Neurol Clin 23 (2005) xiii–xvi

Preface

Multiple Sclerosis

This is the third issue of the Neurologic Clinics of North America tospecifically address multiple sclerosis (MS). Each previous issue hasappeared approximately a decade after its predecessor, and all have reflectedsubstantial interval change in understanding the disease. The last issueheralded the opening of the therapeutic potential for modifying the naturalhistory of disease as it coincided with the approval of interferon beta-1b forthe prevention of MS relapses and anticipated the positive reviews of thepivotal studies of interferon beta-1a and glatiramer acetate for the sameindication. This theme has been expanded greatly in this issue as we appear tobe on the brink of expanding the therapeutic armamentarium to a secondgeneration of therapeutics derived from a fundamental understanding of themolecules that are essential for central nervous system inflammation. Theseadvances have been rather exponential, providing substantial confidence thatby the time MS is revisited in the Neurologic Clinics of North America,control of the disease will be a reality, even if the etiology of the conditionremains nearly as elusive as it was in 1983. Starting with therapy would beputting the cart before the horse; therefore, this issue begins with the criticaladvances over the last decade that lay the foundation for current therapy andpromises for the future.

Two important consensus documents have appeared as a result ofmeetings held under the initiative of the National Multiple Sclerosis Society.The first addresses the usually mundane topic of nosology, attempting toderive a more universal meaning to the type of classifications used to describevarious forms of MS. Consequently, clinicians, investigators and perhapseven patients now use relapsing, secondary progressive, primary progressive,and progressive relapsing designations with better precision. However, it hasalso raised the issue of how one reliably recognizes the differences betweenprogression and the accumulation of disability in stepwise fashion related torelapses and that which occurs in the absence of clinically apparent attacks.The second revisits the diagnostic criteria for MS and revises them, in largepart, to reflect the importance of MRI in extending our ability to image thedisease process. The new diagnostic criteria and clinical classifications of MSare succinctly and ably addressed by Fred Lublin in his article ‘‘Clinical

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Features and Diagnosis of Multiple Sclerosis.’’ The conclusions of theLondon panel on diagnosis will be reviewed in spring 2005 for any necessaryrefinements; however, they already facilitate earlier and more securediagnosis when carefully applied. In the article ‘‘Natural History of MultipleSclerosis,’’ Orhun Kantarci and Brian Weinshenker provide the essentialswith which every clinician should be armed for the future course of MS toprovide informed answers to patients regarding prognosis and to helpbalance decisions on whether and when to initiate therapy. Although it isquite possible that the natural history of MS will change as we gainincreasingly effective management tools, it is also likely that novelbiomarkers (eg, the antibody that may differentiate neuromyelitis opticafrom other forms of relapsing MS) will refine our prognostic skills.

Overwhelmingly, MS is a disease of women in early life, with a shifttoward men later in life. It has long been suspected that understanding theseapparent differences in susceptibility might lead to better disease manage-ment. In ‘‘Gender Issues,’’ Patricia Coyle tackles this subject with aninformed review of the relevant basic and clinical literature. Many will findthis article particularly helpful in providing an essential primer on uniqueissues raised by MS for pregnancy. Completion of the successful initiative tounravel the sequence of the human genome at the turn of this centuryopened the door to the age of molecular medicine. The strong geneticpredisposition to MS and likely influences on presentation and course hasattracted the attention of many. Jorge Oksenberg and Stephen Hauser havelong been in the hunt and provide a detailed status report in ‘‘Genetics ofMultiple Sclerosis.’’ Because the majority of genetically influenced diseasesof man share the extraordinary complexity of MS, a successful approach toone will likely open the door to a more rapid solution of the complexgenetics of others.

With a disease that has been recognized for over 150 years, most mightnot expect that a fresh look at its neuropathology would add muchunderstanding or influence our approach to its therapy. Nevertheless, aninternational consortium of neurologists and pathologists have not onlytaken a new look, but have provided a novel if controversial reclassificationof the findings and acute lesions that suggest fundamental differences in thepathogenesis of the disease with potential profound clinical implications. In‘‘The Pathology of Multiple Sclerosis,’’ Claudia Lucchinetti, Joseph Parisi,and Wolfgang Bruck place their signal findings into the context of currentconcepts of the immunopathogenesis of MS with superb illustrations ofthese newly defined disease types. Pressing issues remain as to whether thesetypes are patient-specific or vary within patient overtime. No doubt thesewill be resolved in time. No matter what emerges, these observations havereinvigorated fresh approaches. Similarly, in their article ‘‘Neuropathobi-ology of Multiple Sclerosis,’’ John Peterson and Bruce Trapp review therediscovery of axonal injury in MS and its importance in potentiallyunderstanding the dynamics of the natural history of the disease. Moreover,

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the application of immunochemical techniques has allowed much betterrecognition of the intracortical pathology associated with the disease. Theirdemonstration of this aspect of the pathology should stimulate thoseinterested in imaging MS to find efficient ways of capturing these lesions invivo. These articles on the evolving pathology of MS are appropriatelyfollowed by a practical approach to modern neuroimaging in whichAnthony Traboulsee, Guojun Zhao, and David Li call on their extensiveexperience (‘‘Neuroimaging in Multiple Sclerosis’’).

Amit Bar-Or nicely sets the stage for understanding modern immuno-therapy in ‘‘Immunology of Multiple Sclerosis.’’ Increasingly, the lessonsderived from experimental allergic encephalomyelitis and other autoimmunemodels have pushed our perceptions of human immunology, particularly asapplied to MS. This article is conceptually rich and draws heavily fromhuman observations. This primer prepares clinicians for the articles onescalating immunotherapy that will follow. One should first stop to gather inthe experience of a seasoned clinician with extensive understanding inmanaging the symptoms of MS. Randy Schapiro provides a structuredapproach in ‘‘Managing Symptoms of Multiple Sclerosis,’’ appropriatelyadmonishing that one must not forget this important art. Ludwig Kapposand Aaron Miller contribute the balanced articles ‘‘Interferons in MultipleSclerosis’’ and ‘‘Glatiramer Acetate in the Treatment of Multiple Sclerosis,’’respectively. These first-generation immunomodulators are likely to remainactive cornerstones of treatment for some time and set the standard by whichnewer therapies will be gauged. In this context, Paul O’Connor, in his article‘‘Natalizumab and Other Monoclonal Antibodies,’’ presages what may bethe first of the second-generation therapies. Pivotal data on natalizumabis under active review by the US Food and Drug Administration, withapproval for general use for the indication relapse reduction in relapsingforms of MS anticipated as early as 2005. Further on the horizon arerepresentatives of at least six classes of mechanistically distinct, orally activemolecules that have already entered phase I to phase III clinical trials. Asdeveloped by Lucchinetti and colleagues and elsewhere, neuroprotection andrepair are increasingly emphasized as MS therapeutic goals. To be sure,control of pathogenetic aberrant immune responses can be considereda limited form of neuroprotection, but the concept is much broader.Hopefully, future issues devoted to MS will feature articles about neuro-protection and repair that are practical and not theoretical.

Unfortunately, the proportion of nonresponders to current-generationimmunomodulators remains unacceptable. Therefore, escalating treatmentto stabilize aggressive cases is frequently considered. In ‘‘Immunosuppres-sive Therapy for Multiple Sclerosis,’’ Susan Gauthier, Guy Buckle, andHoward Weiner carefully review the rationale and available approaches.Harold Atkins and Mark Freedman consider the ultimate extensionsof cytotoxic therapy in ‘‘Immunoablative Therapy as a Treatment for Ag-gressive Multiple Sclerosis.’’ Although many clinicians view bone marrow

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transplantation as far too dangerous for the treatment of MS, it is carefullyconceived trials that will determine its true limits.

Jerry S. Wolinsky, MDDepartment of Neurology

The University of Texas Health Sciences Center at Houston6431 Fannin Street

Houston, TX 77030, USA

E-mail address: jswolinsky@aol.com