Randomised, double blind, placebo controlled study of interferon beta-1a in relapsing-remitting multiple sclerosis analysed by area under disability/time curves.
OBJECTIVES: The commonly employed outcome measures on disability and relapse rates in treatment trials of relapsing-remitting multiple sclerosis have well demonstrated sensitivity to treatment effects, but their clinical interpretation is problematic. An alternative method of analysis, which is more clinically meaningful and statistically appropriate to a condition with a fluctuating disease course, uses the summary measure statistic "area under the disability/time curve (AUC)", to estimate each patient's total in trial morbidity experience. METHODS: The AUC technique was applied in an intention to treat analysis of serial disability data derived from the expanded disability status scale (EDSS), the Scripps neurologic rating scale (SNRS), and the ambulation index (AI), collected during a double blind, randomised, placebo controlled, phase III trial of subcutaneous interferon beta-1a (INFbeta-1a) in relapsing-remitting multiple sclerosis (PRISMS Study). The results were compared with the often quoted "conventional" end point of mean change in rating scores from baseline to trial completion. Analyses were also carried out on subgroups with entry EDSS stratified above and below 3.5. RESULTS: EDSS data analysed by AUC normalised to baseline scores disclosed that both doses of IFNbeta-1a (22 or 44 microg) were superior to placebo (p= 0.008 and 0.013, respectively). In addition, the high dose (44 microg) was more beneficial than placebo using SNRS (p= 0.038) and AI data (p= 0.039). AUC analysis of SNRS scores also showed that for patients with baseline EDSS>3.5, the 44 microg (but not the 22 microg) dose was more advantageous than placebo (p=0.028). CONCLUSIONS: Summary measure analysis using the AUC of serial disability/time plots, confirms and extends the results of conventional end point analysis of disability from the PRISMS Study data. AUC evaluations show that high dose INFbeta-1a (44 microg three times weekly) was beneficial on all of the clinical rating scale scores used in this study. This method provides a statistically powerful and clinically meaningful assessment of treatment effects on in trial disability in patients with multiple sclerosis with fluctuating and highly heterogeneous disease courses. (+info)
Human herpesvirus 6 is latent in peripheral blood of patients with relapsing-remitting multiple sclerosis.
Studies of the association between HHV-6 and multiple sclerosis are hindered by the difficulty in discriminating between latent and active infection. A follow up study was undertaken of patients with multiple sclerosis, searching peripheral blood mononuclear cells for molecular markers associated with HHV-6 latency and lytic replication. The results show that HHV-6 is latent and did not support systemic infection in patients with multiple sclerosis. Likewise, patients with multiple sclerosis did not show any evidence of active infection with other human herpesviruses HHV-7 and HHV-8. (+info)
Investigation of apparent diffusion coefficient and diffusion tensor anisotrophy in acute and chronic multiple sclerosis lesions.
BACKGROUND AND PURPOSE: The various stages of multiple sclerosis (MS) are characterized by de- and remyelination as well as by inflammation. Diffusion MR imaging is sensitive to tissue water motion, which might correspond to these pathologic processes. Our purpose was to demonstrate differences in apparent diffusion coefficient (ADC) and diffusion tensor anisotropy in acute and chronic MS plaques and in normal-appearing brain. METHODS: Twelve MS patients underwent conventional and full-tensor diffusion MR imaging with B = 1221 s/mm2. Derivation of trace ADC and calculation of anisotropic scalars, including eccentricity, relative anisotropy (RA), and fractional anisotropy (FA) was performed on a per-pixel basis. Regions of interest of plaques and normal structures were determined on coregistered maps. MS lesions were classified as acute, subacute, or chronic on the basis of their appearance on conventional images and in relation to clinical findings. RESULTS: Seven patients had acute plaques with a concentric arrangement of alternating high and low signal intensity on diffusion-weighted images. In nine acute lesions, plaque centers had high ADC with reduced anisotropy compared with rim, normal-appearing white matter (NAWM), and chronic lesions. The thin rim of diffusion-weighted hyperintensity surrounding the center showed variable ADC and anisotropic values, which were not statistically different from NAWM. Subacute and chronic MS lesions had intermediate ADC elevations/anisotropic reductions. Calculated FA pixel maps were superior to eccentricity or RA maps; however, quality was limited by signal-to-noise constraints. CONCLUSION: ADC and diffusion anisotropic scalars reflect biophysical changes in the underlying pathology of the demyelinating process. (+info)
Effect of 1-year treatment with interferon-beta1b on thyroid function and autoimmunity in patients with multiple sclerosis.
OBJECTIVE: Interferon-beta (IFN-beta) is a widely used therapy for multiple sclerosis (MS), a demyelinating disease of the central nervous system. This study has evaluated the effect on thyroid function and autoimmunity of a 1-year treatment with IFN-beta1b in patients with MS. PATIENTS: We studied 31 patients (age 34+/-7 years, 21 women) with relapsing-remitting MS during IFN-beta1b treatment of 1 year duration. Systematic thyroid assessment and measurements of serum interleukin-6 (IL-6) levels were performed at baseline and every 3 months during treatment. RESULTS: Sixteen percent of the patients had autoimmune thyroiditis before IFN-beta1b, all positive for anti-peroxidase antibodies. The overall incidence of thyroid dysfunction was 33% over 1 year (10% hyperthyroidism, 23% hypothyroidism). Thyroid autoimmunity developed in 5/26 patients (19%), in one case without dysfunction. In addition to autoantibody positivity at baseline, female gender and the presence of an ultrasound thyroid pattern suggestive of thyroiditis were identified by multiple logistic regression as additional risk predictors for the development of thyroid dysfunction. During IFN-beta1b treatment, serum IL-6 levels rose in a consistent biphasic pattern; there was, however, no difference between patients with or without incident thyroid abnormalities. CONCLUSIONS: We conclude that IFN-beta1b therapy can induce multiple alterations in thyroid function, some of which are unrelated to thyroid autoimmunity. IL-6 measurement is not useful to identify patients prone to develop thyroid abnormalities. Though thyroid dysfunction is generally subclinical and often transient, systematic thyroid assessment should be performed during IFN-beta1b treatment. (+info)
MR imaging quantitation of gray matter involvement in multiple sclerosis and its correlation with disability measures and neurocognitive testing.
BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system and manifests both physical and neurocognitive disabilities. Although predominantly a disease of the white matter, MS is also characterized by lesions in the gray matter. Previous pathologic studies have found that cortical and deep gray matter lesions comprised 5% and 4%, respectively, of total lesions. Using software for lesion detection and quantitation, our study was designed to determine MS involvement in the cortical and deep gray matter and to correlate gray matter lesion load with neurocognitive function and the Kurtzke Expanded Disability Status Scale. METHODS: Using a semiautomated segmentation algorithm that detected and delineated all possible brain MS lesions on MR images, we investigated gray matter lesion volume in 18 patients with untreated relapsing-remitting MS. Cortical and deep gray matter lesions then were correlated with the neurocognitive and physical disability measurements. RESULTS: We found that cortical gray matter lesions comprised approximately 5.7% of the total lesion volume, whereas deep gray matter lesions comprised another 4.6% in this patient cohort. No strong correlations were found between gray matter lesions and disability status or neurocognitive function. CONCLUSION: These results are similar to those found in previous pathologic studies. The cortical lesion load in cases of relapsing-remitting MS, as measured by MR imaging, represents less than 6% of the total lesion volume and does not correlate with disability measures or neurocognitive tests. (+info)
Immunological profile of patients with primary progressive multiple sclerosis. Expression of adhesion molecules.
Adhesion molecules are important in the trafficking of peripheral leucocytes into the central nervous system, a major event in the pathogenesis of multiple sclerosis, which is an inflammatory and demyelinating disease. The latest MRI evidence supports clinical divergence between forms of multiple sclerosis with relapses and the primary progressive form without relapses, which shows fewer and smaller inflammatory lesions. With the aim of elucidating whether different pathogenic mechanisms are involved in primary progressive multiple sclerosis, we compared membrane expression of the adhesion molecules ICAM-1 (CD54), LFA-1alpha (CD11a), VLA-4 [alpha(4)/beta(1) integrin (CD49d/CD29)], L-selectin (CD62L) and ICAM-3 (CD50) in peripheral blood and the serum-soluble forms ICAM-1, L-selectin, VCAM-1 and ICAM-3 in 89 patients (39 with the primary progressive form, 25 with the secondary progressive form and 25 with the relapsing-remitting form) and 38 healthy controls. We found a significant decrease in leucocyte surface expression of most of the adhesion molecules tested and an increase in soluble ICAM-1 and L-selectin levels in secondary progressive and relapsing-remitting multiple sclerosis compared with primary progressive multiple sclerosis, which gave results similar to those in controls. These results, which are supported by MRI evidence, show that trafficking of autoreactive leucocytes through the blood-brain barrier is crucial to the pathogenesis of secondary progressive and relapsing-remitting forms of multiple sclerosis, whereas other mechanisms leading to progressive axonal damage would account for primary progressive forms of the disease. (+info)
Evolution of multiple sclerosis lesions on serial contrast-enhanced T1-weighted and magnetization-transfer MR images.
BACKGROUND AND PURPOSE: Magnetization-transfer imaging is a technique that could provide indirect evidence of the characteristics of multiple sclerosis (MS) lesions. The purpose of this work was to study the evolution of MS lesions on T1-weighted MR images over time and to investigate changes in magnetization-transfer ratio (MTR) values of MS lesions with different initial appearances on contrast-enhanced T1-weighted images. METHODS: Eleven patients with relapsing-remitting MS were studied with MR imaging. The MTRs were calculated for 47 lesions that had been classified according to their appearance on contrast-enhanced T1-weighted images. Each patient was examined at four time points over a 1-year period. The MTR changes observed in the selected lesions were compared with their initial T1-weighted appearance. RESULTS: The lowest MTR values were initially found in hypointense nonenhancing lesions and in ring-enhancing lesions, with both types showing a hypointense center. Changes in MTR values were more dynamic and reversible in ring-enhancing than in hypointense nonenhancing plaques. Nodular-enhancing lesions had slightly lower initial MTRs than did isointense non-enhancing lesions. CONCLUSION: The absence or presence of contrast uptake may indicate a different pathologic basis for hypointense MS lesions on T1-weighted MR images. These differences should be kept in mind when considering T1 lesion load as a surrogate marker of disability in MS. (+info)
Serial analysis of magnetization-transfer histograms and Expanded Disability Status Scale scores in patients with relapsing-remitting multiple sclerosis.
BACKGROUND AND PURPOSE: Magnetization transfer ratio histogram peak height (MTR-HPH) has been shown to correlate with macroscopic and microscopic brain disease in patients with multiple sclerosis (MS). We studied the changes in MTR-HPH and in Kurtzke's Expanded Disability Status Scale (EDSS) scores over time in a group of patients with relapsing-remitting MS. METHODS: Twenty adult patients with relapsing-remitting MS (four men and 16 women) were followed up for a period of 334 to 1313 days. In all, 86 MR imaging studies of the brain were obtained, and MTR-HPH was calculated for each MR examination by using a semiautomated technique. Changes in MTR-HPH were compared between patients over the study's duration. A neurologist specialized in the care of MS patients assessed the EDSS score for each patient as a measure of clinical disability. RESULTS: Serial MR data showed a subtle but significant decline in MTR-HPH with time. No significant changes in EDSS scores were noted over the same period. CONCLUSION: Patients with relapsing-remitting MS have a significant progressive decline in normalized MTR-HPH, which is independent of EDSS score. MTR-HPH measurements can be used to monitor subclinical disease in patients with relapsing-remitting MS over a short time frame of 1 to 4 years. This parameter might be applied in future therapeutic trials to assess its usefulness. (+info)