Multiple Sclerosis Journal

How axonal damage, a major prognostic factor of multiple sclerosis disability progression, is induced, is likely to be multifactorial. Whereas axonal injury has been identified as a consequence of myelin loss, the possibility of an additional direct damage is also suggested. In this context, recent data have highlighted the nodal and perinodal axonal domains of the myelinated neurons as potential targets of the disease process, opening new perspectives in multiple sclerosis pathophysiology.

Natalizumab is a highly effective immunomodulator in the treatment of multiple sclerosis (MS). Treatment with natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), an infection of the central nervous system (CNS) caused by a pathogenic form of the normally benign JC virus (JCV). We searched PubMed and used current data from the natalizumab global safety database to assess risk factors and quantify the risk of PML. Natalizumab treatment duration and prior use of immunosuppressive therapies are established risk factors for development of PML in natalizumab-treated patients. With the development of a reliable and validated assay for detection of antibodies in patients with MS directed against JCV, it is now possible to identify persons who are carriers of JCV. The availability of this assay provides an additional option for risk stratification of PML in patients using or considering natalizumab therapy. Recommendations for clinical management of patients with MS and use of natalizumab are provided based on the presence of these three risk factors. The identification of risk factors that increase the likelihood of PML in natalizumab-treated patients can facilitate benefit–risk discussions between health care professionals and patients. Continued research and data collection will further develop our understanding of PML and the mechanisms by which these risk factors contribute to its development.

Background/Objective: To assess whether abnormalities on functional magnetic resonance imaging (fMRI) are related to cognitive function in patients at presentation with clinically isolated syndrome (CIS) suggestive of multiple sclerosis.

Methods: Eighteen patients with CIS and 15 healthy controls (HCs) performed an adapted fMRI version of the Paced Auditory Serial Addition Test (PASAT). According to their PASAT performance, CIS patients were divided into two groups: 10 with a low PASAT performance (<1 SD from the mean value of HCs) were considered ‘cognitive impairment’ (CI); eight patients were defined as ‘cognitively preserved’ (CP). Between-group differences in the patterns of brain activations and effective connectivity were assessed.

Results: During PASAT, compared to HCs, CIS patients showed increased activations of the bilateral inferior parietal lobe (IPL), bilateral precuneus, bilateral middle frontal gyrus (MFG), left anterior cingulate cortex (ACC), left claustrum, right thalamus and right caudate nucleus. When CIS patients were analyzed, the CI group had a more significant activation of the bilateral IPL than HCs and CP patients. Compared to CP patients, they also had more significant recruitment of the right superior parietal lobe, right cerebellum, left MFG and left ACC. The analysis of effective connectivity showed stronger connections between several regions of the right hemisphere involved in working memory function in CI patients versus CP and HC.

Conclusions: During performance of the PASAT, CIS patients show abnormalities in the patterns of cortical recruitment and connectivity related to the level of their cognitive impairment.

Background: Gender effects are strong in multiple sclerosis (MS), with male patients showing a worse clinical outcome than female patients. Functional reorganization of neural activity may contribute to limit disability, and possible gender differences in this process may have important clinical implications.

Objectives: The aim of this study was to explore gender-related changes in functional connectivity and network efficiency in MS patients. Additionally, we explored the association of functional changes with cognitive function.

Methods: Sixty subjects were included in the study, matched for age, education level and intelligence quotient (IQ). Male and female patients were matched for disability, disease duration and white matter lesion load. Two cognitive domains often impaired in MS, i.e. visuospatial memory and information processing speed, were evaluated in all subjects. Functional connectivity between brain regions and network efficiency was explored using resting-state functional magnetic resonance imaging and graph analysis. Differences in cognitive and functional characteristics between groups, and correlations with cognitive performance, were examined.

Results: Male patients showed worse performance on cognitive tests than female and male controls, while female patients were cognitively normal. Decreases in functional connectivity and network efficiency, observed in male patients, correlated with reduced visuospatial memory (r = −0.6 and r = −0.5, respectively). In the control group, no cognitive differences were found between genders, despite differences in functional connectivity between healthy men and women.

Conclusions: Functional connectivity differences were found in male patients only and were related to impaired visuospatial memory. These results underline the importance of gender in MS and require further investigation in larger and longitudinal studies.

Background: The intrathecal production of immunoglobulin (Ig) is a major biological feature of multiple sclerosis (MS), and immunopathological studies have suggested a primary role of the humoral immune response in causing irreversible brain damage.

Objective: To evaluate whether, in the early phases of MS, intrathecal Ig synthesis correlates with the presence of cortical lesions (CLs), and if their association could predict the clinical course of the disease.

Methods: Eighty-six patients presenting with symptoms and signs suggestive of MS underwent a diagnostic work-up that included magnetic resonance imaging and cerebrospinal fluid examination. The risk ratios (RR) for conversion to MS and for a new disease activity were calculated.

Results: Patients with clinically isolated syndromes (CIS) having CLs and intrathecal synthesis of Ig had the highest risk of conversion to MS (RR = 3.4; Wald 95% CI = 1.7–7.0, p < 0.001) whereas CIS patients without CLs and intrathecal synthesis of Ig had the lowest risk of conversion to MS (RR = 0.1, Wald 95% CI = 0.02–0.7, p < 0.001). The highest risk of having disease-related activity during the follow-up was observed in CIS and relapsing–remitting MS patients showing CLs and intrathecal Ig synthesis (RR = 2.1; Wald 95% CI = 1.5–3.1, p < 0.001) while the lowest in CIS and relapsing–remitting MS patients without CLs and intrathecal Ig synthesis (RR = 0.3; Wald 95% CI = 0.1–0.7, p < 0.001).

Conclusion: We observed that the association of intrathecal immunoglobulin synthesis and CLs was highly predictive of an earlier CIS conversion to MS as well as of a higher disease activity.

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

Objective: To assess NAb impact in the BEYOND study.

Methods: 2244 patients were randomized (2:2:1) to receive IFNβ-1b, either 250 or 500 µg, or glatiramer acetate, 20 mg, and observed for 2–3.5 years. NAb titers were determined every 6 months. A titer ≥20 NU/ml was considered NAb positive. Efficacy was compared between NAb-positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors.

Results: In the IFNβ-1b 250 µg group, NAb-positive titers were detected (≥ once) in 319 patients (37.0%); of these, 112 (35.1%) reverted to NAb-negative status. In the IFNβ-1b 500 µg group, 340 patients (40.7%) became NAb-positive and 119 (35.0%) reverted to NAb-negative status. In both IFNβ groups, especially the 250 µg arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFNβ groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes.

Conclusion: There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNβ-1b is complex.

Background: Patient-reported outcome (PRO) scales are often used in multiple sclerosis (MS) research. Full understanding of items can be influenced by disease worsening, mood disturbances and cognitive problems of the MS patient. Earlier research with the Multiple Sclerosis Impact Scale (MSIS-29) showed that proxy respondents (i.e. partners of patients) can provide useful information.

Objective: To determine agreement between patients and proxy respondents on different MS PRO scales.

Methods: 139 Patients and partners completed the MSIS-29 (Physical and Psychological scale), Multiple Sclerosis Walking Scale (MSWS-12), Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) and Guy’s Neurological Disability Scale (GNDS). We calculated the mean difference and intra-class correlation coefficients (ICC) on scale level and weighted kappas (κ_w) on item level.

Results: On all scales, except MSNQ, the partner score was higher. ICCs were good for MSWS, GNDS and MSIS Physical, and moderate for MSNQ and MSIS Psychological. κ_w was excellent for MSWS items, fair to good for GNDS, MSIS Physical and MSIS Psychological items, and poor for MSNQ items.

Conclusion: Partners of patients with MS can be a useful source of information for several PRO scales, especially when the focus is on physical functioning. For psychological functioning this seems to be less reliable.

Background: Previous studies have described stabilization of aggressive multiple sclerosis (MS) with one-time induction therapy with high-dose cyclophosphamide (HiCy). The long-term benefit of this stabilization followed by conventional therapy has not been explored.

Objective: The objective of this study was to evaluate the safety and clinical outcomes following treatment of relapsing–remitting MS with HiCy induction therapy followed by glatiramer acetate maintenance.

Methods: A retrospective review of a closely followed population of thirty two MS patients treated with HiCy (200mg/kg intravenous infusion over 4 days) followed by maintenance with glatiramer acetate was performed.

Results: Annualized relapse rate was reduced from 1.37 in the 2 years prior to treatment to 0.27 over a mean post-treatment follow-up period of 14 months (range 0.5–33.8). The projected probability of relapse-free survival at 2 years was 0.64 (95% CI 0.37–0.82). The projected probability of Expanded Disability Status Scale (EDSS) progression-free survival at 2 years was 0.77 (95% CI 0.43–0.92). The mean number of gadolinium-enhanced lesions was reduced from 0.86 (SD 1.6) at baseline to 0 at 12 months and 0.08 (SD 0.28) at 15–24 months. A total of 55% of patients had no evidence of disease activity in follow-up. Infectious complications occurred in 47% with no long-term morbidity and no deaths.

Conclusions: Induction therapy with HiCy followed by long-term maintenance with glatiramer acetate is well tolerated in patients with MS, and appears to be efficacious in reducing the risk of relapse, disability progression, and new MRI lesions.

Background: To study a cohort of benign multiple sclerosis (BMS) patients beyond physical disability, including the evaluation of cognitive and social function, as well as fatigue, pain and MRI studies.

Methods: A cohort of 342 patients was prospectively followed for 10.9 ± 0.71 years. Forty-three patients (12.5%) met the BMS diagnosis criteria [Expanded Disability Status Scale (EDSS) < 3 after at least 10 years’ disease duration], undergoing full neurological examination every 6 months. Neuropsychological status, pain, fatigue, social functioning and work-related disability, as well as brain MRIs, were assessed yearly.

Results: By the end of follow-up, 20 of 43 BMS patients (47%) had suffered cognitive impairment and 23 (53.3%) referred depression. Furthermore, 21 (48.8%) reported significant changes in pain intensity, with fatigue and environmental severity scores significantly increasing over time in 33–35% of patients. Finally, 32 BMS patients (74%) showed significant increase in the number of new or enlarging T2 lesions, gadolinium-enhanced lesions, and persistent black holes, without changes in EDSS. Thirty-five of 43 patients (81%) fulfilling the BMS diagnostic criteria showed significant worsening of cognitive function, fatigue, pain or depression during the 10-year follow-up.

Conclusions: Currently accepted criteria for BMS diagnosis may cause overestimation of true prevalence, underscoring the need for routine monitoring of non-motor symptoms and imaging studies, to help physicians improve diagnostic accuracy as well as therapeutic decision-making in this subgroup of MS patients.

Background: Open-label studies are not ideal for providing robust evidence for long-term maintenance of efficacy of medicines, especially where medicines provide symptom relief and where long-term use of a placebo may be problematic and not ethical.

Objective: To evaluate the maintenance of efficacy of Sativex in subjects who have gained long-term symptomatic relief of spasticity in multiple sclerosis (MS), and to assess the impact of sudden medicine withdrawal.

Methods: An enriched enrolment randomized withdrawal study design was used. Eligible subjects with ongoing benefit from Sativex for at least 12 weeks entered this 5-week placebo-controlled, parallel-group, randomized withdrawal study. Each subjects’ previous effective and tolerated dose was continued.

Results: A total of 18 subjects per group were enrolled. Demographics showed a mean duration of MS of 16.4 years, spasticity 12.7 years, mean duration of Sativex use of 3.6 years (median 3.4 years) and a mean daily dose of 8.25 sprays. Primary outcome of time to treatment failure was significantly in favour of Sativex (p = 0.013). Secondary endpoints showed significant changes in the Carer and Subject’s Global Impression of Change scales in favour of Sativex.

Conclusions: Maintenance of Sativex efficacy in long-term symptomatic improvement of spasticity to a group of subjects with MS has been confirmed using this study design.

Recent studies have shown the relevance of the cerebral grey matter involvement in multiple sclerosis (MS). Cortical lesions (CLs), detected by specific MRI sequences, are likely to become a new research outcome in MS studies. The aim of this study was to infer the optimal statistical model describing the distribution of CLs in patients with relapsing–remitting (RR)MS. The negative binomial model gave the best fit to the observed distribution of CLs in a group of 44 RRMS patients with one MRI scan of the brain. This observation has important implications for the statistical analysis of CLs in MS studies.

Since multiple sclerosis (MS) often affects physically active young individuals, it is important to know if exercise can result in increased disease activity. Therefore we used a self-report questionnaire to examine the relationship of different levels of sports activity and relapses in 632 patients with MS. In order to analyse whether subjective recall might have biased the results, we performed, in a subgroup of our sample, an objective assessment of clinical data and physical fitness parameters. We were unable to find any association between sports activity and clinical relapses in either of the two analyses. The group with highest activity even shows the lowermost mean values, standard deviations and range concerning the number of relapses. Our data suggest that physical activity has no significant influence on clinical disease activity.

Interferon-β (IFN-β) stabilizes the blood–brain barrier (BBB) in vitro. Here we investigated the effect of serum from 15 IFN-β-1b-treated multiple sclerosis (MS) patients on the permeability read-outs of small solutes in an in vitro BBB model consisting of human brain microvascular endothelial cells in co-culture with rat astrocytes. The addition of sera from IFN-β-treated patients resulted in a significantly (p < 0.05) reduced permeability as compared with untreated patients. Our findings show that sera from IFN-β-1b-treated MS patients have a stabilizing effect on the in vitro BBB. We suggest an unknown potentially pro-inflammatory factor in the serum of MS patients that may lead to a BBB dysfunction and can be modulated by IFN-β.

Neuromyelitis optica (NMO) is an idiopathic demyelinating disease which predominantly affects the optic nerve and spinal cord. Multiplex NMO pedigrees have been reported but the genetic risk factors conferring this increased familial susceptibility have not yet been determined. OPA1 mutations have recently been identified in families with progressive visual failure and spastic paraparesis, raising the possibility that OPA1 genetic variants could contribute to the aetiology of NMO. We therefore screened for OPA1 in 32 patients with NMO. No pathogenic mutations were found, and none of the 13 single-nucleotide polymorphisms identified were associated with an increased risk of developing NMO.

Neuromyelitis optica (NMO), mainly affecting optic nerve and spinal cord, can also manifest diverse ocular symptoms due to brain abnormalities. We present a cortical oscillopsia without nystagmus or head tremor in a patient with neuromyelitis optica spectrum disorder (NMOSD) with anti-aquaporin 4 antibody. This rare ocular manifestation, which is easily underestimated owing to absence of the typical nystagmus, can be an initial manifestation of NMOSD.