The therapeutic era for MS has begun, and many new, potentially effective treatments are now available. MRI offers a range of techniques which are more reliable and sensitive than any other available approach in detecting brain and spinal cord abnormalities, monitoring their evolution, and providing in vivo information about heterogenous pathological substrates of the MS lesions. Readers will find this volume a valuable summary of the state-of- the art, as well as a useful reference text from which to plan future clinical trials in MS.

Morphological, physiological and pathological evidence demonstrates that ner- vous and immune systems interact not only in maintaining brain homeostasis, but also in causing neurological diseases. The studyofthese interactions repre- sents the basis on which neuroimmunologyhas grown during the years. At pre- sent, several neurological diseases are recognized to be caused by a derange- ment of the immune system in either its regulatory or effector functions. The main scope ofthis book, to discuss how an unbalanced immune system maylead to immune-mediated neurological diseases, is achieved in three parts. The first part provides an overview on how the immune system works. This is propaedeutical to understanding interactions between the immune and ner- vous systems, which are discussed in the second part. The third part of the book focuses on one particular area of neuroimmunology, the immune disor- ders leading to the damage of central and peripheral myelin.Given the opportunity to review first the immune system in itself and then how it operates during immune-mediated demyelinating disorders, we have tried to provide the reader with a basis for clearly understanding how interac- tions between the immune and nervous systems can be protective or pathoge- nic. This knowledge is a prerequisite for a rationale immune intervention tar- geting these disorders.

Immune-mediated neurological disorders present an increasing challenge to neu- rologists. Recent advances have identified new antibodies, new effector mechanisms and new diagnostic tests; these have greatly enhanced our understanding of disease aetiology and opened up therapeutic opportunities, but a critical understanding of this fast -developing field is not easy to find. This volume was conceived following a very successful course on neuroimmu- no logy in Bergamo in 2000, and was written mainly by clinicians who are active in the laboratory. It will help to keep practising neurologists and neuroimmuno- logists abreast of the most recent developments, and to assess new information more critically. Angela Vincent and Gianvito Martino should be congratulated on master-min- ding this timely and practical text. July 2001 J. Newsom-Davis Professor Emeritus University of Oxford Table of Contents Introduction -Approaches to Understanding Immune-Mediated Neurological Disorders: Measuring and Evaluating Autoantibodies to Neuronal Antigens G. MARTINO, A. VINCENT ..**.*...*...*..**...*.**..*...**.**...

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".

This book reviews the main neurobiological, neurophysiological, MRI and clinical features of the early phases of MS. Mechanisms of irreversible axonal damage and the role played by the interaction between glial and axons are highlighted. Contrary to what was thought for a long time the sufficient availability of oligodendrocyte precursor cells to promote remyelination in acute lesions has now been demonstrated. For not understood reasons, remyelination process fails or does not start in many cases, particularly, in the chronic process of the disease. These findings express the importance of the milieu changes induced by inflammatory process in limiting remyelination. Pathological studies demonstrate that in MS destructive processes may be followed by recovering phases in such a way that myelin may be morphologically and functionally reconstructed. This all brings the rationale of early treatments and the results of clinical trials in early MS to the fore as one of the most important questions today.

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.

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.

Immune-mediated neurological disorders present an increasing challenge to neu- rologists. Recent advances have identified new antibodies, new effector mechanisms and new diagnostic tests; these have greatly enhanced our understanding of disease aetiology and opened up therapeutic opportunities, but a critical understanding of this fast -developing field is not easy to find. This volume was conceived following a very successful course on neuroimmu- no logy in Bergamo in 2000, and was written mainly by clinicians who are active in the laboratory. It will help to keep practising neurologists and neuroimmuno- logists abreast of the most recent developments, and to assess new information more critically. Angela Vincent and Gianvito Martino should be congratulated on master-min- ding this timely and practical text. July 2001 J. Newsom-Davis Professor Emeritus University of Oxford Table of Contents Introduction -Approaches to Understanding Immune-Mediated Neurological Disorders: Measuring and Evaluating Autoantibodies to Neuronal Antigens G. MARTINO, A. VINCENT ..**.*...*...*..**...*.**..*...**.**...

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".

There is now evidence that irreversible brain damage accumulates very early in the course of multiple sclerosis. This book reviews the main neurobiological, magnetic resonance imaging, and clinical aspects of the early phases of the dis­ ease. Mechanisms ofirreversible axonal damage and the role played by the inter­ action of glia and the axon are highlighted. In contrast to what was believed for a long time, the sufficient availability of oligodendrocyte precursor cells to promote remyelination in acute lesions has now been demonstrated. For reasons not understood, this remyelination process fails or does not start, particularly in the chronic stages ofthe disease. These findings emphasize the importance of the "milieu" changes induced by an inflammatory process in limiting remyelination. However, first indications are that part of this inflammatory process may have a neuroprotective effect. Pathological studies in multiple sclerosis have now clearly demonstrated that destructive processes may be followed by recovery phases in such a way that myelin may be morphologically and functionally reconstituted. These findings provide the rationale for early treatment and emphasize the importance of clinical trials in early multiple sclerosis. Early treatment is one of the most important aspects in multiple sclerosis today.

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.

Morphological, physiological and pathological evidence demonstrates that ner- vous and immune systems interact not only in maintaining brain homeostasis, but also in causing neurological diseases. The studyofthese interactions repre- sents the basis on which neuroimmunologyhas grown during the years. At pre- sent, several neurological diseases are recognized to be caused by a derange- ment of the immune system in either its regulatory or effector functions. The main scope ofthis book, to discuss how an unbalanced immune system maylead to immune-mediated neurological diseases, is achieved in three parts. The first part provides an overview on how the immune system works. This is propaedeutical to understanding interactions between the immune and ner- vous systems, which are discussed in the second part. The third part of the book focuses on one particular area of neuroimmunology, the immune disor- ders leading to the damage of central and peripheral myelin.Given the opportunity to review first the immune system in itself and then how it operates during immune-mediated demyelinating disorders, we have tried to provide the reader with a basis for clearly understanding how interac- tions between the immune and nervous systems can be protective or pathoge- nic. This knowledge is a prerequisite for a rationale immune intervention tar- geting these disorders.

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 the past few years there have been impressive advances in the implementation of modern MRI techniques for the assessment of MS patients with the ultimate goal to define MRI markers of MS evolution. The authors of this volume not only review these new techniques, such as magnetization transfer (MT) MRI, diffusion-weighted (DW) MRI and proton MR spectroscopy (MRS), that are increasingly being used to monitor MS evolution, but also those, such as functional MRI (fMRI), cell-specific MRI, perfusion MRI, and microscopic imaging with ultra-high field MRI, that are emerging as additional promising tools for improving our understanding of MS pathophysiology. Strengths and weaknesses of all these modern quantitative MRI techniques for the study of MS are extensively covered in this book. The book also provides a valuable summary of the state of the art.

The therapeutic era for MS has begun, and many new, potentially effective treatments are now available. MRI offers a range of techniques which are more reliable and sensitive than any other available approach in detecting brain and spinal cord abnormalities, monitoring their evolution, and providing in vivo information about heterogenous pathological substrates of the MS lesions. Readers will find this volume a valuable summary of the state-of- the art, as well as a useful reference text from which to plan future clinical trials in MS.

Morphological, physiological and pathological evidence demonstrates that ner- vous and immune systems interact not only in maintaining brain homeostasis, but also in causing neurological diseases. The studyofthese interactions repre- sents the basis on which neuroimmunologyhas grown during the years. At pre- sent, several neurological diseases are recognized to be caused by a derange- ment of the immune system in either its regulatory or effector functions. The main scope ofthis book, to discuss how an unbalanced immune system maylead to immune-mediated neurological diseases, is achieved in three parts. The first part provides an overview on how the immune system works. This is propaedeutical to understanding interactions between the immune and ner- vous systems, which are discussed in the second part. The third part of the book focuses on one particular area of neuroimmunology, the immune disor- ders leading to the damage of central and peripheral myelin.Given the opportunity to review first the immune system in itself and then how it operates during immune-mediated demyelinating disorders, we have tried to provide the reader with a basis for clearly understanding how interac- tions between the immune and nervous systems can be protective or pathoge- nic. This knowledge is a prerequisite for a rationale immune intervention tar- geting these disorders.

Immune-mediated neurological disorders present an increasing challenge to neu- rologists. Recent advances have identified new antibodies, new effector mechanisms and new diagnostic tests; these have greatly enhanced our understanding of disease aetiology and opened up therapeutic opportunities, but a critical understanding of this fast -developing field is not easy to find. This volume was conceived following a very successful course on neuroimmu- no logy in Bergamo in 2000, and was written mainly by clinicians who are active in the laboratory. It will help to keep practising neurologists and neuroimmuno- logists abreast of the most recent developments, and to assess new information more critically. Angela Vincent and Gianvito Martino should be congratulated on master-min- ding this timely and practical text. July 2001 J. Newsom-Davis Professor Emeritus University of Oxford Table of Contents Introduction -Approaches to Understanding Immune-Mediated Neurological Disorders: Measuring and Evaluating Autoantibodies to Neuronal Antigens G. MARTINO, A. VINCENT ..**.*...*...*..**...*.**..*...**.**...

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".

This book reviews the main neurobiological, neurophysiological, MRI and clinical features of the early phases of MS. Mechanisms of irreversible axonal damage and the role played by the interaction between glial and axons are highlighted. Contrary to what was thought for a long time the sufficient availability of oligodendrocyte precursor cells to promote remyelination in acute lesions has now been demonstrated. For not understood reasons, remyelination process fails or does not start in many cases, particularly, in the chronic process of the disease. These findings express the importance of the milieu changes induced by inflammatory process in limiting remyelination. Pathological studies demonstrate that in MS destructive processes may be followed by recovering phases in such a way that myelin may be morphologically and functionally reconstructed. This all brings the rationale of early treatments and the results of clinical trials in early MS to the fore as one of the most important questions today.

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.

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.

Immune-mediated neurological disorders present an increasing challenge to neu- rologists. Recent advances have identified new antibodies, new effector mechanisms and new diagnostic tests; these have greatly enhanced our understanding of disease aetiology and opened up therapeutic opportunities, but a critical understanding of this fast -developing field is not easy to find. This volume was conceived following a very successful course on neuroimmu- no logy in Bergamo in 2000, and was written mainly by clinicians who are active in the laboratory. It will help to keep practising neurologists and neuroimmuno- logists abreast of the most recent developments, and to assess new information more critically. Angela Vincent and Gianvito Martino should be congratulated on master-min- ding this timely and practical text. July 2001 J. Newsom-Davis Professor Emeritus University of Oxford Table of Contents Introduction -Approaches to Understanding Immune-Mediated Neurological Disorders: Measuring and Evaluating Autoantibodies to Neuronal Antigens G. MARTINO, A. VINCENT ..**.*...*...*..**...*.**..*...**.**...

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".

There is now evidence that irreversible brain damage accumulates very early in the course of multiple sclerosis. This book reviews the main neurobiological, magnetic resonance imaging, and clinical aspects of the early phases of the dis­ ease. Mechanisms ofirreversible axonal damage and the role played by the inter­ action of glia and the axon are highlighted. In contrast to what was believed for a long time, the sufficient availability of oligodendrocyte precursor cells to promote remyelination in acute lesions has now been demonstrated. For reasons not understood, this remyelination process fails or does not start, particularly in the chronic stages ofthe disease. These findings emphasize the importance of the "milieu" changes induced by an inflammatory process in limiting remyelination. However, first indications are that part of this inflammatory process may have a neuroprotective effect. Pathological studies in multiple sclerosis have now clearly demonstrated that destructive processes may be followed by recovery phases in such a way that myelin may be morphologically and functionally reconstituted. These findings provide the rationale for early treatment and emphasize the importance of clinical trials in early multiple sclerosis. Early treatment is one of the most important aspects in multiple sclerosis today.

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.

Morphological, physiological and pathological evidence demonstrates that ner- vous and immune systems interact not only in maintaining brain homeostasis, but also in causing neurological diseases. The studyofthese interactions repre- sents the basis on which neuroimmunologyhas grown during the years. At pre- sent, several neurological diseases are recognized to be caused by a derange- ment of the immune system in either its regulatory or effector functions. The main scope ofthis book, to discuss how an unbalanced immune system maylead to immune-mediated neurological diseases, is achieved in three parts. The first part provides an overview on how the immune system works. This is propaedeutical to understanding interactions between the immune and ner- vous systems, which are discussed in the second part. The third part of the book focuses on one particular area of neuroimmunology, the immune disor- ders leading to the damage of central and peripheral myelin.Given the opportunity to review first the immune system in itself and then how it operates during immune-mediated demyelinating disorders, we have tried to provide the reader with a basis for clearly understanding how interac- tions between the immune and nervous systems can be protective or pathoge- nic. This knowledge is a prerequisite for a rationale immune intervention tar- geting these disorders.

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 the past few years there have been impressive advances in the implementation of modern MRI techniques for the assessment of MS patients with the ultimate goal to define MRI markers of MS evolution. The authors of this volume not only review these new techniques, such as magnetization transfer (MT) MRI, diffusion-weighted (DW) MRI and proton MR spectroscopy (MRS), that are increasingly being used to monitor MS evolution, but also those, such as functional MRI (fMRI), cell-specific MRI, perfusion MRI, and microscopic imaging with ultra-high field MRI, that are emerging as additional promising tools for improving our understanding of MS pathophysiology. Strengths and weaknesses of all these modern quantitative MRI techniques for the study of MS are extensively covered in this book. The book also provides a valuable summary of the state of the art.