Acamprosate modulates experimental autoimmune encephalomyelitis.

OBJECTIVE: This pilot study aimed to determine the efficacy of acamprosate (N-acetyl homotaurine) in reducing the pathological features of experimental autoimmune encephalomyelitis (EAE) which is an animal model for multiple sclerosis (MS). BACKGROUND: The amino acid taurine has multiple biological activities including immunomodulation and neuromodulation. The synthetic acetylated taurine derivative, acamprosate, which crosses the blood-brain barrier more readily compared to taurine, is currently being used for the prevention of alcohol withdrawal symptoms associated with enhanced glutamatergic receptor function and GABA receptor hypofunction. METHODS: EAE was induced in C57BL/6 female mice with myelin oligodendrocyte glyocoprotein, amino acid 35-55. Mice were treated with 20, 100 and 500 mg/kg acamprosate for 21 days. RESULTS: Neurological scores at disease peak were reduced by 21, 64 and 9% in the 20, 100 and 500 mg/kg groups, respectively. Neurological improvement in the 100 mg/kg group correlated with a reduction in numbers of inflammatory lesions and the extent of CNS demyelination. Blood TNF-α levels were significantly reduced in the 500 mg/kg group. DISCUSSION: Acamprosate and other taurine analogs have a potential for future MS therapy.

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.

Rapid disease course in African Americans with multiple sclerosis.

OBJECTIVE: To investigate utility of a Multiple Sclerosis Severity Scale (MSSS)-based classification system for comparing African American (AA) and white American (WA) multiple sclerosis (MS) subpopulations in the New York State Multiple Sclerosis Consortium (NYSMSC) database. MSSS is a frequency-rank algorithm relating MS disability to disease duration in a large, untreated reference population. Design/ METHODS: Distributions of patients in 6 MSSS-based severity grades were calculated for AA and WA registrants. RESULTS: There were 419 AA and 5,809 WA patients in the NYSMSC, who had EDSS recorded during years 1-30 since symptom onset. Median EDSS was not different in AA and WA (3.5 vs 3.0, p = 0.60), whereas median MSSS in AA was higher than in WA (6.0 vs 4.8, p = 0.001). AA patients were overrepresented in the 2 most severe grades (41.5% vs 29.3% for WA) and underrepresented in the 2 lowest grades (23.4% vs 35.4%; p < 0.001). In multivariable analysis (ordered logistic and median regression), MSSS for AA remained significantly higher than in WA after adjusting for age, gender, disease duration, disease type distribution, and treatment with disease-modifying therapies. CONCLUSIONS: The 6-tiered MSSS grading system is a powerful tool for comparing rate of disease progression in subpopulations of interest. MSSS-based analysis demonstrates that African ancestry is a risk factor for a more rapidly disabling disease course.

Increased tissue damage and lesion volumes in African Americans with multiple sclerosis.

BACKGROUND: African American (AA) patients with multiple sclerosis (MS) have more rapid disease progression and poorer responses to disease-modifying therapies than white American (WA) patients with MS. OBJECTIVES: To investigate brain MRI characteristics in AA compared to WA in a cohort of consecutive patients with MS. METHODS: We studied 567 patients with MS (age: 45.1 +/- SD 9.8 years, disease duration: 13.4 +/- 8.6 years), comprised of 488 WA and 79 AA. All patients obtained clinical and quantitative MRI evaluation. The majority of patients, 96% of AA and 94% of WA, were on disease-modifying therapies. The MRI measures included T1-, T2-, and gadolinium contrast-enhancing (CE) lesion volumes (LV) and CE number, global and tissue-specific brain atrophy, and magnetization transfer ratio (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The associations between race and clinical and MRI measurements were assessed in regression analysis. RESULTS: The MTR values in lesions and in NAGM and NAWM were significantly lower in AA compared to WA. The AA group had 31% greater T2-LV and 101% greater T1-LV compared to WA. The MS Severity Score for AA (mean +/- SD = 4.3 +/- 2.9) was greater than for WA (3.8 +/- 2.5), despite a shorter disease duration in AA, indicating more aggressive clinical disease. CONCLUSIONS: African American patients showed increased tissue damage, as measured by magnetization transfer ratio, and presented higher lesion volumes compared to white Americans. The greater tissue damage and faster lesion volume accumulation may explain the rapid clinical progression in African American patients.

Psychometrics and normative data for the Multiple Sclerosis Functional Composite: replacing the PASAT with the Symbol Digit Modalities Test.

The MS Functional Composite (MSFC) is a continuous scale of neurological disability for patients with multiple sclerosis (MS). Cognition is represented by the Paced Auditory Serial Addition Test (PASAT), although the Symbol Digit Modalities Test (SDMT) has been proposed as a promising alternative. MSFC scores were calculated using either the PASAT or the SDMT with the following reference populations: National Multiple Sclerosis Society (NMSS) Task Force, 400 MS patients, and 100 normal controls. A subgroup of 115 patients was followed longitudinally, with a test-retest interval of 2.3 +/- 1.2 years. Pearson correlations were calculated and analyses of variance (ANOVAs) were used to assess relationships among the MSFC components and composite scores, and differences in performance between patients and controls. Longitudinal changes were also assessed. Logistic regression was performed to determine which MSFC scores are most predictive of diagnosis, course, and work disability. All MSFCs had similar test-retest reliability and correlations with other measures including neurological disability, depression, and fatigue. The SDMT showed slightly better validity with respect to predicting diagnosis, course, and work disability, although the amount of variance accounted for was similar for each version of the MSFC. Our data, derived from a large sample of MS patients and normal controls, supports the validity of both PASAT and SDMT versions of the MSFC. Because the SDMT has slightly better predictive validity and has a relatively easier administration procedure, some clinicians and researchers may wish to replace the PASAT with the SDMT in future calculations of the MSFC using the calculation methods provided in this manuscript.

Subjective fatigue is not associated with cognitive impairment in multiple sclerosis: cross-sectional and longitudinal analysis.

BACKGROUND: Studies in multiple sclerosis (MS) report conflicting conclusions regarding fatigue and cognition, which may partly be due to the use of small sample sizes and frequent reliance on a cross-sectional approach. OBJECTIVE: The ability to distinguish between these two disabling symptoms is necessary in order to properly assess and treat MS patients. METHODS: In a retrospective analysis, we assessed the correlation between fatigue and neuropsychological (NP) testing using a cross-sectional (n = 465) and longitudinal approach (n = 69). Cognition was measured using a comprehensive battery called the Minimal Assessment of Cognitive Function in MS (MACFIMS), and fatigue was measured with the Fatigue Severity Scale (FSS). FSS scores were categorized as normal (or=5.0). Repeat assessments (n = 69) were categorized as improved or worsened by a change in FSS of either 0.5 or 1.0. RESULTS: MS patients had significantly higher FSS scores than normal controls (P < 0.001). No correlation was found between FSS and NP scores in either cross-sectional or longitudinal analyses. Fatigue was moderately correlated with depression, assessed using the Beck Depression Inventory Fast Screen (BDIFS) (r = 0.44, P < 0.001). Longitudinally, there was a medium correlation between change in FSS and BDIFS (r = 0.34, P = 0.001), but no significant differences on NP scores using either definition of change. CONCLUSION: We conclude that self-reported fatigue, while correlated with self-reported depression, is not significantly related to cognitive capacity in MS.

Gender-related differences in MS: a study of conventional and nonconventional MRI measures.

BACKGROUND: Studies showed gender-associated differences in multiple sclerosis (MS) disease evolution and in the evolution of conventional magnetic resonance imaging (MRI) findings. OBJECTIVE: The aim of this study was to investigate gender differences according to a number of conventional and nonconventional MRI measures in patients with MS. METHODS: We examined 763 consecutive patients with MS [499 (19.2% men) relapsing-remitting (RR), 230 (24.8% men) secondary-progressive, and 34 (44.1% men) primary-progressive], 32 (21.9% men) patients with clinically isolated syndrome (CIS), and 101 (30.7% men) normal controls (NC). Patients were assessed using conventional and nonconventional MRI measures. Gender-related MRI differences were investigated using general linear model analysis, corrected for MS disease type. RESULTS: In the total MS group, male patients showed lower normalized peripheral gray matter (GM) (P<0.001) and normalized GM (P=0.011) volumes than female patients. Female patients presented lower normalized white matter (WM) volumes (P=0.011). These gender effects were not observed in NC. Male patients also showed more advanced central atrophy (P=0.022). In RRMS male patients, there was also a higher lateral ventricle volume (P=0.001). The GM-WM normalized ratio was lower for male patients with MS compared with male NC (0.97 vs. 1.09, P<0.001) but not in patients with CIS compared with NC. CONCLUSIONS: There were no significant gender-related differences regarding nonconventional MRI measures. GM and central atrophy are more advanced in male patients, whereas WM atrophy is more advanced in female patients. These gender-related MRI differences may be explained by the effect of sex hormones on brain damage and repair mechanisms.

Repeated assessment of neuropsychological deficits in multiple sclerosis using the Symbol Digit Modalities Test and the MS Neuropsychological Screening Questionnaire.

BACKGROUND: Brief cognitive performance tests and self-report measures of neuropsychological symptoms have been proposed for screening purposes in multiple sclerosis (MS) clinics. To better understand the reliability of screening methods, two tests, the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Screening Questionnaire (MSNQ), were administered to 76 patients with MS and 25 healthy controls, matched on demographic characteristics. METHODS: Tests were administered at monthly intervals, over 6 months. In addition, the Beck Depression Inventory Fast Screen for medical patients (BDIFS) was administered to monitor for changes in depression. Our objectives were to determine the reliability of these measures and the relative contribution of cognitive impairment and depression in predicting self-report MSNQ scores. RESULTS: Results showed that both the SDMT and MSNQ have good to excellent reproducibility over repeated testing. In MS, there are minimal practice effects over successive tests, in the order of 0.2 SD for SDMT and minimal change in the MSNQ. Regression analyses modeled to predict MSNQ based on SDMT and BDIFS showed significant contribution for both, but with the majority of variance being accounted for depression. CONCLUSIONS: We conclude that these brief screening tests provide some independent information about the mental status of patients with MS and are reliable, even when used in monthly, successive examinations.

Interpreting patient/informant discrepancies of reported cognitive symptoms in MS.

Although numerous studies have shown that brain-damaged patients tend to underestimate neuropsychological (NP) impairment when self-ratings are compared to informant ratings, the meaning of such discrepancies is not well studied in multiple sclerosis (MS). We compared patient self- and informant-report questionnaire ratings of NP functioning in 122 MS patients and 37 age- and education-matched normal controls. In addition to completing the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ), participants underwent NP testing and assessment of depression, personality, and neuropsychiatric symptoms. Based on the normal distribution of discrepancy scores, patients were classified according to whether they overestimated or underestimated their cognitive ability, relative to informant ratings. ANOVAs comparing test scores derived from overestimators, underestimators, and accurate estimators were significant for multiple measures of cognitive function, depression, personality, and neuropsychiatric symptoms. Overestimators were characterized by less depression and conscientiousness, and greater degrees of cognitive impairment, euphoric behavioral disinhibition, and unemployment as compared to underestimators. We conclude that patient/informant discrepancy scores on the MSNQ are associated with the aforementioned neuropsychiatric features, and that the MSNQ has potential utility for predicting euphoria and disinhibition syndromes in MS.

Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium.

The objective of this study was to determine the clinical characteristics of multiple sclerosis (MS) in African American (AA) patients in the New York State Multiple Sclerosis Consortium (NYSMSC) patient registry. The NYSMSC is a group of 18 MS centers throughout New York State organized to prospectively assess clinical characteristics of MS patients. AAs comprise 6% (329) of the total NYSMSC registrants (5602). Demographics, disease course, therapy, and socioeconomic status were compared in AA registrants versus nonAfrican Americans (NAA). There was an increased female preponderance and a significantly younger age at diagnosis in the AA group. AA patients were more likely to have greater disability with increased disease duration. No differences were seen in types of MS and use of disease modifying therapies. Our findings suggest a racial influence in MS. Further genetic studies that consider race differences are warranted to elucidate mechanisms of disease susceptibility.

A longitudinal study of T1 hypointense lesions in relapsing MS: MSCRG trial of interferon beta-1a. Multiple Sclerosis Collaborative Research Group.

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 beta-1a (IFNbeta-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 IFNbeta-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 IFNbeta-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.

A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).

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 beta-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.

Screening for atrial fibrillation in the community: a multicenter validation trial.

BACKGROUND: Atrial fibrillation (AF) is an important public health problem. This arrhythmia is common and associated with a high risk of stroke. Further, appropriate interventions in AF can reduce the risk of stroke by approximately 68%. Population studies show that a large group of patients have intermittent or chronic AF that remains unrecognized. If a simple screening test for this arrhythmia could be developed and validated, application of the technique across populations might identify AF patients for early treatment, potentially reducing the incidence of stroke. In this study, we sought to determine whether individuals taken from the general community could be taught to find and classify the pulse of another as very irregular, implying AF, or regular, implying normal sinus rhythm (NSR). The aim was to establish that pulse examination for potential AF could be performed by individuals with sufficient sensitivity and specificity to be effectively used as a screening procedure for this medically important arrhythmia. METHODS: We enrolled 178 subjects selected from the general community from four centers. Subjects received standardized education on the medical importance of AF and its signature, a very irregular pulse. A technique for palpating and characterizing the rhythm of the radial pulse was also taught. Without further coaching, subjects were then asked to find their pulse and then to find and classify the pulse of two models randomly presented who may or may not have had AF. RESULTS: Of the 178 subjects tested, 92% were able to find their own pulse; 17 (9.6%) were unable to find the pulse of one or both patient models and were, therefore, excluded from the study. Of the remaining 161 subjects, 76% (122 of 161) correctly identified the pulse in an AF model, and 86% (139 of 161) correctly identified the pulse in an NSR model. Results did not statistically differ as a function of age, educational status, or location. DISCUSSION: This multicenter trial established that given minimal standardized instructions, subjects from the general community can reliably and consistently find both their pulse as well as the pulse of another and to differentiate a regular pulse from a very irregular pulse. If similar educational programs were widely applied across large populations, periodic screening for AF might lead to earlier diagnosis and appropriate treatment for patients who have this major risk factor for stroke. These screening programs should be focused on the population over the age of 55 where the risk of stroke in AF increases with each decade.

Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG)

BACKGROUND: Interferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment. OBJECTIVES: To determine the incidence and biological significance of NAB to interferon beta-la (IFN-beta-1a; Avonex; Biogen, Cambridge, MA) in MS patients. METHODS: A two-step assay for NAB to IFN-beta-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-beta-1a, and from patients in an ongoing open-label study of IFN-beta-1a. The biological significance of NAB to IFN-beta-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and beta-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-beta-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-beta-1a with the incidence in MS patients who had used only IFN-beta-1b. RESULTS: In patients in the open-label study, development of NAB to IFN-beta-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in beta-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-beta-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-beta-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-beta-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-beta-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. CONCLUSIONS: NAB directed against IFN-beta have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-beta is significantly greater with IFN-beta-1b therapy compared with IFN-beta-1a therapy. Treatment decisions in MS patients treated with IFN-beta should take into account development of NAB.

Comparing the ability of various compositive outcomes to discriminate treatment effects in MS clinical trials. The Multiple Sclerosis Collaborative Research Group (MSCRG).

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-physician-based 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.

Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).

BACKGROUND AND OBJECTIVE: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-1a (IFN beta-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as > or = 1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance. METHODS: Post hoc analyses related to disability outcomes using data collected during the double-blind, placebo-controlled phase III clinical trial. RESULTS: (1) Clinical efficacy related to disability did not depend on the definition of disability progression. A significant benefit in favor of IFN beta-1a was observed when > or = 2.0 point worsening from baseline EDSS was required or when worsening was required to persist for > or = 1.0 year. (2) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFN beta-1a recipients who reached the primary study outcome. (3) Significantly fewer IFN beta-1a recipients progressed to EDSS milestones of 4.0 (relatively severe impairment) or 6.0 (unilateral assistance needed to walk). (4) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFN beta-1a treatment. CONCLUSIONS: The primary clinical outcome for the IFN beta-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFN beta-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.

Thromboembolism prophylaxis in chronic atrial fibrillation. Practice patterns in community and tertiary-care hospitals.

BACKGROUND AND PURPOSE: By 1992, several prospective trials established the efficacy of anticoagulation (AC) and to some extent antiplatelet (AP) agents in the prevention of stroke in the setting of atrial fibrillation (AF). The objective of this study was to determine whether practice patterns in AF stroke prophylaxis reflect the findings of clinical trials and whether stroke prophylaxis in AF differs between community hospitals and tertiary teaching hospitals. METHODS: Retrospectively, 1250 hospital charts were reviewed. After patients who had undergone recent surgery, received treatment for malignancy, or were not in chronic AF on discharge were eliminated, 651 remaining records were analyzed for the presence of 26 clinical factors influencing the selection of thromboembolism prophylaxis. Descriptive statistics and logistic regression were used to analyze the association between clinical and demographic factors and the decision to treat with AC, AP, or no specific antiembolic therapy. RESULTS: Of the 651 patients in AF, 273 (42%) received noemboli prophylaxis while 219 (34%) were treated with AC (warfarin), 146 (22%) were treated with AP, and 13 (2%) received both agents. Patients discharged in AF from community hospitals were significantly less likely to be treated with either AC or AP agents than patients discharged from tertiary centers. A strong bias against thromboembolism prophylaxis with either AC or AP agents in AF existed with age over 45 years. Multivariate logistic regression indicated that the decision to treat was associated only with the presence of prosthetic valve, history of prior stroke, mitral disease, and absence of a recent gastrointestinal bleed or occult blood in stool. Even after adjustment for these factors, a significant bias against treatment with either AC or AP agents with advancing age and discharge from community hospitals remained. CONCLUSIONS: Thromboembolism prophylaxis with either AC or AP agents is underutilized in the setting of AF. Furthermore, factors known to increase the risk of embolization in AF such as age, hypertension, diabetes, and heart disease were not associated with decisions to treat with either AP or AC agents. This study suggests that the use of clinical guidelines suggested by trials of thromboembolism prophylaxis in AF could reduce the incidence of stroke.

Rationale for early treatment with interferon beta-1a in relapsing-remitting multiple sclerosis.

Disease-modifying therapies are now available for the treatment of relapsing-remitting multiple sclerosis (RR-MS). These drugs have transformed the management of RR-MS from simply treating symptomatic disease to providing effective but incomplete prophylaxis against further disease activity. Our ability to modify disease activity is limited to reducing exacerbations and delaying progression of disability. No intervention has yet been shown to reverse disability once it is established. To prevent disability, therapy should be initiated early in the course of the illness. The rationale for early treatment is as follows: (1) a high percentage of patients with clinically definite RR-MS progress from isolated attacks to neurologic impairment and then to disability within a short time; (2) survival in MS is directly related to disability, so delaying the onset of disability could be expected to influence survival; (3) interferon (IFN) beta-1a has been shown to slow the progression of disability when given to RR-MS patients with impairment or mild disability; and (4) magnetic resonance imaging studies indicate that MS patients frequently have evidence of central nervous system inflammation without overt clinical symptoms, and it has been postulated that treatment of subclinical disease as identified by magnetic resonance imaging may improve long-term outcome. IFN-beta reduces the number of new T2-weighted lesions, as well as the number and volume of gadolinium-enhanced lesions. Aggressive early treatment with IFN beta-1a is recommended, particularly for patients with risk factors suggesting an unfavorable prognosis.