Multiple Sclerosis Performance Test: validation of self-administered neuroperformance modules.

BACKGROUND AND PURPOSE: The purpose was to determine the test-retest reliability, practice effects, convergent validity and sensitivity to multiple sclerosis (MS) disability of neuroperformance subtests from the patient self-administered Multiple Sclerosis Performance Test (MSPT) designed to assess low contrast vision (Contrast Sensitivity Test, CST), upper extremity motor function (Manual Dexterity Test, MDT) and lower extremity motor function (Walking Speed Test, WST) and to introduce the concept of regression-based norms to aid clinical interpretation of performance scores using the MSPT cognition test (Processing Speed Test, PST) as an example. METHODS: Substudy 1 assessed test-retest reliability, practice effects and convergent validity of the CST, MDT and WST in 30 MS patients and 30 healthy controls. Substudy 2 examined sensitivity to MS disability in over 600 MS patients as part of their routine clinic assessment. Substudy 3 compared performance on the PST in research volunteers and clinical samples. RESULTS: The CST, MDT and WST were shown to be reliable, valid and sensitive to MS outcomes. Performance was comparable to technician-administered testing. PST performance was poorer in the clinical sample compared with the research volunteer sample. CONCLUSIONS: The self-administered MSPT neuroperformance modules produce reliable, objective metrics that can be used in clinical practice and support outcomes research. Published studies which require patient voluntary consent may underestimate the rate of cognitive dysfunction observed in a clinical setting.

Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing-remitting multiple sclerosis: A retrospective analysis.

BACKGROUND: Changes in gray matter (GM) volume may be a useful measure of tissue loss in multiple sclerosis (MS). OBJECTIVES: To investigate the rate, patterns, and disability correlates of GM volume change in an MS treatment clinical trial. METHODS: Patients (n=140) with relapsing-remitting MS were randomized to intramuscular (IM) interferon (IFN) beta-1a or placebo. Treatment effects on GM fraction (GMF) and white matter (WM) fraction (WMF) changes, differences in rates of GMF and WMF change in year one and two on treatment, and differences in atrophy rates by disease progression status were assessed retrospectively. RESULTS: Significantly less GM atrophy (during year two), but not WM atrophy (at any point), was observed with IM IFN beta-1a compared with placebo. Pseudoatrophy effects were more apparent in WM than in GM; in year one, greater WM volume loss was observed with IM IFN beta-1a than with placebo, whereas GM volume loss was similar between groups. Risk of sustained disability progression was significantly associated with GM, but not WM, atrophy. CONCLUSIONS: These results suggest that GMF change is more meaningful than WMF as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials.

Change in quality of life in patients with relapsing-remitting multiple sclerosis over 2 years in relation to other clinical parameters: results from a trial of intramuscular interferon {beta}-1a.

BACKGROUND: A randomized, placebo-controlled, multicenter study of weekly intramuscular injections of interferon beta-1a (IFNß-1a) in relapsing-remitting multiple sclerosis included the Sickness Impact Profile (SIP), a validated measure of patient-reported quality of life (QoL). OBJECTIVE: To demonstrate the impact of moderate to severe SIP disability at baseline and change in QoL as measured by SIP over 2 years in relation to other study parameters. METHODS: In 158 patients, SIP scores were determined at baseline and 2 years. Scores were correlated with disease progression and treatment. RESULTS: Patients who experienced disability progression, as defined by Expanded Disability Status Scale (EDSS) and annualized relapse rate, during the study demonstrated significant worsening in Physical SIP scores compared with patients who did not progress (p=0.031). In patients with low SIP scores, indicating moderate or severe disability at baseline, treatment with IFNß-1a significantly improved Physical SIP subscores. CONCLUSIONS: Patients with disability progression defined using EDSS, the physician-derived primary outcome measure, had Physical SIP scores indicating worsening disability, validating the physician-derived primary outcome measure using patient self-report. Treatment with IFNß-1a had beneficial effects on QoL in patients with worse SIP scores at baseline.

Gender effects on intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis: analysis of 1406 patients.

BACKGROUND: We aimed to evaluate effects of gender on efficacy and safety of intramuscular (IM) interferon beta (IFNß)-1a in patients with relapsing-remitting MS (RRMS) or clinically isolated syndromes (CIS) characteristic of early MS. METHODS: Pooled data from 1406 (1027 women; 379 men) patients enrolled in five clinical studies of IM IFNß-1a were analyzed. One analysis examined data for all patients treated with IM IFNß-1a from all studies. Separate analyses were conducted of pooled IM IFNß-1a-treated groups from all studies and pooled IFNß-1a-treated and placebo-treated patients from the placebo-controlled studies. Outcome measures included time to first relapse, annualized relapse rate, time to disability progression, number of gadolinium-enhanced lesions, adverse events, laboratory evaluations, and neutralizing antibodies. RESULTS: All efficacy assessments indicated similar treatment effects of IM IFNß-1a in men and women with no significant treatment-by-gender interactions. Women reported more headaches, urinary tract infections, and depression in the analysis; however, these were also common in women who received placebo. Men reported more frequent flu-like symptoms in the placebo-controlled studies only. There were no other differences in the safety profile of IM IFNß-1a between men and women. CONCLUSIONS: We conclude that no significant gender-related differences were found in the efficacy and safety of IM IFNß-1a in patients with RRMS or CIS.

Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study.

Disease-modifying drugs are initiated early and continued for years in patients with multiple sclerosis. Long-term tolerability and impact are not known. The objective of this study was to evaluate long-term tolerability of intramuscular interferon beta-1a and effects on disability and quality of life. Patients were evaluated an average of 15 years after randomization into a placebo-controlled, double-blind trial of intramuscular interferon beta-1a for relapsing multiple sclerosis. Patient-reported Expanded Disability Status Scale, the Short Form-36, a visual analog scale of self-care independence, and a living situation questionnaire were administered. Status was ascertained in 79% (136/172) of eligible patients. Analysis focused on 122 living patients. Despite open-label, non-standardized treatment after the 2-year clinical trial, 46% (n= 56) of the patients remained on intramuscular interferon beta-1a. Expanded Disability Status Scale scores were correlated highly with Short Form-36 subcategories and visual analog scale scores. Patients currently using intramuscular interferon beta-1a had a significantly lower mean Expanded Disability Status Scale score (p= 0.011), less progression to Expanded Disability Status Scale milestones, significantly better scores on the physical component of the Short Form-36 (p< 0.0001), and reported better general health and greater independence. We conclude that patients continuing to use intramuscular interferon beta-1a had less disability and better quality of life compared with patients not currently using intramuscular interferon beta-1a 15 years after randomization into a clinical trial.

Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks.

BACKGROUND AND OBJECTIVES: Brief cognitive tests to monitor cognitive impairment in patients with multiple sclerosis (MS) are needed. METHODS: Performance on monthly administrations of the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Questionnaire (MSNQ) was assessed in 660 patients with MS in 21 countries (109 sites) for 48 weeks in an open-label, safety-extension study of natalizumab. RESULTS: At baseline, the cohort's mean age was 40.1 years, 67.6% were female and the median Expanded Disability Status Scale score was 2.5. Test-retest correlations were high for both SDMT (range 0.89 for weeks 0-4 to 0.96 for weeks 44-48) and MSNQ (0.82 for weeks 0-4 to 0.93 for weeks 44-48). There were no statistically significant effects of geographic region. While SDMT scores improved by 15 points over 48 weeks (p < 0.0001), incremental monthly changes were small (effect size d < 0.3). Similar results were obtained on the MSNQ except that scores moved downward, suggesting fewer cognitive complaints over 48 weeks (p < 0.0001), but again the incremental monthly changes were small (d <-0.2). CONCLUSIONS: These results replicate earlier work in a smaller cohort treated with conventional disease-modifying therapy, and support the reliability of the SDMT and MSNQ as potential screening for monitoring tools for cognition over time.

Using an automated recruitment process to generate an unbiased study sample of multiple sclerosis patients.

The objective of this study was to test the efficiency of an automated recruitment methodology developed as a component of a practical controlled trial to assess the benefits of a Web-based personal health site to guide self-management of multiple sclerosis symptoms called Mellen Center Care On-line. We describe the study's automated recruitment methodology using clinical and administrative databases and assess the comparability between subjects who completed informed consent (IC) forms, and individuals who were invited to participate but did not reply, designated as patient nonresponders (PNR). The IC and PNR groups were compared on demographics, number of physician or advanced practice nurse/physician assistant visits during the 12 months prior to the initial invitation, and level of disability as measured by the Charlson Comorbidity Index (CCI). Out of a total dynamic potential pool of 2,421 patients, 2,041 had been invited to participate, 309 had become ineligible to participate during the study, and 71 individuals remained in the pool at the end of recruitment. The IC group had a slightly greater proportion of females. Both groups were predominantly white with comparable marital status. The groups had comparable mean household income, education level, and commercial insurance. The computed mean CCI was similar between the groups. The only significant difference was that the PNR group had fewer clinic visits in the preceding 12 months. The subjects were highly representative of the target population, indicating that there was little bias in our selection process despite a constantly changing pool of eligible individuals.

Integrity of blood-brain barrier to peroxidase in senescent mice.

The brain distribution of systemically-administered horseradish peroxidase was studied in senescent mice and compared with the distribution in a group of young mice. The distribution of HRP was surveyed in both the experimental and control groups by light and electron microscopy by an observer unaware of the source of the material. No qualitative differences were observed in the brain distribution of systemically-administered HRP in old mice compared to young mice. The results of this study suggest that the blood-brain barrier to HRP is preserved in senescent mice.

Disease-modifying drugs for relapsing-remitting multiple sclerosis and future directions for multiple sclerosis therapeutics.

With the development of effective therapies for multiple sclerosis (MS), therapeutic nihilism, which was so prevalent just 10 years ago, has given way to exuberance and optimism. The current mood is understandable because MS is such a devastating disease. Within 10 years of symptom onset, 50% of patients with MS are unable to carry out household and employment responsibilities; within 15 to 20 years, 50% are unable to walk unassisted; and within 25 years, 50% are unable to walk at all. The average annual cost of MS in the United States has been estimated at greater than $6.8 billion, or $34 103 per person. This review summarizes evidence that disease-modifying drugs can significantly improve the course of patients with relapsing-remitting MS (RRMS) and frames key issues relating to the use of current drugs. Major issues confronting experimental MS therapeutics are discussed.

Cytokine secretion by multiple sclerosis monocytes. Relationship to disease activity.

Autoantigen recognition by specific T cells may initiate a tissue-specific immune response in multiple sclerosis (MS), which is a chronic inflammatory demyelinating disorder. During subsequent nonspecific immune amplification, interleukin 1 beta and tumor necrosis factor alpha are released by cells of the monocyte/macrophage lineage, with the potential to influence profoundly immune regulation systemically or within the central nervous system. Regulation of monocyte inflammatory gene expression may be relevant to the pathogenesis of MS. We investigated spontaneous secretion of interleukin 1 beta, tumor necrosis factor alpha, and prostaglandin E2 with the use of monocytes that we isolated from patients with active (n = 9) and stable (n = 9) MS and from age-matched normal controls (n = 9). The patient groups with MS were matched for age, duration of MS, and disease severity. Patients with active disease were within weeks of the onset of a clinical exacerbation. Monocytes were isolated by density gradient centrifugation, followed by adherence to plastic tissue culture flasks, resulting in a highly purified adherent monocyte preparation. Monocytes from patients with active disease spontaneously secreted less tumor necrosis factor alpha and less prostaglandin E2 compared with that in patients with stable MS, while interleukin 1 beta levels were below the level of assay sensitivity. Levels of interleukin 1 beta and tumor necrosis factor alpha increased to similar levels in response to lipopolysaccharide (0.1 mg/L), indicating that altered cell viability could not account for the observed differences. In response to lipopolysaccharide, prostaglandin E2 levels increased more significantly in patients with stable than active MS, suggesting differential sensitivity to stimuli of arachidonic acid metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Exacerbation rates and adherence to disease type in a prospectively followed-up population with multiple sclerosis. Implications for clinical trials.

Two hundred fifty-four patients with definite multiple sclerosis were followed up prospectively for 1 to 5 years (mean, 2.6 years). None of the patients received immunosuppressive medication. Yearly exacerbation rates and each patient's adherence to initial disease type were determined. Disease type was defined at entry and prospectively each subsequent year as stable, relapsing remitting stable, relapsing remitting progressive, or chronic progressive. Exacerbation rates determined prospectively did not decline significantly during 3 years of follow-up, even if patients were stratified by disease duration. Adherence to the initially assigned disease type was highly variable. When followed up for 2 years, 30% of patients with chronic progressive disease had conditions become stable, 32% of patients with stable disease had conditions become chronic progressive, 20% of patients with relapsing remitting disease had conditions become stable, and 20% of patients with relapsing remitting disease had conditions become chronic progressive. Patients with stable or relapsing remitting stable disease switched to one of the progressive categories as frequently (44%) as patients with progressive disease stabilized (46%). Progression of disease measured by changes in Kurtzke Expanded Disability Status Scores did not differ between the different disease types. The results challenge dogma regarding the natural history of exacerbation rates and the assumption that we can reliably assign patients to a specific disease type. The findings have important implications for understanding the natural history of multiple sclerosis and designing clinical trials.

The GABA-agonist progabide for spasticity in multiple sclerosis.

Thirty-two patients with spasticity due to multiple sclerosis were entered into a randomized, double-blinded, placebo-controlled crossover trial of the gamma-aminobutyric acid agonist, progabide. Each patient was treated with a maximum of 45 mg/kg of progabide during each of two four-week treatment periods, separated by a two-week washout. Twenty-five participants completed the study; seven failed to complete the study due to adverse events. Progabide was associated with lessened spasticity. There was no loss of motor power associated with progabide. The physician, patients, and study nurse coordinator all declared preferences for progabide for treatment of spasticity. Ten participants (40%) chose to remain on progabide in an open, long-term follow-up protocol. Seven serious adverse events occurred. One consisted of fever and weakness without infection; the other six consisted of elevated aspartate aminotransferase and alanine aminotransferase levels, four of which were asymptomatic. All adverse events resolved entirely when the drug was stopped. Progabide is an effective antispastic agent and its antispastic effect is not accompanied by increased motor weakness. The use of the drug, however, is associated with a high incidence of adverse events, which will likely limit progabide's therapeutic usefulness.

Multiple sclerosis. Cerebrospinal fluid immune complexes that bind C1q.

We used a sensitive C1q-binding assay to measure levels of soluble immune complexes in 182 samples of cerebrospinal fluid (CSF) from control patients and patients with multiple sclerosis (MS). Soluble immune complexes in CSF were detected in 16% of patients with progressive MS, 38% of patients with exacerbating-remitting MS, 55% of patients with infectious or inflammatory diseases, 3% of patients with noninflammatory neurologic disorders, and in 0% of control patients with back pain. No correlations were found between the results of the C1q-binding assay and abnormalities of other CSF parameters. These included an elevated level of myelin basic protein, pleocytosis, oligoclonal bands, or an increased IgG level. Because of the lack of correlation to laboratory indexes of disease activity and the nonspecificity of a positive test, the C1q-binding assay seems to have little clinical usefulness in the diagnosis or management of patients with MS.

Isolated idiopathic optic neuritis. Analysis of free kappa-light chains in cerebrospinal fluid and correlation with nuclear magnetic resonance findings.

There is controversy about the frequency with which patients with isolated optic neuritis (ON) subsequently develop clinically definite multiple sclerosis. Furthermore, at the time of isolated ON, there are no features that are both sensitive and accurate in predicting which patients will develop clinically definite multiple sclerosis. We analyzed cerebrospinal fluid (CSF) samples from eight patients with isolated ON and compared the result with the presence of clinically silent brain lesions demonstrated by nuclear magnetic resonance imaging. The single most common laboratory abnormality was an elevated level of free kappa-light chains in CSF. This abnormality was present in five (63%) of eight patients with isolated ON and correlated with the presence of clinically silent brain lesions demonstrated in four of the five patients by nuclear magnetic resonance. The only other laboratory abnormality that correlated with disseminated disease was the presence of oligoclonal bands, but this finding was observed less frequently than was an elevated level of free kappa-chains. Thus, the presence of free kappa-chains in CSF appears to correlate with disseminated disease in patients with isolated ON and may have prognostic value.

Pulmonary function and dysfunction in multiple sclerosis.

Pulmonary function was studied in 25 patients with clinically definite multiple sclerosis with a range of motor impairment. Forced vital capacity (FVC), maximal voluntary ventilation (MVV), and maximal expiratory pressure (MEP) were normal in the ambulatory patients (mean greater than or equal to 80% predicted) but reduced in bedridden patients (mean, 38.5%, 31.6%, and 36.3% predicted; FCV, MVV, and MEP, respectively) and wheelchair-bound patients with upper extremity involvement (mean, 69.4%, 50.4%, and 62.6% predicted; FVC, MVV, and MEP, respectively). Forced vital capacity, MVV, and MEP correlated with Kurtzke Expanded Disability Status scores (tau = -0.72, -0.70, and -0.65) and expiratory muscle weakness occurred most frequently. These findings demonstrate that marked expiratory weakness develops in severely paraparetic patients with multiple sclerosis and the weakness increases as the upper extremities become increasingly involved.

Clinical significance of the multiple sclerosis functional composite: relationship to patient-reported quality of life.

BACKGROUND: The Multiple Sclerosis Functional Composite (MSFC) was recommended by a task force of the National Multiple Sclerosis Society as a new clinical outcome measure for clinical trials. The task force recommended that the MSFC be validated against other measures of the disease, such as patient-reported quality of life. METHODS: Three hundred patients with multiple sclerosis (MS) representing the spectrum of disease severity were included in this cross-sectional study. The MSFC and Kurtzke Expanded Disability Status Scale (EDSS) were used as measures of disease severity. Clinical relevance of the disease severity scores was analyzed using measures included in the Multiple Sclerosis Quality of Life Inventory. The MSFC and EDSS scores were correlated with self-reported employment status, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the Sickness Impact Profile (SIP). RESULTS: The MSFC and EDSS scores were strongly correlated (r = -0.80, P<.001). The MSFC scores were correlated with patient-reported physical functioning (SIP Physical Summary Scale: r = -0.71, P<.001; SF-36 Physical Component Score: r = -0.41, P<.001). The MSFC scores were significantly but more weakly correlated with emotional functioning (SIP Psychosocial Summary Scale: r = -0.34, P<.001). After controlling for EDSS scores, there were significant residual correlations between the MSFC scores and measures of health-related quality of life, suggesting that the MSFC accounts for the variability in health-related quality of life measures not reflected by the EDSS. CONCLUSIONS: The observed strong correlations between MSFC scores and validated measures of self-reported quality of life indicate that the MSFC scores are clinically relevant. This study supports a recommendation by the National Multiple Sclerosis Society Task Force to use the MSFC as a clinical outcome measure.

Recovery from the 'locked-in' syndrome.

Four patients made substantial recovery following the locked-in syndrome of vascular origin. Clinical and radiologic features supported the presence of ventral pontine infarction secondary to basilar artery occlusion. Quadriplegia and mutism persisted for one to 12 weeks before recovery of motor function began. Improvement continued over several years. All patients regained functional though dysarthric speech. Three of the four patients are ambulatory, one without assistance. As a few patients make a notable recovery from the locked-in syndrome resulting from ventral pontine infarction, aggressive supportive therapy should be considered in the early months of the syndrome.

The clinical course of multiple sclerosis during pregnancy and the puerperium.

Eight women with multiple sclerosis were followed up through pregnancy. Clinical conditions, T-cell subsets, and levels of immunoactive pregnancy-associated proteins were measured twice during the pregnancy and twice during the first postpartum year. None of the women's conditions worsened during pregnancy, although one woman reported a slight increase of symptoms. Six of the eight women experienced relapses within the first 7 weeks after delivery. The number and percent of CD8 suppressor T cells were lower, and the CD4 helper-CD8 suppressor T-cell ratio was higher in the pregnant patients with multiple sclerosis compared with pregnant control women throughout pregnancy and the first 6 months post partum. There was no evident relationship between these parameters and clinical disease activity. Levels of alpha-fetoprotein, alpha 2-pregnancy-associated glycoprotein, and pregnancy-associated plasma protein A, all immunosuppressive proteins associated with pregnancy, were not significantly different in pregnant patients with multiple sclerosis and pregnant controls without multiple sclerosis. The study suggested that the risk of clinical relapse after delivery may be higher than has been reported previously. Furthermore, although there were differences in suppressor T cells, they were not predictably linked to changes in clinical disease activity.

Stereotactic biopsy of an active multiple sclerosis lesion. Immunocytochemical analysis and neuropathologic correlation with magnetic resonance imaging.

Stereotactic biopsy of an active multiple sclerosis lesion in a 23-year-old patient with unilateral symptoms and an isolated high-signal-intensity magnetic resonance abnormality yielded 10 serial tissue cores (1.0 x 0.5 cm) spanning 40 mm within and around the lesion. We performed semiquantitative analysis of lymphocyte phenotype, using antisera to CD3, CD4, CD8, and CD22 molecules, in 11 separate perivascular cuffs in three tissue sections from the lesion edge. Total cells in the cuffs varied from 10 to 100; ratios of CD4+/CD8+ cells in individual cuffs varied from 1.3 to 4.7. Although intense parenchymal infiltrates bordered the least cellular cuffs, parenchymal and perivascular cell phenotypes were indistinguishable, arguing against selective trafficking of lymphocytes into tissue. Individual microfoci of cells displaying CD45RA, CD25, and TQ1 antigens were present. The remarkable phenotypic heterogeneity of T lymphocytes in the multiple sclerosis lesion border is consistent with exposure in situ to a diversity of differentiating stimuli. Histologic demyelination correlated very closely with the signal-intensity abnormality observed on magnetic resonance imaging. These studies provide unusual insight into the histologic and immunocytochemical morphologic appearance of the active multiple sclerosis plaque.

Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis.

OBJECTIVES: To examine the relationship between patient-reported depression and adherence to therapy with interferon beta-1b (IFN beta-1b) and to test the hypothesis that treatment of depression is associated with improved adherence. DESIGN: Patients with multiple sclerosis were followed up 6 months after initiating therapy with IFN beta-1b. SETTING: A university outpatient multiple sclerosis center, an academic group practice, and a health maintenance organization. PATIENTS: Eighty-five patients with clinically evident multiple sclerosis taking IFN beta-1b. MAIN OUTCOME MEASURE: Follow-up questionnaire. RESULTS: Thirty-five (41%) of the 85 patients reported new or increased depression within 6 months of initiating therapy with IFN beta-1b. Patients experiencing symptoms of depression were more likely to discontinue therapy. Among the patients reporting new or increased depression, 86% who received psychotherapy or antidepressant medication and 38% of the patients who received no therapy for depression continued the IFN beta-1b therapy (P = .003). Although psychotherapy was used as a treatment option more frequently in university and academic group practice-based multiple sclerosis clinics than in the health maintenance organization (P = .02), the treatment adherence patterns were similar across sites. CONCLUSIONS: These findings support previous findings that patients report increased depression after initiating therapy with IFN beta-1b. Although the source of this depression is unclear, these findings suggest that treating patient-reported depression increases adherence to treatment.