of the normal-appearing tissues. Magnetization transfer and diffusion-weighted MRI can quantify the extent and pathological severity of structural changes occurring within and outside cMRI-visible MS lesions. Proton MR spectroscopy can add information on the biochemical nature of such changes. Finally, functional MRI can provide new insights into the role of cortical adaptive changes in limiting the clinical consequences of MS structural damage. The application of quantitative MR-based techniques is changing dramatically our understanding of how MS causes irreversible disability and there is increasing perception that these methodologies should be more extensively employed in clinical trials to derive innovative information.

Brain↗
PubMed2003

Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging.

PURPOSE OF REVIEW: This review is intended to provide an up-to-date summary of the main functional magnetic resonance imaging studies conducted in patients with multiple sclerosis, and to show how such studies are changing our views on the ability of the multiple sclerosis brain to limit the clinical consequences of irreversible structural tissue damage. RECENT FINDINGS: Brain cortical reorganization is a common phenomenon occurring in patients with multiple sclerosis, independent of disease duration and clinical phenotype, which can be elicited by macroscopic lesions, as well as by the presence of 'occult' multiple sclerosis-related damage of the brain and cervical cord. An increased recruitment of the cerebral networks involved in the performance of given tasks might represent a first step in cortical reorganization with the potential to maintain a normal level of function in the course of multiple sclerosis. The progressive failure of these mechanisms, because of accumulating tissue damage, might, on the one hand, result in the activation of previously silent 'second-order' compensatory areas, and, on the other, contribute to the accumulation of irreversible disability. SUMMARY: Functional magnetic resonance imaging has the potential to provide important information about cortical reorganization following multiple sclerosis-related tissue damage, which should improve our understanding of the factors associated with the accumulation of irreversible disability in this disease. The enhancement of any beneficial effects of this cortical adaptive plasticity should be considered as a potential target of therapy for multiple sclerosis.

Cerebral Cortex↗
PubMed2003

Effects of glatiramer acetate on relapse rate and accumulated disability in multiple sclerosis: meta-analysis of three double-blind, randomized, placebo-controlled clinical trials.

Three randomized, double-blind, placebo-controlled trials have shown that glatiramer acetate (GA) is effective in reducing relapse rate in patients with relapsing-remitting (RR) multiple sclerosis (MS). Using raw data pooled from 540 patients, we performed a meta-analysis of these three trials, to investigate whether the extent of GA efficacy varies according to disease-related variables at study entry. Three regression models were developed to assess the efficacy of GA on the annualized relapse rate (primary outcome measure), on the total number of on-trial relapses and on the time to first relapse. We also explored the efficacy of GA on accumulated disability and the potential role of baseline clinical variables as predictors of relapse-rate variables and treatment efficacy. The mean adjusted annualized relapse rate on study was 1.14 in the pooled placebo-treated subjects and 0.82 in the pooled GA group (P = 0.004), indicating an average reduction in annualized relapse rate of 28%. About a one third reduction of the total number of on-trial relapses was also observed in patients receiving GA (P < 0.0001), who had a median time to the first relapse of 322 days versus a median time to the first relapse of 219 days seen in those receiving placebo (P = 0.01). A beneficial effect on accumulated disability was also found (risk ratio of 0.6; 95%; CI = 0.4-0.9; P = 0.02). The drug assignment (P = 0.004), baseline EDSS score (P = 0.02) and number of relapses during the two years prior to study entry (P = 0.002) were significant predictors of on-trial annualized relapse rate. No other demographic or clinical variable at baseline significantly influenced the treatment effect. This meta-analysis reaffirms the effectiveness of GA in reducing relapse rate and disability accumulation in RRMS, at a magnitude comparable to that of other available immunomodulating treatments. It also suggests that GA efficacy is not significantly influenced by the patients' clinical characteristics at the time of treatment initiation.

Disability Evaluation↗
PubMed2003

Interventions for the prevention of brain atrophy in multiple sclerosis : current status.

The assessment of brain volume changes on serial magnetic resonance imaging (MRI) scans can provide an objective measure of the neurodegenerative component of multiple sclerosis (MS) pathology. Results from placebo-controlled and crossover clinical trials indicate that immunomodulating (e.g. recombinant interferon-beta [IFNbeta]-1a [Rebif] and IFNbeta-1b [Betaferon] and glatiramer acetate [Copaxone]) and immunosuppressive (e.g. cladribine and alemtuzumab) treatments for relapsing-remitting (RR) and secondary progressive MS lack substantial efficacy in preventing the development of brain atrophy, despite the marked effects of these treatments on clinical and MRI outcomes of disease activity. A modest but significant treatment effect on brain atrophy has been reported for patients with RRMS only in one trial of IFNbeta-1a (Avonex) and in another study of long-term corticosteroid therapy.Failure to find a significant treatment benefit in preventing brain atrophy might be the result of inadequate trial designs, including their relatively short durations, which may not be adequate to reveal beneficial effects in a chronic disease like MS. Alternatively, such a failure might indicate that treatments proven to be effective in reducing MS-related inflammation are unable to act with the same efficacy on the most severe and disabling pathological substrates of the disease. The modest correlation between MRI enhancement frequency and brain atrophy observed in the placebo groups of several trials also fits with the concept that the suppression of inflammatory activity in MS is not fully and rapidly associated with a similar effect on the global neurodegenerative process of the disease.

Adjuvants, Immunologic↗
PubMed2003

Short-term correlations between clinical and MR imaging findings in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Despite extensive use of MR imaging to provide markers of multiple sclerosis (MS) activity and accumulated disease burden, the magnitude of the relationship between clinical and MR findings is still debated. Using data from the European/Canadian glatiramer acetate (GA) trial, we investigated short-term correlations between clinical and MR measures of disease activity in patients with relapsing-remitting MS (RRMS). METHODS: In a 9-month, double-blinded, placebo-controlled study, 239 patients with RRMS were randomly assigned to receive 20 mg GA (n = 119) or placebo (n = 120). Clinical assessment included monthly neurologic examinations with Expanded Disability Status Scale scoring and visits for symptoms suggestive of relapse. Dual-echo T2-weighted and pre- and postcontrast T1-weighted brain MR images were obtained at baseline and monthly during follow-up. Contrast-enhancing and new T2-hyperintense lesions were counted, and total T2-hyperintense and T1-hypointense lesion volumes were measured. RESULTS: Significant univariate correlations were found between the number of relapses during the study period and the number of enhancing lesions at baseline (r = 0.25) and during follow-up (r = 0.30) in the study population as a whole. Multivariable analysis showed that two independent factors were more strongly correlated with relapse frequency: the number of relapses during the 2 years before entry and the number of on-trial enhancing lesions, in the whole study population and in the placebo group. CONCLUSION: In RRMS, MR imaging measures of inflammatory activity are modestly but significantly correlated with the occurrence of clinical attacks over the short term. Clinical and MR imaging assessment can provide complementary outcome measures for RRMS trials.

Adult↗
PubMed2003

Quantification of brain damage in cerebrotendinous xanthomatosis with magnetization transfer MR imaging.

BACKGROUND AND PURPOSE: Conventional MR imaging for quantification of brain damage in monitoring the evolution of cerebrotendinous xanthomatosis (CTX) has limitations. Magnetization transfer (MT) MR imaging is overcoming these limitations. Using MT MR imaging, we sought to quantify, in vivo, the extent of brain and cerebellar damage in patients with CTX, with the ulimate goal to investigate the magnitude of the correlation between MT MR imaging findings and clinical disability. METHODS: Conventional and MT MR images of the brain were obtained in nine patients with CTX and in 10 sex- and age-matched healthy volunteers. MT ratio histograms were derived of the whole brain, brain normal-appearing white matter (NAWM), brain normal-appearing gray matter (NAGM), cerebellar NAWM, and cerebellar NAGM. Clinical disability was measured by using the Expanded Disability Status Scale (EDSS). RESULTS: Average MT ratio and peak heights of the whole brain, brain NAWM, and brain NAGM histograms in patients with CTX were significantly lower than the corresponding quantities in the control subjects. All cerebellar NAGM MT ratio histogram-derived metrics and average MT ratio of the cerebellar NAWM histogram in patients with CTX were also significantly lower than the corresponding quantities in the control subjects. Strong correlations were found between the EDSS score and a composite whole-brain MT ratio histogram score (r = 0.77, P <.01) and a composite brain white matter MT ratio histogram score (r = 0.71, P <.03). A strong correlation was also found between the cerebellar functional system score and a composite cerebellar NAWM score (r = 0.72, P <.02). CONCLUSION: The quantitative assessment of brain damage in patients with CTX with use of MT MR imaging can provide powerful measures of disease outcome.

Adult↗
PubMed2003

Inter-sequence and inter-imaging unit variability of diffusion tensor MR imaging histogram-derived metrics of the brain in healthy volunteers.

BACKGROUND AND PURPOSE: Diffusion tensor MR imaging has the potential to improve our ability to monitor several neurologic conditions. As a preliminary step to the assessment of the role of diffusion tensor MR imaging in the context of longitudinal and multicenter studies, we evaluated the effect of sequence-, imaging unit-, and imaging-reimaging-induced variations on diffusion tensor MR imaging quantities derived from histogram analysis of a large portion of the central brain of healthy volunteers. METHODS: Each of eight healthy volunteers underwent imaging on two MR imaging units using three different pulsed gradient spin-echo single shot echo-planar pulse sequences (each of them having a different diffusion gradient scheme). Four additional healthy participants underwent imaging twice on the same imaging unit to assess imaging-reimaging variability. RESULTS: For mean diffusivity histograms, the differences between inter-sequence and inter-imaging unit coefficients of variation were significant for all the considered quantities with P values ranging from.003 to <.001. Also, the inter-imaging unit coefficient of variation for average fractional anisotropy was significantly higher than the corresponding inter-sequence coefficient of variation (P =.002). In general, inter-sequence mean diffusivity histogram-derived metrics (coefficients of variation ranging from 1.72% to 5.56%) were more reproducible than were fractional anisotropy histogram-derived metrics (coefficients of variation ranging from 5.45% to 7.34%). Imaging-reimaging variability was found to fall in the range of inter-sequence coefficients of variation for all the considered quantities. CONCLUSION: This study shows that inter-sequence, imaging-reimaging, and inter-imaging unit variabilities of diffusion tensor MR imaging-derived measurements are relatively low, suggesting that diffusion tensor MR imaging might provide additional measures of outcome with which to assess the evolution of brain structural damage in large scale studies of various neurologic conditions.

Analysis of Variance↗
PubMed2003

Three subsequent single doses of gadolinium chelate for brain MR imaging in multiple sclerosis.

BACKGROUND AND PURPOSE: A triple-dose (TD) of gadolinium chelate is highly sensitive approach for detecting lesion activity in multiple sclerosis (MS). However, individual TD injections do not provide data on the severity of the pathologic process in a population of lesions, and its clinical use is limited by the cost-benefit considerations. Our aim was to determine whether the use of three subsequent single doses (SD) of a gadolinium chelate in brain MR imaging is useful in detecting MS lesions with different patterns of enhancement. METHODS: In 10 patients, T1-weighted spin-echo images were acquired before and after three intravenous administrations of 0.1 mmol/kg of gadodiamide. RESULTS: In all patients, SD images showed six enhancing lesions; double-dose (DD) images, 13; and TD images, 22. Differences between SD and TD and between DD and TD were significant (P <.018). Six lesions (27%) enhanced with all the three doses; seven (32%), with both DD and TD; and nine (41%), with only TD. Proportions of patients with at least one enhancing lesion were, for SD, four of 10; DD, seven of 10; and TD, nine of 10. In defining active disease in these nine patients, we needed only 19 SDs versus the 30 SDs that would have been needed if individual TD injections were used. CONCLUSION: With three subsequent SD injections, the number of enhancing lesions progressively increases. This approach allows the distinction of three levels of enhancement, and it reduces the amount of contrast agent needed to distinguish patients with active MS from those with nonactive MS.

Adult↗
PubMed2003

Coefficient D(av) is more sensitive than fractional anisotropy in monitoring progression of irreversible tissue damage in focal nonactive multiple sclerosis lesions.

BACKGROUND AND PURPOSE: Persistently hypointense lesions on T1-weighted MR images have been shown to correlate with the amount of axonal damage and clinical disability in multiple sclerosis (MS) patients. The purpose of this study was to investigate whether diffusion coefficient D(av) and fractional anisotropy (FA) are able to detect quantifiable differences among three groups of focal nonactive multiple sclerosis (MS) lesions that appear qualitatively different on T1-weighted images. METHODS: Conventional and diffusion tensor MR images of the brain were obtained in 18 patients with relapsing remitting (n = 10) or secondary progressive (n=8) MS and in 18 healthy volunteers. Focal nonactive MS lesions were classified as T1 isointense, T1 mildly hypointense, and T1 severely hypointense on unenhanced T1-weighted images. Differences among groups were assessed with one-way analysis of variance using the T1 lesion appearance as the grouping factor and either FA or coefficient D(av) as the dependent measure. RESULTS: FA was lowest and coefficient D(av) was highest in T1 severely hypointense lesions, and then, in ascending and descending order, respectively, T1 mildly hypointense lesions and T1 isointense lesions. A significant difference in the values of FA was detected only between T1 isointense lesions and T1 severely hypointense lesions (P <.01), whereas no difference was found between T1 mildly hypointense lesions and either one of these two groups. A significant difference was found in the values of coefficient D(av) among all investigated lesion groups. Coefficient D(av) was found to correlate inversely with the T1-weighted contrast ratio (r=-0.58, P <.0001), whereas FA and deltaFA (percentage of FA variation in the lesion, a relative FA measure that minimizes the effect of FA spatial dependence) were not. CONCLUSION: Coefficient D(av) is more sensitive than FA to variations in the degree of T1 hypointensity and, thus, in the amount of the permanent brain tissue damage in patients with MS.

Adolescent↗
PubMed2002

MRI techniques to monitor MS evolution: the present and the future.

Conventional MRI (cMRI) is limited in its ability to provide specific information about pathology in MS. Measures commonly derived from cMRI include T2 lesions, T1-enhanced lesions, atrophy, and possibly T1-hypointense lesions, which have been extensively investigated in many clinical trials. Better MRI measures are needed to advance our understanding of MS and design ideal clinical trials. This article reviews the strengths and weaknesses of the major MRI-based methods used to monitor MS evolution and submits that 1) metrics derived from magnetization transfer MRI, diffusion-weighted MRI, and proton MRS should be implemented to achieve reliable specific in vivo quantification of MS pathology; 2) targeted multiparametric MRI protocols rather than generic application of cMRI should be used in all possible clinical circumstances and trials; and 3) reproducible quantitative MR measures should ideally be used for the assessment of patients but are essential for clinical trials.

Brain↗
PubMed2002

Cognitive dysfunction in patients with mildly disabling relapsing-remitting multiple sclerosis: an exploratory study with diffusion tensor MR imaging.

Previous studies assessing the magnetic resonance imaging (MRI) correlates of cognitive dysfunction in multiple sclerosis (MS) achieved conflicting results. Diffusion tensor (DT)-MRI provides metrics that are sensitive to the macro- and microscopic MS lesion load with increased specificity to the more destructive aspects of MS pathology than conventional imaging. We performed an exploratory study to assess the magnitude of the correlation between quantities derived from DT-MRI and measures of cognitive impairment in patients with relapsing-remitting (RR) MS.T2, T1, DT-MRI scans of the brain and an extensive battery of neuropsychological tests (exploring language, complex reasoning, attention and memory) were obtained from 34 RRMS patients. We measured T2 and T1 lesion volumes (LV) and brain volume. Average lesion mean diffusivity (D) and fractional anisotropy (FA) were calculated. D and FA histograms from the brain tissue (BT), the normal-appearing brain tissue (NABT), the normal-appearing white matter (NAWM) and the normal-appearing gray matter (NAGM) were also obtained. Nine patients (26.5%) were found to be cognitively impaired. Moderate correlations were found between symbol digit modalities test, verbal fluency test and 10/36 spatial recall test scores and T2 LV, T1 LV and average lesion, WBT, NABT, NAWM and NAGM values (r values ranging from -0.30 to -0.53). No correlations were found between any of the neuropsychological test scores and brain volume, average lesion FA and WBT FA.DT-MRI provides quantitative metrics that seem to reflect the severity of language, attention and memory deficits in patients with RRMS. This study also suggests that the extent and the intrinsic nature of the macroscopic lesions as well as the damage of the NAWM and NAGM all contribute to the neuropsychological deficits of RRMS patients.

Adult↗
PubMed2002

Frequency and patterns of subclinical cognitive impairment in patients with ANCA-associated small vessel vasculitides.

We investigated the prevalence of disease-related cognitive impairment in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated small vessel vasculitides (SVV). We studied 43 patients with ANCA-associated SVV (Wegener's granulomatosis (WG), Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MP)), with no evidence of focal neurological deficits and dementia and in whom other potential causes of cognitive decline were carefully excluded. All patients underwent a detailed neuropsychological evaluation and their performances were compared with those of matched healthy controls. Patients were considered to be affected by subclinical cognitive impairment when they had abnormal results in at least two neuropsychological tests. Magnetic resonance imaging (MRI) scans of the brain were also obtained in 11 patients.The average neuropsychological test scores were not significantly different between the SVV patients and the control subjects. Thirteen patients had abnormal results in two tests (seven patients) or three or more tests (six patients). Most frequently, abnormal tests were the Rey Figure Recall (six cases), the Wisconsin Card Sorting Test (six cases), and the reaction times (eight cases). The frequency and extent of brain MRI abnormalities were higher in impaired than in unimpaired patients. This study demonstrates that 30% of clinically nondemented SVV patients can have a subclinical neuropsychological impairment, characterized by mild abstract reasoning loss, mental speed reduction and nonverbal memory impairment. MRI findings in impaired patients are consistent with the presence of an SVV-mediated subcortical damage of the brain.

Adult↗
PubMed2002

MRI metrics as surrogate markers for clinical relapse rate in relapsing-remitting MS patients.

OBJECTIVE: To formally validate metrics derived from conventional MRI as surrogate endpoints for relapse rate in MS. BACKGROUND: Although metrics derived from MRI are used widely in clinical trials of MS, a formal statistical validation of MRI metrics as surrogate endpoints for clinical outcome in MS is lacking. METHODS: A validation procedure was applied to clinical and MRI data collected in the context of a randomized, double-blind, placebo-controlled trial of glatiramer acetate in patients with relapsing-remitting MS. The four Prentice operational criteria were applied to assess surrogacy for the number of new enhancing lesions, the percentage change of T2 lesion volume, and a composite MRI score based on these two metrics. RESULTS: The results of this analysis show that all three MRI measures considered by the authors had a behavior compatible with the Prentice criteria for valid surrogates. The composite MRI score correlated with relapses and accounted for much of the treatment effect on relapse rate. CONCLUSIONS: This preliminary study suggests that conventional MRI metrics might serve as valid surrogate endpoints in MS trials with glatiramer acetate or treatments thought to have a similar mode of action.

Follow-Up Studies↗
PubMed2002

MTR discloses subtle changes in the normal-appearing tissue from relatives of patients with MS.

The presence of normal-appearing brain tissue (NABT) changes was investigated in 30 first-degree relatives of patients with MS, using magnetization transfer ratio (MTR) histograms. When compared with controls, relatives of patients with familial (p = 0.01) and sporadic (p = 0.01) MS had lower NABT MTR histogram peak heights. This study suggests a reduction of truly normal NABT in asymptomatic relatives of patients with MS.

Adult↗
PubMed2002

Irreversible disability and tissue loss in multiple sclerosis: a conventional and magnetization transfer magnetic resonance imaging study of the optic nerves.

OBJECTIVES: To assess, by magnetic resonance imaging, the volumes and magnetization transfer ratio (MTR) values of optic nerves (ONs) from patients with multiple sclerosis (MS) who had incomplete or no visual recovery after optic neuritis; and to compare these quantities with those derived from ONs from patients with MS who showed a marked clinical recovery after optic neuritis, ONs from healthy volunteers, and ONs from patients with Leber hereditary optic neuropathy (LHON). METHODS: Conventional and magnetization transfer magnetic resonance images of the ONs were obtained from 30 patients with MS, 18 healthy volunteers, and 10 patients with LHON. The ON from patients with MS were classified as clinically unaffected (n = 18); clinically affected with recovery (n = 20; visual acuity > or =20/25 at least 6 months after optic neuritis); and clinically affected with incomplete or no recovery (n = 22; visual acuity <20/25 at least 6 months after optic neuritis). The ON volumes and MTR values were measured. RESULTS: Volumes (P =.002) and MTR values (P<.001) of the ONs from patients with MS and incomplete or no recovery were both lower than those of the ONs from patients with MS and recovery, but not different from those of the ONs from patients with LHON. Volumes and MTR values of the affected ONs from patients with MS and recovery did not differ from those of clinically unaffected ONs, which were similar to those of healthy volunteers. CONCLUSION: These findings suggest that, in patients with MS, neurodegeneration is associated with persistent functional deficits secondary to incomplete recovery from relapses.

Adolescent↗
PubMed2002

Assessment of normal-appearing white and gray matter in patients with primary progressive multiple sclerosis: a diffusion-tensor magnetic resonance imaging study.

BACKGROUND: Diffusion-tensor magnetic resonance imaging is sensitive to the more destructive aspects of multiple sclerosis (MS) evolution occurring outside and within T2-visible lesions and, as a consequence, holds promise for providing a more complete picture of primary progressive (PP) MS-related tissue damage than conventional magnetic resonance imaging. OBJECTIVE: To improve our understanding of PPMS by assessing the extent of occult pathological features in the normal-appearing white and gray matter of the brain using diffusion-tensor magnetic resonance imaging. METHODS: Ninety-six patients with PPMS, 47 patients with secondary progressive (SP) MS, and 44 healthy control subjects were studied. T2-hyperintense and T1-hypointense lesion volumes were calculated, and the volume of the whole brain tissue was measured. Diffusion-tensor magnetic resonance imaging scans were postprocessed and analyzed to obtain the mean diffusivity and fractional anisotropy histograms from the brain and from the normal-appearing white and gray matter in isolation. RESULTS: The mean T2-hyperintense and T1-hypointense lesion volumes were lower in patients with PPMS than in patients with SPMS, while the mean absolute brain volumes were similar in the 2 groups. The average lesion diffusivity was significantly higher in patients with SPMS than in patients with PPMS (P<.001). Histogram-derived metrics of the brain tissue and normal-appearing white and gray matter were significantly different between patients with PPMS and healthy subjects (range, P =.004 to <.001). Average diffusivity values were significantly higher in patients with SPMS than in patients with PPMS for all the tissues studied (range, P =.001 to <.001). Fractional anisotropy histogram-derived quantities did not significantly differ between the 2 patient groups (range, P =.94 to.03). CONCLUSION: This study confirms that, in patients with PPMS, normal-appearing white and gray matter are not spared by disease-related pathological processes, although they are affected to a lesser degree than in patients with SPMS.

Adult↗