Multiple Sclerosis: Sormani MP

Polman CH, Reingold SC, Barkhof F, Calabresi PA, Clanet M, Cohen JA, Cutter GR, Freedman MS, Kappos L, Lublin FD, McFarland HF, Metz LM, Miller AE, Montalban X, O'Connor PW, Panitch H, Richert JR, Petkau J, Schwid SR, Sormani MP, Thompson AJ, Weinshenker BG, Wolinsky JS. · Department of Neurology, Free University Medical Center in Amsterdam, PO Box 4075, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #18362273 No free full text.

Abstract: The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Sormani MP, Filippi M. · Unit of Biostatistics, Department of Health Sciences, University of Genoa, Genoa, Italy. · J Neuroimaging. · Pubmed #17425737 No free full text.

Abstract: Since magnetic resonance imaging (MRI) of the brain has proved to be the most important paraclinical tool for diagnosing multiple sclerosis (MS) and monitoring its evolution, methodological and statistical issues related to the use of MRI markers in MS have been the focus of several studies in the past 10 years. While many of these methodological issues have been addressed using standard procedures available from other areas of application of medical statistics, in some cases statistical procedures that are not standard have been developed specifically for MRI variables in MS. Two of the major achievements in the statistical methods applied to the use of MRI variables in MS in the past 10 years were the identification of a parametric model to describe the distribution of MRI lesion counts across patients and the study of the relationships between MRI markers and clinical variables, with the aim to validate MRI parameters as surrogates for clinical progression.

Rocca MA, Mondria T, Valsasina P, Sormani MP, Flach ZH, Te Boekhorst PA, Comi G, Hintzen RQ, Filippi M. · Neuroimaging Research Unit, Scientific Institute and University San Raffaele, Milan, Italy. · AJNR Am J Neuroradiol. · Pubmed #17885242 links to  free full text

Abstract: BACKGROUND AND PURPOSE: In multiple sclerosis (MS), autologous hematopoietic stem cell transplantation (AHSCT) induces a profound suppression of clinical activity and MR imaging-detectable inflammation, but it may be associated with a rapid brain volume loss in the months subsequent to treatment. The aim of this study was to assess how AHSCT affects medium-term evolution of brain atrophy in MS. MATERIALS AND METHODS: MR imaging scans of the brain from 14 patients with rapidly evolving secondary-progressive MS obtained 3 months before and every year after AHSCT for 3 years were analyzed. Baseline normalized brain volumes and longitudinal percentage of brain volume changes (PBVCs) were assessed using the Structural Image Evaluation of Normalized Atrophy software. RESULTS: The median decrease of brain volume was 1.92% over the first year after AHSCT and then declined to 1.35% at the second year and to 0.69% at the third year. The number of enhancing lesions seen on the pretreatment scans was significantly correlated with the PBVCs between baseline and month 12 (r = -0.62; P = .02); no correlation was found with the PBVCs measured over the second and third years. CONCLUSIONS: After AHSCT, the rate of brain tissue loss in patients with MS declines dramatically after the first 2 years. The initial rapid development of brain atrophy may be a late consequence of the pretransplant disease activity and/or a transient result of the intense immunoablative conditioning procedure.

Capello E, Saccardi R, Murialdo A, Gualandi F, Pagliai F, Bacigalupo A, Marmont A, Uccelli A, Inglese M, Bruzzi P, Sormani MP, Cocco E, Meucci G, Massacesi L, Bertolotto A, Lugaresi A, Merelli E, Solari A, Filippi M, Mancardi GL, Anonymous00397. · Department of Neurological Sciences Ophthalmology and Genetics, University of Genoa, Via De' Toni 5, I-16132, Genoa, Italy. · Neurol Sci. · Pubmed #16388358 No free full text.

Abstract: Aggressive forms of multiple sclerosis (MS) represent a limited group of demyelinating diseases that rapidly progress to severe disability. Currently available therapies are poorly effective against these clinical entities. Recently, it has been demonstrated that intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT) can affect the clinical course of individuals with severe MS and completely abrogate the inflammatory activity detected by MRI. We report the result of the Italian phase 2 GITMO study, a multicentre study in which 21 MS patients, who were rapidly deteriorating and not responding to the usual therapeutic strategies, were treated with this procedure. The clinical effect of the treatment is long lasting, with a striking abrogation of inflammation detected by MRI findings. These results support a role for intense immunosuppression followed by ASCT as treatment in rapidly evolving MS cases unresponsive to conventional therapies.

Sormani MP, Bruzzi P, Beckmann K, Kappos L, Miller DH, Polman C, Pozzilli C, Thompson AJ, Wagner K, Filippi M. · Neuroimaging Research Unit, Dept. of Neurology, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · J Neurol. · Pubmed #16021360 No free full text.

Abstract: Whereas the effect of interferons (IFNs) on magnetic resonance imaging (MRI) outcome measures in patients with multiple sclerosis (MS) has been convincingly shown, little work has been done to define the between-patient heterogeneity of treatment response. Our aim was to assess the distribution of the effect of IFNbeta-1b in terms of reduction of active T2 lesions in patients with MS. Using a fixed and a random effects model, we investigated the distribution of active T2 lesions reduction over a three-year follow up in response to treatment with 250 mcg IFNbeta-1b every other day in 695 patients with a complete MRI data-set of the 718 (97 %) enrolled in the European, multicenter, randomised, double-blind, placebo-controlled trial of secondary progressive MS. The two statistical models consistently showed that the between-patient response to IFNbeta-1b, in terms of reduction of active T2 lesions, is highly heterogeneous. Whereas treated patients have a high probability (more than 65%) of showing an active T2 lesion reduction equal to or greater than 60%, there is also a 7% probability for treated patients not to show any reduction of MRI-detected disease activity during the course of the trial or even to have an increase of T2 active lesions. This study might be regarded as a first step toward the definition of markers potentially useful to identify IFNbeta treatment responders and non-responders with regard to T2 lesion activity.

Oreja-Guevara C, Rovaris M, Iannucci G, Valsasina P, Caputo D, Cavarretta R, Sormani MP, Ferrante P, Comi G, Filippi M. · Neuroimaging Unit and Department of Neurology, Scientific Institute and University H San Raffaele, Milan, Italy. · Arch Neurol. · Pubmed #15824256 links to  free full text

Abstract: BACKGROUND: Diffusion tensor magnetic resonance imaging (DT MRI) has the potential to provide in vivo information about tissue microstructure. In multiple sclerosis (MS), DT MRI has disclosed the presence of occult structural damage in the normal-appearing brain tissues. OBJECTIVE: To investigate whether DT MRI is sensitive to longitudinal changes of brain damage that may occur beyond the resolution of T2-weighted images in patients with relapsing-remitting MS. DESIGN: Twenty-six untreated patients with relapsing-remitting MS were followed up for 18 months. Dual-echo, DT and postcontrast T1-weighted MRIs of the brain were obtained at baseline and then every 3 months. Mean diffusivity (D) histograms of normal-appearing gray (GM) and white matter were produced. Total T2-hyperintense and T1-hypointense lesion volumes; normalized whole brain tissue, GM, and white matter volumes; percentage brain volume change between the study entry and exit images; average lesion D; and fractional anisotropy were also calculated. RESULTS: During the study period, a significant decrease of normalized whole brain tissue, average lesion fractional anisotropy and normal-appearing GM D histogram peak height, and a significant increase of average normal-appearing GM D and T2-hyperintense lesion volumes were observed. Changes of normal-appearing GM diffusivity were independent of the concomitant changes of normalized whole brain tissue and GM volumes. CONCLUSIONS: The DT MRI findings show progressive microstructural changes in the normal-appearing GM of patients with untreated relapsing-remitting MS. Such changes do not reflect a concomitant development of brain atrophy and confirm the importance of GM pathology in MS.

Rovaris M, Gallo A, Valsasina P, Benedetti B, Caputo D, Ghezzi A, Montanari E, Sormani MP, Bertolotto A, Mancardi G, Bergamaschi R, Martinelli V, Comi G, Filippi M. · Neuroimaging Research Unit, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Neuroimage. · Pubmed #15670691 No free full text.

Abstract: The mechanisms underlying the progressive course of multiple sclerosis (MS) are not fully understood yet. Since diffusion tensor (DT) MRI can provide quantitative estimates of both MRI-visible and MRI-occult brain damage related to MS, the present study investigated the value of DT MRI-derived measures for the assessment of the short-term accumulation of white and gray matter (GM) pathology in patients with primary progressive (PP) and secondary progressive (SP) MS. Fifty-four patients with PPMS and 22 with SPMS were studied at baseline and after a mean follow-up of 15 months. Dual-echo, T1-weighted, and DT MRI scans of the brain were acquired on both occasions. Total lesion volumes (TLV) and percentage brain volume changes (PBVC) were computed. Mean diffusivity (MD) and fractional anisotropy (FA) maps of the normal-appearing white (NAWM) and gray matter (NAGM) were produced, and histogram analysis was performed. In both patient groups, a significant increase of average lesion MD (P = 0.01) and of average NAGM MD (P = 0.007) was found at follow-up. No significant differences between PPMS and SPMS patient groups were found for the on-study changes of any MRI-derived measure. No significant correlations were found between the percentage changes of DT MRI-derived measures and those of TLV and PBVC. No significant changes of DT MRI-derived measures were observed in age-matched healthy controls over the same study period. Over a 1-year period of follow-up, DT MRI can detect tissue changes beyond the resolution of conventional MRI in the NAGM of patients with progressive MS. The accumulation of DT MRI-detectable gray matter damage does not seem to merely depend upon the concomitant increase of T2-visible lesion load and the reduction of brain volume. These observations suggest that progressive NAGM damage might yet be an additional factor leading to the accumulation of disability in progressive MS.

Filippi M, Rocca MA, Pagani E, Iannucci G, Sormani MP, Fazekas F, Ropele S, Hommes OR, Comi G. · Neuroimaging Research Unit, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Arch Neurol. · Pubmed #15364687 links to  free full text

Abstract: BACKGROUND: Magnetization transfer magnetic resonance imaging (MT MRI) can provide in vivo markers reflecting the severity of multiple sclerosis-related brain damage occurring within and outside T2-visible lesions. OBJECTIVE: To investigate the effect of intravenous immunoglobulin (IVIG) treatment on the accumulation of brain damage in patients with secondary progressive multiple sclerosis (SPMS), measured using MT MRI.Design, Patients, and Intervention Seventy patients with SPMS participating in the European, multicenter, randomized, double-blind, placebo-controlled trial of IVIG in SPMS underwent brain T2-weighted and MT MRI at baseline and after 12 and 24 months. The MT MRI scans were post-processed and analyzed to obtain MT ratio values from T2-visible lesions and MT ratio histograms from the normal-appearing brain tissue (NABT). RESULTS: At baseline, a significant difference was found for NABT MT ratio histogram peak height (P =.003) between treated patients and patients receiving placebo. No significant differences between treated patients and those receiving placebo were found for any of the considered MT MRI-derived metrics in terms of treatment x time interaction. Nevertheless, over the 24-month period, the placebo patients experienced a 6.75% reduction of the NABT MT ratio histogram peak height, whereas treated patients experienced only a 0.92% reduction of the NABT MT ratio histogram peak height. CONCLUSIONS: This study did not show any statistically significant effect of IVIG on MT MRI quantities. Nevertheless, the markedly different percentage change of the NABT MT ratio histogram peak height over time between patients receiving placebo and treated patients suggests a possible role of IVIG treatment in preventing the loss of "truly" normal brain tissue in SPMS patients.

Sormani MP, Bruzzi P, Beckmann K, Wagner K, Miller DH, Kappos L, Filippi M, Anonymous00116. · Unit of Clinical Epidemiology and Trials, National Institute for Cancer Research, Genoa, Italy. · Neurology. · Pubmed #12743232 No free full text.

Abstract: BACKGROUND: Although metrics derived from conventional MRI (cMRI) are widely used as outcome measures in clinical trials of MS, no formal study has been performed to validate cMRI metrics as surrogate endpoints for disability progression in MS. METHODS: A validation procedure was applied to the clinical and MRI data collected in the context of the European randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNbeta-1b) in patients with secondary progressive MS. The Prentice operational criteria were used to assess surrogacy for the number of active lesions seen on the first year T2-weighted MRI scans and the percentage T2 lesion volume change between the baseline and the first year MRI scans. The primary clinical outcome was disability at study exit (3 years), adjusted for the baseline disability. RESULTS: The number of active T2 lesions and the T2 lesion volume percentage change over the first year of the study accounted for 57% of the treatment effect on disability progression over the entire study duration. On the contrary, the same cMRI metrics accounted for 79% of the treatment effect on the relapse rate. CONCLUSIONS: This study shows that the beneficial effect of IFNbeta-1b on disability accumulation in patients with secondary progressive MS is, to a large extent, independent of the changes detected using cMRI. As a consequence, cMRI metrics should not be used as a stand-alone measure of outcome in phase III trials of IFNbeta in secondary progressive MS.

Sormani MP, Bruzzi P, Comi G, Filippi M. · Unit of Clinical Epidemiology and Trials, National Institute for Cancer Research, Genoa, Italy. · Neurology. · Pubmed #11839841 No free full text.

Abstract: 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.

Filippi M, Rovaris M, Rocca MA, Sormani MP, Wolinsky JS, Comi G, Anonymous00208. · Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, Italy. · Neurology. · Pubmed #11524494 No free full text.

Abstract: 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.

Mancardi GL, Saccardi R, Filippi M, Gualandi F, Murialdo A, Inglese M, Marrosu MG, Meucci G, Massacesi L, Lugaresi A, Pagliai F, Sormani MP, Sardanelli F, Marmont A, Anonymous00097. · Department of Neurological Sciences and Vision, University of Genova, Italy. · Neurology. · Pubmed #11445629 No free full text.

Abstract: BACKGROUND: Autologous hematopoietic stem cell transplantation (ASCT) has been recently utilized with encouraging results in patients with poorly controlled MS. OBJECTIVE: To determine in severe cases of MS the effect of ASCT on gadolinium (Gd)-enhanced MRI and to obtain information on clinical course and safety. METHODS: In a cooperative study, 10 patients with rapidly evolving secondary progressive MS were transplanted, after BEAM conditioning regimen (carmustine, etoposide, cytosine-arabinoside, and melphalan), with unmanipulated autologous peripheral blood SC mobilized with high-dose cyclophosphamide (CY; 4 g/m2) and granulocyte-colony-stimulating factor. Triple-dose Gd-enhanced scans were performed monthly for a pretreatment period of 3 months and compared with serial monthly Gd-enhanced MRI for the following 6 months and then once every 3 months. RESULTS: The median follow-up is now 15 months (range 4 to 30 months). The number of Gd-enhancing lesions decreased immediately after mobilization with CY and finally dropped to zero in all cases after the conditioning regimen. The number of new T2-weighted positive lesions paralleled data obtained for Gd-enhanced MRI. Clinically, patients improved slightly or remained stable. CONCLUSION: These results demonstrate that the therapeutic sequence CY-BEAM-ASCT has the capacity to completely suppress MR-enhancing activity, an effect that is sustained with time. The final impact of this procedure on disease course remains to be established.

Rovaris M, Inglese M, van Schijndel RA, Sormani MP, Rodegher M, Comi G, Filippi M. · Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, University of Milan, Via Olgettina, 60, 20132 Milan, Italy. · J Neurol. · Pubmed #11200690 No free full text.

Abstract: 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.

Filippi M, Rovaris M, Iannucci G, Mennea S, Sormani MP, Comi G. · Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, University of Milan, Italy. · Neurology. · Pubmed #11113227 No free full text.

Abstract: 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.

Filippi M, Rovaris M, Rice GP, Sormani MP, Iannucci G, Giacomotti L, Comi G. · Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale San Raffaele, University of Milan, Milan, Italy. · J Neurol Sci. · Pubmed #10865091 No free full text.

Abstract: 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.

Sormani MP, Molyneux PD, Barkhof F, Miller DH, Filippi M. · No affiliation provided · Magn Reson Imaging. · Pubmed #10499687 No free full text.

This publication has no abstract.

Sormani MP, Bonzano L, Roccatagliata L, Cutter GR, Mancardi GL, Bruzzi P. · Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy. · Ann Neurol. · Pubmed #19334061 No free full text.

Abstract: OBJECTIVE: The aim of this work was to evaluate whether the treatment effects on magnetic resonance imaging (MRI) markers at the trial level were able to predict the treatment effects on relapse rate in relapsing-remitting multiple sclerosis. METHODS: We used a pooled analysis of all the published randomized, placebo-controlled clinical trials in relapsing-remitting multiple sclerosis reporting data both on MRI variables and relapses. We extracted data on relapses and on MRI "active" lesions. A regression analysis weighted on trial size and duration was performed to study the relation between the treatment effect on relapses and the treatment effect on MRI lesions. We validated the estimated relation on an independent set of clinical trials satisfying the same inclusion criteria but with a control arm other than placebo. RESULTS: A set of 23 randomized, double-blind, placebo-controlled trials in relapsing-remitting multiple sclerosis was identified, for a total of 63 arms, 40 contrasts, and 6,591 patients. A strong correlation was found between the effect on the relapses and the effect on MRI activity. The adjusted R(2) value of the weighted regression line was 0.81. The regression equation estimated using the placebo-controlled trials gave a satisfactory prediction of the treatment effect on relapses when applied to the validation set. INTERPRETATION: More than 80% of the variance in the effect on relapses between trials is explained by the variance in MRI effects. Smaller and shorter phase II studies based on MRI lesion end points may give indications also on the effect of the treatment on relapse end points.

Rocca MA, Absinta M, Valsasina P, Ciccarelli O, Marino S, Rovira A, Gass A, Wegner C, Enzinger C, Korteweg T, Sormani MP, Mancini L, Thompson AJ, De Stefano N, Montalban X, Hirsch J, Kappos L, Ropele S, Palace J, Barkhof F, Matthews PM, Filippi M. · Department of Neurology, Scientific Institute and University, Ospedale San Raffaele, Milan, Italy. · Hum Brain Mapp. · Pubmed #19034902 No free full text.

Abstract: In this multicenter study, we used dynamic causal modeling to characterize the abnormalities of effective connectivity of the sensorimotor network in 61 patients with multiple sclerosis (MS) compared with 74 age-matched healthy subjects. We also investigated the correlation of such abnormalities with findings derived from structural MRI. In a subgroup of subjects, diffusion tensor (DT) MRI metrics of the corpus callosum and the left corticospinal tract (CST) were also assessed. MS patients showed increased effective connectivity relative to controls between: (a) the left primary SMC and the left dorsal premotor cortex (PMd), (b) the left PMd and the supplementary motor areas (SMA), (c) the left secondary sensorimotor cortex (SII) and the SMA, (d) the right SII and the SMA, (e) the left SII and the right SII, and (f) the right SMC and the SMA. MS patients had relatively reduced effective connectivity between the left SMC and the right cerebellum. No interaction was found between disease group and center. Coefficients of altered connectivity were weakly correlated with brain T2 LV, but moderately correlated with DT MRI-measured damage of the left CST. In conclusion, large multicenter fMRI studies of effective connectivity changes in diseased people are feasible and can facilitate studies with sample size large enough for robust outcomes. Increased effective connectivity in the patients for the simple motor task suggests local network modulation contributing to enhanced long-distance effective connectivity in MS patients. This extends and generalizes previous evidence that enhancement of effective connectivity may provide an important compensatory mechanism in MS.

Sormani MP, Tintorè M, Rovaris M, Rovira A, Vidal X, Bruzzi P, Filippi M, Montalban X. · Biostatistics Unit, Department of Health Sciences (DISSAL), University of Genoa, Italy. · Ann Neurol. · Pubmed #18688811 No free full text.

Abstract: OBJECTIVE: Using different criteria for classifying patients into various stages of a disease can modify the stage-specific prognosis, even though the overall disease course remains unchanged. This is known as the "Will Rogers phenomenon," precluding the use of historical controls for treatment trials. We assessed whether the Will Rogers phenomenon may affect multiple sclerosis (MS) prognosis when applying different diagnostic criteria. METHODS: Patients with a clinically isolated syndrome (CIS) suggestive of MS were studied. After 1 year, each patient was classified as CIS or evolved to MS according to two diagnostic criteria (Poser and McDonald). The outcome for prognosis was the time to reach an Expanded Disability Status Scale score > or = 3.0. RESULTS: 309 patients were studied for a median period of 84 months. After 1 year, 16% of patients had MS according to Poser and 44% according to McDonald criteria. The probability to reach Expanded Disability Status Scale score > or = 3.0 at median follow-up was 11% in CIS patients according to Poser and 7% according to McDonald criteria; it was 46% in MS patients according to Poser and 27% acccording to McDonald criteria. The group with a discordant diagnosis had a worse prognosis than that of CIS patients according to both criteria (p = 0.01), but better than that of MS patients according to both criteria (p = 0.01). INTERPRETATION: The use of different diagnostic criteria may generate spurious improvements in the medium-term prognosis of MS. This calls for caution in using historical controls for MS trials.

Mesaros S, Rocca MA, Sormani MP, Charil A, Comi G, Filippi M. · Neuroimaging Research Unit, Scientific Institute and University H San Raffaele, Via Olgettina 60, 20132, Milan, Italy. · J Neurol. · Pubmed #18584233 No free full text.

Abstract: To assess the value of clinical and MRI variables in predicting short-term brain atrophy accumulation and clinical evolution in a large cohort of patients with RRMS, we studied a cohort of 548 patients, previously enrolled as a placebo arm of a 14-month, double-blind trial of oral glatiramer acetate (GA). A logistic regression model with EDSS progression as the dependent variable was built to assess baseline clinical and MRI variables associated with clinical worsening during follow-up. In 466 patients with complete central brain atrophy assessment, another linear regression model with percentage central brain volume change (PCBVC) as the dependent variable was built to assess baseline clinical and MRI variables associated with atrophy development.A total of 80 patients (15%) had EDSS progression over the follow-up period. Factors independently predicting the probability to have a clinical progression were lower EDSS (OR = 0.78, 95% CI = 0.62-0.97 p = 0.02) and higher T2 LL (OR = 1.022, 95% CI = 1.006-1.038, p = 0.007) at baseline. In the 466 patients with atrophy assessment, PCBVC declined, on average, by -2.0% (SD = 2.8) (p < 0.001) over the follow-up. The multivariate PCBVC analysis revealed that the PCBVC decrease was independently correlated with higher EDSS (p = 0.03) and T2 LL (p = 0.005) at baseline. The squared correlation coefficients of the composite scores made up of EDSS and T2 LL considered together were able to explain only 3 % of the variance in disability progression and only 4 % of the variance of PCBVC.In RRMS patients, clinical and conventional MRI findings at baseline only modestly predict shortterm accumulation of brain atrophy and disability. These data confirm the need to develop clinical and MRI measures more sensitive towards the more disabling aspects of the disease.

Parodi RC, Levrero F, Sormani MP, Pilot A, Mancardi GL, Aliprandi A, Sardanelli F. · Department of Neuroradiology, Ospedale di Imperia, ASL 1 Imperiese, Via Sant'Agata 57, Imperia, Italy. · Radiol Med. · Pubmed #18386130 No free full text.

Abstract: PURPOSE: Identification of new enhancing lesions is a major endpoint of longitudinal brain magnetic resonance (MR) studies of multiple sclerosis (MS). To date, this is a visual, time-consuming procedure. We present here a supervised automated procedure (SAP) aimed at reducing the time needed to identify new MS enhancing lesions. MATERIALS AND METHODS: The SAP uses an algorithm including Cartesian coordinates of the lesions to be compared, their area and a constant (k). The procedure was validated for enhancing lesions on T1-weighted spin-echo images after intravenous administration of 0.1 mmol/kg of paramagnetic contrast agent, randomly selected from a dataset of a longitudinal MR study on ten relapsing-remitting MS patients followed for 2-5 years. During the validation session, two readers decided by consensus whether two lesions, present on the same slice of two examinations performed on subsequent dates, were the same or not. In this way, k was calibrated to obtain the same result from both visual inspection and automatic algorithm output. RESULTS: After evaluating of 25+/-5 (mean+/-standard deviation) lesions in each of ten different sessions with correction of k value, the k value became a stable value (0.45+/-0.05). CONCLUSIONS: Once the suitable value of k was found, SAP was able to identify new enhancing lesions, avoiding visual inspection, which is usually a lengthy procedure.

Rocca MA, Agosta F, Sormani MP, Fernando K, Tintorè M, Korteweg T, Tortorella P, Miller DH, Thompson A, Rovira A, Montalban X, Polman C, Barkhof F, Filippi M. · Neuroimaging Research Unit, Dept. of Neurology, Scientific Institute and University Ospedale, San Raffaele, Via Olgettina, 60, 20132 Milan, Italy. · J Neurol. · Pubmed #18274802 No free full text.

Abstract: OBJECTIVES: To define the extent of overall brain damage in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to identify non-conventional magnetic resonance (MR) metrics predictive of evolution to definite MS. METHODS: Brain conventional and magnetization transfer (MT) MRI scans were obtained from 208 CIS patients and 55 matched healthy controls, recruited in four centres. Patients were assessed clinically at the time of MRI acquisition and after a median period of 3.1 years from disease onset. The following measures were derived: T2, T1 and gadolinium (Gd)- enhancing lesion volumes (LV), normalized brain volume (NBV), MTR histogram-derived quantities of the normal-appearing white matter (NAWM) and grey matter (GM). RESULTS: During the follow-up, 43 % of the patients converted to definite MS. At baseline, a significant inter-centre heterogeneity was detected for T2 LV (p = 0.003), T1 LV (p = 0.006), NBV (p < 0.001) and MTR histogram-derived metrics (p < 0.001). Pooled average MTR values differed between CIS patients and controls for NAWM (p = 0.003) and GM (p = 0.01). Gdactivity and positivity of International Panel (IP) criteria for disease dissemination in space (DIS), but not NAWM and GM MTR and NBV, were associated with evolution to definite MS. The final multivariable model retained only MRI IP criteria for DIS (p = 0.05; HR = 1.66, 95 % CI = 1.00-2.77) as an independent predictor of evolution to definite MS. CONCLUSIONS: Although irreversible tissue injury is present from the earliest clinical stages of MS, macroscopic focal lesions but not "diffuse" brain damage measured by MTR are associated to an increased risk of subsequent development of definite MS in CIS patients.

Rovaris M, Judica E, Sastre-Garriga J, Rovira A, Sormani MP, Benedetti B, Korteweg T, De Stefano N, Khaleeli Z, Montalban X, Barkhof F, Miller DH, Polman C, Thompson AJ, Filippi M. · Neuroimaging Research Unit, Department of Neurology, San Raffaele Scientific Institute, Milan, Italy. · Mult Scler. · Pubmed #18208869 No free full text.

Abstract: Although the mechanisms underlying the accumulation of disability in primary progressive (PP) multiple sclerosis (MS) are still unclear, a major role seems to be played by 'occult' tissue damage. We investigated whether conventional and magnetization transfer (MT) MRI may provide complementary information for the assessment of PPMS severity. Conventional and MT MRI scans from 226 PPMS patients and 84 healthy controls were collected for centralized analysis. The expanded disability status scale (EDSS) score was rated at the time of MRI acquisition. T2 lesion volume, normalized brain volume (NBV) and cervical cord cross-sectional area (CSA) were measured. Magnetization transfer ratio (MTR) histograms from whole brain tissue, normal-appearing white matter and grey matter (NAGM) were also obtained. Mean NBV, CSA and MTR histogram-derived metrics showed significant inter-centre heterogeneity. After correcting for the acquisition centre, pooled average MTR and histogram peak height values were different between PPMS patients and controls for all tissue classes (P-values between 0.03 and 0.0001). More severe brain and cord atrophy and MT MRI-detectable NAGM damage were found in patients who required walking aids than in those who did not (P-values: 0.03, 0.001 and 0.016). A composite score of NBV, CSA, whole brain and NAGM MTR histogram peak height z-scores was correlated with patients' EDSS (r = 0.37, P 0.001). Magnetization transfer MRI might provide information complementary to that given by conventional MRI when assessing PPMS severity. Sequence-related variability of measurements makes the standardization of MT MRI acquisition essential for the design of multicentre studies.

Horsfield MA, Bakshi R, Rovaris M, Rocca MA, Dandamudi VS, Valsasina P, Judica E, Lucchini F, Guttmann CR, Sormani MP, Filippi M. · Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 5WW, UK. · IEEE Trans Med Imaging. · Pubmed #18092737 No free full text.

Abstract: A method for incorporating prior knowledge into the fuzzy connectedness image segmentation framework is presented. This prior knowledge is in the form of probabilistic feature distribution and feature size maps, in a standard anatomical space, and "intensity hints" selected by the user that allow for a skewed distribution of the feature intensity characteristics. The fuzzy affinity between pixels is modified to encapsulate this domain knowledge. The method was tested by using it to segment brain lesions in patients with multiple sclerosis, and the results compared to an established method for lesion outlining based on edge detection and contour following. With the fuzzy connections (FC) method, the user is required to identify each lesion with a mouse click, to provide a set of seed pixels. The algorithm then grows the features from the seeds to define the lesions as a set of objects with fuzzy connectedness above a preset threshold. The FC method gave improved interobserver reproducibility of lesion volumes, and the set of pixels determined to be lesion was more consistent compared to the contouring method. The operator interaction time required to evaluate one subject was reduced from an average of 111 min with contouring to 16 min with the FC method.

Sormani MP, Rovaris M, Comi G, Filippi M. · Neuroimaging Research Unit, San Raffaele Scientific Institute, Milan, Italy. · Neurology. · Pubmed #17875911 No free full text.

Abstract: OBJECTIVE: To generate and validate a composite (clinical and MRI-based) score able to identify individual patients with relapsing-remitting multiple sclerosis (RRMS) with a high risk of experiencing relapses in the short term. METHODS: The study was conducted using data from a working and a validation dataset. The former consisted of 539 patients from the placebo arm of a double-blind, placebo-controlled trial of oral glatiramer acetate (GA) in RRMS. The validation sample consisted of 117 patients from the placebo arm of a double-blind, placebo-controlled trial of subcutaneous GA in RRMS. In the working sample, regression analysis was performed to identify clinical or MRI variables independently predicting the occurrence of relapses. A linear predictive score was calculated using the variables included in the multivariable model and the corresponding estimated coefficients. Such a score was then applied to the validation sample. RESULTS: The variables included in the final model as independent predictors of relapse occurrence were the number of enhancing lesions on a baseline MRI (p < 0.001) and the number of relapses during the previous 2 years (p < 0.001). The resulting score was able to identify patients at high and low risk of relapse occurrence both in the working and in the validation samples. CONCLUSIONS: The composite, clinical/MRI score presented here, which allows us to estimate the short-term risk of relapses in patients with relapsing-remitting multiple sclerosis, may provide us with an additional and useful piece of information for a better planning of phase III trials in multiple sclerosis.