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Subjects with severe chronic spinal cord injury (SCI) are prone to hypothermia when they are exposed to relatively low environmental temperatures that are normally well tolerated by healthy individuals. This impaired thermoregulation is presumably due to disconnection of territories below the SCI from supraspinal thermoregulatory centers. However, it is not known how these territories respond to low temperatures. Using a complete transection at T11 in rats, we examined the responses of the tail to cold (6–9°C) by measuring changes in tail blood flow and skin temperature weekly for 8 wk after SCI. Despite no significant change in baseline mean flow or temperature in the tail, the transection effectively removed the sympathetically mediated supraspinal control of the tail vasculature, since the amplitude of the pulse flow was markedly increased and the natural variations of the mean flow were almost abolished. As expected, the cold challenge before SCI caused a marked drop in mean flow, pulse amplitude, and temperature of the tail. Surprisingly, the drops in mean blood flow and temperature were observed after SCI, although the decrease in flow was slower and the pulse amplitude was not reduced. The results suggest that the cutaneous vasculature of the tail is sensitive to cold and will constrict, despite disconnection from supraspinal centers. This local effect is slow but may be sufficient to maintain some level of thermoregulation to cold. Without this vascular reaction, the effects of SCI on temperature regulation to cold would probably be much worse.

Escalation of therapy regimes to natalizumab or fingolimod are strategies commonly utilised in patients experiencing on-going activity of multiple sclerosis despite treatment with interferon β or glatiramer acetate. However, no evidence comparing the two strategies is available to the author’s knowledge. We have compared the effectiveness of treatment escalation to natalizumab and fingolimod in patients with sub-optimal response to injectable agents. Using MSBase, a large international, observational multiple sclerosis registry, patients with relapsing-remitting disease course and with relapses or disability progression within the 6 months immediately preceding escalation to natalizumab or fingolimod were identified. Quasi-randomisation with propensity score-based matching was used to select sub-populations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses. A total of 792 patients fulfilled the inclusion criteria, and 578 patients were matched (natalizumab n = 407, fingolimod n = 171). No difference in treatment persistence was observed during the censored on-study follow-up (mean 12 months). The post-escalation annualised relapse rates were 0.2 and 0.4 on natalizumab and fingolimod, respectively, with 50% relative difference in relapse hazard ( p p = 0.002). This was driven by 67% higher probability of sustained disability reduction after escalation to natalizumab ( p = 0.025). No difference in sustained disability progression was observed. In patients with active multiple sclerosis despite injectable immunomodulatory therapy, escalation to natalizumab is more effective than escalation to fingolimod in suppressing relapse activity and stimulating reduction of disability.

ObjectivesTo compare clinical and MRI parameters between patients with clinically isolated syndrome and those converting to clinically definite multiple sclerosis within 2 years, to identify volumetric MRI predictors of this conversion and to assess effect of early relapses.MethodsThe SET study comprised 220 patients with clinically isolated syndrome treated with interferon beta (mean age, 29 years; Expanded Disability Status Scale, 1.5). Three patients with missing data were excluded from the analysis. Physical disability, time to clinically definite multiple sclerosis and volumetric MRI data were recorded for 2 years.ResultsPatients reaching clinically definite multiple sclerosis showed impaired recovery of neurological function, faster decrease in corpus callosum cross-sectional area, higher T2 lesion volume and more contrast-enhancing lesions. Six-month decrease in corpus callosum cross-sectional area (≥ 1%) and baseline T2 lesion volume (≥ 5 cm(3)) predicted clinically definite multiple sclerosis within 2 years (hazard ratios 2.5 and 1.8, respectively). Of 22 patients fulfilling both predictive criteria, 83% reached clinically definite multiple sclerosis (hazard ratio 6.5). More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy.ConclusionsNeurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory activity is greater in patients converting to clinically definite multiple sclerosis. Six-month corpus callosum atrophy and baseline T2 lesion volume jointly help predict individual risk of clinically definite multiple sclerosis. Early relapses contribute to permanent damage of the central nervous system.

Jokubaitis, Vilija G./0000-0002-3942-4340; Oreja-Guevara, Celia/0000-0002-9221-5716; Lugaresi, Alessandra/0000-0003-2902-5589; Slee, Mark/0000-0003-4323-2453; Horakova, Dana/0000-0003-1915-0036; Havrdova, Eva Kubala/0000-0002-9543-4359; Sanchez Menoyo, Jose Luis/0000-0003-2634-8294; Prat, Alexandre/0000-0001-6188-0580; Kalincik, Tomas/0000-0003-3778-1376; Butzkueven, Helmut/0000-0003-3940-8727; pucci, eugenio/0000-0001-7606-7330; van Pesch, Vincent/0000-0003-2885-9004; Trojano, Maria/0000-0002-6329-8946 WOS: 000365135700024 PubMed: 26359291 Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events. NHMRC Early Career FellowshipNational Health and Medical Research Council of Australia [1071124]; NHMRC Practitioner FellowshipNational Health and Medical Research Council of Australia [1080518]; NHMRCNational Health and Medical Research Council of Australia [1083539, 1032484]; NHMRC Centre for Research ExcellenceNational Health and Medical Research Council of Australia [1001216]; MSBase Foundation; Merck SeronoMerck SeronoMerck & Company; BiogenBiogen; Novartis Pharma; Bayer-ScheringBayer AG; Sanofi-AventisSanofi-Aventis; BioCSL The work was supported by the NHMRC Early Career Fellowship (1071124), NHMRC Practitioner Fellowship (1080518), NHMRC Project Grants (1083539 and 1032484), NHMRC Centre for Research Excellence (Grant ID 1001216) and the MSBase Foundation. The MSBase Foundation is a not-for-profit organization that receives support from Merck Serono, Biogen, Novartis Pharma, Bayer-Schering, Sanofi-Aventis and BioCSL. The study was conducted separately and apart from the guidance of the sponsors.

Young Wistar rats (aged 12, 25 and 35 days) were exposed to short-term (60 min) hypobaric hypoxia of 41 kPa. Cortical afterdischarges (ADs) were evoked by repeated direct stimulation of the sensorimotor cortex and the duration of ADs was monitored to examine the influence of magnesium sulphate injection (0.3 g/kg b.w.). In 12-day-old hypoxia-exposed rats, an increase of the mean duration of ADs after the repeated stimulation appeared. This effect was prevented by magnesium administration. In 25- and 35-day-old rats exposed to hypoxia a shortening of ADs was registered but no specific effect of magnesium sulphate pretreatment was observed. The brain susceptibility and ability to terminate evoked seizures is discussed.