Evolving concepts in the pathogenesis of multiple sclerosis and their therapeutic implications.

Recent evidence suggests that multiple sclerosis (MS) is a continuously active neuropathologic process, even during the subclinical relapsing/remitting phase of the disease. Patients commonly feel well and function without disability for many years, experiencing only occasional relapses and nondisabling symptoms. In time, many evolve into a pattern of continuously progressive neurologic disability termed secondary progressive MS (SP-MS). SP-MS is hypothesized to occur once disease severity has exceeded a threshold. Above that threshold, compensatory mechanisms are inadequate to maintain normal function, and further disease progression is accompanied by progressively worsening disability. Inflammation dominates the early stage of disease. Progressive axonal pathology may underlie clinical disease progression in later stages. These concepts have important implications related to the diagnosis, methods for patient follow-up, type and timing of disease therapy, and the testing of neuroprotective drugs in MS.

[1]  J. Simon Contrast‐enhanced MR imaging in the evaluation of treatment response and prediction of outcome in multiple sclerosis , 1997, Journal of magnetic resonance imaging : JMRI.

[2]  H Okazaki,et al.  Multiple sclerosis: histopathologic and MR and/or CT correlation in 37 cases at biopsy and three cases at autopsy. , 1991, Radiology.

[3]  V. Tuohy,et al.  A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease , 1996, The Journal of experimental medicine.

[4]  R. Rudick,et al.  Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS , 1999, Neurology.

[5]  F. Barkhof,et al.  Axonal loss in multiple sclerosis lesions: Magnetic resonance imaging insights into substrates of disability , 1999, Annals of neurology.

[6]  D. Arnold Magnetic resonance spectroscopy: imaging axonal damage in MS , 1999, Journal of Neuroimmunology.

[7]  M Filippi,et al.  Magnetization transfer changes in the normal appering white matter precede the appearance of enhancing lesions in patients with multiple sclerosis , 1998, Annals of neurology.

[8]  J S Wolinsky,et al.  Serial proton magnetic resonance spectroscopic imaging, contrast‐enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis , 1998, Annals of neurology.

[9]  K. Nave,et al.  Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. , 1998, Science.

[10]  Jeanelle Sheeder,et al.  Magnetic resonance studies of intramuscular interferon β–1a for relapsing multiple sclerosis , 1998 .

[11]  R. Kinkel,et al.  Diversity and plasticity of self recognition during the development of multiple sclerosis. , 1997, The Journal of clinical investigation.

[12]  Y. L. Lee,et al.  Macrophage inflammatory protein 1‐α mRNA expression in an immortalized microglial cell line and cortical astrocyte cultures , 1995, Journal of neuroscience research.

[13]  J H Simon,et al.  Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. , 2000, The New England journal of medicine.

[14]  R. Rudick,et al.  Axonal transection in the lesions of multiple sclerosis. , 1998, The New England journal of medicine.

[15]  C. Granger,et al.  Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis 1 Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827); the NINDS (NS26321); and Biogen Inc. 1 , 1999, Journal of Neuroimmunology.

[16]  G. Fein,et al.  Biochemical alterations in multiple sclerosis lesions and normal‐appearing white matter detected by in vivo 31P and 1H spectroscopic imaging , 1994, Annals of neurology.

[17]  P M Matthews,et al.  Assessment of lesion pathology in multiple sclerosis using quantitative MRI morphometry and magnetic resonance spectroscopy. , 1996, Brain : a journal of neurology.

[18]  Jia Newcombe,et al.  High Resolution Proton NMR Spectroscopy of Multiple Sclerosis Lesions , 1995, Journal of neurochemistry.

[19]  Jullie W Pan,et al.  Evaluation of multiple sclerosis by 1H spectroscopic imaging at 4.1 T , 1996, Magnetic resonance in medicine.

[20]  P. Matthews,et al.  Imaging of axonal damage in multiple sclerosis: Spatial distribution of magnetic resonance imaging lesions , 1997, Annals of neurology.

[21]  R. Rudick,et al.  Neurodegeneration in Multiple Sclerosis: Relationship to Neurological Disability , 1999 .

[22]  M W Weiner,et al.  1H MRSI of normal appearing white matter in multiple sclerosis , 1997, Multiple sclerosis.

[23]  E. Cabanis,et al.  In vivo localized NMR proton spectroscopy of normal appearing white matter in patients with multiple sclerosis. , 1996, Journal of neuroradiology. Journal de neuroradiologie.

[24]  P. Dupont,et al.  Positron emission tomography, magnetic resonance imaging and proton NMR spectroscopy of white matter in multiple sclerosis , 1997, Multiple sclerosis.

[25]  P. Matthews,et al.  Use of proton magnetic resonance spectroscopy for monitoring disease progression in multiple sclerosis , 1994, Annals of neurology.

[26]  V. Perry,et al.  Axonal damage in acute multiple sclerosis lesions. , 1997, Brain : a journal of neurology.

[27]  Roland Martin,et al.  Using gadolinium‐enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis , 1992, Annals of neurology.

[28]  Virginia M. Y. Lee,et al.  Myelin-Associated Glycoprotein Is a Myelin Signal that Modulates the Caliber of Myelinated Axons , 1998, The Journal of Neuroscience.

[29]  Ludwig Kappos,et al.  Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis , 1999, The Lancet.

[30]  H. Bruhn,et al.  Multiple sclerosis in children: Cerebral metabolic alterations monitored by localized proton magnetic resonance spectroscopy in vivo , 1992, Annals of neurology.

[31]  P M Matthews,et al.  Axonal dysfunction and disability in a relapse of multiple sclerosis: Longitudinal study of a patient , 1997, Neurology.

[32]  M W Weiner,et al.  A serial study of new MS lesions and the white matter from which they arise , 1998, Neurology.

[33]  R. Herndon,et al.  A longitudinal study of brain atrophy in relapsing multiple sclerosis , 1999, Neurology.

[34]  J H Simon,et al.  A longitudinal study of T1 hypointense lesions in relapsing MS , 2000, Neurology.

[35]  J A Frank,et al.  MRI studies of multiple sclerosis: Implications for the natural history of the disease and for monitoring effectiveness of experimental therapies , 1996, Multiple sclerosis.

[36]  B. Bergamasco,et al.  Interferon alpha-2a treatment of relapsing-remitting multiple sclerosis , 1996, Neurology.