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Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland).Die Multiple Sklerose ist eine komplexe, autoimmun vermittelte Erkrankung des zentralen Nervensystems, charakterisiert durch inflammatorische Demyelinisierung sowie axonalen/neuronalen Schaden. Die Zulassung verschiedener verlaufsmodifizierender Therapien und unser verbessertes Verständnis der Krankheitsmechanismen und -entwicklung in den letzten Jahren haben die Prognose und den Verlauf der Erkrankung deutlich verändert. Diese Aktualisierung der Behandlungsempfehlung der Multiple Sklerose Therapie Konsensus Gruppe konzentriert sich auf die wichtigsten Empfehlungen für verlaufsmodifizierende Therapien der Multiplen Sklerose im Jahr 2021. Unsere Empfehlungen basieren auf aktuellen wissenschaftlichen Erkenntnissen und gelten für diejenigen Medikamente, die in weiten Teilen Europas, insbesondere in den deutschsprachigen Ländern (Deutschland, Österreich, Schweiz), zugelassen sind.

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. Results One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0–3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. Conclusion Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

Die Therapie der Multiplen Sklerose hat in den letzten 20 Jahren grose Fortschritte gemacht und ist insbesondere in den vergangenen zehn Jahren vielfaltiger geworden. In der Behandlung wird zwischen milden/moderaten und hochaktiven Verlaufen unterschieden. Die Revision der McDonald-Kriterien in den Jahren 2010 und 2017 erlaubt eine fruhe Diagnosestellung und damit eine fruhzeitige Therapie.

Background: The vsMS survey was conducted to better understand the negative effects of fatigue, cognitive impairment, emotional burden, and decreased physical functioning on the personal, professional, and social lives of individuals with multiple sclerosis (MS). Methods: The vsMS survey was an online survey conducted in Australia, Canada, France, Italy, Spain, the United Kingdom, and the United States that assessed the impact of MS on individuals’ daily activities, emotional well-being, relationships, and employment. Results: The survey included 1075 participants with relapsing-remitting MS. Almost 42% of participants reported that their ability to perform and manage daily activities had worsened during the previous 2 years. More than 50% reported limitations in daily activities due to fatigue, physical weakness, problems with balance/coordination, heat/cold sensitivity, memory problems, numbness/tingling, trouble concentrating, impaired movement/muscle stiffness, and impaired sleeping. Participants also reported a negative effect on emotional and social factors, including self-esteem, general outlook, well-being, maintaining/starting relationships, ability to progress in their career/keep their job, and ability to cope with life roles. Conclusions: These data highlight the importance of addressing the impact of MS and the social and emotional disease burdens on daily activities when planning the care of patients with MS.

Oberstes Prinzip bei der Behandlung der Myasthenia gravis ist die Immunsuppression — so kann in vielen Fallen eine Remission erreicht werden. Bei therapierefraktaren Fallen mussen lebensbedrohliche myasthene Krisen verhindert werden.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), with characteristic inflammatory lesions and demyelination. The clinical benefit of cell-depleting therapies targeting CD20 has emphasized the role of B cells and autoantibodies in MS pathogenesis. We previously introduced an enzyme-linked immunospot spot (ELISpot)-based assay to measure CNS antigen-specific B cells in the blood of MS patients and demonstrated its usefulness as a predictive biomarker for disease activity in measuring the successful outcome of disease-modifying therapies (DMTs). Here we used a planar protein array to investigate CNS-reactive antibodies in the serum of MS patients as well as in B cell culture supernatants after polyclonal stimulation. Anti-CNS antibody reactivity was evident in the sera of the MS cohort, and the antibodies bound a heterogeneous set of molecules, including myelin, axonal cytoskeleton, and ion channel antigens, in individual patients. Immunoglobulin reactivity in supernatants of stimulated B cells was directed against a broad range of CNS antigens. A group of MS patients with a highly active B cell component was identified by the ELISpot assay. Those antibody reactivities remained stable over time. These assays with protein arrays identify MS patients with a highly active B cell population with antibodies directed against a swathe of CNS proteins.

We present the case of an 18 year old Caucasian with known celiac disease, who suffered a severe first attack of acute intermittent porphyria (AIP) with neuropsychiatric symptoms, severe tetraparesis and respiratory insufficiency. Treatment with heme arginate and high-dose intravenous glucose and rigorous rehabilitation resulted in a slow but almost complete recovery of her motor symptoms. To our knowledge this is the first case of acute intermittent porphyria triggered by malnutrition in the context of celiac disease. It is remarkable that the patient showed a favourable outcome despite the severity of her initial symptoms. This case shows the importance of early and systematic symptomatic treatment in patients with severe neurologic manifestation of AIP.

Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis. A full treatment course comprises two treatment cycles given with 1 year of intermission. Further dosing is not routinely recommended in years 3 and 4.The long-term management of patients treated with oral cladribine has not been fully defined on the basis of clinical studies as of yet. The authors provide their expert opinion on this.Based on available evidence and experience from routine clinical use, the authors suggest a structured approach to the long-term management of patients treated with cladribine tablets according to their responder type, i. e. the degree and timing of disease activity, if any, after treatment initiation. Informed treatment decisions require structured patient monitoring by established clinical and imaging parameters. In patients with relevant disease activity in year 3 or 4 and beyond, the use of additional cycle(s) of oral cladribine might become an option. For patients requiring a treatment switch, the choice of therapies primarily includes moderately to highly effective MS drugs.

A popular feature of the Multiple Sclerosis Experts Summit is interactive break-out sessions to discuss various aspects of multiple sclerosis (MS), including MS spasticity and general management of MS patients. The format encourages participation and active discussion, thus providing attendees with the opportunity to exchange their experiences of the day-to-day management of MS in clinical practice. Following feedback provided by each session leader, key messages are summarized and presented in a plenary session by the Summit chair. Topics covered in this year's country break-out sessions included: triggering factors for MS; decision-making in MS and the importance of patients’ risk perception; assessment and management of MS spasticity.

Die Bedeutung von Nahrungsbestandteilen, ihrer moglichen Interaktion mit dem Mikrobiom und ihr Einfluss auf die Multiple Sklerose wurde in den letzten Jahren intensiv untersucht. Die bisherigen Ergebnisse eroffnen neue Perspektiven auf mogliche atiologische Faktoren bei der Entstehung von ZNS-Autoimmunitat, machen aber auch klar, dass wahrscheinlich nicht einzelne Ernahrungsbestandteile eine Rolle spielen, sondern dass das Zusammenspiel vieler verschiedener Faktoren im Vordergrund steht.

Durch die verbesserte neurologische Intensivmedizin konnte die Letalitat des Guillain-Barre-Syndroms in den letzten Jahrzehnten drastisch gesenkt werden. Dennoch bleiben bei etwa 10 –20 % der Patienten zum Teil schwere motorische Behinderungen zuruck. Als Behandlungsmasnahme der ersten Wahl gilt derzeit die Gabe von intravenosen Immunglobulinen, insbesondere bei autonom instabilen Patienten.

Vor dem Hintergrund der sich in den letzten Jahren deutlich vermehrten immuntherapeutischen Therapieoptionen bei Multipler Sklerose (MS) werden verschiedene Therapiestrategien wie die Induktions- versus Eskalationstherapie diskutiert.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland). in press, CA extern

Two pivotal phase 3 teriflunomide studies provided data on relapses, fatigue, and health-related quality of life (HRQoL) in patients with relapsing forms of multiple sclerosis (MS).Using pooled data from the TEMSO (NCT00134563) and TOWER (NCT00751881) studies, we investigated the association between relapse severity, and changes from baseline to Week 108 in fatigue and HRQoL outcomes.Four definitions of relapse severity were applied in this analysis: sequelae post-relapse; relapse leading to hospitalization; relapse requiring intravenous corticosteroids; and intense relapse. We assessed the association between relapse severity and changes in Fatigue Impact Scale score (n=959), physical and mental health component summary scores from the Short Form (SF)-36 questionnaire (n=904), and SF-6D utility index scores (n=820).Irrespective of the definition of relapse severity applied, in patients experiencing severe relapse(s), fatigue was increased and HRQoL was decreased; these changes were statistically significant (p0.0001), and were also clinically significant in many cases. The greatest worsening in fatigue and HRQoL was observed in patients with relapses leading to hospitalization.Given that severe relapses adversely affect patient-reported fatigue and HRQoL, prevention of severe relapses should be an important therapeutic aim in the treatment of patients with MS.

The knee flexion-extension angle is an important criterion for the rehabilitation process after a rupture of the anterior cruciate ligament (ACL), which is a typical sports injury. This paper describes the development and evaluation of a smart knee sleeve, which is capable of calculating the knee flexion-extension angle based on inertial sensors. The output is to be used to supervise and speed up rehabilitation by guiding patients through exercises and giving feedback about the execution. The accuracy of the knee angle calculation was evaluated in a study with twelve healthy subjects performing six different exercises with an optical system as reference. The effects of different functional alignment movements, knee sleeve material and recalibration on the final knee angle were evaluated. The mean absolute error (MAE) of all maxima and minima was calculated and averaged over all subjects and exercises. An MAE of 5.2° compared to the gold standard was achieved while the Pearson correlation was 0.96 for 30 minutes training without recalibration or restart of the system.

Background Fatigue is a major symptom of multiple sclerosis (MS) in patients, and it has been shown to improve with physical exercise. Although fingolimod might lessen fatigue, it is unclear how patients treated with fingolimod react to physical activity regarding fatigue. Objective This study evaluated the effect of an exercise intervention on fatigue in relapsing–remitting MS patients receiving fingolimod. Methods People with MS (PwMS) were randomized to either a structured internet-based exercise program (e-training) or no e-training intervention. The primary endpoint was the change in the Modified Fatigue Impact Scale (mFIS) after six months. Results The primary analysis showed no statistically significant difference between groups in the mFIS change. Subgroup analyses revealed a beneficial effect of physical exercise for PwMS with low aerobic capacity and with low aerobic capacity plus more severe fatigue. The incidence of adverse events was similar in both groups. No cardiovascular events were reported. The majority of PwMS were relapse free. Conclusion Physical exercise benefits on fatigue may depend on the physical capacity of the patient and requires individualized training. Consistent with previous studies, these results suggest that physical exercise generally does not impose a risk and that this holds true also for patients receiving fingolimod. Trial registration: ClinicalTrials.gov, NCT01490840.

Relapsing–remitting multiple sclerosis (RRMS) requires efficient immunomodulatory treatment to reach “no evidence of disease activity” status at best. Alemtuzumab and fingolimod have proved to be efficient options in RRMS with active disease course. Yet, side effects and break-through disease may limit long-time treatment and necessitate switch of medication. Data on efficacy and safety of alemtuzumab following fingolimod treatment are limited, but useful for clinical practice. Clinical and MRI data of 50 RRMS patients with a history of therapy switch from fingolimod to alemtuzumab were retrospectively analyzed. Data were acquired from nine large German MS Centers from 2013 to 2016 and analyzed using descriptive statistics. On average, patients with disease duration of 12.9 years and median EDSS of 3.0 at baseline switched to alemtuzumab after 68 weeks of fingolimod treatment. Thereafter, patients on alemtuzumab were followed for a mean of 64 weeks. The annualized relapse rate decreased from 2.2 in the year prior to 0.34 in the following year after switching to alemtuzumab and EDSS stabilized. In a subgroup of patients (n = 23), MRI data point to a reduction in enhancing (4.47 vs. 0.26) and new/enlarging T2 lesions (5.8 vs. 0.27) after treatment adjustment. Side effects were generally as expected from published data for alemtuzumab (autoimmunity 2/50, severe infections 1/50). One patient suffered combined lethal necrotizing leukoencephalopathy and hemolytic anemia. Therapy switch was highly effective in reducing clinical and MRI surrogates of disease activity and was mainly well tolerated within one year of follow-up. Hence, alemtuzumab constitutes a promising therapy in RRMS with refractory disease activity despite fingolimod treatment. Further studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up.

Trotz der diametral unterschiedlichen Zeitskalen, in denen sich die Krankheitsprozesse und -folgen bei der Multiplen Sklerose (MS) und beim ischamischen Schlaganfall manifestieren, zeigen sich konzeptionelle Parallelen zwischen beiden Erkrankungen, die fur das Management der MS richtungsweisend sind: Entzundliche Erkrankungsaktivitat und konsekutive Neurodegeneration fuhren zu potenziell irreversibler Gewebeschadigung und damit zu bleibender Behinderung. Dementsprechend sind eine fruhzeitige Detektion von Erkrankungsaktivitat und eine zeitnahe Intervention bzw. Therapieoptimierung ausschlaggebend fur eine Verbesserung der langfristigen Prognose, was sich mit dem in der Akuttherapie des ischamischen Schlaganfalls gepragten Begriff „time is brain“ griffig beschreiben lasst. Bei der MS beinhaltet ein „Time-is-brain“-Konzept den Wert einer fruhen Immuntherapie nach Diagnosestellung sowie die Notwendigkeit eines sensitiven strukturierten Monitorings in Verbindung mit fruhzeitiger Therapieoptimierung bei Nachweis von Krankheitsaktivitat unter Therapie. Das ubergeordnete Ziel der Therapie im gesamten Erkrankungsverlauf der MS ist dabei die bestmogliche und anhaltende Kontrolle jeglicher erfassbarer Krankheitsaktivitat, insbesondere in der fruhen Erkrankungsphase. Im Alltag kann die intersektorale Kooperation in regionalen MS-Netzwerken mit spezialisierten Zentren dazu beitragen, die verfugbaren hochwirksamen Medikamente mit ihren jeweils eigenen Nutzen-Risiko-Profilen optimal einzusetzen und damit die Aussicht auf eine langfristige Stabilisierung der Lebensqualitat der MS-Patienten zu erhohen.

Trotz stetiger Neuentwicklungen und Verbesserungen der immunmodulatorischen Langzeittherapie stellt die Therapie des akuten (MS)-Schubes nach wie vor einen wichtigen Bestandteil der MS-Behandlung dar.

Objective Autoantibodies against paranodal proteins have been described in patients with inflammatory neuropathies, but their association with pathology of nodes of Ranvier is unclear. We describe the clinical phenotype and histopathological changes of paranodal architecture of patients with autoantibodies against contactin-1, identified from a cohort with chronic inflammatory demyelinating polyradiculoneuropathy (n=53) and Guillain-Barre syndrome (n=21). Methods We used ELISA to detect autoantibodies against contactin-1. Specificity of the autoantibodies was confirmed by immunoblot assay, binding to contactin-1-transfected human embryonic kidney cells, binding to paranodes of murine teased fibres and preabsorption experiments. Paranodal pathology was investigated by immunofluorescence labelling of dermal myelinated fibres. Results High reactivity to contactin-1 by ELISA was found in four patients with chronic inflammatory demyelinating polyradiculoneuropathy and in none of the patients with Guillain-Barre syndrome, which was confirmed by cell binding assays in all four patients. The four patients presented with a typical clinical picture, namely acute onset of disease and severe motor symptoms, with three patients manifesting action tremor. Immunofluorescence-labelling of paranodal proteins of dermal myelinated fibres revealed disruption of paranodal architecture. Semithin sections showed axonal damage but no classical signs of demyelination. Interpretation We conclude that anti-contactin-1-related neuropathy constitutes a presumably autoantibody-mediated form of inflammatory neuropathy with distinct clinical symptoms and disruption of paranodal architecture as a pathological correlate. Anti-contactin-1-associated neuropathy does not meet morphological criteria of demyelinating neuropathy and therefore, might rather be termed a ‘paranodopathy’ rather than a subtype of demyelinating inflammatory neuropathy.

ObjectiveTo report 3 patients with multiple sclerosis showing severe activation of disease during immunotherapy with alemtuzumab.MethodsRetrospective case series.ResultsPatient 1, a 21-year-old woman, developed severe cognitive impairment, sight deterioration, severe gait ataxia, urinary retention, and extensive progression of cerebral lesion load, including new lesions that exhibited gadolinium ring enhancement and dominance of CD19/20-positive B lymphocytes, 6 months after induction of alemtuzumab. Patient 2, a 28-year-old man, developed left-sided hemihypesthesia and ∼60 new cerebral and spinal lesions including lesions with gadolinium ring enhancement 6 months after induction of alemtuzumab. Patient 3, a 37-year-old woman, developed ataxia and numbness of the left thigh, 16 new gadolinium-positive supratentorial lesions, and partly ring-enhancing and dominance of CD19/20-positive B lymphocytes 6 months after induction of alemtuzumab.ConclusionThis is a case series reporting severe activation of disease during immunotherapy with alemtuzumab. All patients showed onset of symptoms 6 months after induction of alemtuzumab, strikingly similar MRI lesion morphology, and unexpected high total B cell count, which may suggest a B-cell-mediated activation of disease. Whether this is due to different rates of B- and T cell repopulation has to be the subject of further research. Moreover, further effects on the interactions between the adaptive and innate immunity as well as between B and T cell lineages might explain the observed disease activation.

Therapeutische und technische Innovationen der letzten Jahre haben die Versorgung von MS-Patienten erheblich verbessert. Fur eine optimale flachendeckende Versorgung ist allerdings die Etablierung intersektoraler Netzwerke erforderlich, die am sinnvollsten durch regionale Netzwerke getragen und ausgebaut werden kann.

Die wachsende Zahl medikamentoser Therapieoptionen fur die Multiple Sklerose erlaubt es uns, auf die individuellen Wunsche unserer Patienten einzugehen und damit die Therapieadharenz zu starken. Entscheidend ist aber nach wie vor, dass diese Behandlung fruh begonnen und kontinuierlich uberpruft wird.

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing–remitting multiple sclerosis. This post hoc analysis of the Phase III TOWER study evaluated the effects of teriflunomide treatment on five severe relapse outcomes: relapses with sequelae defined by an increase in Expanded Disability Status Scale (EDSS)/functional system (FS) score (sequelae-EDSS/FS) 30 days post relapse; relapses with sequelae defined by the investigator (sequelae-investigator); relapses leading to hospitalization; relapses treated with intravenous corticosteroids; and intense relapses using the definition of Panitch et al. from the EVIDENCE study based on specified increases in EDSS for severe relapses. Adjusted annualized rates for the five severe relapse outcomes were derived using a Poisson model with robust error variance, with treatment, baseline EDSS strata and region as covariates. Compared with placebo, teriflunomide significantly reduced annualized rates of relapses with sequelae-EDSS/FS [14 mg, 36.6 % (p = 0.0021); 7 mg, 31.3 % (p = 0.0104)] and sequelae-investigator [14 mg only, 53.5 % (p = 0.0004)], relapses leading to hospitalization [14 mg only, 33.6 % (p = 0.0155)], relapses requiring intravenous corticosteroids [14 mg, 35.7 % (p = 0.0002); 7 mg, 21.5 % (p = 0.0337)], and intense relapses [14 mg only, 52.5 % (p = 0.0015)]. Patients treated with teriflunomide 14 mg spent significantly fewer nights in hospital for relapse (p = 0.009) and had lower annualized rates of all hospitalizations (p = 0.030). Taken together, the positive effects of teriflunomide on severe relapses indicate that teriflunomide may reduce relapse-related healthcare costs. Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7395-7) contains supplementary material, which is available to authorized users.

Objective: Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in patients receiving natalizumab for multiple sclerosis (MS). JCV detection by quantitative polymer ...

ZusammenfassungFür die verlaufsmodifizierende Basistherapie der schubförmigen Multiplen Sklerose standen bis vor Kurzem ausschließlich injizierbare Präparate zur Verfügung. Mit Dimethylfumarat (DMF, Tecfidera®) wurde erstmals ein orales Medikament für die Basistherapie eingeführt. DMF zeigte in den klinischen Phase-IIIStudien gute Wirksamkeit und Sicherheit. Die orale Gabe kann die Integration der Behandlung in den Alltag der Patienten erleichtern und damit die Therapieadhärenz günstig beeinflussen. DMF erwies sich im klinischen Studienprogramm als gut verträglich. Therapieabbrüche wegen unerwünschter Ereignisse waren selten. Nebenwirkungen z. B. gastrointestinale Symptome und Flush waren meist mild bis mäßig ausgeprägt; ihre Inzidenz war in den ersten 1 bis 3 Monaten nach Therapiebeginn am höchsten und nahm im weiteren Verlauf ab. Reduzierte Initialdosis, Einnahme mit den Mahlzeiten, Gabe üblicher Medikamente zur symptomatischen Therapie, Acetylsalicylsäure als Prämedikation (zeitlich begrenzt) und optional eine vorübergehende Dosisreduktion können diese Symptome reduzieren. Diese Maßnahmen können bei betroffenen Patienten dazu beitragen, die Anfangsphase zu überbrücken und die konsequente, langfristige Therapie mit diesem hochwirksamen Medikament zu sichern.

Background: With a large array of disease modifying therapies (DMTs) for relapsing-remitting MS (RRMS), identifying the optimal treatment option for the individual patient is challenging and switching of immunotherapies is often required. The objective of this study was to systematically investigate reasons for DMT switching in patients on immunotherapies for mild/moderate MS, and provide real-life insights into currently applied therapeutic strategies. Methods: This noninterventional, cross-sectional study (ML29913) at 50 sites in Germany included RRMS patients on therapies for mild/moderate MS who switched immunotherapy in the years 2014–2017. The key outcome variable was the reason to switch, as documented in the medical charts, based on failure of current therapy, cognitive decline, adverse events (AEs), patient wish, or a woman’s wish to become pregnant. Expectations of the new DMT and patients’ assessment of the decision maker were also recorded. Results: The core analysis population included 595 patients, with a mean age of 41.6 years, of which 69.7% were female. More than 60% of patients had at least one relapse within 12 months prior to the switch. The main reasons to switch DMT were failure of current therapy (53.9%), patient wish (22.4%), and AEs (19.0%). Most patients (54.3%) were switched within DMTs for mild/moderate MS; only 43.5% received a subsequent DMT for active/highly active MS. While clinical and outcome-oriented aspects were the most frequently mentioned expectations of the new DMT for physicians, aspects relating to quality of life played a major role for patients. Conclusions: Our data indicate suboptimal usage of DMTs, including monoclonal antibodies, for active/highly active MS in German patients. This illustrates the medical need for DMTs combining high efficacy, low safety risk, and low therapy burden.

Im Zeitalter der Entwicklung vieler neuer Therapieprinzipien stellt sich die Frage nach der Zukunft der injizierbaren Therapeutika wie Beta-Interferone und Glatirameracetet, die sich als Basistherapien der ersten Wahl der schubformigen multiplen Sklerose seit langem fest etabliert haben. Sie haben im Vergleich zu den erst kurzer zugelassenen oder vor der Zulassung stehenden Praparaten, den grosen Vorteil gut bekannter Langzeitvertraglichkeit und -sicherheit. Diese Aspekte spielen in der Beratung der Patienten oft eine sehr wichtige Rolle.

Auf dem Nahrboden einer lange vollig unklaren Pathologie entstanden unzahlige Entstehungstheorien und Behandlungsansatze der Multiplen Sklerose (MS). In den letzten 40 Jahren haben technischer Fortschritt und der Einsatz wissenschaftlicher Forschungsmethoden erheblich dazu beigetragen, den Kenntnisstand bezuglich Entstehung, Diagnostik und Therapie der MS zu erweitern – ein Prozess, der bis heute noch nicht abgeschlossen ist. Die Einstellung zu korperlicher Aktivitat und Anstrengung bei MS hat sich ebenfalls stark verandert. Ein Paradigmenwechsel fuhrte weg von krankheitsauslosenden und -verschlimmernden Aspekten der korperlichen Aktivitat hin zu therapeutischen Chancen, die genutzt werden konnten. Erste Hinweise und Belege fur positive Wirkungen auf Symptome und auch den Krankheitsverlauf wurden jedoch erst mit einer jahrzehntelangen Verzogerung in der vermehrten Forschungsaktivitat Anfang der 1990er Jahre wieder aufgegriffen. Obwohl zahlreiche Nachweise positiver Wirkungen korperlicher Aktivitat vorliegen sind hochwertige Originalarbeiten eher selten, sodass viele Fragen bezuglich spezifischer Trainingswirkungen und -empfehlungen offen bleiben.

Die Eskalationstherapie ist derzeit ein wichtiges, wenn nicht das wichtigste Thema in der offentlichen Therapiediskussion zur Multiplen Sklerose. Dementsprechend ist die Eskalationstherapie per se ein zeitgemases Konzept. Der folgende Beitrag soll daher die Wichtigkeit des unterliegenden Konzeptes erlautern und unterstreichen — besonders vor dem Hintergrund der MS-Therapieziele. Allerdings soll auch die Frage diskutiert werden, ob die Begrifflichkeit „Eskalationstherapie“ tatsachlich noch zeitgemas und zukunftsfahig ist — auch angesichts der zu erwartenden Neuentwicklungen.

BACKGROUND: A polyspecific, intrathecal humoral immune response against neurotropic viruses such as measles, rubella and varicella zoster virus (MRZ reaction, MRZR) is present in 80-100% of patients with multiple sclerosis (MS), but has not to date been evaluated in patients with neuromyelitis optica (NMO). AIMS: To evaluate whether MRZR distinguishes NMO and MS. METHODS: 20 patients with NMO and 42 with MS were included. The intrathecal synthesis of antibodies against measles, rubella and varicella zoster virus was detected by calculation of the respective antibody indices (AI). RESULTS: A positive MRZ reaction, as defined by a combination of at least two positive AIs, was found in 37/42 MS, but in only 1/20 NMO patients (p

The World Wide Web is increasingly used in therapeutic settings. In this regard, internet-based interventions have proven effective in ameliorating several health behaviors, amongst them physical activity behavior. Internet-delivered interventions have shown positive effects on physical activity and physical function in persons with MS (pwMS). In this review we give an overview on several online exercise programs for pwMS and discuss the advantages and drawbacks of web-based interventions. Although participants of online exercise programs reported a high acceptance and satisfaction with the intervention, decreasing compliance was a major issue. A possible remedy might be the implementation of game-design elements to increase compliance and long-term adherence to internet-delivered interventions. In addition we believe that the integration of social networks seems to be a promising strategy.

Background: Natalizumab provides rapid and high-efficacy control of multiple sclerosis disease activity with long-term stabilization. However, the benefits of the drug are countered by a risk of developing progressive multifocal leukoencephalopathy in patients infected with the John Cunningham Virus. Close monitoring is required in patients with increased progressive multifocal leukoencephalopathy risk receiving natalizumab in the long-term for an optimal benefit-risk evaluation. Standardized high-quality monitoring procedures may provide a superior basis for individual benefit and risk evaluation and thus improve treatment decisions. The non-interventional study TRUST was designed to capture natalizumab effectiveness under real-life conditions and to examine alternate approaches for clinical assessments, magnetic resonance imaging monitoring and use of biomarkers for progressive multifocal leukoencephalopathy risk stratification. Methods/Design: TRUST is a non-interventional, multicenter, prospective cohort study conducted at approximately 200 German neurological centers. The study is intended to enroll 1260 relapsing-remitting multiple sclerosis patients with ongoing natalizumab therapy for at least 12 months. Patients will be followed for a period of 3 years, irrespective of treatment changes after study start. Data on clinical, subclinical and patient-centric outcomes will be documented in order to compare the effectiveness of continuous versus discontinued natalizumab treatment. Furthermore, the type and frequency of clinical, magnetic resonance imaging and biomarker assessments, reasons for continuation or discontinuation of therapy and the safety profile of natalizumab will be collected to explore the impact of a systematic patient management approach and its potential impact on patient outcome. Specifically, the role of biomarkers, the use of expert opinions, the impact of high-frequency magnetic resonance imaging assessment for early progressive multifocal leukoencephalopathy detection and the role of additional radiological and clinical expert advice will be explored. Discussion: TRUST was initiated in spring 2014 and enrollment is anticipated to be completed by mid 2016. Annual interim analyses will deliver continuous information and transparency with regard to the patient cohorts and the completeness and quality of data as well as closely monitor any safety signals in the natalizumab-treated cohort. The study’s results may provide insights into opportunities to improve the benefit-risk assessment in clinical practice and support treatment decisions.

Einige Studien zu korperlicher Aktivitat bei MS-Patienten lassen einen verlaufsmodifizierenden Effekt und vorteilhafte Effekte auf die MS-Symptome vermuten. Angesichts der vorliegenden Daten scheint es aber unwahrscheinlich, dass korperliche Aktivitat das Risiko, an MS zu erkranken, reduziert.

In den vergangenen zwolf Monaten verzeichnete die Datenbank PubMed mehr als 5.000 Eintrage unter dem Schlagwort Multiple Sklerose — die hier ausgewahlten und kommentierten Originalarbeiten konnen also nur einen sehr kleinen Teil des Wissenszuwachses — zudem nach den subjektiven Interessen des Autors ausgewahlt — wiedergeben. Sie greifen aber die wesentlichen Entwicklungen und Trends der aktuellen klinischen MS-Forschung auf.

Neurofilament-Leichtketten im Serum scheinen als Marker fur den axonalen Schaden bei fruher MS geeignet und somit einen generellen Anhalt fur das Ausmas der Hirnschadigung und die Krankheitsaktivitat bei MS zu geben.

Das Konzept der B-Zell-Depletion ist bei Multipler Sklerose erfolgreich. Worin besteht der Unterschied zwischen Ocrelizumab und Rituximab?

Since multiple sclerosis (MS) often affects physically active young individuals, it is important to know if exercise can result in increased disease activity. Therefore we used a self-report questionnaire to examine the relationship of different levels of sports activity and relapses in 632 patients with MS. In order to analyse whether subjective recall might have biased the results, we performed, in a subgroup of our sample, an objective assessment of clinical data and physical fitness parameters. We were unable to find any association between sports activity and clinical relapses in either of the two analyses. The group with highest activity even shows the lowermost mean values, standard deviations and range concerning the number of relapses. Our data suggest that physical activity has no significant influence on clinical disease activity.

Occupational exposure limits (OELs) for carbon disulfide vary between 1 and 10 ppm worldwide. They are generally based on health effects observed in viscose industry. Publications after the mid-1970s are reviewed to determine whether there is a scientific justification for an OEL below 10 ppm. The exposure situation in viscose industry is governed by long exposure durations, high exposures in past decades, high peak exposures, former analytical procedures underestimating exposure, and shift work. Three approaches were used to define an OEL based on workplace data: (1) Division of a cumulative exposure index by lifetime exposure duration. This approach ignores the possible existence of a threshold and fails to differentiate between brief high and sustained low exposures. (2) Defining the NOEL/LOEL by mean exposure levels. With a wide range of exposures, effects observed at the mean are driven by high exposures underestimating the true NOEL. (3) Assessment of effects observed at workplaces complying with a predefined exposure limit. Without adverse effects at such a limit this should be the starting point to define the OEL. The most important health effects for carbon disulfide are coronary heart disease, coronary risk factors, retinal angiopathy, color discrimination, effects on peripheral nerves, psychophysiological effects, morphological and other central nervous system (CNS) effects, and fertility and hormonal effects. The data generally support an OEL of 10 ppm. Some uncertainties exist for effects on electrocardiogram (ECG), heart rate, retinal microaneurysms (in Japanese workers), peripheral nerve conduction velocities, some psychophysiological parameters, brain magnetic resonance imaging (MRI; hyperintensive spots), and hearing function. Further investigations on workers under defined long-term exposure conditions might help to come to a final conclusion. Finally, the reproductive capacity of female workers may not be adequately protected at exposures around 10 ppm.

Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. For the very first time, we used molecular ultrasound imaging to intraindividually track changes in angiogenic marker expression after carbon ion irradiation in experimental tumors. Expression of intercellular adhesion molecule-1 (ICAM-1) and of alpha(v)beta(3)-integrin in subcutaneous AT-1 prostate cancers in rats treated with carbon ions (16 Gy) was studied using molecular ultrasound and immunohistochemistry. For this purpose, cyanoacrylate microbubbles were synthesized and linked to specific ligands. The accumulation of targeted microbubbles in tumors was quantified before and 36 hours after irradiation. In addition, tumor vascularization was analyzed using volumetric Doppler ultrasound. In tumors, the accumulation of targeted microbubbles was significantly higher than in nonspecific ones and could be inhibited competitively. Before irradiation, no difference in binding of alpha(v)beta(3)-integrin-specific or ICAM-1-specific microbubbles was observed in treated and untreated animals. After irradiation, however, treated animals showed a significantly higher binding of alpha(v)beta(3)-integrin-specific microbubbles and an enhanced binding of ICAM-1-specific microbubbles than untreated controls. In both groups, a decrease in vascularization occurred during tumor growth, but no significant difference was observed between irradiated and nonirradiated tumors. In conclusion, carbon ion irradiation upregulates ICAM-1 and alpha(v)beta(3)-integrin expression in tumor neovasculature. Molecular ultrasound can indicate the regulation of these markers and thus may help to identify the optimal drugs and time points in individualized therapy regimens.

It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory disease [MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE)]. We observed that double pathology was associated with a significantly earlier onset of disease, a slight increase in the neurological score, an increase in the number of infiltrating cells, and enhanced axonal degeneration compared with wild-type mice and the respective, single mutant controls. Double-mutant PLPtg/PD-1(-/-) mice showed an increased production of interferon-gamma by CNS immune cells at the peak of disease. Neither PD-1 deficiency nor oligodendropathy led to detectable spread of antigenic MHC class I- or class II-restricted epitopes during EAE. However, absence of PD-1 clearly increased the propensity of T lymphocytes to expand, and the number of clonal expansions reliably reflected the severity of the EAE disease course. Our data show that the interplay between immune dysregulation and myelinopathy results in a stable exacerbation of actively induced autoimmune CNS inflammation, suggesting that the combination of several pathological issues contributes significantly to disease susceptibility or relapses in human disease.

Multiple sclerosis is a chronic inflammatory CNS disease which accounts for functional impairment and lasting disability in young adults. Current studies demonstrate that physical activity in patients with MS counteracts depression and fatigue and may improve quality of life. Interventional studies have described a reduction of the functional impairment in MS patients. This report presents information on the effects of physical activity on the immune system and the release of neurotrophic factors, and highlights current data on a potential immunomodulatory effect of exercise in multiple sclerosis.