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). Distal-leg ENFD/morphology in MS DLLBP patients did not differ significantly from that of healthy controls. This study extends the range of ENFD controls and further supports use of ENFD assessment in SFSN.

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. Patients were monitored for an average of 1.8 years (1,467 patient-years) with routine cancer screening evaluations and annual skin examinations by a dermatologist. There was no significant excess of cancers among patients taking CEP-1347 compared with placebo for any cancer type (all P > 0.1). Nonmelanoma skin cancers were the most common cancer type observed. The incidence of melanomas was 20.9 times that predicted in the general population. Most melanomas occurred in patients who had never taken dopaminergic therapy. We found no evidence that CEP-1347 affected cancer incidence within 2 years of follow-up. Melanoma occurrence in our PD patients was greater than predicted compared with the general population and was unrelated to dopaminergic therapy. Clinical surveillance of PD patients for melanoma may be warranted.

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. The primary outcome measure for efficacy was the change in Ashworth Spasticity Scale Score. Although well tolerated, memantine treatment did not demonstrate efficacy in treatment of spasticity in this 12-week small exploratory study.

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. DATATOP placebo subjects had slightly higher total Unified Parkinson's Disease Rating Scale (UPDRS) scores at baseline than PRECEPT placebo subjects (26.1 vs. 23.6, P = 0.03). Time to endpoint was not significantly different. Mean total UPDRS scores at endpoint among those subjects reaching endpoint by 12 months were 48.4 in DATATOP and 37.5 in PRECEPT (P < 0.0001). Baseline disease severity and time to disability requiring dopaminergic therapy were similar in the DATATOP and PRECEPT trials. The threshold for starting dopaminergic treatment was lower in PRECEPT than in the earlier DATATOP study. This may relate to changes in philosophies with respect to starting treatment for Parkinson's disease, but the factors underlying this change remain to be elucidated.

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. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects. MAIN OUTCOME MEASURES: Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial. RESULTS: The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by alpha-tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with alpha-tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinson's Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinson's Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with alpha-tocopherol. CONCLUSIONS: Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.

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. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov, number NCT00127530. FINDINGS: The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0.0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25.2% (95% CI 21.5% to 28.8%) and 4.7% (1.0% to 8.4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (-6.84, 95% CI -9.65 to -4.02) than timed walk non-responders (0.05, -1.48 to 1.57; p=0.0002). Safety data were consistent with previous studies. INTERPRETATION: Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit.

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. Noncontrolled and controlled clinical trials of PUFA supplementation in patients with MS have, however, provided mixed results. These studies had important limitations in design and selection of outcome measures, and these factors might partially explain the inconsistent results. We propose that the potential role of PUFAs as disease-modifying, anti-inflammatory treatments for MS should be revisited in proof-of-concept trials that use accepted MRI outcome measures.

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. A subpopulation of 460 patients (230 from each group) also had serial MRI scans to assess T2-weighted and gadolinium-enhancing lesion number and volume. Treatments were assigned by a computer-generated randomisation list that was stratified by centre. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00078338. FINDINGS: Between February and December, 2004, 764 patients were randomly assigned: 386 to interferon beta-1a and 378 to glatiramer acetate. After 96 weeks, there was no significant difference between groups in time to first relapse (hazard ratio 0.94, 95% CI 0.74 to 1.21; p=0.64). Relapse rates were lower than expected: 258 patients (126 in the interferon beta-1a group and 132 in the glatiramer acetate group) had one or more relapses (the expected number was 460). For secondary outcomes, there were no significant differences for the number and change in volume of T2 active lesions or for the change in the volume of gadolinium-enhancing lesions, although patients treated with interferon beta-1a had significantly fewer gadolinium-enhancing lesions (0.24 vs 0.41 lesions per patient per scan, 95% CI -0.4 to 0.1; p=0.0002). Safety and tolerability profiles were consistent with the known profiles for both compounds. The overall number and severity of adverse events were similar between the treatments and were not an important cause for discontinuation of the trial during the 96 weeks. INTERPRETATION: There was no significant difference between interferon beta-1a and glatiramer acetate in the primary outcome. The ability to predict clinical superiority on the basis of results from previous studies might be limited by a trial population with low disease activity, which is an important consideration for ongoing and future trials in patients with RRMS.

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 0.5 and 1.0 mg daily in 414 levodopa-treated Parkinson patients with motor fluctuations. The proportion of patients with a systolic BP increase of >30 mm Hg was the primary BP end point. In 13 968 self-measured readings at baseline, the proportion of systolic BP values that increased by >30 mm Hg after a meal ranged from 9.5% to 12.9% in the 3 treatment groups. In 25 733 BPs obtained postrandomization, the proportion of values with a >30-mm Hg systolic postprandial increase was 15% in the placebo group, 15% in the rasagiline 0.5-mg group, and 11% in the rasagiline 1-mg group after 3 weeks of double-blind therapy and 13%, 14%, and 12%, respectively, after 26 weeks of treatment (P value was not significant for all of the comparisons among treatment groups). A postprandial increase in systolic BP to >180 mm Hg at any time after randomization was seen in 3.3%, 2.6%, and 2.9% of the placebo, 0.5-mg, and 1.0-mg rasagiline groups, respectively. These data demonstrate that rasagiline did not induce postprandial hypertension in patients with Parkinson disease who were on an unrestricted diet.

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 21.4 months). PARTICIPANTS: Eight hundred four subjects with early PD enrolled in the PRECEPT study. MAIN OUTCOME MEASURES: The primary study end point was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching end point according to quintiles of baseline serum urate concentration, adjusting for sex, age, and other potential covariates. Change in striatal uptake of iodine I 123-labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]beta-CIT), a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects. RESULTS: The adjusted HR of reaching end point declined with increasing baseline concentrations of urate; subjects in the top quintile reached the end point at only half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The percentage of loss in striatal [(123)I]beta-CIT uptake also improved with increasing serum urate concentrations (overall P for trend = .002; men, P = .001; women, P = .43). CONCLUSIONS: These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease-modifying therapy in PD. Trial Registration clinicaltrials.gov Identifier: NCT00040404.

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. We describe a 47-year old woman with recurrent transverse myelitis and a long-standing history of systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APLS). While she did not have a history of optic neuritis, serological testing for the NMO-IgG was positive when she was admitted for her second episode of transverse myelitis. Testing for the NMO-IgG in cases of isolated or recurrent transverse myelitis attributed to current SLE and APLS may help clarify the diagnosis of a distinct disease process likely to cause recurrent and severe disability, warranting more aggressive immunotherapy.

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. The point prevalence of pain in patients with MS is nearly 50%, and approximately 75% of patients report having had pain within one month of assessment. Pain adversely affects most aspects of health-related quality of life, including functional domains such as the ability to work. The presence of pain in patients with MS is associated with increased age, duration of illness, depression, degree of functional impairment, and fatigue. Several different types of pain are found in patients with MS, including extremity pain, trigeminal neuralgia, Lhermitte's sign, painful tonic spasms, back pain, and headache. Putative mechanisms of pain in patients with MS are discussed, and a classification of pain in MS is proposed. Few randomized clinical trials of treatments for MS pain have been conducted, and the limitations of current knowledge regarding approaches for treating MS pain are discussed. Suggestions for future studies that would increase understanding of the natural history, mechanisms, and treatment of pain in patients with MS are presented.

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. In the study, patients with relapsing MS were randomly assigned to SC IFN-beta1a 44 lag TIW (Rebif, Serono Inc., Geneva, Switzerland) or IM IFN-betala 30 mug QW (Avonex, Biogen Idec, Cambridge, Massachusetts) for 1 to 2 years. The primary clinical end point during the comparative phase was the proportion of patients who remained free from relapses; secondary and tertiary clinical end points included the annualized relapse rate and time to first relapse, re- spectively. All clinical and magnetic resonance imaging (MRI) evaluations were performed by blinded assessors. In the crossover phase of the study, patients who were originally randomized to low-dose QW treatment switched to the high-dose TIW treatment for an additional 8 months. Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase. RESULTS: A total of 677 patients were enrolled in the study and evenly randomized to treatment; 605 patients completed the comparative phase and 439 completed the crossover phase. During the comparative phase, a significantly higher proportion of patients in the high-dose TIW treatment group remained free from relapses when compared with patients in the low-dose QW treatment group (adjusted odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.023). The high-dose TIW regimen was also associated with a significant reduction in the annualized relapse rate (-17%; P = 0.033) and a prolonged time to first relapse (hazard ratio, 0.70; P = 0.002). MRI measures of disease activity were significantly reduced in the high-dose TIW group compared with the low-dose QW treatment. During the crossover phase, a 50% reduction in mean relapse rates was observed in patients who converted from low-dose QW treatment to high-dose TIW treatment (P < 0.001), with significant concomitant reductions in MRI activity. Injection-site reactions were significantly more common with high-dose TIW treatment than with low-dose QW treatment (85% vs 33%; P < 0.001). Neutralizing antibody formation was more common with high-dose TIW treatment than with low-dose QW treatment (26% vs 3%; P < 0.001). CONCLUSIONS: The comparative phase of the EVIDENCE study found that treatment of MS with SC IFN-beta1a 44 microg TIW was associated with a significant reduction in clinical and imaging measures of disease activity over 1 to 2 years, when compared with IM IFN-betala 30 microg QW treatment. The crossover phase found that patients who changed from low-dose QW treatment to high-dose TIW treatment experienced enhanced benefits of treatment without a substantial increase in adverse events.

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. Descriptive information for issued wheelchairs was available for 2,154 V-MS and V-SCI. We found that V-MS were significantly less likely to receive higher quality wheelchairs (manual or power) compared with V-SCI (p < 0.001). The disparity in VHA wheelchair prescription between these two groups indicates a need for further research regarding the assistive device prescription process in these populations.

Cognitive function in relapsing multiple sclerosis: minimal changes in a 10-year clinical trial.

BACKGROUND: Although cognitive impairment is common in patients with multiple sclerosis (MS), its value as a clinical trial endpoint remains uncertain. For example, in the randomized, blinded, pivotal trial of glatiramer acetate (GA) in patients with relapsing MS, improvements occurred in neuropsychological test scores during 2 years of treatment regardless of whether patients received GA or placebo, likely due to practice effects. OBJECTIVES: To assess long-term changes in neuropsychological status following 10 years of prospective evaluation in a typical immunotherapy trial cohort. METHODS: Participants in the ongoing open-label GA extension study repeated the Brief Repeatable Battery of Neuropsychological Tests an average of 10.6+/-0.4 years after their initial baseline evaluation. RESULTS: Mean scores on tests of memory and semantic retrieval were not significantly changed over 10 years of follow-up, but tests of attention showed declines for the group as a whole. Using a threshold of a 0.5 SD decline to define significant worsening, individual tests showed declines in 27-49% of participants and a composite score showed worsening in 19%. Controlling for age, gender, and education level, cognitive tests tended to worsen more in participants with better baseline cognitive test scores and higher EDSS scores. Changes in cognitive test scores during the first 2 years of observation were predictive of 10-year changes. CONCLUSIONS: Most patients with relapsing MS had stable cognitive performance during 10 years of prospective evaluation, some of which may be related to a therapeutic effect of GA. Because cognitive changes occur slowly on average, they may not be responsive enough to serve as useful endpoints in studies of course-modifying therapies in relapsing MS.

Effects of tyramine administration in Parkinson's disease patients treated with selective MAO-B inhibitor rasagiline.

Rasagiline is a novel, potent, and selective MAO-B inhibitor shown to be effective for Parkinson's disease. Traditional nonselective MAO inhibitors have been associated with dietary tyramine interactions that can induce hypertensive reactions. To test safety, tyramine challenges (50-75 mg) were performed in 72 rasagiline-treated and 38 placebo-treated Parkinson's disease (PD) patients at the end of two double-blind placebo-controlled trials of rasagiline. An abnormal pressor response was prespecified as three consecutive measurements of systolic blood pressure (BP) increases of >or= 30 mm Hg and/or bradycardia of < 40 beats/min. In the first study involving 55 patients with early PD on rasagiline monotherapy, no patients randomized to rasagiline (1 mg/2 mg; n = 38) or placebo (n = 17) developed systolic BP (SBP) or heart rate changes indicative of a tyramine reaction. In the second trial involving 55 levodopa-treated patients, 3 of 22 subjects on rasagiline 0.5 mg/day and 1 of 21 subjects on placebo developed asymptomatic, self-limiting SBP elevations >or= 30 mm Hg on three measurements. No subject on 1 mg/day rasagiline (0/12) experienced significant BP or heart rate changes following tyramine ingestion. These data demonstrate that rasagiline 0.5 to 2 mg daily is not associated with clinically significant tyramine reactions and can be used as monotherapy or adjunct to levodopa in PD patients without specific dietary tyramine restriction.

Immune response to influenza vaccine is maintained in patients with multiple sclerosis receiving interferon beta-1a.

Immunologic response was assessed prospectively using influenza vaccine in 86 patients with multiple sclerosis (MS) who were taking interferon beta-1a and 77 patients who were not taking interferon. Blood samples were assayed for hemagglutination inhibition (HI) titers 0, 21, and 28 days after immunization. The two groups were similar in the proportion of patients achieving an HI titer of 40 or greater, the prespecified primary end point and on all secondary indicators of immune response.

Enhanced benefit of increasing interferon beta-1a dose and frequency in relapsing multiple sclerosis: the EVIDENCE Study.

BACKGROUND: The EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study demonstrated that patients with multiple sclerosis (MS) who initiate interferon beta-1a therapy with 44 microg 3 times weekly (TIW) were less likely to have a relapse or activity on magnetic resonance imaging (MRI) compared with those who initiate therapy at a dosage of 30 microg 1 time weekly (QW). OBJECTIVE: To determine the effect of changing the dosage from 30 microg QW to 44 microg TIW in this extension of the EVIDENCE Study. DESIGN/PATIENTS: Patients with relapsing MS originally randomized to interferon beta-1a, 30 microg QW, during the comparative phase of the study changed to 44 microg TIW, whereas patients originally randomized to 44 microg TIW continued that regimen. Patients were followed up, on average, for an additional 32 weeks. MAIN OUTCOME MEASURE: The within-patient pretransition to post-transition change in relapse rate. RESULTS: At the transition visit, 223 (73%) of 306 patients receiving 30 microg QW converted to 44 microg TIW, and 272 (91%) of 299 receiving 44-microg TIW continued the same therapy. The post-transition annualized relapse rate decreased from 0.64 to 0.32 for patients increasing the dose (P<.001) and from 0.46 to 0.34 for patients continuing 44-microg TIW (P = .03). The change was greater in those increasing dose and frequency (P = .047). Patients converting to the 44-mug TIW regimen had fewer active lesions on T2-weighted MRI compared with before the transition (P = .02), whereas those continuing the 44-microg TIW regimen had no significant change in T2 active lesions. Patients who converted to high-dose/high-frequency interferon beta-1a therapy had increased rates of adverse events and treatment terminations consistent with the initiation of high-dose subcutaneous interferon therapy. CONCLUSIONS: Patients receiving interferon beta-1a improved on clinical and MRI disease measures when they changed from 30 microg QW to 44 microg TIW.