Cerebrospinal fluid immunoglobulin G promotes oligodendrocyte progenitor cell migration.

Multiple sclerosis (MS) is characterized by demyelination of the CNS with associated neurological deficits. Remyelination can occur but is often incomplete. The process of myelin repair requires the proliferation and migration of oligodendrocyte progenitor cells (OPC) into the lesion from the neighboring areas. OPC migration is altered by several factors, including antibodies that bind to OPC surface proteins. We have previously reported elevated anti-OSP/claudin-11 antibodies in the cerebrospinal fluid (CSF) of MS patients and that anti-OSP/claudin-11 antibodies generated in rabbits can inhibit OPC migration. In the study presented here, we investigated the effect of CSF IgG from MS patients and controls on OPC migration in culture. Rat OPC cultured with CSF from MS patients tended to migrate more than those cultured with control CSF, but this did not reach statistical significance. To determine whether the IgG fraction in the CSF influenced migration, we removed it using protein-A sepharose. A dramatic decrease in OPC migration was found in both MS (45 +/- 24 vs.16 +/- 9) and control (40 +/- 19 vs. 22 +/- 13) samples after IgG was removed (P <.05). Anti-OSP/claudin-11 antibody concentration did not significantly correlate with OPC migration. These data demonstrate that CSF IgG promotes OPC migration. Identification of the specific IgG fraction responsible for this effect could lead to novel therapies to promote recovery in MS.

Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial.

The aim of this study was to assess the long-term safety and efficacy of glatiramer acetate (GA) for patients with multiple sclerosis (MS) who received active treatment versus those on placebo for approximately 30 months (24-35 months) before receiving GA during a six-year organized, prospective open label study. Entry required two relapses in the previous two years and an Expanded Disability Status Scale (EDSS) score of 0-5. Patients (251) were equally randomized to daily subcutaneous GA, 20 mg, or to placebo. After approximately 30 months, 208 patients continued in an open label study: 101 continued on GA and 107 switched from placebo to active drug. Groups were well matched at randomization and entry to the open label study. Patients always on GA showed a steady decline in relapses: a mean of 1.5 per year at entry, a mean of 0.42 over the entire six years (95% CI = 0.34-0.51), a 72% reduction (P = 0.0001). They averaged a relapse every four + years (yearly rate 0.23 in year six) and 26/101 remain relapse free. Patients did less well if on placebo for 30 months, but relapses then declined, and by year six the rates were similar. Of patients always on GA, 69% showed neurological improvement of > or = 1 EDSS steps or remained stable compared with 57% if GA treatment was delayed. Of relapse-free patients always on GA over six years, only three of 26 (11%) were worse by > or = 1 EDSS steps, whereas nine of 21 (43%) in the placebo/active group were worse (P < 0.03). Disability, measured every six months, showed that the group of patients always on GA was relatively stable over the six years, while the group who received placebo for the first two-and-a-half years did significantly less well. Daily injections of GA were well tolerated. This longest ever organized MS treatment trial shows that delaying therapy with GA increases the risk of neurologic disability, reinforcing the rationale for using GA as a first-line treatment early in the course of relapsing-remitting MS.

T-cell responses to oligodendrocyte-specific protein in multiple sclerosis.

Oligodendrocyte-specific protein (OSP) is concentrated in CNS myelin and is a potential autoantigen in the development of multiple sclerosis (MS). We performed proliferation assays with lymphocytes from MS patients and normal controls. OSP peptide-induced proliferation was common in relapsing-remitting MS and controls samples but was less pronounced in samples from secondary progressive MS subjects. These data demonstrate that OSP-reactive T cells are part of the normal immune repertoire and therefore have the potential to contribute to the pathogenesis of MS. Given the lack of specificity to MS, OSP-reactive T-cells are unlikely to be solely responsible for the disease process.

Immunologic therapy for secondary and primary progressive multiple sclerosis.

Multiple sclerosis (MS) is generally considered an immune-mediated demyelinating disease, and treatments designed to modify the course of MS are immunosuppressive or immunomodulatory. Although most people with MS have a relapsing-remitting course initially, the majority will eventually experience a more gradual decline in neurologic function, termed secondary progressive MS. Some patients have gradual worsening from the beginning, termed primary progressive MS. Recent pathologic studies have revealed that axonal injury and neuronal degeneration are much more prominent in MS than previously recognized, and may be the explanation for the gradual decline in neurologic function that characterizes progressive MS. The results of several clinical trials in MS indicate that suppression of the immune-mediated inflammation may decrease the relapse rate in MS, but not stop the progressive loss of neurologic function. There are many promising approaches to this clinical dilemma, but none has been proven to be effective in stopping or retarding progressive MS. More well-designed, controlled, blinded, randomized clinical trials are needed to test these putative therapies. In the mean time, we should avoid subjecting patients to potentially dangerous and unproven regimens.

Factors related to agreement between self-reported and conventional Expanded Disability Status Scale (EDSS) scores.

BACKGROUND: Although the Expanded Disability Status Scale (EDSS) remains a widely used scale for evaluating impairments in people with multiple sclerosis (MS), EDSS assessments are infeasible in certain situations. A self-administered version of the EDSS would be potentially useful if it yielded similar results as the conventional physician-based version. METHODS: We developed a self-administered patient questionnaire to obtain ratings of neurologic impairments, and developed algorithms to estimate EDSS scores. We mailed the questionnaires to all new consecutive patients scheduled to be seen at an MS clinic. Questionnaires were completed prior to the visit and traditional EDSS ratings were made by one of two neurologists at the visit. One hundred and forty-six pairs of patient questionnaires and physician EDSS assessments were obtained. RESULTS: Kappa values for agreement between the physician's EDSS scores and the questionnaire-derived scores were 0.13 (for exact agreement), 0.39 (+/-0.5 EDSS steps), and 0.56 (+/-1.0 EDSS steps). A scatterplot showed that agreement was best at EDSS scores <3.0 and >5.0. Better agreement was obtained when patients had a higher level of education, and when the physician was more certain of the diagnosis of MS. CONCLUSIONS: While the self-assessed EDSS scores do not agree highly enough to take the place of conventional EDSS scores, they may be sufficient for MS trial screening or for assessing outcomes across broad categories of disability.

Management of multiple sclerosis across managed care and fee-for-service systems.

OBJECTIVE: To measure and compare care for adults with MS across managed care and fee-for-service (FFS) health systems. METHODS: The authors sampled adults with MS having physician visits over a 2-year period from a group model health maintenance organization (HMO) in southern California, from a midwestern independent practice association (IPA) model managed care plan, and from the FFS portion of the practices of a random sample of southern California neurologists. The authors mailed surveys to subjects in mid-1996; 930 of 1,164 (80%) of those eligible responded. The authors measured sociodemographic and clinical characteristics, management of recent changes in mobility, bladder control, and fatigue, use of a disease-modifying agent, assessment of general health symptoms and issues, and unmet information needs. The authors adjusted comparisons between systems for comorbidity, disease severity, and disease type. RESULTS: The groups differed on most sociodemographic and clinical characteristics. There were few differences in symptom management; differences that did exist tended toward more referrals or treatment for the FFS group. Access to the disease-modifying agent available at the time of the survey did not differ across systems, although patients' perceptions of the rationale for not using the drug did vary. General health issues and symptoms were more often assessed in the FFS and IPA systems than in the HMO, but improvement was needed across all three systems of care. There were substantial unmet information needs in all groups and especially high ones in the FFS and HMO samples. CONCLUSIONS: Strategies to improve care for people with MS should be developed and evaluated, particularly in areas like symptom assessment and meeting patient information needs. Where variations in service delivery exist, longitudinal studies are also needed to evaluate the potential impact on outcomes and to evaluate reasons for variation.

Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group.

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone) reduced the relapse rate and slowed accumulation of disability for patients with relapsing - remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34 - 0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis. Multiple Sclerosis (2000) 6 255 - 266

General neurologist and subspecialist care for multiple sclerosis: patients' perceptions.

OBJECTIVE: To compare general neurologists and MS specialists on patients' clinical characteristics and MS care as perceived by patients with MS. METHODS: We sampled all adult patients with MS having physician visits over a 2-year period from a Midwestern managed-care organization and from the fee-for-service portion of 23 randomly selected California neurologists' practices. In mid-1996, 694 subjects were mailed questionnaires; 532 (77%) responded. Sociodemographic/clinical characteristics, recent utilization of services/treatments, unmet needs, symptom care, and research participation were measured. Of 502 subjects (94%) who indicated their usual physician providing MS care was a neurologist, 217 (43%) reported having a general neurologist and 285 (57%) reported having an MS specialist. Comparisons between these two groups were adjusted for comorbidity and disease severity. RESULTS: General neurologist and MS specialist patient groups did not differ on any sociodemographic or clinical characteristic except age (p<0.05). Although health care utilization generally was similar, higher proportions of the MS specialist group were aware of or had discussed interferon beta-1b (IFNbeta-1b) with their physician (p<0.05) and were currently taking it (p<0.05); a smaller proportion of the MS specialist group reported stopping it because of side effects (p<0.01). Overall, levels of unmet need and care for recent symptoms were similar, but the MS specialist group reported more confidence in their physician/carefulness in listening (p<0.05). Twice as many MS specialist subjects had participated in nondrug research (p<0.05); drug study participation was similar. CONCLUSIONS: Patients' perceptions of their care were similar in most ways for those who designated their main MS provider as a general neurologist compared to an MS specialist; however, care differed in potentially important areas. Prospective, longitudinal studies are needed to measure and relate neurologists' training, experience, knowledge, and MS patient volume with both process and outcome measures of quality of MS care.

A humoral response to oligodendrocyte-specific protein in MS: a potential molecular mimic.

OBJECTIVE: To determine the antibody response to oligodendrocyte-specific protein (OSP) in patients with MS. BACKGROUND: OSP is a recently identified CNS-specific myelin protein that is abundant and therefore a candidate autoantigen in MS. METHODS: The presence of anti-OSP antibodies was determined using Western blot analysis, peptide blots, and ELISA in patients with MS and in other neurologic and normal control subjects. RESULTS: Using Western blot analysis, seven patients with relapsing-remitting MS (RRMS) were found to contain anti-OSP antibodies in their CSF that were not present in control subjects. Peptide mapping determined that the antibody response was directed to a seven aa peptide (OSP 114-120), which has 71% homology with several common pathogenic proteins. Using OSP 114-120 as antigen, ELISAs were performed on CSF from 85 MS and 51 control patients. Eighty percent of the samples from RRMS patients followed at the University of California at Los Angeles had an ELISA reading above 0.55 optical density units, whereas all 20 control CSF samples had values less than 0.55 U. Similar results were found in specimens from an outside research bank. ELISAs performed on CSF using homologous viral peptides as antigen showed a close correlation with anti-OSP 114-120 ELISA readings, and in some, the readings were higher than those using OSP peptides. CONCLUSIONS: There is a specific humoral response directed against a region of OSP in RRMS patients that cross-reacts with several common viral peptides. This suggests a possible role for molecular mimicry in the development of MS.

Pentoxifylline is not a promising treatment for multiple sclerosis in progression phase.

Fourteen MS patients took pentoxifylline at varying doses for up to 24 months. In vitro production of tumor necrosis factor alpha was reduced in patients taking 2,400 to 3,200 mg/day of pentoxifylline for 12 weeks or more. Twelve of the 14 patients experienced worsening of the disease during the study according to clinical, MRI, or visual evoked potential criteria. These results provide no hint of efficacy for pentoxifylline as a treatment for MS in progression phase.

Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group.

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.

Comparison of a generic to disease-targeted health-related quality-of-life measures for multiple sclerosis.

Evaluation of the relative contributions of generic and disease-targeted measures to assessing health-related quality of life (HRQOL) for chronic conditions is needed to help in selection of appropriate measures. We administered a generic HRQOL measure (the Short Form-36 [SF-36]), three disease-targeted supplemental scales to the SF-36, and two disease-targeted HRQOL instruments to 171 adults with multiple sclerosis. Most scales yielded adequate variability, internal consistency reliability, and test-retest reliability. The relationship between each measure and four primary "criterion" variables were assessed: overall symptom severity in the prior year; ambulation status; days unable to work or attend school in the prior month: and a rating of overall quality of life. Results indicate that the disease-targeted scales provided unique information not captured by the generic measure. We conclude that if a generic measure of HRQOL is desirable for a given study of multiple sclerosis, additional information will be gained by supplementing that measure with selected scales.

A comparison of health-related quality of life in patients with epilepsy, diabetes and multiple sclerosis.

The purpose of this investigation was to compare self-reported health-related quality of life (HRQOL) in epilepsy compared to another neurological condition or a non-neurological chronic illness. Patients with epilepsy (N = 271), multiple sclerosis (N = 85) and diabetes (N = 555) completed a generic measure of HRQOL (RAND 36-Item Health Survey 1.0 (SF-36)), and the eight SF-36 scale scores were compared across groups, adjusting for differences in sociodemographic characteristics and co-morbid medical conditions. Patients with multiple sclerosis reported significantly worse HRQOL compared to both the epilepsy and diabetes groups (who did not differ from one another) on the Physical Functioning, Role Limitations-Physical, Energy, and Social Function scales. Patients with epilepsy and multiple sclerosis did not differ from one another but reported significantly lower HRQOL scores than the diabetes group on the Emotional Well-Being and Role Limitations-Emotional scales. However, the epilepsy group reported better health perceptions compared to the diabetes and multiple sclerosis patients. Generic measures of HRQOL appear useful in identifying some effects of neurological disease, but disease-targeted supplements may be required to more clearly identify the impact of epilepsy on quality of life.

Comparative evaluations of neuroperformance and clinical outcome assessments in chronic progressive multiple sclerosis: I. Reliability, validity and sensitivity to disease progression. Multiple Sclerosis Study Group.

There remains controversy regarding the most sensitive and valid outcome assessments to use in multiple sclerosis (MS) clinical trials. A double blind, placebo controlled, parallel group multicenter clinical trial to evaluate the clinical efficacy of cyclosporine A in chronic progressive MS incorporated several major clinical and performance outcome assessment modalities and a large sample size, both of which provide a unique opportunity to explore the relationship among MS disease status and the various outcome measures over time. The measures included a structured neurological examination, the Kurtzke Functional System scales and Expanded Disability Status Score, and the Incapacity Status Scale from the MS Minimal Record of Disability, the Harvard Ambulation Index, and neuroperformance testing. A test-retest reliability index, principal component analyses and a signal-to-noise ratio metric were used to comparatively evaluate the reliability, validity and sensitivity to disease progression of the various outcome assessments. The goal was to provide a rational basis for selection of behavioral outcome assessments in future MS clinical trials by identifying the primary dimensions of MS measured by the candidate outcome assessments and providing an objective basis for selecting tests that are most sensitive to MS disease and its progression over a two year trial period. We conclude that the components of the major clinical and performance measures show excellent reliability and cross validation. Principal component analyses of all outcome assessments yielded six primary underlying factors for describing disease status in chronic progressive MS that included lower extremity/pyramidal dysfunction, cerebellar/brainstem and upper extremity dysfunction, somatosensory dysfunction, visual dysfunction, mental or intellectual dysfunction and bowel/bladder problems. Signal-to-noise ratios indicated that upper and lower extremity composites of neuroperformance test items provided the most sensitive indicators of MS disease progression in the placebo group over the 2 year trial period.

Polypharmacy in multiple sclerosis.

The goal of this article is to describe therapeutic approaches to multiple sclerosis (MS) which may be applicable to other human conditions such as epilepsy. Polypharmacy is very commonly employed in MS and it is likely to increase in the future. This paper is written with the premise that therapeutic principles and practices underlying the care of patients with MS may be useful for the treatment of people with epilepsy. We will point out some of the analogies between MS and epilepsy and we will describe the polypharmacy approach employed to treat patients with MS. We will review current information as to the etiology and pathogenesis of MS and describe potential therapeutic targets derived from this knowledge. We will identify or suggest certain therapeutic principles underlying polypharmacy in MS which may be relevant to epilepsy or other conditions. Finally, we will describe some of the obstacles to expanding rational polypharmacy and how we might overcome these problems.

Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.

We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

A health-related quality of life measure for multiple sclerosis.

The need for measures of health-related quality of life (HRQOL) for clinical effectiveness research and for quality of care research, particularly for chronic diseases, is increasingly recognized. We assessed a measure of HRQOL for people with multiple sclerosis, a chronic neurological condition. We used the RAND 36-Item Health Survey 1.0 (aka SF-36) as a generic core measure, to enable comparisons of HRQOL of patients with multiple sclerosis to those of other patient populations and to the general population. To enhance comparisons within groups of multiple sclerosis patients, these items were supplemented with 18 additional items in the areas of health distress (four items), sexual function (four items), satisfaction with sexual function (one item), overall quality of life (two items), cognitive function (four items), energy (one item), pain (one item), and social function (one item). The final measure, the Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument, contains 52 items distributed into 12 scales, and two single items. Internal consistency reliability estimates for the 12 multi-item scales ranged from 0.75 to 0.96 in a sample of 179 patients with multiple sclerosis. Test-retest intraclass correlation coefficients ranged from 0.66 to 0.96. Exploratory factor analysis confirmed two underlying dimensions of physical health and mental health. Construct validity was supported by significant associates between MSQOL-54 scales and degree of multiple sclerosis symptom severity in the prior year, level of ambulation, employment limitations due to health, admission to hospital in the previous year, and depressive symptoms.

Design strategies in multiple sclerosis clinical trials. The Cyclosporine Multiple Sclerosis Study Group.

After analyzing our natural history data on the course of multiple sclerosis (MS) in more than 500 patients followed for 20 years and our experience in several therapeutic trials, we concluded that a phase III (full) trial for efficacy should have certain properties. For a power of 0.8, alpha of 0.05, and attrition rate of 10% per year, we think the trial should have a minimum sample size of 130 (65 in each arm; placebo versus active) if the design is based upon the proportion of subjects worsening by clinical measures. No stratification by entry Extended Disability Status Scale score is needed if worsening is defined as a change of 1.0 units (2 to 0.5 steps) maintained for 90 days for an entry score of 1 to 5.0 units; or 0.5 units (1 to 0.5 steps) if the entry score is 5.5 to 7 units. We need not stratify by course (relapsing-remitting versus relapsing-progressive) but are less certain about progression from the onset. No run-in period is required to define "activity." Minimum time for treatment is 3 years. We review the justification for our conclusions; modifications in sample size that are necessary if survival analysis is used; impact of the interferon-beta trial (future trials will have an "active" control); and alternative strategies possible if magnetic resonance imaging serves as the primary outcome.