Management and outcome of CSF-JC virus PCR-negative PML in a natalizumab-treated patient with MS.

Objective: To describe the diagnosis and management of a 49-year-old woman with multiple sclerosis (MS) developing a progressive hemiparesis and expanding MRI lesion suspicious of progressive multifocal leukoencephalopathy (PML) 19 months after starting natalizumab.

Results: Polyomavirus JC (JCV)-specific qPCR in CSF was repeatedly negative, but JCV-specific antibodies indicated intrathecal production. Brain biopsy tissue taken 17 weeks after natalizumab discontinuation and plasmapheresis was positive for JCV DNA with characteristic rearrangements of the noncoding control region, but histology and immunohistochemistry were not informative except for pathologic features compatible with immune reconstitution inflammatory syndrome.

Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial.

Background: B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-remitting multiple sclerosis.

Methods: We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries.

Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS.

Standard clinical endpoints in multiple sclerosis (MS) studies, such as disability progression defined by the expanded disability status scale (EDSS) and annualized relapse rate, may not fully reflect all aspects of therapeutic benefit experienced by patients. Pivotal studies showed that natalizumab is effective both as monotherapy (AFFIRM study) and in combination with interferon beta-1a (IFNβ-1a) (SENTINEL study) in patients with relapsing MS. We present AFFIRM and SENTINEL data demonstrating the efficacy of natalizumab on prespecified tertiary endpoints, including extent of confirmed change in EDSS score from baseline, time to sustained progression to EDSS milestone scores, hospitalizations, corticosteroid use, and time to confirmed progression of cognitive deficits.

Randomized trial of oral teriflunomide for relapsing multiple sclerosis.

Background: Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis.

Methods: We concluded a randomized trial involving 1088 patients with multiple sclerosis, 18 to 55 years of age, with a score of 0 to 5.5 on the Expanded Disability Status Scale and at least one relapse in the previous year or at least two relapses in the previous 2 years.

Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial.

Background: The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFNβ-1b) on clinical and radiographic outcomes is controversial.

Objective: To assess NAb impact in the BEYOND study.

Methods: 2244 patients were randomized (2:2:1) to receive IFNβ-1b, either 250 or 500 µg, or glatiramer acetate, 20 mg, and observed for 2-3.

Multiple Sclerosis Severity Scale and whole-brain N-acetylaspartate concentration for patients' assessment.

Background: The ability to predict the course of multiple sclerosis (MS) is highly desirable but lacking.

Objective: To test whether the MS Severity Scale (MSSS) and global neuronal viability, assessed through the quantification of the whole-brain N-acetylaspartate concentration (WBNAA), concur or complement the assessment of individual patients' disease course.

Methods: The MSSS and average WBNAA loss rate (ΔWBNAA, extrapolated based on one current measurement and the assumption that at disease onset neural sparing was similar to healthy controls, obtained with proton magnetic resonance (MR) spectroscopy and magnetic resonance imaging (MRI)) from 61 patients with MS (18 male and 43 female) with long disease duration (15 years or more) were retrospectively examined.

Effect of BG-12 on contrast-enhanced lesions in patients with relapsing--remitting multiple sclerosis: subgroup analyses from the phase 2b study.

Background: In a phase 2b study in patients with relapsing-remitting MS (RRMS), BG-12 240 mg three times daily significantly reduced the number of new gadolinium-enhanced (Gd+) lesions from weeks 12 to 24 (primary end point) by 69% compared with placebo.

Objective: In this analysis, the effect of BG-12 240 mg three times daily on the number of Gd+ lesions from weeks 12 to 24 was evaluated in subgroups based on baseline disease characteristics and demographics.

Methods: Two hundred and fifty-seven patients were randomized equally to receive BG-12 (120 mg once daily or three times daily or 240 mg three times daily) or placebo.

Prediction of long-term disability in multiple sclerosis.

Background: Little is known about the predictive value of neurophysiological measures for the long-term course of multiple sclerosis (MS).

Objective: To prospectively investigate whether combined visual (VEP) and motor evoked potentials (MEP) allow prediction of disability over 14 years.

Methods: A total of 30 patients with relapsing-remitting and secondary progressive MS were prospectively investigated with VEPs, MEPs and the Expanded Disability Status Scale (EDSS) at entry (T0) and after 6, 12 and 24 months, and with cranial MRI scans at entry (T2-weighted and gadolinium-enhanced T1-weighted images).

Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome.

Objective: To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b).

Methods: In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 μg IFNβ-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNβ-1b for up to 5 years.

Fingolimod for multiple sclerosis: mechanism of action, clinical outcomes, and future directions.

The oral sphingosine 1-phosphate receptor (S1PR) modulator fingolimod functionally antagonizes S1PR hereby blocking lymphocyte egress from secondary lymphoid organs to the peripheral blood circulation. This results in a reduction in peripheral lymphocyte counts, including potentially encephalitogenic T cells. In patients with relapsing multiple sclerosis fingolimod has been shown to be an effective treatment.

Combined evoked potentials as markers and predictors of disability in early multiple sclerosis.

Objective: To prospectively assess combined evoked potentials (EP) as markers and predictors of the disease course of early MS over 3 years.

Methods: Fifty patients in the early phase of relapsing remitting MS prospectively received visual, somatosensory and motor EP and EDSS assessments at baseline (T1) and at 6 months intervals during 3 years. Spearman rank correlation was used to determine the relationship between z-transformed EP-latencies (z-EPL) and EDSS.

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy.

Can the functional assessment of multiple sclerosis adapt to changing needs? A psychometric validation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis.

Background: The Functional Assessment of Multiple Sclerosis (FAMS) is widely used in clinical trial programmes; however, it was developed before the rise in trials targeted at early stage multiple sclerosis (MS) and clinically isolated syndrome (CIS).

Objective: The aim of this study was to assess the psychometric properties of the FAMS within two clinically distinct populations, CIS and early relapsing-remitting MS (RRMS), and discern the appropriateness of the FAMS within these populations.

Methods: Secondary analysis was conducted on FAMS data from two clinical trials assessing interferon beta-1b in early RRMS and CIS.

Oral fingolimod (FTY720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study.

Background: Health-related quality of life (HRQoL) worsens with multiple sclerosis (MS) relapses and disease progression. Common symptoms including depression and fatigue may contribute to poor HRQoL.

Objectives: To report exploratory analyses assessing the impact of fingolimod (FTY720) on HRQoL and depression in a phase II study of relapsing MS.

Mannose-binding lectin deficiency is associated with smaller infarction size and favorable outcome in ischemic stroke patients.

Background: The Mannose-binding lectin (MBL) pathway of complement plays a pivotal role in the pathogenesis of ischemia/reperfusion (I/R) injury after experimental ischemic stroke. As comparable data in human ischemic stroke are limited, we investigated in more detail the association of MBL deficiency with infarction volume and functional outcome in a large cohort of patients receiving intravenous thrombolysis or conservative treatment.

Methodology/principal Findings: In a post hoc analysis of a prospective cohort study, admission MBL concentrations were determined in 353 consecutive patients with an acute ischemic stroke of whom 287 and 66 patients received conservative and thrombolytic treatment, respectively.

Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability.

Background: Although grey matter damage in multiple sclerosis is currently recognized, determinants of grey matter volume and its relationship with disability are not yet clear.

Objectives: The objectives of the study were to measure grey and white matter volumes across different disease phenotypes; identify MRI parameters associated with grey matter volume; and study grey and white matter volume as explanatory variables for clinical impairment.

Methods: This is a cross-sectional study in which MRI data of 95 clinically isolated syndrome, 657 relapsing-remitting, 125 secondary-progressive and 50 primary-progressive multiple sclerosis patients from three centres were acquired.

Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy.

Objective: Natalizumab, a therapy for multiple sclerosis (MS), has been associated with progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the CNS associated with the JC virus. We assessed clinical outcomes and identified variables associated with survival in 35 patients with natalizumab-associated PML.

Methods: Physicians provided Karnofsky scores and narrative descriptions of clinical status.

Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study.

Background: In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod.

Methods: Patients randomly assigned to receive 0.

Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis.

Background: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies.

Objectives: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS.

Methods: Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005.

Longitudinal gray matter changes in multiple sclerosis--differential scanner and overall disease-related effects.

Voxel-based morphometry (VBM) has been used repeatedly in single-center studies to investigate regional gray matter (GM) atrophy in multiple sclerosis (MS). In multi-center trials, across-scanner variations might interfere with the detection of disease-specific structural abnormalities, thereby potentially limiting the use of VBM. Here we evaluated longitudinally inter-site differences and inter-site comparability of regional GM in MS using VBM.

Interferon β-1b and glatiramer acetate effects on permanent black hole evolution.

Objective: To compare interferon β-1b (IFNβ-1b) and glatiramer acetate (GA) on new lesion (NL) (gadolinium-enhancing, new T2) evolution into permanent black holes (PBH)--a marker of irreversible tissue damage--in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: BEYOND was a large, phase III, clinical trial comparing IFNβ-1b 250 μg, IFNβ-1b 500 μg, and GA (2:2:1). Patient scans were reexamined post hoc for PBH in a rater-blinded manner.

Antigen-specific adaptive immune responses in fingolimod-treated multiple sclerosis patients.

T cells exit secondary lymphoid organs along a sphingosine1-phosphate (S1P) gradient and, accordingly, are reduced in blood upon fingolimod-mediated S1P-receptor (S1PR)-blockade. Serving as a model of adaptive immunity, we characterized cellular and humoral immune responses to influenza vaccine in fingolimod-treated patients with multiple sclerosis (MS) and in untreated healthy controls. Although the mode of action of fingolimod might predict reduced immunity, vaccine-triggered T cells accumulated normally in blood despite efficient S1PR-blockade.