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Background Several disease modifying drugs (DMDs) have been approved for the treatment of multiple sclerosis (MS), however, little is known about their differential impact on peripheral blood (PB) B cell subsets. Methods We performed a cross sectional study on PB B cells in MS patients treated with interferon-β (n = 25), glatiramer acetate (n = 19), dimethyl fumarate (n = 15), fingolimod (n = 16) or natalizumab (n = 22), untreated MS patients (n = 20), and in patients with non-inflammatory neurological diseases (n = 12). Besides analyzing routine laboratory data, flow cytometry was performed to analyze naïve B cells (CD19+CD20+CD27-IgD+), non-class switched (CD19+CD20+CD27+IgD+) and class-switched memory B cells (CD19+CD20+CD27+IgD-), double negative B cells (CD19+CD20lowCD27-IgD-) and plasmablasts (CD19+CD20lowCD27+CD38++). Results Treatment associated changes were found for the overall B cell pool as well as for all B cell subsets. Natalizumab increased absolute numbers and percentage of all B cells mainly by expanding the memory B cell pool. Fingolimod decreased absolute numbers of all B cell subsets and the percentage of total B cells. Fingolimod, dimethyl fumarate and interferon-β treatments were associated with an increase in the fraction of naïve B cells while class switched and non-class switched memory B cells showed decreased percentages. Conclusion Our results highlight differential effects of DMDs on the PB B cell compartment. Across the examined treatments, a decreased percentage of memory B cells was found in dimethyl fumarate, interferon-β and fingolimod treated patients which might contribute to the drugs’ mode of action in MS. Further studies are necessary to decipher the exact role of B cell subsets during MS pathogenesis.

Susac's syndrome (SuS) is a rare, probably autoimmune endotheliopathy of the central nervous system, retina and inner ear. It is characterized by a clinical triad of encephalopathy, branch retinal artery occlusions (BRAOs) and sensorineural hearing loss. To date, more than 300 cases of SuS have been reported in the literature. However, SuS remains an under- and misdiagnosed entity in the clinical setting. This report presents an exemplary case of a patient, who was initially misdiagnosed with relapsing-remitting multiple sclerosis. At initial presentation, the patient did not demonstrate the complete clinical triad, and the interval between symptom onset and diagnosis was 4 months. Typical diagnostic features, which enabled the diagnosis of SuS were: a) MRI findings with T2-hyperintense snowball-like lesions of the corpus callosum and subcortical white matter and hyperintense lesions in diffusionweighted imaging with reduced apparent diffusion coefficient; b) BRAOs and vessel wall hyperfluorescence in fluorescein angiography and a significant thickness reduction of the inner retinal layers in optical coherence tomography; c) bilateral sensorineural hearing loss. The patient was aggressively treated with cyclophosphamide, rituximab, glucocorticoids and acetylsalicylic acid with a good response to therapy. This report draws attention to the need to take SuS into consideration in the differential diagnosis at the interface of neurological, psychiatric, ophthalmological and otorhinolaryngological disorders. As SuS may result in severe and persistent neurological deficits, an interdisciplinary collaboration is fundamental for the prompt diagnosis and initiation of adequate immunosuppressive treatment.

Susac’s syndrome (SuS) is a rare, probably autoimmune endotheliopathy of the central nervous system, retina and inner ear. It is characterized by a clinical triad of encephalopathy, branch retinal artery occlusions (BRAOs) and sensorineural hearing loss. To date, more than 300 cases of SuS have been reported in the literature. However, SuS remains an under- and misdiagnosed entity in the clinical setting. This report presents an exemplary case of a patient, who was initially misdiagnosed with relapsing-remitting multiple sclerosis. At initial presentation, the patient did not demonstrate the complete clinical triad, and the interval between symptom onset and diagnosis was 4 months. Typical diagnostic features, which enabled the diagnosis of SuS were: a) MRI findings with T2-hyperintense snowball-like lesions of the corpus callosum and subcortical white matter and hyperintense lesions in diffusionweighted imaging with reduced apparent diffusion coefficient; b) BRAOs and vessel wall hyperfluorescence in fluorescein angiography and a significant thickness reduction of the inner retinal layers in optical coherence tomography; c) bilateral sensorineural hearing loss. The patient was aggressively treated with cyclophosphamide, rituximab, glucocorticoids and acetylsalicylic acid with a good response to therapy. This report draws attention to the need to take SuS into consideration in the differential diagnosis at the interface of neurological, psychiatric, ophthalmological and otorhinolaryngological disorders. As SuS may result in severe and persistent neurological deficits, an interdisciplinary collaboration is fundamental for the prompt diagnosis and initiation of adequate immunosuppressive treatment.

Glatiramer acetate (GA) is an approved therapy for relapsing-remitting multiple sclerosis, but its efficacy for the prevention of attacks in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. We did a multicenter retrospective analysis of GA-treated patients with NMOSD, identified through a national registry. Annualized relapse rate and expanded disability status scale (EDSS) were the main outcome measures. We identified 23 GA-treated patients (21 female, 16 aquaporin-4 antibody-positive). GA was given for

The presented study investigates the functional role of GABA in somatosensory processing, using a combined neuropharmacological-neuroimaging approach. Three different GABA agonists (GABAA: alprazolam, ethanol; GABAB: baclofen) were investigated in a double blind cross-over design in 16 male participants, accomplishing a tactile perception task. Somatosensory evoked magnetic fields modulated by GABAR-agonists and placebo were recorded using whole-head magnetoencephalography. Peak latencies and amplitudes of primary (SI) and secondary (SII) somatosensory cortex source activities confirmed the previously reported role of GABA as a modulator of somatosensory processing. Significant inhibitory effects on the latency of SII and on the amplitude of SI and SII were found exclusively for alprazolam, a positive allosteric modulator at GABAA receptors. The GABAB agonist baclofen did not have any modulatory effect. Moreover, we investigated whether the observed effects of alprazolam on the level of SII were explainable by the mere propagation of activity from SI to SII modulated by GABAA receptors, independently from any further GABAA-mediated inhibition in SII. By estimating the transfer function between SI and SII activation under placebo conditions, we were able to predict SII activity for the administration of GABA receptors agonists under the assumption that GABA exclusively acts at the level of SI. By comparing measured and predicted data, we propose a model in which the initial activation of SI is modulated through GABAA receptors and subsequently propagated to SII, without any significant further inhibition. In addition, initial GABAA effects in SI appear to be strongly potentiated with time, selectively in SI but not in SII.

The therapeutic application of brain stimulation is still limited to relatively few indications and small groups of patients due to variable efficacy. Individualization of stimulation parameters by employing a closed-loop system, i.e. synchronization of stimulation with endogenous brain activity with millisecond precision, has the potential to significantly improve the therapeutic efficacy when compared to open-loop systems. In this article the theoretical and experimental results are reviewed including first clinical trials that support the superiority of closed-loop brain stimulation, fundamental aspects in the development of closed loop methods are discussed and clinical studies which could quantify an increase in effectiveness are summarized. A significant increase in the indications for therapeutic applications of closed-loop systems is to be expected in the near future.

Zusammenfassung Gegenstand und Ziel: Das Bestreben, die routinemäßige Kastration der gesunden Hündin als Elektiveingriff so schonend wie möglich für das Tier zu gestalten, führte zur Entwicklung verschiedener laparoskopischer Operationsverfahren, deren Akzeptanz jedoch bislang hinter den Erwartungen zurückgeblieben ist. In der vorliegenden Arbeit soll durch Einsatz neuer oder verbesserter minimal invasiver Technologien gezeigt werden, wie das Operations-Prozedere optimiert werden kann. Material und Methoden: Zwischen Juni 2001 und Dezember 2003 wurden 28 Hündinnen ovariohysterektomiert (n = 27) oder ovariektomiert (n = 1). Die Eingriffe erfolgten unter Zuhilfenahme von optischen Trokaren, verschiedenen Blut-und Gewebekoagulationssystemen (Hochfrequenzstrom, Ultraschall) sowie endoskopischen Klammernahtgeräten. Ergebnisse: Alle minimal invasiven Operationen verliefen erfolgreich. Die Dauer des Eingriffs betrug durchschnittlich 57 Minuten. In keinem Fall war ein Konvertieren zum offenen chirurgischen Vorgehen notwendig. Sechs Monate bis zweieinhalb Jahre post operationem zeigte keine der Hündinnen Symptome einer Läufigkeit oder Harninkontinenz. Schlussfolgerungen und klinische Relevanz: Die Vorteile der minimal invasiven Operationsmethode konnten vor allem wegen der verwendeten neuen Technologien (z. B. modifizierte HF-Technik Ligasure®) eindrucksvoll unter Beweis gestellt werden. Die beschriebene standardisierte Vorgehensweise zur laparoskopischen Ovariohysterektomie der Hündin vereinfacht den Eingriff und steigert so die chirurgische Effizienz gegenüber der konventionellen Laparotomie.

Megadolichobasilar anomaly, a dilatant arteriopathy of the basilar artery attributable to chronic arterial hypertension, can cause cranial nerve compression syndromes of the cerebellopontine angle or infarcts of the vertebrobasilar circulation. In this paper, we report on a patient with known megadolichobasilar anomaly and a partially thrombosed fusiform aneurysm of the basilar artery, who presented with acute-onset vertigo and subsequent deafness due to thromboembolic occlusion of the labyrinthine artery. Because of the vascular origin of the patient's symptoms, his vertigo disappeared over time while the deafness persisted.

Previous transcranial magnetic stimulation (TMS) studies showed exercise-induced depression of motor evoked potentials (MEP). The purpose of the present study was to evaluate changes in MEP size and central motor conduction time (CMCT) after various kinds of exercise of daily life and sports. Changes of both central and peripheral motor conduction were recorded immediately after predominantly aerobic (climbing stairs and jogging) and anaerobic (press-ups, dumb-bell holding, and 400 m-run) exercise. Strength exercise resulted in a significant decrease of MEP amplitudes. Exhausting press-ups reduced the mean MEP amplitude by 33% as compared to pre-exercise value, exhausting dumb-bell holding reduced the mean MEP amplitude by 66%. Aerobic exercises (climbing 600 steps and jogging 50 minutes) did not significantly change MEP amplitudes. The compound motor action potentials (registered after supramaximal peripheral electrical stimulation) remained unchanged after each paradigm. CMCT was not significantly altered by any of the exercises under investigation. Peripheral motor conduction time (PMCT) was slightly lengthened by 4% after isometric dumb-bell holding. PMCT and total motor conduction time were decreased after aerobic exercises, probably due to an increase of temperature of the lower extremities. In conclusion, TMS is a suitable technique for objective evaluation of central fatigue. The present study is the first to show its possible use in sports medicine, indicating that only exhaustive or strength exercises result in reduced MEPs.

Hirayama disease is a juvenile benign distal upper limb muscular atrophy rarely observed in Europe, usually monomelic involving C7-Th1 innervated muscles. It is characterized by insidious onset and a self-limited course within a few years. The pathogenesis of this mostly sporadic disease is not fully clarified. Cervical flexion myelopathy with mechanical ischemic damage of spinal motoneurons is the best established pathogenetic hypothesis, but neurodegenerative and autoimmune causes are also debated. Typically, young men of Asian origin are affected. Here we describe three German Caucasian patients with Hirayama disease and provide an up-to-date review of the literature.

The ability to induce cortical plasticity with non-invasive brain stimulation (NBS) techniques has provided novel and exciting opportunities for examining the role of the human cortex during a variety of behaviours. Additionally, and importantly, the induction of lasting changes in cortical excitability can, under some conditions, reversibly modify behaviour and interact with normal learning. Such findings have driven a large number of recent studies examining whether by using such approaches it might be possible to induce functionally significant changes in patients with a large variety of neurological and psychiatric conditions including stroke, Parkinson's disease and depression. However, even in neurologically normal subjects the variability in the neurophysiological and behavioural response to such brain stimulation techniques is high. This variability at present limits the therapeutic usefulness of these techniques. The cause of this variability is multifactorial and to some degree still unknown. However, a number of factors that can influence the induction of plasticity have been identified. This review will summarise what is known about the causes of variability in healthy subjects and propose additional factors that are likely to be important determinants. A greater understanding of these determinants is critical for optimising the therapeutic applications of non-invasive brain stimulation techniques.

Dieser Beitrag geht auf die diagnostische Wertigkeit verschiedener TMS Kennwerte zum Nachweis demyelinisierender und axonaler Schadigungen des kortikospinalen Traktes bei Patienten mit multipler Sklerose (MS) ein. Insbesondere werden durch konventionelle Einzelpuls-TMS ausgeloste motorisch evozierte Potenziale (MEP) und zentralmotorische Leitungszeiten sowie durch die Tripel-Stimulations-Technik (TST) ausgeloste MEP besprochen. Die Sensitivitat der TMS Kennwerte zum paraklinischen Nachweis einer raumlichen Dissemination von Lasionen des ZNS ist der Magnetresonanztomografie (MRT) deutlich unterlegen. Im Gegensatz zur MRT konnen TMS Kennwerte jedoch den demyelinisierenden Charakter einer Schadigung identifizieren. Des Weiteren zeigen MEPs und die mittels TST bestimmten MEP Amplituden einen engeren Zusammenhang mit klinisch-motorischen Defiziten als die MRT und konnen Verbesserungen klinisch-motorischer Defizite im Rahmen einer Schubbehandlung mit Kortikosteroiden widerspiegeln. Im Vergleich zur konventionellen MRT korrelieren multimodale evozierte Potenziale (EP) unter Einschluss der MEPs in transversalen und longitudinalen Studien besser mit dem klinischen Behinderungsgrad der MS Patienten gemessen mit der Expanded Disability Status Scale (EDSS). Zusatzlich konnen multimodale EPs unter Einschluss der MEPs zur Prognoseabschatzung bei Patienten mit klinisch definitiver MS dienen.

Megadolichobasilar anomaly, a dilatant arteriopathy of the basilar artery attributable to chronic arterial hypertension, can cause cranial nerve compression syndromes of the cerebellopontine angle or infarcts of the vertebrobasilar circulation. In this paper, we report on a patient with known megadolichobasilar anomaly and a partially thrombosed fusiform aneurysm of the basilar artery, who presented with acute-onset vertigo and subsequent deafness due to thromboembolic occlusion of the labyrinthine artery. Because of the vascular origin of the patient's symptoms, his vertigo disappeared over time while the deafness persisted.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique, which can alter cortical excitability in human subjects for hours beyond the period of stimulation. Therefore, it has therapeutic potential in neurological and psychiatric disorders associated with alterations in cortical excitability. However, rTMS-induced effects remain poorly understood at the molecular and cellular level. This presentation will provide a review on recent findings from other groups on repetitive magnetic stimulation effects on immediate early gene expression (such as c-fos and zif268), protein expression (such as parvalbumin and calbindin in inhibitory interneurons), or markers of neuroplasticity (such as BDNF and GluR1 subunit of AMPA receptor). Furthermore, recent evidence from our group will be provided that repetitive magnetic stimulation can induce a long-lasting increase in glutamatergic synaptic strength, which is accompanied by structural remodeling of dendritic spines and postsynaptic NMDA-receptor-mediated accumulation of GluA1-containing AMPA-receptors. Together, there is accumulating evidence that the repetitive magnetic stimulation induces specific changes of gene and protein regulation and ultimately functional and structural synaptic plasticity at the cellular level. Repetitive magnetic stimulation in small animals, slices and cell cultures may provide useful experimental models for development and prediction of therapeutically effective rTMS protocols in humans.

There has been increased interest in the ability of the adult human nervous system to reorganize and adapt to environmental changes throughout life. This ability has been termed "plasticity." Plastic changes in the cerebral cortex have been studied: (a) as modifications of sensory or motor cortical representation of specific body parts (cortical maps, body representation level); and (b) as changes in the efficacy of existing synapses or generation of new synapses (neuronal or synaptic level). In this review, we describe paradigms used to study mechanisms of plasticity in the intact human motor system, the functional relevance of such plasticity, and possible ways to modulate it.