Article abstract-Background: Episodic inflammation in the CNS during the early stages of MS results in progressive disability years later, presumably due to myelin and axonal injury. MRI demonstrates ongoing disease activity during the early disease stage, even in some patients who are stable clinically. The optimal MRI measure for the destructive pathologic process is uncertain, however. Methods: In this post-hoc study, MRI scans were analyzed from patients with relapsing MS participating in a placebo-controlled trial of interferon ␤-1a. The brain parenchymal fraction, defined as the ratio of brain parenchymal volume to the total volume within the brain surface contour, was used to measure whole brain atrophy. The relationship between disease features and brain atrophy and effect of interferon ␤-1a were determined. Results: MS patients had significant brain atrophy that worsened during each of 2 years of observation. In many patients, brain atrophy worsened without clinical disease activity. Baseline clinical and MRI abnormalities were not strongly related to the rate of brain atrophy during the subsequent 2 years. Treatment with interferon ␤-1a resulted in a reduction in brain atrophy progression during the second year of the clinical trial. Conclusions: Patients with relapsing-remitting MS have measurable amounts of whole brain atrophy that worsens yearly, in most cases without clinical manifestations. The brain parenchymal fraction is a marker for destructive pathologic processes ongoing in relapsing MS patients, and appears useful in demonstrating treatment effects in controlled clinical trials. Key words: MS-MRI-Brain atrophyInterferon beta. NEUROLOGY 1999;53:1698-1704 Individual MS patients face an unpredictable future during the relapsing-remitting stage of the disease, because severity is highly variable and accurate predictors of long-term outcome are lacking. Recurrent inflammation in optic nerves, brain, and spinal cord damages myelin and axons, leading to intermittent neurologic symptoms initially, and progressive disability later in the disease. Over 50% of patients with relapsing-remitting MS (RRMS) enter the secondary progressive disease stage, which is associated with more continuous physical, neuropsychologic, and socioeconomic decline. Clinical features during the early relapsing-remitting stage are not very accurate in predicting when an individual patient will enter the secondary progressive disease stage.The poor predictive value of clinical features during RRMS may relate to ongoing subclinical disease activity, evident on MRI. Serial MRI scans demonstrate that new lesions occur 5 to 10 times as often as clinical relapses.1-3 The predictive value of MRIbased disease markers has been studied for T2 hyperintense lesions. It was shown that the volume of T2 hyperintense lesions seen on cranial MRI scans at the time of first symptoms predicted subsequent clinical disease progression. 4 This supports the use of MRI as a surrogate marker in MS, but the optimal MRI measure is unknown.Recent studie...

No abstract

During the first 45 days after intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV), the levels of mRNAs encoding chemokines MCP-1/CCL2, RANTES/CCL5, and IP-10/CXCL10 in the central nervous system (CNS) are closely related to the sites of virus gene expression and tissue inflammation. In the present study, these chemokines were monitored during the latter 135 days of a 6-month course of TMEVinduced disease in susceptible (PLJ) or resistant (C57BL/6) mice that possessed or lacked either CD4 ؉ or CD8 ؉ T cells. These data were additionally correlated to mouse genotype, virus persistence in the CNS, antiviral antibody titers, mortality, and the severity of neurological disease. Surprisingly, the major determinant of chemokine expression was virus persistence: the factors of susceptible or resistant genotype, severity of neuropathology, and presence or absence of regulatory T cells exerted minimal effects. Our observations indicated that chemokine expression in the CNS in this chronic viral disorder was intrinsic to the CNS innate immune response to infection and was not governed by elements of the adaptive immune system.Theiler's murine encephalomyelitis virus (TMEV) infection of the central nervous system (CNS) causes poliomyelitis that is rapidly cleared in susceptible and resistant mouse strains but is succeeded by viral persistence and inflammatory demyelination in susceptible strains of mice (7,19,21,31,33). By thorough analysis of congenic strains, the determinants of susceptibility have been mapped to both major histocompatibility complex (MHC) and non-MHC genes (19). This genetic analysis has been extended by studying TMEV disease in genetargeted mice. Recent results revealed that both CD4 and CD8 cells were required to control infection (16). CD4 ϩ cells additionally provided protection against neurological deficits that result from inflammatory demyelination (16,28).Chemokines constitute a family of peptides that act through specific high-affinity receptors (3). In concert with adhesion molecules, they define both physiological and pathological leukocyte migration patterns (5). Expression of chemokines has been defined for early time points after TMEV infection but not in chronic disease (15). Further, the regulation of TMEVinduced chemokine expression in CD4-and CD8-deficient mice has not been addressed. We used real-time reverse transcriptase PCR (RT-PCR) to evaluate CNS chemokine expression in susceptible and resistant mice, with or without deletion of CD4 or CD8 genes, across a 6-month time course of disease. These data were correlated with viral persistence, clinical deficits, mortality, and serum-neutralizing antiviral antibodies.These analyses allowed us to determine how quantitative or qualitative CNS chemokine expression was determined by the presence or absence of CD4 ϩ or CD8 ϩ T cells by susceptible or resistant genotype or by persistent viral replication. We found that quantitative and qualitative aspects of CNS chemokine expression in TMEV-infected mice were not consi...