Reduced Myelin Signal in Normal-appearing White Matter in Neuromyelitis Optica Measured by 7T Magnetic Resonance Imaging

Whether the integrity of normal-appearing white matter (NAWM) is preserved in neuromyelitis optica spectrum disorders (NMOSD) is open to debate. To examine whether the tissue integrity of NAWM in NMOSD is compromised compared to that in healthy controls and patients with multiple sclerosis (MS), we prospectively enrolled 14 patients with NMOSD, 12 patients with MS, and 10 controls for clinical functional assessments and quantitative imaging, including T1 relaxation time (T1) and magnetization transfer ratio (MTR) at 7 Tesla. Cognitive performance on the Paced Auditory Serial Addition Test with a 3-second interstimulus interval (PASAT-3) was significantly lower in the NMOSD compared to the MS group (mean number of correct answers, 34.1 vs. 47.6; p=.006), but there were no differences in disease duration or disability. Histograms of T1 and MTR maps of NAWM demonstrated a decreased peak height in patients with NMOSD compared to the healthy controls, but not compared to patients with MS. Using 7T quantitative magnetic resonance imaging (MRI), this study showed that the NAWM in patients with NMOSD is abnormal, with reduced myelin signal; this was not previously observed using MRI at a lower field strength

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial

Introduction: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, ‘Multiple Sclerosis International Stem Cell Transplant, MIST’, showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. Methods and analysis: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve ‘no evidence of disease activity’ during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. Ethics and dissemination: The study was approved by the Yorkshire and Humber—Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. Trial registration number: ISRCTN88667898

Trunk movement in Parkinson's disease during rising from seated position

Parkinson's disease (PD) is associated with particular difficulties rising from a seated position. Little is known about the mechanisms of sit-to-stand in this condition. We sought to define trunk movement during sit-to-stand in a group of patients with PD. Six patients and seven normal volunteers were studied using a six camera ELITE motion analysis system (BTS, Milan, Italy), which permitted data collection in the coronal, sagittal, and transverse planes. Retroreflective markers were positioned along the spine at C7, T3, T6, T9, T12, L3, and the sacrum. Whole-trunk kinematics and the movement at the six different trunk markers were recorded during rising. PD patients have a significantly greater degree of trunk flexion than controls, showing a significant increase in angular velocity of the trunk in the sagittal plane. The total range of movement of trunk rotation was significantly smaller in the PD group, but lateral movement in the trunk was greater than normal. These data suggest that patients with early PD compensate for their difficulties rising from a chair by generating greater trunk flexion at higher angular velocity, thus developing greater forward momentum. This process results in a decrease in the duration of the unstable transitional phase of sit-to-stand, allowing PD patients to reach the upright position as easily and safely as possible. Small rotational movements are an effective way to maintain the centre of mass within the base of support during sit-to-stand. This mechanism appears to be denied to the PD patients who may use increased movements in the coronal plane as an alternative strategy

Effect of bilateral subthalamic nucleus stimulation on balance and finger control in Parkinson's disease.

Item does not contain fulltextWe aimed to quantify the effects of bilateral subthalamic nucleus (STN) stimulation in Parkinson's disease (PD) on stance and gait ("axial"motor control), and related this to effects on finger movements ("appendicular" motor control). Fourteen PD patients and 20 matched controls participated. Subjects completed several balance and gait tasks (standing with eyes open or closed, on a normal or foam surface; retropulsion test; walking with eyes closed; walking up and down stairs; Get Up and Go test). Postural control was quantified using trunk sway measurements (angle and angular velocity) in the roll and pitch directions. Subjects further performed a pinch grip reaction time task, where we measured isometric grip forces, as well as movement and reaction times. Patients were examined with STN stimulators switched on or off (order randomised across patients), always after a supramaximal levodopa dosage. STN stimulation improved postural control, as reflected by a reduced trunk sway tremor during stance, a reduced duration for all gait tasks, an increased trunk pitch velocity while rising from a chair, and improved roll stability. STN stimulation also improved finger control, as reflected by a reduced time to reach maximum grip force, without altering reaction times and maximum force levels. Improvements in finger control timing did not correlate with reduced task durations during gait. We conclude that STN stimulation affords improvement of postural control in PD, over and above optimal drug treatment. STN stimulation also provides a simultaneous effect on distal and axial motor control. Because improvements in distal and axial motor control were not correlated, we assume that these effects are mediated by stimulation of different structures within the STN

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

reserved328Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS.Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3.0-6.5 were randomly assigned (2: 1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials. gov, number NCT01665144.Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16.8 years (SD 8.3), and the mean time since conversion to SPMS was 3.8 years (SD 3.5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0.79, 95% CI 0.65-0.95; relative risk reduction 21%; p=0.013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.mixedKappos L.; Bar-Or A.; Cree B.A.C.; Fox R.J.; Giovannoni G.; Gold R.; Vermersch P.; Arnold D.L.; Arnould S.; Scherz T.; Wolf C.; Wallstrom E.; Dahlke F.; Achiron A.; Achtnichts L.; Agan K.; Akman-Demir G.; Allen A.B.; Antel J.P.; Antiguedad A.R.; Apperson M.; Applebee A.M.; Ayuso G.I.; Baba M.; Bajenaru O.; Balasa R.; Balci B.P.; Barnett M.; Bass A.; Becker V.U.; Bejinariu M.; Bergh F.T.; Bergmann A.; Bernitsas E.; Berthele A.; Bhan V.; Bischof F.; Bjork R.J.; Blevins G.; Boehringer M.; Boerner T.; Bonek R.; Bowen J.D.; Bowling A.; Boyko A.N.; Boz C.; Bracknies V.; Braune S.; Brescia Morra V.; Brochet B.; Brola W.; Brownstone P.K.; Brozman M.; Brunet D.; Buraga I.; Burnett M.; Buttmann M.; Butzkueven H.; Cahill J.; Calkwood J.C.; Camu W.; Cascione M.; Castelnovo G.; Centonze D.; Cerqueira J.; Chan A.; Cimprichova A.; Cohan S.; Comi G.; Conway J.; Cooper J.A.; Corboy J.; Correale J.; Costell B.; Cottrell D.A.; Coyle P.K.; Craner M.; Cui L.; Cunha L.; Czlonkowska A.; da Silva A.M.; de Sa J.; de Seze J.; Debouverie M.; Debruyne J.; Decoo D.; Defer G.; Derfuss T.; Deri N.H.; Dihenia B.; Dioszeghy P.; Donath V.; Dubois B.; Duddy M.; Duquette P.; Edan G.; Efendi H.; Elias S.; Emrich P.J.; Estruch B.C.; Evdoshenko E.P.; Faiss J.; Fedyanin A.S.; Feneberg W.; Fermont J.; Fernandez O.F.; Ferrer F.C.; Fink K.; Ford H.; Ford C.; Francia A.; Freedman M.; Frishberg B.; Galgani S.; Garmany G.P.; Gehring K.; Gitt J.; Gobbi C.; Goldstick L.P.; Gonzalez R.A.; Grandmaison F.; Grigoriadis N.; Grigorova O.; Grimaldi L.M.E.; Gross J.; Gross-Paju K.; Gudesblatt M.; Guillaume D.; Haas J.; Hancinova V.; Hancu A.; Hardiman O.; Harmjanz A.; Heidenreich F.R.; Hengstman G.J.D.; Herbert J.; Herring M.; Hodgkinson S.; Hoffmann O.M.; Hofmann W.E.; Honeycutt W.D.; Hua L.H.; Huang D.; Huang Y.; Huang D.; Hupperts R.; Imre P.; Jacobs A.K.; Jakab G.; Jasinska E.; Kaida K.; Kalnina J.; Kaprelyan A.; Karelis G.; Karussis D.; Katz A.; Khabirov F.A.; Khatri B.; Kimura T.; Kister I.; Kizlaitiene R.; Klimova E.; Koehler J.; Komatineni A.; Kornhuber A.; Kovacs K.; Koves A.; Kozubski W.; Krastev G.; Krupp L.B.; Kurca E.; Lassek C.; Laureys G.; Lee L.; Lensch E.; Leutmezer F.; Li H.; Linker R.A.; Linnebank M.; Liskova P.; Llanera C.; Lu J.; Lutterotti A.; Lycke J.; Macdonell R.; Maciejowski M.; Maeurer M.; Magzhanov R.V.; Maida E.-M.; Malciene L.; Mao-Draayer Y.; Marfia G.A.; Markowitz C.; Mastorodimos V.; Matyas K.; Meca-Lallana J.; Merino J.A.G.; Mihetiu I.G.; Milanov I.; Miller A.E.; Millers A.; Mirabella M.; Mizuno M.; Montalban X.; Montoya L.; Mori M.; Mueller S.; Nakahara J.; Nakatsuji Y.; Newsome S.; Nicholas R.; Nielsen A.S.; Nikfekr E.; Nocentini U.; Nohara C.; Nomura K.; Odinak M.M.; Olsson T.; van Oosten B.W.; Oreja-Guevara C.; Oschmann P.; Overell J.; Pachner A.; Panczel G.; Pandolfo M.; Papeix C.; Patrucco L.; Pelletier J.; Piedrabuena R.; Pless M.; Polzer U.; Pozsegovits K.; Rastenyte D.; Rauer S.; Reifschneider G.; Rey R.; Rizvi S.A.; Robertson D.; Rodriguez J.M.; Rog D.; Roshanisefat H.; Rowe V.; Rozsa C.; Rubin S.; Rusek S.; Sacca F.; Saida T.; Salgado A.V.; Sanchez V.E.F.; Sanders K.; Satori M.; Sazonov D.V.; Scarpini E.A.; Schlegel E.; Schluep M.; Schmidt S.; Scholz E.; Schrijver H.M.; Schwab M.; Schwartz R.; Scott J.; Selmaj K.; Shafer S.; Sharrack B.; Shchukin I.A.; Shimizu Y.; Shotekov P.; Siever A.; Sigel K.-O.; Silliman S.; Simo M.; Simu M.; Sinay V.; Siquier A.E.; Siva A.; Skoda O.; Solomon A.; Stangel M.; Stefoski D.; Steingo B.; Stolyarov I.D.; Stourac P.; Strassburger-Krogias K.; Strauss E.; Stuve O.; Tarnev I.; Tavernarakis A.; Tello C.R.; Terzi M.; Ticha V.; Ticmeanu M.; Tiel-Wilck K.; Toomsoo T.; Tubridy N.; Tullman M.J.; Tumani H.; Turcani P.; Turner B.; Uccelli A.; Urtaza F.J.O.; Vachova M.; Valikovics A.; Walter S.; Van Wijmeersch B.; Vanopdenbosch L.; Weber J.R.; Weiss S.; Weissert R.; Vermersch P.; West T.; Wiendl H.; Wiertlewski S.; Wildemann B.; Willekens B.; Visser L.H.; Vorobeychik G.; Xu X.; Yamamura T.; Yang Y.N.; Yelamos S.M.; Yeung M.; Zacharias A.; Zelkowitz M.; Zettl U.; Zhang M.; Zhou H.; Zieman U.; Ziemssen T.Kappos, L.; Bar-Or, A.; Cree, B. A. C.; Fox, R. J.; Giovannoni, G.; Gold, R.; Vermersch, P.; Arnold, D. L.; Arnould, S.; Scherz, T.; Wolf, C.; Wallstrom, E.; Dahlke, F.; Achiron, A.; Achtnichts, L.; Agan, K.; Akman-Demir, G.; Allen, A. B.; Antel, J. P.; Antiguedad, A. R.; Apperson, M.; Applebee, A. M.; Ayuso, G. I.; Baba, M.; Bajenaru, O.; Balasa, R.; Balci, B. P.; Barnett, M.; Bass, A.; Becker, V. U.; Bejinariu, M.; Bergh, F. T.; Bergmann, A.; Bernitsas, E.; Berthele, A.; Bhan, V.; Bischof, F.; Bjork, R. J.; Blevins, G.; Boehringer, M.; Boerner, T.; Bonek, R.; Bowen, J. D.; Bowling, A.; Boyko, A. N.; Boz, C.; Bracknies, V.; Braune, S.; Brescia Morra, V.; Brochet, B.; Brola, W.; Brownstone, P. K.; Brozman, M.; Brunet, D.; Buraga, I.; Burnett, M.; Buttmann, M.; Butzkueven, H.; Cahill, J.; Calkwood, J. C.; Camu, W.; Cascione, M.; Castelnovo, G.; Centonze, D.; Cerqueira, J.; Chan, A.; Cimprichova, A.; Cohan, S.; Comi, G.; Conway, J.; Cooper, J. A.; Corboy, J.; Correale, J.; Costell, B.; Cottrell, D. A.; Coyle, P. K.; Craner, M.; Cui, L.; Cunha, L.; Czlonkowska, A.; da Silva, A. M.; de Sa, J.; de Seze, J.; Debouverie, M.; Debruyne, J.; Decoo, D.; Defer, G.; Derfuss, T.; Deri, N. H.; Dihenia, B.; Dioszeghy, P.; Donath, V.; Dubois, B.; Duddy, M.; Duquette, P.; Edan, G.; Efendi, H.; Elias, S.; Emrich, P. J.; Estruch, B. C.; Evdoshenko, E. P.; Faiss, J.; Fedyanin, A. S.; Feneberg, W.; Fermont, J.; Fernandez, O. F.; Ferrer, F. C.; Fink, K.; Ford, H.; Ford, C.; Francia, A.; Freedman, M.; Frishberg, B.; Galgani, S.; Garmany, G. P.; Gehring, K.; Gitt, J.; Gobbi, C.; Goldstick, L. P.; Gonzalez, R. A.; Grandmaison, F.; Grigoriadis, N.; Grigorova, O.; Grimaldi, L. M. E.; Gross, J.; Gross-Paju, K.; Gudesblatt, M.; Guillaume, D.; Haas, J.; Hancinova, V.; Hancu, A.; Hardiman, O.; Harmjanz, A.; Heidenreich, F. R.; Hengstman, G. J. D.; Herbert, J.; Herring, M.; Hodgkinson, S.; Hoffmann, O. M.; Hofmann, W. E.; Honeycutt, W. D.; Hua, L. H.; Huang, D.; Huang, Y.; Huang, D.; Hupperts, R.; Imre, P.; Jacobs, A. K.; Jakab, G.; Jasinska, E.; Kaida, K.; Kalnina, J.; Kaprelyan, A.; Karelis, G.; Karussis, D.; Katz, A.; Khabirov, F. A.; Khatri, B.; Kimura, T.; Kister, I.; Kizlaitiene, R.; Klimova, E.; Koehler, J.; Komatineni, A.; Kornhuber, A.; Kovacs, K.; Koves, A.; Kozubski, W.; Krastev, G.; Krupp, L. B.; Kurca, E.; Lassek, C.; Laureys, G.; Lee, L.; Lensch, E.; Leutmezer, F.; Li, H.; Linker, R. A.; Linnebank, M.; Liskova, P.; Llanera, C.; Lu, J.; Lutterotti, A.; Lycke, J.; Macdonell, R.; Maciejowski, M.; Maeurer, M.; Magzhanov, R. V.; Maida, E. -M.; Malciene, L.; Mao-Draayer, Y.; Marfia, G. A.; Markowitz, C.; Mastorodimos, V.; Matyas, K.; Meca-Lallana, J.; Merino, J. A. G.; Mihetiu, I. G.; Milanov, I.; Miller, A. E.; Millers, A.; Mirabella, M.; Mizuno, M.; Montalban, X.; Montoya, L.; Mori, M.; Mueller, S.; Nakahara, J.; Nakatsuji, Y.; Newsome, S.; Nicholas, R.; Nielsen, A. S.; Nikfekr, E.; Nocentini, U.; Nohara, C.; Nomura, K.; Odinak, M. M.; Olsson, T.; van Oosten, B. W.; Oreja-Guevara, C.; Oschmann, P.; Overell, J.; Pachner, A.; Panczel, G.; Pandolfo, M.; Papeix, C.; Patrucco, L.; Pelletier, J.; Piedrabuena, R.; Pless, M.; Polzer, U.; Pozsegovits, K.; Rastenyte, D.; Rauer, S.; Reifschneider, G.; Rey, R.; Rizvi, S. A.; Robertson, D.; Rodriguez, J. M.; Rog, D.; Roshanisefat, H.; Rowe, V.; Rozsa, C.; Rubin, S.; Rusek, S.; Sacca, F.; Saida, T.; Salgado, A. V.; Sanchez, V. E. F.; Sanders, K.; Satori, M.; Sazonov, D. V.; Scarpini, E. A.; Schlegel, E.; Schluep, M.; Schmidt, S.; Scholz, E.; Schrijver, H. M.; Schwab, M.; Schwartz, R.; Scott, J.; Selmaj, K.; Shafer, S.; Sharrack, B.; Shchukin, I. A.; Shimizu, Y.; Shotekov, P.; Siever, A.; Sigel, K. -O.; Silliman, S.; Simo, M.; Simu, M.; Sinay, V.; Siquier, A. E.; Siva, A.; Skoda, O.; Solomon, A.; Stangel, M.; Stefoski, D.; Steingo, B.; Stolyarov, I. D.; Stourac, P.; Strassburger-Krogias, K.; Strauss, E.; Stuve, O.; Tarnev, I.; Tavernarakis, A.; Tello, C. R.; Terzi, M.; Ticha, V.; Ticmeanu, M.; Tiel-Wilck, K.; Toomsoo, T.; Tubridy, N.; Tullman, M. J.; Tumani, H.; Turcani, P.; Turner, B.; Uccelli, A.; Urtaza, F. J. O.; Vachova, M.; Valikovics, A.; Walter, S.; Van Wijmeersch, B.; Vanopdenbosch, L.; Weber, J. R.; Weiss, S.; Weissert, R.; Vermersch, P.; West, T.; Wiendl, H.; Wiertlewski, S.; Wildemann, B.; Willekens, B.; Visser, L. H.; Vorobeychik, G.; Xu, X.; Yamamura, T.; Yang, Y. N.; Yelamos, S. M.; Yeung, M.; Zacharias, A.; Zelkowitz, M.; Zettl, U.; Zhang, M.; Zhou, H.; Zieman, U.; Ziemssen, T