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Objective: To investigate the value of Expanded Disability Status Scale (EDSS) worsening sustained for at least 6 months and other parameters as predictors for disability status., Design: Retrospective analysis of the Multiple Sclerosis Collaborative Research Group study data., Setting: The intramuscular interferon beta-1a pivotal trial was a double-blind, placebo-controlled phase 3 study., Participants: Patients with relapsing-remitting multiple sclerosis who received at least 2 years of treatment and completed an EDSS evaluation 8 years postrandomization., Intervention: Thirty micrograms of intramuscular interferon beta-1a or placebo once weekly during the 2-year clinical trial., Main Outcome Measures: Positive predictive values for 6-month sustained progression during 2 years were calculated to determine the ability to predict disability status at 8 years. A multivariate logistic regression model was used to assess the relationship between predictors and EDSS milestones at follow-up., Results: Forty-five patients had sustained 6-month EDSS progression during the clinical trial and 115 did not. Progression during the trial was the strongest predictor of reaching EDSS milestones at the follow-up visit, 8 years after randomization. Other independent predictors were treatment arm assignment and baseline EDSS score., Conclusion: In this phase 3 clinical trial of intramuscular interferon beta-1a, compared with effects of treatment, baseline EDSS score, and number of relapses during the study, worsening of 1 point or more on EDSS from baseline lasting 6 months was the strongest predictor of clinically significant disability 8 years after randomization into the clinical trial.

Background: Gray matter magnetic resonance imaging T2 hypointensity, a marker of iron deposition, is associated with clinical impairment and brain atrophy in cross-sectional studies of multiple sclerosis. Treatment with intramuscular interferon beta-1a limits brain atrophy in the second year of treatment., Objective: To test whether T2 hypointensity predicts brain atrophy and whether interferon affects this relationship., Design: Post hoc analysis., Setting: A multicenter treatment trial conducted at tertiary care comprehensive multiple sclerosis centers. Patients Patients with multiple sclerosis who took part in a 2-year clinical trial in which they received intramuscular interferon beta-1a (30 mug/wk) or placebo., Main Outcome Measures: Deep gray matter T2 hypointensity, brain parenchymal fraction (BPF), and total T2, gadolinium-enhancing, and T1 lesion volumes., Results: T2 hypointensity in various gray matter areas correlated with baseline BPF (r = 0.19-0.39; P = .001-.03). In placebo-treated patients (n = 68), baseline T2 hypointensity predicted the change in BPF in the first year and throughout 2 years (r = 0.26-0.42; P<.001-.03). T2 hypointensity was chosen in regression modeling as the best predictor of BPF change at the 1-year (R(2) = 0.23; P = .002) and 2-year (R(2) = 0.33; P<.001) time points after accounting for all magnetic resonance imaging variables. In the interferon group (n = 65), no relationship existed between baseline T2 hypointensity and BPF change., Conclusions: Gray matter T2 hypointensity predicts the progression of brain atrophy in placebo- but not interferon beta-1a-treated patients. This predictive effect is seen as early as the first year. We hypothesize that interferon beta may exert its effect on brain atrophy in part by reducing a cascade of events that involve iron deposition as a mediator of neurotoxicity or as a disease epiphenomenon.

Background: Atrophy is recognized as a measure of destructive changes in multiple sclerosis (MS). The time course and pathologic mechanisms of atrophy development are not well understood. Significant atrophy was reported to occur within 9 to 12 months in relapsing remitting MS., Objectives: To test whether atrophy can be detected over short time intervals, and to evaluate its relationship to inflammation., Design and Methods: Prior to randomization to a treatment trial, 138 untreated patients with relapsing remitting MS had 3 magnetic resonance imaging scans within a mean +/- SD follow-up of 76 +/- 20.2 days. Brain parenchymal fraction (BPF), a normalized measure of whole brain volume, the proportion of active (gadolinium-enhancing) scans, and the volume of T1-weighted gadolinium-enhancing and T2-weighted hyperintense lesions were determined at all time points. An annualized atrophy rate was estimated by calculating a regression slope., Results: The median Expanded Disability Status Scale score was 3.5, the mean disease duration was 7.6, and the mean age was 38.5 years. The BPF decreased significantly by -0.229% from scan 1 to scan 3, while the proportion of active scans remained high (65%, 63%, and 67%). The BPF change was only weakly correlated to the volume of T1-weighted gadolinium-enhancing lesions in scan 1 (r = -0.185). The estimated annualized atrophy rate was -1.06% (95% confidence interval, -1.50% to -0.62%)., Conclusions: The annualized atrophy rate found in this study is comparable with rates reported previously. Measurements of BPF allow detection of atrophy over short time intervals in active disease. The short-term relationship of inflammation to atrophy development was weak. Brain parenchymal fraction might be a promising measure in future phase 2 studies of agents, with an expected effect on tissue-destructive pathologic mechanisms of MS.

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.

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.

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.

Multiple sclerosis (MS) and other chronic illnesses can drastically decrease quality of life (QOL), but there has been little systematic study of QOL in patients with chronic medical diseases. We analyzed QOL in 68 patients with MS, 164 patients with inflammatory bowel disease, and 75 patients with rheumatoid arthritis. The previously validated test instrument was a standardized interview consisting of 41 questions clustered in four subscales: functional and economic scale, social and recreational scale, affect and life in general scale, and medical problems scale. Patients were included in the study if they had a definite medical diagnosis and disease duration of 10 years or longer. In the patients with MS, Kurtzke's Expanded Disability Status Scale correlated strongly only with the medical problems score. Of Kurtzke's Functional System Scales, only the visual Functional System Scores was correlated with total QOL and subscale scores, suggesting that vision is strongly related to QOL. Duration of MS was unrelated to QOL scores. There were significant differences between patients with MS, inflammatory bowel disease, and rheumatoid arthritis on the subscale and total QOL scores. Results suggested that QOL was best in the inflammatory bowel disease group and worst in the MS group. Numerous statistically significant differences on individual questions were evident, suggesting that unique clinical profiles differentially characterize these diseases. Assessments of QOL are a meaningful addition to impairment scales, such as Kurtzke's Expanded Disability Status Scale. Furthermore, QOL scores may meaningfully measure the impact of a chronic medical disease, such as MS, compare the impacts of different diseases, and assess the effects of therapeutic intervention.

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)

Magnetic resonance imaging (MRI) may demonstrate disease activity in a number of ways in patients with multiple sclerosis. Newly appearing MRI lesions, gadolinium-enhancing lesions, and enlargement of preexisting lesions are frequently taken as evidence of disease activity. Furthermore, serial MRI studies have been stated to be more sensitive than repeated neurologic examinations in detecting disease activity. We assessed the validity of using lesion enlargement as a measure of disease activity by repeatedly measuring the area of all MRI lesions in four patients with multiple sclerosis. The size-frequency distribution in all patients was similar, with 80% of the lesions measuring less than 0.67 cm2. The median coefficient of variation for three successive lesion measurements was inversely related to lesion area, ranging from 22.6% for the more common smaller lesions (less than 0.67 cm2) to 12.1% for larger lesions. Based on these coefficients of variation, a change in a particular lesion exceeding 45.2% for a baseline lesion smaller than 0.67 cm2 and 24.2% for a baseline lesion greater than or equal to 0.67 cm2 should be required to exclude a change due to measurement variability. It remains necessary to determine the number of lesions that must change when multiple lesions are present in the baseline MRI to reliably exclude chance occurrence when establishing MRI-evident disease activity. Guidelines for determining these criteria are presented, as are the limitations inherent in the statistical model employed to make these determinations.

Existing diagnostic criteria for multiple sclerosis present significant limitations when assessing multiplex families for three reasons: (1) restricting age of onset to 10 to 50 years is likely to exclude 10% of patients known to have a later onset, (2) diagnoses based on subjective information can potentially result in a false-positive diagnosis, and (3) including progressive myelopathies occurring within families, particularly when highly symmetrical, may result in the improper inclusion of genetically determined neurological diseases such as familial spastic paraparesis. The validity of any molecular genetic approach for determining disease susceptibility critically depends on diagnostic accuracy. We present adapted diagnostic criteria that address each of these diagnostic pitfalls unique to multiplex multiple sclerosis family research.

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.

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.

Various neurologic disorders may be diagnosed incorrectly as multiple sclerosis (MS) since there is no test that is entirely specific for the disease. We report ten patients who met clinical criteria for probable or definite MS and who were given incorrect diagnoses. All of the patients were subsequently shown to have alternative diagnoses, three of which were directly treatable. From these illustrative cases, five characteristics were identified that alerted us to the possibility of an alternative diagnosis. We have called these characteristics "red flags," and suggest that they may be useful as features casting doubt on the diagnosis of MS if used judiciously in conjunction with clinical diagnostic criteria.

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.

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.

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.

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.

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.

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.