David H. Mattson

The measurement of ambulatory impairment in multiple sclerosis

The objective of this study was to examine the relationships between continuous measures of ambulatory impairment in MS patients and their ordinal counterparts. Much of the disability caused by MS is due to ambulatory impairment. The Expanded Disability Severity Scale (EDSS) and the Ambulation Index (AI) are ordinal measures of MS severity based largely on the maximal distance subjects can walk (Dmax) and the time to walk 8 m (T8), respectively. At EDSS levels 6.0 to 7.0 and AI levels 3 to 6, scores are defined more by the use of ambulatory aids, rather than by Dmax or T8. We determined Dmax (up to 500 m), T8, the EDSS score, and the AI in 237 ambulatory MS patients. The maximal distance subjects could walk and T8 were strongly related to their ordinal counterparts (Spearman r = 0.65 and 0.91, respectively), but the continuous measures showed considerable variability within EDSS and AI levels that the ordinal scales did not reflect. Most of the variability occurred at EDSS levels 6.0 to 7.0 and AI levels 3 to 6. Because the use of an aid did not clearly predict Dmax or T8, many patients in these ranges had better ambulatory function based on the continuous measures than those with less disability according to the ordinal scales. We found that Dmax and T8 provide more precise information about ambulatory impairment in MS than do the EDSS and AI, allowing better discrimination of differences between patients and potentially greater sensitivity to detect therapeutic effects in clinical trials.

Frequency and significance of antinuclear antibodies in multiple sclerosis

In a prospective sample of patients with multiple sclerosis (MS) we found a high frequency of antinuclear antibodies (ANA), 22.5%, confirming results from previous studies. ANA occurrence did not correlate with gender, age, duration of MS, MS course, or disability in either the prospective and retrospective samples of MS patients. In 16 patients with MS tested at two time points, ANA occurrence did correlate with MS disease activity. This suggests that the high frequency of ANA in MS reflects ongoing immune dysregulation.

Frequency of anti‐nuclear antibodies in multiple sclerosis

Article abstract—We found anti-nuclear antibodies (ANA) in 26.7% of 150 relapsing-remitting and in 30.4% of 23 chronic progressive definite multiple sclerosis (MS) patients bv retromective chart review. These Datients did not have systemic hpus emhemato&. Since ANA are not pathogenically relevant in MS, they are false-positive, and likely reflect systemic immune dys-regulation in MS.

Analysis of a sequenced cDNA library from multiple sclerosis lesions

To identify genes that are expressed in MS pathogenesis, we have analyzed a normalized cDNA library made from mRNA obtained from CNS lesions of a patient with primary progressive MS. Complementary DNA clones obtained from this library were subjected to automated DNA sequencing to generate expressed sequence tags. Analysis of this MS cDNA library revealed the presence of 54 cDNAs that were associated with immune activation and indicated the presence of an ongoing inflammatory response with evidence of both cell-mediated and humoral immune responses. The surprising finding was that 16 of the cDNAs encoded autoantigens associated with seven other autoimmune disorders, while only three of these 16 autoantigen cDNAs were present in a similarly constructed adult brain library. Such aberrant autoantigen expression could provide a source of secondary autoimmune stimulation that could contribute to the ongoing inflammatory response in MS. In addition, two cDNAs were found that mapped to a known MS susceptibility locus (5p14-p12): one encoded an excitatory amino acid transporter and the other a human homologue of the Drosophila disabled gene. This approach to the molecular biology of MS pathogenesis may help to illuminate previously unappreciated aspects of this disease.

Association of human herpesvirus 6 with the demyelinative lesions of progressive multifocal leukoencephalopathy

Progressive Multifocal Leukoencephalopathy (PML) is a primary demyelinating disease of the central nervous system occurring almost exclusively in individuals with impaired cell-mediated immunity. The JC polyoma virus has been accepted as the etiologic agent ofPML. Using a two-step in-situ polymerase chain reaction procedure to amplify and detect genomic DNA of human herpesvirus-6 (HHV6) in formalin-fixed paraffin-embedded archival brain tissues, a high frequency of infected cells was consistently detected in PML white matter both within and surrounding demyelinative lesions and HHV6 genome was found mainly within oligodendrocytes. Lesser amounts of HHV6 genome were detected in most normal, AIDS, and other neurological disease control tissues. Immunocytochemistry for HHV6 antigens showed actively infected nuclei of swollen oligodendrocytic morphology only within the demyelinative lesions of PML but not in adjacent uninvolved tissue. In addition, no HHV6 antigens were detectable in control tissues including brains of individuals with HIV-1 encephalopathy but without PML. Double immunohistochemical staining for JC virus large T antigen and HHV6 antigens demonstrated co-labeling of many swollen intralesional oligodendrocytes in the PML cases. The evidence suggests that HHV6 activation in conjunction with JC virus infection is associated with the demyelinative lesions of PML.

The Cost-Effectiveness of Magnetic Resonance Imaging for Patients with Equivocal Neurological Symptoms

OBJECTIVE To determine the incremental cost-effectiveness of magnetic resonance imaging (MRI) and computed tomography (CT) in young adults presenting with equivocal neurological signs and symptoms. DESIGNS AND METHODS A decision analysis of long-term survival using accuracy data from a diagnostic technology assessment of MRI and CT in patients with suspected multiple sclerosis, information from the medical literature, and clinical assumptions. MAIN RESULTS In the baseline analysis, at 30% likelihood of an underlying neurologic disease, MRI use has an incremental cost of

DNA sequences of the genes that encode the CTL-defined HLA-A2 variants M7 and DK1

101,670 for each additional quality-adjusted life-year saved compared with

Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

20,290 for CT use. As the probability of disease increases, further MRI use becomes a cost-effective alternative costing

Perils and pitfalls of magnetic resonance imaging in the diagnosis of multiple sclerosis

30,000 for each quality-adjusted life-year saved. If a negative MRI result provides reassurance, the incremental costs of immediate MRI use decreases and falls below

Association of human herpesvirus 6 (HHV6) with demyelinating lesions

25,000 for each quality-adjusted life-year saved no matter the likelihood of disease. CONCLUSIONS For most individuals with neurological symptoms or signs, CT imaging is cost-effective while MR imaging is not. The cost-effectiveness of MRI use, however, improves as the likelihood of an underlying neurological disease increases. For selected patients who highly value diagnostic information, MRI is a reasonable and cost-effective use of medical resources when even the likelihood of disease is quite low (5%).