Achieving valid patient-reported outcomes measurement: a lesson from fatigue in multiple sclerosis.

Background: The increasing influence of patient-reported outcome (PRO) measurement instruments indicates their scrutiny has never been more crucial. Above all, PRO instruments should be valid: shown to assess what they purport to assess.

Objectives: To evaluate a widely used fatigue PRO instrument, highlight key issues in understanding PRO instrument validity, demonstrate limitations of those approaches and justify notable changes in the validation process.

Randomized controlled trial of atorvastatin in clinically isolated syndrome: the STAyCIS study.

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.

Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study.

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.

Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis.

Objectives: The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT).

Methods: Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT).

Broadening the spectrum of controls for skin biopsy in painful neuropathies.

Epidermal nerve fiber density (ENFD) is useful in the evaluation of small-fiber neuropathies (SFSNs). A recent evidence-based review highlighted the need to broaden the spectrum of ENFD controls to include lower limb pain states other than polyneuropathy. We studied epidermal innervation in multiple sclerosis (MS) and distal lower limb burning pain (DLLBP).

Cancer incidence in a trial of an antiapoptotic agent for Parkinson's disease.

We performed a placebo-controlled trial of CEP-1347, an inhibitor of neuronal apoptotic cell death, in patients with early Parkinson's disease (PD) to determine whether long-term therapy would slow disability progression. This also provided an opportunity to monitor cancer incidence in a large cohort of PD patients followed prospectively including periods before and after patients developed disability requiring dopaminergic therapy. This was a multicenter study of 806 patients with early PD, without disability requiring dopaminergic therapy, assigned randomly to placebo or one of three doses of CEP-1347.

A randomized trial of memantine as treatment for spasticity in multiple sclerosis.

We report the results of a single center randomized, double-blind, placebo-controlled, parallel group trial of memantine in adults with multiple sclerosis and spasticity conducted over 12 weeks. Eligible MS patients had to have an Ashworth spasticity rating of 2 or higher in at least one lower extremity muscle group. Subjects were randomized to receive either placebo or memantine 10 mg twice a day.

A comparison of treatment thresholds in two large Parkinson's disease clinical trial cohorts.

Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) and Parkinson Research Examination of CEP-1347 Trial (PRECEPT) were two clinical trials of potential disease-modifying agents for Parkinson's disease that used the time to reaching disability sufficient to require dopaminergic therapy as the primary endpoint. To compare the thresholds for initiating dopaminergic treatment for Parkinson's disease between the two studies, conducted fifteen years apart. Baseline and 12-month endpoint characteristics for subjects in the placebo arms of the two studies were compared.

Urate as a predictor of the rate of clinical decline in Parkinson disease.

Background: The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant.

Objective: To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD.

Design, Setting, And Participants: Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial.

Assessing disability progression with the Multiple Sclerosis Functional Composite.

Background: The initial Multiple Sclerosis Functional Composite (MSFC) proposal was a three-part composite of quantitative measures of ambulation, upper extremity function, and cognitive function expressed as a single composite Z-score. However, the clinical meaning of an MSFC Z-score change is not obvious. This study instead used MSFC component data to define a patient-specific disease progression event.

Proof of concept studies for tissue-protective agents in multiple sclerosis.

Background: There is considerable interest in tissue-protective treatments for multiple sclerosis (MS).

Methods And Objectives: We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods.

Results: Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3-6 months after starting treatment) to the final visit 1 year later.

Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.

Background: Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis.

Methods: We undertook a randomised, multicentre, double-blind, controlled phase III trial.

Polyunsaturated fatty acids and their potential therapeutic role in multiple sclerosis.

Considerable interest has been shown in the potential anti-inflammatory effects of polyunsaturated fatty acids (PUFAs) in multiple sclerosis (MS) and other autoimmune inflammatory disorders. Studies suggest a modest association between consumption of low levels of unsaturated fat and an increased incidence of MS. Moreover, in vitro and in vivo studies have demonstrated that omega-3 and omega-6 PUFA supplementation can reduce immune-cell activation via a number of complex pathways.

Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial.

Background: Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis (RRMS), but no published randomised trials have directly compared these two drugs. Our aim in the REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS.

Methods: In this multicentre, randomised, comparative, parallel-group, open-label study, patients with RRMS diagnosed with the McDonald criteria who had had at least one relapse within the previous 12 months were randomised to receive 44 mug subcutaneous interferon beta-1a three times per week or 20 mg subcutaneous glatiramer acetate once per day for 96 weeks to assess the time to first relapse.

Transtelephonic home blood pressure to assess the monoamine oxidase-B inhibitor rasagiline in Parkinson disease.

Monoamine oxidase inhibitors are associated with dietary tyramine interactions that can induce hypertensive crises. Rasagiline mesylate is a novel irreversible selective monoamine oxidase type B inhibitor for Parkinson disease that may have a low risk of interaction with dietary tyramine because of its selectivity. To study interactions of rasagiline with diets unrestricted in tyramine-containing foods, we incorporated transtelephonic, self-monitoring of the blood pressure (BP) into a randomized, placebo-controlled trial of rasagiline 0.

Dose comparison trial of sustained-release fampridine in multiple sclerosis.

Objective: To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS).

Method: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks.

Quantitative risk-benefit analysis of natalizumab.

Objective: To model the long-term risks and benefits of natalizumab in individuals with relapsing multiple sclerosis (MS).

Methods: We created a Markov model to evaluate treatment effects on reducing relapses and slowing disease progression using published natural history data and clinical trial results. Health changes, measured in quality-adjusted life-years (QALYs), were based on patient health preferences.

Serum urate as a predictor of clinical and radiographic progression in Parkinson disease.

Objective: To determine whether concentration of serum urate, a purine metabolite and potent antioxidant that has been linked to a reduced risk of Parkinson disease (PD), predicts prognosis in PD.

Design: Prospective study.

Setting: The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which investigated the effects of a potential neuroprotectant on rates of PD progression, was conducted between April 2002 and August 2005 (average follow-up time 21.

Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment.

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions.

Neuromyelitis optica spectrum disorder in a patient with systemic lupus erythematosus and anti-phospholipid antibody syndrome.

Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system characterized by severe episodes of optic nerve and spinal cord inflammation. NMO-IgG (anti-aquaporin-4) has been recently described as a sensitive and specific marker for NMO. As there have been prior published reports of an association between NMO and systemic autoimmune diseases, the prognostic value of the antibody test in these cases is uncertain.

Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis.

Background: Interferon (IFN)-beta therapy represents an important advance in the management of relapsing multiple sclerosis (MS), but information about the relative benefits and risks of available preparations is limited.

Objective: This report describes the full results of the Evidence of Interferon Dose-response-European North American Comparative Efficacy (EVIDENCE) study, combining analyses that were previously reported in separate publications for different phases of the study.

Methods: The EVIDENCE study was a multicenter, randomized, assessor-blinded comparison of 2 IFN-beta dosing regimens.

Comparison of mobility device delivery within Department of Veterans Affairs for individuals with multiple sclerosis versus spinal cord injury.

Individuals with multiple sclerosis (MS) report decreased satisfaction with their mobility devices compared with individuals with spinal cord injuries (SCIs). This study (1) investigated the demographic differences between veterans with MS (V-MS) and veterans with SCI (V-SCI) who were issued a wheelchair by the Veterans Health Administration (VHA) and (2) described differences in mobility device prescription. We merged two VHA databases to obtain demographic and wheelchair information for all V-MS and V-SCI in 2000 and 2001.

Pain associated with multiple sclerosis: systematic review and proposed classification.

Pain is common in patients with multiple sclerosis (MS), but estimates of its prevalence have varied widely. The literature describing pain in MS patients spans four decades and has employed a range of different methodologies. We undertook a systematic review in order to summarize current understanding of the association between MS and pain and provide a basis for the design and interpretation of future studies.

Quantifying the risks and benefits of natalizumab in relapsing multiple sclerosis.

Using published data, we quantified the risk and benefits of natalizumab in relapsing multiple sclerosis using quality-adjusted life years (QALYs) as a metric. Over the first 2 years of therapy, the negative health effects from progressive multifocal leukoencephalopathy were small (loss of 0.001 QALYs) relative to the positive effects on relapses and disability resulting in 0.

MRI features of pediatric multiple sclerosis.

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.