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Characterizing the Mechanisms of Progression in Multiple Sclerosis
Evidence and New Hypotheses for Future Directions
E. M. Frohman, MD, PhD;
M. Filippi, MD;
O. Stuve, MD, PhD;
S. G. Waxman, MD, PhD;
J. Corboy, MD;
J. T. Phillips, MD, PhD;
C. Lucchinetti, MD;
J. Wilken, PhD;
N. Karandikar, MD, PhD;
B. Hemmer, MD;
N. Monson, PhD;
J. De Keyser, MD;
H. Hartung, MD, PhD;
L. Steinman, MD;
J. R. Oksenberg, PhD;
B. A. C. Cree, MD, PhD;
S. Hauser, MD;
M. K. Racke, MD
Arch Neurol. 2005;62:1345-1356.
Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.
Author Affiliations: Departments of Neurology (Drs Frohman, Karandikar, Monson, and Racke), Ophthalmology (Dr Frohman), and Pathology (Dr Karandikar) and Center for Immunology (Dr Racke), University of Texas Southwestern Medical Center at Dallas; Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy (Dr Filippi); Department of Neurology, Heinrich Heine University, Dusseldorf, Germany (Drs Stuve, Hemmer, and Hartung); Department of Neurology, Yale University, New Haven, Conn (Dr Waxman); Department of Neurology, University of Colorado, Boulder (Dr Corboy); Texas Neurology, Dallas (Dr Phillips); Department of Neurology, Mayo Clinic, Rochester, Minn (Dr Lucchinetti); Division of Neuropsychology, Department of Veterans Affairs, Washington, DC (Dr Wilken); Department of Neurology, University of Groningen, Groningen, the Netherlands (Dr DeKeyser); Department of Neurology, Stanford University, Stanford, Calif (Dr Steinman); and Department of Neurology, University of California, San Francisco (Drs Oksenberg, Cree, Hauser, and Racke).
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