Multiple Sclerosis Journal

Susceptibility-weighted imaging (SWI) is an iron-sensitive magnetic resonance imaging (MRI) method that has shown iron-related lesions in multiple sclerosis (MS) patients. The contribution of deoxyhemoglobin to the signals seen in SWI has not been well characterized in MS.

To determine if SWI lesions (seen as focal hypointensities) exist in the experimental autoimmune encephalomyelitis (EAE) animal model of MS, and to determine whether the lesions relate to iron deposits, inflammation, demyelination, and/or deoxyhemoglobin in the vasculature.

We performed SWI on the lumbar spinal cord and cerebellum of EAE and control mice (both complete Freund’s adjuvant/pertussis toxin (CFA/PTX)-immunized and naive). We also performed SWI on mice before and after perfusion (to remove blood from vessels). SWI lesions were counted and their locations were compared to histology for iron, myelin and inflammation.

SWI lesions were found to exist in the EAE model. Many lesions seen by SWI were not present after perfusion, especially at the grey/white matter boundary of the lumbar spinal cord and in the cerebellum, indicating that these lesion signals were associated with deoxyhemoglobin present in the lumen of vessels. We also observed SWI lesions in the white matter of the lumbar spinal cord that corresponded to iron deposition, inflammation and demyelination. In the cerebellum, SWI lesions were present in white matter tracts, where we found histological evidence of inflammatory perivascular cuffs.

SWI lesions exist in EAE mice. Many lesions seen in SWI were a result of deoxyhemoglobin in the blood, and so may indicate areas of hypoxia. A smaller number of SWI lesions coincided with parenchymal iron, demyelination, and/or inflammation.

There are modest correlations between multiple sclerosis (MS) disability and white matter lesion (WML) volumes, as measured by T2-weighted (T2w) magnetic resonance imaging (MRI) scans (T2-WML). This may partly reflect pathological heterogeneity in WMLs, which is not apparent on T2w scans.

To determine if ADvanced IMage Algebra (ADIMA), a novel MRI post-processing method, can reveal WML heterogeneity from proton-density weighted (PDw) and T2w images.

We obtained conventional PDw and T2w images from 10 patients with relapsing–remitting MS (RRMS) and ADIMA images were calculated from these. We classified all WML into bright (ADIMA-b) and dark (ADIMA-d) sub-regions, which were segmented. We obtained conventional T2-WML and T1-WML volumes for comparison, as well as the following quantitative magnetic resonance parameters: magnetisation transfer ratio (MTR), T1 and T2. Also, we assessed the reproducibility of the segmentation for ADIMA-b, ADIMA-d and T2-WML.

Our study’s ADIMA-derived volumes correlated with conventional lesion volumes (p < 0.05). ADIMA-b exhibited higher T1 and T2, and lower MTR than the T2-WML (p < 0.001). Despite the similarity in T1 values between ADIMA-b and T1-WML, these regions were only partly overlapping with each other. ADIMA-d exhibited quantitative characteristics similar to T2-WML; however, they were only partly overlapping. Mean intra- and inter-observer coefficients of variation for ADIMA-b, ADIMA-d and T2-WML volumes were all < 6 % and < 10 %, respectively.

ADIMA enabled the simple classification of WML into two groups having different quantitative magnetic resonance properties, which can be reproducibly distinguished.

The aim of this study is to report the clinical profile and outcome of longitudinally extensive transverse myelitis (LETM).

We prospectively studied adult patients who presented with LETM from January 2008 to December 2011. Information on demographic, clinical course, magnetic resonance imaging (MRI) and outcome was collected. HLA-DRB1 genotype was compared with those of 225 normal controls and patients with MS (228) and neuromyelitis optica (NMO) (22).

In total, 23 patients (16 female) with a median age of 44.5 years (range: 20–77 years) were included. Most (74%) had moderate–severe disability at nadir (48% non-ambulatory), normal/non-multiple sclerosis (MS) brain MRI (96%) and a median MRI cord lesion of 5 vertebral segments (range: 3–19). Laboratory analysis showed cerebrospinal fluid pleocytosis (45%), NMO-IgG (9%), antinuclear antibodies (70%), and genotype HLA-DRB1*13 (57%). The frequency of DRB1*13 genotype was higher compared with controls (p=0.002), MS (p=0.001) and NMO (p= 0.003) patients. After a median follow-up of 32 months, one patient converted to MS, two had relapsing LETM with NMO-IgG, and 20 remained as idiopathic with recurrences in four (20%). Twelve (52%) patients recovered with minimal disability (Expanded Disability Status Scale (EDSS) <2.5) and three (13%) remained wheelchair dependent. Disability at nadir was associated with the final outcome and extension of the spinal cord lesion with risk of recurrence. Recurrence was not associated with worse outcome.

Inflammatory LETM is mostly idiopathic with a good outcome. It includes a relatively homogenous group of patients with an overrepresentation of the HLA-DRB1*13 genotype. EDSS at nadir is a predictor of the final outcome and extension of the myelitis of the recurrence risk.

We designed a prospective case-control study of patients with clinically isolated syndrome (CIS) and Relapsing–Remitting Multiple Sclerosis (RRMS) with an Expanded Disability Status Score (EDSS) of ≤2, compared with age-and-sex-matched healthy controls, to test the hypothesis that chronic cerebrospinal venous insufficiency (CCSVI) is more prevalent in patients with CIS or mild MS.

All subjects were examined using a Siemens Antares duplex ultrasound machine. The internal jugular, vertebral and intracranial veins were studied in subjects in both supine and sitting postures. The sonographer was blind to the subject’s clinical status. Measures included the criteria proposed by Zamboni and volume flow. Presence of CCSVI was defined as ≥2 Zamboni criteria.

Seventy patient-control pairs were recruited, with 11 males and 59 females in each group. Only one subject, a control, satisfied the Zamboni definition of CCSVI; however, 19 patients and 13 controls had abnormalities as defined by Zamboni, the difference largely caused by a higher prevalence in patients of internal jugular vein (IJV) stenosis, defined as a cross-sectional area ≤0.3cm². This difference disappeared with a more rigorous stenosis definition. Further analysis revealed there was IJV valve variation in seven patients and one control.

Our findings indicate that CCSVI, as defined by the Zamboni ultrasound criteria, is not present in CIS and mild RRMS (EDSS ≤2), providing further evidence that CCSVI does not have a causal role in MS; however, we found an apparent increase in IJV variation in patients with CIS or mild MS that would warrant further investigation.

A small proportion of multiple sclerosis (MS) patients treated with natalizumab develop anti-drug antibodies.

The objective of this paper is to characterize the anti-natalizumab antibody response and to investigate differences between persistently and transiently antibody-positive patients.

Screening for anti-natalizumab antibodies was performed using a standardized bridging ELISA. Antibody-positive samples were further analyzed for IgM and IgG1–4 antibodies using ELISA and ImmunoCAP®.

Anti-natalizumab antibodies developed in 57 of 1379 (4.1%) treated patients after a median treatment duration of three months. Of the positive patients, 20 (35%) patients reverted to negative, 19 (33%) patients were confirmed persistently positive and 18 (32%) patients were unconfirmed positive. Significantly higher anti-natalizumab antibody levels were detected in persistently compared to transiently positive patients. A cutoff value predicting persistence of antibodies could be determined with a sensitivity of 0.84 and a specificity of 0.80. IgM and IgG4 antibody levels were significantly higher in persistently compared to transiently positive patients, and IgG1, IgG2 and IgG4 increased significantly over time.

The level of total anti-natalizumab antibodies in a first positive sample can be used to predict patients at risk for persisting antibody positivity. However, neither IgM nor IgG1–4 antibodies could be used to discriminate between transiently and persistently positive patients.

It is currently unknown whether early immunomodulatory treatment in relapsing–remitting MS (RRMS) can delay the transition to secondary progression (SP).

To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort.

We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995–2004, n = 730) and a historical population-based incidence cohort (onset 1950–64, n = 186). We retrospectively analyzed the difference in time to SP, termed the “period effect” within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis.

We found that the “period” affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53).

Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.

Baseline Expanded Disability Status Scale (EDSS) is usually based on a single measurement. Here we evaluated whether using a baseline EDSS derived from two pre-treatment measurements improves the detection of progression events and the ability to demonstrate a therapeutic effect in delaying MS disability progression.

Real data from OLYMPUS, a phase II/III randomized, placebo-controlled trial of rituximab in patients with primary progressive multiple sclerosis (PPMS), as well as simulated data were analyzed. Several definitions of baseline EDSS were used to capture sustained disability progression (SDP) events. Variations in the EDSS were estimated by linear mixed-effect models.

Selecting the higher of two baseline EDSS scores lowered the number of SDP events in both treatment groups, so decreasing sensitivity, and reduced the number of false SDP events, so increasing specificity. Conversely, selecting the lower of two baseline scores increased sensitivity but decreased specificity. Increased power (~7% based on the simulation study) was observed when the average of screening and Week 0 EDSS scores was used for baseline.

Baseline EDSS derived from two pre-treatment EDSS measurements may enhance the ability of detecting a therapeutic effect in slowing disability progression in PPMS. This strategy could be implemented in future clinical trials of patients with MS.

While there is an increasing body of evidence supporting the efficacy of exercise in people with multiple sclerosis (MS), additional information on the effectiveness of combining aerobic and resistance training, and yoga is required.

This study evaluated the effectiveness of community exercise interventions for people with MS having minimal gait impairment.

A multi-centred, block-randomised, assessor-blinded, controlled trial was conducted. Participants were randomised in groups of eight to physiotherapist (PT)-led exercise (n = 80), yoga (n = 77), fitness instructor (FI)-led exercise (n = 86) and they took part in weekly community-based group exercise sessions. Those in the control group were asked not to change of their exercise habits (n = 71). The primary outcome was the Multiple Sclerosis Impact Scale (MSIS) 29v2 physical component, measured before and after the 10-week intervention. Secondary outcomes were the MSIS 29v2 psychological component, the Modified Fatigue Impact Scale (MFIS) and the 6-Minute Walk Test (6MWT).

The group x time interaction approached significance for the MSIS-29v2 physical component (f = 2.48, p = 0.061) and MFIS total (f = 2.50, p = 0.06), and it was significant for the MFIS physical subscale (f = 4.23, p = 0.006). All three exercise interventions led to a statistically significant improvement on the MSIS-29 psychological component and both the MFIS total and physical subscales, which were greater than the control (p < 0.05). Only the PT-led and FI-led interventions significantly improved the MSIS-29 physical and 6MWT to levels greater than the control (p < 0.05).

This study provides evidence for the positive effect of exercise on the physical impact of MS and fatigue. The group nature of the classes may have contributed to the positive effects seen on the psychological impact of MS.

Although there are many studies evaluating exercise interventions, few studies have evaluated the effect at follow-up.

This paper presents follow-up data for participants who completed the exercise interventions in a large randomised controlled trial.

One hundred twenty-one people with multiple sclerosis (MS) with minimal gait impairment who completed 10 weeks of community-based exercise interventions were evaluated by a blinded assessor 12 weeks after the intervention. The primary outcome measure was the Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29,v2) physical component. Other outcomes were the MSIS-29 psychological component, the Modified Fatigue Impact Scale (MFIS) and the 6-minute walk test (6MWT) distance.

The positive effect on the physical impact of MS was not maintained from baseline to follow-up (−1.6, 95% CI −0.8, 4.0, p=0.189). The psychological impact and the impact of fatigue remained significantly improved (−3.5, 95% CI −6.1, −1.0, p = 0.006 and −4.68, 95% CI −6.9, −2.5, p < 0.001, respectively). There was no time effect for the 6MWT (f = 1.76, p = 0.179) although the trend suggests reversal of the benefits gained from the physiotherapist (PT)- and fitness instructor (FI)-led intervention.

The maintained benefit on the psychological impact of MS and fatigue may have important personal and socioeconomic consequences; however, it is important to find ways to maintain the physical benefits of exercise over the long term.

Cognitive impairment is a common symptom of multiple sclerosis (MS), but little is known about cognitive decline in patients in the long-term course of progressive MS. Because advancing age is the most significant risk factor for Alzheimer’s Disease (AD), AD-related pathology must be considered in elderly patients with MS. Amnestic mild cognitive impairment (aMCI) represents the prodromal phase of AD with subjects showing memory impairment that does not improve with recognition testing.

We sought to identify disease-dependent deterioration patterns by comparing elderly patients with secondary progressive MS (SPMS) and with aMCI using the Consortium to Establish a Registry for Alzheimer’s Disease test battery.

This study included 120 age-, education- and gender-matched participants, including healthy controls (n=40), SPMS patients (n=40), and aMCI patients (n=40).

Episodic memory deficits appeared in the long-term course of SPMS. Deficits were associated with deterioration of executive function, but not impairment of memory storage as recognition was preserved in SPMS in contrast to the patients with aMCI.

Through neuropsychological testing, MS-related episodic memory impairment due to deteriorated executive function can be distinguished from AD-related encoding and storage deficits. Hence, neuropsychological testing may help to identify AD-related pathology in SPMS patients.

Hand dysfunction is common in multiple sclerosis (MS). Recent interest has focused on incorporating patient-reported outcome (PRO) instruments into clinical trials. Nevertheless, examinations are rare in MS of existing manual ability measures.

The objective of this paper is to evaluate the 23-item ABILHAND, developed for use after stroke, in people with MS, comparing the findings from two psychometric approaches.

We analysed ABILHAND data from 300 people with MS using: 1) traditional psychometric methods (data completeness, scaling assumptions, reliability, internal and external construct validity); and 2) Rasch measurement methods (including targeting, item response category ordering, data fit to the Rasch model, spread of item locations, item scoring bias, item stability, reliability, person response validity).

Traditional psychometric methods implied ABILHAND was reliable and valid in this sample. Rasch measurement methods supported this finding. The three-category scoring function worked as intended and item fit to Rasch model expectations was acceptable. The 23 items (location range −3.16 to +2.73 logits) mapped a continuum of manual ability. Reliability was high (Person Separation Index (PSI) = 0.95).

Both psychometric evaluations supported ABILHAND as a robust manual ability PRO measure for MS. Rasch measurement methods were more informative and, consistent with its role of detecting anomalies, identified ways of advancing further ABILHAND’s measurement performance to reduce any potential for type II errors in clinical trials.