Objective: To report safety and efficacy outcomes from up to 9 years of treatment with teriflunomide in an extension (NCT00803049) of the pivotal phase 3 Teriflunomide Multiple Sclerosis Oral (TEMSO) trial (NCT00134563). Methods: A total of 742 patients entered the extension. Teriflunomide-treated patients continued the original dose; those previously receiving placebo were randomized 1:1 to teriflunomide 14 mg or 7 mg. Results: By June 2013, median (maximum) teriflunomide exposure exceeded 190 (325) weeks per patient; 468 patients (63%) remained on treatment. Teriflunomide was well-tolerated with continued exposure. The most common adverse events (AEs) matched those in the core study. In extension year 1, first AEs of transient liver enzyme increases or reversible hair thinning were generally attributable to patients switching from placebo to teriflunomide. Approximately 11% of patients discontinued treatment owing to AEs. Twenty percent of patients experienced serious AEs. There were 3 deaths unrelated to teriflunomide. Soon after the extension started, annualized relapse rates and gadolinium-enhancing T1 lesion counts fell in patients switching from placebo to teriflunomide, remaining low thereafter. Disability remained stable in all treatment groups (median Expanded Disability Status Scale score ≤2.5; probability of 12-week disability progression ≤0.48). Conclusions: In the TEMSO extension, safety observations were consistent with the core trial, with no new or unexpected AEs in patients receiving teriflunomide for up to 9 years. Disease activity decreased in patients switching from placebo and remained low in patients continuing on teriflunomide. Classification of evidence: This study provides Class III evidence that long-term treatment with teriflunomide is well-tolerated and efficacy of teriflunomide is maintained long-term.

Aims: Recent studies showed that Fas expression in leukocytes differs during the course of disease in MS. Fas can regulate a chronic immune response by inducing apoptosis through FADD and Caspase 8. Binding of cFlip instead of Caspase 8 changes the signalling towards survival. Our objective was to characterize the mRNA-expression levels of Fas, FADD, Caspase 8 and cFlip in peripheral blood mononuclear cells in relapsing-remitting (RR) MS and in leukocytes from the spleen and the CNS in EAE.

We investigated the expression of intercellular adhesion molecules ICAM-1 and ICAM-3 on peripheral blood mononuclear cells in a subgroup of 34 patients with relapsing-remitting multiple sclerosis who were treated orally with the chemokine receptor 1 antagonist BX 471 in a 16-week, randomised, double-blind, placebo-controlled phase II study. ICAM-1 and ICAM-3 expression was measured by flow cytometry at different time points during and after therapy and compared using multivariate analysis of variance and non-parametric Mann Whitney test. ICAM-3 expression on CD14( +) peripheral blood mononuclear cells was increased in the verum group under therapy, but did not differ significantly between the verum and placebo groups. Most likely, this trend represents a small epiphenomenon only mediated by receptor cross-talk and feedback mechanisms.

Hintergrund: Der N. hypoglossus innerviert rein motorisch die Zungenmuskulatur. Er verlässt die Medulla oblongata unterhalb der Olive nach lateral und den Schädel durch den Canalis hypoglossi hinter der A.carotis interna, kreuzt die A. carotis externa und verläuft zur Zungenmuskulatur. Die seltene isolierte beidseitige Parese der Nn. hypoglossi tritt am häufigsten bei Schädelbasisfrakturen, iatrogen im Rahmen von Operationen, Intubationen und bei Bestrahlungen auf. Weitere Ursachen sind beidseitige Dissektionen der Aa. carotides internae, rheumatische Erkrankungen oder Knochenmetastasen der Schädelbasis.

Fragestellung: Studien zeigen, dass bei ca. 2/3 früher RR-MS-Patienten mehr als zwei spinale Läsionen vorliegen. In den Zulassungsstudien für GLAT und β-Interferone wurden keine spinalen MRTs durchgeführt. Daher ist bisher keine Aussage möglich, welchen Einfluss eine ausgeprägte spinale Läsionslast auf Wirksamkeit und Verträglichkeit der Basistherapeutika hat.

Die Integrierte Versorgung MS in Hessen startete Ende 2005 gemeinsam mit der BARMER. Im Rahmen der Qualitätssicherung haben wir die Daten der ersten 120 eingeschriebenen Patienten ausgewertet. In die statistische Auswertung gingen die Daten von 116 Patienten ein, die mindestens einen Patientenfragebogen und eine Quartalsrechnung aufwiesen, der durchschnittliche Beobachtungszeitraum war 12,5 Monate.

Seit dem 01.07.2005 besteht zwischen dem Universitätsklinikum Gießen und der Barmer Ersatzkasse in Hessen ein Vertrag zur Integrierten Versorgung der an Multiple Sklerose erkrankten Patienten. Derzeit sind 197 Patienten in der Integrierten Versorgung MS eingeschrieben.

Background Blood–brain barrier (BBB) breakdown is an early event in the pathogenesis of multiple sclerosis (MS). In a previous study we have found a direct stabilization of barrier characteristics after treatment of bovine brain capillary endothelial cells (BCECs) with human recombinant interferon-β-1a (IFN-β-1a) in an in vitro BBB model. In the present study we examined the effect of human recombinant IFN-β-1a on the barrier properties of BCECs derived from four different species including humans to predict treatment efficacy of IFN-β-1a in MS patients. Methods We used primary bovine and porcine BCECs, as well as human and murine BCEC cell lines. We investigated the influence of human recombinant IFN-β-1a on the paracellular permeability for 3H-inulin and 14C-sucrose across monolayers of bovine, human, and murine BCECs. In addition, the transendothelial electrical resistance (TEER) was determined in in vitro systems applying porcine and murine BCECS. Results We found a stabilizing effect on the barrier characteristics of BCECs after pretreatment with IFN-β-1a in all applied in vitro models: addition of IFN-β-1a resulted in a significant decrease of the paracellular permeability across monolayers of human, bovine, and murine BCECs. Furthermore, the TEER was significantly increased after pretreatment of porcine and murine BCECs with IFN-β-1a. Conclusion Our data suggest that BBB stabilization by IFN-β-1a may contribute to its beneficial effects in the treatment of MS. A human in vitro BBB model might be useful as bioassay for testing the treatment efficacy of drugs in MS.

Einleitung: Einer der zentralen pathogenetischen Schritte bei der Multiplen Sklerose (MS) ist eine Störung der Blut-Hirns-Schranke (BHS). Ausgangspunkt für die aktuelle Studie war der Nachweis eines direkten stabilisierenden Effekts von Interferon-ß (IFN-ß)auf die BHS mithilfe eines sehr aufwändigen in vitro-Modells. In der aktuellen Studie wurde das komplexe bovine Modell schrittweise modifiziert mit dem Ziel, einen humanen in vitro-Bioassay zu entwickeln, um den möglichen Therapieerfolg einer IFN-ß-Therapie für den einzelnen MS-Patienten zu beurteilen.

OBJECTIVES:In a pilot study we found a correlation of the clinical outcome with adhesion molecule (AM) concentrations in ventricular cerebrospinal fluid (CSF) but not in serum in patients with intracerebral haemorrhage. We now determined the time course of AM concentration in CSF and serum after basal ganglia haemorrhage (BGH) in order to further uncover pathogenetic mechanisms.MATERIALS AND METHODS:We included 11 patients with acute BGH and ventricular tamponade in which an extraventricular drainage had been applied to treat ventricular ballonade. Paired CSF and serum samples were obtained within 8 h after onset of BGH, as well as on the consecutive days 2, 4, 6, and 8, respectively. The concentrations of soluble ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) in CSF and serum were measured by enzyme-linked immunosorbent assay. Moreover, we determined blood volume and perifocal oedema by a semi-automated planimetry technique from initial cranial computed tomography scans.RESULTS:sICAM-1 and sVCAM-1 levels in CSF were highest within the first hours after onset of BGH, then decreased significantly (P < 0.005 and <0.05, respectively) on day 2 and slightly increased thereafter. Furthermore, BGH volume was significantly correlated with the concentrations of sICAM-1 (r = 0.63, P < 0.05) and sVCAM-1 (r = 0.66, P < 0.05) in ventricular CSF but not in serum.CONCLUSIONS:Our results might indicate that the local inflammatory reaction is pronounced early after onset of BGH and appears to be restricted to the central nervous system. Moreover, AM concentrations measured early after BGH onset correlated stronger with radiological and clinical data than follow-up measurements.

Fragestellung: Ein 54-jähriger männlicher Patient wies seit anderthalb Jahren eine allmähliche Visusverschlechterung auf. Zusätzlich trat eine Gangunsicherheit auf. Windpocken waren in der Kindheit nicht aufgefallen, allerdings war es sieben Monate vor Auftreten der Erstsymptomatik zu einem Kontakt mit einer an Windpocken erkrankten Person gekommen.

Die Multiple Sklerose (MS) ist die häufigste chronische neurologische Erkrankung des jungen Erwachsenenalters mit ca. 160000 Erkrankten in Deutschland. Die Erkrankung ist durch eine hohe interindividuelle Variabilität des Krankheitsverlaufs gekennzeichnet. Im Krankheitsverlauf kommt es nach 10 Jahren bei 70% der (unbehandelten) Patienten zu einer Gehbehinderung, 70% entwickeln kognitive Defizite, 40–75% eine Depression. Daraus resultieren hohe volkswirtschaftliche Kosten. Mittlerweile stehen sehr wirksame kausale Therapieansätze zur Verfügung, die besonders im Frühstadium der Erkrankung helfen.

Fragestellung: Die gewebsspezifisch exprimierten TNFRSF(TNF-Rezeptor-Superfamile)1A und -B transduzieren Apoptose bzw. Inflammation. Im Rahmen der EAE ist die Signalübertragung über TNFRSF1A für die Apoptose von T-Zellen entscheidend. Eine Erniedrigung der leukozytären Apoptose könnte ein vermehrtes Übertreten autoreaktiver T-Zellen ins ZNS und somit ein Andauern der Entzündung bewirken. Die Bifurkation des proapoptotischen bzw. entzündlichen Signaltransduktionsweges findet beim TNF-Rezeptor-assoziierten DD-Protein (TRADD) statt. Zu Beginn der Signaltransduktion sind weiterhin TRAF2 (TNF-Rezeptor-assoziierter Faktor 2), RIP (Rezeptorinteragierendes Protein) und FADD (Fas-assoziiertes DD-Protein) von Bedeutung. Wir untersuchten deren Genexpression beim natürlichen Verlauf der verschiedenen Formen von Multipler Sklerose.

The updated recommendations presented here reflect new developments in the diagnostic work-up and immunotherapy of multiple sclerosis (MS) as well as optimization of medical care for MS patients. Monoclonal antibodies provide considerable improvement of treatment, but their use in basic therapy is restricted by their side effect profile. Thus, for the time being, natalizumab is only approved for monotherapy after basic treatment has failed or for rapidly progressive relapsing-remitting MS. In contrast, long-term data on recombinant beta-interferons and glatiramer acetate (Copaxone((R))) show that even after several years no unexpected side effects occur and that a prolonged therapeutic effect can be assumed which correlates with the dose or frequency of treatment. Recently IFN-beta 1b (Betaferon((R))) was approved for prophylactic treatment after the first attack (clinically isolated syndrome, CIS). During treatment with beta-interferons, neutralizing antibodies can emerge with possible loss of effectivity. In contrast, antibodies play no role in treatment with glatiramer acetate. During or after therapy with mitoxantrone, serious side effects (cardiomyopathy, acute myeloid leukemia) appeared in 0.2-0.4% of cases. Plasmapheresis is limited to individual curative attempts in escalating therapy of a severe attack. According to the revised McDonald criteria, the diagnosis of MS can be made as early as the occurrence of the first attack (CIS). Recommendations for optimized care of MS patients are also new, thus implementing a resolution of the European Parliament.