OBJECTIVE:To test efficacy and safety of atorvastatin in subjects with clinically isolated syndrome (CIS).METHODS:Subjects with CIS were enrolled in a phase II, double-blind, placebo-controlled, 14-center randomized trial testing 80 mg atorvastatin on clinical and brain MRI activity. Brain MRIs were performed quarterly. The primary endpoint (PEP) was development of ≥ 3 new T2 lesions, or one clinical relapse within 12 months. Subjects meeting the PEP were offered additional weekly interferon β-1a (IFNβ-1a).RESULTS:Due to slow recruitment, enrollment was discontinued after 81 of 152 planned subjects with CIS were randomized and initiated study drug. Median (interquartile range) numbers of T2 and gadolinium-enhancing (Gd) lesions were 15.0 (22.0) and 0.0 (0.0) at baseline. A total of 53.1% of atorvastatin recipients (n = 26/49) met PEP compared to 56.3% of placebo recipients (n = 18/32) (p = 0.82). Eleven atorvastatin subjects (22.4%) and 7 placebo subjects (21.9%) met the PEP by clinical criteria. Proportion of subjects who did not develop new T2 lesions up to month 12 or to starting IFNβ-1a was 55.3% in the atorvastatin and 27.6% in the placebo group (p = 0.03). Likelihood of remaining free of new T2 lesions was significantly greater in the atorvastatin group compared with placebo (odds ratio [OR] = 4.34, p = 0.01). Likelihood of remaining free of Gd lesions tended to be higher in the atorvastatin group (OR = 2.72, p = 0.11). Overall, atorvastatin was well tolerated. No clear antagonistic effect of atorvastatin plus IFNβ-1a was observed on MRI measures.CONCLUSION:Atorvastatin treatment significantly decreased development of new brain MRI T2 lesion activity, although it did not achieve the composite clinical and imaging PEP.CLASSIFICATION OF EVIDENCE:This study provided Class II evidence that atorvastatin did not reduce the proportion of patients with CIS meeting imaging and clinical criteria for starting immunomodulating therapy after 12 months, compared to placebo. In an analysis of a secondary endpoint (Class III), atorvastatin was associated with a reduced risk for developing new T2 lesions.

Objective: To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) in the United States compared to basic supportive therapy without DMT for patients with relapsing multiple sclerosis (MS). Methods: Using data from a longitudinal MS survey, we generated 10-year disease progression paths for an MS cohort. We used first-order annual Markov models to estimate transitional probabilities. Costs associated with losses of employment were obtained from the Bureau of Labor Statistics. Medical costs were estimated using the Centers for Medicare and Medicaid Services reimbursement rates and other sources. Outcomes were measured as gains in quality-adjusted life-years (QALY) and relapse-free years. Monte Carlo simulations, resampling methods, and sensitivity analyses were conducted to evaluate model uncertainty. Results: Using DMT for 10 years resulted in modest health gains for all DMTs compared to treatment without DMT (0.082 QALY or <1 quality-adjusted month gain for glatiramer acetate, and 0.126–0.192 QALY gain for interferons). The cost-effectiveness of all DMTs far exceeded $800,000/QALY. Reducing the cost of DMTs had by far the greatest impact on the cost-effectiveness of these treatments (e.g., cost reduction by 67% would improve the probability of Avonex being cost-effective at $164,000/QALY to 50%). Compared to treating patients with all levels of disease, starting DMT earlier was associated with a lower (more favorable) incremental cost-effectiveness ratio compared to initiating treatment at any disease state. Conclusion: Use of DMT in MS results in health gains that come at a very high cost.

BACKGROUND:MRI has revolutionized the diagnostic accuracy of multiple sclerosis (MS) in adults, and is now used extensively to evaluate efficacy of immunomodulatory therapies. Although MRI has also been used to aid in the diagnosis and care of children with MS, the MRI features of MS in children are less well understood.METHODS:The present review summarizes the available literature on MRI in pediatric MS, outlines the specific features of other disorders affecting the CNS white matter in children, compares the MRI appearance of MS in children to seminal neuroimaging studies in adult-onset MS, and discusses the potential role of advanced MRI technologies in delineating the underlying pathobiology of acquired demyelinating disease in children.RESULTS:Although the MRI features of MS in children have similarity to adult-onset MS, children tend to have fewer lesions and a lower propensity for lesions to enhance with gadolinium. The MRI findings in children presenting with a clinical phenotype of acute disseminated encephalomyelitis may be indistinguishable from the first attack of MS.CONCLUSIONS:MRI criteria specific for pediatric-onset multiple sclerosis (MS) and criteria predictive of MS outcome in children experiencing a first demyelinating event will be challenged by the overlap in MRI features between acute monophasic demyelinating syndromes and MS, particularly in younger children. Emergence of new clinically silent lesions on MRI scans separated by at least 3 months is characteristic of MS. Newer MRI techniques evaluating white matter biochemistry and integrity in the youngest MS patients may provide new insights into the relative contributions of inflammation and neurodegeneration in MS.

Methods: Fifteen major and minor ST-related adverse events (AEs) (fever, hypotension, hypertension, tachycardia, diarrhea, agitation, ataxia, confusion, emotional lability, myoclonus, nervouseness, sleep disorder, dyspnea, hyperventilation, sweating) were assessed. For each AE a Fisher Exact 2-tailed test was used to compare the incidence rate (per 100 subjects) in the rasagiline+antidepressant group vs. rasagiline-only group. Possible ST cases (combination of 4 major or 3 major + 2 minor AEs) and terminations due to AEs were followed.

The objective of this study was to determine the effects of rasagiline as monotherapy on quality of life (QOL) in patients with early Parkinson's disease (PD). Rasagiline, a potent, second-generation, irreversible, selective monoamine oxidase B inhibitor improves PD symptoms in patients with early PD. Patients with early untreated PD were randomly assigned to once-daily rasagiline 1 mg/day, rasagiline 2 mg/ day, or placebo in a 6-month, double-blind trial (n = 404). At the end of 6 months, patients entered the preplanned, active-treatment phase in which those receiving 1 mg/day and 2 mg/day of rasagiline continued on their previously assigned dosages and those receiving placebo switched to rasagiline 2 mg/day, while maintaining blinding to treatment assignments. QOL was measured with the Parkinson's Disease Quality of Life questionnaire (PDQUALIF) at 0, 14, 26, and 52 weeks after randomization. Analysis of the change in PDQUALIF scores from baseline to 6 months showed adjusted treatment effects (with 95% confidence interval) favoring rasagiline over placebo of -2.91 units (-5.19, -0.64, P = 0.01) for the 1 mg/day group and -2.74 units (-5.02, -0.45, P = 0.02) for the 2 mg/day. Subscore analysis attributed most of this benefit L to the self-image/sexuality domain. At 12 months (n = 266), with all groups receiving rasagiline for at least 6 months, no significant differences in PDQUALIF scores were seen between groups. Rasagiline improved QOL compared with placebo. This QOL improvement appears to be accounted for primarily by the symptomatic benefit of rasagiline. (C) 2006 Movement Disorder Society.

BACKGROUND Motor fluctuations are a common complication in patients with Parkinson disease (PD) receiving long-term levodopa therapy. Slowed gastric emptying and poor solubility of levodopa in the gastrointestinal tract may delay the onset of drug benefit after dosing. Etilevodopa is an ethyl-ester prodrug of levodopa that has greater gastric solubility, passes quickly into the small intestine, is rapidly hydrolyzed to levodopa, and has a shortened time to maximum levodopa concentration. OBJECTIVE To determine the efficacy, safety, and tolerability of etilevodopa in patients with PD who have motor fluctuations. DESIGN A double-blind, randomized, comparative clinical trial. SETTING Forty-four sites in the United States and Canada. PATIENTS Three hundred twenty-seven patients with PD who had a latency of at least 90 minutes total daily time to "on" (TTON) after levodopa dosing. INTERVENTION Treatment with either etilevodopa-carbidopa or levodopa-carbidopa for 18 weeks. MAIN OUTCOME MEASURE Change from baseline in total daily TTON as measured using home diaries. RESULTS The reduction in mean total daily TTON from baseline to treatment was 0.58 hour in the etilevodopa-carbidopa group and 0.79 hour in the levodopa-carbidopa group (P = .24). There was no significant difference between the etilevodopa-carbidopa and levodopa-carbidopa groups in the reduction of response failures (-6.82% vs -4.69%; P = .20). Total daily "off" time improved in the etilevodopa-carbidopa (-0.85 hour) and levodopa-carbidopa (-0.87 hour) groups without an increase in on time with troublesome dyskinesias. CONCLUSION Despite the theoretical pharmacokinetic advantage of etilevodopa, there was no improvement in TTON, response failures, or off time compared with levodopa.

BACKGROUND:Cognitive and behavioral adverse events (AEs) such as hallucinations, confusion, depression, somnolence and other sleep disorders commonly limit effective management of motor symptoms in PD. Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a novel, second-generation, selective, irreversible monoamine oxidase type B inhibitor, demonstrated in monotherapy and adjunctive trials to be effective for PD with excellent tolerability. METHODS:The occurrence of cognitive and behavioral AEs and the change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) part I mental subscores were reviewed in two multicenter, randomized, placebo-controlled, 26-week trials of rasagiline for early and moderate-to-advanced patients with PD. The UPDRS is a multi-item rating scale specific to PD; part I rates the patient's intellectual impairment, thought disorders, depression and motivation/initiative. RESULTS:The TEMPO study evaluated rasagiline monotherapy in early PD patients (n=404). The PRESTO study evaluated rasagiline as adjunctive therapy in moderate-to-advanced PD patients with motor complications who were receiving optimized levodopa/carbidopa (n=472). In the analysis of adverse event reporting for both studies, no cognitive and behavioral AE in either the rasagiline 1 mg or placebo groups exceeded 10% of the study population and the frequency differences between rasagiline 1 mg and placebo never exceeded 3%. There was no adverse effect on the UPDRS mental subscore relative to placebo in either of the two studies. CONCLUSION:Rasagiline 1 mg once daily improves PD symptoms and motor fluctuations in early and moderate-to-advanced PD patients without causing significant cognitive and behavioral AE or adverse changes in mentation, behavior and mood.