The 12-item Multiple Sclerosis Walking Scale (12-MSWS) is a validated questionnaire which assessed walking function; it has been widely adopted in multiple sclerosis (MS) clinical research.
Identify and validate clinically meaningful 12-MSWS benchmarks in MS.
Cross-sectional study of 159 MS patients permitted identification of clinically meaningful 12-MSWS benchmarks based on their relationship to real-life anchors. Identified 12-MSWS benchmarks were then validated in a second population of 96 subjects using measures of ambulation, cognition, and patient-reported outcomes.
12-MSWS score of 0–24.99 was associated with working outside the home and assistance-free mobility; 25–49.99 was associated with gait disability and difficulty doing housework; 50–74.99 was associated with unemployment, government healthcare, cane use, and difficulty performing instrumental activities of daily living (IADLs); and 75–100 was associated with change in occupation due to walking, mobility impairment requiring bilateral assistance, and inability to perform IADLs. During the validation step, strong linear associations were identified between 12-MSWS benchmarks and other MS-related disability outcome measures, including ambulatory and non-ambulatory measures.
We have identified clinically meaningful 12-MSWS benchmarks which define four groups differentiated by increasing levels of mobility impairment and associated loss of functional independence. These data provide insight into how 12-MSWS translate to meaningful functional limitations in MS.
Mendelian randomization (MR) studies have demonstrated strong support for an association between genetically increased body mass index and risk of multiple sclerosis (MS). The adipokine adiponectin may be a potential mechanism linking body mass to risk of MS.
To evaluate whether genetically increased adiponectin levels influence risk of MS.
Using genome-wide significant single nucleotide polymorphisms (SNPs) for adiponectin, we undertook an MR study to estimate the effect of adiponectin on MS. This method prevents bias due to reverse causation and minimizes bias due to confounding. Sensitivity analyses were performed to evaluate the assumptions of MR.
MR analyses did not support a role for genetically elevated adiponectin in risk of MS (odds ratio (OR) = 0.93 per unit increase in natural-log-transformed adiponectin, equivalent to a two-standard deviation increase in adiponectin on the absolute scale; 95% confidence interval (CI) = 0.66–1.33; p = 0.61). Further MR analysis suggested that genetic variation at the adiponectin gene, which influences adiponectin level, does not impact MS risk. Sensitivity analyses, including MR-Egger regression, suggested no bias due to pleiotropy.
Lifelong genetically increased adiponectin levels in humans have no clear effect on risk of MS. Other biological factors driving the association between body mass and MS should be investigated.
Multiple sclerosis (MS) is characterised by a diffuse inflammatory response mediated by microglia and astrocytes. Brain translocator protein (TSPO) positron-emission tomography (PET) and [myo-inositol] magnetic resonance spectroscopy (MRS) were used together to assess this.
To explore the in vivo relationships between MRS and PET [11C]PBR28 in MS over a range of brain inflammatory burden.
A total of 23 patients were studied. TSPO PET imaging with [11C]PBR28, single voxel MRS and conventional magnetic resonance imaging (MRI) sequences were undertaken. Disability was assessed by Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC).
[11C]PBR28 uptake and [myo-inositol] were not associated. When the whole cohort was stratified by higher [11C]PBR28 inflammatory burden, [myo-inositol] was positively correlated to [11C]PBR28 uptake (Spearman’s = 0.685, p = 0.014). Moderate correlations were found between [11C]PBR28 uptake and both MRS creatine normalised N-acetyl aspartate (NAA) concentration and grey matter volume. MSFC was correlated with grey matter volume ( = 0.535, p = 0.009). There were no associations between other imaging or clinical measures.
MRS [myo-inositol] and PET [11C]PBR28 measure independent inflammatory processes which may be more commonly found together with more severe inflammatory disease. Microglial activation measured by [11C]PBR28 uptake was associated with loss of neuronal integrity and grey matter atrophy.
To assess the decision-making impairment in patients with multiple sclerosis (MS) and how they relate to other cognitive domains.
We performed a cross-sectional analysis in 84 patients with MS, and 21 matched healthy controls using four tasks taken from behavioral economics: (1) risk preferences, (2) choice consistency, (3) delay of gratification, and (4) rate of learning. All tasks were conducted using real-world reward outcomes (food or money) in different real-life conditions. Participants underwent cognitive examination using the Brief Repeatable Battery-Neuropsychology.
Patients showed higher risk aversion (general propensity to choose the lottery was 0.51 vs 0.64, p = 0.009), a trend to choose more immediate rewards over larger but delayed rewards (p = 0.108), and had longer reactions times (p = 0.033). Choice consistency and learning rates were not different between groups. Progressive patients chose slower than relapsing patients. In relation to general cognitive impairments, we found correlations between impaired decision-making and impaired verbal memory (r = 0.29, p = 0.009), visual memory (r = –0.37, p = 0.001), and reduced processing speed (r = –0.32, p = 0.001). Normalized gray matter volume correlated with deliberation time (r = –0.32, p = 0.005).
Patients with MS suffer significant decision-making impairments, even at the early stages of the disease, and may affect patients’ quality and social life.
Cerebrospinal fluid (CSF) immunoglobulin free light chains (FLC) have been suggested as quantitative alternative to oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS). However, little is known on their role in predicting clinical and paraclinical disease progression, particularly in early stages.
To assess the prognostic value of FLC in OCB-positive patients with clinically isolated syndrome (CIS) suggestive of MS and early MS.
We determined FLC kappa (KFLC) and lambda (LFLC) in CSF and serum by nephelometry in 61 patients (CIS (n = 48), relapsing-remitting multiple sclerosis (n = 13)) and 60 non-inflammatory neurological controls. Median clinical follow-up time in CIS was 4.8 years (interquartile range (IQR), 1.5–6.5 years). Patients underwent 3T magnetic resonance imaging (MRI) at baseline and follow-up (median time interval, 2.2 years; IQR, 1.0–3.7 years) to determine T2 lesion load (T2LL) and percent brain volume change (PBVC).
CSF FLC were significantly increased in CIS/MS compared to controls (all p < 0.001). A lower KFLC/LFLC CSF ratio was associated with CIS-clinically definite multiple sclerosis (CDMS) conversion (hazard ratio (HR) = 2.89; 95% confidence interval (CI) = 1.17–7.14; p < 0.05). No correlations were found for FLC variables with T2LL or PBVC.
Our study confirms increased intrathecal synthesis of FLC in CIS/MS which supports their diagnostic contribution. The KFLC/LFLC CSF ratio appears to have a prognostic value in CIS beyond OCB.
Alemtuzumab was superior on clinical and magnetic resonance imaging (MRI) outcomes versus subcutaneous interferon beta-1a in phase 3 trials in patients with relapsing-remitting multiple sclerosis.
To examine quality-of-life (QoL) outcomes in the alemtuzumab phase 3 trials.
Patients who were treatment naive (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I [CARE-MS I]) or had an inadequate response to prior therapy (CARE-MS II) received annual courses of alemtuzumab 12 mg/day at baseline (5 days) and Month 12 (3 days) or subcutaneous interferon beta-1a 44 µg three times/week. QoL was measured every 6 or 12 months using Functional Assessment of Multiple Sclerosis (FAMS), European Quality of Life-5 Dimensions (EQ-5D) and its visual analog scale (EQ-VAS), and 36-Item Short-Form Survey (SF-36).
Statistically significant improvements from baseline with alemtuzumab were observed on all three QoL instruments at the earliest post-baseline assessment and sustained through Year 2. Statistically significant greater QoL improvements over subcutaneous interferon beta-1a were seen at all time points in CARE-MS II with FAMS, EQ-VAS and SF-36 physical component summary, and in CARE-MS I with FAMS.
Patients treated with alemtuzumab had improvements in physical, mental, and emotional QoL regardless of treatment history. Improvements were significantly greater with alemtuzumab versus subcutaneous interferon beta-1a on both disease-specific and general measures of QoL.
To evaluate the effectiveness and tolerance of mycophenolate mofetil (MMF) as a first-line treatment in neuromyelitis optica spectrum disorder (NMOSD).
In all, 67 NMOSD patients treated by MMF as first-line therapy, from the NOMADMUS cohort were included. A total of 65 fulfilled 2015 NMOSD criteria, and 5 were myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG) positive. Effectiveness was evaluated on percentage of patients continuing MMF, percentage of patients free of relapse, pre- and post-treatment change in the annualized relapse rate (ARR), and Expanded Disability Status Scale (EDSS).
Among 67 patients, 40 (59.7%) continued treatment till last follow-up. A total of 33 (49.3%) were relapse-free. The median ARR decreased from one pre-treatment to zero post-treatment. Of 53 patients with complete EDSS data, the score improved or stabilized in 44 (83%; p < 0.05). Effectiveness was observed in aquaporin-4 (AQP4)-IgG (57.8% continued treatment, 46.7% relapse-free), MOG-IgG (3/5 continued treatment, 4/5 relapse-free), and seronegative NMOSD (64.7% continued treatment, 61.3% relapse-free). In 16 patients with associated steroids, 13 (81.2%) continued MMF till last follow-up versus 15 of 28 (53.6%) in the non-steroid group. Nine patients discontinued treatment for tolerability purpose.
MMF showed effectiveness and good tolerability as a first-line therapy in NMOSD, whatever the AQP4-IgG status. Concomitant use of oral steroids at start could limit the risk of treatment failure.
Previous studies have documented far lower employment participation rates for people with multiple sclerosis (PwMS) compared to the general population. In a large national sample of PwMS, we examined employment status, longitudinal changes in employment and the provision of modifications to work role/environment from 2010 to 2013.
Employment data were collected through the Australian MS Longitudinal Study from 2010 to 2013, with 1260 people responding to all four surveys. Employment rates were compared with the Australian general population. The survey included questions on the provision of modifications to employees’ work role and work environment.
Employment (full- and part-time) increased from 48.8% in 2010 to 57.8% in 2013, mainly due to increases in male full-time employment. The employment gap between PwMS and the general population fell from 14.3% in 2010 to 3.5% in 2013. Male employment rates, however, remain significantly lower than the general population. The majority of PwMS who required adjustments to either their work role or environment received them.
The gap in employment between PwMS and the general population has substantially reduced from 2010 to 2013, with organisations responding positively to requests for work role/environment adjustments.
Multiple sclerosis (MS) patients are impaired in motor and cognitive performance, but the extent to which these deficits are magnified by aging is unknown. In one prior study, differences in cognitive processing speed between MS patients and healthy individuals were of similar magnitude across the lifespan. Here, we have improved on this work by expanding assessment to multiple cognitive domains and motor functioning.
To determine whether the degree of cognitive and motor dysfunction in MS is magnified with increasing age.
In all, 698 MS patients (aged 29–71 years) and 226 healthy controls (HCs; aged 18–72 years) completed neuroperformance tests covering ambulation, upper extremity function, information processing speed, and memory.
Linear regression models predicting cognitive and motor function revealed main effects of MS/HC diagnosis, age, and education across all measures. There was also an interaction between age and diagnosis on measures of motor function, but not on cognitive outcomes.
The progression of motor decline is amplified by aging in MS. However, the degree of cognitive impairment does not vary across the lifespan. Thus, evidence of accelerated cognitive impairment in older adults with MS may signal the presence of other age-related cognitive pathologies.
Characteristics at clinically isolated syndrome (CIS) examination assist in identification of patient at highest risk of early second attack and could benefit the most from early disease-modifying drugs (DMDs).
To examine determinants of second attack and validate a prognostic nomogram for individualised risk assessment of clinical conversion.
Patients with CIS were prospectively followed up in the MSBase Incident Study. Predictors of clinical conversion were analysed using Cox proportional hazards regression. Prognostic nomograms were derived to calculate conversion probability and validated using concordance indices.
A total of 3296 patients from 50 clinics in 22 countries were followed up for a median (inter-quartile range (IQR)) of 1.92 years (0.90, 3.71). In all, 1953 (59.3%) patients recorded a second attack. Higher Expanded Disability Status Scale (EDSS) at baseline, first symptom location, oligoclonal bands and various brain and spinal magnetic resonance imaging (MRI) metrics were all predictors of conversion. Conversely, older age and DMD exposure post-CIS were associated with reduced rates. Prognostic nomograms demonstrated high concordance between estimated and observed conversion probabilities.
This multinational study shows that age at CIS onset, DMD exposure, EDSS, multiple brain and spinal MRI criteria and oligoclonal bands are associated with shorter time to relapse. Nomogram assessment may be useful in clinical practice for estimating future clinical conversion.
Sexual dysfunction (SD) is common among people with multiple sclerosis, but there is limited information on its relationships.
This national study examines the relationships between sexual function with demographic factors, physical function, fatigue and depression.
Participants in the Trajectories of Outcomes in Neurological Conditions (TONiC) study completed the measures of fatigue, physical function and depression together with the Multiple Sclerosis Intimacy and Sexuality Questionnaire-15 (MSISQ-15), which covers sexual function (primary), symptoms that interfere with sexual function (secondary) and psychological issues (tertiary). All ordinal scores from the measures were converted to interval scale latent estimates via the Rasch model and used as single indicator latent variables in path analysis.
From 722 patients, 538 were sexually active of whom 431 (80.1%) answered questions on sexual functioning. Of these, only 18.5% reported no impact on any aspect of sexual function. Dysfunction was linked to disease subtype and Expanded Disability Status Scale (EDSS). Subtype influenced the relationship between symptoms and sexual function, which was fully mediated by psychological factors in secondary progressive patients. Depression was not directly associated with sexual functioning, but appeared as a consequence of the psychological issues associated with SD.
SD is common among participants in this UK-wide study, and psychological aspects of SD contributed to depression.
The injury of visual pathway and abnormalities of visual processing speed (VPS) are frequent in MS, but their association remains unexplored.
To evaluate the impact of posterior visual pathway structural and functional integrity on VPS of MS patients.
Cross-sectional study of 30 MS patients and 28 controls, evaluating the association of a VPS tests composite (Salthouse Perceptual Comparison test, Trail Making Test A and Symbol Digit Modalities Test) with 3T MRI visual cortex thickness, optic radiations (OR) diffusion tensor imaging indexes, and medial visual component (MVC) functional connectivity (FC) (MVC-MVC FC (iFC) and MVC-brain FC (eFC)) by linear regression, removing the effect of premorbid IQ, fatigue, and depression.
V2 atrophy, lower OR fractional anisotropy (FA) and MVC FC significantly influenced VPS in MS (at none or lesser extent in controls), even after removing the effect of Expanded Disability Status Scale and previous optic neuritis (V2 (r2 = 0.210): β = +0.366, p = 0.046; OR FA (r2 = 0.243): β = +0.378, p = 0.034; MVC iFC, for example, left cuneus (r2 = 0.450): β = –0.613, p < 0.001; MVC eFC, for example, right precuneus-postcentral gyrus (r2 = 0.368): β = –0.466, p = 0.002).
Posterior visual pathway integrity, structural (V2 thickness and OR FA) and functional (MVC FC), may explain respectively up to 24% and 45% of VPS variability in MS.
The importance of the innate immune system in multiple sclerosis (MS) is increasingly recognized and the role of natural killer (NK) cells in controlling autoimmunity may be an important modulator of disease activity.
To examine NK subsets in MS patients on different treatments and to evaluate the role of NK subsets as indicators for disease activity.
We measured NK subset levels in blood obtained from 110 relapsing-remitting MS patients. Patients were either off treatment or on treatment with natalizumab, fingolimod, glatiramer acetate or beta-interferon. Disease activity was defined according to ‘No Evidence of Disease Activity’ (NEDA) criteria within an observation period of up to 2.4 years. The mean NK subset levels were compared among treatment groups using multivariate analysis of variance (ANOVA) and association analysis with disease activity performed using multi-factor logistic regression.
Our analysis revealed differences in NK cells and subsets on treatment compared to off treatment (p < 0.0005). A high proportion of bright NK cells were significantly associated with stable magnetic resonance imaging (MRI) imaging after adjusting for treatment effects (p < 0.05).
The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.
Imbalance leading to falls is common in people with multiple sclerosis (PwMS).
To evaluate the effects of a balance group exercise programme (CoDuSe) on balance and walking in PwMS (Expanded Disability Status Scale, 4.0–7.5).
A multi-centre, randomized, controlled single-blinded pilot study with random allocation to early or late start of exercise, with the latter group serving as control group for the physical function measures. In total, 14 supervised 60-minute exercise sessions were delivered over 7 weeks. Pretest–posttest analyses were conducted for self-reported near falls and falls in the group starting late. Primary outcome was Berg Balance Scale (BBS). A total of 51 participants were initially enrolled; three were lost to follow-up.
Post-intervention, the exercise group showed statistically significant improvement (p = 0.015) in BBS and borderline significant improvement in MS Walking Scale (p = 0.051), both with large effect sizes (3.66; –2.89). No other significant differences were found between groups. In the group starting late, numbers of falls and near falls were statistically significantly reduced after exercise compared to before (p < 0.001; p < 0.004).
This pilot study suggests that the CoDuSe exercise improved balance and reduced perceived walking limitations, compared to no exercise. The intervention reduced falls and near falls frequency.
While cigarette and passive smoking have been identified as modifiable risk factors for multiple sclerosis (MS), there is no report regarding Waterpipe smoking–MS association.
We examined the association of Waterpipe, tobacco, and passive smoking with MS.
Population-based incident case–control study in Iran with 547 incident cases and 1057 general population controls (7 August 2013–17 February 2015). Logistic regression model was used. Multiplicative along with additive interaction was assessed using product term and Synergy Index (SI), respectively, and the population attributable fractions (PAFs) were calculated.
Having ever smoked Waterpipe, tobacco, or being exposed to passive smoking were all significantly associated with MS (odds ratio (OR) = 1.77 (1.36–2.31), OR = 1.69 (1.24–2.31), and OR = 1.85 (1.48–2.32), respectively). Clear dose–response associations were observed with the duration exposed (p < 0.001 for all three) and the amount smoked (p < 0.001 for Waterpipe and tobacco). Those who had all three types of smoking had an odds that was 4.1 times higher than those without any type. The three types of smoking jointly contributed to 30.9% of the MS incidence.
We identified Waterpipe smoking as a novel risk factor for MS. Given the global increase in Waterpipe smoking, especially among young adults, this finding reinforces the need for public health interventional and educational programs to combat this global increase.
Results from previous studies on a possible interaction between smoking and Epstein–Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting.
To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS.
Within the case–control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale.
Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis (p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66–1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): –0.98, 95% CI: –2.05–0.15, p = 0.09).
Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.
Despite cognitive tests have been validated in multiple sclerosis (MS), a neuropsychological evaluation is not implemented in the Expanded Disability Status Scale (EDSS) scoring.
We used the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and orientation tests (OTs) to measure the cerebral functional system (CFS) score and to evaluate its impact on the EDSS. We compared EDSS calculated as usual (Native-EDSS) and after the use of the BICAMS and OT (NPS-EDSS).
We tested 604 MS patients with BICAMS, OTs, and EDSS. In all, 384 patients (63.6%) had at least one altered test at the BICAMS. Older age, lower education, higher Native-EDSS, and male gender were independently associated with at least one impaired BICAMS test. Native-EDSS was different from NPS-EDSS (–0.112; p < 0.001) in 99 patients (16%). When considering patients with a Native-EDSS <= 4.0, the proportion of miscalculated EDSS was 25%.
The use of brief neuropsychological tests leads to a more accurate CFS assessment in two-thirds of MS patients, and a more accurate EDSS calculation in 25% of patients with a score <=4.0. This may help clinicians to better recognize cognitive impairment in everyday clinical practice, especially in the case of isolated cognitive worsening.
Many studies in multiple sclerosis (MS) have investigated the retina. Little, however, is known about the effect of MS on the cornea, which is innervated by the trigeminal nerve. It is the site of neural-immune interaction with local dendritic cells reacting in response to environmental stimuli.
This study aims to investigate the effect of MS on corneal nerve fibres and dendritic cells in the subbasal nerve plexus using in vivo confocal microscopy (IVCM).
We measured the corneal nerve fibre and dendritic cell density in 26 MS patients and matched healthy controls using a Heidelberg Retina Tomograph with cornea module. Disease severity was assessed with the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale, visual acuity and retinal optical coherence tomography.
We observed significant reduction in total corneal nerve fibre density in MS patients compared to controls. Dendritic cell density was similar in both groups. Reduced total nerve fibre density was associated with worse clinical severity but not with previous clinical trigeminal symptoms, retinal neuro-axonal damage, visual acuity or disease duration.
Corneal nerve fibre density is a promising new imaging marker for the assessment of disease severity in MS and should be investigated further.
Leptomeningeal contrast enhancement (LM CE) has been recently described in multiple sclerosis (MS) patients as a potential in vivo marker of cortical pathology.
To investigate the association of LM CE and development of cortical atrophy in 50 MS patients (27 relapsing-remitting (RR) and 23 secondary-progressive (SP)) followed for 5 years.
The presence and number of LM CE foci were assessed only at the 5-year follow-up using three-dimensional (3D) fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequence obtained 10 minutes after single dose of gadolinium injection on 3T scanner. The percentage change in whole brain, cortical and deep gray matter (GM) volumes, and lesion volume (LV) was measured between baseline and the 5-year follow-up.
In total, 25 (50%) of MS patients had LM CE at the 5-year follow-up. Significantly more SPMS patients (12, 85.7%) had multiple LM CE foci, compared to those with RRMS (2, 18.2%) (p = 0.001). MS patients with LM CE showed significantly greater percentage decrease in total GM (–3.6% vs –2%, d = 0.80, p = 0.006) and cortical (–3.4% vs –1.8%, d = 0.84, p = 0.007) volumes and greater percentage increase in ventricular cerebrospinal fluid (vCSF) volume (22.8% vs 9.9%, d = 0.90, p = 0.003) over the follow-up, compared to those without.
In this retrospective, pilot, observational longitudinal study, the presence of LM CE was associated with progression of cortical atrophy over 5 years.
New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab.
A total of 75 patients with clinically stable relapsing–remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period.
The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1–7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment (p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression.
A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.
We investigated whether diffusion tensor imaging (DTI) could reveal early hippocampal damage and clinically relevant correlates of memory impairment in persons with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS).
A total of 37 persons with CIS, 32 with MS and 36 controls prospectively included from 2011 to 2014 were tested for cognitive performances and scanned with 3T-magnetic resonance imaging (MRI) to assess volumetric and DTI changes within the hippocampus, whole brain volume and T2-lesion load.
While there was no hippocampal atrophy in the CIS group, hippocampal fractional anisotropy (FA) was significantly decreased compared to controls. Decrease in hippocampal FA together with increased mean diffusivity (MD) was even more prominent in MS patients. In CIS, hippocampal MD was correlated with episodic verbal memory performance (r = –0.57, p = 0.0002 and odds ratio (OR) = 0.058, 95% confidence interval (CI) = 0.0057–0.59, p = 0.016 adjusted for age, gender, depression and T2-lesion load), but not with cognitive tasks unrelated to hippocampal functions. Hippocampal MD was the only variable discriminating memory-impaired from memory-preserved persons with CIS (area under the curve (AUC) = 0.77, sensitivity = 90.0%, specificity = 70.3%, positive predictive value (PPV) = 52.9%, negative predictive value (NPV) = 95.0%).
DTI alterations within the hippocampus might reflect early neurodegenerative processes that are correlated with episodic memory performance, discriminating persons with CIS according to their memory status.
Stable disease course may prompt consideration of disease-modifying treatment (DMT) discontinuation in relapsing–remitting multiple sclerosis (RRMS).
To investigate the clinical outcome after DMT discontinuation and to identify predictive factors supporting decision-making.
We included 221 RRMS patients, who discontinued DMT after >=12 months and had documented follow-up >=2 years after discontinuation. Hazard ratios (HRs) with 95% confidence intervals (CIs) regarding relapse and disability progression after DMT discontinuation were calculated from Cox regression models.
Age >45 years at discontinuation (HR = 0.47, CI = 0.23–0.95, p = 0.038), absence of relapses for >=4 years on DMT before discontinuation (HR = 0.29, CI = 0.10–0.82, p = 0.020) and absence of contrast enhancing lesions (HR = 0.46, CI = 0.28–0.78, p = 0.004) were independent predictors of absence of relapse after discontinuation. Age >45 years and absence of relapses >=4 years on DMT combined had an HR of 0.06 (CI = 0.01–0.44, p < 0.001). Higher Expanded Disability Status Scale (EDSS) at discontinuation, age >45 years and longer disease duration were significantly associated with disability progression after discontinuation.
While freedom from further disease activity is generally unpredictable, there is a subset of patients (age >=45 years, DMT intake >=4 years without evidence of clinical or radiological disease activity) having a high likelihood of remaining relapse-free after DMT discontinuation. However, close clinical monitoring for recurrent disease activity is mandatory after discontinuing treatment.
The spectrum of central nervous system–idiopathic inflammatory demyelinating disease (CNS-IIDD) in the elderly is uncertain.
To describe the clinical, radiological, and pathological features of a cohort of 30 pathologically proven CNS-IIDD patients >=65 years.
Elderly multiple sclerosis (MS)/clinically isolated syndrome (CIS) patients were compared to a cohort of 125 patients with pathologically proven MS/CIS and symptom onset <65 years.
Median age at symptom onset was 69 years (interquartile range (IQR) = 68–75). Median follow-up was 1.9 years (IQR = 1.0–5.6). Diagnoses were MS (14/30), CIS (11/30), neuromyelitis optica (NMO; 4/30), and acute disseminated encephalomyelitis (ADEM; 1/30). Disability was higher in patients with MS/CIS >=65 compared to patients <65 (median Expanded Disability Status Scale (EDSS) 4 (IQR = 2.5–7) vs 2.5 (IQR = 1.5–4); p = 0.002). When compared to patients <65 years, there was no difference in the lesion size, number of patients fulfilling Barkhof’s criteria, edema, or mass effect. Confluent demyelination was observed in 27 patients (MS/CIS (23/25), NMO (4)), 2 had a mixed perivenular/confluent pattern (MS (1), ADEM (1)), and 1 patient with MS had a mixed confluent/perivenular/coalescent pattern. Early active lesions were found in 19/30 patients ((MS (4), CIS (13), NMO (2); 53%). Cortical demyelination was present in 7/12 (58%) patients (MS (3), CIS(3), ADEM (1)).
A spectrum of CNS-IIDD can develop in the elderly, with presenting symptoms similar to younger patients. Early diagnosis of CNS demyelinating disease is essential to avoid invasive and disabling procedures.
To investigate the role of cerebellar sub-regions on motor and cognitive performance in multiple sclerosis (MS) patients.
Whole and sub-regional cerebellar volumes, brain volumes, T2 hyperintense lesion volumes (LV), and motor performance scores were obtained from 95 relapse-onset MS patients and 32 healthy controls (HC). MS patients also underwent an evaluation of working memory and processing speed functions. Cerebellar anterior and posterior lobes were segmented using the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12). Multivariate linear regression models assessed the relationship between magnetic resonance imaging (MRI) measures and motor/cognitive scores.
Compared to HC, only secondary progressive multiple sclerosis (SPMS) patients had lower cerebellar volumes (total and posterior cerebellum). In MS patients, lower anterior cerebellar volume and brain T2 LV predicted worse motor performance, whereas lower posterior cerebellar volume and brain T2 LV predicted poor cognitive performance. Global measures of brain volume and infratentorial T2 LV were not selected by the final multivariate models.
Cerebellar volumetric abnormalities are likely to play an important contribution to explain motor and cognitive performance in MS patients. Consistently with functional mapping studies, cerebellar posterior–inferior volume accounted for variance in cognitive measures, whereas anterior cerebellar volume accounted for variance in motor performance, supporting the assessment of cerebellar damage at sub-regional level.
Neuromyelitis optica spectrum disorder with aquaporin4-immunoglobulin G (NMOSD-AQP4) is an inflammatory disease characterised by a high female predominance. However, the effect of gender in patients with NMOSD-AQP4 has not been fully evaluated.
The aim of this study was to determine the effect of gender in clinical manifestations and prognosis of patients with NMOSD-AQP4.
The demographics, clinical and radiological characteristics, pattern reversal visual evoked potential (VEP) test results, and prognosis of 102 patients (18 males) with NMOSD-AQP4 were assessed.
Male patients had a higher age at onset (48.7 vs 41 years, p = 0.037) and less optic neuritis as the onset attack (17% vs 44%, p = 0.026), higher tendency to manifest as isolated myelitis over the follow-up period (67% vs 28%, p = 0.005), fewer optic neuritis attacks per year (0.08 vs 0.27, p < 0.001), and shorter relative P100 latency on VEP testing (97.1% vs 108.3%, p = 0.001). Moreover, male gender was significantly associated with the absence of optic neuritis attacks over the follow-up period independent of their age of onset.
In NMOSD-AQP4 patients, gender impacts on disease onset age and site of attack. This may be an important clue in identifying NMOSD-AQP4 patients with limited manifestations as well as in predicting their clinical courses.
The aim of this study was to identify factors influencing the long-term clinical progression of multiple sclerosis (MS). A special objective was to investigate whether early treatment decisions influence outcome.
We included 639 patients diagnosed with MS from 2001 to 2007. The median follow-up time was 99 months (8.25 years). Cox regression models were applied to identify factors correlating with the outcome variable defined as time from treatment start to irreversible score 4 of the Expanded Disability Status Scale (EDSS).
Patients initiated on treatment later had a greater risk of reaching EDSS 4 (hazard ratio of 1.074 (95% confidence interval (CI), 1.048–1.101)), increased by 7.4% for every year of delay in treatment start after MS onset. Patients who started treatment after 3 years from MS onset reached the outcome sooner with hazard ratio of 2.64 (95% CI, 1.71–4.08) compared with the patients who started treatment within 1 year from MS onset. Baseline EDSS and age at onset were found to be predictive factors of disability progression.
Early treatment initiation was associated with a better clinical outcome. In addition, we confirmed the well-established prognostic factors of late age at onset and early disability.
Neurodegeneration plays a major role in determining disability in multiple sclerosis (MS) patients. Hence, there is increasing need to identify reliable biomarkers, which could serve as prognostic measure of disease progression.
To assess whether cerebrospinal fluid (CSF) tau and β-amyloid (Aβ) levels were altered in newly diagnosed MS patients and correlated with disability. Moreover, we investigated whether these CSF biomarkers associate with macroscopic brain tissue damage measures.
CSF Aβ and tau levels were determined by enzyme-linked immunosorbent assay in CSF samples from 48 newly diagnosed MS patients, followed-up clinically for 3 years by recording their Expanded Disability Status Scale score at 6-month intervals, and 45 controls. All patients underwent magnetic resonance imaging at baseline and at the end of follow-up to quantify their lesion load (LL).
CSF Aβ levels were significantly reduced in patients compared to controls (p < 0.001). Lower CSF Aβ levels at baseline were a disability predictor at 3-year follow-up (p = 0.009). CSF tau levels correlated with T2- and T1-LL (p < 0.001).
CSF Aβ reduction is a promising biomarker of neurodegeneration and may predict patients’ clinical outcome. Therefore, CSF Aβ should be considered as a potential biomarker of prognostic value.
The measurement of health state utility values (HSUVs) for a representative sample of Australian people with multiple sclerosis (MS) has not previously been performed.
Our main aim was to quantify the HSUVs for different levels of disease severities in Australian people with MS.
HSUVs were calculated by employing a ‘judgement-based’ method that essentially creates EQ-5D-3L profiles based on WHOQOL-100 responses and then applying utility weights to each level in each dimension. A stepwise linear regression was used to evaluate the relationship between HSUVs and disease severity, classified as mild (Expanded Disability Status Scale (EDSS) levels: 0–3.5), moderate (EDSS levels: 4–6) and severe (EDSS levels: 6.5–9.5).
Mean HSUV for all people with MS was 0.53 (95% confidence interval (CI): 0.52–0.54). Utility decreased with increasing disease severity: 0.61 (95% CI: 0.60–0.62), 0.51 (95% CI: 0.50–0.52) and 0.40 (95% CI: 0.38–0.43) for mild, moderate and severe disease, respectively. Adjusted differences in mean HSUV between the three severity groups were statistically significant.
For the first time in Australia, we have quantified the impact of increasing severity of MS on health utility of people with MS. The HSUVs we have generated will be useful in further health economic analyses of interventions that slow progression of MS.
There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS).
The aim of this study was to compare the prevalence and profile of CI across MS disease subtypes and assess its clinical determinants.
Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop test in consecutive patients with MS referred to six Italian centers. CI was defined as impairment in >= 2 cognitive domains.
A total of 1040 patients were included, 167 with clinically isolated syndrome (CIS), 759 with relapsing remitting (RR), 74 with secondary progressive (SP), and 40 with primary progressive (PP) disease course. The overall prevalence of CI was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP. The severity of impairment and the number of involved domains were significantly higher in SP and primary progressive multiple sclerosis (PPMS) than in CIS and RR. In multivariable logistic regression analysis, the presence of CI was significantly associated with higher Expanded Disability Status Scale (EDSS) and older age.
CI is present in all MS subtypes since the clinical onset and its frequency is increased in the progressive forms, but these differences seem to be more associated with patient age and physical disability than to disease subtype per se.
Multiple sclerosis (MS) is a neurological disorder that causes significantly reduced ability to work, and the Expanded Disability Status Scale (EDSS) is one of the main predictors for reduced work ability.
To investigate how work requirements, flexible work conditions and disease-modifying drugs (DMDs) influence the work ability in relation to different EDSS grades in two MS populations.
Work ability was studied in two MS populations: one in the southern and one in the northern part of Sweden, both demographically similar. In the latter population, more active work-promoting interventions have been practised and second-generation DMDs have been widely used from the onset of disease for several years.
The proportion of MS patients who participated in the workforce or studied was significantly higher in the northern compared with the southern population (p < 0.001). The employees in the northern population had significantly lower requirements, greater adapted work conditions and were able to work more hours per week. Higher EDSS was associated with lower reduction in number of worked hours per week in the northern population (p = 0.042).
Our data indicated that treatment strategy and adjusted work conditions have impact on work ability in MS.
Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases.
To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)).
Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset.
A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p < 0.001). Interval between onset and diagnosis of NMO/SD was longer in women than in men (mean 54 vs 27 months; p = 0.023). In women, attacks occurring <=40 years of age were more likely to show complete remission (p = 0.003) and better response to high-dose intravenous steroids (p = 0.005) compared to woman at >40 years.
Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.
The relationship between cortical lesions (CLs) and white matter lesions (WMLs) in multiple sclerosis (MS) is poorly understood. Pathological studies support a topographical association between CLs and underlying subcortical WMLs and suggest CLs may play a role in both disease initiation and progression. We hypothesized that cortical MS lesions are physically connected to white matter MS lesions via axonal connections.
To assess the presence of CL-WML connectivity utilizing novel magnetic resonance imaging (MRI) methodology.
In all, 28 relapsing-remitting MS patients and 25 controls received 3 T MRI scans, including double inversion recovery (DIR) for CL detection coupled with diffusion tensor imaging (DTI). CL and WML maps were created, and DTI was used to calculate inter-lesional connectivity and volumetric connectivity indices.
All patients showed inter-lesional WML connectivity (median 76% of WMLs connected to another WML; interquartile range (IQR), 58%–88%). On average, 52% of detected CLs per patient were connected to at least one WML (IQR, 42%–71%). Volumetric connectivity analysis showed significantly elevated cortical lesion ratios in MS patients (median, 2.3; IQR, 1.6–3.3) compared to null MS and healthy control datasets (p < 0.001).
These findings provide strong evidence of inter-lesional connectivity between CLs and WMLs, supporting our hypothesis of intrinsic CL-WML connectivity.
Inflammation in neuromyelitis optica (NMO) is triggered by a serum antibody against the aquaporin-4 (AQP4). This process requires antibody penetration of the blood–brain barrier (BBB), but the mechanisms for BBB disruption in NMO remain unknown.
We examined whether changes in cerebrospinal fluid (CSF) and serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and cytokines are associated with BBB disruption in NMO.
The concentrations 9 MMPs, 4 TIMPs, and 14 cytokines were measured by multiplex assay in CSF and serum samples from 29 NMO patients, 29 relapsing-remitting multiple sclerosis (MS) patients, and 27 patients with other neurological disorders. We also performed immunohistochemistry for MMP-2 and TIMP-1 expression in post-mortem brain tissues from NMO patients.
NMO patients exhibited significantly elevated MMP-2, TIMP-1, interleukin-6, and MMP-2/TIMP-2 ratio in CSF (but not sera) than the other groups. The CSF/serum albumin ratio, an index of BBB permeability, was most strongly correlated with CSF MMP-2 concentration, which in turn correlated with CSF interleukin-6 levels. Immunohistochemistry revealed MMP-2- and TIMP-1-positive cells surrounding vessels in NMO lesions.
In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).
Little is known about the consequences of parental multiple sclerosis (MS) on offspring’s socioeconomic circumstances.
To investigate employment, disability pension and income in offspring of parents with MS compared with matched reference persons in a nationwide register-based cohort study.
All Danish-born persons with onset of MS during 1950–1986 were retrieved from the Danish Multiple Sclerosis Registry. Their offspring were identified using the Civil Registration System. One random offspring from each sibship was matched by sex and year of birth with eight random reference persons.
We included 2456 MS offspring and 19,648 reference persons. At age 30, employment was lower among MS offspring than reference children (odds ratio (OR): 0.89; 95% confidence interval (CI): 0.84–0.95; p = 0.0003), and they more often received disability pension (OR: 1.31; 95% CI: 1.15–1.50; p < 0.0001) at ages 30 and 40 but not at age 50. Although the mean income was not significantly lower for the MS offspring cohort, most of them attained an annual personal income below 250,000 DKK (Danish krone), that is, ~33,650 EUR (OR: 0.91; 95% CI: 0.84–0.99; p = 0.04).
Having had a parent with MS may affect employment and increase the risk of disability pension and low income in adult life.
Depression in multiple sclerosis (MS) patients is common but may stay untreated. Physical limitations impede face-to-face treatment. Internet-based treatment is therefore a promising tool for treating depression in MS.
To investigate effectiveness of a guided Internet-based problem-solving treatment (IPST) for depressed MS patients.
MS patients with moderate or severe depressive symptoms were randomly assigned to IPST or a wait list control. Primary outcome was the change in depressive symptoms defined by a change in sum score on the Beck Depression Inventory Second Edition (BDI-II). Assessments took place at baseline (T0), within a week after the intervention (T1), and at 4 months follow-up (T2). Analyses were based on the intention-to-treat principle.
A total of 171 patients were randomized to IPST (n = 85) or a wait list control (n = 86). T1 was completed by 152 (89%) and T2 by 131 patients (77%). The IPST group and wait list control showed large significant improvements in depressive symptoms, but no differences were found between groups at T1 (d = 0.23; 95% confidence interval (CI) = (–4.03, 1.08); p = 0.259) and T2 (d = 0.01; 95% CI = (–2.80, 2.98); p = 0.953).
We found no indication that IPST for MS patients with moderate or severe depression is effective in reducing depressive symptoms compared to a waiting list. Large improvements in the wait list control were unexpected and are discussed.
Since 1959, multiple sclerosis (MS) prevalence has been estimated for the east coast Australian city of Newcastle. Previous surveys, conducted in 1988 and 2003, have described an increase in the prevalence and incidence of MS.
In this study, we evaluated whether these trends continue and provide 50 years of MS epidemiological follow-up for this southern hemisphere city.
Expressed per 100,000 people, prevalence of MS in Newcastle was calculated for those with a confirmed diagnosis of MS on 9 August 2011 and incidence based on the number of cases with MS diagnosis made during the preceding decade. Data were age-standardised to the total Australian population. Statistical comparisons were undertaken using Poisson regression analysis.
In 2011, the estimate of MS prevalence was 124.2, with female-to-male ratio reaching 3.1, a 53% increase in female predominance since 1996. MS incidence increased to 6.7, with a significantly higher proportion of new female cases since the previous survey.
Prevalence of MS in Newcastle has risen linearly and is contributed to by a substantial increase in new cases over the preceding decade. Female predominance of MS cases continues to increase with a new diagnosis three times more likely in women.
In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power.
To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power.
We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (>=3.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power.
There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power.
Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS.
Previous studies have postulated an association between dentate nucleus T1 hyperintensity and multiple sclerosis (MS)-related progressive neurodegeneration. Therefore, MS patients have been excluded from most studies investigating brain deposition of gadolinium-based contrast agents (GBCAs).
To study the hypothesis that dentate nucleus T1 hyperintensity in MS patients is associated with GBCA administration.
In a cohort of 97 MS patients, the dentate-to-pons signal intensity ratio (DPSIR) was calculated for 265 consecutive T1-weighted magnetic resonance (MR) scans (including sessions with and without the administration of GBCA). Patients exclusively received either gadopentetate dimeglumine (Gd-DTPA, linear) or gadobutrol (Gd-BT-DO3A, macrocyclic).
In patients receiving Gd-DTPA, DPSIR increased significantly between the first and the last scan (+0.009, p < 0.001), and following magnetic resonance imaging (MRI) with Gd-DTPA administration as compared to following an MRI without Gd-DTPA administration (+0.005 vs –0.001; p = 0.022). Additionally, there was a positive linear relationship between the number of Gd-DTPA administrations and the increase in DPSIR (p = 0.017). No DPSIR increase was observed after Gd-BT-DO3A administration.
Dentate nucleus T1 hyperintensity in MS patients is associated with Gd-DTPA (but not Gd-BT-DO3A) administration, suggesting an alternative explanation for the association of T1 hyperintensity with disease duration and severity.
Neuromyelitis optica spectrum disorder (NMOSD) patients may be at increased risk of venous thromboembolism (VTE) not only due to ambulatory disability but also due to systemic autoimmune and inflammatory mechanisms altering the hemostatic balance.
To compare the risk of VTE in NMOSD versus multiple sclerosis (MS) patients hospitalized for acute relapses.
Hospital admissions for MS or NMOSD exacerbations were retrospectively identified. Demographics and medical history were recorded. The relationship between visit diagnosis and presence of VTE within 6 weeks of relapse onset was assessed by univariate logistic regression. A multivariate model evaluated the relationship between diagnosis, age, race, gender, body mass index (BMI), disease modifying therapy use, oral corticosteroid use, oral contraceptive use, smoking, length of stay (LOS), and ambulatory status on VTE risk.
A total of 30 NMOSD patients had 55 hospitalizations; 179 MS patients had 264 hospitalizations. Six NMOSD patients and one MS patient had VTE. NMOSD visits compared to MS visits had an odds ratio (OR) of VTE of 32.2 (p = 0.002). NMOSD was more likely to be associated with VTE (OR = 17.4; p = 0.01) controlling for age, LOS, and ambulatory disability.
NMOSD may be a risk factor for VTE. Larger prospective studies are required to confirm this risk and determine implications for prophylaxis.
Multiple sclerosis (MS) is associated with considerable morbidity and serious disability, but little is known of the long-term impact of the disease on work ability.
To assess sick leave (short-term absence) and disability pension (long-term absence) before and after diagnosis of MS.
Patients with MS in Sweden were identified in a nationwide disease-specific register and matched with general population controls. Sick leave and disability pension were measured before and after index (i.e. the MS diagnosis date).
The final sample comprised 6092 patients and 60,345 controls (mean age 39 years; 70% female). The mean annual prevalence of sick leave ranged from 12% the first year after index to 23% after 11 years among patients and from 13% to 13% among controls. Corresponding estimates for disability pension were 12% and 55% for patients and 7% and 9% for controls. Significant differences in sick leave were observed up to 15 years before index and 3 years for disability pension.
Patients with MS in Sweden have elevated levels of sick leave and disability pension up to 15 years before disease diagnosis. Our results highlight the burden of disease on affected patients and society and underscore the substantial unmet medical need.
Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study.
To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study.
Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5–7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of >=1 point (>=0.5 for EDSS 6–7) or a >=20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits.
A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo.
MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.
Increased oxidative stress leads to loss of glutathione (GSH). We have reported lower cerebral GSH in patients with secondary progressive multiple sclerosis (SPMS), indicating the involvement of oxidative stress in multiple sclerosis (MS) pathophysiology.
This study expanded upon our earlier work by examining longitudinal changes in cerebral GSH in patients with SPMS in relation to their clinical status.
A total of 13 patients with SPMS (Expanded Disability Status Scale (EDSS) = 4.0–6.5; MS duration = 21.2 ± 8.7 years) and 12 controls were studied over 3–5 years. GSH mapping was acquired from frontal and parietal regions using a multiple quantum chemical shift imaging technique at 3 T. Clinical assessments of the patient’s disability included EDSS, gait, motor strength, ataxia, tremor, brainstem function and vision changes.
Brain GSH concentrations in patients were lower than those in controls for both baseline and 3- to 5-year follow-ups. Longitudinal GSH changes of patients were associated with their neurologist’s blinded appraisal of their clinical progression. Patients judged to have worsening clinical status had significantly greater declines in frontal GSH concentrations than those with stable clinical status.
GSH provides a distinct measure associated with the disease progression in SPMS, possibly due to its dynamic alignment with pathogenic processes of MS related to oxidative stress.
The soluble isoform of the interferon-β (IFN-β) receptor (sIFNAR2) could modulate the activity of both endogenous and systemically administered IFN-β. Previously, we described lower serum sIFNAR2 levels in untreated multiple sclerosis (MS) than in healthy controls (HCs).
To assess sIFNAR2 levels in a new cohort of MS patients and HCs, as well as in patients with clinically isolated syndrome (CIS) and with other inflammatory neurological disorders (OIND) and to assess its ability as a diagnostic biomarker.
The cross-sectional study included 148 MS (84 treatment naive and 64 treated), 87 CIS, 42 OIND, and 96 HCs. Longitudinal study included 94 MS pretreatment and after 1 year of therapy with IFN-β, glatiramer acetate (GA), or natalizumab. sIFNAR2 serum levels were measured by a quantitative ELISA developed and validated in our laboratory.
Naive MS and CIS patients showed significantly lower sIFNAR2 levels than HCs and OIND patients. The sensitivity and specificity to discriminate between MS and OIND, for a sIFNAR2 cutoff value of 122.02 ng/mL, were 70.1%, and 79.4%, respectively. sIFNAR2 increased significantly in IFN-β-treated patients during the first year of therapy in contrast to GA- and natalizumab-treated patients who showed non-significant changes.
The results suggest that sIFNAR2 could be a potential diagnostic biomarker for MS.
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are autoimmune inflammatory demyelinating diseases of the central nervous system. Although distinguished by clinicoradiological and demographic features, early manifestations can be similar complicating management. Antibodies against aquaporin-4 support the diagnosis of NMOSD but are negative in some patients. Therefore, there is unmet need for biomarkers that enable early diagnosis and disease-specific intervention.
We investigated whether plasma complement proteins are altered in MS and NMOSD and provide biomarkers that distinguish these diseases.
Plasma from 54 NMOSD, 40 MS and 69 control donors was tested in multiplex assays measuring complement activation products and proteins. Using logistic regression, we tested whether combinations of complement analytes distinguished NMOSD from controls and MS.
All activation products were elevated in NMOSD compared to either control or MS. Four complement proteins (C1inh, C1s, C5 and FH) were higher in NMOSD compared to MS or controls. A model comprising C1inh and terminal complement complex (TCC) distinguished NMOSD from MS (area under the curve (AUC): 0.98), while C1inh and C5 distinguished NMOSD from controls (AUC: 0.94).
NMOSD is distinguished from MS by plasma complement biomarkers. Selected complement analytes enable differential diagnosis. Findings support trials of anti-complement therapies in NMOSD.
Cognitive impairment (CI) cannot be diagnosed by magnetic resonance imaging (MRI). Functional magnetic resonance imaging (fMRI) paradigms, such as the immediate/delayed memory task (I/DMT), detect varying degrees of working memory (WM). Preliminary findings using I/DMT showed differences in blood oxygenation level dependent (BOLD) activation between impaired (MSCI, n = 12) and non-impaired (MSNI, n = 9) multiple sclerosis (MS) patients.
The aim of the study was to confirm CI detection based on I/DMT BOLD activation in a larger cohort of MS patients. The role of T2 lesion volume (LV) and Expanded Disability Status Scale (EDSS) in magnitude of BOLD signal was also sought.
A total of 50 patients (EDSS mean (m) = 3.2, disease duration (DD) m = 12 years, and age m = 40 years) underwent the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) and I/DMT. Working memory activation (WMa) represents BOLD signal during DMT minus signal during IMT. CI was based on MACFIMS.
A total of 10 MSNI, 30 MSCI, and 4 borderline patients were included in the analyses. Analysis of variance (ANOVA) showed MSNI had significantly greater WMa than MSCI, in the left prefrontal cortex and left supplementary motor area (p = 0.032). Regression analysis showed significant inverse correlations between WMa and T2 LV/EDSS in similar areas (p = 0.005, 0.004, respectively).
I/DMT-based BOLD activation detects CI in MS. Larger studies are needed to confirm these findings.
There is substantial evidence that stress increases multiple sclerosis disease activity, but limited evidence on its association with the onset of multiple sclerosis.
To examine the association between stressful life events and risk of first demyelinating event (FDE).
This was a multicentre incident case–control study. Cases (n = 282 with first diagnosis of central nervous system (CNS) demyelination, including n = 216 with ‘classic FDE’) were aged 18–59 years. Controls without CNS demyelination (n = 558) were matched to cases on age, sex and study region. Stressful life events were assessed using a questionnaire based on the Social Readjustment Rating Scale.
Those who suffered from a serious illness in the previous 12 months were more likely to have an FDE (odds ratio (OR) = 2.35 (1.36, 4.06), p = 0.002), and when we limited our reference group to those who had no stressful life events, the magnitude of effect became stronger (OR = 5.41 (1.80, 16.28)). The total stress number and stress load were not convincingly associated with the risk of an FDE.
Cases were more likely to report a serious illness in the previous 12 months, which could suggest that a non-specific illness provides an additional strain to an already predisposed immune system.
The aim was to investigate predictive values of coping styles, clinical and demographic factors on time to unemployment in patients diagnosed with multiple sclerosis (MS) during 1998–2002 in Norway.
All patients (N = 108) diagnosed with MS 1998–2002 in Hordaland and Rogaland counties, Western Norway, were invited to participate in the long-term follow-up study in 2002. Baseline recordings included disability scoring (Expanded Disability Status Scale (EDSS)), fatigue (Fatigue Severity Scale (FSS)), depression (Beck Depression Inventory (BDI)), and questionnaire assessing coping (the Dispositional Coping Styles Scale (COPE)). Logistic regression analysis was used to identify factors associated with unemployed at baseline, and Cox regression analysis to identify factors at baseline associated with time to unemployment during follow-up.
In all, 41 (44%) were employed at baseline. After 13 years follow-up in 2015, mean disease duration of 22 years, 16 (17%) were still employed. Median time from baseline to unemployment was 6 years (±5). Older age at diagnosis, female gender, and depression were associated with patients being unemployed at baseline. Female gender, long disease duration, and denial as avoidant coping strategy at baseline predicted shorter time to unemployment.
Avoidant coping style, female gender, and longer disease duration were associated with shorter time to unemployment. These factors should be considered when advising patients on MS and future employment.
Progressive multifocal leukoencephalopathy (PML) is an emerging complication of immunosuppressive therapies, especially natalizumab in multiple sclerosis (MS). Factors associated with functional outcome of natalizumab-associated PML (natalizumab-PML) have not been sufficiently described.
We retrospectively analyzed medical records of all patients with natalizumab-PML (n = 32) treated in our hospital since 2009. Disability measured by Expanded Disability Status Scale (EDSS) at two different time points (highest available EDSS during PML and last available EDSS after PML diagnosis) served as functional outcome parameters. Clinical, laboratory, and imaging data were analyzed for association with functional outcome by applying Spearman’s rho and multivariate regression analysis.
In all, 31/32 patients survived PML. A poor functional outcome was associated with higher age, higher initial John Cunningham virus (JCV) copy number in cerebrospinal fluid (CSF), and more extensive PML lesions on initial magnetic resonance imaging (MRI). No association between functional outcome and the duration of natalizumab therapy or a delayed PML diagnosis was observed.
This study will be useful for neurological practice to estimate functional outcome or disease severity of natalizumab-PML in primary care settings.
To investigate levels of oxysterols in healthy control (HC) and multiple sclerosis (MS) patients and their interdependence with demographic, clinical characteristics, and cholesterol biomarkers.
This study included 550 subjects (203 HC, 221 relapsing–remitting MS (RR-MS), 126 progressive MS (P-MS)). A complete lipid profile including total cholesterol (TC); high-density lipoprotein–cholesterol (HDL-C); low-density lipoprotein–cholesterol (LDL-C); apolipoproteins (Apo) A1, A2, B, and E; C-reactive protein (CRP); 24-hydroxycholesterol (HC); 25-HC; 27-HC; 7α-HC; and 7-ketocholesterol (KC) was obtained. Lipoprotein particle sizing by proton nuclear magnetic resonance (H1 NMR) was available for 432 subjects.
The levels of 24-HC, 27-HC, and 7α-HC (all p < 0.015) were lower in MS compared to HC, and 7-KC was higher in P-MS compared to RR-MS (p < 0.001). TC, LDL-C, and ApoB were associated with higher levels of all oxysterols (all p < 0.05) in HC. In MS, LDL-C was associated with higher levels of 24-HC, 25-HC, 7-KC, and 7α-HC (all p < 0.05), while TC and ApoB were associated with increased levels of all oxysterols (all p < 0.005).
The findings of lower 24-HC, 27-HC, and 7α-HC in MS compared to HC and higher 7-KC in P-MS compared to RR-MS indicate that the oxysterol network is disrupted in MS.
The international panel for neuromyelitis optica (NMO) diagnosis has proposed diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD).
We assessed the impact of these criteria on diagnostic rates in a large cohort of patients.
We identified and applied the 2006 and 2015 criteria to all patients (n = 176) seen in the NMO and non-multiple sclerosis central nervous system demyelination clinic (part of the UK NMO service) from January 2013 to May 2015.
The 2006 criteria classified 63 of 176 (36%) patients as NMO. A total of 42 patients (67%) were aquaporin 4 (AQP4) immunoglobulin G (IgG) +ve and 21 (33%) AQP4 IgG –ve. The 2015 criteria classified 111 of 176 (63%) patients as NMOSD, of which 81 (73%) were AQP4 IgG +ve and 30 (27%) were AQP4 IgG –ve. There was an increase of 48 patients (76%) diagnosed as NMOSD using the new criteria.
Application of the 2015 criteria led to a rise in diagnosis of NMOSD by 76%. The rise in the AQP4 IgG +ve group contributed 62% and the seronegative group contributed 14%.
The 1-year placebo-controlled (PC) phase of the Glatiramer Acetate Low-Frequency Administration (GALA) study showed that glatiramer acetate 40 mg/mL three times weekly (GA40) significantly reduced annualized relapse rate (ARR) and magnetic resonance imaging (MRI) activity in patients with relapsing–remitting multiple sclerosis. Patients completing the PC phase were invited to an open-label (OL) extension.
To evaluate the effects of early start (ES) and delayed start (DS) of GA40 over 3 years.
A total of 97.2% of patients completing the PC phase received GA40 in the OL extension. ES (n = 943) patients received GA40 throughout; DS (n = 461) patients received placebo during the PC phase and GA40 during the OL phase. Relapse, MRI, disease progression, and safety were evaluated.
A total of 1041 patients completed 3 years of follow-up. During the OL phase, ES and DS patients showed comparable ARRs (0.20–0.22) and similar numbers of gadolinium-enhancing T1 (p = 0.49) and new or enlarging T2 lesions (p = 0.51) at Year 3. ES patients showed significantly smaller changes in gray matter volume than DS patients from Months 12 to 36 (mean difference, 0.371%; p = 0.015), with similar trend in whole-brain volume (p = 0.080). Adverse events were mild, consistent with the well-established glatiramer acetate (GA) safety profile.
GA40 conferred treatment benefit over 3 years: sustained low ARR and lesion activity and favorable safety.
Fatigue is a prevalent and functionally disabling symptom for individuals living with multiple sclerosis (MS) which is poorly understood and multifactorial in etiology. Bladder dysfunction is another common MS symptom which limits social engagement and quality of life. To manage bladder issues, individuals with MS tend to limit their fluid intake, which may contribute to a low-hydration (LoH) state and fatigue.
To evaluate the relationship between patient-reported MS fatigue, bladder dysfunction, and hydration status.
We performed a prospective cross-sectional study in 50 women with MS. Participants submitted a random urine sample and completed several fatigue-related surveys. Using a urine specific gravity (USG) threshold of 1.015, we classified MS subjects into two groups: high-hydration (HiH) and LoH states.
LoH status was more common in MS subjects with bladder dysfunction. Statistically significant differences in self-reported Fatigue Performance Scale were observed between HiH and LoH subjects (p = 0.022). USG was significantly correlated with fatigue as measured by the MS Fatigue Severity Scale (FSS) score (r = 0.328, p = 0.020).
Hydration status correlates with self-reported fatigue, with lower fatigue scores found in those with HiH status (USG < 1.015).
Recently, pruritus has been recognised as an important association with neuromyelitis optica spectrum disorders (NMOSD).
To determine the clinical and radiological characteristics of patients with NMOSD and pruritus.
Among 57 consecutive patients with NMOSD, 15 (26.3% women) reported pruritus. All had aquaporin-4 (AQP4) antibodies. The mean age was 34.5 ± 9.1 years, age at onset was 31.3 ± 11.0 years and the duration of illness was 3.9 ± 3.1 years. Pruritus preceded the neurological disturbances in all the patients. Predominant patients experienced pruritus in the cervical dermatome (66.7%) followed by cervicothoracic region (13.3%), trigeminal nerve (13.3%) and lumbar region (6.7%). Lesions extending from cervicomedullary junction up to the thoracic segment was the most common site of affection (40%) followed by cervicothoracic (26.7%), cervicomedullary junction to cervical cord (13.3%), cervical cord (6.7%) and thoracic segment (6.7%).
This report is one of the largest series reporting the close association of pruritus with onset of neurological symptoms in NMOSD. It highlights the importance of recognising this rare symptom which may help in making a correct diagnosis in a patient with suspected demyelinating disorder. In a patient with NMOSD, early treatment with immunomodulation during pruritus may prevent or minimise occurrence of neurological dysfunction.
Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS). Although cognitive impairment (CI) affects a large proportion of MS patients, only few data are available about its prognostic value associated with advanced magnetic resonance imaging (MRI) metrics.
We aimed at investigating the relationship between the early CI and the disease progression over 8-year follow-up in MS patients.
We conducted a retrospective 8-year longitudinal study involving 78 patients with relapsing-remitting MS, who completed neuropsychological examination and structural MRI at the time of diagnosis. Each patient was clinically evaluated every 6 months, and cortical thickness was quantified at baseline and at the end of the follow-up. Patients were classified as having normal cognition and mild or severe CI.
The results show that CI at the time of diagnosis is a good predictor of conversion to definite MS (p < 0.001), disability progression (p < 0.001), as well as of transition to secondary progressive phase (p < 0.001) and of cortical thinning (p < 0.001).
We confirmed and extended the evidence that early CI might be helpful in the identification of MS patients at high risk of disability progression and poor clinical outcome and should be considered as a marker of most aggressive pathology.
Multiple sclerosis (MS) is thought to be T cell mediated but the mechanisms eliciting such a dysregulated adaptative immune response remain enigmatic.
To examine the activation profile of antigen-presenting cells (APCs) in MS.
A total of 98 study subjects were enrolled including patients suffering from relapsing–remitting, secondary- and primary-progressive (PP) MS, other inflammatory neurological diseases, and healthy controls. Blood monocytes and B cells were stimulated using specific ligands of toll-like receptors (TLRs) or inflammasomes or Epstein–Barr virus (EBV) particles. Their activation profile was determined before or after stimulation by flow cytometry (CD40, CD80, CD83, CD86, and human leukocyte antigen–antigen D related (HLA-DR)) and Luminex assay, measuring the concentration of eight cytokines in culture supernatants. Differences among groups were assessed in a linear model framework.
We demonstrate that relapsing MS patients exhibit an increased expression of HLA-DR and CD40 ex vivo, mostly at the surface of B cells. Specific stimulations of TLR or inflammasomes enhance the expression of components of the immunological synapse and the cytokine secretion but without differences between categories of study subjects.
These data suggest that the activation profile of B cells is increased in MS. However, the perception of the danger signal by B lymphocytes and monocytes does not seem to be different in MS patients as compared to control subjects.
Robotic training is commonly used to assist walking training in patients affected by multiple sclerosis (MS) with non-conclusive results.
To compare the effect of robot-assisted gait training (RAGT) with that of conventional walking training (CWT) on gait competencies, global ability, fatigue and spasticity in a group of severely affected patients with MS.
A pilot, single-blind randomized controlled trial was conducted in 43 severe (Expanded Disability Status Scale (EDSS) score of 6–7.5) and non-autonomous ambulant in-patients with MS. Experimental group performed 12 sessions of RAGT, whereas control group performed the same amount of CWT. Primary outcome measures were gait ability assessed by 2 minutes walking test and Functional Ambulatory Category; secondary outcomes were global ability (modified Barthel Index), global mobility (Rivermead Mobility Index), severity of disease (EDSS) and subjectively perceived fatigue (Fatigue Severity Scale).
The number of subjects who achieved a clinical significant improvement was significantly higher in RAGT than in CWT (p < 0.05 for both primary outcome measures). RAGT also led to an improvement in all the other clinical parameters (global ability: p < 0.001, global mobility: p < 0.001, EDSS: p = 0.014 and fatigue: p = 0.001).
RAGT improved the walking competencies in non-autonomous ambulant patients with MS, with benefits in terms of perceived fatigue.
Spinal cord pathology is an important substrate for long-term disability in multiple sclerosis (MS).
To investigate longitudinal changes in spinal cord lesions and atrophy in patients with a non-spinal clinically isolated syndrome (CIS), and how they relate to the development of disability.
In all, 131 patients with a non-spinal CIS had brain and spinal cord imaging at the time of CIS and approximately 5 years later (median: 5.2 years, range: 3.0–7.9 years). Brain magnetic resonance imaging (MRI) measures consisted of T2-hyperintense and T1-hypointense lesion loads plus brain atrophy. Spinal cord MRI measures consisted of lesion number and the upper cervical cord cross-sectional area (UCCA). Disability was measured using the Expanded Disability Status Scale (EDSS). Multiple linear regression was used to identify independent predictors of disability after 5 years.
During follow-up, 93 (71%) patients were diagnosed with MS. Baseline spinal cord lesion number, change in cord lesion number and change in UCCA were independently associated with EDSS (R2 = 0.53) at follow-up. Including brain T2 lesion load and brain atrophy only modestly increased the predictive power of the model (R2 = 0.64).
Asymptomatic spinal cord lesions and spinal cord atrophy contribute to the development of MS-related disability over the first 5 years after a non-spinal CIS.
Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS).
To evaluate a treatment effect of EPO on progressive MS.
This was a single-center, randomized, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6.5 and clinical progression without relapses in the 2 preceding years. The primary outcome was the change in a composite measure of maximum gait distance, hand dexterity, and cognition from baseline to 24 weeks.
A total of 50 patients completed the study. Venesection was performed often but no thromboembolic events occurred. We found no difference in the primary outcome between the EPO and the placebo group using the intention-to-treat principle (p = 0.22). None of the secondary outcomes, neither clinical nor magnetic resonance imaging (MRI) measures showed any significant differences.
This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS.
Intermittent theta burst stimulation (iTBS) of the primary motor cortex improves transiently lower limbs spasticity in multiple sclerosis (MS). However, the cerebral mechanisms underlying this effect have never been investigated.
To assess whether modulation of spasticity induced by iTBS is underlined by functional reorganization of the primary motor cortices.
A total of 17 patients with MS suffering from lower limbs spasticity were randomized to receive real iTBS or sham iTBS during the first half of a 5-week indoor rehabilitation programme. Spasticity was assessed using the Modified Ashworth Scale and the Visual Analogue Scale at baseline, after the stimulation session and at the end of the rehabilitation programme. Resting-state functional magnetic resonance imaging (fMRI) was performed at the three time points, and brain functional networks topology was analysed using graph-theoretical approach.
At the end of stimulation, improvement of spasticity was greater in real iTBS group than in sham iTBS group (p = 0.026). iTBS had a significant effect on the balance of the connectivity degree between the stimulated and the homologous primary motor cortex (p = 0.005). Changes in inter-hemispheric balance were correlated with improvement of spasticity (rho = 0.56, p = 0.015).
This longitudinal resting-state fMRI study evidences that functional reorganization of the primary motor cortices may underlie the effect of iTBS on spasticity in MS.
Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune-mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS).
To evaluate efficacy and safety of abatacept in RRMS.
ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a Phase II, randomized, double-blind, placebo-controlled, multi-center trial. In all, 65 of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks.
No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated.
The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS.
Objective and reproducible evaluation of data quality is of paramount importance for studies of ‘real-world’ observational data. Here, we summarise a standardised data quality, density and generalisability process implemented by MSBase, a global multiple sclerosis (MS) cohort study.
Error rate, data density score and generalisability score were developed using all 35,869 patients enrolled in MSBase as of November 2015. The data density score was calculated across six domains (follow-up, demography, visits, MS relapses, paraclinical data and therapy) and emphasised data completeness. The error rate evaluated syntactic accuracy and consistency of data. The generalisability score evaluated believability of the demographic and treatment information. Correlations among the three scores and the number of patients per centre were evaluated.
Errors were identified at the median rate of 3 per 100 patient-years. The generalisability score indicated the samples’ representativeness of the known MS epidemiology. Moderate correlation between the density and generalisability scores ( = 0.58) and a weak correlation between the error rate and the other two scores ( = –0.32 to –0.33) were observed. The generalisability score was strongly correlated with centre size ( = 0.79).
The implemented scores enable objective evaluation of the quality of observational MS data, with an impact on the design of future analyses.
The dentate nucleus, which is the largest of the cerebellar nuclei, plays a critical role in movement and cognition. The aim of our study was to assess any changes in dentate functional connectivity (FC) in adult relapsing remitting multiple sclerosis (RR-MS) patients and to investigate possible clinical correlates.
In all, 54 patients and 24 healthy subjects (HS) underwent multimodal magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), three-dimensional-T1-weighted and resting state (RS) functional images; they also underwent a cognitive evaluation, that is, attention and information processing speed, by means of the Paced Auditory Serial Addition Test (PASAT). Patients were also scored according to Expanded Disability Status Scale (EDSS). RS-MRI data were analysed using FMRIB Software Library (FSL) tools, with the seed-based method to identify dentate FC.
When compared with HS, patients exhibited brain atrophy and widespread DTI abnormalities, as well as greater FC between the dentate nucleus and cortical areas, particularly in the frontal and parietal lobes. Within these areas, FC in patients correlated inversely with clinical impairment. Finally, FC correlated inversely with lesion load and microstructural brain damage.
Our findings indicate that dentate FC at rest is altered in MS patients. Whether these functional changes are induced by the disease and play a compensatory role remains to be established.
Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity.
Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients (n = 33), untreated RRMS patients (n = 13), and healthy controls (n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients.
Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untreated patients and healthy controls. Whereas group comparison for CD4+IL-17+ numbers also differed, CD4+IFN-+ and CD4+IL-22+ counts were not increased. CD4+IL-17+ cells not only expressed but also secreted IL-17. In natalizumab-treated patients, IL-17+ cell frequency was found to correlate with T1-hypointense lesions, but was not an indicator for rebound activity after treatment discontinuation, except in one patient who experienced a fulminant rebound, and interestingly, in whom the highest IL-17+ cell levels were observed.
Increased lymphocytes and CD4+IL-17+ cells in the blood of RRMS patients receiving natalizumab corroborate the drug’s mechanism of action, that is, blocking transmigration to CNS. Correlation between IL-17-expressing lymphocytes and T1-hypointense lesions underlines the important role of these cells in the disease pathology.
The Treatment Satisfaction Questionnaire for Medication (TSQM) was designed to assess patient treatment satisfaction in chronic diseases. Its performance has not been examined in multiple sclerosis (MS). The 14 items of the TSQM cover four domains: Effectiveness, Side Effects, Convenience, and Global Satisfaction.
To evaluate performance of the TSQM in patients with relapsing MS, using data collected from the TENERE study (NCT00883337), in which 324 patients received oral teriflunomide or subcutaneous interferon beta-1a for >=48 weeks.
Five measurement properties were examined using traditional psychometric methods: data completeness, scale-to-sample targeting, scaling assumptions, reliability (including test–retest), and construct validity (internal: item-level scaling success, confirmatory factor analysis, and exploratory factor analysis; external: convergence, discrimination, and group differences).
There were few (<2%) missing item data; domain scores could be computed for all patients. Score distributions were skewed toward higher satisfaction; two domains had marked ceiling effects. Scaling assumptions were supported. Internal consistency reliability was high (Cronbach’s α > 0.90). Internal validity tests supported item groupings. Correlations supported convergent and discriminant construct validity; hypothesis testing supported group differences validity.
This investigation found the TSQM to be a useful tool, exhibiting good psychometric measurement properties in patients with relapsing MS in the TENERE study.
To define values of normalized brain volume (NBV) that can be categorized as low, medium, or high, according to baseline characteristics of relapsing-remitting multiple sclerosis (RRMS) patients.
Expected NBV (eNBV) was calculated for each patient based on age, disease duration, sex, baseline Expanded Disability Status Scale (EDSS), and T2-lesion volume, entering these variables into a multiple regression model run on 2342 RRMS patients (pooled FREEDOMS/FREEDOMS-II population). According to the difference between their observed NBV and their eNBV, patients were classified as having low NBV, medium NBV, or high NBV. We evaluated whether these NBV categories were clinically meaningful by assessing correlation with disability worsening.
The distribution of differences between observed NBV and eNBV was used to categorize patients as having low NBV, medium NBV or high NBV. Taking the high-NBV group as reference, the hazard ratios (HRs) for 2-year disability worsening, adjusted for treatment effect, were 1.23 (95% confidence interval (CI): 0.92–1.63, p = 0.16) for the medium NBV and 1.75 (95% CI: 1.26–2.44, p = 0.001) for the low NBV. The predictive value of NBV groups was preserved over 4 years. Treatment effect appeared more evident in low-NBV patients (HR = 0.58) than in medium-NBV (HR = 0.72) and in high-NBV (HR = 0.80) patients; however, the difference was not significant (p = 0.57).
RRMS patients can be categorized into disability risk groups based on individual eNBV values according to baseline demographics and clinical characteristics.
To improve the consistency of standardized Expanded Disability Status Scale (EDSS) assessments, an electronic data capture tool and analysis tool was developed, Neurostatus e-Scoring (NESC). This tool allows real-time feedback by comparing entries with established scoring rules.
To test whether using NESC reduces inconsistencies as compared to the paper-and-pencil version of the Expanded Disability Status Scale (pEDSS).
In all, 100 multiple sclerosis (MS) patients were assessed in random order on the same day by pairs of neurologists, one using pEDSS and one NESC. We compared inter-rater reliability and frequency of inconsistencies in Neurostatus subscores, functional system (FS) scores, ambulation and EDSS steps.
Inconsistencies of any type were more likely to occur when using pEDSS (mean odds ratio (95% confidence interval (CI)) = 2.93 (1.62; 5.29)). This was also the case for FS score inconsistencies (2.54 (1.40; 4.61)) and more likely for patients in the lower EDSS range (<=3.5 vs >3.5) (5.32 (1.19; 23.77)). Overall, inter-rater agreement for the assessed Neurostatus subscores was high (median and inter-quartile range = 0.84 (0.73, 0.81)).
Our data provide class II evidence that the use of NESC increases consistency of standardized EDSS assessments, and may thus have the potential to decrease noise and increase power of MS clinical trials.
Heterogeneity in disease course exists within multiple sclerosis (MS) subtypes.
The objective was to estimate disease course heterogeneity over three distinct onset periods (pre-1995, 1995–2004, and 2005–present) for men and women.
Group-based trajectory model (GBTM) was used to estimate clusters of patients following stable or unstable disease progression trajectories based on the Expanded Disability Status Scale (EDSS). Inception cohorts were generated from the Montreal Neurological Institute MS Clinic registry. Stable trajectories were defined as an EDSS <=3.0 and change <=1 point over the study period. Annualized relapse rate (ARR) based on the first 5 years of disease was an explanatory variable.
Proportion of women classified as stable was 0% for pre-1995, 69.0% for 1995–2004, and 83.9% post-2005; for men, these proportions were 18.4%, 41.4%, and 53.8%, respectively. Men had lower percentage of stable disease than women in both post-1995 cohorts (chi-square p < 0.0001). ARR was associated with higher disability trajectories in both post-1995 cohort (odds ratios >1.0) but not in the pre-1995 cohort.
Large proportions of patients remain stable at their initial disability level for at least 15 years. Higher ARR increases the odds of patients being in a higher disability trajectory in the latter cohorts.
Poor adherence to the disease-modifying therapies (DMTs) for multiple sclerosis (MS) may attenuate clinical benefit. A better understanding of characteristics associated with non-adherence could improve outcomes.
To evaluate characteristics associated with non-adherence to injectable DMTs.
Consecutive patients from four Canadian MS Clinics were assessed at three time points over two years. Clinical and demographic information included self-reported DMT use, missed doses in the previous 30 days, health behaviors, and comorbidities. Non-adherence was defined as <80% of expected doses taken. We employed generalized estimating equations to examine characteristics associated with non-adherence at all time points with findings reported as adjusted odds ratios (OR).
In all, 485 participants reported use of an injectable DMT, of whom 107 (22.1%) were non-adherent over the study period. Non-adherence was associated with a lower Expanded Disability Status Scale score (0–2.5 vs 3.0–5.5, OR: 1.80; 95% confidence interval (CI): 1.06–3.04), disease duration (<=5 vs <5 years, OR: 2.23; 95% CI: 1.10–4.52), alcohol dependence (OR: 2.14; 95% CI: 1.23–3.75), and self-reported cognitive difficulties, measured by the Health Utilities Index-3 (OR: 1.55; 95% CI: 1.08–2.22).
Nearly one-quarter of participants were non-adherent during the study. Alcohol dependence, perceived cognitive difficulties, longer disease duration, and mild disability status were associated with non-adherence. These characteristics may help healthcare professionals identify patients at greatest risk of poor adherence.
We investigated clinical, behavioural and functional magnetic resonance imaging (fMRI) correlates of working memory load in relapse-onset multiple sclerosis (MS) patients.
In total, 12 clinically isolated syndromes (CIS) patients at risk of MS, 38 relapsing-remitting multiple sclerosis (RRMS), 22 secondary progressive multiple sclerosis (SPMS) and 24 healthy controls (HC) performed an N-back fMRI task. Correlations between fMRI abnormalities and clinico-behavioural and structural magnetic resonance imaging (MRI) measures were assessed.
Participants activated brain regions of the working memory network, especially in fronto-parietal lobes and cerebellum, and deactivated areas of the default mode network (DMN). During the N-back load contrast, compared to HC, the three groups of MS patients had a common pattern of decreased activation of the right superior parietal lobule, left inferior parietal lobule and left middle frontal gyrus. Areas specifically more active in CIS patients compared to the other study groups were found in the left medial superior frontal gyrus and right anterior cingulate cortex, whereas SPMS patients selectively activated the left parahippocampal gyrus and left superior temporal pole (STP). Worse accuracy and global cognitive scores correlated with increased STP activation.
Load-dependent alterations of working memory network recruitment occur in MS. Frontal hyperactivation is maintained in CIS and lost in SPMS. Abnormal recruitment of DMN areas is related to worse cognitive and behavioural outcomes.
Brain volume loss (BVL) is a key outcome in multiple sclerosis (MS) trials. Natalizumab is highly effective on inflammation with moderate impact on atrophy.
To explore BVL in patients receiving natalizumab with an emphasis on grey matter (GM).
We performed a retrospective post hoc analysis of BVL in 38 patients receiving natalizumab for 3 years using longitudinal voxel-based morphometry (VBM) and FreeSurfer.
Significant BVL was observed during first year: brain parenchymal fraction (BPF): –1.12% (p < 0.001); white matter fraction (WMF): –0.9% (p = 0.001); grey matter fraction (GMF): –1.28% (p = 0.002). GM loss was found using VBM in bilateral cerebellum, cingulum, left > right fronto-parietal cortex, right > left hippocampus and left caudate. FreeSurfer showed significant volume losses in subcortical GM, brainstem and cerebellum, and cortical thinning in the left insula. In the second year, only WMF decrease (–0.6%; p = 0.015) was observed with no VBM changes, although FreeSurfer detected significant volume loss in thalamus, hippocampus and cerebellum. Baseline gadolinium enhancement influenced WMF and BPF changes during the first year, but not GMF. Patients with confirmed Expanded Disability Status Scale (EDSS) worsening at 3 years had lower baseline GMF and left thalamus volume and greater BVL over follow-up.
BVL develops mainly during the first year of natalizumab therapy. GM changes are independent of baseline inflammation and correlate with disability.
At autopsy, 20%–40% of chronic multiple sclerosis (MS) lesions are labeled "slowly expanding" and feature myelin phagocytosis at the lesion edge. As pathological lesion classification relies on a single, terminal time point, the rate of lesion expansion cannot be directly measured.
To study long-term volume changes in individual MS lesions.
Volumes of individual lesions on proton density magnetic resonance imaging (MRI) acquired between 1992 and 2015 were measured in 22 individuals (one lesion per person). After correction for acquisition protocol, a mixed model evaluated lesion volume changes.
The mean (standard deviation) lesion volume at baseline was 142 (82) mL, falling to 74 (51) mL after 16 (3) years. All lesions shrank over time. Change in lesion volume did not correlate with change in supratentorial brain volume (p = 0.33). In simulations, the results could be explained by a process of slow radial expansion superimposed on substantially more rapid resorption of damaged tissue.
We noted sustained radiological contraction of MS lesions, a surprising result given that fresh myelin breakdown products within chronic active lesions are observed relatively frequently at autopsy. Therefore, the primary pathological process in chronic lesions, even those described as "slowly expanding," is likely to be tissue loss.
Recent studies have revealed that the disruption of the blood–brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS).
We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS).
We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity.
We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NF) B p65 expression in the BMECs. Exposure to SPMS patients’ sera also increased the protein levels of ICAM-1 and phospho-NFB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3.
Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.
Elevated antibody levels against Epstein–Barr virus (EBV) and a poor vitamin D status are environmental factors that may interact in relapsing-remitting multiple sclerosis (RRMS) aetiology.
To examine effects of high-dose oral vitamin D3 supplementation on antibody levels against EBV nuclear antigen 1 (EBNA1) in RRMS.
Serum 25-hydroxyvitamin D3 (25(OH)D) and immunoglobulin G antibody levels against EBNA1 (whole protein and amino acid 385–420 fragment), EBV viral capsid antigen (VCA), cytomegalovirus (CMV) and varicella zoster virus (VZV) were measured in 68 RRMS patients enrolled in a 96-week randomised double-blinded placebo-controlled clinical trial of oral vitamin D3 supplementation (20,000 IU/week) (NCT00785473).
The mean 25(OH)D level more than doubled in the vitamin D group and was significantly higher than in the placebo group at study conclusion (123.2 versus 61.8 nmol/L, p < 0.001). Compared to the placebo group, both anti-EBNA1 protein and fragment antibody levels decreased in the vitamin D group from baseline to week 48 (p = 0.038 and p = 0.004, respectively), but not from baseline to week 96. Vitamin D3 supplementation did not affect antibodies against VCA, CMV or VZV.
The results indicate that high-dose oral vitamin D3 supplementation can affect humoral immune responses against the latent EBV antigen EBNA1 in RRMS.
To examine disease progression in ‘aggressive’ multiple sclerosis (MS), British Columbia, Canada (1980–2009).
Aggressive (or ‘malignant’) MS was defined as Expanded Disability Status Scale (EDSS) >=6 within 5 years from onset. The first EDSS >=6 was termed ‘baseline’. Within 2, 3 and 5 years post-baseline, patients were categorized as follows: ‘worsened’ or ‘improved’, relative to baseline EDSS (the remainder exhibited no change or had no new scores). The associations between patient characteristics (sex, relapsing onset/primary progressive, onset age, onset symptoms, disease duration, cumulative prior relapses and baseline EDSS) and worsening in disability were examined longitudinally using logistic regression.
Of the 225/4341 (5.2%) aggressive/malignant MS patients, 134 (59.6%) were female, 167 (74.2%) were relapsing onset, 94 (41.8%) had received disease-modifying drugs at some point and the mean follow-up was 8.7 years. The proportion of patients who ‘worsened’ increased from 40.4% to 57.8%, while those who ‘improved’ varied little (range, 8.9%–10.2%). The odds of worsening increased with disease duration (adjusted odds ratio (AOR) = 1.36; 95% confidence interval (CI) = 1.22–1.52) and the presence of primary progressive (vs relapsing-onset) MS (AOR = 1.85; 95% CI = 1.01–3.38).
Apart from disease duration and a primary progressive course, no clinically useful associations of subsequent disease worsening in patients with aggressive/malignant MS were identified.
To assess retinal ganglion cell (RGC) injury and sex differences in axon loss in pediatric multiple sclerosis (MS).
This is a cross-sectional evaluation of consecutive pediatric MS subjects and controls. Eyes with acute optic neuritis (ON) within 6 months of visit were excluded. Spectral domain optical coherence tomography (OCT) included peripapillary ring and macular scans with post-acquisition segmentation of retinal layers using automated software (Heidelberg v1.8.6.0). Generalized estimating equations (GEEs) measured associations of sex, history of ON, disease duration, and age with OCT outcomes.
In all, 53 MS subjects (100 eyes, median disease duration = 1.0 years, interquartile range (IQR) = 0.3, 2.5) were compared to 19 control subjects (38 eyes). Eyes with history of ON showed reduced retinal nerve fiber layer (RNFL: –26.8 µm, 95% confidence interval (CI) = –38.9, –14.8, p < 0.001) and 26% lower ganglion cell layer (GCL) volumes (–0.12 mm3, 95% CI = –0.16, –0.072, p < 0.001) compared to control eyes. Non-ON MS eyes had lower temporal RNFL (–11.9 µm, 95% CI = –18.6, –5.3, p < 0.001) and GCL volumes (–0.036 mm3, 95% CI = –0.06, –0.011, p = 0.004) than control eyes. In MS eyes, males versus females had lower global RNFL (–9.4 µm, 95% CI = –17.4, –1.33, p = 0.022) and in ON eyes had lower temporal quadrant RNFL (–9.6 µm, 95% CI = –15.1, –4.15, p = 0.001).
Subclinical retinal injury occurs in pediatric-onset MS patients without a history of ON. As in adult-onset MS, substantial GCL thinning is present in eyes with prior ON. Finally, greater retinal axonal injury occurs in boys compared to girls.
Alterations of intestinal permeability (IP) may contribute to the pathophysiology of immune-mediated diseases.
We investigated the possible association between IP changes and multiple sclerosis (MS).
We studied 22 patients with relapsing–remitting multiple sclerosis (RRMS) and 18 age- and sex-matched healthy donors (HDs), including five twin pairs (one concordant, and four discordant for disease). Measurement of lactulose (L) and mannitol (M; two non-metabolized sugars) levels in urine samples, after an oral load, allowed to quantify gut dysfunction.
The proportion of participants with increased IP was significantly higher in patients than in HDs (16/22 (73%) versus 5/18 (28%); p = 0.001). Accordingly, the L/M urinary ratio showed significantly higher values in patients than in controls (p = 0.0284). Urinary mannitol concentration was significantly lower in patients than in controls (p = 0.022), suggesting a deficit of absorption from intestinal lumen. Such changes did not appear related to patients’ clinical–radiological features.
The relatively high proportion of IP changes in RR-MS patients seems to confirm our work hypothesis and warrants more work to confirm the result on a larger sample, and to understand the implications for related immunological disturbances and intestinal microbiota alterations. Our finding may also have relevance for oral treatments, recently introduced in clinical practice.
Although temporal lobe pathology may explain some of the symptoms of multiple sclerosis (MS), its role in the pathogenesis of seizures has not been clarified yet.
To investigate the role of temporal lobe damage in MS patients suffering from epilepsy, by the application of advanced multimodal 3T magnetic resonance imaging (MRI) analysis.
A total of 23 relapsing remitting MS patients who had epileptic seizures (RRMS/E) and 23 disease duration matched RRMS patients without any history of seizures were enrolled. Each patient underwent advanced 3T MRI protocol specifically conceived to evaluate grey matter (GM) damage. This includes grey matter lesions (GMLs) identification, evaluation of regional cortical thickness and indices derived from the Neurite Orientation Dispersion and Density Imaging model.
Regional analysis revealed that in RRMS/E, the regions most affected by GMLs were the hippocampus (14.2%), the lateral temporal lobe (13.5%), the cingulate (10.0%) and the insula (8.4%). Cortical thinning and alteration of diffusion metrics were observed in several regions of temporal lobe, in insular cortex and in cingulate gyrus of RRMS/E compared to RRMS (p< 0.05 for all comparisons).
Compared to RRMS, RRMS/E showed more severe damage of temporal lobe, which exceeds what would be expected on the basis of the global GM damage observed.
The pathology of multiple sclerosis (MS) consists of demyelination and neuronal injury, which occur early in the disease; yet, remission phases indicate repair. Whether and how the central nervous system (CNS) maintains homeostasis to counteract clinical impairment is not known.
We analyse the structural connectivity of white matter (WM) and grey matter (GM) networks to understand the absence of clinical decline as the disease progresses.
A total of 138 relapsing–remitting MS patients (classified into six groups by disease duration) and 32 healthy controls were investigated using 3-Tesla magnetic resonance imaging (MRI). Networks were analysed using graph theoretical approaches based on connectivity patterns derived from diffusion-tensor imaging with probabilistic tractography for WM and voxel-based morphometry and regional-volume-correlation matrix for GM.
In the first year after disease onset, WM networks evolved to a structure of increased modularity, strengthened local connectivity and increased local clustering while no clinical decline occurred. GM networks showed a similar dynamic of increasing modularity. This modified connectivity pattern mainly involved the cerebellum, cingulum and temporo-parietal regions. Clinical impairment was associated at later disease stages with a divergence of the network patterns.
Our findings suggest that network functionality in MS is maintained through structural adaptation towards increased local and modular connectivity, patterns linked to adaptability and homeostasis.
In multiple sclerosis (MS), microRNA (miRNA) dysregulation is mostly reported in different immune cells, but less information is available on circulating miRNAs that exert strong biomarker potential due to their exceptional stability in body fluids.
The aim of this study was to profile expression of circulating miRNAs in primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS) and assess their association with neurological worsening.
The expressions of 84 different miRNAs were profiled in serum of 83 subjects (62 MS and 21 controls) using miScript miRNA techniques. First, they were screened on 18 PPMS and 10 controls; thereafter, 10 most aberrantly expressed miRNAs were validated on a larger cohort.
In comparison with controls, upregulation of miR-191-5p was found in both progressive MS subtypes, while miR-376c-3p was overexpressed only in PPMS. Additionally, upregulation of miR-128-3p and miR-24-3p was detected in PPMS when compared to controls and SPMS. Progression index correlated with miR-128-3p in PPMS and miR-375 in SPMS.
We detected overexpression of four miRNAs that have not been previously associated with progressive forms of MS. The increased expression of circulating miR-191-5p seems to be associated with progressive forms of MS, while miR-128-3p seems to be associated mostly with PPMS.
A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy.
We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT.
Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions.
Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was –0.23% per year, consistent with the rate expected from normal aging.
Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of "committed" tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.
No evidence of disease activity (NEDA) has been proposed as a new treatment goal in multiple sclerosis (MS). NEDA-3 status is defined as the absence of magnetic resonance imaging (MRI; new/enlarging/enhancing lesions and increased whole brain volume loss in NEDA-4) and clinical disease activity.
To investigate the persistence of NEDA status over long-term follow-up in MS patients treated with weekly intramuscular interferon beta-1a.
We included 192 patients after the first demyelinating event suggestive of MS, that is, clinically isolated syndrome (CIS) and 162 relapsing-remitting MS (RRMS) patients.
NEDA-3 status was observed in 40.1% of CIS and 20.4% of RRMS patients after 1 year. After 4 years, 10.1% of CIS patients had NEDA-3 status. After 10 years, none of the RRMS patients had NEDA-3 status. Only 4.6% of CIS and 1.0% of RRMS patients maintained NEDA-4 status after 4 years. Loss of NEDA-3 status after the first year was associated with a higher risk of disability progression (hazard ratio (HR) = 2.3–4.0; p = 0.005–0.03) over 6 years.
Despite intramuscular interferon beta-1a treatment, loss of NEDA status occurred in the vast majority of individuals. Loss of NEDA status during the first year was associated with disability progression over long-term follow-up; however, specificity for individual patient was low.
Comorbidities are known to affect multiple sclerosis (MS) patients in a number of ways, including delaying time to diagnosis and reducing health-related quality of life.
To determine the impact of hypertension, hyperlipidemia, diabetes mellitus, and obstructive lung disease on disease course in MS patients.
The Knowledge Program is a database linked to our electronic medical record allowing capture of patient and clinician reported outcomes. Through Knowledge Program query and chart review, we identified all relapsing-remitting MS patients seen between 1 January 2010 and 29 May 2012 and acquired their magnetic resonance imaging (MRI) results and comorbidities. Linear and logistic regression models with adjustment for important covariates were used to determine whether the comorbidities affected outcomes over a 3-year period.
Hypertension, diabetes, and obstructive lung disease, but not hyperlipidemia, impacted clinical outcomes, including walking speed, self-reported disability, and depression. Hypertension had the greatest effect. The presence of multiple comorbidities had a cumulative effect on clinical outcomes. MRI outcomes were unaffected by comorbidities.
This 3-year longitudinal study revealed that all comorbidities tested except hyperlipidemia impacted clinical outcomes and a cumulative effect with multiple comorbidities was observed. Consideration of comorbid conditions is essential in MS patient care.
Natalizumab and fingolimod have not been compared in controlled trials but only in observational studies, with inconclusive results.
The objective of this study is to compare the effect of natalizumab and fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS).
We included all consecutive RRMS patients switched from first-line agents (glatiramer acetate/interferons) to natalizumab or fingolimod, with a follow-up of 24 months. Data of relapses, Expanded Disability Status Scale score and brain magnetic resonance imaging (MRI) scans were collected. We used propensity score (PS) matching and intention-to-treat analysis.
We retained 102 patients in each cohort after PS matching, with similar baseline characteristics. More patients discontinued natalizumab compared to fingolimod (33% vs 11%, p < 0.001), mainly for progressive multifocal leukoencephalopathy (PML) concern. No serious adverse events occurred in the two cohorts. Compared to fingolimod, the natalizumab group presented a higher percentage of relapse-free patients (66% vs 80%, p = 0.015), a higher percentage of disability-improved patients (6% vs 15%, p = 0.033), a lower percentage of MRI-active patients (38% vs 14%, p = 0.001) and a higher percentage of patients with no evidence of disease activity (NEDA-3; 44% vs 70%, p < 0.001) after 2 years of follow-up. Disability worsening was not statistically different in the two groups.
Natalizumab is superior to fingolimod in RRMS patients non-responding to first-line agents.
We have recently suggested that delayed visual evoked potential (VEP) latencies in the fellow eye (FE) of optic neuritis patients reflect a cortical adaptive process, to compensate for the delayed arrival of visual information via the affected eye (AE).
To define the cortical mechanism that underlies this adaptive process.
Cortical activations to moving stimuli and connectivity patterns within the visual network were tested using functional magnetic resonance imaging (MRI) in 11 recovered optic neuritis patients and in 11 matched controls.
Reduced cortical activation in early but not in higher visual areas was seen in both eyes, compared to controls. VEP latencies in the AEs inversely correlated with activation in motion-related visual cortices. Inter-eye differences in VEP latencies inversely correlated with cortical activation following FE stimulation, throughout the visual hierarchy. Functional correlation between visual regions was more pronounced in the FE compared with the AE.
The different correlation patterns between VEP latencies and cortical activation in the AE and FE support different pathophysiology of VEP prolongation in each eye. Similar cortical activation patterns in both eyes and the fact that stronger links between early and higher visual areas were found following FE stimulation suggest a cortical modulatory process in the FE.
Much effort has been expended on identifying the genetic determinants of multiple sclerosis (MS). Existing large-scale genome-wide association study (GWAS) datasets provide strong support for using pathway and network-based analysis methods to investigate the mechanisms underlying MS. However, no shared genetic pathways have been identified to date.
We hypothesize that shared genetic pathways may indeed exist in different MS-GWAS datasets.
Here, we report results from a three-stage analysis of GWAS and expression datasets. In stage 1, we conducted multiple pathway analyses of two MS-GWAS datasets. In stage 2, we performed a candidate pathway analysis of the large-scale MS-GWAS dataset. In stage 3, we performed a pathway analysis using the dysregulated MS gene list from seven human MS case–control expression datasets.
In stage 1, we identified 15 shared pathways. In stage 2, we successfully replicated 14 of these 15 significant pathways. In stage 3, we found that dysregulated MS genes were significantly enriched in 10 of 15 MS risk pathways identified in stages 1 and 2.
We report shared genetic pathways in different MS-GWAS datasets and highlight some new MS risk pathways. Our findings provide new insights on the genetic determinants of MS.
Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit–risk profile for patients with relapsing–remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM.
We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE).
In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID.
For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1–5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia.
Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.
Body fluid and structural imaging biomarkers give information on neurodegeneration. The relationship over time is not known in multiple sclerosis.
To investigate the temporal relationship of elevated cerebrospinal fluid (CSF) neurofilament (Nf) protein levels, a biomarker for axonal loss, with magnetic resonance imaging (MRI) atrophy measures.
In patients with multiple sclerosis, CSF Nf heavy chain (NfH) phosphoform levels were quantified at baseline and dichotomised into ‘normal’ and ‘high’. Atrophy was assessed by MRI at baseline and 15-year follow-up using SIENAX and FreeSurfer software.
High baseline CSF NfHSMI35 levels predicted pronounced atrophy at 15-year follow-up (odds ratio (OR): 36, p < 0.01), in the absence of baseline brain atrophy (OR: 28, p < 0.05), for the averaged MRI normalised brain volume (1.44 L vs 1.33 L, p < 0.05), normalised grey matter volume (0.77 L vs 0.69 L, p < 0.01) and putamen (12.7 mL vs 10.7 mL, p < 0.05). Region-specific calculations including the spinal cord showed that a power of >80% is reached with 14–50 patients.
These data suggest that high CSF NfH levels are an early predictor of later brain and spinal cord atrophy using structural imaging biomarkers and can be investigated in reasonably sized patient cohorts.
The conflicting results from studies on socioeconomic status (SES) and multiple sclerosis (MS) risk might be due to a change in the distribution of environmental exposures over time or to methodological limitations in previous research.
To examine the association between SES and MS risk during 50 years.
We included patients registered in Norwegian MS registries and prevalence studies born between 1930 and 1979, and identified their siblings and parents using the Norwegian Population Registry. Information on education was retrieved from the National Education Registry, categorized into four levels (primary, secondary, undergraduate and graduate) and compared in patients and siblings using conditional logistic regression.
A total of 4494 MS patients and 9193 of their siblings were included in the analyses. Level of education was inversely associated with MS risk (p trend < 0.001) with an odds ratio (OR) of 0.73 (95% confidence interval (CI): 0.59–0.90) when comparing the highest and lowest levels. The effect estimates did not vary markedly between participants born before or after the median year of birth (1958), but we observed a significant effect modification by parental education (p = 0.047).
Level of education was inversely associated with MS risk, and the estimates were similar in the earliest and latest birth cohorts.
Several reports indicate changes to prevalence, incidence, female-to-male ratio in multiple sclerosis. Diagnostic criteria, course definitions and clinical management of the disease have also undergone change during the recent decades.
To investigate temporal trends in the diagnosis of primary progressive multiple sclerosis (PPMS) in Sweden.
Through the Swedish MS registry we investigated the proportion of PPMS diagnosis in birth, diagnosis and age period cohorts using Poisson regression.
A total of 16,915 patients were categorised into six birth-cohorts from 1946 to 1975 and seven date-of-diagnosis-cohorts from 1980 to 2014. We observed a decrease in the uncorrected analysis of diagnosis of PPMS from 19.2% to 2.2% and an average decrease of 23% (p < 0.001) per 5-year birth-cohort in the adjusted analysis. An average 21% (p < 0.001) decrease per diagnosis-cohort was seen. In the age-specific diagnosis period cohorts the same decreasing trend of PPMS diagnosis was observed in almost all groups.
The diagnosis of PPMS has significantly decreased in Sweden specifically after introduction of disease-modifying treatments. Such decrease can have severe impacts on the future research on PPMS. Our data also suggest that the current trend to emphasise presence or absence of inflammatory activity is already reflected in clinical practice.
Motor imagery and rhythmic auditory stimulation are physiotherapy strategies for walking rehabilitation.
To investigate the effect of motor imagery combined with rhythmic cueing on walking, fatigue and quality of life (QoL) in people with multiple sclerosis (MS).
Individuals with MS and Expanded Disability Status Scale scores of 1.5–4.5 were randomised into one of three groups: 17 minutes of motor imagery, six times per week, for 4 weeks, with music (A) or metronome cues (B), both with verbal cueing, and (C) controls. Primary outcomes were walking speed (Timed 25-Foot Walk) and distance (6-Minute Walk Test). Secondary outcomes were walking perception (Multiple Sclerosis Walking Scale-12), fatigue (Modified Fatigue Impact Scale) and QoL (Short Form-36 Health Survey, Multiple Sclerosis Impact Scale-29, Euroquol-5D-3L Questionnaire).
Of the 112 participants randomised, 101 completed the study. Compared to controls, both interventions significantly improved walking speed, distance and perception. Significant improvements in cognitive but not psychosocial fatigue were seen in the intervention groups, and physical fatigue improved only in the music-based group. Both interventions improved QoL; however, music-cued motor imagery was superior at improving health-related QoL.
Rhythmic-cued motor imagery improves walking, fatigue and QoL in people with MS, with music-cued motor imagery being more effective.
Natalizumab and fingolimod were approved for treatment of active relapsing-remitting multiple sclerosis (RRMS) in Denmark in 2006 and 2011, respectively. There have been no randomized head-to-head studies comparing the two drugs.
To compare the clinical efficacy of natalizumab and fingolimod.
Data on all Danish RRMS patients who started their first second-line treatment with natalizumab or fingolimod from July 2011 to March 2015 were prospectively recorded in the Danish Multiple Sclerosis (MS) Treatment Register. The two treatment arms were 1:1 propensity score matched by baseline covariates using ‘nearest neighbour’ method.
Propensity score matching left 928 of 1309 RRMS cases, 464 in each treatment group. The on-treatment annualized relapse rate was 0.296 (95% confidence interval (CI): 0.26–0.34) for natalizumab and 0.307 (95% CI: 0.27–0.35) for fingolimod. The adjusted relapse rate ratio was 0.93 (95% CI: 0.74–1.17; p = 0.53). Mean time to first relapse was 2.55 and 2.56 years, respectively (p = 0.76). There was no difference in change of Expanded Disability Status Scale (EDSS).
We found no differences in clinical disease activity between natalizumab- and fingolimod-treated RRMS patients in this real-life observational study. However, the lack of magnetic resonance imaging (MRI) data for the propensity score matching may conceal a higher efficacy of natalizumab.
This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis.
Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted.
In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p < 0.001). Relapses of all phenotypes promoted disability accumulation, with the most pronounced increase associated with pyramidal (β = 0.27 (0.25–0.29)), cerebellar (β = 0.35 (0.30–0.39)) and bowel/bladder (β = 0.42 (0.35–0.49)) phenotypes (mean (95% confidence interval)). Higher incidence of each relapse phenotype was associated with an increase in disability in the corresponding neurological domain, as well as anatomically related domains.
Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.
Disease progression and treatment efficacy vary among individuals with multiple sclerosis. Reliable predictors of individual disease outcomes are lacking.
To examine the accuracy of the early prediction of 12-year disability outcomes using clinical and magnetic resonance imaging (MRI) parameters.
A total of 177 patients from the original Avonex-Steroids-Azathioprine study were included. Participants underwent 3-month clinical follow-ups. Cox models were used to model the associations between clinical and MRI markers at baseline or after 12 months with sustained disability progression (SDP) over the 12-year observation period.
At baseline, T2 lesion number, T1 and T2 lesion volumes, corpus callosum (CC), and thalamic fraction were the best predictors of SDP (hazard ratio (HR) = 1.7–4.6; p <= 0.001–0.012). At 12 months, Expanded Disability Status Scale (EDSS) and its change, number of new or enlarging T2 lesions, and CC volume % change were the best predictors of SDP over the follow-up (HR = 1.7–3.5; p <= 0.001–0.017). A composite score was generated from a subset of the best predictors of SDP. Scores of >=4 had greater specificity (90%–100%) and were associated with greater cumulative risk of SDP (HR = 3.2–21.6; p < 0.001) compared to the individual predictors.
The combination of established MRI and clinical indices with MRI volumetric predictors improves the prediction of SDP over long-term follow-up and may provide valuable information for therapeutic decisions.
Vitamin D sufficiency is associated with better inflammatory outcomes in multiple sclerosis (MS). We hypothesize that it is also associated with better long-term neurodegenerative measures.
To show that vitamin D sufficient patients (25-hydroxy vitamin D (25(OH)D) > 80 nmol/L) have better optical coherence tomography (OCT) neuroaxonal measures of ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) thickness after optic neuritis.
In this prospective cohort study, acute optic neuritis patients underwent OCT and serum 25(OH)D assessments at baseline and at month 6, with comparisons between vitamin D sufficient and insufficient patients, and men and women. Potential confounding variables were evaluated.
Of 49 enrolled, 36 had complete, analyzable data. At baseline, vitamin D insufficiency was associated with greater RNFL thickness (134.3 vs. 95.2 µm; p = 0.003) in affected eyes. At month 6, insufficient patients had greater GCL thinning (GCL inter-eye difference: 14.2 vs. 4.0 µm, p = 0.008). Men had greater RNFL and GCL thinning than women (GCL: 61.2 vs. 69.6 µm, p = 0.036).
Acutely, in optic neuritis, RNFL thickness is increased with vitamin D insufficiency. Chronically, neuronal, and possibly axonal loss are associated with vitamin D insufficiency and male gender, suggesting vitamin D and female gender may confer neuroprotection in optic neuritis, and possibly, central nervous system (CNS) inflammatory disease.
Severe rebound multiple sclerosis (MS) activity is a life-threatening complication of natalizumab (NTZ) withdrawal, for which pathogenesis and treatment are still unclear. We report the immunological and pathological characterization of a case of central nervous system (CNS) inflammatory demyelination after NTZ discontinuation.
To understand the pathophysiology of this neuroinflammatory condition.
Antemortem blood and cerebrospinal fluid (CSF) analysis was compared with postmortem pathological studies, as well as with novel flow cytometry characterization of immune cells isolated from the CNS parenchyma.
Pathological analysis of the brain revealed the presence of innumerable active inflammatory demyelinating lesions typical of immunopathological pattern II. Monocytes/macrophages and B cells were enriched in the CNS parenchyma compared to the CSF. Numerous plasma cells were present in the lesions, but CD8 T lymphocytes were predominant in the parenchyma, as opposed to CD4 in the CSF. CNS-infiltrating lymphocytes expressed high levels of adhesion molecules, granzyme B (GzB), interferon-gamma (IFN-), and interleukin (IL)-17.
Our results underline the differences in immune cell populations between the CSF and the CNS parenchyma, and suggest that aggressive immunosuppressive therapy targeting both T and B lymphocytes is warranted to control the overwhelming CNS inflammation.
Cognitive dysfunction in multiple sclerosis (MS) causes numerous limitations in activities of daily living.
To develop an improved method of cognitive assessment in people with MS using novel real-world distracters.
A sample of 99 people with MS and 55 demographically matched healthy controls underwent testing with the Minimal Assessment of Cognitive Functioning in Multiple Sclerosis (MACFIMS) and a modified version of the computerized Symbol Digit Modalities Test (c-SDMT). Half of the subjects completed the c-SDMT with built-in real-world distracters and half without.
The mean time on the c-SDMT was significantly greater in MS subjects than healthy controls for both distracter (p = 0.001) and non-distracter (p < 0.001) versions. Significantly more MS subjects were impaired on the c-SDMT with distracters than the traditional SDMT (47.1% vs 30.3%, p = 0.04). There were no differences in impairment between the c-SDMT with and without distracters (47.1% vs 37.5%, p = 0.34). The distracter version had a sensitivity of 81% and specificity of 88% in detecting global cognitive impairment.
The incorporation of distracters improves the sensitivity of a validated computerized version of the SDMT relative to the non-distracter and traditional versions and offers a quick and easy means of detecting cognitive impairment in people with MS.
The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function.
To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment.
Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm (n = 215) data, we analyzed disability progression using a novel progression endpoint, "EDSS-Plus," defined as progression on >=1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed >=24 weeks apart and with a >=20% minimum threshold change for T25FW and 9HPT.
Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors’ times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone.
The 24-week confirmed minimum worsening of >=20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.
A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis.
The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing–remitting multiple sclerosis.
This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months.
A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (–0.38% and –0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months.
Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing–remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing–remitting multiple sclerosis.
The disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) vary in their mode of action and when therapies are changed, the consequences on inflammatory and degenerative processes are largely unknown.
We investigated the effect of switching from other DMTs to fingolimod on cerebrospinal fluid (CSF) biomarkers.
43 RRMS patients were followed up after 4–12 months of fingolimod treatment. Concentrations of C-X-C motif chemokine 13 (CXCL13), chemokine (C-C motif) ligand 2 (CCL2), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light protein (NFL), and neurogranin (NGRN) were analyzed by enzyme-linked immunosorbent assay (ELISA), while chitotriosidase (CHIT1) was analyzed by spectrofluorometry.
The levels of NFL, CXCL13, and CHI3L1 decreased (p < 0.05) after fingolimod treatment. Subgroup analysis revealed a reduction in NFL (p < 0.001), CXCL13 (p = 0.001), CHI3L1 (p < 0.001), and CHIT1 (p = 0.002) in patients previously treated with first-line therapies. In contrast, the levels of all analyzed biomarkers were essentially unchanged in patients switching from natalizumab.
We found reduced inflammatory activity (CXCL13, CHI3L1, and CHIT1) and reduced axonal damage (NFL) in patients switching from first-line DMTs to fingolimod. Biomarker levels in patients switching from natalizumab indicate similar effects on inflammatory and degenerative processes. The CSF biomarkers provide an additional measure of treatment efficacy.
Retinal atrophy in multiple sclerosis (MS) is secondary to optic nerve focal inflammation and to injury of the posterior visual pathway.
To investigate the contribution of cortical lesions (CLs) to retinal pathology in primary-progressive multiple sclerosis (PPMS).
We performed a cross-sectional evaluation of 25 patients and 20 controls, relating magnetic resonance imaging (MRI) metrics of visual pathway integrity with parameters derived from spectral-domain optical coherence tomography (peripapillary retinal nerve fiber layer (RNFL) thickness, ganglion cell + inner plexiform layer (GCIPL) thickness, and macular volume (MV)).
Mean RNFL, GCIPL thickness, and MV were significantly reduced in patients compared to controls. MV and GCIPL thickness were significantly correlated with visual acuity. RNFL thinning was associated with thalamus and visual cortex volume (respectively, p = 0.01 and p < 0.05). In addition to thalamic volume, GCIPL thinning was associated with CLs and intracortical lesion number and volume, leucocortical lesion volume (all p <= 0.05) while MV decrease was associated with CLs volume (p = 0.05) and intracortical lesion number and volume (p < 0.05).
Our results suggest that RNFL thinning and GCIPL thinning/MV decrease may be explained by alternative mechanisms including retrograde trans-synaptic degeneration and/or a common pathophysiologic process affecting both the brain with CLs and the retina with neuronal loss.
Incidence and prevalence rates of multiple sclerosis (MS) are generally higher in White populations than in other ethnic groups. Relevant studies in the United Kingdom were conducted over 30 years ago.
To provide updated ethnicity-specific MS prevalence rates in the United Kingdom.
Electronic records from general practices (GPs) in four east London boroughs were queried for the number of people diagnosed with MS, grouped by ethnicity, into 5-year age bands. Compared against total registered GP patients in the area (c. 900,000), the age-standardised MS prevalence was calculated by ethnic group.
The overall age-standardised prevalence of MS was 111 per 100,000 (152 for women and 70 for men), and 180, 74 and 29 for the White, Black and South Asian populations, respectively. The sex ratios (female:male) were 2.2:1, 2.1:1 and 2.8:1, respectively.
MS prevalence was considerably lower among Black and South Asian populations, compared to the White population, by 59% and 84%, respectively. However, compared to available data in Africa and South Asia, MS is several times more prevalent among Black people and South Asians living in the United Kingdom than their territorial ancestry.
Using diffusion tensor imaging (DTI), it was previously found that demyelinated gray matter (GM) lesions have increased fractional anisotropy (FA) when compared to normal-appearing gray matter (NAGM) in multiple sclerosis (MS). The biological substrate underlying this FA change is so far unclear; both neurodegenerative changes and microglial activation have been proposed as causal contributors.
To test the proposed hypothesis that microglia activation is responsible for increased FA in cortical GM lesions.
We investigated post-mortem cortical DTI changes in hemispheric, coronally cut sections and investigated the underlying histopathology using immunohistochemistry.
Overall, there were few activated microglia/macrophages, and no difference between GM lesions and NAGM was observed. However, cell density was increased in GM lesions compared to NAGM (309.67 ± standard deviation (SD) 124.44 vs 249.95 ± SD 56.75, p = 0.002).
FA increase was not due to lesional and non-lesional differences in microglia activation and/or proliferation. We found an increase in general cellular density without a notable difference in cellular size, that is, tissue compaction, as a possible alternative explanation.
To compare the frequency and pattern of cognitive impairment (CI) between patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS).
A total of 82 NMOSD patients, 58 MS patients, and 45 healthy controls (HCs) underwent a neuropsychological assessment.
CI was observed in 29% of NMOSD and 50% of MS patients (p < 0.001); CI was considered present if a patient scored lower than the fifth percentile compared with HCs in at least three domains. A lower frequency of CI was consistently found when CI was indicated by at least two failed tests (p < 0.001). MS patients performed worse than did NMOSD patients on verbal learning and verbal and visual memory tests. Levels of education and depression and the interval from disease onset to treatment were associated with a negative influence on cognition in patients with NMOSD.
CI in patients with NMOSD may be not as common as in patients with MS. MS patients exhibited severe impairment, particularly on learning and memory tests, compared with NMOSD patients. Differential prevalence and patterns of CI between NMOSD and MS patients suggest that the two diseases have different mechanisms of brain injury.
Epidemiological findings suggest a relationship between multiple sclerosis (MS) and cardiovascular disease (CVD) risk factors, although the nature of this relationship is not well understood.
We used genome-wide association study (GWAS) data to identify shared genetic factors (pleiotropy) between MS and CVD risk factors.
Using summary statistics from a large, recent GWAS (total n > 250,000 individuals), we investigated overlap in single nucleotide polymorphisms (SNPs) associated with MS and a number of CVD risk factors including triglycerides (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, body mass index, waist-to-hip ratio, type 2 diabetes, systolic blood pressure, and C-reactive protein level.
Using conditional enrichment plots, we found 30-fold enrichment of MS SNPs for different levels of association with LDL and TG SNPs, with a corresponding reduction in conditional false discovery rate (FDR). We identified 133 pleiotropic loci outside the extended major histocompatibility complex with conditional FDR < 0.01, of which 65 are novel. These pleiotropic loci were located on 21 different chromosomes. Our findings point to overlapping pathobiology between clinically diagnosed MS and cardiovascular risk factors and identify novel common variants associated with increased MS risk.
It is unclear whether fatigue is a consequence or a predictive trait of disease worsening.
To investigate the predictive value of fatigue toward conversion to confirmed moderate–severe disability in patients with relapsing-remitting multiple sclerosis (RRMS).
We retrospectively selected from the Comprehensive Longitudinal Investigations in MS at the Brigham and Women’s Hospital (CLIMB) study cohort RRMS patients who converted to confirmed (>=2 years) Expanded Disability Status Scale (EDSS) score >=3 within a follow-up period >=3 years. We contrasted the Modified Fatigue Impact Scale (MFIS) score of 33 converters, obtained at least 1 year before conversion to EDSS >=3, with that of 33 non-converter RRMS patients matched for baseline characteristics.
Total MFIS score was higher in converter versus non-converter MS patients (median 37 vs 13; p < 0.0001). EDSS and Center for Epidemiological Studies Depression scale (CES-D) scores were also higher in the converters (median EDSS 1.5 vs 0, p < 0.0001; median CES-D 30 vs 24, p < 0.0001) and were both associated with MFIS score (EDSS: rho = 0.42, p = 0.0005; CES-D: rho = 0.72, p < 0.0001). After adjusting for EDSS and CES-D in multivariate analysis, MFIS remained a significant predictor of subsequent conversion to confirmed EDSS >=3.
Fatigue is a promising indicator of risk for conversion to confirmed moderate–severe disability in RRMS patients.
Cognitive and motor abilities in multiple sclerosis (MS) are typically quantified using reliable, consensus standard tests validated in the MS population. While these performance measures are associated with vocational disability in parametric analyses, translation of raw scores into anchors reflecting clinically relevant, functional impairment requires further research.
To examine performance-based motor and cognitive outcomes among definitive anchors that designate varying degrees of functional impairment, thereby establishing benchmarks for score interpretation.
We evaluated MS patients and healthy controls, all undergoing a brief test battery. Outcomes were derived from the MS Functional Composite (MSFC) and the Brief International Cognitive Assessment for MS (BICAMS). Functional impairment anchors were (1) disability benefits, (2) employed with negative work events, and (3) employed without problems.
All measures yielded statistically significant differences across all levels of work status, after accounting for the effects of age and education. Benchmark values distinguished the functional impairment groups. When evaluated in combination, the Timed 25-Foot Walk and the Symbol Digit Modalities Test were the most robust predictors of functional decline.
We have established benchmark scores for popular motor and cognitive tests that are associated with specific degrees of impairment in work status.
The transparent ocular structure enables quantitative analysis of microvasculature of retina, a neuronal tissue affected by multiple sclerosis (MS).
The aim of this study was to determine whether the retinal blood flow velocity and flow volume at the macula are impaired in patients with relapsing remitting multiple sclerosis (RRMS).
A total of 17 RRMS patients and 17 age- and gender-matched healthy subjects were assessed. A retinal function imager was used to measure the blood flow velocity of retinal arterioles and venules and to calculate the total perifoveal blood flow volume.
The blood flow velocities of the retinal arterioles (3.34 ± 0.89 mm/s) and venules (2.61 ± 0.6 mm/s) were significantly lower in MS patients than normal subjects (arteriole: 4.10 ± 0.87 mm/s; venule: 3.22 ± 0.65 mm/s, both p = 0.01). In addition, the total perifoveal blood flow volume in arterioles (3.74 ± 1.64 nL/s) and venules (3.81 ± 1.60 nL/s) were significantly lower in MS patients than in normal subjects (arteriole: 4.87 ± 1.41 nL/s, p = 0.02; venule: 4.71 ± 1.64 nL/s, p = 0.04).
The impaired retinal microcirculation in RRMS patients indicates microvascular dysfunction in MS.
Although many individuals with multiple sclerosis (MS) experience depression, there are no studies on the frequency and effect of peripartum depression among parents with MS.
To examine the frequency of peripartum depression in individuals with MS and its potential association with children’s psychiatric disorders.
We conducted a cohort study in British Columbia, Canada, using linked health databases, of parents with MS and their children, and age-matched unaffected parent–child dyads. The diagnosis of peripartum depression, MS and psychiatric disorders in children was based on information from hospital admission, physician visit and drug prescription claims.
Peripartum depression was significantly more common among MS parents (n = 360) versus unaffected (n = 1207) parents (25.8% vs 18.5%, p value 0.02), especially among MS affected fathers versus unaffected fathers (25.7% vs 10.2%, p value < 0.001). The incidence of psychiatric disorders in children was 3.3 and 2.7 per 100 child-years among children with and without an MS parent, respectively. The rate of psychiatric disorders was significantly higher in children with an MS parent (vs without, hazard ratio (HR): 1.34; 95% confidence interval (CI): 1.03–1.74) and among children with parents who had peripartum depression (HR: 1.87; 95% CI: 1.36–2.55).
Parental MS is associated with a higher risk of peripartum depression and increases the risk of psychiatric disorders in children.
We explored the evolution of brain atrophy in relation to development of confirmed disability progression (CDP) on serial 1.5T magnetic resonance imaging (MRI) scans over a 10-year period in 181 patients with early relapsing–remitting multiple sclerosis (RRMS).
At 10-year follow-up, they were divided into those with (100) or without (76) CDP (confirmed after 48 weeks). Changes in whole brain (WB), cortical, gray matter (GM), white matter, and ventricular cerebrospinal fluid (vCSF) volumes were calculated on three-dimensional T1-weighted (3D-T1) scans between all available time points.
In multiple sclerosis (MS) patients with CDP compared to those without, the greatest effect size percentage volume change from baseline to follow-up was detected for WB (d = 0.55, –7.5% vs –5.2%, p < 0.001), followed by vCSF (d = 0.51, +41.1% vs +25.7%, p < 0.001), cortical (d = 0.49, –7.7% vs –6.2%, p = 0.001), and GM (d = 0.40, –7.1% vs –5.8%, p = 0.006) volumes. Mixed-effects model analysis, adjusted for age, sex, and treatment change, showed significant interactions between CDP status and percentage changes for WB and vCSF (p < 0.001), cortical (p = 0.02), and GM (p = 0.04) volumes.
WB and cortical atrophy, and enlargement of vCSF spaces are associated with development of CDP on serial yearly MRI assessments over a period of 10 years.
Glycosylation alterations have been associated with the development of several human diseases and their animal models, including multiple sclerosis.
We aimed to determine whether immunoglobulin G galactosylation might be changed in multiple sclerosis.
Immunoglobulin G was isolated from serum and cerebrospinal fluid of patients with multiple sclerosis or viral meningitis and control patients without history of inflammatory or autoimmune disease. A lectin-based assay was used to investigate potential galactosylation modifications of immunoglobulin G.
Galactosylation of immunoglobulin G isolated from cerebrospinal fluid of control patients was found to be age- and gender-dependent. In addition, immunoglobulin G galactosylation was significantly altered in cerebrospinal fluid but not in serum of multiple sclerosis patients. Furthermore, this modification was correlated with an active progression of multiple sclerosis. Finally, the loss of galactosyl moieties was not simply associated with inflammation as no such change was detected in viral meningitis patients characterized by brain inflammation.
The Multiple Sclerosis Walking Scale-12 (MSWS-12) measures walking ability from the patients’ perspective. We examined the quality of the MSWS-12 using an item response theory model, the graded response model (GRM).
A total of 625 unique Dutch multiple sclerosis (MS) patients were included. After testing for unidimensionality, monotonicity, and absence of local dependence, a GRM was fit and item characteristics were assessed. Differential item functioning (DIF) for the variables gender, age, duration of MS, type of MS and severity of MS, reliability, total test information, and standard error of the trait level () were investigated.
Confirmatory factor analysis showed a unidimensional structure of the 12 items of the scale, explaining 88% of the variance. Item 2 did not fit into the GRM model. Reliability was 0.93. Items 8 and 9 (of the 11 and 12 item version respectively) showed DIF on the variable severity, based on the Expanded Disability Status Scale (EDSS). However, the EDSS is strongly related to the content of both items.
Our results confirm the good quality of the MSWS-12. The trait level () scores and item parameters of both the 12- and 11-item versions were highly comparable, although we do not suggest to change the content of the MSWS-12.
Myelin oligodendrocyte glycoprotein (MOG) antibodies have been described in children with acute disseminated encephalomyelitis (ADEM), recurrent optic neuritis, neuromyelitis optica spectrum disorders and more recently in children with multiphasic disseminated encephalomyelitis (MDEM).
To delineate the clinical, cerebrospinal fluid (CSF) and radiological features of paediatric MDEM with MOG antibodies.
Clinical course, serum antibodies, CSF, magnetic resonance imaging (MRI) studies and outcome of paediatric MDEM patients were reviewed.
A total of 8 children with two or more episodes of ADEM were identified from a cohort of 295 children with acute demyelinating events. All children had persisting MOG antibodies (median titre: 1:1280). All ADEM episodes included encephalopathy, polyfocal neurological signs and a typical MRI. Apart from ADEM episodes, three children had further clinical attacks without encephalopathy. Median age at initial presentation was 3 years (range: 1–7 years) and median follow-up 4 years (range: 1–8 years). New ADEM episodes were associated with new neurological signs and new MRI lesions. Clinical outcome did range from normal (four of the eight) to mild or moderate impairment (four of the eight). A total of four children received monthly immunoglobulin treatment during the disease course.
Children with MDEM and persisting MOG antibodies constitute a distinct entity of relapsing demyelinating events and extend the spectrum of MOG antibody–associated diseases.
The multiple sclerosis (MS) clinical course and relapses frequency before progression vary widely.
To investigate the influence of age on the MS phenotype.
Among 751 primary progressive (PP = 217) and secondary progressive (SP = 534) MS patients from the London Ontario database, we assessed the relationship of age on the relapse frequency and on the progressive phase evolution, and the impact of relapses on the age at onset of progression.
Age at onset did not influence the early attacks frequency, but patients younger at onset had larger number of total attacks before progression (age = 27.4, 31.0 and 32.8 mean years; >=4, 2–3 and 1 relapses, respectively) and longer latency to SP. Although frequent early relapses predicted younger age at SP onset, patients with no attacks (primary progressive multiple sclerosis (PPMS)), or 1, 2–3 and >=4 relapses during the relapsing-remitting phase started progressing at similar age (38.6, 41.3, 41.4 and 39.2 mean years, respectively). The age at onset of progressive phase did not affect its evolution.
Age strongly influences the phenotype before progression. Relapsing-remitting patients younger at onset are more likely to display a predominantly inflammatory course, yet relapses number does not affect the age at onset of progression.
The study of cognitive reserve (CR) in relationship with cognitive impairment (CI) in pediatric-onset multiple sclerosis (POMS) may provide cues to identifying subjects at higher risk of impairment and scope for therapeutic strategies.
To assess the potential impact of CR on cognition in a cohort of POMS patients.
In all, 48 POMS patients were followed up for 4.7 ± 0.4 years. CI was defined as the failure of >=3 tests on an extensive neuropsychological battery. Change of neuropsychological performance was assessed through the Reliable Change Index (RCI) method. At baseline, CR was estimated by measuring the intelligence quotient (IQ). The relationships were assessed through multivariable regression analyses.
At baseline, CI was detected in 14/48 (29.2%) patients. Two out of 57 healthy control (HC; 3.5%) met the same criteria of CI (p < 0.001). A deteriorating cognitive performance using the RCI method was observed in 18/48 patients (37.6%). Among the 34 cases who were cognitively preserved at baseline, a higher reserve predicted stable/improving performance (odds ratio (OR) = 1.11; 95% confidence interval (CI): 1.03–1.20; p = 0.006).
Our results suggest that higher CR in POMS patients may protect from CI, particularly in subjects with initial cognitive preservation, providing relevant implications for counseling and rehabilitation strategies.
Histopathological studies have revealed four different immunopathological patterns of lesion pathology in early multiple sclerosis (MS). Pattern II MS is characterised by immunoglobulin and complement deposition in addition to T-cell and macrophage infiltration and is more likely to respond to plasma exchange therapy, suggesting a contribution of autoantibodies.
To assess the frequency of anti-myelin oligodendrocyte glycoprotein (MOG), anti-M1-aquaporin-4 (AQP4), anti-M23-AQP4, anti-N-methyl-
Thirty-nine serum samples from patients with MS who had undergone brain biopsy (n = 24; including 13 from patients with pattern II MS) and from histopathologically non-classified MS patients (n = 15) were tested for anti-MOG, anti-M1-AQP4, anti-M23-AQP4, anti-NMDAR, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-type glutamate receptors (AMPAR), anti-gamma-aminobutyric acid receptors (GABABR), anti-leucine-rich, glioma-activated protein 1 (LGI1), anti-contactin-associated protein 2 (CASPR2), anti-dipeptidyl-peptidase-like protein-6 (DPPX), anti-Tr/Delta/notch-like epidermal growth factor–related receptor (DNER), anti-Hu, anti-Yo, anti-Ri, anti-Ma1/Ma2, anti-CV2/collapsin response mediator protein 5 (CRMP5), anti-glutamic acid decarboxylase (GAD), anti-amphiphysin, anti-Ca/RhoGTPase-activating protein 26 (ARHGAP26), anti-Sj/inositol-1,4,5-trisphosphate receptor 1 (ITPR1), anti-Homer3, anti-carbonic anhydrase–related protein (CARPVIII), anti-protein kinase gamma (PKCgamma), anti-glutamate receptor delta 2 (GluRdelta2), anti-metabotropic glutamate receptor 1 (mGluR1) and anti-mGluR5, as well as for anti-glial nuclei antibodies (AGNA) and Purkinje cell antibody 2 (PCA2).
Antibodies to MOG belonging to the complement-activating immunoglobulin G1 (IgG1) subclass were detected in a patient with pattern II MS. Detailed brain biopsy findings are shown.
This is the largest study on established anti-neural antibodies performed in MS so far. MOG-IgG may play a role in a small percentage of patients diagnosed with pattern II MS.
Cognitive impairment affects 40%–68% of relapsing-remitting multiple sclerosis (RRMS) patients. Gray matter (GM) demyelination is complicit in cognitive impairment, yet cortical lesions are challenging to image clinically. We wanted to determine whether cortical cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) differences exist between cognitively impaired (CI) and unimpaired (NI) RRMS.
Prospective study of healthy controls (n = 19), CI (n = 20), and NI (n = 19) undergoing magnetic resonance imaging (MRI) and cognitive testing <1 week apart. White matter (WM) T2 hyperintense lesions and T1 black holes were traced. General linear regression assessed the relationship between lobar WM volume and cortical and WM CBF, CBV, and MTT. Relationship between global and lobar cortical CBF, CBV, and MTT and cognitive impairment was tested using a generalized linear model. Adjusted Bonferroni p < 0.005 was considered significant.
No significant differences for age, gender, disease duration, and any fractional brain or lesion volume were demonstrated for RRMS subgroups. Expanded Disability Status Scale (EDSS) and Hospital Anxiety and Depression Scale–Depression (HADS-D) were higher in CI. Lobar cortical CBF and CBV were associated with cognitive impairment (p < 0.0001) after controlling for confounders. Cortical CBV accounted for 7.2% of cognitive impairment increasing to 8.7% with cortical CBF (p = 0.06), while WM and cortical CBF accounted for 8.2% of variance (p = 0.04).
Significant cortical CBF and CBV reduction was present in CI compared to NI in the absence of structural differences.
A functional cortico-subcortical disconnection has been recognized in fatigued multiple sclerosis (MS) patients. Normal appearing white matter (NAWM) damage might contribute to the abovementioned disconnectivity.
To assess the relationship between fatigue and microstructural NAWM damage in relapsing-remitting (RR) MS.
Sixty RRMS patients and 29 healthy controls (HC) underwent a magnetic resonance imaging (MRI) protocol including diffusion tensor imaging (DTI). Patients with a mean Fatigue Severity Scale (FSS) score >= 4 were considered fatigued (fatigued MS (F-MS)). Tract-based spatial statistics were applied for voxel-wise analysis of DTI indices. A correlation analysis was performed between FSS score and DTI indices in the entire MS group.
Thirty MS patients were F-MS. Compared to HC, F-MS patients showed a more extensive NAWM damage than not fatigued MS (NF-MS) patients, with additional damage in the following tracts: frontal and occipital juxtacortical fibers, external capsule, uncinate fasciculus, forceps minor, superior longitudinal fasciculus, cingulum, and pons. No differences were found between F-MS and NF-MS patients. Fatigue severity correlated to DTI abnormalities of corona radiata, cingulum, corpus callosum, forceps minor, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, thalamus and anterior thalamic radiation, cerebral peduncle, and midbrain.
Fatigue is associated to a widespread microstructural NAWM damage, particularly in associative tracts connected to frontal lobes.
To investigate the dynamic temporal changes of brain resting-state functional connectivity (RS-FC) following mental effort in multiple sclerosis (MS) patients with cognitive fatigue (CF).
Twenty-two MS patients, 11 with (F) and 11 without CF, and 12 healthy controls were included. Separate RS-FC scans were acquired on a 3T MR scanner immediately before (t0), immediately after (t1) and 30 minutes after (t2) execution of the paced auditory serial addition test (PASAT), a cognitively demanding task. Subjectively perceived CF after PASAT execution was also assessed. RS-FC changes were investigated by using a data-driven approach (the Intrinsic Connectivity Contrast-power), complemented by a priori defined regions of interest analyses.
The F-group patients experienced stronger RS-FC at t2 between the left superior frontal gyrus (L-SFG) and occipital, frontal and temporal areas, which increased over time after PASAT execution. In the F-group patients, the L-SFG was hyperconnected at t1 with the left caudate nucleus and hypoconnected at t2 with the left anterior thalamus. These variations were correlated with both subjectively perceived and clinically assessed CF, and—for the left thalamus—with PASAT performance.
The development of cortico–cortical and cortico–subcortical hyperconnectivity following mental effort is related to CF symptoms in MS patients.
The compensatory effect of brain functional connectivity enhancement in relapsing-remitting multiple sclerosis (RRMS) remains controversial.
To characterize the relationships between brain functional connectivity changes and disability progression in RRMS.
Long-range connectivity, short-range connectivity, and density of connections were assessed using graph theoretical analysis of resting-state functional magnetic resonance imaging (fMRI) data acquired in 38 RRMS patients (disease duration: 120 ± 32 months) and 24 controls. All subjects were explored at baseline and all patients and six controls 2 years later.
At baseline, levels of long-range and short-range brain functional connectivity were higher in patients compared to controls. During the follow-up, decrease in connections’ density was inversely correlated with disability progression. Post-hoc analysis evidenced differential evolution of brain functional connectivity metrics in patients according to their level of disability at baseline: while patients with lowest disability at baseline experienced an increase in all connectivity metrics during the follow-up, patients with higher disability at baseline showed a decrease in the connectivity metrics. In these patients, decrease in the connectivity metrics was associated with disability progression.
The study provides two main findings: (1) brain functional connectivity enhancement decreases during the disease course after reaching a maximal level, and (2) decrease in brain functional connectivity enhancement participates in disability progression.
Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS).
We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk.
We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size (Neff) = 5555) and a large MS GWAS (Neff = 15,231).
We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 (p = 4.11 x 10–9). A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP (p = 3.32 x 10–20). By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance (p < 5 x 10–8).
Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.
Multiple sclerosis (MS) patients frequently have postural control impairment but quantitative posturography is difficult to perform in clinical care. Recent technology facilitates new posturography approaches.
To evaluate construct validity of visual perceptive computing (VPC) for static posturography to study postural control in MS patients.
A total of 90 MS patients and 59 healthy controls (HCs) performed three stance tests: open, closed and tandem stance. Static posturography was performed using a VPC system with Microsoft Kinect. Clinical assessments included Expanded Disability Status Scale (EDSS), Timed-25-Foot-Walk, Short-Maximum-Speed-Walk and 12-item MS Walking Scale (MSWS-12) questionnaire. Reliability was assessed with intra-class correlation coefficients at retest.
As a group, MS patients performed worse than HCs in all tests. The closed stance test showed best applicability and reliability. With closed eyes, in 36.7% of patients, the three-dimensional mean angular sway velocity (MSV-3D) was above HCs’ 95th percentile. Higher MSV-3D was associated with decreased walking speed (p < 0.001); worse clinical scores, mainly attributable to the cerebellar functional system score (p < 0.001); and reflected in self-reported walking disability (MSWS-12, p < 0.001).
Postural control can be reliably assessed by VPC-based static posturography in patients with MS. Abnormal postural control seems to predominantly reflect involvement of cerebellar circuits with impact on gait and walking disability.
To evaluate clinical fluid-attenuated inversion recovery (FLAIR)* 3T magnetic resonance imaging (MRI), which is sensitive to perivenular inflammatory demyelinating lesions, in diagnosing multiple sclerosis (MS).
Central veins may be a distinguishing feature of MS lesions. FLAIR*, a combined contrast derived from clinical MRI scans, has not been studied as a clinical tool for diagnosing MS.
Two experienced MS neurologists evaluated 87 scan pairs (T2-FLAIR/FLAIR*), separately and side-by-side, from 68 MS cases, 8 healthy volunteers, and 11 individuals with other neurological diseases. Raters judged cases based on experience, published criteria, and a visual assessment of the "40% rule," whereby MS is favored if >40% of lesions demonstrate a central vein. Diagnostic accuracy was determined with area under the receiver operating characteristic curve (AUC), and inter-rater reliability was assessed with Cohen’s kappa ().
Diagnostic accuracy was high: rater 1, AUC 0.94 (95% confidence interval: 0.89, 0.97) for T2-FLAIR, 0.95 (0.92, 0.98) for FLAIR*; rater 2, 0.94 (0.90, 0.98) and 0.90 (0.85, 0.95). AUC improved when images were considered together: rater 1, 0.99 (0.98, 1.00); rater 2, 0.98 (0.96, 0.99). Inter-rater agreement was substantial for T2-FLAIR ( = 0.68) and FLAIR* ( = 0.74), despite low agreement on the 40% rule ( = 0.47) (
Joint clinical evaluation of T2-FLAIR and FLAIR* images modestly improves diagnostic accuracy for MS and does not require counting lesions with central veins.
Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility.
To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS.
Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models.
Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04–1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (pixn = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58–0.88, p = 0.002; in DRB1*15– HR = 0.96, 95% CI = 0.83–1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate.
We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors.
Lipocalin 2 (LCN2) may be involved in the immunopathogenesis of multiple sclerosis (MS) and might further impact on iron homoeostasis. Brain iron accumulates in MS; however, the association to iron-related proteins is still unsolved.
To investigate cerebrospinal fluid (CSF) and serum LCN2, transferrin (Trf) and ferritin in early MS in relation to disease evolution and longitudinal brain iron accumulation.
We analysed CSF and serum LCN2 by enzyme-linked immunosorbent assay (ELISA) and Trf and ferritin by nephelometry in 55 patients (45 clinically isolated syndrome (CIS), 10 MS, median clinical follow-up 4.8 years) and 63 controls. In patients, we assessed sub-cortical grey matter iron by 3T magnetic resonance imaging (MRI) R2* relaxometry (median imaging follow-up 2.2 years).
Compared to controls serum (p < 0.01), CSF (p < 0.001) LCN2 and CSF Trf (p < 0.001) levels were reduced in the patients. CSF LCN2 correlated with CSF Trf (r = 0.5, p < 0.001). In clinically stable patients, CSF LCN2 levels correlated with basal ganglia iron accumulation (r = 0.5, p < 0.05). In CIS, higher CSF LCN2 levels were associated with conversion to clinically definite MS (p < 0.05).
We demonstrate altered LCN2 regulation in early MS and provide first evidence for this to be possibly linked to both clinical MS activity and iron accumulation in the basal ganglia.
Prolonged-release fampridine (PR-fampridine, 4-aminopyridine) increases walking speed in the timed 25-foot walk test (T25FW) in some patients (timed-walk responders) with multiple sclerosis (MS).
To explore the effects of PR-fampridine on different aspects of walking function and to identify associated gait modifications in subjects with MS.
In this prospective, randomized, placebo-controlled, double-blind, phase II study (FAMPKIN; clinicaltrials.gov, NCT01576354), subjects received a 6-week course of oral placebo or PR-fampridine treatment (10 mg, twice daily) before crossing over. Using 3D-motion-analysis, kinematic and kinetic parameters were assessed during treadmill walking (primary endpoint). Clinical outcome measures included T25FW, 6-minute walk test (6MWT), and balance scales. Physical activity in everyday life was measured with an accelerometer device.
Data from 55 patients were suitable for analysis. Seventeen subjects were timed-walk responders under PR-fampridine. For the total study population and for responders, a significant increase in walking speed (T25FW) and distance (6MWT) was observed. Gait pattern changes were found at the single-subject level and correlated with improvements in the T25FW and 6MWT. Physical activity was increased in responders.
PR-fampridine improves walking speed, endurance, and everyday physical activity in a subset of subjects with MS and leads to individual modifications of the gait pattern.
Lesions with different extents of myelin pathology are found at autopsy in multiple sclerosis (MS), but the differences are not discernible in magnetic resonance imaging (MRI).
To determine whether analysis of the local spectrum in MRI is sensitive to lesion differences in myelin integrity.
We imaged fresh brain slices from 21 MS patients using 1.5T scanners. White matter lesions were identified in T2-weighted MRI, matched to corresponding specimens, and then classified into five categories in histology: pre-active (intact myelin); active, chronic active, chronic inactive (complete demyelination); and remyelinated lesions. Voxel-based frequency spectrum was calculated using T2-weighted MRI to characterize lesion structure (image texture).
MRI texture heterogeneity resulting from all spectral scales was greater in completely demyelinated lesions than in myelin-preserved lesions (p = 0.02) and normal-appearing white matter (p < 0.01). Moreover, the spectral distribution pattern over low-frequency scales differentiated demyelinated lesions from remyelinated and pre-active lesions (p < 0.01), where different lesion types also showed distinct texture scales.
Using multi-scale spectral analysis, it may be possible for standard MRI to evaluate myelin integrity in MS lesions. This can be critical for monitoring disease activity and assessing remyelination therapies for MS patients.
Microglia-mediated proteolysis of the triggering receptor expressed on myeloid cells-2 (TREM-2) produces soluble TREM-2 (sTREM-2) that can be measured in cerebrospinal fluid (CSF) samples. Loss-of-function mutations in TREM2 or in the gene encoding its adaptor protein cause the rare Nasu–Hakola disease (NHD). Multiple sclerosis (MS) is an autoimmune disease that in common with NHD is characterized by demyelination and microglial activation.
To investigate the potential utility of sTREM-2 as a biomarker for MS and to follow treatment effects.
sTREM-2 was analyzed in CSF samples from subjects with MS (N = 59); relapsing-remitting MS (RRMS) (N = 36), secondary progressive MS (SPMS) (N = 20) and primary progressive MS (PPMS) (N = 3), and controls (N = 27). CSF levels of sTREM-2 were also assessed before and after treatment of patients with natalizumab or mitoxantrone.
CSF levels of sTREM-2 were significantly increased in patients with RRMS, SPMS, and PPMS compared with controls. After natalizumab treatment, the levels of sTREM-2 were normalized to control levels. The levels of sTREM-2 were also reduced after mitoxantrone treatment.
Increased CSF levels of sTREM-2, a new marker of microglial activation, in MS and normalization upon treatment with either natalizumab or mitoxantrone support a role for microglial activation in active MS.
In less than a decade, genomewide association studies have identified over 100 single-nucleotide variants that are associated with increased risk of developing multiple sclerosis. However, since these studies have focused almost exclusively on European populations, it is unclear what role these variants might play in determining risk in other ethnic groups.
To assess the effects of European multiple sclerosis–associated risk variants in the south Asian population.
Using a combination of chip-based genotyping and next-generation sequencing, we have assessed 109 European-associated variants in a total of 270 cases and 555 controls from the south Asian population.
We found that two-thirds of the tested variants (72/109) showed over representation of the European risk allele in south Asian cases (p < 0.0003). In the rest of the Immunochip array, the most associated variant was rs7318477 which maps close to TNFSF13B, the gene for the B-cell-related protein BAFF.
Our data indicate substantial overlap in genetic risk architecture between Europeans and south Asians and suggest that the aetiology of the disease may be largely independent of ethnicity.
Neurofilament light chain (NfL) levels in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients correlate with the degree of neuronal injury. To date, little is known about NfL concentrations in the serum of relapsing remitting multiple sclerosis (RRMS) patients and their relationship with CSF levels and magnetic resonance imaging (MRI) measures of disease severity. We aimed to validate the quantification of NfL in serum samples of RRMS, as a biofluid source easily accessible for longitudinal studies.
A total of 31 RRMS patients underwent CSF and serum sampling. After a median time of 3.6 years, 19 of these RRMS patients, 10 newly recruited RRMS patients and 18 healthy controls had a 3T MRI and serum sampling. NfL concentrations were determined by electrochemiluminescence immunoassay.
NfL levels in serum were highly correlated to levels in CSF (r = 0.62, p = 0.0002). Concentrations in serum were higher in patients than in controls at baseline (p = 0.004) and follow-up (p = 0.0009) and did not change over time (p = 0.56). Serum NfL levels correlated with white matter (WM) lesion volume (r = 0.68, p < 0.0001), mean T1 (r = 0.40, p = 0.034) and T2* relaxation time (r = 0.49, p = 0.007) and with magnetization transfer ratio in normal appearing WM (r = –0.41, p = 0.029).
CSF and serum NfL levels were highly correlated, and serum concentrations were increased in RRMS. Serum NfL levels correlated with MRI markers of WM disease severity. Our findings further support longitudinal studies of serum NfL as a potential biomarker of on-going disease progression and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.
Detection of cortical abnormalities in relapsing-remitting multiple sclerosis (RRMS) remains elusive. Structural magnetic resonance imaging (MRI) measures of cortical integrity are limited, although functional techniques such as pseudo-continuous arterial spin labeling (pCASL) show promise as a surrogate marker of disease severity. We sought to determine the utility of pCASL to assess cortical cerebral blood flow (CBF) in RRMS patients with (RRMS-I) and without (RRMS-NI) cognitive impairment.
A total of 19 age-matched healthy controls and 39 RRMS patients were prospectively recruited. Cognition was assessed using the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery. Cortical CBF was compared between groups using a mass univariate voxel-based morphometric analysis accounting for demographic and structural variable covariates.
Cognitive impairment was present in 51.3% of patients. Significant CBF reduction was present in the RRMS-I compared to other groups in left frontal and right superior frontal cortex. Compared to healthy controls, RRMS-I displayed reduced CBF in the frontal, limbic, parietal and temporal cortex, and putamen/thalamus. RRMS-I demonstrated reduced left superior frontal lobe cortical CBF compared to RRMS-NI. No significant cortical CBF differences were present between healthy controls and RRMS-NI.
Significant cortical CBF reduction occurs in RRMS-I compared to healthy controls and RRMS-NI in anatomically significant regions after controlling for structural and demographic differences.
Depression is a common co-morbidity in patients with multiple sclerosis (MS). While somatic symptoms of MS correlate with depression levels, it is unclear whether the clinical presentation of MS-associated depression differs from patients with "idiopathic" major depressive disorder (MDD).
To compare the clinical phenotype of depression among MS and idiopathic MDD patients.
Mean relative contribution of individual Beck Depression Inventory-II (BDI-II) items was evaluated among n = 139 patients with relapsing-remitting MS and n = 85 MDD patients without somatic illness. Next, comparisons were repeated in n = 38 MS with clinically relevant depressive symptoms (BDI-II > 19) and n = 38 MDD patients matched for sex, age, and depression severity. Finally, the underlying construct of depression was compared across groups using confirmatory factor analysis (CFA).
Comparisons on a whole-group level produced the expected differences along somatic/non-somatic symptoms. However, when appropriately controlling for depression severity, age, and sex, only four items contributed differentially to BDI-II total scores in MS versus MDD. CFA suggested that the underlying depression construct is essentially identical in both groups.
The clinical phenotype of "idiopathic" MDD and MS-associated depression appears similar when adequately examined. The relevance of these findings for psychotherapeutic approaches for MS-associated depression should be explored in future studies.
It has been suggested that onset of multiple sclerosis (MS) is preceded by a clinically silent period of up to 10 years.
Examine whether such a period should be associated with poor self-rated health (SRH).
Information on SRH before pregnancy was ascertained among 80,848 women participating in the Danish National Birth Cohort (DNBC) 1996–2002. Women were followed for MS from enrolment in DNBC in the 16th week of pregnancy until 31 December 2011. Associations between SRH and MS were evaluated by means of hazard ratios (HR) with 95% confidence intervals (CIs) using Cox proportional hazard models.
During on average 11.7 years of follow-up, 239 women were diagnosed with MS. Overall, neither women with fair (HR = 1.09 (95% CI = 0.83–1.41), n = 113) nor poor pre-pregnancy SRH (HR = 0.94 (95% CI = 0.47–1.87), n = 9) were at an increased risk of MS compared with women reporting very good pre-pregnancy SRH. Supplementary analyses showed no significant differences in MS risk in consecutive periods of follow-up.
In this first prospective cohort study assessing MS risk as a function of SRH, we found no indication of a long period of poor SRH prior to MS. Our findings based on pregnant women may not necessarily apply to all women.
While our knowledge of white matter (WM) pathology underlying cognitive impairment in relapsing remitting multiple sclerosis (MS) is increasing, equivalent understanding in those with secondary progressive (SP) MS lags behind.
The aim of this study is to examine whether the extent and severity of WM tract damage differ between cognitively impaired (CI) and cognitively preserved (CP) secondary progressive multiple sclerosis (SPMS) patients.
Conventional magnetic resonance imaging (MRI) and diffusion MRI were acquired from 30 SPMS patients and 32 healthy controls (HC). Cognitive domains commonly affected in MS patients were assessed. Linear regression was used to predict cognition. Diffusion measures were compared between groups using tract-based spatial statistics (TBSS).
A total of 12 patients were classified as CI, and processing speed was the most commonly affected domain. The final regression model including demographic variables and radial diffusivity explained the greatest variance of cognitive performance (R2 = 0.48, p = 0.002). SPMS patients showed widespread loss of WM integrity throughout the WM skeleton when compared with HC. When compared with CP patients, CI patients showed more extensive and severe damage of several WM tracts, including the fornix, superior longitudinal fasciculus and forceps major.
Loss of WM integrity assessed using TBSS helps to explain cognitive decline in SPMS patients.
Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease.
To assess the role of RANTES in the regulation of cortical excitability.
We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro.
CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP.
RANTES correlates with inflammation and synaptic excitability in MS brains.
‘No evidence of disease activity’ (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression (‘NEDA-3’), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression.
To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 (‘NEDA-4’)
We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%–1.2%).
At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01–4.41; p < 0.0001).
NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.
Exposure to parental chronic illness is associated with adverse developmental outcomes.
We examined the association between parental multiple sclerosis (MS) and parental MS-related clinical factors on developmental health.
We conducted a population-based cohort study in British Columbia, Canada, using linked health databases. The outcome was childhood development at 5 years of age, expressed as vulnerability on the Early Development Instrument (EDI). Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression.
MS-affected parents (n = 783) were older, more likely to be English speakers, and had higher rates of mental health morbidity (39.6% vs 22.2%, p < 0.001) than unaffected parents (n = 2988). In the adjusted models, children of mothers with MS (aOR = 0.62, 95% CI = 0.44–0.87), but not children of the fathers with MS, had a lower risk of vulnerability on the social development domain of the EDI. However, mental health comorbidity (aOR = 1.62, 95% CI = 1.05–2.50) and physical comorbidity (aOR = 1.67, 95% CI = 1.05–2.64) among mothers with MS were associated with increased vulnerability on the EDI.
Maternal MS, but not paternal MS, was associated with lower rates of developmental vulnerability on the social development domain. However, mental and physical comorbidity among MS-affected mothers were associated with increased developmental vulnerability in children.
Cortical gray matter (GM) demyelination is frequent and clinically relevant in multiple sclerosis (MS). Quantitative magnetic resonance imaging (qMRI) sequences such as magnetization transfer ratio (MTR) and quantitative R2* (qR2*) can capture pathological subtleties missed by conventional magnetic resonance imaging (MRI) sequences. Although differences in MTR and qR2* have been reported between lesional and non-lesional tissue, differences between lesion types or lesion types and myelin density matched normal-appearing gray matter (NAGM) have not been found or investigated.
Identify quantitative differences in histopathologically verified GM lesion types and matched NAGM at ultra-high field strength.
Using 7T post-mortem MRI, MRI lesions were marked on T2 images and co-registered to the calculated MTR and qR2* maps for further evaluation. In all, 15 brain slices were collected, containing a total of 74 cortical GM lesions and 45 areas of NAGM.
Intracortical lesions had lower MTR and qR2* values compared to NAGM. Type I lesions showed lower MTR than type III lesions. Type III lesions showed lower MTR than matched NAGM, and type I and IV lesions showed lower qR2* than matched NAGM.
qMRI at 7T can provide additional information on extent of cortical pathology, especially concerning subpial lesions. This may be relevant for monitoring disease progression and potential treatment effects.
In multiple sclerosis (MS), pathophysiology of fatigue is only partially known.
The aim of this study was to investigate whether the attention-induced modulation on short- and long-term cortical plasticity mechanisms in primary motor area (M1) is abnormal in patients with MS-related fatigue.
All participants underwent 5-Hz repetitive transcranial magnetic stimulation (rTMS), reflecting short-term plasticity, and paired associative stimulation (PAS), reflecting long-term plasticity, and were asked to focus their attention on the hand contralateral to the M1 stimulated. A group of age-matched healthy subjects acted as control.
In patients with MS, 5-Hz rTMS and PAS failed to induce the normal increase in motor-evoked potential (MEP). During the attention-demanding condition, 5-Hz rTMS- and PAS-induced responses differed in patients with MS with and without fatigue. Whereas in patients with fatigue neither technique induced the attention-induced MEP increase, in patients without fatigue they both increased the MEP response, although they did so less efficiently than in healthy subjects. Attention-induced changes in short-term cortical plasticity inversely correlated with fatigue severity.
Short-term and long-term plasticity mechanisms are abnormal in MS possibly owing to widespread changes in ion-channel expression. Fatigue in MS reflects disrupted cortical attentional networks related to movement control.
White matter lesions are frequently detected using brain magnetic resonance imaging (MRI) performed for various indications. Most are microangiopathic, but demyelination, including multiple sclerosis (MS), is an important cause; conventional MRI cannot always distinguish between these pathologies. The proportion of lesions with a central vein on 7-T T2*-weighted MRI prospectively distinguishes demyelination from microangiopathic lesions.
To test whether 3-T T2*-weighted MRI can differentiate MS from microangiopathic brain lesions.
A total of 40 patients were studied. Initially, a test cohort of 10 patients with MS and 10 patients with microangiopathic white matter lesions underwent 3-T T2*-weighted brain MRI. Anonymised scans were analysed blind to clinical data, and simple diagnostic rules were devised. These rules were applied to a validation cohort of 20 patients (13 with MS and 7 with microangiopathic lesions) by a blinded observer.
Within the test cohort, all patients with MS had central veins visible in >45% of brain lesions, while the rest had central veins visible in <45% of lesions. By applying diagnostic rules to the validation cohort, all remaining patients were correctly categorised.
3-T T2*-weighted brain MRI distinguishes perivenous MS lesions from microangiopathic lesions. Clinical application of this technique could supplement existing diagnostic algorithms.
In natalizumab-treated multiple sclerosis (MS) patients, magnetic resonance imaging (MRI) is considered as a sensitive tool in detecting both MS disease activity and progressive multifocal leukoencephalopathy (PML).
To investigate the performance of neuroradiologists using brain MRI in detecting new MS lesions and asymptomatic PML lesions and in differentiating between MS and PML lesions in natalizumab-treated MS patients. The secondary aim was to investigate interrater variability.
In this retrospective diagnostic study, four blinded neuroradiologists assessed reference and follow-up brain MRI scans of 48 natalizumab-treated MS patients with new asymptomatic PML lesions (n = 21) or new MS lesions (n = 20) or no new lesions (n = 7). Sensitivity and specificity for detection of new lesions in general (MS and PML lesions), MS and PML lesion differentiation, and PML detection were determined. Interrater agreement was calculated.
Overall sensitivity and specificity for the detection of new lesions, regardless of the nature of the lesions, were 77.4% and 89.3%, respectively; for PML-MS lesion differentiation, 74.2% and 84.7%, respectively; and for asymptomatic PML lesion detection, 59.5% and 91.7%, respectively. Interrater agreement for the tested categories was fair to moderate.
The diagnostic performance of trained neuroradiologists using brain MRI in pharmacovigilance of natalizumab-treated MS patients is moderately good. Interrater agreement among trained readers is fair to moderate.
No large-scale studies have compared the efficacy of intravenous methylprednisolone pulse therapy (IVMP) for multiple sclerosis (MS) and neuromyelitis optica (NMO).
To explain differences in treatment responses of MS and NMO patients to IVMP.
Changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of IVMP completion were obtained in 2010 at 28 institutions, and retrospectively collated from 271 MS (478 courses) and 73 NMO (118 courses) cases.
In MS patients, decreased EDSS score was significant after the first (–0.8 ± 0.9), second (–0.7 ± 0.9), and third (–0.7 ± 0.8) courses (p < 0.05), but not after the fourth (–0.3 ± 0.7) and fifth (–0.5 ± 0.6). However, decreased EDSS score was only significant after the first course (–0.5 ± 1.5, p < 0.05) in NMO patients. EDSS score was significantly decreased in MS compared with NMO patients at the first course (p < 0.05), but not thereafter. Model analysis for EDSS score improvement at the first course, adjusting for covariates, showed significantly greater decreases in MS compared with NMO patients (p < 0.05).
IVMP is effective in MS from the first to third courses, and in NMO at the first course. Additionally, IVMP is more efficacious in MS than NMO patients, even at the first course.
Patient-Reported Expanded Disability Status Scale (PREDSS) tools are an attractive alternative to the Expanded Disability Status Scale (EDSS) during long term or geographically challenging studies, or in pressured clinical service environments.
Because the studies reporting these tools have used different metrics to compare the PREDSS and EDSS, we undertook an individual patient data level analysis of all available tools.
Spearman’s rho and the Bland–Altman method were used to assess correlation and agreement respectively.
A systematic search for validated PREDSS tools covering the full EDSS range identified eight such tools. Individual patient data were available for five PREDSS tools. Excellent correlation was observed between EDSS and PREDSS with all tools. A higher level of agreement was observed with increasing levels of disability. In all tools, the 95% limits of agreement were greater than the minimum EDSS difference considered to be clinically significant. However, the intra-class coefficient was greater than that reported for EDSS raters of mixed seniority. The visual functional system was identified as the most significant predictor of the PREDSS–EDSS difference.
This analysis will (1) enable researchers and service providers to make an informed choice of PREDSS tool, depending on their individual requirements, and (2) facilitate improvement of current PREDSS tools.
Gray matter (GM) pathology has high clinical relevance in multiple sclerosis (MS), but conventional magnetic resonance imaging (MRI) is insufficiently sensitive to visualize the rather subtle damage.
To investigate whether high spatial resolution T1-relaxation time (T1-RT) measurements can detect changes in the normal-appearing GM of patients with long-standing MS and whether these changes are associated with physical and cognitive impairment.
High spatial resolution (1.05 x 1.05 x 1.2 mm3) T1-RT measurements were performed at 3 T in 156 long-standing MS patients and 54 healthy controls. T1-RT histogram parameters in several regions were analyzed to investigate group differences. Stepwise linear regression analyses were used to assess the relation of T1-RT with physical and cognitive impairment.
In both thalamus and cortex, T1-RT histogram skewness was higher in patients than controls. In the cortex, this was driven by the frontal and temporal lobes. No differences were found in other GM histogram parameters. Cortical skewness, thalamus volume, and average white matter (WM) lesion T1-RT emerged as the strongest predictors for cognitive performance (adjusted R2 = 0.39).
Subtle GM damage was present in the cortex and thalamus of MS patients, as indicated by increased T1-RT skewness. Increased cortical skewness emerged as an independent predictor of cognitive dysfunction.
Acquired demyelinating syndromes (ADS) have the potential to negatively impact cerebellar growth, given the proclivity for infratentorial lesions in pediatric-onset multiple sclerosis (MS) and ADS.
To investigate cerebellar growth longitudinally in pediatric ADS.
Cerebellar volumes from 472 magnetic resonance imaging (MRI) scans of 98 patients with monophasic ADS (monoADS), monophasic acute disseminated encephalomyelitis (ADEM), and MS (49 girls; mean age: 11.4 years at first scan, mean follow-up: 3.1 years) imaged serially from onset and 897 MRI scans of 418 healthy children (223 girls, mean age: 11.3 years, mean follow-up: 2.9 years) were segmented automatically, analyzed with mixed-effect models, and compared with cerebral volume.
Cerebellar developmental trajectories followed a U-shaped curve, showing larger volumes in boys (p < 0.001). Cerebellar volumes in all three patient groups failed to reach age-expected trajectories, leading to significantly smaller volumes, notably in the posterior lobes. Cerebellar volume reductions were of a similar magnitude to cerebral volume reductions. Cerebellar white matter volume declined in MS and ADEM patients over time, while in monoADS patients it remained similar to controls. Cerebellar volumes did not correlate either with lesion volumes at onset or with physical disability.
MonoADS, ADEM, and MS in childhood lead to impaired age-expected growth of the cerebellum.
Deep gray matter (DGM) atrophy is common in multiple sclerosis (MS), but no studies have investigated surface-based structure changes over time with respect to healthy controls (HCs). Moreover, the relationship between cognition and the spatio-temporal evolution of DGM atrophy is poorly understood.
To explore DGM structural differences between MS and HCs over time in relation to neuropsychological (NP) outcomes.
The participants were 44 relapsing-remitting and 20 secondary progressive MS patients and 22 HCs. All were scanned using 3T magnetic resonance imaging (MRI) at baseline and 3-year follow-up. NP examination emphasized consensus standard tests of processing speed and memory. We performed both volumetric and shape analysis of DGM structures and assessed their relationships with cognition.
Compared to HCs, MS patients presented with significantly smaller DGM volumes. For the thalamus and caudate, differences in shape were mostly localized along the lateral ventricles. NP outcomes were related to both volume and shape of the DGM structures. Over 3 years, decreased cognitive processing speed was related to localized atrophy on the anterior and superior surface of the left thalamus.
These findings highlight the role of atrophy in the anterior nucleus of the thalamus and its relation to cognitive decline in MS.
Neuromyelitis optica (NMO)–systemic lupus erythematosus (SLE) association is a rare condition characterized by multiple autoantibodies.
To examine if, during the evolution of NMO, anti-AQP4 responses are part of polyclonal B cell activation, and if T cell responses contribute.
In 19 samples of six patients who developed NMO during SLE, we examined the correlation of AQP4-IgG1 and IgM with (i) anti-MOG IgG and IgM, (ii) anti-nuclear, anti-nucleosome and anti-dsDNA IgG antibodies, (iii) cytokines and chemokines in the serum and (iv) longitudinal relation to NMO relapses/remission.
AQP4-IgG1 was present 1–2–5 years before the first NMO relapse. During relapse, AQP4-IgG1, ANA, anti-dsDNA and anti-nucleosome antibodies were elevated. Anti-MOG IgG/IgM and AQP4-IgM antibodies were not detected. AQP4-IgG1 antibodies correlated with concentration of anti-nucleosome, IFN-,interferon-gamma-induced CCL10/IP-10 and CCL17/TARC (p<0.05, respectively). CCL17/TARC correlated with levels of anti-nucleosome and anti-dsDNA (p<0.05, respectively). Compared to healthy subjects, concentration of IFN- and CCL17/TARC was higher in NMO/SLE (p<0.05).
AQP4-IgG1 antibodies are present in the sera years before the first NMO attack in patients with SLE; elevation of anti-AQP4 is part of a polyclonal B cell response during NMO relapses; in spite of multiple autoantibodies in the serum, MOG antibodies were not present; Th1 responses accompany autoantibody responses in NMO/SLE.
Deason K, Miller-Little WA and Stüve O. Natalizumab and monocytes in multiple sclerosis: The dim haze of mystery and the enchantment of pursuit. Multiple Scleroris Journal 2015; DOI:
The above editorial, originally published online on the 26th of May 2015 and amended on the 5th of October 2015, was published in error.
SAGE offers its apologies for this mistake.
Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear understanding of its application and durability of effect in clinical practice has yet to evolve.
To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab.
Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review.
One hundred patients were identified with a mean follow-up of 6.1 years (range 1–13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty-seven patients developed secondary autoimmunity.
Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime.
Deep gray matter (DGM) is affected in relapsing–remitting multiple sclerosis (RRMS) and may be studied using short-term longitudinal MRI.
To investigate two-year changes in spin-echo transverse relaxation rate (R2) and atrophy in DGM, and its relationship with disease severity in RRMS patients.
Twenty six RRMS patients and 26 matched controls were imaged at 4.7 T. Multiecho spin-echo R2 maps and atrophy measurements were obtained in DGM at baseline and two-year follow-up. Differences between MRI measures and correlations to disease severity were examined.
After two years, mean R2 values in the globus pallidus and pulvinar increased by ~4% (p<0.001) in patients and <1.7% in controls. Two-year changes in R2 showed significant correlation to disease severity in the globus pallidus, pulvinar, substantia nigra, and thalamus. Multiple regression of the two-year R2 difference using these four DGM structures as variables, yielded high correlation with disease severity (r=0.83, p<0.001). Two-year changes in volume and R2 showed significant correlation only for the globus pallidus in multiple sclerosis (MS) (p<0.05).
Two-year difference R2 measurements in DGM correlate to disease severity in MS. R2 mapping and atrophy measurements over two years can be used to identify changes in DGM in MS.
Using functional magnetic resonance imaging (fMRI) during a motor task, we investigated the functional correlates of central fatigue in multiple sclerosis (MS), and adaptation of motor network recruitment during a prolonged effort.
Motor fMRI was obtained from 79 MS patients (50 fatigued (F), 29 non-fatigued (nF)) and 26 matched healthy controls (HC). Cognitive and physical fatigue were rated using the Modified Fatigue Impact Scale (MFIS).
Compared to HC and nF patients, F-MS patients experienced reduced activations of the left middle temporal gyrus, left supplementary motor area (SMA), bilateral superior frontal gyrus, left postcentral gyrus and basal ganglia regions. They also showed increased activation of the right middle frontal gyrus (MFG). Time-modulation analysis showed a reduced activity of the SMA and right precentral gyrus, and increased activity of the basal ganglia in HC. Such a trend was impaired in F-MS patients. In MS patients, increased MFG activity was related to MFIS scores. Physical MFIS score was related to a reduced recruitment of the right thalamus and SMA.
Abnormalities and impaired timing of activation between different areas of the motor and executive networks occur in F-MS patients. The dysfunction of critical cortical areas contributes to the occurrence of central fatigue.
MiRNA-181c, miRNA-633 and miRNA-922 have been reported to be deregulated in multiple sclerosis.
To investigate the association between miRNA-181c, miRNA-633 and miRNA-922 and conversion from clinically isolated syndrome (CIS) to relapsing–remitting multiple sclerosis (RRMS); and to compare microRNAs in cerebrospinal fluid (CSF) and serum with regard to dysfunction of the blood–CSF barrier.
CSF and serum miRNA-181c, miRNA-633 and miRNA-922 were retrospectively determined by quantitative real-time polymerase chain reaction in CIS patients with (CIS-RRMS) and without (CIS-CIS) conversion to RRMS within 1 year.
Thirty of 58 CIS patients developed RRMS. Cerebrospinal fluid miRNA-922, serum miRNA-922 and cerebrospinal fluid miRNA-181c were significantly higher in CIS-RRMS compared to CIS-CIS (P=0.027, P=0.048, P=0.029, respectively). High levels of cerebrospinal fluid miRNA-181c were independently associated with conversion from CIS to RRMS in multivariate Cox regression analysis (hazard ratio 2.99, 95% confidence interval 1.41–6.34, P=0.005). A combination of high cerebrospinal fluid miRNA-181c, younger age and more than nine lesions on magnetic resonance imaging showed the highest specificity (96%) and positive predictive value (94%) for conversion from CIS to RRMS. MiRNA-181c was higher in serum than in cerebrospinal fluid (P <0.001), while miRNA-633 and miRNA-922 were no different in cerebrospinal fluid and serum. Cerebrospinal fluid/serum albumin quotients did not correlate with microRNAs in cerebrospinal fluid (all P>0.711).
Cerebrospinal fluid miRNA-181c might serve as a biomarker for early conversion to RRMS. Moreover, our data suggest an intrathecal origin of microRNAs detected in the cerebrospinal fluid.
Pain is considered a frequent symptom in multiple sclerosis. Neuropathic pain is the type of pain most closely related to the pathology of multiple sclerosis and its prevalence estimates vary largely.
We prospectively assessed the prevalence of neuropathic pain in patients with early multiple sclerosis and investigated the association of neuropathic pain with other clinical parameters.
A total of 377 outpatients with multiple sclerosis at an early disease stage were included in this prospective study. Mean disease duration was 4.2 years, mean Expanded Disability Status Scale (EDSS) score was 1.6, 96.8% of patients were classified as having relapsing–remitting multiple sclerosis. Neuropathic pain was assessed using the PainDETECT questionnaire (PDQ). Depression, fatigue and cognition were assessed using the Beck Depression Inventory (BDI), the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Paced Auditory Serial Addition Test.
PDQ scores indicative of neuropathic pain were found in 4.2% of patients. Regression analysis revealed EDSS, BDI and FMSC scores as strongest predictors of PDQ scores.
Neuropathic pain appears to be less frequent in early multiple sclerosis than expected and is significantly associated with disability, depression and fatigue. The assessment and therapy of pain in multiple sclerosis should thus take into account neuropsychiatric symptoms already at early disease stages.
Vitamin D deficit is considered an important risk factor for many inflammatory and autoimmune diseases.
To investigate the influence of the multiple sclerosis (MS)-associated regulatory variant rs10877013 on the expression of genes involved in vitamin D activation (CYP27B1), vitamin D receptor (VDR), and vitamin D degradation (CYP24A1) under inflammatory environment or vitamin D.
We used lipopolysaccharide and interferon-gamma (LPS+IFN) activated monocytes from 119 individuals and vitamin D-stimulated lymphoblastoid cell lines (LCLs, n = 109) of 1000 genomes to quantify the mRNA expression of vitamin D genes by quantitative reverse transcription polymerase chain reaction (RT-qPCR).
We found that CYP27B1 mRNA expression level was associated with the rs10877013 genotypes (p = 5.0E-6) in LPS+IFN treated monocytes, but not in vitamin D-stimulated LCLs. Inversely, rs10877013 genotypes were associated with VDR expression in LCLs (p = 6.0E-4) but not in monocytes. Finally, CYP24A1 was highly induced by the active form of vitamin D and its expression correlated with the expression of VDR in LCLs but neither the MS-associated variant in the region (rs2248359) nor any other variant located in 1 Mb around CYP24A1 was associated with its expression.
The MS-associated variant rs10877013 is a genetic determinant that affects the functioning of the vitamin D system linking environmental and genetic factors.
Previous studies in patients with multiple sclerosis (MS) have shown an association between high serum 25-hydroxyvitamin D (25[OH]D) levels and decreased inflammatory activity.
The purpose of this study was to examine the association between 25(OH)D levels and axonal injury in MS. Cerebrospinal fluid neurofilament light (CSF-NFL) was used as a marker for axonal injury.
Patients were identified through clinical practice at the Department of Neurology in Umeå University Hospital, Sweden. Blood draw, magnetic resonance imaging, scoring of disability and lumbar puncture were performed at inclusion in 153 patients, and also at median 12 months follow-up in 87 patients. For analyses of serum 25(OH)D levels and CSF-NFL, enzyme-linked immunosorbent assays were used.
There was an inverse association between serum 25(OH)D and CSF-NFL levels in categorical (dichotomized at 75 or 100 nmol/l) analyses. A dose-response effect for 25(OH)D levels on CSF-NFL levels (p for trend=0.034) was also present. Serum 25(OH)D levels above 100 nmol/l were associated with lower CSF-NFL levels independently of ongoing MS treatment.
High 25(OH)D levels are associated with decreased axonal injury in MS.
Both smoking and exposure to passive smoking have repeatedly been associated with increased multiple sclerosis (MS) risk, but have never before been studied together. We assessed the public health impact of these factors.
In a Swedish population-based case-control study (2455 cases, 5336 controls), we calculated odds ratios of developing MS associated with different categories of tobacco smoke exposure, together with 95% confidence intervals, by using logistic regression. The excess proportion of cases attributable to smoking and passive smoking was calculated as a percentage.
Both smoking and exposure to passive smoking contribute to MS risk in a dose-dependent manner. At the population level, 20.4% of all cases were attributable to smoke exposure. Among subjects carrying the genetic risk factor HLA-DRB1*15 but lacking HLA-A*02, 41% of the MS cases were attributable to smoking.
From a public health perspective, the impact of smoking and passive smoking on MS risk is considerable. Preventive measures in order to reduce tobacco smoke exposure are, therefore, essential. In particular, individuals with a history of MS in the family should be informed regarding the impact of smoking on the risk of MS, and the importance of preventing their children from being exposed to passive smoke.
Dimethyl fumarate (DMF) alters the phenotype of circulating immune cells and causes lymphopenia in a subpopulation of treated multiple sclerosis (MS) patients.
To phenotypically characterize circulating leukocytes in DMF-treated MS patients.
Cross-sectional observational comparisons of peripheral blood from DMF-treated MS patients (n = 17 lymphopenic and n = 24 non-lymphopenic), untreated MS patients (n = 17) and healthy controls (n = 23); immunophenotyped using flow cytometry. Longitudinal samples were analyzed for 13 DMF-treated patients.
Lymphopenic DMF-treated patients had significantly fewer circulating CD8+ and CD4+ T cells, CD56dim natural killer (NK) cells, CD19+ B cells and plasmacytoid dendritic cells when compared to controls. CXCR3+ and CCR6+ expression was disproportionately reduced among CD4+ T cells, while the proportion of T-regulatory (T-reg) cells was unchanged. DMF did not affect circulating CD56hi NKcells, monocytes or myeloid dendritic cells. Whether lymphopenic or not, DMF-treated patients had a lower proportion of circulating central and effector memory T cells and concomitant expansion of naïve T cells compared to the controls.
DMF shifts the immunophenotypes of circulating T cells, causing a reduction of memory cells and a relative expansion of naïve cells, regardless of the absolute lymphocyte count. This may represent one mechanism of action of the drug. Lymphopenic patients had a disproportionate loss of CD8+ T-cells, which may affect their immunocompetence.
Depression is common in patients with multiple sclerosis (MS), although the brain mechanisms of this psychiatric condition in MS are poorly understood. Specifically, it remains to be determined whether depression in MS is related to altered activity and functional connectivity patterns within limbic circuits.
Seventy-seven MS patients with variable levels of depression (as assessed via the Beck Depression Inventory) underwent functional magnetic resonance imaging while performing an emotional processing task. To conduct the functional connectivity analyses, the bilateral amygdala and hippocampus, two areas critically involved in the pathophysiology of depression, were chosen as ‘seed’ regions. Multiple regression models were used to assess how depression in MS patients was correlated with the activity and functional connectivity patterns within the limbic system.
Depression scores in MS patients were negatively correlated: (1) with the activity in the subgenual cingulate cortex; (2) with the functional connectivity between the hippocampus and orbitofrontal cortex as well as the dorsolateral prefrontal cortex, and (3) with the functional connectivity between the amygdala and dorsolateral prefrontal cortex.
Our study showed that individual differences in depression in MS patients were significantly associated with altered regional activity and functional connectivity patterns within the limbic system.
Macrophages are important components of inflammatory processes in multiple sclerosis, closely linked to axonal loss, and can now be observed in vivo using ultra-small superparamagnetic iron oxide (USPIO). In the present 1-year longitudinal study, we aimed to determine the prevalence and the impact on tissue injury of macrophage infiltration in patients after the first clinical event of multiple sclerosis.
Thirty-five patients, 32 years mean age, were imaged in a mean of 66 days after their first event using conventional magnetic resonance imaging, gadolinium (Gd) to probe blood–brain barrier integrity, USPIO to study macrophage infiltration and magnetization transfer ratio (MTR) to assess tissue structure integrity. Statistics were performed using two-group repeated-measures ANOVA. Any patient received treatment at baseline.
At baseline, patients showed 17 USPIO-positive lesions reflecting infiltration of macrophages present from the onset. This infiltration was associated with local higher loss of tissue structure as emphasized by significant lower MTRnorm values (p<0.03) in USPIO+/Gd+ lesions (n=16; MTRnormUSPIO+/Gd+=0.78 at baseline, MTRnormUSPIO+/Gd+=0.81 at M12) relative to USPIO-/Gd+ lesions (n=67; MTRnormUSPIO-/Gd+=0.82 at baseline, MTRnormUSPIO–/Gd+=0.85 at M12). No interaction in MTR values was observed during the 12 months follow-up (lesion type x time).
Infiltration of activated macrophages evidenced by USPIO enhancement, is present at the onset of multiple sclerosis and is associated with higher and persistent local loss of tissue structure. Macrophage infiltration affects more tissue structure while tissue recovery during the following year has a similar pattern for USPIO and Gd-enhanced lesions, leading to relative higher persistent local loss of tissue structure in lesions showing USPIO enhancement at baseline.
The frequency of paediatric-onset multiple sclerosis (POMS) and the precise risk of secondary progression of disease are largely unknown in the Middle East. This cross-sectional cohort study assessed the risk and examined prognostic factors for time to onset of secondary progressive multiple sclerosis (SPMS) in a cohort of POMS patients.
The Kuwait National MS Registry database was used to identify a cohort of POMS cases (diagnosed at age <18 years) from 1994 to 2013. Data were abstracted from patients’ records. A Cox proportional hazards model was used to evaluate the prognostic significance of the variables considered.
Of 808 multiple sclerosis (MS) patients, 127 (15.7%) were POMS cases. The median age (years) at disease onset was 16.0 (range 6.5–17.9). Of 127 POMS cases, 20 (15.8%) developed SPMS. A multivariable Cox proportional hazards model showed that at MS onset, brainstem involvement (adjusted hazard ratio 5.71; 95% confidence interval 1.53–21.30; P=0.010), and POMS patient age at MS onset (adjusted hazard ratio 1.38; 95% confidence interval 1.01–1.88; P=0.042) were significantly associated with the increased risk of a secondary progressive disease course.
This study showed that POMS patients with brainstem/cerebellar presentation and a relatively higher age at MS onset had disposition for SPMS and warrant an aggressive therapeutic approach.
Advanced magnetic resonance imaging (MRI) techniques provide a window into pathological processes in multiple sclerosis (MS). Nevertheless, to date only few studies have performed sodium MRI in MS.
We analysed total sodium concentration (TSC) in hyperacute, acute and chronic lesions in MS with 23Na MRI.
23Na MRI and 1H MRI were performed in 65 MS patients and 10 healthy controls (HC). Mean TSC was quantified in all MS lesions with a diameter of >5 mm and in the normal appearing white and grey matter (NAWM, NAGM).
TSC in the NAWM and the NAGM of MS patients was significantly higher compared to HC (WM: 37.51 ± 2.65 mM versus 35.17 ± 3.40 mM; GM: 43.64 ± 2.75 mM versus 40.09 ± 4.64 mM). Acute and chronic MS lesions showed elevated TSC levels of different extent (contrast-enhancing lesions (49.07 ± 6.99 mM), T1 hypointense lesions (45.06 ± 6.26 mM) and remaining T1 isointense lesions (39.88 ± 5.54 mM)). However, non-enhancing hyperacute lesions with a reduced apparent diffusion coefficient showed a TSC comparable to the NAWM (37.22 ± 4.62 mM).
TSC is not only a sensitive marker of the severity of chronic tissue abnormalities in MS but is also highly sensitive to opening of the blood–brain barrier and vasogenic tissue oedema in contrast-enhancing lesions.
Inflammatory cytokines produced by cells of the immune system are believed to play a central role in the pathogenesis of multiple sclerosis (MS). Innate lymphoid cells (ILCs) have been shown to produce and secrete a wide range of the cytokines involved in MS pathogenesis; however, a possible implication of ILCs in MS development and disease progression has not been investigated.
With this study, we aimed to clarify a potential role of ILCs in the early stages of MS.
Using flow cytometry, we analysed the prevalence and phenotype of ILCs in the cerebrospinal fluid (CSF) of patients experiencing their first or second demyelinating event. We found a substantial increase in both frequency and number of ILCs, in particular the LTi subset, as compared to healthy controls. We also found an association between CSF pleocytosis and an increased frequency of LTi cells in the CSF, suggesting a favoured recruitment of blood derived LTi cells.
Our data suggests a role for ILCs, and in particular the LTi subset, in the early stages of MS. This finding represents an important contribution to the understanding of early inflammation in MS, and adds new knowledge beneficial for future MS therapies.
Progranulin (GRN) is a multifunctional protein involved in inflammation and repair, and also a neurotrophic factor critical for neuronal survival. Progranulin is strongly expressed in multiple sclerosis (MS) brains by macrophages and microglia.
In this study we evaluated GRN genetic variability in 400 MS patients, in correlation with clinical variables such as disease severity and relapse recovery. We also evaluated serum progranulin levels in the different groups of GRN variants carriers.
We found that incomplete recovery after a relapse is correlated with an increased frequency of the rs9897526 A allele (odds ratio (OR) 4.367, p = 0.005). A more severe disease course (Multiple Sclerosis Severity Score > 5) is correlated with an increased frequency of the rs9897526 A allele (OR 1.886, p = 0.002) and of the rs5848 T allele (OR 1.580, p = 0.019). Carriers of the variants associated with a more severe disease course (rs9897526 A, rs5848 T) have significantly lower levels of circulating progranulin (80.5 ± 9.1 ng/mL vs. 165.7 ng/mL, p = 0.01).
GRN genetic polymorphisms likely influence disease course and relapse recovery in MS.
Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters.
This study aimed at verifying and integrating both parameters into one algorithm for risk stratification.
Multicentric, international cohorts of natalizumab-treated MS patients were assessed for JCV index (1921 control patients and nine pre-PML patients) and CD62L (1410 control patients and 17 pre-PML patients).
CD62L values correlate with JCV serostatus, as well as JCV index values. Low CD62L in natalizumab-treated patients was confirmed and validated as a biomarker for PML risk with the risk factor "CD62L low" increasing a patient’s relative risk 55-fold (p < 0.0001). Validation efforts established 86% sensitivity/91% specificity for CD62L and 100% sensitivity/59% specificity for JCV index as predictors of PML. Using both parameters identified 1.9% of natalizumab-treated patients in the reference center as the risk group.
Both JCV index and CD62L have merit for risk stratification and share a potential biological relationship with implications for general PML etiology. A risk algorithm incorporating both biomarkers could strongly reduce PML incidence.
Fingolimod modulates sphingosine-1-phosphate receptors that are also found in cardiovascular tissue.
To investigate the effects of fingolimod on cardiac autonomic regulation prospectively.
Twenty-seven relapsing–remitting multiple sclerosis patients underwent 24-hour electrocardiogram recording before, at the first day of fingolimod treatment (1d) and after three months of continuous dosing (3mo). The time interval between two consecutive R-peaks (RR-interval) was measured. Cardiac autonomic regulation was assessed by the various parameters of heart rate variability. Parasympathetic stimulation prolongs the RR-interval and increases heart rate variability while the effects of sympathetic stimulation are mainly the opposite. The low frequency/high frequency ratio reflects sympathovagal balance.
From baseline to 1d, a prolongation of the RR-interval (P<0.001), an increase in the values of various heart rate variability parameters (P<0.05 to P<0.001) and a decrease in the low frequency/high frequency ratio (P<0.05) were demonstrated. At 3mo, although the RR-interval remained longer (P<0.01), the values of various heart rate variability parameters were lower (P<0.01 to P<0.001) as compared to baseline. At 3mo, the low frequency/high frequency ratio (P<0.05) was higher in men than in women although no such difference was found at baseline or at 1d.
After an initial increase in parasympathetic regulation, continuous fingolimod dosing shifts cardiac autonomic regulation towards sympathetic predominance, especially in men. Careful follow-up of fingolimod-treated relapsing–remitting multiple sclerosis patients is warranted as sympathetic predominance associates generally with impaired outcome.
ClinicalTrials.cov: NCT01704183
In the article The use of gaming technology for rehabilitation in people with multiple sclerosis, DOI:
Exergaming studies. published trial methodology 25-FWT: 25 Foot Walk Time; ABC: Activities-specific Balance Confidence; AI: Ambulation Index; BBS: Berg Balance Score; CoP: Centre of Pressure; EDSS: Expanded Disability Status Scale; EQ-5D-5L: EuroQual 5 Dimensions-5 Levels; FRT: Functional Reach Test; FSI: Fatigue Symptom Inventory; FSST: Four Square Step Test; GLTEQ: Godin Leisure-Time Exercise Questionnaire; HADS: Hospital Anxiety and Depression Scale; MFIS: Modified Fatigue Impact Scale; MMSE: Mini-Mental State Examination; MS: Multiple Sclerosis; MSIS-29: Multiple Sclerosis Impact Scale; MSSE: Multiple Sclerosis Self-Efficacy Scale; MSWS-12: MS Walking Scale; QoL: Quality of Life; RCT: Randomized Control Trial; RPE: Ratings of Perceived Exertion; SCI-ESES: Spinal Cord Injury Exercise Self-Efficacy Scale; SF-36: Short-Form Health Survey; SOT: Sensory Organization Test; TUG: Timed-Up-and-Go.
Improvements pre- vs. post-test: Number of steps and push-ups; Eyes/open closed, single leg balance on firm surface.
Post-test vs. follow-up (14 weeks): measures returned to baseline.
Participants: See Plow and Finlayson31
Intervention: All participants were prescribed a three-times-a-week exercise programme – see Plow and Finalyson.31
Improvements in Non-exercise group pre- vs. post-test: Dynamic Gait Index.
Wii vs. non-exercise at follow-up: No significant difference.
Physical activity: GLTEQ, ActivPAL.
Hand dexterity/coordination: Nine-hole peg test.
Self-efficacy: SCI-ESES, MSSE.
Psychological well-being and QoL: HADS, EQ-5D-5L, MSIS-29, FSI, SF-36v2. Adherence to training.
Few reports describe the influence pregnancy has on the annualized relapse rate (ARR) in neuromyelitis optica spectrum disorder (NMOSD).
To examine pregnancy-related attacks (attacks during pregnancy or within 1 year postpartum) and identify the risk factors for an attack in Japanese NMOSD patients.
We retrospectively reviewed 139 Japanese women whom had aquaporin-4 (AQP4) antibody-positive NMOSD. Among the 114 patients with information, 47 women had 56 pregnancies. We compared the ARR before, during and after pregnancy.
Of the 47 NMOSD patients with pregnancy, 22 women (46.8%) had a pregnancy-related attack of the disease (either an onset event or a relapse). The ARR was significantly higher in the first 3 months postpartum (1.80 ± 2.04), than before the pregnancy (0.57 ± 1.16; p = 0.0043) and did not significantly decrease during pregnancy. The ARR before hospitalization and treatment was analyzable in 55 patients without pregnancy and was 1.09 ± 1.17. Among the 11 patients with onset before pregnancy, nine patients had a pregnancy-related attack with a relapse in the previous year, and their immunosuppression was discontinued or made to be at low doses; while the two patients on higher-dose therapies were relapse-free.
In the present study, pregnancy-related attack was common in NMOSD, and unlike in multiple sclerosis, the ARR was not reduced during pregnancy. Discontinued or insufficient immunosuppression appeared to increase the risk of pregnancy-related attack.
Multiple sclerosis (MS) is a white and grey matter disease of the central nervous system (CNS). It is recognized that cortical damage (i.e. focal lesions and atrophy) plays a role in determining the accumulation of physical and cognitive disability that is observed in patients with progressive MS. To date, an association of cortical lesions with clinical relapses has not been described.
We report clinical and magnetic resonance imaging (MRI) findings of five relapsing–remitting MS (RRMS) patients who had clinical relapses characterized by the acute appearance of cortical symptoms, due to the development of large, snake-like, cortical inflammatory lesions. Symptoms were: acute Wernicke’s aphasia mimicking stroke; agraphia with acalculia, not associated to a motor deficit nor linguistic disturbance; hyposthenia of the left arm, followed by muscle twitching of the hand, spreading to arm and face; acute onset of left lower limb paroxysmal hypertonia; and temporal lobe status epilepticus, with psychotic symptoms.
Cortical relapses may occur in MS. MRI examination in MS should include sequences, such as double inversion recovery (DIR) or phase sensitive inversion recovery (PSIR), that are aimed at visualizing cortical lesions, especially in the presence of symptoms of cortical dysfunction. Our observation further stresses and extends the clinical relevance of cortical pathology in MS.
Acute optic neuritis is often in association with multiple sclerosis (MS). Proinflammatory cytokines trigger neuronal damage in neuroinflammatory disorders but their role in optic neuritis is poorly investigated.
The objective of this work is to investigate the associations of intrathecal contents of proinflammatory cytokines with transient and persistent dysfunctions after optic neuritis.
In 50 MS patients followed for up to six months, cerebrospinal fluid (CSF) levels of IL-1β, TNF and IL-8 were determined, along with clinical, neurophysiological and morphological measures of optic neuritis severity.
Visual impairment, measured by high- and low-contrast visual acuity, and delayed visual-evoked potential (VEP) latencies were significantly correlated to IL-8 levels during optic neuritis. IL-8 at the time of optic neuritis was also associated with persistent demyelination and final axonal loss, inferred by VEP and optical coherence tomography measures, respectively. Contents of IL-8 were correlated to functional visual outcomes, being higher among patients with incomplete recovery. Multivariate analysis confirmed that IL-8 significantly predicted final visual acuity, at equal values of demographics and baseline visual scores.
Our study points to IL-8 as the main inflammatory cytokine associated with demyelination and secondary neurodegeneration in the optic nerve after optic neuritis.
Sexual dysfunction (SD) affects up to 80% of multiple sclerosis (MS) patients and pelvic floor muscles (PFMs) play an important role in the sexual function of these patients.
The objective of this paper is to evaluate the impact of a rehabilitation program to treat lower urinary tract symptoms on SD of women with MS.
Thirty MS women were randomly allocated to one of three groups: pelvic floor muscle training (PFMT) with electromyographic (EMG) biofeedback and sham neuromuscular electrostimulation (NMES) (Group I), PFMT with EMG biofeedback and intravaginal NMES (Group II), and PFMT with EMG biofeedback and transcutaneous tibial nerve stimulation (TTNS) (Group III). Assessments, before and after the treatment, included: PFM function, PFM tone, flexibility of the vaginal opening and ability to relax the PFMs, and the Female Sexual Function Index (FSFI) questionnaire.
After treatment, all groups showed improvements in all domains of the PERFECT scheme. PFM tone and flexibility of the vaginal opening was lower after the intervention only for Group II. All groups improved in arousal, lubrication, satisfaction and total score domains of the FSFI questionnaire.
This study indicates that PFMT alone or in combination with intravaginal NMES or TTNS contributes to the improvement of SD.
Natalizumab is approved for treatment of active forms of relapsing–remitting multiple sclerosis (MS) based on a pivotal phase III study comprising patients aged 18–50 years. The effect of natalizumab has not been specifically studied in older patients.
We analyzed age-dependent effects on treatment-related outcome measures in 1872 patients, 189 of whom were aged 50 or more, included in the Swedish post-marketing natalizumab surveillance program.
In three MS centers registry data for patients aged >50 years were validated.
At baseline older patients had longer disease duration, higher Expanded Disability Status Scale (EDSS) and lower Symbol Digit Modality Test (SDMT) scores than younger patients. The influence from natalizumab on outcome measures was significantly reduced and 18.7% of patients >50 years stopped treatment for lack of effect compared to 7.7% in the younger age group. At baseline, the cerebrospinal fluid levels of the chemokine CXCL13 and the leukocyte cell count were negatively correlated with age in a smaller subgroup of patients.
These results were in agreement with previous findings suggesting that inflammation is more pronounced in younger patients and therefore the beneficial effects of potent anti-inflammatory treatments are subsiding with older ages.
We aimed to evaluate the effect of slow-release (SR) Fampridine on multiple outcome measures reflecting different domains, and to compare the responsiveness of the Six Spot Step Test (SSST) and the Timed 25 Foot Walk (T25FW).
For this study 108 participants were included. On day 0 they were tested with the T25FW, the SSST, the 9-Hole Peg Test (9-HPT), the 5 Times Sit-To-Stand test (5-STS) and the Symbol Digit Modalities Test (SDMT). Four weeks of treatment with SR Fampridine 10 mg BID was commenced. Participants were tested again after 26–28 days of treatment.
Mean changes observed were: SSST –3.4±6.4s (p<0.001), T25FW –1.2±3.7s (p<0.001), 9-HPT –1.2±6.0s (p<0.001), 5- STS –3.4±7.2s (p<0.001) and SDMT 1.4±4.8 a.u. (p=0.003). Change on the SSST differed significantly from T25FW (SSST 17.0±19.6% vs. T25FW 11.2±17.1%, p=0.0013). Some 48.6% were found to have a meaningful change on the SSST compared with 25.7% on the T25FW. The response to treatment with SR Fampridine did not correlate with age, sex, Expanded Disability Status Scale and disease duration.
SR Fampridine treatment has significant effects on different domains including upper and lower body and cognition. Furthermore, the SSST is more responsive to the effect of SR Fampridine than is the T25FW.
ClinicalTrials.gov identifier: NCT01656148
Depression is a common comorbidity in multiple sclerosis (MS), but little is known about its long-term prognosis. Depression in the general population is usually episodic with relatively short-lasting depressive episodes. In this study we investigate the long-term prognosis of depression in MS.
Using data from a large longitudinal observational study and from the Calgary MS clinic database, we investigated changes in Center for Epidemiological Studies Depression Scale (CESD) scores in MS patients over four years of follow-up. We used logistic regression to investigate the association of the factors sex, age, disease duration, Expanded Disability Status Scale (EDSS), depression at baseline, and antidepressant use with depression at each year of follow-up.
CESD scores remained largely stable, or decreased slightly over four years of follow-up, whereas EDSS scores steadily increased. Depression at baseline was the strongest predictor of depression at follow-up; the other factors were not or not consistently associated with depression at follow-up. As expected, antidepressant use was associated with a greater risk of depression at follow-up. Starting and stopping antidepressant treatment during follow-up was not associated with the risk of depression at follow-up or with significant change in CESD scores.
In contrast to depression in the general population, depression in MS is largely chronic, which suggests a different pathophysiology.
The lack of prospective trial data comparing certain multiple sclerosis (MS) therapies could be addressed with observational research.
The objective of this paper is to investigate outcomes of natalizumab versus fingolimod treatment in an MS cohort using a novel method of patient selection.
We reviewed entries from our clinic’s database for all relapsing–remitting MS patients started on fingolimod and natalizumab where JCV serology was used to determine treatment. We analyzed each group for time to first relapse and in a second analysis, time to first relapse or gadolinium-enhancing lesion.
Sixty-nine patients on natalizumab and 36 on fingolimod met our inclusion criteria and had adequate follow-up for analysis. The baseline clinical characteristics at the time of treatment switch were similar. With a mean follow-up of 1.5 years for both treatment groups, there was a trend favoring natalizumab in time to first relapse, although this was not statistically significant (2.20 (0.87, 5.55) p = 0.095). There was a significant difference in the secondary outcome, time to relapse or gadolinium-enhancing lesion (2.31 (1.03, 5.17) p = 0.041), favoring natalizumab. Adjusted analyses favored natalizumab for both outcomes (p < 0.05).
This work employed an observational study design where treatment allocation by JCV serology allowed for treatment groups with well-balanced characteristics.
Natalizumab has shown its efficacy in reducing multiple sclerosis (MS) relapses and progression of disability; however, it has been associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML). The differential expression of microRNA (miRNA), the small non-coding RNAs that regulate gene expression, in natalizumab-treated patients has been reported and miRNA have also been described as good candidates for disease biomarkers.
To characterize the effect of natalizumab therapy on the miRNA expression pattern and to search for miRNAs that can predict PML on an individual basis.
The expression of 754 microRNAs was measured in blood samples from 19 relapsing–remitting MS patients at three time points during natalizumab therapy, using TaqMan OpenArray panels. Two patients included in this study developed PML after more than 2 years of therapy.
We found that the expression level of three miRNAs (let-7c, miR-125a-5p and miR-642) was affected after 6 months of therapy (t6). Furthermore, we observed a differential expression of another three miRNAs (miR-320, miR-320b and miR-629) between the PML and non-PML groups after 12 months of treatment (t12); and a positive correlation was found between therapy time and the expression of miR-320.
Natalizumab modified the expression levels of three miRNAs after a 6-month treatment. We suggest miR-320, miR-320b and miR-629 as possible biomarkers for individual PML risk assessment.
Patients with multiple sclerosis (MS) have a deficiency of circulating CD8+ T cells, which might impair control of Epstein–Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells.
Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course.
We used flow cytometry to analyze the memory phenotypes of T cells in the blood of 118 MS patients and 112 healthy subjects.
MS patients had a decreased frequency of EM (CD45RA–CD62L–) and EMRA (CD45RA+CD62L–) CD8+ T cells, which was present at the onset of disease and persisted throughout the clinical course. The frequencies of CD4+ EM and EMRA T cells were normal.
Deficiency of effector memory CD8+ T cells is an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV.
Previous reports indicate an association between Epstein-Barr virus (EBV) antibody levels and multiple sclerosis (MS) disease activity, but the results have been conflicting.
The objective of this paper is to study if EBV antibody levels reflect MRI disease activity in MS and examine the potential for EBV antibody levels as biomarkers for treatment response.
A total of 87 MS patients were followed for two years prior to and during interferon beta (IFNB) treatment, with MRI examinations and serum measurement of IgM and IgG antibodies to viral capsid antigen (VCA), EBV nuclear antigen 1 (EBNA-1) and early antigen (EA). Associations between EBV antibody levels and MRI activity were assessed by a logistic regression model.
Higher anti-EBNA-1 IgG levels were associated with increased MRI activity, OR = 2.95 (95% CI 1.07–8.10; p = 0.036) for combined unique activity (CUA; the sum of T1Gd+ lesions and new or enlarging T2 lesions). Although most patients were anti-VCA IgM negative, there was an inverse association, OR = 0.32 (95% CI 0.12–0.84; p = 0.021) with CUA during IFNB treatment.
This study supports an association between anti-EBNA-1 IgG levels and MS disease activity. We also found an inverse association with anti-VCA IgM levels during IFNB treatment not previously described, indicating anti-VCA IgM as a possible biomarker for IFNB treatment response.
Risks of natalizumab (NAT) therapy have to be weighed against disease recurrence after stopping NAT.
The objective of this paper is to identify risk factors for recurrence of relapses after switching from NAT to fingolimod (FTY) in relapsing–remitting multiple sclerosis (RRMS).
Patients (n = 33) were treated with NAT for ≥1 year, and then switched to FTY within 24 weeks (mean follow-up on FTY 81.1 (SD 26.5) weeks). Annual relapse rates (ARR) and Expanded Disability Status Scale scores (EDSS) were assessed. Descriptive statistics, univariate logistic regression analysis, and receiver operating characteristic curves were conducted.
Overall, 20 patients (61%) had relapses after discontinuation of NAT and 16 (48%) during FTY therapy. The maximum incidence of relapses occurred between weeks 13–24 post-NAT. The last EDSS during the switching period predicted relapses during subsequent FTY therapy. EDSS >3 separated most powerfully between the groups (sensitivity 64%, specificity 88%) and significantly predicted relapses (relative risk 3.27, 95% CI: 1.5–7.3). Seventy-five percent of patients with EDSS ≤ 3 remained free of relapses, compared to 18% of patients with EDSS >3.
There was an increase of the ARR in the first year after switching from NAT to FTY. Last EDSS during the switching period was a predictor of relapses during FTY.
The 2010 McDonald criteria allow diagnosing multiple sclerosis (MS) with one magnetic resonance imaging (MRI) scan. Nevertheless, not all patients at risk fulfil criteria at baseline. Other predictive factors (PFs) are: age ≤40 years, positive oligoclonal bands (OBs), and ≥3 periventricular lesions.
The purpose of this study was to evaluate the 2010 McDonald criteria performance and to assess other PFs in patients without dissemination in space (DIS).
Patients with clinically isolated syndrome (CIS) underwent baseline MRI and OB determination with clinical and radiological follow-up. Adjusted hazard ratios (aHRs) for clinically definite MS were estimated for DIS, dissemination in time (DIT), and DIS+DIT. Diagnostic properties at two years were calculated. In cases without DIS, combinations of ≥2 PFs were assessed.
A total of 652 patients were recruited; aHRs were 3.8 (2.5–5.8) for DIS, 4.2 (1.9–9.2) for DIT, and 8.6 (5.4–13.8) for DIS+DIT. Sensitivities were 69.6%, 42.3%, and 36.4%, and specificities were 67.3%, 87.9%, and 90.2%, respectively. In patients without DIS, aHRs varied between 2.7–5.5 and specificities ranged from 73.5–89.7% for PF combinations.
The high specificity of the 2010 McDonald criteria is confirmed. In patients without DIS, PF combinations could be helpful in identifying those at risk for MS.
To characterize neuropsychological (NP) test performance during multiple sclerosis (MS) relapse and recovery.
Clinical status was assessed with NP testing and Expanded Disability Status Scale (EDSS) in 24 relapsing patients, and 24 individually-matched, stable controls. All presented with cognitive symptoms as indicated by patient, clinician or caregiver perceived decline, but were free of optic neuritis, ataxia and upper extremity weakness that could compromise NP testing. The presence of enhancing magnetic resonance imaging (MRI) lesions was considered confirmatory of relapse. Relapsing patients were treated with corticosteroids. NP testing and EDSS were compared to pre-relapse baseline levels, and three-month, post-relapse, follow-up.
Analyses revealed significant decline on the Symbol Digit Modalities Test (SDMT) (p=0.005) and worsening on EDSS (p=0.019). Impairment was observed at the point of relapse in cases but not controls. The groups were no longer different at three-month follow-up. The increment of decline on SDMT was 3.5 raw score points, or roughly 6%.
This is the first study to assess NP status changes during MS relapse using well established, reliable metrics. The presence of a clinically meaningful event is substantiated by decline in NP testing, observed or reported cognitive change, and in a subset of patients, gadolinium-enhancing MRI lesions.
There is accumulating data suggesting an association between serum lipids, apolipoproteins and disability in multiple sclerosis (MS).
To investigate the associations between serum lipids, apolipoproteins and disability in MS.
A cohort of 178 participants with clinically-definite MS in southern Tasmania, Australia were prospectively followed from 2002 – 2005, and serum samples were obtained at study entry and at each biannual review, to measure lipid profile and apolipoprotein levels. Associations with disability and annual change in disability were evaluated using linear regression and multilevel mixed-effects linear regression.
In the unadjusted analyses, nearly all lipid-related variables were positively associated with Expanded Disability Status Scale (EDSS). After adjustment for confounders, total cholesterol (TC) (p = 0.037), apolipoprotein B (ApoB) (p = 0.003), and the apolipoprotein B to apolipoprotein A-I ratio (ApoB/ApoA-I ratio) (p = 0.018) were independently associated with a higher EDSS. Higher body mass index (BMI) was also independently associated with higher EDSS (p = 0.013). With the progression analysis, the total cholesterol to high density lipoprotein (HDL) ratio (TC/HDL ratio) (p = 0.029) was prospectively associated with subsequent change in EDSS.
In this prospective population-based cohort study, an adverse lipid profile was associated with high levels of MS disability and disease progression. Improving serum lipids may be beneficial for MS patients, to potentially improve clinical outcomes and vascular comorbidities.
Interleukin-7 (IL-7) is a non-redundant cytokine for T-cell development and survival. The IL-7 signaling pathway has been genetically and functionally associated with several autoimmune diseases including multiple sclerosis (MS).
The objective of this paper is to elucidate the effect of the widely used immunomodulatory MS therapy interferon beta (IFNβ) on IL-7 homeostasis.
Swedish MS patients were screened for IL-7 concentration in serum and blood cell counts. IL-7 receptor alpha chain (IL-7Rα) expression was determined by semi-quantitative real-time polymerase chain reaction (PCR) and flow cytometry.
IFNβ treatment led to significantly increased serum IL-7 levels (mean: 17 pg/ml) compared with healthy controls (mean: 7.6 pg/ml) and natalizumab-treated patients (mean: 5.3 pg/ml). In vitro and in vivo, peripheral blood leukocytes showed decreased IL-7Rα expression and IL-7 consumption upon IFNβ exposure, suggesting that their IL-7 responsiveness is impaired during treatment.
MS patients undergoing IFNβ treatment have increased serum IL-7 levels and decreased IL-7 consumption. Given IL-7’s important role in T-cell immunity, this relationship may be highly relevant for IFNβ’s treatment efficacy.
The majority of patients with multiple sclerosis (MS) present with spinal cord pathology. Spinal cord atrophy is thought to be a marker of disease severity, but in long-disease duration its relation to brain pathology and clinical disability is largely unknown.
Our aim was to investigate mean upper cervical cord area (MUCCA) in patients with long-standing MS and assess its relation to brain magnetic resonance imaging (MRI) measures and clinical disability.
MUCCA was measured in 196 MS patients and 55 healthy controls using 3DT1-weighted cervical images obtained at 3T MRI. Clinical disability was measured using the Expanded Disability Status Scale (EDSS), Nine-Hole-Peg test (9-HPT), and 25 feet Timed Walk Test (TWT). Stepwise linear regression was performed to assess the association between MUCCA and MRI measures, and between MUCCA and clinical disability.
MUCCA was smaller (mean 11.7%) in MS patients compared with healthy controls (72.56±9.82 and 82.24±7.80 mm2 respectively; p<0.001), most prominently in male patients. MUCCA was associated with normalized brain volume, and number of cervical cord lesions. MUCCA was independently associated with EDSS, TWT, and 9-HPT.
MUCCA was reduced in MS patients compared with healthy controls. It provides a relevant marker for clinical disability in long-standing disease, independent of other MRI measures.
Patients with multiple sclerosis (MS) lose brain volume (BV) faster than healthy individuals.
Our purpose, within the 12-month phase 3 TRANSFORMS study, was to examine the effect of treatment on BV loss in patient subgroups, establish correlations between baseline normalized BV (NBV) and baseline disease parameters, to identify variables predictive of baseline NBV and on-study percentage BV change (PBVC), and to establish correlations between on-study PBVC and on-study efficacy outcomes.
Patients received fingolimod 0.5 mg or 1.25 mg, or intramuscular (IM) interferon β-1a (IFNβ-1a) for 12 months. The effect of treatment on PBVC was examined in patient demographic, disease and magnetic resonance imaging (MRI) characteristic subgroups. Pearson’s correlation analyses and a stepwise linear regression model were used to identify variables predictive of NBV and PBVC.
Fingolimod reduced BV loss over 12 months versus IFNβ-1a IM in all patient subgroups assessed, including individuals with or without gadolinium (Gd)-enhancing lesions at baseline. Baseline T1 hypointense lesion volume had the strongest correlation with baseline NBV. Baseline Gd-enhancing T1 lesion count was most predictive of change in PBVC over 12 months.
Our results improve understanding of the contributions of different baseline demographic, clinical and MRI characteristics to NBV, including factors that may be predictive of future BV loss
Iron accumulation in deep grey matter (GM) structures is a consistent finding in multiple sclerosis (MS) patients. This study focused on the identification of independent determinants of iron accumulation using R2* mapping.
Ninety-seven MS patients and 81 healthy controls were included in this multicentre study. R2* mapping was performed on 3T MRI systems. R2*in deep GM was corrected for age and was related to disease duration, disability, T2 lesion load and brain volume.
Compared to controls, R2* was increased in all deep GM regions of MS patients except the globus pallidus and the substantia nigra. R2* increase was most pronounced in the progressive stage of the disease and independently predicted by disease duration and disability. Reduced cortical volume was not associated with iron accumulation in the deep GM with the exception of the substantia nigra and the red nucleus. In lesions, R2* was inversely correlated with disease duration and higher total lesion load.
Iron accumulation in deep GM of MS patients is most strongly and independently associated with duration and severity of the disease. Additional associations between cortical GM atrophy and deep GM iron accumulation appear to exist in a region specific manner.
Potential differences between primary progressive (PP) and relapsing–remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g. perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI.
Previous magnetic resonance imaging (MRI) studies have demonstrated increased iron deposition in the basal ganglia of multiple sclerosis (MS) patients. However, it is not clear whether these alterations are associated with changes of iron metabolism in body fluids.
The purpose of this study was to investigate if iron metabolism markers in cerebrospinal fluid (CSF) and serum of clinically isolated syndrome (CIS) and MS patients differ from controls and how they relate to clinical and imaging parameters.
We analysed serum ferritin, transferrin and soluble transferrin-receptor and CSF ferritin and transferrin by nephelometry in non-anaemic CIS (n=60) or early MS (n=14) patients and 68 controls. In CIS/MS we additionally assessed the T2 lesion load.
CSF transferrin was significantly decreased in CIS/MS compared to controls (p<0.001), while no significant differences were seen in serum. Higher CSF transferrin levels correlated with lower physical disability scores (r= –0.3, p<0.05). CSF transferrin levels did not correlate with other clinical data and the T2 lesion load.
Our biochemical study provides evidence that altered iron homeostasis within the brain occurs in the very early phases of the disease, and suggests that the transporter protein transferrin may play a role in the increased iron deposition known to occur in the brain of MS patients.
The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype.
Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis.
Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8–5, p = 10-14). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease.
Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.
Little information exists about how cognitive impairment in multiple sclerosis (MS) patients impacts on their caregivers’ health-related quality of life (HRQoL).
The objective of this paper is to examine the extent to which cognitive impairment in MS patients contributes to caregivers’ HRQoL.
A total of 63 MS patients, 63 caregivers and 59 matched controls were recruited. Patients and controls underwent a neuropsychological assessment, including tests of working memory, speed of information processing, executive function, and verbal fluency. HRQoL of the caregivers was assessed by CAREQOL-MS. In logistic regression models, we adjusted for the effects of confounding variables. In these models, the dependent variable was the CAREQOL-MS (higher median of CAREQOL-MS (worse HRQoL) vs. lower median of CAREQOL-MS (better HRQoL) (reference)), and the independent variable was the impairment on each neuropsychological test vs. its integrity (reference).
Cognitive impairment in MS patients was significantly associated with worse caregiver HRQoL (adjusted odds ratio (OR) = 3.10, 95% confidence interval (CI) = 1.07–11.55, p = 0.04). In secondary analyses in which each neuropsychological test was entered in the analyses separately, only Symbol Digit Modalities Test (a measurement of information processing speed) impairment (OR = 4.22, 95%, CI = 1.16–14.53, p = 0.03) was significantly associated with worse caregiver HRQoL.
MS patients’ caregivers’ HRQoL is significantly influenced by information processing speed impairment of MS patients.
auto-antibodies against the potassium channel inward rectifying potassium channel 4.1 (Kir4.1) have previously been identified in 46% of patients with multiple sclerosis (MS).
to confirm these findings.
we evaluated the presence of anti-Kir4.1 antibodies by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence in 268 MS patients, 46 patients with other neurological diseases (OND) and 45 healthy controls.
anti-Kir4.1 antibodies were found in 7.5% of MS patients, 4.3% of OND patients and 4.4% of healthy controls. Immunofluorescence analysis did not identify any specific staining.
we confirmed the presence of anti-Kir4.1 antibodies in MS patients, but at a much lower prevalence than previously reported.
The 29-item Multiple Sclerosis Impact Scale (MSIS-29) was developed to examine the impact of multiple sclerosis (MS) on physical and psychological functioning from a patient’s perspective.
To determine the responder definition (RD) of the MSIS-29 physical impact subscale (PHYS) in a group of patients with relapsing–remitting MS (RRMS) participating in a clinical trial.
Data from the SELECT trial comparing daclizumab high-yield process with placebo in patients with RRMS were used. Physical function was evaluated in SELECT using three patient-reported outcomes measures and the Expanded Disability Status Scale (EDSS). Anchor- and distribution-based methods were used to identify an RD for the MSIS-29.
Results across the anchor-based approach suggested MSIS-29 PHYS RD values of 6.91 (mean), 7.14 (median) and 7.50 (mode). Distribution-based RD estimates ranged from 6.24 to 10.40. An RD of 7.50 was selected as the most appropriate threshold for physical worsening based on corresponding changes in the EDSS (primary anchor of interest).
These findings indicate that a ≥7.50 point worsening on the MSIS-29 PHYS is a reasonable and practical threshold for identifying patients with RRMS who have experienced a clinically significant change in the physical impact of MS.
Using diffusion tensor magnetic resonance imaging (DT MRI), we analyzed the architectural integrity of the brain white matter (WM) from a large cohort of MS patients to identify the structural substrates of the concomitant presence of depression and fatigue.
Brain dual-echo, 3D T1-weighted and DT MRI scans were acquired from 147 MS patients and 90 gender- and age-matched healthy controls (HCs). Patients were stratified by the presence of depression (92 depressed (D), 55 not depressed (nD)) and fatigue (81 fatigued (F), 66 not fatigued (nF)). Sixty-five patients had co-occurrence of depression and fatigue (DF). Whole-brain voxel-wise comparisons of WM DT MRI abnormalities were performed using tract-based-spatial-statistics (TBSS). Tract-specific analyses were run in brain WM tracts using standard-space templates.
Whole-brain voxel-wise analysis yielded no significant differences between patient subgroups. At tract-specific analysis, DF patients had reduced fractional anisotropy (FA) of the forceps minor. Reduced FA of the right anterior thalamic radiation and right uncinate fasciculus was found in F-MS vs not F-MS patients after correcting for depression. No significant differences were found between D vs not D-MS patients, after correcting for fatigue.
This study provides evidence for partially overlapping damage to frontal and fronto-temporal pathways underlying depression and fatigue in MS.
Genome-wide association studies (GWAS) have identified over 100 germline variants that influence susceptibility to multiple sclerosis, most of which map within or near to genes with immunological function. However, the role of somatic mutations in multiple sclerosis has not been investigated.
The objective of this paper is to explore the role that somatic mutations might play in the development of multiple sclerosis.
We exome-sequenced in total 21 individual CD4+ lymphocytes isolated from cerebrospinal fluid of two patients. In addition we sequenced DNA from the patients’ peripheral blood to serve as germline reference.
In comparison with the respective germline sequence, each cell differed at an average of 1784 positions, but as anticipated subsequent analysis confirms that most, if not all, of these potential mutations are likely to represent artefacts generated during the amplification of a single genome and/or by sequencing. Fifty-six of the potential mutations were predicted to have likely functional effects on genes that have previously been implicated by GWAS, including three in the CD6 gene.
More robust methods applied to larger numbers of cells will be needed to define the role of somatic mutations.
The aim of this study was to investigate whether the use of fenoterol, a beta2-adrenergic agonist, was associated with multiple sclerosis (MS) risk by conducting a total population-based case-control study in Taiwan.
A total of 578 patients with newly diagnosed MS who had a severely disabling disease (SDD) certificate between January 1, 2002 and December 1, 2008 comprised the case group. These cases were compared with 2890 gender-, age-, residence-, and insurance premium-matched controls. Fenoterol use was analyzed using a conditional logistic regression model that controlled for asthma, chronic obstructive pulmonary disease (COPD), salbutamol and steroid use.
Compared with the group of people who did not use fenoterol, the adjusted odds ratios were 0.67 (95% confidence interval (CI) = 0.48–0.93, p = 0.016) for the group prescribed fenoterol below 2.25 cumulative defined daily dose (cDDD) and 0.49 (95% CI = 0.33–0.71, p < 0.001) for the group with a cumulative fenoterol use of more than 2.25 cDDD. The dose-response relationship was similar within the non-asthma patients. The associations were similar between males and females, but differences between age groups were observed.
The results of this study suggest that fenoterol use may reduce the risk of MS.
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.
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.
In a prospective observational study, data on the Multiple Sclerosis Impact Scale (MSIS-29 physical) and Multiple Sclerosis Walking Scale (MSWS-12) were obtained from 137 patient-proxy couples at baseline and at two-year follow-up. Demographic and disease-related variables explaining agreement or disagreement between patients and proxies were investigated using linear regression analyses.
Full agreement was found in 56% (MSIS) and 62% (MSWS) of the patient-proxy couples. Complete disagreement was very rare for both scales (2% MSIS, 5% MSWS). When patients were more positive than proxies, a higher age, longer disease duration, longer patient-proxy relationship and increased levels of depression, anxiety and caregiver burden in proxies were observed.
In the majority of the patient-proxy couples there was agreement. Proxies can serve as a valuable source of information, but caution remains essential when using scores from proxies.
Gonadal steroids may modulate disease course in multiple sclerosis (MS).
To assess the prevalence and clinical associations of hypogonadism in men with MS.
Male patients, aged 18–65 years, with relapsing–remitting MS (RRMS) or clinically-isolated syndrome (CIS) and their first symptom < 10 years prior were selected from a longitudinal clinical study. We measured their hormones in stored morning blood samples, and collected their Expanded Disability Status Scale (EDSS) scores every 6 months and their Symbol Digit Modalities Test (SDMT) results annually.
Our analysis included 96 men with a mean age of 40 years, EDSS of 1.1 and disease duration of 4.6 years. Of these men, 39% were hypogonadal (total testosterone < 288 ng/dL); none showed compensatory elevations in luteinizing hormone. Their low testosterone levels and testosterone:estradiol ratios were negatively correlated with body mass index (BMI) and leptin, and showed no correlation with 25-hydroxy-vitamin D levels. In our primary cross-sectional analyses, there was a negative age-adjusted correlation between total testosterone and EDSS (p = 0.044). In the age-adjusted longitudinal analyses, higher baseline testosterone levels were associated with less decline in SDMT (p = 0.012).
Men with MS may experience hypogonadotropic hypogonadism. Low testosterone levels may be associated with worse clinical outcomes. A potential neuroprotective role for testosterone warrants further investigation.
The Expanded Disability Status Scale (EDSS) has low sensitivity and reliability for detecting sustained disability progression (SDP) in multiple sclerosis (MS) trials.
This study evaluated composite disability end points as alternatives to EDSS alone.
SDP rates were determined using 96-week data from the Olympus trial (rituximab in patients with primary progressive MS). SDP was analyzed using composite disability end points: SDP in EDSS, timed 25-foot walk test (T25FWT), or 9-hole peg test (9HPT) (composite A); SDP in T25FWT or 9HPT (composite B); SDP in EDSS and (T25FWT or 9HPT) (composite C); and SDP in any two (EDSS, T25FWT, and 9HPT) (composite D).
Overall agreements between EDSS and other disability measures in defining SDP were 66%–73%. Composite A showed similar treatment effect estimate versus EDSS alone with much higher SDP rates. Composite B, C, and D all showed larger treatment effect estimate with different or similar SDP rates versus EDSS alone. Using composite A (24-week confirmation only), B, C, or D could reduce sample sizes needed for MS trials.
Composite end points including multiple accepted disability measures could be superior to EDSS alone in analyzing disability progression and should be considered in future MS trials.
Pediatric-onset multiple sclerosis (MS) patients represent a subpopulation who are diagnosed during the course of development. Social cognitive deficits have recently been recognized in adults with MS. It is critical to identify whether these youngest patients with the disorder are also at risk.
To determine whether pediatric-onset MS is associated with social cognitive deficits.
Consecutively-recruited participants with pediatric-onset MS were compared to a group of age- and gender-matched healthy controls on Theory of Mind (ToM) task performance. Tasks measured facial affect recognition (Reading the Mind in the Eyes Test), detecting social faux pas (Faux Pas Test), and understanding the perspective of another (False Beliefs Task).
Twenty-eight (28) pediatric-onset MS participants (median age 17 years) and 32 healthy controls (median age 16 years) completed the study. The MS participants performed worse than controls on all three ToM tasks: Reading the Mind in the Eyes Test (p = 0.008), the Faux Pas Test (p = 0.009), and the False Beliefs Task (p = 0.06). While more MS than control participants were impaired on a measure of information processing speed (the Symbol Digit Modalities Test; 38% versus 6%), it did not account for the differences in ToM performance.
Social cognition may represent an area of cognitive functioning affected by MS in the pediatric-onset population. These processes are especially important to study in younger patients as they may have long range implications for social adjustment, employment, and well-being.
Azathioprine (AZA) is a common immunosuppressive drug used for relapse prevention in neuromyelitis optica (NMO).
The objective of this paper is to assess efficacy, tolerability and retention of AZA in a large NMO cohort.
We conducted a retrospective review of medical records of 103 aquaporin-4 antibody-positive NMO and NMO spectrum disorder (NMOSD) patients treated with AZA.
This is the largest reported cohort of AQP4-Ab positive patients treated with AZA. Eighty-nine per cent (n = 92) had reduction in median annualised relapse rates from 1.5 (IQR 0.6–4.0) to 0 (IQR 0–0.27, p < 0.00005) with treatment. Sixty-one per cent (n = 63) remained relapse free at a median follow-up of 18 months. Neurological function improved or stabilised in 78%. At last follow-up, treatment was discontinued in 46% (n = 47). Of these, 62% (n = 29) were because of side effects, 19% (n = 9) because of death, 15% (n = 7) because of ongoing disease activity, and 2% (n = 1) because of pregnancy. Using Kaplan-Meyer curves, we estimate that 73%, 58%, 47% and 33% of patients will remain on AZA for longer than one, three, five and 10 years, respectively, after initiation of treatment.
AZA is a modestly effective treatment for NMO. However, many patients discontinue AZA over time and this seems to reflect poor tolerability more than lack of efficacy.
Susceptibility-based MRI offers a unique opportunity to study neurological diseases such as multiple sclerosis (MS). In this work, we assessed a three-dimensional segmented echo-planar-imaging (3D-EPI) sequence to rapidly acquire high-resolution T2*-weighted and phase contrast images of the whole brain. We also assessed if these images could depict important features of MS at clinical field strength, and we tested the effect of a gadolinium-based contrast agent (GBCA) on these images.
The 3D-EPI acquisition was performed on four healthy volunteers and 15 MS cases on a 3T scanner. The 3D sagittal images of the whole brain were acquired with a voxel size of 0.55 x 0.55 x 0.55 mm3 in less than 4 minutes. For the MS cases, the 3D-EPI acquisition was performed before, during, and after intravenous GBCA injection.
Both T2*-weighted and phase-contrast images from the 3D-EPI acquisition were sensitive to the presence of lesions, parenchymal veins, and tissue iron. Conspicuity of the veins was enhanced when images were obtained during injection of GBCA.
We propose this rapid imaging sequence for investigating, in a clinical setting, the spatiotemporal relationship between small parenchymal veins, iron deposition, and lesions in MS patient brains.
Neurodegeneration plays an important role in permanent disability in multiple sclerosis (MS).
The objective of this paper is to determine whether progressive neurodegeneration occurs in MS eyes without clinically evident inflammation.
Retinal nerve fiver layer thickness (RNFLT) and ganglion cell-inner plexiform layer thickness (GCIPT) were measured using Cirrus optical coherence tomography (OCT) in 133 relapsing–remitting MS (RRMS) patients (149 non-optic neuritis (ON), 97 ON eyes, last ON ≥6 months). Ninety-three patients were scanned at two visits. Percentages of abnormal GCIPT vs RNFLT (<5% of machine norms) in cross-sectional data were compared. Relations between RNFLT/GCIPT and MS duration (cross-sectional) and follow-up time (longitudinal) were assessed.
GCIPT was abnormal in more eyes than RNFLT (27% vs 16% p = 0.004 in non-ON, 82% vs 72% p = 0.007 in ON). RNFLT and GCIPT decreased with MS duration by –0.49 µm/yr (p = 0.0001) and –0.36 (p = 0.005) for non-ON; –0.52 (p = 0.003) and –0.41 (p = 0.007) for ON. RNFLT and GCIPT decreased with follow-up time by –1.49 µm/yr (p < 0.0001) and –0.53 (p = 0.004) for non-ON, –1.27 (p = 0.002) and –0.49 (p = 0.04) for ON.
In RRMS eyes without clinically evident inflammation, progressive loss of RNFLT and GCIPT occurred, supporting the need for neuroprotection in addition to suppression of autoimmune responses and inflammation.
In patients with relapsing–remitting multiple sclerosis (RRMS), a scoring system based on new magnetic resonance imaging (MRI) active lesions, relapses and sustained disability progression after a 1-year treatment with IFNβ predicted patient disability progression over time; however, this score had not been tested in patients receiving glatiramer acetate (GA).
The objective of this study was to evaluate whether this previous scoring system can also be applied to patients treated with GA.
This was a prospective, longitudinal study of 151 RRMS patients treated with GA. Their scores were constructed, based on the clinical and MRI activity after 1 year of therapy. Regression analysis was performed, in order to identify the response variables.
The total possible score range was 0–3. Patients with a score of ≥ 2 and those with clinical activity (with or without MRI activity) during their first year of treatment were at increased risk of continuing with relapses and/or sustained disability in the next 2 years (odds ratio (OR): 38.8; p < 0.0001 and OR: 7.8; p < 0.009, respectively).
In RRMS patients treated with GA, a combination of clinical activity measures may have prognostic value for identifying patients with disease activity in the next 2 years of therapy.
Injection of lysolecithin in the central nervous system results in demyelination accompanied by local activation of microglia and recruitment of monocytes. Positron-emission tomography (PET) imaging, using specific tracers, may be an adequate technique to monitor these events in vivo and therefore may become a tool for monitoring disease progression in multiple sclerosis (MS) patients.
The objective of this paper is to evaluate the potential of PET imaging in monitoring local lesions, using [11C]MeDAS, [11C]PK11195 and [18F]FDG as PET tracers for myelin density, microglia activation and glucose metabolism, respectively.
Sprague-Dawley rats were stereotactically injected with either 1% lysolecithin or saline in the corpus callosum and striatum of the right brain hemisphere. PET imaging was performed three days, one week and four weeks after injection. Animals were terminated after PET imaging and the brains were explanted for (immuno)histochemical analysis.
PET imaging was able to detect local demyelination induced by lysolecithin in the corpus callosum and striatum with [11C]MeDAS and concomitant microglia activation and monocyte recruitment with [11C]PK11195. [18F]FDG imaging demonstrated that glucose metabolism was maintained in the demyelinated lesions.
PET imaging with multiple tracers allows simultaneous in vivo monitoring of myelin density, neuroinflammation and brain metabolism in small MS-like lesions, indicating its potential to monitor disease progression in MS patients.
Acute transverse myelitis (ATM) in children is a rare and often severe disease for which there are few known prognostic factors, particularly the subsequent risk of multiple sclerosis (MS) diagnosis.
To determine the clinical course and prognostic factors after a first episode of ATM in children.
Thirty children below 16 years of age diagnosed with a first neurological episode of ATM were included retrospectively. Clinical evaluation, treatment, laboratory, and MRI data were collected.
Median age at onset was 11 years (range 3–15 years). Follow-up data were available for a median of 4 years (range 0.5–16.7 years). Five patients subsequently had a diagnosis of MS (17%), which was associated with acute partial transverse myelitis (odds ratio 5; 95% confidence interval 2.3–11), with a 60% probability of having a relapse at five years (p < 0.01). The 2011 Verhey criteria correctly identified MS in children with the highest specificity (96%) and sensitivity (80%).
Acute partial transverse myelitis and brain MRI abnormalities at initial presentation are significantly predictive of a subsequent diagnosis of MS in children with ATM. These findings suggest that closer brain MRI monitoring after acute partial transverse myelitis might make the earlier introduction of disease-modifying therapies possible.
Vocational interventions aimed at increasing job retention for people with multiple sclerosis (MS) are reliant upon a partnership with a supportive work environment. A better understanding of the types of psychosocial support that are most conducive to retaining employees’ sense of work-efficacy will enhance the success of interventions aimed at reducing workplace barriers to job maintenance.
The objective of this study is to identify the types of psychosocial support that people with MS require post-disclosure, in order to maintain their employment status. In particular, we examined the roles of psychological safety and work-efficacy.
We interviewed 40 employees with MS either individually (n = 25) or within three focus groups (n = 15). These interviews were audio-taped and the content analysed, using an inductive thematic approach.
Themes to emerge in organisational responses to disclosure were: a focus on ability (leading to enhanced perceptions of psychological safety and higher work-efficacy) and on disability (leading to diminished psychological safety and reduced perceptions of work-efficacy).
Organisational responses to disclosure demonstrating trust and inclusive decision making, and focussing on employee abilities, enhance perceptions of psychological safety at work. This increases the likelihood that employees with MS will retain their sense of work-efficacy and reduce their intentions to leave.
Patients with multiple sclerosis (MS) demonstrate slower and more variable performance on attention and information processing speed tasks. Greater variability in cognitive task performance has been shown to be an important predictor of neurologic status and provides a unique measure of cognitive performance in MS patients.
This study investigated alterations in resting-state functional connectivity associated with within-person performance variability in MS patients.
Relapsing–remitting MS patients and matched healthy controls completed structural MRI and resting-state fMRI (rsfMRI) scans, as well as tests of information processing speed. Performance variability was calculated from reaction time tests of processing speed. rsfMRI connectivity was investigated within regions associated with the default mode network (DMN). Relations between performance variability and functional connectivity in the DMN within MS patients were evaluated.
MS patients demonstrated greater reaction time performance variability compared to healthy controls (p<0.05). For MS patients, more stable performance on a complex processing speed task was associated with greater resting-state connectivity between the ventral medial prefrontal cortex and the frontal pole.
Among MS patients, greater functional connectivity between medial prefrontal and frontal pole regions appears to facilitate performance stability on complex speed-dependent information processing tasks.
MicroRNAs (miRNAs) have emerged as a family of post-transcriptional regulators of gene expression that mediate diverse aspects of immunity. MiRNA dysregulation has been found in multiple sclerosis (MS), reflecting the growing need to identify disease-specific miRNA expression signatures. Our previous low-density array studies reveal differential miR-126 expression in the CD4+T cells of untreated relapsing–remitting MS (RRMS) patients. Here, we investigated miR-126 expression in natalizumab-treated patients.
We isolated CD4+ T cells from untreated (n = 12) and natalizumab-treated MS patients (n = 24), and from healthy volunteers (n = 12). We analyzed the expression of miRNAs and potential targets by real time reverse transcription polymerase chain reaction (RT-PCR). We assessed specific inhibition of miR-126, in vitro.
MiR-126 was down-regulated in cells of patients under natalizumab treatment and up-regulated during relapse, supporting a regulatory role in MS immunopathogenesis. MiR-126 expression correlated with the expression of POU2AF1, a regulator of Spi-B that binds to the promoter/enhancer sequences of JC virus (JCV), the pathogen of progressive multifocal leukoencephalopathy (PML), a rare complication of natalizumab treatment. The same trend was found for Spi-B. Strong up-regulation of both genes appeared to be treatment duration-dependent. Specific inhibition experiments supported the link between the expression of miR-126 and POU2AF1/Spi-B.
Our findings provided deeper insight into the mode of action of natalizumab, with possible implications for understanding both the effects of natalizumab on MS activity and its specific adverse event profile.
Cognitive dysfunction in multiple sclerosis (MS) has a large impact on the quality of life and is poorly understood.
The aim of this study was to investigate functional network integrity in MS, and relate this to cognitive dysfunction and physical disability.
Resting state fMRI scans were included of 128 MS patients and 50 controls. Eigenvector centrality mapping (ECM) was applied, a graph analysis technique that ranks the importance of brain regions based on their connectivity patterns. Significant ECM changes were related to physical disability and cognitive dysfunction.
In MS patients, ECM values were increased in bilateral thalamus and posterior cingulate (PCC) areas, and decreased in sensorimotor and ventral stream areas. Sensorimotor ECM decreases were related to higher EDSS (rho = –0.24, p = 0.007), while ventral stream decreases were related to poorer average cognition (rho = 0.23, p = 0.009). The thalamus displayed increased connectivity to sensorimotor and ventral stream areas.
In MS, areas in the ventral stream and sensorimotor cortex appear to become less central in the entire functional network of the brain, which is associated with clinico-cognitive dysfunction. The thalamus, however, displays increased connectivity with these areas. These findings may aid in further elucidating the function of functional reorganization processes in MS.
To assess the sensitivity of optic coherence tomography (OCT) and visual evoked potentials (VEPs) to visual pathway abnormalities in multiple sclerosis (MS).
A total of 40 MS subjects, 28 with optic neuritis (ON) at least 3 months before (bilateral in 5), underwent assessment of visual acuity, Expanded Disability Status Scale (EDSS), OCT and VEPs, the latter quantified with a 0–4 conventional score.
OCT and VEPs were abnormal in 36% and 56% respectively in all eyes (p=0.11), 68% and 86% in eyes with previous ON (p=0.12), and in 19% versus 40% in eyes without ON history (p=0.007). Combining VEP and OCT increased sensitivity to 89% in ON and 44% in non-ON eyes. Considering all eyes, global retinal nerve fibre layer (RNFL) thickness and VEP score were significantly correlated between them (=–0.63, p<0.001) and with EDSS (RNFL: =0.40, p<0.001; VEP score: =0.47, p<0.001). Disease duration correlated with VEP score (=0.25, p=0.025) and RNFL thickness (=–0.71, p<0.001).
In eyes without ON, VEPs were more frequently abnormal than OCT, while the two techniques showed similar sensitivity in eyes previously affected by ON. The correlation of VEPs and OCT measures with disability prompts further exploration of the two techniques as potential markers of disease burden.
Non-enhancing black holes (neBHs) are more common in multiple sclerosis (MS) patients with longer disease durations and progressive disease subtypes.
Our aim was to analyse the added value of neBHs in patients with clinically isolated syndromes (CISs) for predicting conversion to clinically definite MS (CDMS).
Patients were classified based on the presence or absence of neBHs and on the number of Barkhof–Tintoré (B-T) criteria fulfilled. Dissemination in space (DIS) was defined as the presence of at least three of the four B-T criteria. Dissemination in time (DIT)1 was defined by simultaneous presence of enhancing and non-enhancing lesions. DIT2 was defined by simultaneous presence of neBHs and T2 lesions not apparent on T1-weighted images.
Focal T2-hyperintense brain lesions were identified in 87.7% of the 520 CIS patients, and 41.4% of them presented at least one neBH. Patients meeting DIS, DIT1, and DIT2 had a significantly higher rate of conversion to CDMS. After adjusting for DIS, only patients who fulfilled DIT1 preserved a significant increase in CDMS conversion.
Non-enhancing black holes in CIS patients are associated with a higher risk of conversion to CDMS. However, the predictive value of this finding is lost when added to the DIS criteria.
The development of predictors of multiple sclerosis (MS) disability is difficult due to the complex interplay of pathophysiological and adaptive processes.
The purpose of this study was to investigate whether combined evoked potential (EP)-measures allow prediction of MS disability after 20 years.
We examined 28 patients with clinically definite MS according to Poser’s criteria with Expanded Disability Status Scale (EDSS) scores, combined visual and motor EPs at entry (T0), 6 (T1), 12 (T2) and 24 (T3) months, and a cranial magnetic resonance imaging (MRI) scan at T0 and T2. EDSS testing was repeated at year 14 (T4) and year 20 (T5). Spearman rank correlation was used. We performed a multivariable regression analysis to examine predictive relationships of the sum of z-transformed EP latencies (s-EPT0) and other baseline variables with EDSST5.
We found that s-EPT0 correlated with EDSST5 (rho=0.72, p<0.0001) and EDSST5-T0 (rho=0.50, p=0.006). Backward selection resulted in the prediction model: E (EDSST5)=3.91–2.22xtherapy+0.079xage+0.057xs-EPT0 (Model 1, R2=0.58) with therapy as binary variable (1=any disease-modifying therapy between T3 and T5, 0=no therapy). Neither EDSST0 nor T2-lesion or gadolinium (Gd)-enhancing lesion quantities at T0 improved prediction of EDSST5. The area under the receiver operating characteristic (ROC) curve was 0.89 for model 1.
These results further support a role for combined EP-measures as predictors of long-term disability in MS.
Myelin-specific T cells are implicated in multiple sclerosis (MS) and drive experimental autoimmune encephalomyelitis (EAE). EAE is commonly induced with short peptides, whereas in MS, whole myelin proteins are available for immune response. We asked whether immunization with the immunoglobulin-like domain of myelin oligodendrocyte glycoprotein (MOGIgd, residues 1–125) might induce distinct CD4+ T-cell response and/or a stronger CD8+ T-cell response, compared to the 21 amino acid immunodominant MHC II-associating peptide (p35–55).
Compare both EAE and T-cell responses in C57BL/6 mice immunized with MOGIgd and MOG p35–55.
Cytokine production, and chemokine receptor expression by CD4+ and CD8+ T cells in the mouse central nervous system (CNS), were analyzed by flow cytometry.
MOGIgd triggered progression to more severe EAE than MOG p35–55, despite similar time of onset and overall incidence. EAE in MOGIgd-immunized mice was characterized by an increased percentage of CXCR3+ interferon--producing CD4+ T cells in CNS. The CD8+ T-cell response to both immunogens was similar.
Increased incidence of severe disease following MOGIgd immunization, accompanied by an increased percentage of CD4+ T cells in the CNS expressing CXCR3 and producing interferon-, identifies a pathogenic role for interferon- that is not seen when disease is induced with a single Major Histocompatibility Complex (MHC) II-associating epitope.
Pathological abnormalities including demyelination and neuronal loss are reported in the outer cortex in multiple sclerosis (MS).
We investigated for in vivo evidence of outer cortical abnormalities by measuring the magnetisation transfer ratio (MTR) in MS patients of different subgroups.
Forty-four relapsing–remitting (RR) (mean age 41.9 years, median Expanded Disability Status Scale (EDSS) 2.0), 25 secondary progressive (SP) (54.1 years, EDSS 6.5) and 19 primary progressive (PP) (53.1 years, EDSS 6.0) MS patients and 35 healthy control subjects (mean age 39.2 years) were studied. Three-dimensional (3D) 1x1x1mm3 T1-weighted images and MTR data were acquired. The cortex was segmented, then subdivided into outer and inner bands, and MTR values were calculated for each band.
In a pairwise analysis, mean outer cortical MTR was lower than mean inner cortical MTR in all MS groups and controls (p<0.001). Compared with controls, outer cortical MTR was decreased in SPMS (p<0.001) and RRMS (p<0.01), but not PPMS. Outer cortical MTR was lower in SPMS than PPMS (p<0.01) and RRMS (p<0.01).
Lower outer than inner cortical MTR in healthy controls may reflect differences in myelin content. The lowest outer cortical MTR was seen in SPMS and is consistent with more extensive outer cortical (including subpial) pathology, such as demyelination and neuronal loss, as observed in post-mortem studies of SPMS patients.
Interactions between TIRC7 (a novel seven-transmembrane receptor on activated lymphocytes) and its ligand HLA-DR might be involved in the inflammatory process in multiple sclerosis (MS).
Methods comprised immunohistochemistry and microscopy on archival MS autopsies, proliferation-, cytokine-, and surface-staining assays using peripheral blood lymphocytes (PBLs) from MS patients and an in vitro model.
TIRC7 was expressed in brain-infiltrating lymphocytes and strongly correlated with disease activity in MS. TIRC7 expression was reduced in T cells and induced in B cells in PBLs obtained from MS patients. After ex vivo activation, T cell expression of TIRC7 was restored in patients with active MS disease. The interaction of TIRC7+ T lymphocytes with cells expressing HLA-DR on their surface led to T cell proliferation and activation whereas an anti-TIRC7 mAb preventing interactions with its ligand inhibited proliferation and Th1 and Th17 cytokine expression in T cells obtained from MS patients and in myelin basic protein-specific T cell clone.
Our findings suggest that TIRC7 is involved in inflammation in MS and anti-TIRC7 mAb can prevent immune activation via selective inhibition of Th1- and Th17-associated cytokine expression. This targeting approach may become a novel treatment option for MS.
Increased levels of antibodies to neurofilament light protein (NF-L) in biological fluids have been found to reflect neuroinflammatory responses and neurodegeneration in multiple sclerosis (MS).
To evaluate whether levels of serum antibodies against NF-L correlate with clinical variants and treatment response in MS.
The autoantibody reactivity to NF-L protein was tested in serum samples from patients with relapsing–remitting MS (RRMS) (n=22) and secondary progressive MS (SPMS) (n=26). Two other cohorts of RRMS patients under treatment with natalizumab were analysed cross-sectionally (n=16) and longitudinally (n=24). The follow-up samples were taken at 6, 12, 18 and 24 months after treatment, and the NF-L antibody levels were compared against baseline levels.
NF-L antibodies were higher in MS clinical groups than healthy controls and in RRMS compared to SPMS patients (p<0.001). NF-L antibody levels were lower in natalizumab treated than in untreated patients (p<0.001). In the longitudinal series, NF-L antibody levels decreased over time and a significant difference was found following 24 months of treatment compared with baseline measurements (p=0.001).
Drug efficacy in MS treatment indicates the potential use of monitoring the content of antibodies against the NF-L chain as a predictive biomarker of treatment response in MS.
The female preponderance in incidence of multiple sclerosis (MS) calls for investigations into sex differences in comorbidity with other autoimmune diseases (ADs).
To determine whether male and female patients with MS have a higher frequency of autoimmune comorbidity than controls, and to describe the type and frequency of ADs that are associated with MS.
Our database was established by linkage of the Danish MS Registry to The Danish National Patient Register and consisted of 1403 patients of both sexes with clinical onset of MS between 2000 and 2004, and 25 matched controls for every case.
None of the ADs occurred more frequently in female cases than in controls. Male cases were more likely to have Type I diabetes mellitus (odds ratio (OR) = 3.34; 95% CI 1.40 – 7.02; p < 0.008), Crohn’s disease (OR = 5.03; 95% CI 1.18 – 16.10; p = 0.03) and systemic lupus erythematosus (OR = 12.55; 95% CI 1.62 – 69.95; p = 0.02) than male controls.
Autoimmune disorders are rare, but some of them tend to occur together with MS at a higher rate than in controls. Although women are generally more prone to ADs than men, significantly increased occurrence of other ADs were only found in male MS patients.
Although aquaporin-4 (AQP4) is widely expressed in the human brain cortex, lesions are rare in neuromyelitis optica (NMO) spectrum disorders (NMOSD). Recently, however, several studies have demonstrated occult structural brain atrophy in NMO.
This study aims to investigate magnetic resonance imaging (MRI) patterns of gray matter (GM) and white matter (WM) abnormalities in patients with NMOSD and to assess the visual pathway integrity during disease duration correlation of the retinal nerve fiber layer (RNFL) and pericalcarine cortex thickness.
Twenty-one patients with NMOSD and 34 matched healthy controls underwent both high-field MRI (3T) high-resolution T1-weighted and diffusion-tensor MRI. Voxel-based morphometry, cortical analyses (Freesurfer) and diffusion-tensor imaging (DTI) analyses (TBSS-FSL) were used to investigate brain abnormalities. In addition, RNFL measurement by optic-coherence tomography (OCT) was performed.
We demonstrate that NMOSD is associated with GM and WM atrophy, encompassing more frequently the motor, sensory and visual pathways, and that the extent of GM atrophy correlates with disease duration. Furthermore, we demonstrate for the first time a correlation between RNFL and pericalcarine cortical thickness, with cortical atrophy evolving over the course of disease.
Our findings indicate a role for retrograde and anterograde neurodegeneration in GM atrophy in NMOSD. However, the presence atrophy encompassing almost all lobes suggests that additional pathomechanisms might also be involved.
The Comunicazione medico-paziente nella Sclerosi Multipla – Revised (COSM-R) is a patient self-assessed questionnaire probing the moment of multiple sclerosis (MS) diagnosis disclosure (section 1, five items) and following period (section 2, 15 items).
This study examined COSM-R dimensionality and measurement properties through Rasch analysis (partial-credit model) and proposed a revised questionnaire.
Cross-sectional COSM-R data were obtained from 1068 people with MS (PwMS, 1065 questionnaires) participating in four studies (102 centres). Mean age was 40 years (range 17–73); 70% were women; 53% were from Northern, 25% from Central, and 21% from Southern Italy.
Unidimensionality was not confirmed for COSM-R section 1, but was for section 2 after removal of three items. The revised instrument (COSM-S, Shortened) consisted of the original five-item checklist (section 1), modified by removing the table grouping of three items, and 12 of the original 15 section 2 items, which could now be summed and transformed into an interval scale. Scores were higher for items assessing emotional satisfaction than for those assessing informational satisfaction.
The proposed COSM-S is a composite measure of satisfaction with MS diagnosis communication with improved metric properties over the original COSM-R, and whose section 2 satisfies Rasch model expectations.
The immunogenicity of influenza vaccines in MS patients undergoing immunomodulatory treatment is not well studied.
This explorative study investigated the influence of immunomodulatory treatment on MS patients receiving pandemic H1N1 (swine flu) vaccination in 2009 and seasonal influenza vaccination in 2010.
We investigated the immune response to pandemic H1N1 vaccination among 113 MS patients and 216 controls during the pandemic of 2009. We also investigated the serological response to seasonal influenza vaccination (2010 – 2011 season) among 49 vaccinated and 62 non-vaccinated MS patients, versus 73 controls. We evaluated these vaccine responses by haemagglutination inhibition assay.
MS patients receiving immunomodulatory treatment had reduced protection (27.4%), compared to controls (43.5%) (p = 0.006), after pandemic H1N1 vaccination (2009). The rates of protection were not influenced by interferon beta treatment (44.4% protected), but were reduced among patients receiving glatiramer acetate (21.6%), natalizumab (23.5%), and mitoxantrone (0.0%). A similar pattern emerged after MS patients received a seasonal influenza vaccination in 2010.
These findings suggest that MS patients receiving immunomodulatory therapies other than interferon beta should be considered for a vaccine response analysis and perhaps be offered a second dose of the vaccine, in cases of insufficient protection.
Exercise programmes that can demonstrate evidence of long-lasting clinical effectiveness are needed for people with multiple sclerosis (PwMS).
The objective of this study was to assess the effects of a practically implemented exercise programme on self-directed exercise behaviour and important health outcomes in PwMS to nine months of follow-up.
We conducted a parallel-arm, randomised controlled trial: 120 PwMS (Expanded Disability Status Scale (EDSS) 1.0–6.5) randomised to a three-month exercise intervention plus usual care, or usual care only. Two supervised plus one home-exercise session (weeks 1–6) were followed by one supervised and two home-exercise sessions (weeks 7–12). Cognitive-behavioural techniques promoted long-term exercise behaviour change. Outcomes were blindly assessed at baseline and at three and nine months after randomisation. The primary outcome was self-reported exercise behaviour (Godin Leisure Time Exercise Questionnaire (GLTEQ)). Secondary outcomes included fatigue and health-related quality of life (HRQoL).
The intervention increased self-reported exercise (9.6 points; 95% CI: 2.0 to 17.3 points; p = 0.01) and improved fatigue (p < 0.0001) and many HRQoL domains (p ≤ 0.03) at three months. The improvements in emotional well-being (p = 0.01), social function (p = 0.004) and overall quality of life (p = 0.001) were sustained for nine months.
This pragmatic approach to implementing exercise increases self-reported exercise behaviour, improves fatigue and leads to a sustained enhancement of HRQoL domains in PwMS.
The SIMS-Trial showed that the ‘Sapere Migliora’ information aid (IA) for newly diagnosed people with multiple sclerosis (PwMS) effectively improved patient knowledge and satisfaction with care.
The objectives of this paper are to assess the effectiveness of the IA in clinical practice and to compare the whole IA with the take-home booklet/website component alone.
After updating the IA and replacing the CD with a website, a prospective, open-label non-randomised controlled trial compared the whole IA (group A, five SIMS-Trial centres) to take-home (group B, 16 centres). One month after the intervention, participants completed the MS Knowledge Questionnaire (MSKQ), care satisfaction questionnaire (COSM-R) (primary study outcomes), Hospital and Anxiety Depression Scale, and ad hoc questionnaire appraising the IA.
We enrolled 159 newly diagnosed PwMS (May 2012–March 2013). Drop-outs were four of 77 (5%, group A) and 11/82 (13%, group B). Primary endpoint (highest tertile both for MSKQ and COSM-R section 2 scores) was achieved by 38/77 (49%) group A and 33/82 (40%) group B (p = 0.25). Attainment of secondary outcomes was also similar between groups.
This study shows that the entire IA is not superior to the booklet/website alone, and that both are comparable in efficacy to the intervention arm of the SIMS-Trial.
ISRCTN78940214.
There is a well-documented increase in the risk of multiple sclerosis (MS) when migrating from a region of low prevalence to one of high prevalence.
We present here an investigation of MS prevalence and candidate environmental and genetic risk factors among Iranian immigrants to British Columbia (BC), Canada.
MS cases of Iranian ancestry were ascertained from a population-based Canadian study. We collected blood samples for genetic and serological analyses, and administered a personal history questionnaire to the cases.
The crude prevalence of MS in this population of Iranian ancestry was 287/100,000 (95% CI: 229 – 356/100,000). MS cases were more likely to have a history of infectious mononucleosis (odds ratio (OR) = 7.5; p = 0.005) and smoking (OR = 17.0; p < 0.0001), as compared to healthy controls from previous studies in Iran. Cases were also more likely than controls to have been born between April and September (OR = 2.1; p = 0.019).
The prevalence of MS among Iranian immigrants to Canada is greater than the overall prevalence of MS in Iran by a factor of at least four, and is similar to that recently observed among Iranian immigrants in other western nations. No major genetic susceptibility variants were identified, suggesting the environment in Canada may be what is increasing the risk of MS in this population.
The objective of this paper is to estimate the association between multiple sclerosis (MS) and measures of sun exposure in specific age periods in Norway and Italy.
A total of 1660 MS patients and 3050 controls from Italy and Norway who participated in a multinational case-control study (EnvIMS) reported sun habits during childhood and adolescence.
A significant association between infrequent summer outdoor activity and increased MS risk was found in Norway and in Italy. The association was strongest between the ages of 16 and 18 years in Norway (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.30–2.59), and between birth and age 5 years in Italy (OR 1.56, 95% CI 1.16–2.10). In Italy a significant association was also found during winter (OR 1.42, 95% CI 1.03–1.97). Frequent sunscreen use between birth and the age of 6 years was associated with MS in Norway (OR 1.44, 95% CI 1.08–1.93) after adjusting for outdoor activity during the same period. Red hair (OR 1.67, 95% CI 1.06–2.63) and blonde hair (OR 1.36, 95% CI 1.09–1.70) were associated with MS after adjusting for outdoor activity and sunscreen use.
Converging evidence from different measures underlines the beneficial effect of sun exposure on MS risk.
The heterogeneity of the disease course in multiple sclerosis (MS) remains a challenge for patient management and clinical trials.
The objective of this paper is to investigate the relationship between disease course heterogeneity and retinal layer thicknesses in MS.
A total of 230 MS patients and 63 healthy control subjects were included. Spectral-domain OCT scanning of the peripapillary and macular regions was performed, followed by automated eight-layer segmentation. Generalised estimation equations were used for comparisons. Receiver operating characteristic (ROC) curves were calculated for distinguishing a benign from a typical disease course.
Primary progressive patients showed relative preservation of inner retinal layers, compared to the relapsing onset MS types. Only in MS eyes without optic neuritis did patients with typical MS show more severe thinning of the inner retinal layers (RNFL to INL) compared to patients with a benign disease course, even after an average disease course of 20 years.
The thicknesses, particularly of the innermost retinal layers (RNFL, GCC), were significantly related to the heterogeneous disease course in MS. The relative preservation of these layers in primary progressive and benign MS suggests rather limited susceptibility of the retina to neurodegeneration, which may be relevant for future neurodegenerative treatment trials employing OCT as a secondary outcome measure in primary progressive MS.
Patient-reported outcomes are important for clinical research and care, yet administering and scoring the questionnaires requires considerable effort and time. The Patient Reported Outcomes Measurement Information System (PROMIS) could considerably reduce administrative obstacles and lessen survey burden for participants.
Assess the feasibility and validity of PROMIS, compared to commonly-used legacy measures for multiple sclerosis (MS).
In this cross-sectional survey, 133 participants with confirmed MS completed legacy surveys and PROMIS Computerized Adaptive Tests (CATs) for depression, anxiety, pain, fatigue and physical function. We conducted a multi-trait, multi-method analysis and verified results with confirmatory factor analysis.
The correlations between PROMIS and the corresponding legacy measures were large (0.67 to 0.87). The multi-trait, multi-method criteria were generally well met, providing good evidence of the validity of PROMIS measures. PROMIS surveys asked fewer questions and required substantially less time to complete than the legacy scales.
Our results provide evidence of the construct validity of PROMIS for use with MS patients. Several aspects of the PROMIS CATs made them an important resource, including: (a) less time was required to complete them; (b) missing data was reduced; and (c) the automatic scoring referenced the general population. Our findings support the use of PROMIS in MS research and may have broader implications for clinical care, as well.
Colour vision assessment correlates with damage of the visual pathway and might be informative of overall brain damage in multiple sclerosis (MS).
The objective of this paper is to investigate the association between impaired colour vision and disease severity.
We performed neurological and ophthalmic examinations, as well as magnetic resonance imaging (MRI) and optical coherence tomography (OCT) analyses, on 108 MS patients, both at baseline and after a follow-up of one year. Colour vision was evaluated by Hardy, Rand and Rittler plates. Dyschromatopsia was defined if colour vision was impaired in either eye, except for participants with optic neuritis (ON), for whom only the unaffected eye was considered. We used general linear models adjusted for sex, age, disease duration and MS treatment for comparing presence of dyschromatopsia and disease severity.
Impaired colour vision in non-ON eyes was detected in 21 out of 108 patients at baseline. At baseline, patients with dyschromatopsia had lower Multiple Sclerosis Functional Composite (MSFC) scores and Brief Repeatable Battery-Neuropsychology executive function scores than those participants with normal colour vision. In addition, these patients had thinner retinal nerve fiber layer (RNFL), and smaller macular volume, normalized brain volume and normalized gray matter volume (NGMV) at baseline. Moreover, participants with incident dyschromatopsia after one-year follow-up had a greater disability measured by the Expanded Disability Status Scale and MSFC-20 and a greater decrease in NGMV than participants with normal colour vision.
Colour vision impairment is associated with greater MS severity.
The Expanded Disability Status Scale (EDSS) is the most widely employed ordinal disability scale in multiple sclerosis (MS). However, how far apart the individual EDSS levels are along the disability spectrum has not been formally quantified.
The objective of this paper is to generate refined disability weights (DWs) for each of the ordinal EDSS levels.
We performed the person trade-off (PTO) procedure to derive DWs of five representative EDSS categories (2, 4, 6, 7 and 9), and DWs of the remaining EDSS categories were assigned by linear interpolation. The modified Delphi process was used to achieve consensus among raters.
DWs were 0.021 for EDSS 2, 0.199 for EDSS 4, 0.313 for EDSS 6, 0.617 for EDSS 7, and 0.926 for EDSS 9. Panel members achieved a high degree of consensus for each DW, as indicated by low coefficients of variation.
Our DWs confirmed that EDSS is an ordinal scale with highly variable intervals. The availability of DW for each EDSS level allows direct comparison of each MS outcome state with other health states and provides a foundation for the estimation of the disability-adjusted life-years lost of individual patients.
In a retrospective study, we have previously shown that work ability was improved after the initiation of natalizumab treatment in relapsing–remitting multiple sclerosis (RRMS). In another prospective trial (TYNERGY) the effect on MS-related fatigue was evaluated after 12 months of treatment with natalizumab. A comprehensive Capacity for Work Questionnaire (CWQ) was used to collect data regarding number of working hours and sickness absence. The predefined intention-to-treat analysis regarding work ability did not, however, show significant results.
The objective of this paper is to assess the amount of sick leave in RRMS before and after one year of natalizumab treatment and correlate it to fatigue and walking ability.
This is a post-hoc analysis of the complete data from the CWQ used in the TYNERGY trial.
MS patients receiving sickness benefit before start of treatment reduced their sickness benefit by an absolute change of 33% after one year of natalizumab treatment. Younger age and improvement of walking ability correlated significantly with reduction of sick leave.
This ad-hoc analysis of prospectively collected data supported our previous retrospective study and thus indicates a positive relationship between natalizumab treatment and improvement in work ability.
Multiple sclerosis (MS) is thought to be caused by T-cell mediated autoimmune dysfunction. Risk of developing MS is influenced by environmental and genetic factors. Modifiable differences in DNA methylation are recognized as epigenetic contributors to MS risk and may provide a valuable link between environmental exposure and inherited genetic systems.
To identify methylation changes associated with MS, we performed a genome-wide DNA methylation analysis of CD4+ T cells from 30 patients with relapsing–remitting MS and 28 healthy controls using Illumina 450K methylation arrays.
A striking differential methylation signal was observed at chr. 6p21, with a peak signal at HLA-DRB1. After prioritisation, we identified a panel of 74 CpGs associated with MS in this cohort. Most notably we found evidence of a major effect CpG island in DRB1 in MS cases (pFDR < 3 x 10–3). In addition, we found 55 non-HLA CpGs that exhibited differential methylation, many of which localise to genes previously linked to MS.
Our findings provide the first evidence for association of DNA methylation at HLA-DRB1 in relation to MS risk. Further studies are now warranted to validate and understand how these findings are involved in MS pathology.
Diffuse abnormalities are known to occur within the brain tissue of multiple sclerosis (MS) patients that is "normal appearing" on T1-weighted and T2-weighted magnetic resonance images.
With the goal of exploring the sensitivity of novel MRI parameters to detect such abnormalities, we implemented an inversion-prepared magnetization transfer (MT) protocol and adiabatic T1 and T2 rotating frame relaxation methods.
Nine relapsing–remitting MS patients and seven healthy controls were recruited. Relaxation parameters were measured in a single slice just above the lateral ventricles and approximately parallel to the AC-PC line.
The MT ratio of regions encompassing the normal-appearing white matter (NAWM) was different in MS patients as compared with controls (p = 0.043); however, the T1 measured during off-resonance irradiation (T1sat) was substantially more sensitive than the MT ratio for detecting differences between groups (p = 0.0006). Adiabatic T1 was significantly prolonged in the NAWM of MS patents as compared to controls (by 6%, p = 0.026), while no differences were found among groups for T2. No differences among groups were observed in the cortical gray matter for any relaxation parameter.
The results suggest degenerative processes occurring in the NAWM of MS, likely not accompanied by significant abnormalities in iron content.
In multiple sclerosis (MS), the location of focal lesions does not always correlate with clinical symptoms, suggesting disconnection as a major pathophysiological mechanism. Resting-state (RS) functional magnetic resonance imaging (fMRI) is believed to reflect brain functional connectivity (FC) within specific neuronal networks.
RS-fMRI was used to investigate changes in FC within two critical networks for the understanding of MS disabilities, namely, the sensory-motor network (SMN) and the default-mode network (DMN), respectively, implicated in sensory-motor and cognitive functions.
Thirty-four relapsing–remitting (RR), 14 secondary progressive (SP) MS patients and 25 healthy controls underwent MRI at 3T, including conventional images, T1-weighted volumes, and RS-fMRI sequences. Independent component analysis (ICA) was employed to extract maps of the relevant RS networks for every participant. Group analyses were performed to assess changes in FC within the SMN and DMN in the two MS phenotypes.
Increased FC was found in both networks of MS patients. Interestingly, specific changes in either direction were observed also between RR and SP MS groups.
FC changes seem to parallel patients’ clinical state and capability of compensating for the severity of clinical/cognitive disabilities.
Few data are available for patients with a late onset (≥ 50 years) of neuromyelitis optica (LONMO) or neuromyelitis optica spectrum disease (LONMOSD), defined by an optic neuritis/longitudinally extensive transverse myelitis with aquaporin-4 antibodies (AQP4-Ab).
To characterize LONMO and LONMOSD, and to analyze their predictive factors of disability and death.
We identified 430 patients from four cohorts of NMO/NMOSD in France, Germany, Turkey and UK. We extracted the late onset patients and analyzed them for predictive factors of disability and death, using the Cox proportional model.
We followed up on 63 patients with LONMO and 45 with LONMOSD during a mean of 4.6 years. This LONMO/LONMOSD cohort was mainly of Caucasian origin (93%), women (80%), seropositive for AQP4-Ab (85%) and from 50 to 82.5 years of age at onset. No progressive course was noted. At last follow-up, the median Expanded Disability Status Scale (EDSS) scores were 5.5 and 6 in the LONMO and LONMOSD groups, respectively. Outcome was mainly characterized by motor disability and relatively good visual function. At last follow-up, 14 patients had died, including seven (50%) due to acute myelitis and six (43%) because of opportunistic infections. The EDSS 4 score was independently predicted by an older age at onset, as a continuous variable after 50 years of age. Death was predicted by two independent factors: an older age at onset and a high annualized relapse rate.
LONMO/LONMOSD is particularly severe, with a high rate of motor impairment and death.
Smoking may contribute to the induction of neutralizing antibodies to interferon β-1a.
In this study, we aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of multiple sclerosis.
This report is based on 1338 natalizumab-treated multiple sclerosis patients included in either of two Swedish case-control studies in which information on smoking habits was collected. Using logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies, by calculating odds ratios with 95% confidence intervals.
Compared with nonsmokers, the odds ratio of developing anti-natalizumab antibodies was 2.4 (95% CI 1.2–4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking. When smoking within two years prior to screening was considered, the odds ratio of developing anti-natalizumab antibodies was 2.7 (1.5–5.1).
The finding strengthens our hypothesis of the lungs as immune-reactive organs on irritation in relation to autoimmune responses, and may also be of clinical relevance since antibodies against natalizumab abrogate the therapeutic effect of the treatment.
The contribution of genetic variants underlying the susceptibility to different clinical courses of multiple sclerosis (MS) is still unclear.
The aim of the study is to evaluate and compare the proportion of liability explained by common SNPs and the genetic burden of MS-associated SNPs in progressive onset (PrMS) and bout-onset (BOMS) cases.
We estimated the proportion of variance in disease liability explained by 296,391 autosomal SNPs in cohorts of Italian PrMS and BOMS patients using the genome-wide complex trait analysis (GCTA) tool, and we calculated a weighted genetic risk score (wGRS) based on the known MS-associated loci.
Our results identified that common SNPs explain a greater proportion of phenotypic variance in BOMS (36.5%±10.1%) than PrMS (20.8%±6.0%) cases, and a trend of decrease was observed when testing primary progressive (PPMS) without brain MRI inflammatory activity (p = 7.9 x 10–3). Similarly, the wGRS and the variance explained by MS-associated SNPs were higher in BOMS than PPMS in males (wGRS: 6.63 vs 6.51, p = 0.04; explained variance: 4.8%±1.5% vs 1.7%±0.6%; p = 0.05).
Our results suggest that the liability of disease is better captured by common genetic variants in BOMS than PrMS cases. The absence of inflammatory activity and male gender further raise the difference between clinical courses.
Factors driving disease-modifying therapy (DMT) switch behavior are not well understood.
The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT.
This retrospective study analyzed patients with relapsing–remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon β or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event.
Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset (p = 0.012), MS diagnosis (p = 0.004), DMT initiation (p < 0.001), and first MS event (p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1–12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1–7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1–5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2–4.1; p = 0.009).
Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation.
For many employees with multiple sclerosis (MS), disclosure of their diagnosis at work is seen as a high-risk strategy that might lead to diminished perceptions of their capabilities by supervisors and colleagues, if not outright discrimination. The consequence of this mistrust surrounding the disclosure process is that employees with MS may leave it until too late to effectively manage symptoms at work.
The objective of this paper is to statistically evaluate the relationship between disclosure of diagnosis at work and maintenance of employment.
Three annual, large-sample self-report surveys of MS patients prospectively examined the relationship between disclosure of diagnosis at work and employment status. A total of 1438 people responded to all three surveys. Of employed persons in 2010 (n = 946), 673 also responded to the 2012 survey. Of these 673 respondents 564 were still employed.
People who had disclosed their MS status to an employer were more likely to remain in employment in Year 3. The effect of disclosure in predicting employment status remained after controlling for age, gender, hours worked and level of disability.
This study provides the first empirical support for the positive role of disclosure in maintaining employment status, measured both as job retention and tenure in current employment.
The objective of this paper is to investigate the pattern of abnormalities and establish the diagnostic power of multifocal objective pupil perimetry (mfPOP) in multiple sclerosis (MS).
A prospective study enrolling 35 normal (47.9 ± 16.8 years, 22 females) and 85 MS subjects (49.8 ± 11.3 years, 62 females; 72 relapsing–remitting (RR), and 13 primary or secondary progressives (PorS)). EDSS scores for the RR and PorS groups were 3.53 ± 1.04 (mean ± SD), and 5.9 ± 1.43, respectively. mfPOP responses were obtained from 44 regions/visual field. Each region was analysed according to response time-to-peak and standardised amplitude (AmpStd). Predictive power was measured by percentage area under the receiver operator curve (%AUC).
mfPOP responses showed a significant reduction of 0.69 ± 0.04 dB (mean ± SE) in AmpStd and significantly delayed time-to-peak of 25.95 ± 0.89 ms (mean ± SE) in MS subjects compared to control subjects (p<0.001). %AUC was greater for time-to-peak than AmpStd both for RR and PorS patients. Diagnostic power followed the EDSS scores but not a history of optic neuritis.
mfPOP is well tolerated and potentially has a role in the diagnosis and assessment of patients with MS.
To determine the long-term effect of natalizumab (NTZ) treatment on the expression of integrins and chemokine receptors involved in the migration of T cells towards the central nervous system (CNS).
We drew the blood of 23 patients just before starting NTZ therapy and every 12 months thereafter, for up to 48 months of treatment. We assessed the ex-vivo expression of phenotype markers (CCR7 and CD45RA), CNS-addressing integrins (CD11a, CD49d and CD29) and chemokine receptors (CXCR3 and CCR6) in CD4+ or CD8+ T-cell subsets by flow cytometry.
As compared to the pre-NTZ values, there was a marked increase in central memory (CCR7+/CD45RA-) CD4+ T cells and in effector memory (CCR7-/CD45RA-) CD8+ T cells at 12 and 24 months. In addition to an expected downregulation of both VLA-4 subunits (CD49d/CD29), we also found decreased T-cell expression of CXCR3 at 12 months, and of CD11a (LFA-1 αL subunit) at 12 months, but mostly at 24 months of NTZ treatment.
Our data show a nadir of CD11a expression at 2 years of NTZ treatment, at the peak of incidence of progressive multifocal leukoencephalopathy (PML), indirectly suggesting that a lack of these molecules may play a role in the onset of PML in NTZ-treated patients.
Optic neuritis (ON) may be the first symptom of a central nervous system demyelinating, systemic or infectious disease but few patients experience recurrent episodes and have a negative workup.
This disorder, named relapsing optic neuritis (RON), is poorly described in the literature and still presents a particular challenge in diagnosis and management.
We describe the clinical, laboratory, magnetic resonance imaging (MRI) and disability course of RON in a French cohort of 62 patients, based on a multicentre, retrospective, observational study.
In our cohort, we identified two distinct groups of RON patients. The first is characterised by relapsing inflammatory optic neuritis (RION, 68%), which is non-progressive, whereas the second presented as a chronic relapsing inflammatory optic neuritis (CRION, 32%), which is progressive. We have noted more cases with steroid dependence in the CRION group than the RION group (42% vs 10%). The long-term visual prognosis was more severe in CRION patients and neuromyelitis optica-immunoglobulin G (NMO-IgG)-positive patients.
RON is likely a separate entity corresponding to an autoimmune disease that differs from multiple sclerosis (MS), NMO and vasculitis. We provide a new classification system based on a better understanding of RON which could allow an improved management by early treatment of poor prognosis forms.
To identify clinical predictors of effectiveness of a motor rehabilitation treatment in a cohort of multiple sclerosis (MS) patients.
We analysed 212 consecutive patients who underwent a short-term (3–7 weeks) intensive (two hours per day, five days per week), individualised, goal-oriented inpatient rehabilitation program. Activity limitation and impairment were measured on admission and discharge of the rehabilitation trial using the motor sub-items of the Functional Independence Measure (mFIM) and the Expanded Disability Status Scale (EDSS) score. Multivariate logistic regression models have been tested to evaluate the role of clinical baseline features on rehabilitation effectiveness.
According to pre-defined outcome measures, 75.1% of MS patients improved in either activity limitation (≥5 points delta mFIM) or impairment (≥1.0 delta EDSS score if baseline EDSS was ≤5.5, or ≥0.5 if baseline EDSS was >5.5), and 35.4% of MS patients improved in both outcomes. A relapsing-remitting course of disease, a more severe baseline impairment and activity limitation level, a shorter disease duration and a less severe balance dysfunction were predictive of the effectiveness of rehabilitation.
These data confirm that an intensive inpatient rehabilitation program is able to produce a short-term relevant improvement on clinical and functional outcome measures and suggest some clinical features which can be considered as potential predictors of the outcome of rehabilitative intervention.
The importance of Qa-1 restricted CD8+ T cells in regulating autoreactive T cell responses has been demonstrated in animal models for autoimmune disorders, including multiple sclerosis (MS).
We hypothesize that their human variant, HLA-E restricted CD8+ T cells, fulfills a similar regulatory role in man and that these cells are of importance in MS.
A large cohort of MS patients and healthy controls was genotyped for the two known HLA-E polymorphisms. Flow cytometry was used to determine HLA-E expression kinetics and to phenotype HLA-E restricted CD8+ T cells. Immunohistochemistry was performed to investigate HLA-E expression in the central nervous system (CNS) of MS patients.
HLA-E is upregulated on immune cells upon in vitro activation and this upregulation is polymorphism-dependent for T and B cells. T and B cells in lesions of MS patients show enhanced HLA-E expression. Furthermore, NKG2C+CD8+ T cells of MS patients have a significantly lower Foxp3 expression, while NKG2A+CD8+ T cells of MS patients produce higher levels of pro-inflammatory cytokines compared to those of healthy individuals.
Our study indicates that the HLA-E system is altered in MS and could play a regulatory role in disease.
Multiple sclerosis (MS) is a neurological disease characterised by central nervous system inflammation, demyelination, axonal degeneration and neuronal injury. Preventing neuronal and axon damage is of paramount importance in attempts to prevent disease progression. Intact axonal transport mechanisms are crucial to axonal integrity and evidence suggests these mechanisms are disrupted in MS. Anterograde axonal transport is mediated to a large extent through the kinesin superfamily proteins. Recently, certain kinesin superfamily proteins (KIF5A, KIF1B and KIF21B) were implicated in MS pathology.
To investigate the expression of KIF5A, KIF21B and KIF1B in MS and control post-mortem grey matter.
Using both quantitative real-time polymerase chain reaction (PCR) and Immunodot-blots assays, we analysed the expression of kinesin superfamily proteins in 27 MS cases and 13 control cases not linked to neurological disease.
We have shown significant reductions in KIF5A, KIF21B and KIF1B messenger ribonucleic acid (mRNA) expression and also KIF5A protein expression in MS grey matter, as compared to control grey matter.
We have shown significant reductions in mRNA and protein levels of axonal motor proteins in the grey matter of MS cases, which may have important implications for the pathogenesis of neuronal/axonal injury in the disease.
Neuromyelitis optica (NMO) is a severe autoimmune disease of the central nervous system characterized by spinal cord and optic nerve involvement. Brainstem manifestations have recently been described.
To evaluate the time of occurrence, the frequency and the characteristics of brainstem symptoms in a cohort of patients with NMO according to the ethnic background and the serologic status for anti-aquaporin-4 antibodies (AQP4-abs).
We performed a multicenter study of 258 patients with NMO according to the 2006 Wingerchuk criteria and we evaluated prospectively the frequency, the date of onset and the duration of various brainstem signs in this population.
Brainstem signs were observed in 81 patients (31.4%). The most frequently observed signs were vomiting (33.1%), hiccups (22.3%), oculomotor dysfunction (19.8%), pruritus (12.4%), followed by hearing loss (2.5%), facial palsy (2.5%), vertigo or vestibular ataxia (1.7%), trigeminal neuralgia (2.5%) and other cranial nerve signs (3.3%). They were inaugural in 44 patients (54.3%). The prevalence was higher in the non-Caucasian population (36.6%) than in the Caucasian population (26%) (p<0.05) and was higher in AQP4-ab-seropositive patients (32.7%) than in seronegative patients (26%) (not significant).
This study confirms the high frequency of brainstem symptoms in NMO with a majority of vomiting and hiccups. The prevalence of these manifestations was higher in the non Caucasian population.
The objectives of this study were to evaluate the rate of JC virus (JCV) seroconversion/seroreversion in a French cohort of multiple sclerosis (MS) patients receiving natalizumab (NTZ), describe the characteristics of this population, identify risk factors for JCV seropositivity and analyse the additional value of quantitative JCV serology results in this context.
MS patients from two French MS centres, whose JCV serological status in 2011 while receiving NTZ was known (n=357; first-generation enzyme-linked immunosorbent assay (ELISA) test (Gen1)), were proposed for inclusion in this study. We evaluated the rate of JCV seroconversion over a period of one year with a second-generation ELISA test (Gen2; n=303) and analysed the quantitative results. Multivariate analysis was performed to identify risk factors for JCV seropositivity.
Among the patients with Gen2 JCV serology (n=303) that had been JCV-seronegative one year before (n=165), the rate of JCV seroconversion was 26.67% (44/165). We observed a higher proportion of anti-JCV antibody seroconverters (14.5%) than expected (≤3%) but also increasing index values of anti-JCV antibody over time.
Our data suggest that JCV reactivation occurs during NTZ therapy and leads to an increase in the anti-JCV antibodies titre, thus making them more easily detectable by the second-generation ELISA test.
Reduction in peripheral blood lymphocytes is an expected pharmacodynamic outcome of fingolimod therapy.
The objective of this article is to evaluate lymphocyte dynamics during and after fingolimod therapy and assess the relationship between lymphocyte counts and infections.
Lymphocyte counts and their relationship with infections were evaluated in three multiple sclerosis (MS) populations: (Group A) FREEDOMS phase 3 core study group (n = 1272); (Group B) All Studies group (one phase 2 and two phase 3 studies, plus their extensions; n = 2315); and (Group C) Follow-up group (after fingolimod discontinuation; n = 538).
Administration of fingolimod 0.5 mg led to reductions in lymphocyte counts to a steady-state of 24%–30% of baseline values within two weeks, which remained stable while on therapy. Following fingolimod discontinuation, average counts exceeded the lower limit of normal range within six to eight weeks, and were 80% of baseline values by three months. In Group A, infection rates per patient-year were 1.4 with placebo and 1.0 in fingolimod-treated patients who had the lowest lymphocyte counts (< 0.2 x 109/l). No evidence was seen for an increase in serious or opportunistic infections.
Fingolimod induces a rapid and reversible reduction in lymphocyte counts without an increase in infections relative to placebo. Because fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient.
Neutralizing antibodies (NAbs) to interferon β (IFNβ) products that develop during treatment are associated with a loss of clinical efficacy.
The aim of this study was to investigate the influence of smoking habits on the risk of developing NAbs to IFNβ, in the treatment of multiple sclerosis (MS).
This report is based on 695 MS patients treated with IFNβ-1a, included in two Swedish case-control studies that collected information on smoking habits. Using logistic regression, the development of NAbs to IFNβ-1a among current smokers was compared with that of non-smokers, by calculating the odds ratio (OR) with a 95% confidence interval (CI).
Current smokers showed an increased risk of developing NAbs to IFNβ-1a, compared with non-smokers (OR 1.9; 95% CI 1.3–2.8; p = 0.002). There were no gender differences. We observed no association between past smoking and the risk of developing NAbs to IFNβ-1a.
The finding that current smokers have an increased risk of developing NAbs to IFNβ-1a has implications, both for the practical care and the treatment of MS; it also provides an interesting perspective of the lungs as an immune-reactive organ, reacting upon irritation.
Multiple sclerosis (MS) is characterised by inflammatory lesions of the central nervous system. Interferon beta-1b (IFNB-1b) has been shown to improve clinical and magnetic resonance imaging (MRI) measures for patients with MS.
To evaluate whether IFNB-1b in patients presenting with clinically isolated syndromes (CIS) prevented persisting T1 hypointensities on MRI (persistent black holes (PBHs)).
In the placebo-controlled phase, patients (n = 468) were initially randomised to IFNB-1b (n = 292) or placebo (n = 176) for two years or clinically definite MS (CDMS). In the open-label phase (n = 418), both groups were offered IFNB-1b for up to five years. Lesions were classified as PBHs if T1 hypointensity persisted throughout the last available scan (minimum time one year).
A total of 435 patients were evaluable for analysis. The number of PBHs/patient was lower in the early rather than the delayed treatment arm during both phases (.42 vs .71, p = .0102 and .70 vs 1.17, p = .0121). Exploratory analyses identified baseline characteristics that affected rate of conversion.
Although the rate of lesions that converted to PBH showed no significant differences between groups, the numbers of PBHs per patient out of new lesions was significantly lower in IFNB-1b patients compared to patients on placebo. Trial registration number: NCT00544037.
Deep gray matter lesions have been reported in patients with acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), and neuromyelitis optica (NMO).
The purpose of this study was to compare the features of deep gray matter lesions on magnetic resonance imaging (MRI) among adult patients with ADEM, MS, and NMO.
Ninety-five adult patients with ADEM (n=12), MS (n=60), and NMO (n=23) who had deep gray matter lesions on MRI were enrolled. Morphological features of deep gray matter lesions among these patients were assessed.
Putamen involvement was more common in patients with ADEM than in patients with MS and NMO. Differing from children, thalamus involvement might not be helpful in differentiating ADEM from MS in adults. Hypothalamus involvement was more common in patients with NMO than in patients with ADEM and MS. More importantly, bilateral hypothalamus involvement was more helpful in differentiating NMO from MS. The diameter of the thalamus lesions in patients with ADEM was larger than that in patients with NMO.
Morphological features of deep gray matter lesions vary among adult patients with ADEM, MS, and NMO, and may be helpful in distinguishing these diseases.
Risk factors for multiple sclerosis (MS) include human leukocyte antigen (HLA)-DR and Epstein-Barr virus (EBV)-specific antibody responses, including an epitope within EBV nuclear antigen 1 (EBNA-1) that is of recent interest.
The objective of this paper is to assess case-control associations between MS risk and anti-EBV antibody levels as well as HLA-DR profiles, gender and age in a population-based cohort.
Serological responses to EBV were measured in 426 MS patients and 186 healthy controls. HLA-DR typing was performed using sequence-based methods.
MS patients had significantly higher levels of antibodies against epitope-specific and polyspecific EBNA-1 and viral capsid antigen (VCA), compared with controls (all p < 10–15). In regression analyses, anti-EBNA-1 and anti-VCA antibody levels, protective HLA-DR*04/07/09 alleles and gender (all p < 0.003) contributed independently to a model that classified cases and controls with an odds ratio > 20 (sensitivity 92%, specificity 64%). Notably, the strong influence of high-risk HLA-DR alleles was abrogated after inclusion of EBV serology results.
The ability to discriminate MS cases and controls can be substantially enhanced by including anti-EBV serology as well as HLA-DR risk profiles. These findings support the relevance of EBV-specific immunity in MS pathogenesis, and implicate both HLA-dependent and HLA-independent immune responses against EBNA-1 as prominent disease risk factors.
Chronic inflammation leads to gray matter damage in progressive multiple sclerosis (MS), but the mechanism linking inflammation and neurodegeneration is unclear.
The objective of this paper is to investigate the synaptic mechanism of inflammatory neurodegeneration in progressive forms of MS.
Cytokine and neurofilament-light were determined in cerebrospinal fluid (CSF) of MS patients. In vitro electrophysiology and cell swelling experiments were performed to measure the effects of inflammatory cytokines in the CSF of MS patients on synaptic transmission and neuronal integrity.
Tumor necrosis factor-α (TNF) was higher in CSF of progressive MS subjects, and caused excitotoxic neuronal death in vitro. In murine brain slices incubated in the presence of CSF from progressive MS, in fact, we observed increased spontaneous excitatory postsynaptic currents (sEPSCs) and glutamate-mediated neuronal swelling through a mechanism dependent on enhanced TNF signaling. We also suggested a pathogenic role of B cells in TNF CSF increase, exacerbation of glutamatergic transmission and neuronal damage, since CNS depletion of B cells with intrathecal rituximab caused a dramatic reduction of TNF levels, of TNF-induced sEPSC alterations, and of neurofilament CSF concentrations in a patient with progressive MS.
Our results point to TNF as a primary neurotoxic molecule in progressive forms of MS.
Possible associations between childbearing patterns and multiple sclerosis (MS) risk have been studied for a long time, with conflicting results. We aimed to investigate the influence of reproductive history on MS risk.
Using a Swedish population-based case-control study involving incident cases of MS (1798 cases, 3907 controls), we calculated odds ratios (OR) for MS comparing parents with childless subjects together with 95% confidence intervals (CI) employing logistic regression.
Overall, there was an association between having children and reduced MS risk among both sexes. Subjects who had become parents within five years prior to the index year had a substantially reduced risk of developing MS (OR 0.6, 95% CI 0.5–0.8 for women, and OR 0.4, 95% CI 0.3–0.6 for men). No association between having children and MS risk was observed when more than 10 years had passed since the birth of the last child. We found no association between increasing offspring number and MS risk.
The observed association between reproductive history and MS risk is restricted to a limited time period preceding the index year, with similar findings in both sexes, which contradicts biologic impact of pregnancy on MS risk and argues in favor of reverse causality, i.e. that fecundity is affected by yet-undiagnosed MS.
The modulating effects of the multiple sclerosis (MS) risk-associated single-nucleotide polymorphisms (SNPs) on MS clinical course are not well established.
The objective of this paper is to investigate whether known MS risk-associated SNPs were associated with clinical course, and whether these SNPs modified the 25(OH)D-relapse association.
Using a prospective cohort of 141 participants with relapsing–remitting MS and genotype data followed between 2002 and 2005, genotype-vitamin D interactions and the genetic predictors of relapse were assessed using survival analysis, and genetic predictors of 25(OH)D and disability progression were evaluated by multilevel mixed-effects linear regression.
While no SNP reached statistical significance after multiple testing, five SNPs were associated with relapse, with significant cumulative genotype risk effects and two demonstrated significant allele dose-response. Two SNPs altered the 25(OH)D-relapse association with significant allele dose-response. Five SNPs modified levels of 25(OH)D, with significant cumulative genotype ‘risk’ effect, and three demonstrated significant allele dose-response. We found no consistent evidence for an association between any SNPs and disability.
Our study provides evidence for an association between known MS risk-associated SNPs and relapse. Our findings indicate gene-environment interactions may be an important mechanism on MS clinical course, and provide support for the role of vitamin D in MS relapse.
Several viruses were reported as co-factors triggering the pathogenesis of multiple sclerosis (MS), including the endogenous retroviruses of the HERV-W family, that were also proposed as biomarkers of disease progression and therapy outcome.
The objective of this article is to clarify whether in MS patients treatment with natalizumab has effects on MSRV/syncytin-1/HERV-W expression and the possible relationship with disease outcome.
Peripheral blood mononuclear cells were collected from 22 patients with relapsing–remitting disease, at entry and after three, six and 12 months of treatment with natalizumab. The cell subpopulations and the expression of MSRVenv/syncytin-1/HERV-Wenv were analyzed by flow cytometry and by discriminatory env-specific RT-PCR assays.
By flow cytometry the relative amounts of T, NK and monocyte subpopulations were shown to remain fairly constant. A relative increase of B lymphocytes was observed at three to six months (p = 0.033). The MSRVenv and syncitin-1 transcripts were reduced at six to 12 months of therapy (p = 0.0001). Accordingly, at month 12, the plasma-membrane levels of the HERV-Wenv protein were reduced (p = 0.0001). B cells, NK and monocytes but not T cells expressed the HERV-Wenv protein. None of the patients relapsed during therapy.
Effective therapy with natalizumab downregulates MSRV/syncytin-1/HERV-W expression.
The accrual of brain focal pathology is considered a good substrate of disability in relapsing–remitting multiple sclerosis (RRMS). However, knowledge on long-term lesion evolution and its relationship with disability progression is poor.
The objective of this paper is to evaluate in RRMS the long-term clinical relevance of brain lesion evolution.
In 58 RRMS patients we acquired, using the same scanner and protocol, brain magnetic resonance imaging (MRI) at baseline and 10±0.5 years later. MRI data were correlated with disability changes as measured by the Expanded Disability Status Scale (EDSS).
The annualized 10-year lesion volume (LV) growth was +0.25±0.5 cm3 (+6.7±8.7%) for T2-weighted (T2-W) lesions and +0.20±0.31 cm3 (+11.5±12.3%) for T1-weighted (T1-W) lesions. The univariate analysis showed moderate correlations between baseline MRI measures and EDSS at 10 years (p < 0.001). Also, 10-year EDSS worsening correlated with LV growth and the number of new/enlarging lesions measured over the same period (p < 0.005). In the stepwise multiple regression analysis, EDSS worsening over 10 years was best correlated with the combination of baseline T1-W lesion count and increasing T1-W LV (R = 0.61, p < 0.001).
In RRMS patients, long-term brain lesion accrual is associated with worsening in clinical disability. This is particularly true for hypointense, destructive lesions.
Chronic cerebrospinal venous insufficiency (CCSVI) was implicated in the pathophysiology of multiple sclerosis (MS).
We evaluated neurosonography (NS), magnetic resonance venography (MRV), and transluminal venography (TLV) in subsets of MS patients drawn from a single-center, prospective, case-control study of 206 MS and 70 non-MS volunteers.
As previously reported, findings on high-resolution B-mode NS imaging with color and spectral Doppler of the extracranial and intracranial venous drainage consistent with CCSVI were similar among MS and non-MS volunteers (3.88% vs 7.14%; p = 0.266). Ninety-nine MS participants consented to intravascular contrast-enhanced 3D MRV to assess their major systemic and intracranial venous circulation, and 40 advanced to TLV that included pressure measurements of the superior vena cava, internal jugular, brachiocephalic, and azygous veins.
NS findings and MRV patterns were discrepant for 26/98 evaluable subjects, including four with abnormal findings on NS that had normal venous anatomy by MRV. In no instance were TLV pressure gradients indicative of clinically significant functional stenosis encountered. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties.
Our findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process.
Degeneration of central nervous system normal appearing white matter (NAWM) underlies disability and progression in multiple sclerosis (MS). Axon loss typifies NAWM degeneration.
The objective of this paper is to assess correlation between cortical lesion load and magnetisation transfer ratio (MTR) of the NAWM in MS. This was in order to test the hypothesis that cortical lesions cause NAWM degeneration.
Nineteen patients with MS underwent 7 Tesla magnetisation-prepared-rapid-acquisition-gradient-echo (MPRAGE), and magnetisation transfer ratio (MTR) brain magnetic resonance imaging (MRI). Cortical lesions were identified using MPRAGE and MTR images of cortical ribbons. White matter lesions (WMLs) were segmented using MPRAGE images. WML maps were subtracted from white matter volumes to produce NAWM masks. Pearson correlation was calculated for NAWM MTR vs cortical lesion load, and WML volumes.
Cortical lesion volumes and counts all had significant correlation with NAWM mean MTR. The strongest correlation was with cortical lesion volumes obtained using MTR images (r = –0.6874, p = 0.0006). WML volume had no significant correlation with NAWM mean MTR (r = –0.08706, p = 0.3615).
Our findings are consistent with the hypothesis that cortical lesions cause NAWM degeneration. This implicates cortical lesions in the pathogenesis of NAWM axon loss, which underpins long-term disability and progression in MS.
Progenitor cells from the subventricular zone (SVZ) of the lateral ventricles are assumed to contribute to remyelination and resolution of black holes (BHs) in multiple sclerosis (MS). This process may depend on the distance between the lesion and the SVZ.
The objective of this paper is to investigate the relationship between lesion-to-ventricle (LV) distance and persistence of new BHs.
We analysed the magnetic resonance images (MRIs) of 289 relapsing–remitting (RR) MS patients, obtained during a multi-centre, placebo-controlled phase II trial over one year.
Overall, 112/289 patients showed 367 new BHs at the beginning of the trial. Of these, 225 were located in 94/112 patients at the level of the lateral ventricles on axial MRIs and included in this analysis. In total, 86/225 (38%) BHs persisted at month 12. LV distance in persistent BHs (PBHs) was not longer than in transient BHs. In fact PBHs tended to be closer to the SVZ than transient BHs. A generalised linear mixed multivariate model adjusted for BHs clustered within a patient and including patient- as well as lesion-specific factors revealed size, ring contrast enhancement, and shorter LV distance as independent predictors for BH persistence.
Location of BHs close to the lateral ventricles does not appear to favourably influence the resolution of new BHs in RRMS.
The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of multiple sclerosis (MS) patients.
A total of 241 relapsing–remitting (RR) MS patients were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4.
We concluded that conversion from RR to SP (OR 0.79; CI 0.7–0.9), progression of EDSS (OR 0.85; CI 0.77–0.93), achievement of EDSS 4 (OR 0.8; CI 0.7–0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82–0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9–4.36), (OR 2.7; CI 1.7–4.2), (HR 3.86; CI 1.94–7.70)).
BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients with a relatively long and mild disease.
MicroRNAs (miRNAs) are short, noncoding RNAs with gene regulatory functions whose expression profiles may serve as disease biomarkers.
The objective of this study was to perform a comprehensive analysis of miRNA expression profiles in blood of patients with a clinically isolated syndrome (CIS) or relapsing–remitting multiple sclerosis (RRMS) including next-generation sequencing (NGS).
miRNA expression was analyzed in whole blood samples from treatment-naïve patients with CIS (n = 25) or RRMS (n = 25) and 50 healthy controls by NGS, microarray analysis, and quantitative real-time polymerase chain reaction (qRT-PCR).
In patients with CIS/RRMS, NGS and microarray analysis identified 38 and eight significantly deregulated miRNAs, respectively. Three of these miRNAs were found to be significantly up- (hsa-miR-16-2-3p) or downregulated (hsa-miR-20a-5p, hsa-miR-7-1-3p) by both methods. Another five of the miRNAs significantly deregulated in the NGS screen showed the same direction of regulation in the microarray analysis. qRT-PCR confirmed the direction of regulation for all eight and was significant for three miRNAs.
This study identifies a set of miRNAs deregulated in CIS/RRMS and reconfirms the previously reported underexpression of hsa-miR-20a-5p in MS. hsa-miR-20a-5p and the other validated miRNAs may represent promising candidates for future evaluation as biomarkers for MS and could be of relevance in the pathophysiology of this disease.
Longitudinal magnetic resonance imaging (MRI) studies show that a fraction of the multiple sclerosis (MS) T2-lesions contain T1-hypointense components that may persist to represent severe, irreversible tissue damage. It is not known why certain lesions convert to persistent T1-hypointense lesions.
We hypothesized that the T1-hypointense lesions disproportionately distribute in the more hypoperfused areas of the brain. Here we investigated the association between hypoperfusion and T1-hypointense lesion distributions.
MRI and cerebral blood flow (CBF) data were acquired on 45 multiple sclerosis (MS) patients and 20 healthy controls. CBF maps were generated using pseudo-continuous arterial spin labeling technique. The lesion probability distribution maps were superimposed on the CBF maps.
Two distinct CBF clusters were observed in the white matter (WM) both in healthy controls and MS patients. An overall reduction in CBF was observed in MS patients compared to healthy controls. The majority of the T1-hypointense lesions were concentrated almost exclusively in the WM regions with lower CBF. The T2-hyperintense lesions were more generally distributed in both higher and lower perfused WM.
This study suggests an association between hypoperfusion and T1-hypointense lesions.
Conventional magnetic resonance imaging (MRI) methods do not quantify the severity of multiple sclerosis (MS) white matter lesions or measure pathology within normal-appearing white matter (NAWM).
Gradient Echo Plural Contrast Imaging (GEPCI), a fast MRI technique producing inherently co-registered images for qualitative and quantitative assessment of MS, was used to 1) correlate with disability; 2) distinguish clinical MS subtypes; 3) determine prevalence of veins co-localized within lesions in WM.
Thirty subjects representing relapsing–remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) subtypes were scanned with clinical and GEPCI protocols. Standard measures of physical disability and cognition were correlated with magnetic resonance metrics. Lesions with central veins were counted for RRMS subjects.
Tissue damage load (TDL-GEPCI) and lesion load (LL-GEPCI) derived with GEPCI correlated better with MS functional composite (MSFC) measures and most other neurologic measures than lesion load derived with FLAIR (LL-FLAIR). GEPCI correctly classified clinical subtypes in 70% subjects. A central vein could be identified in 76% of WM lesions in RRMS subjects on GEPCI T2*-SWI images.
GEPCI lesion metrics correlated better with neurologic disability than lesion load derived using FLAIR imaging, and showed promise in classifying clinical subtypes of MS. These improvements are likely attributable to the ability of GEPCI to quantify tissue damage.
Growing evidence suggests that vitamin D deficiency may be one of the most important environmental factors for the development of multiple sclerosis (MS).
The objectives of this paper are to evaluate serum 25-hydroxyvitamin D (25(OH)D) levels in patients with clinically isolated syndromes (CIS) and to examine whether they are related to MS risk.
This is a retrospective study of 100 CIS patients hospitalized from 2000 to 2009 at San Raffaele Hospital, Milan, Italy. We evaluated baseline 25(OH)D level as well as clinical, brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data.
A total of 52% of CIS patients had vitamin D deficiency (25(OH)D < 50 nmol/l). During follow-up (median: 7.17 years), 55 patients developed clinically definite MS (CDMS). Patients with very low (< 10th percentile) and low (< 25th percentile) 25(OH)D levels were particularly at risk of CDMS (HRs (95% CIs): 2.12 (0.91–4.96) and 1.61 (0.85–3.03), respectively), while no further reduction in the HRs of disease was observed at high levels of 25(OH)D. This association was even stronger after adjustment for additional risk factors for CDMS development (HRs (95% CIs) for 25(OH)D levels < 10th and 25th percentiles: 3.34 (1.32–8.45) and 2.04 (0.96–4.36), respectively).
Low serum vitamin D is associated with increased MS risk in patients with CIS.
The objective of this paper is to explore differences in resting-state functional connectivity between cognitively impaired and preserved multiple sclerosis (MS) patients.
Sixty MS patients and 18 controls were assessed with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). A global Z score of the BRB-N was obtained and allowed us to classify MS patients as cognitively impaired and cognitively preserved (n = 30 per group). Functional connectivity was assessed by independent component analysis of resting-state networks (RSNs) related to cognition: the default mode network, left and right frontoparietal and salience network. Between-group differences were evaluated and a regression analysis was performed to describe relationships among cognitive status, functional connectivity and radiological variables.
Compared to cognitively preserved patients and healthy controls, cognitively impaired patients showed a lesser degree of functional connectivity in all RSNs explored. Cognitively preserved patients presented less connectivity than the control group in the left frontoparietal network. Global Z scores were positively and negatively correlated with brain parenchymal fraction and lesion volume, respectively.
Decreased cognitive performance is accompanied by reduced resting state functional connectivity and directly related to brain damage. These results support the use of connectivity as a powerful tool to monitor and predict cognitive impairment in MS patients.
Spinal magnetic resonance imaging (MRI) finding of longitudinally extensive spinal cord lesions (LESCL) extending over three vertebral segments and involvements of spinal central gray matter have been reported in patients with neuromyelitis optica (NMO).
We aimed to review spinal MRI findings in NMO and multiple sclerosis (MS), and to determine whether the "bright spotty lesions" (BSLs) are a discriminative finding of NMO.
For this study, 24 consecutive patients with NMO and 34 patients with MS were enrolled. BSLs were defined as very hyperintense spotty lesions on axial T2WI. We also studied the length, distribution, signal homogeneity, size, and presence of contrast-enhanced lesions.
BSLs were more frequently found in patients with NMO (54%) than in those with MS (3%; p < 0.01). LESCL were found in 67% of the NMO patients. BSLs were seen in 63% of the patients without LESCL. BSLs or LESCL were found in 88% of the NMO patients. Inhomogeneous lesions, transversally extensive lesions, and central lesions were more frequently seen in NMO than in MS.
BSLs are a newly defined spinal MRI finding specifically seen in NMO. In combination with LESCL, BSLs can help differentiate patients with NMO from those with MS with higher sensitivity than LESCL alone.
To objectively evaluate the visual function, and the relationship between disability and optic nerve dysfunction, in patients with multiple sclerosis (MS) and optic neuritis (ON), using multifocal visual evoked potentials (mfVEP).
This observational, cross-sectional study assessed 28 consecutive patients with clinically definite MS, according to the McDonald criteria, and 19 age-matched healthy subjects. Disability was recorded using the Expanded Disability Status Scale (EDSS) score. The patients’ mfVEP were compared to their clinical, psychophysical (Humphrey perimetry) and structural (optic coherence tomography (OCT)) diagnostic test data.
We observed a significant agreement between mfVEP amplitude and Humphrey perimetry/OCT in MS-ON eyes, and between mfVEP amplitude and OCT in MS but non-ON eyes. We found significant differences in EDSS score between patients with abnormal and normal mfVEP amplitudes. Abnormal mfVEP amplitude defects (from interocular and monocular probability analysis) were found in 67.9% and 73.7% of the MS-ON and MS-non-ON group eyes, respectively. Delayed mfVEP latencies (interocular and monocular probability analysis) were seen in 70.3% and 73.7% of the MS-ON and MS-non-ON groups, respectively.
We found a significant relationship between mfVEP amplitude and disease severity, as measured by EDSS score, that suggested there is a role for mfVEP amplitude as a functional biomarker of axonal loss in MS.
Diagnostic magnetic resonance imaging (MRI) criteria have not been sufficiently validated in pediatric multiple sclerosis (MS) despite differences in epidemiologic data and clinical disease courses between pediatric and adult MS.
The objective of this paper is to evaluate the diagnostic applicability and validity of the revised McDonald diagnostic criteria 2010 in a large cohort of pediatric-onset MS patients (POMS) and compare them to previously recommended MRI-based classifications. Furthermore, we aimed to investigate the contribution of spinal cord lesions to the revised McDonald criteria 2010.
A cohort of 85 patients with definite MS, age at onset 2.8–18 years, was analyzed in a retrospective multicenter study. Number and regional distribution of T2w and contrast-enhancing T1w lesions at initial and follow-up MRIs were main outcome measures.
In 62% of POMS the initial MRI within four weeks after symptom onset was sufficient to diagnose MS according to the revised McDonald criteria 2010. In a subcohort of patients with spinal MRI at first presentation, 10% reached the dissemination in space (DIS) and dissemination in time (DIT) criteria only by the inclusion of contrast-enhancing spinal lesions.
The revised McDonald criteria 2010 facilitate the diagnosis of POMS already at first presentation. The addition of a spinal cord MRI was helpful only in selected cases.
Involvement of selected central nervous system (CNS) regions has been associated with depression and fatigue in MS. We assessed whether specific regional patterns of lesion distribution and atrophy of the gray (GM) and white matter (WM) are associated with these symptoms in MS.
Brain dual-echo and 3D T1-weighted images were acquired from 123 MS patients (69 depressed (D), 54 non-depressed (nD), 64 fatigued, 59 non-fatigued) and 90 controls. Lesion distribution, GM and WM atrophy were estimated using VBM and SPM8.
Gender, age, disease duration and conventional MRI characteristics did not differ between D-MS and nD-MS patients. Fatigued patients experienced higher EDSS and depression than non-fatigued ones. Lesion distribution and WM atrophy were not related to depression and fatigue. Atrophy of regions in the frontal, parietal and occipital lobes had a combined effect on depression and fatigue. Atrophy of the left middle frontal gyrus and right inferior frontal gyrus were selectively related to depression. No specific pattern of GM atrophy was found to be related to fatigue.
Depression in MS is linked to atrophy of cortical regions located in the bilateral frontal lobes. A distributed pattern of GM atrophy contributes to the concomitant presence of depression and fatigue in these patients.
Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease.
The Magnetic Imaging in MS (MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS.
Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups).
In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability.
Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.
There is preliminary evidence on the positive effects of neuropsychological rehabilitation on cognition in multiple sclerosis (MS), but the generalisability of the findings is limited by methodological problems.
The aim of the present study was to determine the effects of strategy-oriented neuropsychological rehabilitation on MS.
A total of 102 relapsing–remitting MS patients with subjective and objective attentional deficits were randomised into an intervention and a control group. Neuropsychological assessments were performed at baseline, at three months immediately after the intervention, and at six months. Patients in the intervention group received neuropsychological rehabilitation once a week in 60-minute sessions for 13 consecutive weeks. The control group received no intervention.
Neuropsychological rehabilitation including computer-based attention and working memory retraining, psychoeducation, strategy learning and psychological support did not improve cognitive performance but had a positive effect on perceived cognitive deficits. The intervention group perceived significantly fewer deficits than the control group both immediately after the intervention and at six months. The personal rehabilitation goals were also well achieved.
Strategy-oriented neuropsychological rehabilitation did not improve cognitive performance but reduced perceived cognitive deficits in MS.
In multiple sclerosis (MS) regional grey matter (GM) atrophy has been associated with disability progression.
The aim of this study was to compare regional GM volume changes in relapsing–remitting MS (RRMS) patients with progressive and stable disability, using voxel-based morphometry (VBM).
We acquired baseline and 1-year follow-up 3-dimensional (3D) T1-weighted magnetic resonance imaging (MRI) data of RRMS patients, using two 1.5-Tesla scanners. Patients were matched pair-wise with respect to age, gender, disease duration, medication, scanner and baseline Expanded Disability Status Scale (EDSS) into 13 pairs, with either progressive EDSS (≥ 1 point change y-1) or stable EDSS, as well as into 29 pairs with either progressive Multiple Sclerosis Functional Composite (MSFC) at ≥ 0.25% decrease in y-1 in any component, or stable MSFC. We analysed longitudinal regional differences in GM volumes in the progressive and stable EDSS and MSFC groups, respectively, using VBM.
Significant GM volume reductions occurred in the right precuneus, in the progressive EDSS group. Differential between-group effects occurred in the right precuneus and in the postcentral gyrus. Further longitudinal GM volume reductions occurred in the right orbicular gyrus, in the progressive MSFC group, but no between-group differences were observed (non-stationary cluster-wise inference, all Pcorrected < 0.05).
These results suggested a direct association of disability progression and regional GM atrophy in RRMS.
Mitochondrial dysfunction is an established feature of multiple sclerosis (MS). We recently described high levels of mitochondrial DNA (mtDNA) deletions within respiratory enzyme-deficient (lacking mitochondrial respiratory chain complex IV with intact complex II) neurons and choroid plexus epithelial cells in progressive MS.
The objective of this paper is to determine whether respiratory enzyme deficiency and mtDNA deletions in MS were in excess of age-related changes within muscle, which, like neurons, are post-mitotic cells that frequently harbour mtDNA deletions with ageing and in disease.
In progressive MS cases (n=17), known to harbour an excess of mtDNA deletions in the central nervous system (CNS), and controls (n=15), we studied muscle (paraspinal) and explored mitochondria in single fibres. Histochemistry, immunohistochemistry, laser microdissection, real-time polymerase chain reaction (PCR), long-range PCR and sequencing were used to resolve the single muscle fibres.
The percentage of respiratory enzyme-deficient muscle fibres, mtDNA deletion level and percentage of muscle fibres harbouring high levels of mtDNA deletions were not significantly different in MS compared with controls.
Our findings do not provide support to the existence of a diffuse mitochondrial abnormality involving multiple systems in MS. Understanding the cause(s) of the CNS mitochondrial dysfunction in progressive MS remains a research priority.
Magnetic resonance imaging (MRI) can provide in vivo assessment of tissue damage, allowing evaluation of multiple sclerosis (MS) lesion evolution over time – a perspective not obtainable with postmortem histopathology. Relapsing–remitting experimental autoimmune encephalomyelitis (EAE) is an experimental model of MS that can be induced in the common marmoset, a small new world primate, and that causes perivenular white matter (WM) lesions similar to those observed in MS.
Brain lesion development and evolution were studied in vivo and postmortem in four marmosets with EAE through serial T2- and T2*-weighted scans at 7-tesla. Supratentorial WM lesions were identified and characterized.
Of 97 lesions observed, 86 (88%) were clearly perivenular, and 62 (72%) developed around veins that were visible even prior to EAE induction. The perivenular configuration was confirmed by postmortem histopathology. Most affected veins, and their related perivascular Virchow-Robin spaces, passed into the subarachnoid space rather than the ventricles.
As in human MS, the intimate association between small veins and EAE lesions in the marmoset can be studied with serial in vivo MRI. This further strengthens the usefulness of this model for understanding the process of perivenular lesion development and accompanying tissue destruction in MS.
microRNAs (miRNAs) regulate the expression of the genome at the post-transcriptional level. They play a role in autoimmunity and inflammation, and show potential for use as therapeutic targets in many diseases. With the recent detection of miRNAs in body fluids, the possibility for using miRNAs as diagnostic biomarkers has emerged.
We assessed whether miRNAs contribute to the altered immune activation state in relapsing–remitting multiple sclerosis (RRMS) patients and investigated the possible use of miRNAs as diagnostic biomarkers in multiple sclerosis (MS).
We performed global miRNA expression profiling analysis in peripheral blood mononuclear cells (PBMCs) and selected miRNAs were measured in plasma. We detected expression of miRNAs by real-time qPCR and compared results with cytokines related to inflammation and disease activity. Selected miRNAs were analyzed in PBMC subpopulations, after isolating them by magnetic bead separation.
We found that among validated miRNAs, let-7d correlated with the pro-inflammatory cytokine interleukin-1B. The miR-145 was 3-fold up-regulated in MS patients; its possible use as a diagnostic biomarker in PBMCs, plasma and serum was confirmed by ROC-curve analysis (Area under the curve (AUC) 0.785, p = 0.0004; 0.785, p = 0.004; 0.981, P < 0.0001, respectively).
RRMS patients in remission had altered expression of miRNAs. We validated miR-145 as a potential diagnostic biomarker for the diagnosis of MS in blood, plasma and serum.
Currently no valid surrogate marker exists for primary progressive multiple sclerosis (PPMS).
Our aim was to prospectively investigate multimodal evoked potentials (EPs) as markers and predictors of the disease course in PPMS.
Twenty-two PPMS patients were prospectively examined with visual, somatosensory and motor EPs and Expanded Disability Status Scale (EDSS) assessments at baseline (T0) and at six-month intervals over three years. Spearman rank correlation was used to determine the relationship between EP measures and EDSS. The relationship between disease evolution and a numerical score derived from z-transformed EP-latencies (s-EP-Q) and baseline characteristics was further assessed using multivariable linear regression analysis.
s-EP-Q correlated with EDSS score at all points in time in cross-sectional comparison (0.53≤rs ≤0.68; 0.0007≤p≤0.0232) and also longitudinally by trend (rs=0.46, p=0.0740). The s-EP-QT0 correlated with the EDSS score at year 3 (T6) (rs=0.77, p<0.0001). The s-EP-Q changes became statistically significant six months before corresponding changes were seen in the EDSS score. EDSST6 as predicted by EDSST6= –1.027+0.037* age+0.217* s-EP-QT0 + 0.695* EDSST0 correlated with the observed values (rs=0.92, p<0.0001).
Multimodal EPs correlate well with disability in PPMS, and allow some prediction of the disease course over three years. These findings support a role of EPs as surrogate markers in clinical trials in PPMS.
To evaluate whether balance deficit in patients with multiple sclerosis (MS), as assessed with eyes opened (EO) and closed (EC), is associated with damage of different structures of the central nervous system (CNS).
Fifty patients with MS and 20 healthy controls (HCs) underwent static posturography to calculate the body’s center of pressure displacement (COP path) with EO and EC. They were scanned using a 3.0T magnet to obtain PD/T2 and 3D-T1-weighted images of the brain and spinal cord. We determined the mid-sagittal cerebellum area (MSCA) and upper cervical cord cross-sectional area (UCCA). We also measured the patients’ lesion volumes (T2-LVs) on the whole brain and at different infratentorial levels.
MS patients had wider COP paths with both EO and EC (p < 0.001), and lower values in both MSCA (p = 0.01) and UCCA (p = 0.008) than HCs. The COP path with EO was associated with MSCA (Beta = – 0.58; p = 0.004) and T2-LV on middle cerebellar peduncles (Beta = 0.59; p = 0.002). The COP path with EC was associated with UCCA (Beta= – 22.74; p = 0.003) and brainstem T2-LV (Beta = 0.52; p = 0.01).
Balance deficit in MS was related to atrophy of both the cerebellum and spinal cord, but the extent of COP path under the two different conditions (EO or EC) implied different patterns of damage in the CNS.
Magnetic resonance imaging (MRI) criteria play an important role in making an earlier diagnosis of multiple sclerosis (MS) in patients presenting with clinically isolated syndrome.
The objective of this paper is to determine whether MRI criteria may be used to distinguish MS from primary and secondary central nervous system (CNS) vasculitis, lupus, and Sjogren’s syndrome.
MRI criteria were applied retrospectively to images for patients with clinically definite MS (CDMS), primary CNS vasculitis, secondary CNS vasculitis, and autoimmune disorders including systemic lupus erythematosus (SLE) and Sjogren’s syndrome. Classical statistics and Bayesian analyses were performed.
Overall modified Barkhof’s MRI criteria were statistically significant in distinguishing CDMS (60%) from SLE/Sjogren’s syndrome (17%, p = 0.0173) but not in distinguishing CDMS from primary CNS vasculitis (50%, p = 0.7376) or secondary CNS vasculitis (58%, p = 1.0000). Four of the five other MRI criteria tested were demonstrated to be superior to modified Barkhof’s criteria in predicting MS: nine or more T2 lesions (a component of Barkhof’s criteria), one or more ovoid periventricular T2 lesions, one or more perpendicular periventricular T2 lesions, and one or more T2 lesions larger than 6 mm.
MRI criteria, including the modified Barkhof’s criteria, were unsuccessful in distinguishing MS from primary CNS vasculitis or secondary CNS vasculitis and mildly successful in distinguishing MS from SLE/Sjogren’s syndrome.
Suppression of activation of pathogenic CD4+ T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS.
We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease.
CD4+ T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73–92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated.
The secretion of pro-inflammatory cytokines by CD4+ T cells was decreased in the presence of CRYAB in a subset of relapsing–remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Further, there was a correlation for higher levels of miR181a microRNA, a marker upregulated in tolerant CD8+ T cells, in CD4+ T cells of MS patients that displayed suppressed cytokine production (responders).
CRYAB may be capable of suppressing the activation of CD4+ T cells from a subset of RRMS patients who appear to have less disability but similar age and disease duration.
The cerebrospinal (CSF) constitutes a specific immune micro-environment to the central nervous system, thus it may contain specific biomarkers involved in the pathogenesis of multiple sclerosis (MS).
We aimed to study a large array of inflammatory CSF biomarkers in patients with suspected MS to recognize potential early diagnostic markers.
CSF samples were obtained from 115 patients who presented with neurological symptomatology suggestive of MS as follows: clinically isolated syndrome (CIS) = 49, relapsing–remitting multiple sclerosis (RRMS) = 29, and other neurologic disorders (OND) = 37. Protein expression profiles of 30 inflammatory biomarkers were measured by multiplex Luminex bead assay and further analyzed by group comparison statistics, correlation studies and receiver-operating characteristic (ROC) analysis.
Interleukin-12 subunit p40 (IL12p40) demonstrated a significant differential expression pattern between the groups (CIS vs OND: p = 1.17*10–7; RRMS vs OND: p = 4.98*10–5), with higher levels in CIS and RRMS patients. ROC analysis demonstrated excellent diagnostic performance of IL12p40 for discrimination between CIS and OND patients (area under the curve = 0.87 (95% CI 0.78–0.93), p = 0.0001). No associations were found with disease activity or severity measures.
An increased IL12p40 level characterizes the CSF of MS patients and appears to be helpful in identifying CIS and OND patients early in the process of clinical diagnostic assessment.
Two human herpesviruses, human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), have been repeatedly linked to multiple sclerosis (MS).
The aim of this study was to investigate HHV-6 and EBV reactive oligoclonal bands (OCBs), and viral DNA in the intrathecal compartment in MS.
The reactivity of OCBs in cerebrospinal fluid (CSF) for EBV and HHV-6 antigens and stability of virus reactive OCBs over time were studied in a well-characterized MS patient cohort. Associations between virus reactive OCBs and viral DNA in CSF (and any clinical and/or radiological findings) were investigated.
Of patients with MS, 38% had OCBs reactive to either one of the viruses studied, compared to none in the patients with other inflammatory neurological diseases (p=0.005). The banding pattern of virus reactive OCBs remained the same over time. Furthermore, MS patients with viral DNA in CSF had more contrast enhancing lesions (CELs).
The stable presence of herpesvirus reactive OCBs in CSF further strengthens the association of MS with these viruses. The finding that herpesviruses might be linked to the appearance of active lesions warrants investigation of new therapeutic strategies to treat these viruses in MS.
In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression.
The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13).
CSF was obtained from 35 patients with PMS before and after 12–24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays.
The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline.
Our data imply that 12–24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.
Axonal and neuronal damage are widely accepted as key events in the disease course of multiple sclerosis. However, it has been unclear to date at which stage in disease evolution neurodegeneration begins and whether neuronal damage can occur even in the absence of acute inflammatory attacks.
To characterize inner retinal layer changes in patients with clinically isolated syndrome (CIS).
45 patients with CIS and age- and sex-matched healthy controls were investigated using spectral domain optical coherence tomography. Patients’ eyes were stratified into the following categories according to history of optic neuritis (ON): eyes with clinically-diagnosed ON (CIS-ON), eyes with suspected subclinical ON (CIS-SON) as indicated by a visual evoked potential latency of >115ms and eyes unaffected by ON (CIS-NON).
CIS-NON eyes showed significant reduction of ganglion cell- and inner plexiform layer and a topography similar to that of CIS-ON eyes. Seven eyes were characterized as CIS-SON and likewise showed significant retinal layer thinning. The most pronounced thinning was present in CIS-ON eyes.
Our findings indicate that retinal pathology does occur already in CIS. Intraretinal layer segmentation may be an easily applicable, non-invasive method for early detection of retinal pathology in patients unaffected by ON.
Urinary disorders that lead to urological complications are frequent in multiple sclerosis, resulting in diminished quality of life. Urinary management guidelines are scarce and targeted to neuro-urology specialists.
This study aimed to construct and validate an algorithm dedicated to neurologists and general practitioners to facilitate first-line evaluation and treatment of urinary disorders associated with multiple sclerosis.
49 items concerning urological symptom evaluation and therapeutic strategies were derived from literature analysis and evaluated by an expert panel. The Delphi method established consensus between the experts and allowed development of the First-Line Urological Evaluation in Multiple Sclerosis (FLUE-MS) algorithm. Two questions from the Urinary Bothersome Questionnaire in Multiple Sclerosis were included and their validation to verify comprehensiveness and acceptability was also conducted.
Three rounds of expert review obtained consensus of all 49 items and allowed finalisation of the algorithm. Comprehension and acceptability of two Urinary Bothersome Questionnaire in Multiple Sclerosis questions were verified (mean comprehensiveness score: 1.99/2 [99.7% total comprehensiveness], mean acceptability score: 1.99/2 [99.1% complete acceptability]).
The FLUE-MS algorithm was designed for neurologists and general practitioners, enabling identification of ‘red flags’, timely patient referral to specialist neuro-urology units, and appropriate first-line therapy.
Retinal nerve fiber layer (RNFL) loss occurs with multiple sclerosis and after optic neuritis. Vision or RNFL changes at presentation of optic neuritis are not predictive of outcome, but vision loss at 1 month correlates with vision deficits at 6 months. We hypothesized that RFNL thinning at 1 month would predict RNFL loss at 6 months.
We prospectively studied the RNFL by optical coherence tomography (OCT) and scanning laser polarimetry (SLP), and determined the threshold field mean deviation, in 25 subjects with acute optic neuritis over a 6-month period. RNFL values, including the amount of thinning at 1-month, were correlated with 6-month outcome.
Baseline visual performance and RNFL values were similar for eyes grouped by 1 month RNFL thinning. Eyes with 1 month RNFL thinning had greater and significant RNFL thinning at 6 months, for all quadrants by OCT and for the nasal and inferior quadrants by SLP. RNFL thinning by OCT and SLP at 1 month correlated with 6-month OCT (r = 0.58; p = 0.006) and SLP (r = 0.59; p = 0.002) RNFL thinning, respectively.
Early RNFL loss at 1 month was predictive of the RNFL thinning at 6 months, which corroborated the importance of the 1-month time point for predicting the outcome of an optic neuritis attack.
Lifestyle factors prior to a first clinical demyelinating event (FCD), a disorder often preceding the development of clinically definite multiple sclerosis (MS), have not previously been examined in detail. Past tobacco smoking has been consistently associated with MS.
This was a multicentre incident case-control study. Cases (n = 282) were aged 18–59 years with an FCD and resident within one of four Australian centres (from latitudes 27°S to 43°S), from 1 November 2003 to 31 December 2006. Controls (n = 558) were matched to cases on age, sex and study region, without CNS demyelination. Exposures measured included current and past tobacco and marijuana, alcohol and beverage use, physical activity patterns, blood pressure and physical anthropometry.
A history of smoking ever was associated with FCD risk (AOR 1.89 (95%CL 1.82, 3.52)). Marijuana use was not associated with FCD risk after adjusting for confounders such as smoking ever but the estimates were imprecise because of a low prevalence of use. Alcohol consumption was common and not associated with FCD risk. No case-control differences in blood pressure or physical anthropometry were observed.
Past tobacco smoking was positively associated with a risk of FCD but most other lifestyle factors were not. Prevention efforts against type 2 diabetes and cardiovascular disease by increasing physical activity and reducing obesity are unlikely to alter MS incidence, and more targeted campaigns will be required.
Neuropsychological testing requires considerable time, expense, and expertise to administer. These factors can limit patient access. Computerized cognitive testing has been proposed as an alternative.
The objective of this paper is to validate a brief, simple-to-use computer-generated cognitive assessment screening battery for multiple sclerosis (MS) patients that has minimal motor involvement.
A sample of 96 MS patients and 98 healthy controls completed a computer-generated battery that included the Stroop, Symbol Digit Modalities Test (C-SDMT), a two- and four-second visual analog of the Paced Auditory Serial Addition Test (PVSAT-2, PVSAT-4), and simple and choice reaction time tests. The Minimal Assessment of Cognitive Function in MS was used to define cognitive impairment in the MS sample.
Each newly developed test successfully distinguished between cognitively impaired patients and healthy controls as well as cognitively intact patients. A combination of three computerized tests (C-SDMT, PVSAT-2, PVSAT-4) with a mean administration time of 10 minutes had a sensitivity of 82.5% and specificity of 87.5% in detecting cognitive impairment. Good test-retest reliability was obtained for each measure.
Good sensitivity and specificity, brevity, ease of administration, and a limited motor component highlight the feasibility of introducing this computer-generated cognitive screening instrument in a busy MS clinic.
Although multiple sclerosis (MS) often implies substantial disability, there is little knowledge about sick leave and disability pension among MS patients.
The purpose of this study was to estimate the prevalence rates of sick leave and disability pension among MS patients and to explore how socio-demographics are associated with such rates.
The register data of all people who lived in Sweden in 2005 and were 16–64 years old was used to identify 9721 MS patients and matched controls. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and effect modifications were evaluated with Wald X2 tests.
In 2005, 61.7% of the MS patients were on partial or full disability pension compared to 14.2% among the controls. Of the others, 36.8% had ≥1 sick-leave spell for >14 days during that year. Socio-demographics were similarly associated with sick leave and disability pension among MS patients and controls, with the noteworthy exceptions that female gender and immigration status were less potent risk factors in the MS population (p<0.05).
In spite of widespread access to modern health care including disease-modifying drugs, the majority of MS patients of working ages were on a disability pension. Strategies enabling MS patients to retain their footing in the labour market are needed.
Multiple sclerosis (MS) has a major impact on health and is a substantial burden on patients and society. We estimated the annual costs of MS in Australia from individual and societal perspectives using data from the Australian MS Longitudinal Study (AMSLS) and prevalence figures from 2010.
Direct and indirect costs were estimated from a subsample of 712 AMSLS subjects who completed baseline and follow-up economic impact surveys. All costs are in 2010 Australian dollars (AUD).
Annual costs per person with MS were AUD48,945 (95% CI: 45,138 to 52,752). Total costs were AUD1.042 (0.9707 to 1.1227) billion based on a prevalence of 21,283. The largest component was indirect costs due to loss of productivity (48%). Costs increased with increasing disability: AUD36,369, AUD58,890 and AUD65,305 per patient per year for mild, moderate and severe disability, respectively. Total costs of MS to Australian society have increased 58% between 2005 and 2010.
This study confirms that MS imposes a substantial burden on Australian society, particularly impacting on productivity. The burden increases with worsening disability associated with the disease. Investment in interventions that slow progression, as well as resources, services and environments that assist people with MS to retain employment, is supported.
The impact of global and tissue-specific brain atrophy on conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS) is not fully gauged.
We aimed to determine the magnitude and clinical relevance of brain volume dynamics in the first year after a CIS.
We assessed 176 patients with CIS within 3 months of onset, clinically and by conventional magnetic resonance imaging (MRI) scans, at baseline and 1 year after clinical onset. We determined the percentage of brain volume change (PBVC) and the brain parenchymal (BPF), grey matter (GMF) and white matter (WMF) fractions.
The mean follow-up time was 53 months (SD = 16.8): 76 patients (43%) experienced a second attack, 32 (18%) fulfilled MRI-only 2005 McDonald criteria and 68 (39%) remained as CIS. Statistically significant decreases in the volume measures tested were observed in patients with a second attack, for BPF and PBVC; in both MS groups for GMF; whereas in all groups, the WMF was unchanged. Patients with a second attack had larger PBVC decreases (– 0.65% versus + 0.059%; p < 0.001). PBVC decreases below – 0.817% independently predicted shorter times to a second attack.
Global brain and grey matter volume loss occurred within the first year after a CIS; brain volume loss predicted conversion to MS.
Multiple sclerosis (MS) is a progressive disease of the central nervous system that affects cognition. Short-term treatment with interferon-beta-1b (IFN-b-1b) has been shown to have beneficial effects on cognition.
The objective of this paper is to evaluate the effects of IFN-b-1b on cognitive functioning in patients with MS over the course of 16 years.
Sixteen subjects with relapsing–remitting MS participated in the study. Nine of these subjects received IFN-b-1b, while seven received placebo treatment in the pivotal MS trial. After five years, all subjects were switched to IFN-b-1b treatment. At two and four years into the study, all subjects underwent a brief neuropsychological test battery, magnetic resonance imaging (MRI), and neurologic ratings; measures were repeated at 16 years.
Across the total cohort, cognitive functioning remained relatively stable over the course of 16 years. The placebo/IFN-b-b group exhibited increased visual memory performance relative to the IFN-b-1b treatment group, but had a greater decline in verbal memory. Initial MRI lesion load demonstrated a significant, negative correlation with overall cognitive performance at 16 years (p = 0.00).
We conclude that IFN-b-1b has beneficial effects on long-term cognition outcomes in MS.
The objective of this paper is to investigate demographic and disease factors associated with changes in employment role and status in multiple sclerosis (MS).
Questionnaires on current symptoms, employment status and factors associated with changes in employment were sent to a community sample of 566 MS patients.
A total of 221 completed questionnaires were analysed. Of 169 employed at diagnosis, 43.3% had left employment at a mean of 11.9 years after disease onset. Of those still employed, 55% had changed their role or working hours to accommodate symptoms relating to their disease. These patients reported greater fatigue (p = 0.001), pain (p = 0.033) and memory problems (p = 0.038) than those whose employment had remained unaffected. Multinomial logistic regression revealed the factors most strongly predictive of employment status were disability level, years of education, disease duration and fatigue (p = 0.032).
Despite changes to public perceptions and legislative protection over the last 20 years, high rates of MS patients still leave the workforce prematurely, reduce working hours or change employment roles. These data have significant implications when considering social and economic impacts of MS, support the value of employment metrics as long-term outcome measures, and demonstrate the need to improve employment requirements and flexibility of working practices in individuals with MS.
Multiple sclerosis (MS) is associated with high rates of early retirement (ER).
A German cohort of MS patients and healthy control subjects (HCs) were compared cross-sectionally to investigate disease- and non-disease-specific factors that are associated with employment status (ES) in MS and to identify predictors of ES in MS.
A total of 39 ER MS patients, 48 employed MS patients, and 37 HCs completed a brief neuropsychological battery and questionnaires related to depressive symptoms, fatigue, health-related quality of life (HrQoL) and health locus of control (HLC). Neurological disability was assessed by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC).
ER compared with employed MS patients scored significantly higher in neurological disability, depressive symptoms and fatigue and significantly lower in cognitive functioning and HrQoL. Further, both groups differed with regard to age, education, disease course and duration but not in HLC. Neurological disability, age and fatigue were identified as significant predictors of ES in MS.
ES in MS was associated with demographic aspects, neurological and cognitive status, depressive symptoms, fatigue and HrQoL but was not associated with HLC. Findings confirm neurological disability, age and fatigue as independent predictors of ES in MS.
People with multiple sclerosis (MS) experience frequent falls, which are associated with impairments and limitations to activities and participations.
The objective of this paper is to evaluate falls risk factors using robust clinical measures.
A total of 150 individuals (confirmed MS diagnosis, Expanded Disability Status Scale (EDSS) 3.5–6.5) were recruited, with 148 participants included in the final analysis. Demographic data were collected and performance assessed in eight predictor measures (Physiological Profile Assessment (PPA), Brief Ataxia Rating scale, Ashworth scale (Ashworth), Modified Falls Efficacy scale, Symbol Digit Modalities Test, dual-task interference, lying/standing blood pressure, static/dynamic visual acuity). Participants prospectively recorded falls over three months using a daily diary. People were classified as "fallers" based on reports of ≥ two falls.
A total of 104 participants recorded 672 falls; 78 (52.7%) reported ≥ two falls. Continence issues, previous falls history and use of prescribed medications were each associated with increased risk of being a "faller". Ashworth and PPA risk score contributed significantly to a logistic regression model predicting faller/non-faller classification. The reduced model (Ashworth, PPA, EDSS) showed fair-to-good predictive ability (ROC c-statistic 0.73, sensitivity 70%, specificity 69%).
This study confirms the high prevalence of falls in ambulant people with MS. Important potentially modifiable risk factors are identified, suggesting aspects to target in falls interventions.
Multiple sclerosis (MS) patients are predisposed to thyroid abnormalities, but the risk for pregnancy-related thyroid pathology among MS patients has not been evaluated.
The objectives of this research are to prospectively evaluate the prevalence of thyroid autoimmunity among MS patients in relation to pregnancy, and to investigate its impact on pregnancy outcome, postpartum depression and fatigue.
Forty-six pregnant MS patients underwent repeat testing for serum thyroid antibodies (Abs), clinical evaluation and thyroid hormone measurement. Results were compared to 35 age-matched healthy mothers.
At six months postpartum 35.3% of MS patients presented elevated levels of thyroid Abs compared to 5.7% of controls, p = 0.01. Mean thyroid Ab concentrations among MS patients were significantly reduced during pregnancy and returned to maximal levels at six months postpartum. The proportion of individuals with postpartum thyroid dysfunction did not differ significantly between MS patients and healthy controls (3.4% vs 2.9%, p = 1.00). Elevated thyroid Ab levels did not increase the risk for adverse pregnancy outcome, fatigue or postpartum depression.
Considering the tendency of MS mothers to develop thyroid autoimmunity postpartum and in association to treatments, we recommend screening MS patients for thyroid dysfunction (TSH) during early pregnancy and after delivery.
It has been previously shown that CB1 cannabinoid receptor agonism using cannabis extracts alleviates spasticity in both a mouse experimental autoimmune encephalomyelitis (EAE) model and multiple sclerosis (MS) in humans. However, this action can be associated with dose-limiting side effects.
We hypothesised that blockade of anandamide (endocannabinoid) degradation would inhibit spasticity, whilst avoiding overt cannabimimetic effects.
Spasticity eventually developed following the induction of EAE in either wild-type or congenic fatty acid amide hydrolase (FAAH)-deficient Biozzi ABH mice. These animals were treated with a variety of different FAAH inhibitors and the effect on the degree of limb stiffness was assessed using a strain gauge.
Control of spasticity was achieved using FAAH inhibitors CAY100400, CAY100402 and URB597, which was sustained following repeated administrations. Therapeutic activity occurred in the absence of overt cannabimimetic effects. Importantly, the therapeutic value of the target could be definitively validated as the treatment activity was lost in FAAH-deficient mice. Spasticity was also controlled by a selective monoacyl glycerol lipase inhibitor, JZL184.
This study demonstrates definitively that FAAH inhibitors provide a new class of anti-spastic agents that may have utility in treating spasticity in MS and avoid the dose-limiting side effects associated with cannabis use.
Acute disseminated encephalomyelitis (ADEM) and relapsing–remitting multiple sclerosis (RRMS) share overlapping clinical, radiologic and laboratory features at onset. Because autoantibodies may contribute to the pathogenesis of both diseases, we sought to identify autoantibody biomarkers that are capable of distinguishing them.
We used custom antigen arrays to profile anti-myelin-peptide autoantibodies in sera derived from individuals with pediatric ADEM (n = 15), pediatric multiple sclerosis (Ped MS; n = 11) and adult MS (n = 15). Using isotype-specific secondary antibodies, we profiled both IgG and IgM reactivities. We used Statistical Analysis of Microarrays software to confirm the differences in autoantibody reactivity profiles between ADEM and MS samples. We used Prediction Analysis of Microarrays software to generate and validate prediction algorithms, based on the autoantibody reactivity profiles.
ADEM was characterized by IgG autoantibodies targeting epitopes derived from myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein, and alpha-B-crystallin. In contrast, MS was characterized by IgM autoantibodies targeting myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein and oligodendrocyte-specific protein. We generated and validated prediction algorithms that distinguish ADEM serum (sensitivity 62–86%; specificity 56–79%) from MS serum (sensitivity 40–87%; specificity 62–86%) on the basis of combined IgG and IgM anti-myelin autoantibody reactivity to a small number of myelin peptides.
Combined profiles of serum IgG and IgM autoantibodies identified myelin antigens that may be useful for distinguishing MS from ADEM. Further studies are required to establish clinical utility. Further biological assays are required to delineate the pathogenic potential of these antibodies.
Clinical intuition suggests that a sharp increase in the number of enhancing lesions should signal an increased risk of relapse. The ‘rule of five’ recommends that subjects exhibiting at least five lesions over the baseline level be referred for closer monitoring. This rule has been used as an informal safety criterion with limited formal evaluation.
The purpose of this study was to determine the best threshold for the rule and to demonstrate its predictive validity for risk of subsequent relapses for multiple sclerosis (MS) trials.
We used logistic regression modeling to apply the rule to patient data from a phase II clinical trial. Predictive validity was ascertained using rate ratios and receiver operating characteristic (ROC) curves.
We found that, for these data, a threshold of five lesions over the baseline constituted the best definition of a threshold. Overall, 35% of subjects broke the rule at least once. Breaking the rule increased the odds of imminent relapse by a factor of 3.2 (95% confidence interval (CI): 1.8–5.5).
Breaking the rule of five was found to be a significant predictor of an imminent relapse. Length of follow-up and the number of lesions discovered via magnetic resonance imaging (MRI) were also significant predictors of relapse.
Assessing walking impairment in those with multiple sclerosis (MS) is common, however little is known about the reliability, precision and clinically important change of walking outcomes.
The purpose of this study was to determine the reliability, precision and clinically important change of the Timed 25-Foot Walk (T25FW), Six-Minute Walk (6MW), Multiple Sclerosis Walking Scale-12 (MSWS-12) and accelerometry.
Data were collected from 82 persons with MS at two time points, six months apart. Analyses were undertaken for the whole sample and stratified based on disability level and usage of walking aids. Intraclass correlation coefficient (ICC) analyses established reliability: standard error of measurement (SEM) and coefficient of variation (CV) determined precision; and minimal detectable change (MDC) defined clinically important change.
All outcome measures were reliable with precision and MDC varying between measures in the whole sample: T25FW: ICC=0.991; SEM=1 s; CV=6.2%; MDC=2.7 s (36%), 6MW: ICC=0.959; SEM=32 m; CV=6.2%; MDC=88 m (20%), MSWS-12: ICC=0.927; SEM=8; CV=27%; MDC=22 (53%), accelerometry counts/day: ICC=0.883; SEM=28450; CV=17%; MDC=78860 (52%), accelerometry steps/day: ICC=0.907; SEM=726; CV=16%; MDC=2011 (45%). Variation in these estimates was seen based on disability level and walking aid.
The reliability of these outcomes is good and falls within acceptable ranges. Precision and clinically important change estimates provide guidelines for interpreting these outcomes in clinical and research settings.
The purpose of this study was to determine the prevalence of multiple sclerosis (MS) in Australia in 2010 using a novel method based on Australia-wide prescription data for MS-specific disease modifying agents. The results obtained were validated against two other prevalence estimates.
We obtained the total number of scripts for medications that were used exclusively for the treatment of MS written in Australia for the period January–December 2010. The percentage of MS patients using medications (42–55%) was taken from state-specific surveys of MS Society clients. To estimate prevalence we divided the annual number of scripts dispensed by 12 and adjusted for penetration of medications by state.
The prevalence of MS in Australia in 2010 calculated using the prescription method was 21,283 people (95.5/100,000). This compared to 21,200 people (95.2/100,000) obtained from the Australian Bureau of Statistics (ABS) Survey of Disability, Ageing and Carers (SDAC) survey of 2009 and 20,471 people (91.9/100,000) using MS Society client numbers. Prevalence increased with increasing latitude, with the prevalence for Tasmania over seven times that of the Northern Territory. Results were sensitive to the percentage of people with MS being treated.
Calculation of prevalence of MS using nation-wide prescription data is a novel method that generates results similar to other potentially more resource-intensive methods.
The risk of multiple sclerosis (MS) is dependent on multiple variables, including geographical location. There is increasing interest in the early recognition and treatment of MS in children.
Using univariate and multivariate analysis, we determined the clinical and radiological features that were predictive of MS in 88 children from New South Wales, Australia, with a first acute demyelinating syndrome (ADS) who were followed for a minimum of one year. We tested the McDonald, KIDMUS, Callen and Verhey MRI criteria for paediatric MS.
After a mean follow-up of 5.2 years, 13/88 (15%) of children had MS. Using multivariate analysis, preceding infection was protective of MS, and corpus callosal lesions, the combined presence of both well and poorly demarcated lesions, and contrast-enhancing lesions on MRI were predictive of MS. The sensitivity and specificity of the respective radiological criteria were McDonald 2005 (69%, 68%), McDonald 2010 (58%, 95%), KIDMUS (8%, 100%), Callen (69%, 85%) and Verhey (62%, 84%). When McDonald 2010 criteria were applied to baseline and serial scans, the sensitivity and specificity was 91% and 93%.
Despite the long follow-up, the risk of MS appears lower in New South Wales children compared to previously reported cohorts. Radiological features are more predictive than clinical features in predicting MS. The McDonald 2010 criteria performed well although the dissemination in time criteria on baseline scans is difficult to apply to children with encephalopathy.
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.
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.
A two-phase evaluation of the 40-item Fatigue Impact scale (FIS): a qualitative evaluation of content and face validity using expert opinion (n=30) and a modified Delphi technique; a quantitative psychometric evaluation of internal and external construct validity of data from 333 people with multiple sclerosis using traditional and modern methods.
Qualitative evaluation did not support content or face validity of the FIS. Expert opinion agreed with the subscale placement of 23 items (58%), and classified all 40 items as being non-specific to fatigue impact. Nevertheless, standard quantitative psychometric evaluations implied, largely, FIS subscales were reliable and valid.
Standard quantitative ‘psychometric’ evaluations of PRO instrument validity can be misleading. Evaluation of existing PRO instruments requires both qualitative and statistical methods. Development of new PRO instruments requires stronger conceptual underpinning, clearer definitions of the substantive variables for measurement and hypothesis-testing experimental designs.
Optic radiation (OR) damage occurs in multiple sclerosis (MS).
The purpose of this study was to explore the contribution of local and distant mechanisms associated with OR damage in MS.
Diffusion tensor (DT) magnetic resonance imaging (MRI) tractography probability maps of the ORs were derived from 102 MS patients and 11 controls. Between-group differences of OR normal-appearing white matter (NAWM) damage and topographical distribution of OR damage were assessed using quantitative and voxel-wise analyses, considering the influence of previous optic neuritis (ON+) and T2 OR lesions (T2 OR+).
OR NAWM diffusivity abnormalities were more severe in ON+ patients vs patients without previous optic neuritis (ON–) and T2 OR+ vs T2 OR– patients. Damage to the anterior portions of the ORs was more severe in ON+ vs ON– patients. Compared to controls and T2 OR– patients, T2 OR+ patients experienced a more distributed pattern of DT MRI abnormalities along the ORs, with an increased axial diffusivity limited to the anterior portions of the ORs. In T2 OR+ group, ON+ vs ON– patients showed DT MRI abnormalities in the middle portion of the ORs, in correspondence with focal lesions. OR damage correlated with OR T2 lesion volume, visual dysfunction and optic nerve atrophy.
Both trans-synaptic degeneration secondary to optic nerve damage and Wallerian degeneration due to local T2 lesions contribute to OR damage in MS.
Obesity in late adolescence has been associated with an increased risk of multiple sclerosis (MS); however, it is not known if body size in childhood is associated with MS risk.
Using a prospective design we examined whether body mass index (BMI) at ages 7–13 years was associated with MS risk among 302,043 individuals in the Copenhagen School Health Records Register (CSHRR). Linking the CSHRR with the Danish MS registry yielded 774 MS cases (501 girls, 273 boys). We used Cox proportional hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs).
Among girls, at each age 7–13 years, a one-unit increase in BMI z-score was associated with an increased risk of MS (HRage 7=1.20, 95% CI: 1.10–1.30; HRage 13=1.18, 95% CI: 1.08–1.28). Girls who were ≥95th percentile for BMI had a 1.61–1.95-fold increased risk of MS as compared to girls <85th percentile. The associations were attenuated in boys. The pooled HR for a one-unit increase in BMI z-score at age 7 years was 1.17 (95% CI: 1.09–1.26) and at age 13 years was 1.15 (95% CI: 1.07–1.24).
Having a high BMI in early life is a risk factor for MS, but the mechanisms underlying the association remain to be elucidated.
The antibody reactivity against Epstein-Barr nuclear antigen-1 (EBNA-1), and 25-hydroxyvitamin D (25(OH)D) status have been associated with multiple sclerosis (MS) risk. Interaction between these two factors has been proposed.
The objective of this paper is to examine the association between antibody reactivity against EBNA-1 and five EBNA-1 domains, and the risk of MS, and to examine if these antibodies and 25(OH)D status interact regarding MS risk in prospectively collected blood samples.
Antibody reactivity and 25(OH)D levels were measured using ELISAs in n = 192 MS cases and n = 384 matched controls. The risk of MS was analysed using matched logistic regression. Interaction on the additive scale was assessed.
The risk of MS increased across tertiles of antibody reactivity against EBNA-1, domain EBNA-1402–502, and domain EBNA-1385–420; p trends < 0.001. In young individuals (below median age at sampling, < 26.4 years), these associations were stronger, and 25(OH)D levels correlated inversely to antibody reactivity against EBNA-1 and the EBNA-1 domains. No statistical interaction was found.
We confirm that increased antibody reactivity against EBNA-1 is a risk factor of MS. 25(OH)D status might influence the immune response towards Epstein-Barr virus in young subjects, and thereby modulate MS risk.
The G allele of NOTCH4 rs422951 is protective against demyelinating disease in Japanese.
The purpose of this study was to assess the relation of the G allele to neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) and multiple sclerosis (MS) and the interaction between the G allele and HLA-DRB1 alleles, and to clarify any association of the G allele with clinical features.
DNA sequencing was used to genotype 106 NMO/NMOSD patients, 118 MS patients and 152 healthy controls (HCs) for rs422951.
G allele frequency in MS patients, but not that in NMO/NMOSD patients, was lower than that in HCs (8.9% vs 21.7%, p<0.0001, odds ratio (OR)=0.35). HLA-DRB1*0405 was positively associated with MS (OR=2.22, pcorr=0.0380) while DRB1*0901 was negatively associated (OR=0.32, pcorr =0.0114). Logistic regression analyses revealed that, after adjusting for gender and either HLA-DRB1*0405 or DRB1*0901, rs422951 was associated with MS in the dominant model (OR=0.37, 95% confidence interval (CI)= 0.20–0.66, p=0.0012). Haplotype analyses identified two susceptible and three resistant haplotypes formed from rs422951 and either HLA-DRB1*0405 or DRB1*0901. There were no statistically significant differences in clinical features between G allele carriers and non-G allele carriers.
This NOTCH4 missense mutation decreased the risk for developing MS in Japanese, but did not affect clinical features of those who had already developed the disease.
There is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH)).
We evaluated the analytical and clinical performance of the UmanDiagnostics NF-light® enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) of a group of 148 patients with clinically isolated syndrome (CIS) or multiple sclerosis (MS), and 72 controls. We compared our results with referring levels of our previously-developed CSF NfHSMI35 assay.
Exposure to room temperature (up to 8 days) or repetitive thawing (up to 4 thaws) did not influence measurement of NfL concentrations. Values of NfL were higher in all disease stages of CIS/MS, in comparison to controls (p ≤ 0.001). NfL levels correlated with the Expanded Disability Status Scale (EDSS) score in patients with relapsing disease (rs = 0.31; p = 0.002), spinal cord relapses and with CSF markers of acute inflammation. The ability of NfL to distinguish patients from controls was greater than that of NfHSMI35 in both CIS patients (p = 0.001) and all MS stages grouped together (p = 0.035).
NfL proved to be a stable protein, an important prerequisite for a reliable biomarker, and the NF-light® ELISA performed better in discriminating patients from controls, compared with the ECL-NfHSMI35 immunoassay. We confirmed and expanded upon previous findings regarding neurofilaments as quantitative markers of neurodegeneration. Our results further support the role of neurofilaments as a potential surrogate measure for neuroprotective treatment in MS studies.
Determining responsiveness of measures across different samples and settings is important for selecting measures of mobility and understanding multiple sclerosis (MS) study results. Currently such information is limited.
This exploratory study examined the relative responsiveness of four mobility measures (walking velocity, 6-minute walk distance, Rivermead Mobility Index and MS Walking Scale) in a community sample (n = 70), after three annual assessments. Distribution based estimates and anchor-based methods (comparison against transition questions) determined responsiveness. A head-to-head comparison was made.
While variations in individuals occurred, the group mean change scores for all measures was small, suggesting that there was minimal deterioration in the total sample. Consistent with this, total sample Effect Size (ES) was negligible to small (ES –0.32 to +0.03) for all measures. Differentiation between sub-groups, defined by the participants’ perception of change in mobility over the past year (transition questions), showed that some instruments could detect clinically significant changes (small sample sizes limited this interpretation). Correlation analyses between change scores demonstrated that these measures captured related, but different information (r < 0.364).
The measures were broadly comparable in detecting mobility changes in this community sample. These correlations highlight that in selection of measures, one should also consider the discrete mobility dimension that the intervention intends to impact.
Over some 50 years, field surveys have shown that the prevalence of multiple sclerosis (MS) increases with increasing distance from the equator in both the northern and the southern hemispheres. Such a latitudinal gradient has been found in field surveys of MS prevalence carried out at different times in various local regions of Australia.
The objective of this paper is to use a pharmacoepidemiological approach to obtain whole of population estimates of the prevalence of MS in the various Australian states and territories from the use of MS disease-modifying drugs used to treat relapsing–remitting MS (RRMS).
We analysed the dispensed use of subsidised RRMS drugs by jurisdiction.
In the 2005–2008 period, the calculated mean treated RRMS prevalence in Australia ranged from 7.5 per 100,000 in the far north to 53.2 per 100,000 in the extreme south and was linearly related to increasing southerly latitude. Public domain Australian data suggested that multiplying this prevalence by a factor of 2.2 (to account for untreated RRMS and other types of MS) may provide a measure of the prevalence of all varieties of the disease.
These findings provide contemporary and more comprehensive evidence for the gradient of MS prevalence with latitude in Australia than has previously been available.
Surveying volunteer members of a multiple sclerosis registry is a very cost-effective way of assessing the impact of the disease on life outcomes. However, whether the data from such a study can be generalised to the whole population of persons living with MS in a country or region is unclear.
Here we compare the demographic and disease characteristics of participants in one such study, the Australian Multiple Sclerosis Longitudinal Study (AMSLS), with two well-characterised MS prevalence studies with near-complete ascertainment of MS in their study regions.
Although some differences were found, these largely represented the effects of geography (sex ratios) and local factors (national immunomodulatory therapy prescribing requirements), and the cohorts were otherwise comparable. Overall, despite comprising only 12–16% of MS cases in Australia, the AMSLS is highly representative of the MS population.
Therefore with some minor caveats, the AMSLS data can be generalised to the whole Australasian MS population. Volunteer disease registries such as this can be highly representative and provide an excellent convenience sample when studying rare conditions such as MS.
Obtaining and maintaining suitable employment can be a significant challenge for people with multiple sclerosis (MS).
The objective of this article is to identify what vocational rehabilitation (VR) services helped MS clients obtain and maintain employment, after controlling for the effect of demographic covariates and disability-related government benefits.
We retrieved data from the Rehabilitation Services Administration (RSA) 911 database in the fiscal year (FY) 2009, and used VR services as predictors to predict employment outcomes of people with MS by hierarchical logistic regression.
A total of 924 out of 1920 MS clients (48.1%) were successfully employed after receiving VR services. Logistic regression analysis results indicated that cash benefits (OR =0.51, p < 0.001) and public medical benefits (OR =0.76, p < 0.01) were negatively associated with employment outcomes, whereas counseling and guidance (OR = 1.68, p < 0.001), job placement assistance (OR = 2.43, p < 0.001), on-the-job supports (OR = 1.62, p < 0.01), maintenance services (OR = 1.59, p < 0.01), and assistive technology services (OR =2.09, p < 0.001) were significant predictors of positive employment outcomes.
VR services were found to be associated with employment status. MS patients experiencing problems obtaining or maintaining employment should be encouraged to pursue services from state VR agencies.
Vitamin D deficiency is widely prevalent in India. The association between vitamin D status and multiple sclerosis (MS) has not been previously studied in Indians.
The objective of this paper is to determine whether vitamin D status is associated with MS in India.
In this study 110 MS patients and 108 matched controls were included. Serum 25-hydroxyvitamin D (25(OH)D) was measured in 63 patients in relapse, 77 patients in remission and all controls. Quantity of sun exposure in childhood and body mass index (BMI) were calculated. Patients and controls were genotyped for HLA-DRB1*1501.
Patients had significantly lower 25(OH)D levels than matched controls (p = 0.003), and patients in relapse had a significantly lower vitamin D level as compared to those in remission (p = 0.001). Vitamin D deficiency (< 50 nmol/l) was seen in a higher proportion of cases (71.8%) than controls (53.7%) (p = 0.01). Higher quartiles of vitamin D (> 58 nmol/l) showed an inverse relationship with MS (OR = 0.28, CI = 0.11–0.68, p= 0.005). This effect persisted after adjusting for sun exposure.
The results of our study indicated that serum 25(OH)D shows an inverse relationship with MS in the Indian population. Reverse causality cannot be excluded.
Apart from a recent study reporting a 2- to 3-fold increased risk of multiple sclerosis (MS) among women and men who were delivered by Cesarean section (C-section), little attention has been given to the possible association between mode of delivery and the risk of MS.
We studied the association between C-section and risk of MS, in a cohort of 1.7 million Danes born from 1973 to 2005.
Information on C-section and MS was obtained from the Danish Medical Birth Register and the Danish MS Register, respectively. The association between C-section and MS was evaluated by means of MS incidence rate ratios (RR) with 95% confidence intervals (CI) obtained in log-linear Poisson regression analyses.
There were 930 cases of MS in the study cohort, of whom 80 (9%) were delivered by C-section. Overall, we found there was no significant association between C-section and risk of MS (RR = 1.17; 0.92–1.46). Analyses stratified by sex revealed no unusual risk of MS for women (RR = 1.08: 0.80–1.42) nor men (RR = 1.37: 0.91–1.98). A supplementary sibling-matched Cox regression analysis likewise suggested there was no excess risk of MS in persons delivered by C-section (HR = 1.03; 0.63–1.69).
Mode of delivery appears to be unimportant in relation to MS development in the offspring.
The elucidation of mechanistic aspects of relapsing–remitting multiple sclerosis (RRMS) pathogenesis may offer valuable insights into diagnostic decisions and medical treatment.
Two lysosomal proteases, cathepsins S and D (CatS and CatD), display an exclusive pattern of expression in CD34+ hematopoietic stem cells (HSCs) from peripheral blood of acute MS (A-MS) patients (n = 20). While both enzymes normally exist as precursor forms in the HSCs of healthy individuals (n = 30), the same cells from A-MS patients consistently exhibit mature enzymes. Further, mature cathepsins are expressed at lower rates in stable MS subjects (S-MS, n = 15) and revert to precursor proteins after interferon-β1a treatment (n = 5). Mature CatD and CatS were induced in HSCs of healthy donors that were either co-cultured with PBMCs of A-MS patients or exposed to their plasma, suggesting a functional involvement of soluble agents. Following HSC exposure to several cytokines known to be implicated in MS, and based on relative cytokine levels displayed in A-MS, S-MS and control individuals, we identified IL-16 as a specific cell signaling factor associated with cathepsin processing.
These data point to an evident correlation between CatS and CatD expression and MS clinical stage, and define a biochemical trait in HSCs with functional, medical, and diagnostic relevance.
The incidence of multiple sclerosis (MS) in Denmark has doubled in women since 1970, whereas it has been almost unchanged in men.
To investigate whether age at first childbirth and number of births have an effect on the risk of developing MS.
The cohort consisted of 1403 patients with MS of both sexes, identified through the Danish Multiple Sclerosis Registry, with clinical onset between 2000 and 2004. For each case, 25 control persons were drawn by random from the Danish Civil Registration System matched by sex, year of birth, and residential municipality.
More female cases than controls had no childbirths or fewer births before clinical onset (p=0.018) but only in the last five years preceding onset (p<0.0001). Childbirths within five years before clinical onset reduced the risk of MS onset in women: OR=0.54 (95% CI 0.41–0.70, p<0.0001) for one child and OR=0.68 (95% CI 0.53–0.87, p=0.002) for more than one child. Parental age at first childbirth had no effect on the risk of MS.
The data did not suggest reversed causality between childbirth and MS.
In MS, the relationship between lesions within cerebral white matter (WM) and atrophy within deep gray matter (GM) is unclear.
To investigate the spatial relationship between WM lesions and deep GM atrophy.
We performed a cross-sectional structural magnetic resonance imaging (MRI) study (3 Tesla) in 249 patients with clinically-isolated syndrome or relapsing–remitting MS (Expanded Disability Status Scale score: median, 1.0; range, 0–4) and in 49 healthy controls. Preprocessing of T1-weighted and fluid-attenuated T2-weighted images resulted in normalized GM images and WM lesion probability maps. We performed two voxel-wise analyses: 1. We localized GM atrophy and confirmed that it is most pronounced within deep GM; 2. We searched for a spatial relationship between WM lesions and deep GM atrophy; to this end we analyzed WM lesion probability maps by voxel-wise multiple regression, including four variables derived from maxima of regional deep GM atrophy (caudate and pulvinar, each left and right).
Atrophy of each deep GM region was explained by ipsilateral WM lesion probability, in the area most densely connected to the respective deep GM region.
We demonstrated that WM lesions and deep GM atrophy are spatially related. Our results are best compatible with the hypothesis that WM lesions contribute to deep GM atrophy through axonal pathology.
Recent studies have shown a decrease in annualised relapse rates (ARRs) in placebo groups of randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS).
We conducted a systematic literature search of RCTs in RMS. Data on eligibility criteria and baseline characteristics were extracted and tested for significant trends over time. A meta-regression was conducted to estimate their contribution to the decrease of trial ARRs over time.
We identified 56 studies. Patient age at baseline (p < 0.001), mean duration of multiple sclerosis (MS) at baseline (p = 0.048), size of treatment groups (p = 0.003), Oxford Quality Scale scores (p = 0.021), and the number of eligibility criteria (p<0.001) increased significantly, whereas pre-trial ARR (p = 0.001), the time span over which pre-trial ARR was calculated (p < 0.001), and the duration of placebo-controlled follow-up (p = 0.006) decreased significantly over time. In meta-regression of trial placebo ARR, the temporal trend was found to be insignificant, with major factors explaining the variation: pre-trial ARR, the number of years used to calculate pre-trial ARR and study duration.
The observed decline in trial ARRs may result from decreasing pre-trial ARRs and a shorter time period over which pre-trial ARRs were calculated. Increasing patient age and duration of illness may also contribute.
The objective of this article is to evaluate in multiple sclerosis (MS) patients the prevalence of persistent complaints of visual disturbances and the mechanisms and resulting functional disability of persistent visual complaints (PVCs).
Firstly, the prevalence of PVCs was calculated in 303 MS patients. MS-related data of patients with or without PVCs were compared. Secondly, 70 patients with PVCs performed an extensive neuro-ophthalmologic assessment and a vision-related quality of life questionnaire, the National Eye Institute Visual Functionary Questionnaire (NEI-VFQ-25).
PVCs were reported in 105 MS patients (34.6%). Patients with PVCs had more frequently primary progressive MS (30.5% vs 13.6%) and more neuro-ophthalmologic relapses (1.97 vs 1.36) than patients without PVCs. In the mechanisms/disability study, an afferent visual and an ocular-motor pathways dysfunction were respectively diagnosed in 41 and 59 patients, mostly related to bilateral optic neuropathy and bilateral internuclear ophthalmoplegia. The NEI-VFQ 25 score was poor and significantly correlated with the number of impaired neuro-ophthalmologic tests.
Our study emphasizes the high prevalence of PVC in MS patients. Regarding the nature of neuro-ophthalmologic deficit, our results suggest that persistent optic neuropathy, as part of the progressive evolution of the disease, is not rare. We also demonstrate that isolated ocular motor dysfunctions induce visual disability in daily life.
Cognitive impairment in multiple sclerosis (MS) primarily applies to information processing speed (IPS).
To evaluate psychometric properties of a new digit/symbol substitution test in healthy subjects and patients with MS, and assess its ability to detect IPS impairment in patients with MS.
A sample of MS patients, 60 relapsing–remitting (RRMS) and 41 primary progressive MS (PPMS), and 415 healthy controls (HCs) underwent an IPS battery, including assessment of reaction times of subtests of the Test of Attentional Performance battery and a newly developed in-house digit/symbol substitution task, the Computerised Speed Cognitive Test (CSCT). The CSCT was additionally evaluated in a second cohort of 31 RRMS and 12 progressive MS patients, for comparison with the Symbol Digit Modalities Test (SDMT).
The CSCT had good reliability in both HCs and patients with MS. It showed a weak practice effect at the 6-month time point. This test had good ecological validity in MS patients. There was a strong correlation between the CSCT with the SDMT and with other IPS tests in patients with MS. The CSCT had the best sensitivity for predicting IPS impairment and was one of the most accurate tests among the IPS battery.
The CSCT appeared as a good candidate for detecting IPS impairment in MS patients.
Gray-matter (GM) atrophy is strongly predictive of cognitive impairment in multiple sclerosis (MS) patients. The thalamus is the region where the atrophy/cognition correlation is most robust. However, few studies have assessed diffusion tensor imaging (DTI) metrics within the thalamus.
This study was designed to determine if thalamus white matter DTI predicts cognitive impairment after accounting for the effects of volume loss.
We enrolled 75 MS patients and 18 healthy controls undergoing 3T brain magnetic resonance imaging (MRI). Thalamus volumes were calculated on 3D T1 images. Voxelwise analyses of DTI metrics were performed within the thalamic white matter tracts. Neuropsychological (NP) testing, acquired using consensus standard methods, contributed measures of memory, cognitive processing speed and executive function.
All cognitive tests were significantly predicted (R2 =0.31, p<0.001) by thalamus volume after accounting for influence of demographics. Mean diffusivity was retained in regression models predicting all cognitive tests, adding from 7–13% of additional explained variance (p<0.02) after accounting for thalamus volume.
We confirm the significant role of thalamus atrophy in MS-associated cognitive disorder, and further report that subtle thalamus pathology as detected by DTI adds incremental explained variance in predicting cognitive impairment.
Alemtuzumab is a monoclonal antibody directed against CD52 that depletes T and B lymphocytes.
To evaluate the treatment effect of alemtuzumab on low-contrast vision in relapsing–remitting multiple sclerosis (RRMS) patients.
This was a pre-defined exploratory analysis within a randomized, rater-blinded trial (CAMMS223) that was run at 49 academic medical centers in the US and in Europe. Patients with untreated, early, RRMS (McDonald, n = 334) were randomized 1:1:1 to subcutaneous interferon beta-1a (IFNB-1a), or alemtuzumab 12 mg or 24 mg. Visual contrast sensitivity was measured for each eye at baseline and quarterly, with Pelli-Robson charts.
The eyes of patients in the pooled alemtuzumab group (versus IFNB-1a) had a greater than 2-fold higher rate of both 3-month and 6-month sustained visual improvement, of at least 0.3 log units (2 triplets, 6 letters) (At 3 months the hazard ratio (HR) = 2.26; CI = 1.19 to 4.31; P = 0.013; and at 6 months the HR = 2.44; CI =1.16 to 5.15; P = 0.019), and they had a lower risk of 3- and 6-month sustained worsening of at least 0.15 log units (1 triplet, 3 letters) (At 3 months the HR = 0.58; CI = 0.38 to 0.89; P = 0.012; and at 6 months HR = 0.55; CI=0.35 to 0.87; P = 0.010). Over the 36-month study period, the eyes of patients in the pooled alemtuzumab group improved in mean contrast sensitivity to a greater extent than those in the IFNB-1a group (0.080 log units versus 0.038 log units; P = 0.0102).
Alemtuzumab was associated with a greater chance of improved contrast sensitivity in patients with RRMS and may delay the worsening of visual function. Contrast sensitivity testing was sensitive to treatment effects, even within an active comparator study design. These results support the validity of low-contrast vision testing as a clinical outcome in MS trials.
Cortical lesions (CLs) have been reported to be a better predictor for cognitive impairment than white matter (WM) lesions in relapsing–remitting multiple sclerosis (RRMS).
The objectives of this article are to investigate the contribution of CLs and WM lesions to cognitive impairment in 91 patients with MS and clinically isolated syndrome, and to test potential associations of CLs and WM lesions with fatigue and depression.
Lesions were scored and segmented on 3D double inversion recovery sequences, according to their location (cortical, WM). Normalised grey matter volume was also determined. Cognitive performance was assessed with the SDMT and PASAT-3, fatigue with the FSMC and depression with the German version of the CES-D.
CL volume did not correlate with fatigue or depression, but correlated significantly with both neuropsychological outcome measures: PASAT-3 (r = –0.275, p = 0.009) and SDMT (r = –0.377, p < 0.001). Multiple regression analyses with age, WM lesions, CLs and GM volume as independent variables, however, did not reveal CL volume as a significant predictor of neuropsychological outcomes, whereas WM lesion volume significantly predicted SDMT and by trend PASAT performance.
These findings suggest a role of WM lesions in the development of cognitive deficits, especially information-processing speed, which may be higher than previously assumed.
CES-D: Center for Epidemiologic Studies Depression scale (ADS-L: Allgemeine Depressions Skala-L, German version of CES-D), CIS: clinically isolated syndrome, CL: cortical lesion, DIR: double inversion recovery, EDSS: Expanded Disability Status Scale, FSMC: fatigue scale for motor and cognitive functions, GM: grey matter, MRI: magnetic resonance imaging, MS: multiple sclerosis, PASAT-3: paced auditory serial addition test 3s, PPMS: primary progressive multiple sclerosis, RRMS: relapsing–remitting multiple sclerosis, SDMT: symbol digit modalities test, SPM: statistical parametric mapping, SPMS: secondary progressive multiple sclerosis, WM: white matter
Mycobacterium avium subspecies paratuberculosis (MAP) is an infectious factor recently found in association with multiple sclerosis (MS) in Sardinia.
The objectives of this study were to confirm this association and evaluate its role in clinical features.
A total of 436 patients and 264 healthy controls (HCs) were included. We examined the blood of each individual for MAPDNA and MAP2694 antibodies using IS900-specific PCR and ELISA, respectively. Differences in MAP presence between the MS group and HCs were evaluated. In MS patients, we considered: gender, age, age at onset, duration of disease, course, EDSS, therapy, relapse/steroids at study time, and oligoclonal bands (OBs).
MAPDNA and MAP2694 antibodies were detected in 68 MS and six HCs (p = 1.14 x 10–11), and 123 MS and 10 HCs (p = 2.59 x 10–23), respectively. OBs were found with reduced frequency in MAP-positive patients (OR = 0.52; p = 0.02). MAP2694 antibodies were detected more in patients receiving MS treatments (OR = 2.26; p = 0.01), and MAPDNA in subjects on steroids (OR = 2.65; p = 0.02).
Our study confirmed the association of MAP and MS in Sardinia. The low OB frequency in MAP patients suggests a peripheral role as a trigger in autoimmunity. MAP positivity might be influenced by steroids and MS therapy. Studies in other populations are needed to confirm the role of MAP in MS.
The purpose of this study was to determine the effects of oral teriflunomide on multiple sclerosis (MS) pathology inferred by magnetic resonance imaging (MRI).
Patients (n=1088) with relapsing MS were randomized to once-daily teriflunomide 7 mg or 14 mg, or placebo, for 108 weeks. MRI was recorded at baseline, 24, 48, 72 and 108 weeks. Annualized relapse rate and confirmed progression of disability (sustained ≥12 weeks) were the primary and key secondary outcomes. The principal MRI outcome was change in total lesion volume.
After 108 weeks, increase in total lesion volume was 67.4% (p=0.0003) and 39.4% (p=0.0317) lower in the 14 and 7 mg dose groups versus placebo. Other measures favoring teriflunomide were accumulated enhanced lesions, combined unique activity, T2-hyperintense and T1-hypointense component lesion volumes, white matter volume, and a composite MRI score; all were significant for teriflunomide 14 mg and most significant for 7 mg versus placebo.
Teriflunomide provided benefits on brain MRI activity across multiple measures, with a dose effect evident on several markers. These effects were also consistent across selected subgroups of the study population. These findings complement clinical data showing significant teriflunomide-related reductions in relapse rate and disease progression, and demonstrate containment of MRI-defined disease progression.
There is an urgent need for biomarkers in multiple sclerosis (MS) that can reliably measure ongoing disease activity relative to inflammation, neurodegeneration, and demyelination/remyelination. Fetuin-A was recently identified as a potential biomarker in MS cerebrospinal fluid (CSF). Fetuin-A has diverse functions, including a role in immune pathways.
The objective of this research is to investigate whether fetuin-A is a direct indicator of disease activity.
We measured fetuin-A in CSF and plasma of patients with MS and correlated these findings to clinical disease activity and natalizumab response. Fetuin-A expression was characterized in MS brain tissue and in experimental autoimmune encephalomyelitis (EAE) mice. We also examined the pathogenic role of fetuin-A in EAE using fetuin-A-deficient mice.
Elevated CSF fetuin-A correlated with disease activity in MS. In natalizumab-treated patients, CSF fetuin-A levels were reduced one year post-treatment, correlating with therapeutic response. Fetuin-A was markedly elevated in demyelinated lesions and in gray matter within MS brain tissue. Similarly, fetuin-A was elevated in degenerating neurons around demyelinated lesions in EAE. Fetuin-A-deficient mice demonstrated delayed onset and reduced severity of EAE symptoms.
Our results show that CSF fetuin-A is a biomarker of disease activity and natalizumab response in MS. Neuronal expression of fetuin-A suggests that fetuin-A may play a pathological role in the disease process.
Compromised learning and cognitive fatigue are critical clinical features in multiple sclerosis.
This study was designed to determine the effect of repeated exposures within and across study visits on performance measures of learning and cognitive fatigue in relapsing–remitting multiple sclerosis (RRMS).
Thirty patients with RRMS and 30 controls were recruited. Using a burst measurement design (i.e. repeated assessments within and across study visits) the oral version of the Symbol Digit Modalities Test (SDMT) was administered three times during the baseline and two consecutive monthly follow-up visits for a total of nine test administrations. Learning was assessed within and across study visits whereas cognitive fatigue was assessed during the course of each test administration that was divided into three 30-second intervals.
Linear mixed-effect models revealed compromised learning within (95% CI: 2.6355 to 3.9867) and across (95% CI: 1.3250 to 3.1861) visits and worse cognitive fatigue (95% CI: –2.1761 to –0.1720) in patients with RRMS compared with controls. Among patients with RRMS, worse self-rated cognitive dysfunction predicted poor learning within (95% CI: –0.1112 to –0.0020) and across (95% CI: –0.0724 to –0.0106) visits.
Burst design is optimal to study learning and cognitive fatigue. This methodology, using the SDMT or other time-efficient tests as outcome measures, can be successfully implemented in longitudinal studies and clinical trials.
Fatigue is a common symptom in multiple sclerosis (MS) and is an important determinant of overall well-being and disability.
To assess the frequency with which fatigue precedes the diagnosis of MS using a retrospective database analysis.
Between January 1, 2003 and September 30, 2008, patients diagnosed with fatigue with and without fatigue-related medications within a 3-year period prior to newly diagnosed MS were identified from the MarketScan Databases. All statistical analysis was performed using SAS.
Of the 16,976 patients with MS in the overall population, 5305 (31.3%) were newly diagnosed with MS and had three years of continuous healthcare coverage prior to MS diagnosis. Of these patients, 1534 (28.9%) were labeled with chronic fatigue syndrome (ICD9-780.71) or malaise or fatigue (ICD9-780.79) prior to the diagnosis of MS. One-third of these patients were labeled with fatigue one to two years before the diagnosis; 30.8% were diagnosed only with fatigue and had no other MS symptoms prior to their MS diagnosis. Among the patients diagnosed with fatigue, 10.4% were also prescribed medication for fatigue.
This study demonstrates that fatigue may herald MS, often by years. A careful history for transient neurological symptoms and a physical examination is warranted in any patient presenting with fatigue.
Treatment with natalizumab, a humanized monoclonal antibody against alpha4beta1 integrin, is associated with an increase in lymphoid progenitor cells and B cells in peripheral blood.
The objective of this study was to examine the impact of natalizumab therapy on serum levels of total IgG, IgA and IgM in patients with multiple sclerosis (MS).
In two independent cross-sectional patient cohorts, serum levels of IgG, IgA and IgM were compared between patients treated with natalizumab and those not receiving natalizumab. Further, serum levels of IgG, IgA and IgM before and during natalizumab treatment were compared in two longitudinal patient cohorts.
In patients treated with natalizumab, serum IgM and IgG levels were significantly lower compared with therapy naïve patients (p<0.0001). IgM levels significantly decreased after initiation of natalizumab treatment in both longitudinal patient cohorts (p<0.01). Moreover, patients treated with natalizumab showed a time-dependent decrease in IgM levels during the first 2 years of treatment.
Natalizumab treatment leads to a significant decrease in serum IgM and IgG levels in patients with MS. IgM levels decrease with treatment duration during the first 2 years of treatment. These findings might support the hypothesis that natalizumab interferes with homing of B cells, possibly leading to impaired differentiation into plasma cells and subsequently disturbed immunoglobulin synthesis.
Cerebral blood flow (CBF) is reduced in normal-appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but the underlying mechanism is unknown.
The objective of this article is to assess the relationship between reduced NAWM CBF and both axonal mitochondrial metabolism and astrocytic phosphocreatine (PCr) metabolism.
Ten healthy controls and 25 MS subjects were studied with 3 Tesla magnetic resonance imaging. CBF was measured using pseudo-continuous arterial spin labeling. N-acetylaspartate/creatine (NAA/Cr) ratios (axonal mitochondrial metabolism) were obtained using 1H-MR spectroscopy and PCr/β-ATP ratios using 31P-MR spectroscopy. In centrum semiovale NAWM, we assessed correlations between CBF and both NAA/Cr and PCr/β-ATP ratios.
Subjects with MS had a widespread reduction in CBF of NAWM (centrum semiovale, periventricular, frontal and occipital), and gray matter (frontoparietal cortex and thalamus). Compared to controls, NAA/Cr in NAWM of the centrum semiovale of MS subjects was decreased, whereas PCr/β-ATP was increased. We found no correlations between CBF and PCr/β-ATP. CBF and NAA/Cr correlated in controls (p = 0.02), but not in MS subjects (p = 0.68).
Our results suggest that in MS patients there is no relationship between reduced CBF in NAWM and impaired axonal mitochondrial metabolism or astrocytic PCr metabolism.
Neuromyelitis optica (NMO) is an inflammatory disease associated with optic neuritis and myelitis. Recently, several studies showed that optical coherence tomography (OCT) could be an interesting method for the evaluation of disease severity; however, to date there are no studies with a longitudinal follow-up of visual function in NMO. The aim of this study was to assess the ability of OCT to evaluate the progression of visual dysfunction in NMO.
A group of 30 NMO patients (thus, 60 eyes), comprised of 20 women and 10 men with a mean age of 43.7 +/– 12.3 years, were prospectively evaluated clinically and by a whole neuro-ophthalmological work-up, including: visual acuity (VA), fundoscopy, visual evoked potential (VEP), visual field (VF) and optical coherence tomography (OCT). All patients were tested at baseline (after a mean disease duration of 6.1 years) and after a mean time of follow-up of 18 months (range: 12–36 months).
Mean VA was similar at the two evaluation times (0.77 +/– 0.36 versus 0.77 +/– 0.35). The mean VF defect decreased slightly, but the difference was not significant (–5.9 +/– 1.3 dB versus –5.3 +/– 1.3 dB). In contrast, the mean retinal thickness seen on OCT decreased from 87.4 +/– 23.3 µm to 79.7 +/- 22.4 µm (p = 0.006). These modifications were only observed in eyes with a past or a recent history of optic neuritis (–15.1 µm; p < 0.001) and not in eyes without any history of optic neuritis (–2.4 µm; not significant). Also, they occurred independently of the occurrence of relapses (n = 13) and especially optic neuritis episodes; however, the number of optic neuritis episodes was low (n = 5).
OCT seems to be a more sensitive test than VA or VF for monitoring ophthalmological function in NMO and it seems to be helpful for the detection of infra-clinical episodes in patients with a past history of optic neuritis. Our results suggest that this easily performed technique should be used in the follow-up of NMO, but complementary studies are warranted to confirm its interest at an individual level.
The validity of self-rated anxiety inventories in people with multiple sclerosis (pwMS) is unclear. However, the appropriateness of self-reported depression scales has been widely examined. Given somatic symptom overlap between depression and MS, research emphasises caution when using such scales.
This study evaluates symptom overlap between anxiety and MS in a group of 33 individuals with MS, using the Beck Anxiety Inventory (BAI).
Participants underwent a neurological examination and completed the BAI.
A novel procedure using hierarchical cluster analysis revealed three distinct symptom clusters. Cluster one (‘wobbliness’ and ‘unsteady’) grouped separately from all other BAI items. These symptoms are well-recognised MS-related symptoms and we question whether their endorsement in pwMS can be considered to reflect anxiety. A modified 19-item BAI (mBAI) was created which excludes cluster one items. This removal reduced the number of MS participants considered ‘anxious’ by 21.21% (low threshold) and altered the level of anxiety severity for a further 27.27%.
Based on these data, it is suggested that, as with depression measures, researchers and clinicians should exercise caution when using brief screening measures for anxiety in pwMS.
Multiple sclerosis (MS) in Asia is thought to have different clinical characteristics from MS in Western countries; however, previous studies in Asia were performed without properly differentiating neuromyelitis optica (NMO) from MS.
To evaluate the clinical characteristics of MS in Korea after careful exclusion of potential explanations other than MS, particularly NMO spectrum disorder (NMOSD).
This study is a retrospective review of consecutive MS patients attending five referral hospitals in Korea. All patients’ MS diagnoses were re-evaluated.
Of the 105 patients, 70 were female and 35 were male. The mean age of onset was 30.4 years and the mean disease duration was 5.4 years. On initial magnetic resonance imaging (MRI), 58% and 64% fulfilled the criteria for dissemination in space for the 2005 and 2010 McDonald criteria, respectively. Spinal cord lesions were observed in 78% of patients, primarily present as multiple small lesions with a mean length of 0.9 vertebral segments. The median time from disease onset to an Expanded Disability Status Scale 6 was 20 years.
After careful exclusion of NMOSD, we found that the clinical pattern of MS in Korea does not fundamentally differ from that seen in Western countries.
The real-life relevance of frequently applied clinical arm tests is not well known in multiple sclerosis (MS).
This study aimed to determine the relation between real-life arm performance and clinical tests in MS.
Thirty wheelchair-bound MS patients and 30 healthy controls were included. Actual and perceived real-life arm performance was measured by using accelerometry and a self-reported measure (Motor Activity Log). Clinical tests on ‘body functions & structures’ (JAMAR handgrip strength, Motricity Index (MI), Fugl Meyer (FM)) and ‘activity’ level (Nine Hole Peg Test (NHPT), Action Research Arm test) of the International Classification of Functioning were conducted. Statistical analyses were performed separately for current dominant and non-dominant arm.
For all outcome measures, MS patients scored with both arms significantly lower than the control group. Higher correlations between actual arm performance and clinical tests were found for the non-dominant arm (0.63–0.80). The FM (55%) was a good predictor of actual arm performance, while the MI (46%) and NHPT (55%) were good predictors of perceived arm performance.
Real-life arm performance is decreased in wheelchair-bound MS patients and can be best predicted by measures on ‘body functions & structures’ level and fine motor control. Hand dominance influenced the magnitude of relationships.
Multiple sclerosis (MS) is an autoimmune disorder where a breakdown in the integrity of the blood-brain barrier is thought to allow lymphocytes to enter the central nervous system.
The purpose of this study was to examine gene expression profiles between MS patients and healthy controls to identify genes intimately involved in the pathobiology of MS.
Whole-genome gene expression analysis was performed using peripheral blood mononuclear cells from 39 healthy controls and 37 MS patients, 24 MS patients receiving no disease modifying therapy and 13 MS patients receiving interferon-beta (IFN-beta). Pathway analysis was performed to identify pathways dysregulated in MS.
Gene expression profiling of MS identified a signature of predominately immune associated genes. The plasminogen activation pathway contained an over-representation of significantly differentially expressed genes, including matrix metallopeptidase 9 (MMP9). Treatment with IFN-beta ameliorated the over-expression of MMP9, however the expression of two genes, plasminogen activator urokinase (PLAU) and serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), forming part of the plasminogen activation pathway were not affected by IFN-beta therapy.
High expression levels of MMP9 have been associated with MS and the breakdown of the blood-brain barrier, while IFN-beta therapy decreases MMP9 expression. We confirm altered MMP9 expression in MS, and identify dysregulation within the plasminogen activation cascade, a pathway involved in the activation of MMP9.
Retinal nerve fiber layer (RNFL) thickness has been linked to brain atrophy in multiple sclerosis (MS). However, little is known about retinal atrophy in ‘benign’ MS. We compared RNFL thickness in benign MS with healthy controls.
Patients with benign MS (Expanded Disability Status Scale (EDSS) ≤ 3; ≥15 years’ disease duration), identified through the British Columbia MS database, along with age-matched healthy controls, were recruited. RNFL thickness was measured using spectral-domain optical coherence tomography. Analysis of variance (ANOVA) was used to compare groups. The association between RNFL thickness and MS patient characteristics was examined via linear mixed-effects models (adjusting for within-patient inter-eye correlations and history of optic neuritis (ON), where appropriate).
Overall, 29 benign MS patients and 29 healthy controls were included, totaling 116 eyes. RNFL thickness was lowest for the benign MS eyes, with and then without a history of ON, followed by healthy controls (mean=73.2 µm, SD ± 0.4; 89.9 µm, SD ± 12.5; 96.7 µm, SD ± 10.4; p<0.02). RNFL thickness was associated with a history of ON (p<0.0001), but not EDSS or disease duration (p>0.1).
RNFL thickness was lower in patients with benign MS than healthy controls, regardless of the previous history of ON. However, no association was found between RNFL values and disability or MS disease duration.
The International Panel on Diagnosis of Multiple Sclerosis has proposed new magnetic resonance imaging (MRI) criteria for the diagnosis of multiple sclerosis (MS) in patients with clinically isolated syndrome (CIS). We aimed to evaluate these new criteria in a cohort of patients from Buenos Aires, Argentina.
Patients with CIS, in whom MRI was performed within three months of onset of symptoms, were included between January 2005–June 2010. Poser or McDonald 2005 criteria were used as gold standard diagnostic criteria for MS. MRI was assessed by a blind evaluator identifying recently diagnostic MS criteria. New criteria sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were determined.
Altogether 101 patients were included. Of these, 86 patients converted to MS (McDonald 2005/Poser) during the follow-up. The mean follow-up time was 7.3±3.2 years (range 1.8–11 years). Sensitivity was 84%, specificity 80%, PPV 96%, NPV 46% and accuracy 82%. The sub-analysis applied only to non-European descendants (mestizos, natives and zambos) showed a high level of accuracy for these new diagnostic criteria in this local ethnic/genetic population (sensitivity 77%, specificity 72%, PPV 94%, NPV 38%).
This study assessing McDonald 2010 criteria in a Latin-American population may contribute to its international validation.
Studies of the risk of cardiovascular diseases (CVDs) in patients with multiple sclerosis (MS) have the potential to improve our understanding of the etiology of and the heterogeneity of prognosis and outcomes.
To investigate the risk of myocardial infarction (MI), stroke, heart failure (HF), and atrial fibrillation (AF) or Flutter in MS patients with different ethnicity, both female and male.
Using Poisson regression, we performed a nationwide study in Sweden to investigate the association between the diagnosis of MS and the risk of MI, stroke, HF, or AF/Flutter in 8281 patients who were hospitalized due to MS from 1987 through 2009, plus 76,640 matched control individuals. We performed stratified analyses by sex, age at follow-up and country of birth.
Among MS patients, the incidence rate ratio for MI was 1.85 (95% confidence interval (CI) 1.59 to 2.15), for stroke was 1.71 (95% CI 1.46 to 2.00), for HF was 1.97 (95% CI 1.52 to 2.56) and for AF/Flutter was 0.63 (95% CI 0.46 to 0.87), as compared with individuals without MS. The increased risks were particularly prominent for women. These associations remained after stratification by sex, age and country of birth.
We recommend careful surveillance and preventive CVDs measures among MS patients, particularly among the women.
Background: Few studies have analysed long-term effects of immunomodulatory disease modifying drugs (DMDs).
Objective: Assessment of the efficacy of DMDs on long-term evolution of multiple sclerosis, using a Bayesian approach to overcome methodological problems related to open-label studies.
Methods: MS patients from three different Italian multiple sclerosis centres were divided into subgroups according to the presence of treatment in their disease history before the endpoint, which was represented by secondary progression. Patients were stratified on the basis of the risk score BREMS (Bayesian risk estimate for multiple sclerosis), which is able to predict the unfavourable long-term evolution of MS at an early stage.
Results: We analysed data from 1178 patients with a relapsing form of multiple sclerosis at onset and at least 10 years of disease duration, treated (59%) or untreated with DMDs. The risk of secondary progression was significantly lower in patients treated with DMDs, regardless of the initial prognosis predicted by BREMS.
Conclusions: DMDs significantly reduce the risk of multiple sclerosis progression both in patients with initial high-risk and patients with initial low-risk. These findings reinforce the role of DMDs in modifying the natural course of the disease, suggesting that they have a positive effect not only on the inflammatory but also on the neurodegenerative process. The study also confirms the capability of the BREMS score to predict MS evolution.
Corrigendum to 25-hydroxyvitamin D in cerebrospinal fluid during relapse and remission of multiple sclerosis by Trygve Holmø, Stine Marit Moen, Thomas A Gundersen, Michael F Holick, Enrico Fainardi, Massimiliano Castellazzi and Ilaria Casetta. 15(11) 1280-1285 [DOI: 10.1177/1352458509107008]. The third author name was published incorrectly. The correct name is 'Thomas E Gundersen'.
Corrigendum to 'Clinical vigilance for progressive multifocal leukoencephalopathy in the context of natalizumab use' by Carlo Tornatore and David B Clifford. Multiple Sclerosis 15(S4) S16-S25 [DOI: 10.1177/1352458509347130].
Corrigendum to Season of birth and not vitamin D receptor promoter polymorphisms is a risk factor for multiple sclerosis by DA Fernandes de Abreu, MC Babron I, C Rebeix, J Fontenille, D Yaouanq, B Brassat, F Fontaine, F Clerget-Darpoux, F Jehan and Feron. Mult Scler 2009; 15: 1146???1152 [DOI: 10.1177/1352458509106780]. The author names were published incorrectly. The correct names are: DA Fernandes de Abreu, MC Babron, I Rebeix, C Fontenille, J Yaouanq, D Brassat, B Fontaine, F Clerget-Darpoux, F Jehan, and F Feron