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In the last few years, increasing effort has been devoted to better define the characteristics of tissue damage occurring outside MRI-visible lesions in patients with multiple sclerosis (MS) and, as a consequence, to improve our understanding of the disease pathobiology and of the mechanisms leading to the accumulation of irreversible disability. This book provides an updated review of the results obtained by leading research groups in this field. The potential clinical applications of what has been shown so far, as well as the areas for future research in the study of normal-appearing white and gray matter damage in MS are extensively discussed, making this book a valuable tool for clinical neurologists who are involved in the daily-life care of MS patients and for neuroscientists involved in MS research.

Recent years have witnessed dramatic advances in the development and use of magnetic resonance imaging (MRI) techniques that can provide quantitative measures with some degree of pathological specificity for the heterogeneous substrates of multiple sclerosis (MS). Magnetic resonance spectroscopy (MRS) is one of the most promising of these techniques. Thanks to MRS, axonal damage is no longer considered an end-stage phenomenon typical of only the most destructive lesions and the most unfortunate cases, but rather as a major component of the MS pathology of lesions and normal-appearing white matter at all the phases of the disease. This new concept is rapidly changing our understanding of MS pathophysiology and, as a consequence, the therapeutic strategies to modify the disease course favorably. Many of the authors have pionereed the use of MRS in MS, thus contributing to the foundation of the'axonal hypothesis'.

We have entered an exciting period in the study of multiple sclerosis and its treatment. Central to this progress has been the introduction of magnetic reso­ nance techniques. When Young and his colleagues published the first images of the brain in multiple sclerosis at the end of 1981, it was at once obvious that magnetic resonance imaging would playa major role in diagnosis. Intuitively one felt that it would also have a role in increasing our understanding of the pathogenesis of the disease and in monitoring treatment. And so it has proved. Important problems however remain, perhaps the most important of which at present is the weak predictive power of standard magnetic resonance ima­ ging methods in determining the possibility of progression of impairment and disability. Recently, there have been advances which promise to overcome some of these problems, but decisions about what approach to adopt in selecting patients for clinical trials and which techniques to use in monitoring treatment during their course are still difficult. In this book, Dr. Filippi and his colleagues have assembled an outstanding group of contributors whose work is central to the progress that is being made. The coverage of the issues involved in the use of magnetic resonance techniques in assessing therapeutic effect is comprehensive and, though the field is chan­ ging rapidly, the principles and much of the detail in the book are likely to have lasting value.

'Why are there no effective treatments for my condition? Why do researchers exclude patients with primary progressive multiple sclerosis from enrolling in clinical trials? Please let me know if you hear of studies that I might be allowed to enter or treatments that I could try for my condition.'Thus, in recent years, the sad lament of the patient with primary progressive MS (PPMS). This variant, often in the guise of a chronic progressive myelopathy or, less commonly, progressive cerebellar or bulbar dysfunction, usually responds poorly to corticosteroids and rarely seems to benefit to a significant degree from intensive immunosuppressive treatments. In recent years, most randomized clin­ ical trials have excluded PPMS patients on two counts. Clinical worsening devel­ ops slowly in PPMS and may not be recognized during the course of a 2-or 3-year trial even in untreated control patients. This factor alone adds to the potential for a type 2 error or, at the very least, inflates the sample size and duration of the trial. In addition, there is mounting evidence that progressive axonal degeneration and neuronal loss (rather than active, recurrent inflammation) may be important components of the pathology in this form of the disease. Although contemporary trials are evaluating whether PPMS patients may benefit from treatment with the ~-interferons and glatiramer acetate, preliminary, uncontrolled clinical experi­ ence suggests that the results may not be dramatic.

In multiple sclerosis (MS), conventional magnetic resonance imaging (cMRI) has proved to be a valuable tool to increase diagnostic confidence and for monitoring the efficacy of experimental treatment. However, cMRI has limited specificity and accuracy of cMRI to the most disabling aspects of the MS pathology, known to occur in and outside macroscopic lesions. Modern quantitative MR techniques have the potential to overcome the limitations of cMRI, and their application is changing dramatically our understanding of how MS causes irreversible disability. In detail, there is an increasing body of MR evidence that MS is not only a white matter disease and does not only cause focal lesions, as well as that neurodegeneration is an important aspect of the disease (since the earliest clinical phases), which is only partially related to inflammatory changes. There is also increasing perception that modern MR methodologies should be more extensively employed in clinical trials to derive innovative information. Written by world-renowned scientists, the volume provides a state-of-the-art on the most recent MRI techniques related to MS, and it will bi and indispensable tool for all those working in this field.