Karl Wende

A longitudinal study of brain atrophy in relapsing multiple sclerosis

Objective: To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of interferon β-1a (Avonex). Methods: All subjects had mild to moderate disability, with baseline expanded disability status scores ranging from 1.0 to 3.5, and at least two relapses in the 3 years before study entry. Atrophy measures included third and lateral ventricle width, brain width, and corpus callosum area. Results: Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years. Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years. Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width. Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement. Conclusion: In patients with relapsing MS and only mild to moderate disability, significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions. Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.

Neuropsychological effects of interferon β-1a in relapsing multiple sclerosis

Cognitive dysfunction is common in multiple sclerosis (MS), yet few studies have examined effects of treatment on neuropsychological (NP) performance. To evaluate the effects of interferon β‐1a (IFNβ‐1a, 30 μg administered intramuscularly once weekly [Avonex]) on cognitive function, a Comprehensive NP Battery was administered at baseline and week 104 to relapsing MS patients in the phase III study, 166 of whom completed both assessments. A Brief NP Battery was also administered at 6‐month intervals. The primary NP outcome measure was 2‐year change on the Comprehensive NP Battery, grouped into domains of information processing and learning/memory (set A), visuospatial abilities and problem solving (set B), and verbal abilities and attention span (set C). NP effects were most pronounced in cognitive domains vulnerable to MS: IFNβ‐1a had a significant beneficial effect on the set A composite, with a favorable trend evident on set B. Secondary outcome analyses revealed significant between‐group differences in slopes for Brief NP Battery performance and time to sustained deterioration in a Paced Auditory Serial Addition Test processing rate, favoring the IFNβ‐1a group. These results support and extend previous observations of significant beneficial effects of IFNβ‐1a for relapsing MS. Ann Neurol 2000;48:885–892

Inter‐ and intrarater scoring agreement using grades 1.0 to 3.5 of the Kurtzke Expanded Disability Status Scale (EDSS)

We determined inter- and intrarater Kurtzke Expanded Disability Status Scale (EDSS) scoring agreement for four trained examining physicians who evaluated 10 clinically stable multiple sclerosis patients. These patients had previously been determined to have EDSS scores of 1.0 to 3.5 and were scheduled to participate in a funded clinical trial of intramuscular recombinant interferon-beta. Intrarater reliability was greater than interrater reliability for scoring the EDSS and all of its component functional systems scores (FSS). Specifically, individual examiners were able to reproduce three serial examination scores on the same patient on the same day (intrarater agreement) within 1.0 EDSS or 2.0 individual FSS points. Reproducible scoring across examiners (interrater agreement), however, could only be accomplished within 1.5 EDSS or 3.0 individual FSS points. Additionally, the interrater scoring variability in our patients is greater than that previously reported for patients with higher EDSS scores. We conclude that clinical trials that employ the EDSS as an outcome measure of treatment efficacy should include inter- and intrarater agreement data for all examining physicians. Most importantly, studies using a single examining physician to evaluate individual patients throughout the course of a clinical trial will require less change in the EDSS to reliably measure disease activity than will studies using more than one examining physician to evaluate individual patients throughout the trial.

A longitudinal study of T1 hypointense lesions in relapsing MS MSCRG trial of interferon β-1a

Background: T1 hypointense lesions (T1 black holes) are focal areas of relatively severe CNS tissue damage detected by MRI in patients with MS. Objective: To determine the natural history of T1 hypointense lesions in relapsing MS and the utility of T1 hypointense lesions as outcome measures in MS clinical trials. Methods: MR studies were from the Multiple Sclerosis Collaborative Research Group trial. Longitudinal results are reported in 80 placebo- and 80 interferon β-1a (IFNβ-1a)–treated patients with mild to moderate disability relapsing-remitting MS. Results: There was a small but significant correlation between T1 hypointense lesion volume and disability at baseline and on trial (r = 0.22, r = 0.28). In placebo patients there was a 29.2% increase in the mean volume of T1 hypointense lesions (median 124.5 mm3) over 2 years (p < 0.001 for change from baseline), as compared to an 11.8% increase (median 40 mm3) in the IFNβ-1a–treated patients (change from baseline not significant). These treatment group comparisons did not quite reach significance. The most significant contributor to change in T1 hypointense lesions was the baseline number of enhancing lesions (model r2 = 0.554). Placebo patients with more active disease, defined by enhancing lesions at baseline, were the only group to show a significant increase in T1 hypointense lesion volume from baseline. Conclusion: The development of T1 hypointense lesions is strongly influenced by prior inflammatory disease activity, as indicated by enhancing lesions. These results suggest that treatment with once weekly IM IFNβ-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.

A profile of multiple sclerosis: The New York State Multiple Sclerosis Consortium

We have obtained a current profile of multiple sclerosis (MS) in New York State through a centralized patient registry and standardized data collection instrument associated with the New York State Multiple Sclerosis Consortium of 12 MS centers located throughout the state. Data from the first 3019 patients with clinically definite MS revealed a clear relationship between MS disease type, duration of disease, and severity of physical disability. Patients with relapsing disease had disease durations approximately half as long as those with progressive forms of the disease (means approximately 6 years versus 11 years). The majority of patients with relapsing disease had Expanded Disability Status Scale (EDSS) scores of 4.0 or less (self-sustained, fully ambulatory), whereas the majority of patients with progressive disease types had EDSS scores of 6.0 or greater (at least unilateral assist for walking). These findings emphasize the importance of early intervention in patients with relapsing disease to slow or prevent the accumulation of physical disability associated with progressive types of disease. Progressive disease was associated with lack of full-time employment and being disabled before the age of 60 years. Patients with relapsing disease were more likely to be employed and have private forms of insurance, whereas patients with progressive types of disease were more likely to have government-supported insurance to cover medical expenses.

Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis

Abstract Background and objective : This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNβ-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex®, Biogen). The clinical trial demonstrated that IFNβ-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNβ-1a therapy on these CSF abnormalities. Methods : CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. Results : (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNβ-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. Conclusions : The current study documents significant reductions in CSF WBC counts in patients treated with IFNβ-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.BACKGROUND AND OBJECTIVE This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNbeta-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex , Biogen). The clinical trial demonstrated that IFNbeta-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNbeta-1a therapy on these CSF abnormalities. METHODS CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. RESULTS (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNbeta-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. CONCLUSIONS The current study documents significant reductions in CSF WBC counts in patients treated with IFNbeta-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

Are quantitative functional measures more sensitive to worsening MS than traditional measures

Article abstract The authors used data collected prospectively during a multicenter trial in 133 patients with secondary progressive MS to assess the relative sensitivity of quantitative functional tests and traditional measures, including the Expanded Disability Status Scale (EDSS) and Ambulation Index. Quantitative functional measures worsened in 69% of patients during an average of 6 months of observation, whereas the Clinical Global Impression of Change worsened in 33% and the EDSS worsened in 25% of patients. These changes should be interpreted in the context of the test–retest reliability for each measure.

Comparing the ability of various compositive outcomes to discriminate treatment effects in MS clinical trials

We compared the ability of the Kurtzke Expanded Disability Status Scale (EDSS) and a composite outcome of non-physician-based measures of time to ambulate 25 feet (TA) and manual dexterity (the Box and Block Test [BBT], and 9-Hole Peg Test [9HPT]) to discriminate treatment effects in the Phase III study of interferon beta-1a. A log-rank comparison of Kaplan-Meier curves by treatment group showed the non-physicianbased composite of BBT, 9HPT, and TA was of comparable sensitivity (P=0.013) in discriminating sustained treatment failure as the EDSS alone (P=0.029). The composite of BBT, 9HPT, TA, and EDSS was more sensitive (P=0.009) in discriminating sustained treatment failure than the EDSS alone. Compositive outcomes of the EDSS and non-physician-based measures of manual dexterity and timed ambulation provide an appealing strategy to reduce the number of patients required to discriminate treatment effects in MS clinical trials.

Predictive immunophenotypes: Disease-related profile in chronic fatigue syndrome

There is a growing body of evidence supporting the theory that problems with immune function play an important role in chronic fatigue syndrome (CFS).