Multiple Sclerosis: Filippi M

Frohman EM, Goodin DS, Calabresi PA, Corboy JR, Coyle PK, Filippi M, Frank JA, Galetta SL, Grossman RI, Hawker K, Kachuck NJ, Levin MC, Phillips JT, Racke MK, Rivera VM, Stuart WH, Anonymous00118. · University of Texas Southwestern Medical Center at Dallas, USA. · Neurology. · Pubmed #12963748 No free full text.

Abstract: Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.

Comi G, Kappos L, Clanet M, Ebers G, Fassas A, Fazekas F, Filippi M, Hartung HP, Hertenstein B, Karussis D, Martino G, Tyndall A, van der Meché FG. · Multiple Sclerosis Centre, San Raffaele Scientific Institute, Milan, Italy. · J Neurol. · Pubmed #10896270 No free full text.

Abstract: Recent reports suggest the possible beneficial effects of haemopoietic stem cell transplantation (HSCT) in autoimmune diseases such as multiple sclerosis (MS). The definition of the risk/benefit ratio for such a treatment is perceived as a major issue for the neurological community worldwide. The First Consensus Conference on Bone Marrow Transplantation in Patients with Multiple Sclerosis was held in Milan, Italy on 21 February 1998. Participants from 16 European, North American, and South American countries discussed the guidelines for performing HSCT in MS. This conference was organized in order to: (a) define criteria for patient selection; (b) define transplantation procedures to maximize efficacy of the treatment and minimize its toxicity; (c) standardize patient outcome evaluation; and (d) establish an international working group to evaluate the efficacy and safety of HSCT in MS and to study the immunological changes related to HSCT in MS patients. During the meeting in Milan agreement was reached on: (a) the preparation and distribution of a consensus report on HSCT in MS and (b) the design of an open trial for an initial assessment of the safety and efficacy of HSCT in MS. The consensus reached during the meeting and the design of the clinical trial are summarized in this contribution.

Filippi M, Agosta F. · No affiliation provided · J Neuroimaging. · Pubmed #19192041 No free full text.

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Filippi M. · No affiliation provided · Neuroimaging Clin N Am. · Pubmed #19064195 No free full text.

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Filippi M, Hartung HP. · No affiliation provided · Ann Neurol. · Pubmed #17894367 No free full text.

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Filippi M, Rocca MA. · No affiliation provided · J Neurol Sci. · Pubmed #17658555 No free full text.

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Frohman EM, Havrdova E, Lublin F, Barkhof F, Achiron A, Sharief MK, Stuve O, Racke MK, Steinman L, Weiner H, Olek M, Zivadinov R, Corboy J, Raine C, Cutter G, Richert J, Filippi M. · Departments of Neurology and Ophthalmology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA. · Arch Neurol. · Pubmed #16606781 No free full text.

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Rocca MA, Filippi M. · No affiliation provided · J Neurol Sci. · Pubmed #16451805 No free full text.

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Rovaris M, Filippi M. · No affiliation provided · J Neurol Sci. · Pubmed #16023141 No free full text.

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Filippi M, Rocca MA. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #15258204 links to  free full text

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Comi G, Rocca MA, Filippi M. · No affiliation provided · Eur Neurol. · Pubmed #15159597 links to  free full text

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Horsfield MA, Filippi M. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #12876224 links to  free full text

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Filippi M. · No affiliation provided · J Neurol Sci. · Pubmed #11266683 No free full text.

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Rovaris M, Barkhof F, Calabrese M, De Stefano N, Fazekas F, Miller DH, Montalban X, Polman C, Rocca MA, Thompson AJ, Yousry TA, Filippi M. · Multiple Sclerosis Centre, Scientific Institute Santa Maria Nascente, Fondazione Don Gnocchi, Milan, Italy. · Neurology. · Pubmed #19433744 No free full text.

Abstract: It is well known that the current classification of patients with benign multiple sclerosis (BMS), i.e., those with absent or minimal locomotor disability several years after disease onset, suffers from not having any prognostic value for the subsequent evolution of multiple sclerosis (MS). The identification of markers predictive of the longer-term course of MS will help define BMS more reliably and would allow better counseling of patients, particularly when advising on the initiation of a disease-modifying treatment. MRI-based evidence suggests that there are three potential, but not mutually exclusive, explanations for the scarce clinical impact of BMS: 1) the paucity of tissue damage within and outside MS lesions; 2) the relative sparing of clinically eloquent regions; and 3) the presence of effective compensatory mechanisms. In addition, the results of correlative MRI/neuropsychology studies underpin the need for a new definition of BMS, which should consider the maintenance of a normal cognitive profile as an additional criterion.

Filippi M, Rocca MA. · Neuroimaging Research Unit, Department of Neurology, San Raffaele Scientific Institute and University, Via Olgettina, 60-20132, Milan, Italy. · Neuroimaging Clin N Am. · Pubmed #19064200 No free full text.

Abstract: A variable effectiveness of reparative and recovery mechanisms following tissue damage is among the factors that might contribute to explaining resolution of symptoms and maintenance of a normal level of function in patients who have multiple sclerosis (MS). The application of functional MR imaging in MS has shown that cortical changes do occur after white matter injury and that these changes can contribute to limiting the clinical outcome of such damage. Conversely, the failure or exhaustion of the adaptive properties of the cerebral cortex with increasing disease duration and burden might be among the factors responsible for the accumulation of fixed neurologic deficits in patients who have MS.

Rovaris M, Agosta F, Pagani E, Filippi M. · Neuroimaging Research Unit, Department of Neurology, San Raffaele Scientific Institute and University, Via Olgettina, 60-20132, Milan, Italy. · Neuroimaging Clin N Am. · Pubmed #19064198 No free full text.

Abstract: Diffusion tensor (DT) MR imaging is able to detect and quantify multiple sclerosis (MS)-related tissue damage within and outside T2-visible lesions. DT MR imaging has also been shown to be sensitive to the evolution of MS damage over time and to provide in vivo correlates of MS clinical severity and paraclinical markers of long-term disease evolution. Recent developments of DT MR imaging postprocessing techniques, such as tractography and voxelwise analysis, are likely to improve our understanding of the mechanisms associated with the accumulation of disability in MS. Important issues remain to be addressed, such as a detailed definition of the actual features underlying diffusion changes in MS and the potential of the technique in the differential diagnosis of MS.

Filippi M, Rocca MA. · Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Neurol Sci. · Pubmed #18941722 No free full text.

Abstract: Advanced magnetic resonance imaging (MRI) approaches are extensively used for the assessment of central nervous system (CNS) damage in patients with multiple sclerosis (MS) and allied white matter diseases. Through their ability to obtain simultaneous measures of abnormalities of structure and function at a global and regional level, these techniques, which include magnetization transfer MRI, diffusion tensor MRI and proton MR spectroscopy, are contributing to filling the voids between clinical and MRI measures. As a consequence, they are dramatically improving our understanding of the mechanisms related to the accumulation of irreversible disability in these conditions. Future improvements, including the development of new sequences and post-processing methods as well as the use of high-field MRI, despite being a major technical challenge, hold new and exciting promise.

Zivadinov R, Reder AT, Filippi M, Minagar A, Stüve O, Lassmann H, Racke MK, Dwyer MG, Frohman EM, Khan O. · Buffalo Neuroimaging Analysis Center, Jacobs Neurological Institute, 100 High Street, Buffalo, NY 14203, USA. · Neurology. · Pubmed #18606968 No free full text.

Abstract: Disease-modifying agents (DMAs), including interferon beta (IFNbeta) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNbeta administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNbeta demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non-tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss.

Bakshi R, Thompson AJ, Rocca MA, Pelletier D, Dousset V, Barkhof F, Inglese M, Guttmann CR, Horsfield MA, Filippi M. · Center for Neurological Imaging, Partners Multiple Sclerosis Center, Departments of Neurology and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Lancet Neurol. · Pubmed #18565455 links to  free full text

Abstract: Many promising MRI approaches for research or clinical management of multiple sclerosis (MS) have recently emerged, or are under development or refinement. Advanced MRI methods need to be assessed to determine whether they allow earlier diagnosis or better identification of phenotypes. Improved post-processing should allow more efficient and complete extraction of information from images. Magnetic resonance spectroscopy should improve in sensitivity and specificity with higher field strengths and should enable the detection of a wider array of metabolites. Diffusion imaging is moving closer to the goal of defining structural connectivity and, thereby, determining the functional significance of lesions at specific locations. Cell-specific imaging now seems feasible with new magnetic resonance contrast agents. The imaging of myelin water fraction brings the hope of providing a specific measure of myelin content. Ultra-high-field MRI increases sensitivity, but also presents new technical challenges. Here, we review these recent developments in MRI for MS, and also look forward to refinements in spinal-cord imaging, optic-nerve imaging, perfusion MRI, and functional MRI. Advances in MRI should improve our ability to diagnose, monitor, and understand the pathophysiology of MS.

Bar-Zohar D, Agosta F, Goldstaub D, Filippi M. · Multiple Sclerosis and Autoimmune Diseases Section, Innovative Research and Development, Teva Pharmaceutical Industries, Netanya, Israel. · Mult Scler. · Pubmed #18424478 No free full text.

Abstract: Magnetic resonance imaging (MRI) has revolutionized the diagnosis and management of patients with multiple sclerosis (MS). Conventional MRI metrics are employed as primary endpoints in proof-of-concept clinical trials evaluating new drugs for MS and as secondary endpoints in definitive phase III trials. Metrics derived from non-conventional MRI techniques are now emerging and hold significant promise since they appear to be more correlated with the most disabling features of MS. However, none of these has been approved for use as a surrogate endpoint for accumulation of physical disability, which is the most important clinical endpoint of this disease. Taking into account the large numbers of patients needed, the extensive exposure to placebo, and the relatively long duration required for phase III clinical trials to show a meaningful effect on progression of disability, the need for a valid, reliable, and objective paraclinical marker of disease evolution cannot be overemphasized. This paper reviews the most up-to-date data regarding MRI techniques, their relationship with central nervous system pathology, as well as with clinical endpoints, and proposes future insights into the use of MRI metrics as surrogate endpoints in clinical trials of MS.

Seewann A, Enzinger C, Filippi M, Barkhof F, Rovira A, Gass A, Miller D, Montalban X, Thompson A, Yousry T, Tintore M, de Stefano N, Palace J, Rovaris M, Polman C, Fazekas F, Anonymous00221. · Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036, Graz, Austria. · J Neurol. · Pubmed #18004634 No free full text.

Abstract: BACKGROUND : Idiopathic inflammatory demyelinating lesions (IIDL) of the brain usually present with a morphologic pattern characteristic of multiple sclerosis (MS). Atypical appearances of IIDLs also exist, however, and can pose significant diagnostic problems and uncertainty regarding prognosis and adequate therapy. We attempted to improve upon this situation by reviewing the literature. METHODS : We performed a PubMed search from January 1984 through December 2004 for articles in English reporting on IIDLs which had been considered as morphologically atypical (66 articles; 270 cases reported). From these publications 69 individual patient reports allowed the extraction of adequate information on magnetic resonance imaging (MRI) and associated disease characteristics. RESULTS : Reported atypical IIDLs most frequently manifested as large ring-like lesions (n = 27) which are now considered quite suggestive of an antibodymediated form of MS. Truly atypical IIDLs were less common and exhibited appearances which we termed megacystic (n = 8), Balolike (n = 11) and diffusely infiltrating (n = 11). Despite limitations imposed by the absence of original data the inter-rater agreement in defining these subtypes of atypical IIDLs was moderate to substantial (kappa 0.48-0.68) and we noted trends for their association with certain demographic, clinical and paraclinical variables. INTERPRETATION : We suggest that IIDLs reported as atypical in the literature can be segregated into several distinct subtypes based on their MRI appearance. The recognition of these patterns may be useful for the differential diagnosis and for a future classification. Because of the limitations inherent in our review this will have to be confirmed by a prospective registry.

De Stefano N, Filippi M, Miller D, Pouwels PJ, Rovira A, Gass A, Enzinger C, Matthews PM, Arnold DL. · Department of Neurological and Behavioral Sciences, University of Siena, Viale Bracci 2, 53100 Siena, Italy. · Neurology. · Pubmed #17998486 No free full text.

Abstract: Proton MR spectroscopy (MRS) allows noninvasive characterization of chemical-pathologic changes in the brain. In patients with multiple sclerosis (MS), proton MRS reveals chemical pathology in focal inflammatory lesions as well as in regions of the brain that are not associated with structural abnormalities on conventional MRI. In MS studies, it has been particularly useful as a method for the assessment of neurodegeneration based on decreases in the levels of the neuro-axonal marker compound, N-acetylaspartate. Also, MRS has provided evidence of chemical pathology and repair involving non-neuronal brain cells based on changes in metabolites, including choline, myo-inositol, glutamate, and GABA. Despite its greater pathologic specificity for axonal integrity compared to conventional MRI, MRS has been used only infrequently in clinical trials. This prompted us to review current MRS clinical applications in MS, discuss the potential and limitations of the technique, and suggest recommendations for the application of MRS to clinical trials.

Filippi M, Rocca MA. · Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Hospital San Raffaele, Milan, Italy. · Neurotherapeutics. · Pubmed #17599705 No free full text.

Abstract: Magnetic resonance imaging is highly sensitive in revealing CNS abnormalities associated with several neurological conditions, but lacks specificity for their pathological substrates. In addition, MRI does not allow evaluation of the presence and extent of damage in regions that appear normal on conventional MRI sequences and that postmortem studies have shown to be affected by pathology. Quantitative MR-based techniques with increased pathological specificity to the heterogeneous substrates of CNS pathology have the potential to overcome such limitations. Among these techniques, one of the most extensively used for the assessment of CNS disorders is magnetization transfer MRI (MT-MRI). The application of this technique for the assessment of damage in macroscopic lesions, in normal-appearing white and gray matter, and in the spinal cord and optic nerve of patients with several neurological conditions is providing important in vivo information-dramatically improving our understanding of the factors associated with the appearance of clinical symptoms and the accumulation of irreversible disability. MT-MRI also has the potential to contribute to the diagnostic evaluation of several neurological conditions and to improve our ability to monitor treatment efficacy in experimental trials.

Filippi M, Valsasina P, Rocca M. · Neuroimaging Research Unit,Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Int MS J. · Pubmed #17509248 links to  free full text

Abstract: The classical view of MS as an inflammatory-demyelinating condition affecting the white matter (WM) of the central nervous system (CNS) has recently been challenged by the results of several magnetic resonance imaging (MRI) studies. These consistently show grey matter (GM) involvement, which correlates only moderately with the extent of WM pathology. Here we summarize how conventional and modern imaging-based techniques have quantified GM damage in MS, in terms of focal lesions, diffuse tissue abnormalities and irreversible tissue loss. Results from functional MRI studies, together with these new findings, are contributing to a significant change in our MS understanding. MS is now viewed as a global CNS condition, affecting both WM and GM, which has an early and important neurodegenerative component.

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.