In this independent, multicentre post-marketing study we directly compared the effectiveness of natalizumab (NTZ), fingolimod (FNG) and self-injectable drugs (INJ), in non-responders to first immunomodulating treatment and in highly active treatment-naïve patients with multiple sclerosis. As main outcome measure we considered the proportions of patients with no evidence of disease activity (NEDA-3), defined as absence of relapses, disability worsening and radiological activity. A total of 567 non-responders to interferon beta (IFNB) or glatiramer acetate (GA) [dataset A] and 216 highly active treatment-naïves [dataset B] were followed up to 24 months from the beginning of NTZ, FNG or INJ, i.e. switching from IFNB to GA or viceversa (in the case of non-responders) or starting high-dose IFNB (in the case of highly active treatment-naïves). Propensity score matching in a 1:1:1 ratio was used to select only patients with similar baseline characteristics, retaining 330 and 120 patients in dataset A and B, respectively. In dataset A, the 24-month proportion with NEDA-3 was greater in both NTZ group (67%) and FNG group (42%) than in INJ group (35%) (p ≤ 0.016); however, NTZ was superior to FNG in promoting the attainment of NEDA-3 status (p = 0.034). In dataset B, the 24-month proportion with NEDA-3 was greater in NTZ group (75%) and FNG group (67%) than in INJ group (40%), but the small cohort sizes most likely prevented the detection of any statistically significant difference. Our study provides real-world evidence that NTZ was more effective than both FNG and INJ in non-responders, while it could seem that, in highly active treatment-naïves, NTZ was as effective as FNG and both were superior to INJ.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18–49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5–17.9) for paediatric-onset and 6.3 (4.9–8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9–4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.

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Background and Purpose-We sought to determine whether the introduction of EEG monitoring during head-up tilt testing could significantly improve the understanding of the cerebral events occurring during tilt-induced vasovagal syncope and the potential danger to the patient of this diagnostic procedure. Methods-EEG monitoring was performed during head-up tilt testing in a group of 63 consecutive patients (27 males and 36 females; mean age, 41.5 years) with a history of recurrent syncope of unknown origin despite extensive clinical and laboratory assessment. Results-Syncope occurred in 27 of 63 patients (42.8%) during head-up tilt testing and was found to be cardioinhibitory in 11 of 27 (40.7%) and vasodepressor in 16 of 27 (59.3%). All patients with a negative response to head-up tilt testing showed no significant EEG modifications. In patients with vasodepressor syncope, a generalized high-amplitude, 4-to 5-Hz (theta range) slowing of EEG activity appeared at the onset of syncope, followed by an increase of brain-wave amplitude with the reduction of frequency at 1.5 to 3 Hz (delta range). The return to the supine position was associated with brain-wave amplitude reduction and frequency increase to 4 to 5 Hz, followed by restoration of a normal EEG pattern and arousal (mean total duration of syncope, 23.2 seconds.). In patients with cardioinhibitory syncope, a generalized high-amplitude EEG slowing in the theta range was noted at the onset of syncope, followed by a brain-wave amplitude increase and slowing in the delta range. A sudden reduction of brain-wave amplitude then ensued, leading to the disappearance of electrocerebral activity ("flat" EEG). The return to the supine position did not allow either the immediate resolution of EEG abnormalities or consciousness recovery, both of which occurred after a further time interval (mean total duration of syncope, 41.4 seconds.). Conclusions-EEG monitoring during head-up tilt testing allowed recording and systematic description of electrocerebral abnormalities developing in the course of tilt-induced vasovagal syncope.