White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis.

Background And Purpose: Natalizumab treatment strongly affects relapsing-remitting multiple sclerosis, possibly by restraining white matter damage. This study investigated changes in white matter diffusivity in patients with relapsing-remitting multiple sclerosis during their first year of natalizumab treatment by using diffusion tensor imaging.

Materials And Methods: The study included patients with relapsing-remitting multiple sclerosis initiating natalizumab at baseline (n = 22), patients with relapsing-remitting multiple sclerosis continuing interferon-β or glatiramer acetate (n = 17), and healthy controls (n = 12).

Moving toward earlier treatment of multiple sclerosis: Findings from a decade of clinical trials and implications for clinical practice.

The first clinical presentation of multiple sclerosis (MS) is usually a single episode of typical symptoms and signs and is designated a "first clinical demyelinating event" (FCDE) or a "clinically isolated syndrome". Patients with an FCDE who show 'silent' magnetic resonance imaging lesions are at high risk of further clinical events and therefore of meeting the criteria for the diagnosis of clinically definite MS (CDMS). Here we review five Phase III trials, in which treatment with the following disease-modifying drugs (DMDs) was initiated at this early stage: interferon beta (ETOMS, CHAMPS, BENEFIT, and REFLEX) and glatiramer acetate (PreCISe).

Enhanced axonal metabolism during early natalizumab treatment in relapsing-remitting multiple sclerosis.

Background And Purpose: The considerable clinical effect of natalizumab in patients with relapsing-remitting multiple sclerosis might be explained by its possible beneficial effect on axonal functioning. In this longitudinal study, the effect of natalizumab on absolute concentrations of total N-acetylaspartate, a marker for neuronal integrity, and other brain metabolites is investigated in patients with relapsing-remitting multiple sclerosis by using MR spectroscopic imaging.

Materials And Methods: In this explorative observational study, 25 patients with relapsing-remitting multiple sclerosis initiating natalizumab treatment were included and scanned every 6 months for 18 months.

Longitudinal JCV serology in multiple sclerosis patients preceding natalizumab-associated progressive multifocal leukoencephalopathy.

The presence of anti-John Cunningham Virus (JCV) antibodies is a risk factor for the development of progressive multifocal leukoencephalopathy (PML) in MS patients treated with natalizumab. It has been suggested that an increase in serum anti-JCV antibody index precedes the development of PML. We here describe extensive longitudinal serum anti-JCV antibody indexes of four MS patients who developed PML.

Functional brain networks: linking thalamic atrophy to clinical disability in multiple sclerosis, a multimodal fMRI and MEG study.

Thalamic atrophy is known to be one of the most important predictors for clinical dysfunction in multiple sclerosis (MS). As the thalamus is highly connected to many cortical areas, this suggests that thalamic atrophy is associated with disruption of cortical functional networks. We investigated this thalamo-cortical system to explain the presence of physical and cognitive problems in MS.

Molecular mechanism underlying the impact of vitamin D on disease activity of MS.

Objective: Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.

Methods: This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome.

Toward the use of proxy reports for estimating long-term patient-reported outcomes in multiple sclerosis.

Background: Assessment of disease impact in multiple sclerosis (MS) is usually driven by information obtained directly from patients using patient-reported outcomes. However, when patients' response in longitudinal studies is less reliable or missing, proxy respondents may be used.

Objective: The objective of this paper is to evaluate whether long-term patient scores can be reliably estimated using scores obtained from proxies.

Multiple sclerosis: current knowledge and future outlook.

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal loss. The etiology of MS is unknown; however, environmental and genetic factors play a key role in the development of MS. Diagnostic criteria have been adapted to facilitate earlier diagnosis with increased sensitivity and specificity.

Application of serum natalizumab levels during plasma exchange in MS patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment. Restoring immune function by plasmapheresis/immunoadsorption (PLEX/IA) is important for the outcome of PML. We report on four multiple sclerosis (MS) patients whom developed PML during natalizumab treatment, in whom we measured serum natalizumab concentrations before and during PLEX.

Disruption of structural and functional networks in long-standing multiple sclerosis.

Both gray matter atrophy and disruption of functional networks are important predictors for physical disability and cognitive impairment in multiple sclerosis (MS), yet their relationship is poorly understood. Graph theory provides a modality invariant framework to analyze patterns of gray matter morphology and functional coactivation. We investigated, how gray matter and functional networks were affected within the same MS sample and examined their interrelationship.

Detecting clinically-relevant changes in progressive multiple sclerosis.

Objective: To investigate which changes in different clinical outcome measures contribute most to increased disease impact, as reported by the patient, in progressive multiple sclerosis (MS).

Methods: From a cohort of prospectively-followed MS patients, we selected progressive patients with two visits, 4-6 years apart. We assessed long-term changes on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Guy's Neurological Disability Scale (GNDS).

Bidirectional trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis.

Objective: To investigate the coexistence of anterograde and retrograde trans-synaptic axonal degeneration, and to explore the relationship between selective visual pathway damage and global brain involvement in longstanding multiple sclerosis (MS).

Methods: In this single-centre, cross-sectional study, patients with longstanding MS (N=222) and healthy controls (HC, N=62) were included. We analysed thickness of retinal layers (optical coherence tomography), damage within optic radiations (OR) (lesion volume and fractional anisotropy and mean diffusivity by diffusion tensor imaging) and atrophy of the visual cortex and that of grey and white matter of the whole-brain (structural MRI).

A computer-based screening method for distress in patients with multiple sclerosis: a feasibility study.

Background: In multiple sclerosis (MS) patients, symptoms of anxiety, depression, pain, and cognitive impairment are highly prevalent and contribute to lower wellbeing. As these physical and psychological symptoms of distress often stay unnoticed, regular screening could offer possibilities to identify and refer impaired patients to appropriate care.

Objective: The aim of our study was to pilot a new computer-based method in 43 MS patients to efficiently screen for a variety of psychological and physical symptoms of distress.

Defining the clinical course of multiple sclerosis: the 2013 revisions.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS.

Morphological features of MS lesions on FLAIR* at 7 T and their relation to patient characteristics.

Recently, a new MRI technique was developed at 3 Tesla (T), called fluid attenuated inversion recovery* (FLAIR*). In this study, we implemented FLAIR* in an existing MS cohort at 7 T, to investigate whether we could corroborate results of previous 7 T studies that introduced specific MS lesion characteristics. Furthermore, we aimed to investigate the meaning of these lesion characteristics by relating them to clinical characteristics of the MS patient.

Structural degree predicts functional network connectivity: a multimodal resting-state fMRI and MEG study.

Communication between neuronal populations in the human brain is characterized by complex functional interactions across time and space. Recent studies have demonstrated that these functional interactions depend on the underlying structural connections at an aggregate level. Multiple imaging modalities can be used to investigate the relation between the structural connections between brain regions and their functional interactions at multiple timescales.

Do patient and proxy agree? Long-term changes in multiple sclerosis physical impact and walking ability on patient-reported outcome scales.

Background: Patient-reported outcome scales (PROs) are useful in monitoring changes in multiple sclerosis (MS) over time. Although these scales are reliable and valid measures in longitudinal studies in MS patients, it is unknown what the impact is when obtaining longitudinal data from proxies.

Objective: The objective of this paper is to compare longitudinal changes in patient and proxy responses on PROs assessing physical impact of MS and walking ability.

Client-centred therapy in multiple sclerosis: more intensive diagnostic evaluation and less intensive treatment.

Objective: Despite beneficial effects on communication and process measures, client-centred practice has been shown to result in poor functional outcomes. To examine a potential explanation for poor functional outcomes, this paper aims to assess whether in client-centred therapy more time is spent on diagnostic consultation and less time on actual treatment compared to usual care.

Method: A multicentre cluster randomised controlled trial was performed.

A dam for retrograde axonal degeneration in multiple sclerosis?

Objective: Trans-synaptic axonal degeneration is a mechanism by which neurodegeneration can spread from a sick to a healthy neuron in the central nervous system. This study investigated to what extent trans-synaptic axonal degeneration takes place within the visual pathway in multiple sclerosis (MS).

Methods: A single-centre study, including patients with long-standing MS and healthy controls.

Vitamin D as an early predictor of multiple sclerosis activity and progression.

Importance: It remains unclear whether vitamin D insufficiency, which is common in individuals with multiple sclerosis (MS), has an adverse effect on MS outcomes.

Objectives: To determine whether serum concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, predict disease activity and prognosis in patients with a first event suggestive of MS (clinically isolated syndrome).

Design, Setting, And Participants: The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment study was a randomized trial originally designed to evaluate the impact of early vs delayed interferon beta-1b treatment in patients with clinically isolated syndrome.

Patient subgroup analyses of the treatment effect of subcutaneous interferon β-1a on development of multiple sclerosis in the randomized controlled REFLEX study.

The REFLEX study (NCT00404352) established that subcutaneous (sc) interferon (IFN) β-1a reduced the risks of McDonald MS (2005 criteria) and clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event suggestive of MS. The aim of this subgroup analysis was to assess the treatment effect of sc IFN β-1a in patient subgroups defined by baseline disease and demographic characteristics (age, sex, use of steroids at the first event, classification of first event as mono- or multifocal, presence/absence of gadolinium-enhancing lesions, count of <9 or ≥9 T2 lesions), and by diagnosis of MS using the revised McDonald 2010 MS criteria. Patients were randomized to the serum-free formulation of IFN β-1a, 44 μg sc three times weekly or once weekly, or placebo, for 24 months or until diagnosis of CDMS.

Disease course heterogeneity and OCT in multiple sclerosis.

Background: The heterogeneity of the disease course in multiple sclerosis (MS) remains a challenge for patient management and clinical trials.

Objective: The objective of this paper is to investigate the relationship between disease course heterogeneity and retinal layer thicknesses in MS.

Methods: A total of 230 MS patients and 63 healthy control subjects were included.

Changes in functional network centrality underlie cognitive dysfunction and physical disability in multiple sclerosis.

Background: Cognitive dysfunction in multiple sclerosis (MS) has a large impact on the quality of life and is poorly understood.

Objective: The aim of this study was to investigate functional network integrity in MS, and relate this to cognitive dysfunction and physical disability.

Methods: Resting state fMRI scans were included of 128 MS patients and 50 controls.

Efficacy of subcutaneous interferon β-1a on MRI outcomes in a randomised controlled trial of patients with clinically isolated syndromes.

Aim: The REbif FLEXible dosing in early MS (REFLEX) study compared several brain MRI outcomes in patients presenting with clinically isolated syndromes suggestive of multiple sclerosis and treated with two dose-frequencies of subcutaneous interferon (IFN) β-1a or placebo.

Methods: Patients were randomised (1:1:1) to IFN β-1a, 44 µg subcutaneously three times a week or once a week, or placebo three times a week for up to 24 months. MRI scans were performed every 3 months, or every 6 months if the patient developed clinically definite multiple sclerosis.