A growing body of literature indicates that the natural course of multiple sclerosis can be influenced by a number of factors. Strong evidence suggests that relapses can be triggered by infections, the postpartum period and stressful life events. Vaccinations against influenza, hepatitis B and tetanus appear to be safe. Surgery, general and epidural anaesthesia, and physical trauma are not associated with an increased risk of relapses. Factors that have been associated with a reduced relapse rate are pregnancy, exclusive breastfeeding, sunlight exposure and higher vitamin D levels. A number of medications, including hormonal fertility treatment, seem to be able to trigger relapses. Factors that may worsen progression of disability include stressful life events, radiotherapy to the head, low levels of physical activity and low vitamin D levels. Strong evidence suggests that smoking promotes disease progression, both clinically and on brain magnetic resonance imaging. There is no evidence for an increased progression of disability following childbirth in women with multiple sclerosis. Moderate alcohol intake and exercise might have a neuroprotective effect, but this needs to be confirmed.

Optic neuritis provides an in vivo model to study demyelination. The effects of myelin loss and recovery can be measured by the latency of the multifocal visual evoked potentials. We investigated whether the extent of initial inflammatory demyelination in optic neuritis correlates with the remyelinating capacity of the optic nerve. Forty subjects with acute unilateral optic neuritis and good visual recovery underwent multifocal visual evoked potentials testing at 1, 3, 6 and 12 months. Average latency changes were analyzed. Extensive latency delay at baseline significantly improved over time with rate of recovery slowed down after 6 months. Magnitude of latency recovery was independent of initial latency delay. Latency recovery ranged from 7 to 17 ms across the whole patient cohort (average = 11.3 (3.1) ms) despite the fact that in a number of cases the baseline latency delay was more than 35—40 ms. Optic nerve lesions tend to remyelinate at a particular rate irrespective of the size of the initial demyelinated zone with smaller lesions accomplishing recovery more completely. The extent of the initial inflammatory demyelination is probably the single most important factor determining completeness of remyelination. The time period favorable to remyelination is likely to be within the first 6 months after the attack.

Multiple sclerosis patients without cerebrospinal fluid oligoclonal IgG bands have been proposed to constitute an immunogenetically distinct subgroup of multiple sclerosis that may also differ in terms of prognosis. A proportion of patients with multiple sclerosis receiving IFNβ develop neutralizing antibodies, which interfere with treatment efficacy. Evidence suggests that the likelihood of developing neutralizing antibodies is partly genetically determined. Here, we hypothesized that absence of oligoclonal IgG bands reflects a property of B-cell responses in oligoclonal IgG band-negative patients characterized by a lessened propensity to develop neutralizing antibodies. We aimed to compare the development of neutralizing antibodies against IFNβ between oligoclonal IgG band-negative and oligoclonal IgG band-positive multiple sclerosis patients. Treatment, oligoclonal IgG band and neutralizing antibody information was obtained for 2219 patients from the Swedish multiple sclerosis registry and the Swedish neutralizing antibody registry. Additional data on genotype was available for 532 patients. A correlation was found between oligoclonal IgG band negativity and neutralizing antibody negativity (p = 0.02). This difference was confined to neutralizing antibodies against IFNβ-1a, since oligoclonal IgG band-negative patients were, to a lesser extent, neutralizing antibody positive compared with oligoclonal IgG band-positive patients if treated with IFNβ-1a (12% vs. 23%; p = 0.005). No difference was observed for IFNβ-1b-treated patients (44% vs. 46%). We propose that oligoclonal IgG band-negative patients differ immunologically from oligoclonal IgG band-positive patients, potentially influenced by distinct HLA-DRB1 alleles.

Background: Interferon-β1b (IFN-β1b), an effective treatment for multiple sclerosis (MS), lessens disease severity in MS patients. However, the mechanisms of its immunoregulatory and anti-inflammatory effects in MS remain only partially understood. Matrix metalloproteinases (MMP) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are involved in blood brain barrier disruption and formation of MS lesions. Th1/Th17 cytokines e.g. interleukins IL-12p40, IL-17, and IL-23, are associated with MS disease activity and are significant players in pathogenesis of MS.

Objective: During a 1-year prospective study, we serially measured serum MMP-8, MMP-9, TIMP-1, IL-12p40, IL-17, and IL-23 in 24 patients with relapsing—remitting MS. We compared the results to clinical course and to brain magnetic resonance imaging. IFN-β1b decreased serum MMP-8 and MMP-9 (not TIMP-1).

Results: The sustained treatment with IFN-β1b attenuated the pro-inflammatory environment by significantly reducing the serum IL-12p40, IL-23, and showed a trend for decreasing IL-17. Decreased serum MMP-8, MMP-9, IL-12 and IL-23 levels were correlated with a decrease in the number of contrast-enhanced T2-weighted lesions.

Conclusion: Early treatment of MS with IFN-β1b may stabilize clinical disease by attenuating levels of inflammatory cytokines and MMPs. Serial measurement of inflammatory mediators may serve as sensitive markers to gauge therapeutic responses to IFN-β1b during the first year of treatment.

The objective of this study was to investigate whether the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid (CSF) influences the response to treatment with beta-interferon in relapsing—remitting multiple sclerosis (RRMS) patients. We performed a collaborative prospective study including RRMS patients with brain MRI and LS-OCMB studies performed before starting interferon treatment. The primary endpoint was the risk of having a relapse after treatment initiation. Secondary endpoints included relapse rate, relapse-rate reduction, proportion of relapse-free patients and proportion of patients with sustained disability increase during follow-up. One-hundred and two patients were included. After a mean follow-up of 37.4 months, the risk of suffering a relapse was two-fold higher in patients with LS-OCMB (hazard ratio 2.0, 95% confidence interval 1.1—3.8). LS-OCMB+ patients showed lower reduction in relapse rate (51.8% versus 80.8%; p < 0.0001), higher relapse rate in the first year (0.8 versus 0.2; p = 0.001), lower proportion of relapse-free patients (25% versus 61.3%; p = 0.003), and higher proportion of patients with sustained 1.0 increase in the Expanded Disability Status Score (45% versus 12.9%; p = 0.0003). In conclusion, LS-OCMB can have an influence on the response to interferon treatment in RRMS patients. They could be used as a biological marker to predict high inflammatory activity after treatment.

Objective: To estimate the incidence and severity of nocebo responses in trials of symptomatic treatments (STs) and disease-modifying treatments (DMTs) for multiple sclerosis (MS).

Methods: We conducted a systematic Medline search for all randomised, placebo-controlled MS trials published between 1989 and 2009. Meta-analysis of the incidence of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited adverse events. Nocebo severity was calculated from the percentage of placebo-treated patients that dropped-out due to drug-related adverse events.

Results: Data were extracted from 56 DMT and 44 ST eligible trials. The pooled incidence of nocebo responses was 74.4% (95% CI: 69.92—88.30) in DMT trials and 25.3% (95% CI: 15.24—36.90) in ST trials and was significantly higher in the former (p < 0.0001). The pooled nocebo severity was 2.1% (95% CI: 1.6—2.67) in DMT and 2.34% (95% CI: 1.54—3.29) in ST trials. Meta-regression analysis revealed a higher nocebo incidence in parallel design ST studies compared to crossover ones (p = 0.013) and a higher nocebo severity in phase II ST studies compared to phase III ones (p = 0.0001). Nocebo severity in DMT trials exhibited an association with the year of study publication (p = 0.011) and the frequency of drug administration (p = 0.0082).

Conclusions: Nocebo responses in MS trials are substantial and appear to have increased significantly in recent years with important implications for both trial design and clinical practice. Furthermore, nocebo responses exhibit an association with medication and trial-related factors.

Optical coherence tomography (OCT) is a non-invasive method to quantify neurodegeneration as an outcome in multiple sclerosis clinical trials; however, no data exist on Cirrus spectral domain optical coherence tomography (SD-OCT) reproducibility in patients with multiple sclerosis. The objective of this study was to determine the protocol for achieving optimal inter-visit, inter-rater, and intra-rater reproducibility for studies performed on healthy controls and multiple sclerosis patients utilizing novel high-definition SD-OCT. This is a prospective study of inter-visit, inter-rater, and intra-rater reproducibility in multiple sclerosis patients (n = 58) and healthy controls (n = 32) on Cirrus-HD SD-OCT. Excellent reproducibility of average and quadrantic retinal nerve fiber layer (RNFL) thickness values, average macular thickness (AMT), and total macular volume (TMV) [measured by intraclass correlation coefficient (ICC)] was found for inter-visit (healthy controls: mean RNFL = 0.97, quadrant range = 0.92—0.97, AMT = 0.97, TMV = 0.92), inter-rater (MS: mean RNFL = 0.97, quadrant = 0.94—0.98, AMT = 0.99, TMV = 0.96; healthy controls: mean RNFL = 0.97, quadrant = 0.94—0.97, AMT = 0.98, TMV = 0.99), and intra-rater (MS patients: mean RNFL = 0.99, quadrant = 0.83—0.99, AMT = 0.97, TMV = 0.98) reproducibility. The reproducibility of retinal measures derived by Cirrus HD-OCT, especially quadrantic values, is excellent. Specific procedures for OCT acquisition and analysis of retinal imaging metrics using SD-OCT technology may improve the application of this novel technology in multiple sclerosis.

Many phase I/II clinical trials in multiple sclerosis use gadolinium-enhanced lesions as the outcome measure. The best scanning interval and analysis for this outcome has not been determined. The objective of this study was to compare timing schemes and analysis techniques in terms of power for phase I/II clinical trials. Data were simulated under four scenarios assuming a negative binomial distribution for the number of new lesions and an exponential distribution for the duration of enhancement. The first scenario assumed an immediate treatment effect on the number of new lesions, while the second scenario assumed a delayed treatment effect. The third scenario assumed a higher proportion of patients had no new lesions, and the final scenario assumed an immediate treatment effect on the duration of enhancement. For each scenario, power for a six-month trial with 100 patients per arm was calculated using 10 analysis strategies. The scanning intervals tested were monthly scans, bimonthly scans and a single end-of-study scan. In addition, cost-effectiveness of each trial design and analysis was compared. Negative binomial regression models for the total number of new lesions were the most powerful analyses under an immediate treatment effect, and repeated measures models with a categorical time effect were the most powerful analyses under a delayed treatment effect. Although monthly scans generally provided most power, this design was also most costly. Designs with fewer scans per patient provide similar power and are more cost-effective. Negative binomial regression models are more powerful than non-parametric approaches.