Search

Multiple sclerosis (MS) is a neurological disorder characterized by inflammatory demyelination and neurodegeneration in the central nervous system. Until recently, disease-modifying treatment was based on agents requiring parenteral delivery, thus limiting long-term compliance. Basic treatments such as beta-interferon provide only moderate efficacy, and although therapies for second-line treatment and highly active MS are more effective, they are associated with potentially severe side effects. Fingolimod (Gilenya®) is the first oral treatment of MS and has recently been approved as single disease-modifying therapy in highly active relapsing-remitting multiple sclerosis (RRMS) for adult patients with high disease activity despite basic treatment (beta-interferon) and for treatment-naïve patients with rapidly evolving severe RRMS. At a scientific meeting that took place in Vienna on November 18th, 2011, experts from ten Central and Eastern European countries discussed the clinical benefits and potential risks of fingolimod for MS, suggested how the new therapy fits within the current treatment algorithm and provided expert opinion for the selection and management of patients., peer-reviewed

In multiple sclerosis (MS) the individual disease courses are very heterogeneous among patients and biomarkers for setting the diagnosis and the estimation of the prognosis for individual patients would be very helpful. For this purpose, we are developing a multidisciplinary method and workflow for the quantitative, spatial, and spatiotemporal analysis and characterization of MS lesion patterns from MRI with geostatistics.We worked on a small data set involving three synthetic and three real-world MS lesion patterns, covering a wide range of possible MS lesion configurations. After brain normalization, MS lesions were extracted and the resulting binary 3-dimensional models of MS lesion patterns were subject to geostatistical indicator variography in three orthogonal directions.By applying geostatistical indicator variography, we were able to describe the 3-dimensional spatial structure of MS lesion patterns in a standardized manner. Fitting a model function to the empirical variograms, spatial characteristics of the MS lesion patterns could be expressed and quantified by two parameters. An orthogonal plot of these parameters enabled a well-arranged comparison of the involved MS lesion patterns.This method in development is a promising candidate to complement standard image-based statistics by incorporating spatial quantification. The work flow is generic and not limited to analyzing MS lesion patterns. It can be completely automated for the screening of radiological archives.

Objective: To elucidate the role of tumor necrosis factor (TNF) receptor signal transduction in multiple sclerosis (MS). Methods: We performed a cross-sectional analysis of the gene expression of TRAF2 (TNF receptor-associated factor 2) and RIP (receptor-interacting protein) in peripheral blood leukocytes of 23 relapsing-remitting (RR), 19 secondary progressive (SP) and 12 primary progressive (PP) MS patients as well as of 29 healthy controls by quantitative RT-PCR. Additionally, we monitored a subgroup of 15 RRMS patients longitudinally every 3 months over a 9-month time period. Results: TRAF2 expression was significantly elevated in RRMS patients compared to the other disease courses (p < 0.005, respectively) and the control group (p < 0.009). RIP expression was significantly elevated in the patient groups compared to the healthy group (phealthy-RR < 0.002; phealthy-PP < 0.003; phealthy-SP < 0.06). Neither variable changed over the 9-month time course. Conclusion: TRAF2 and RIP1 elevation in leukocytes might be interpreted as the molecular equivalent of an elevated general inflammatory activity in MS patients compared to healthy control persons. TRAF2 elevation in RRMS reinforces the concept that different pathophysiological and immunological processes sustain RRMS and SPMS or PPMS.

Introduction: Stroke is the third leading cause of death in the US and the leading cause of major disability. A large variety of drugs and new therapeutic strategies are the basis for modern stroke therapy. There is scientific evidence for the effectiveness of only a few coagulation-inhibiting drugs for stroke prevention and treatment, but a lot of clinical trials have been conducted or are ongoing in order to gain more scientific data on stroke management and therapy. Areas covered: This paper gives a general overview of modern coagulation-inhibiting drugs discovered and investigated for prevention or acute stroke therapy and offers prospects of future therapy options. Expert opinion: Without the development of more cost-effective future therapies and implementation of extended prevention programs, stroke will remain the leading cause of disability. There is still a strong need for the discovery of novel drug therapies that effectively avoid blood clotting and stroke without increasing the risk of hemorr...

ZusammenfassungNatalizumab (Tysabri) kann in seiner Eigenschaft als blockierender Antikörper des alpha-4-Integrins auf der Oberfläche von Immunzellen mittels Durchflusszytometrie nachgewiesen werden. Wir untersuchten, ob sich der Sättigungsgrad von Immunzellen mit Natalizumab als Biomarker für ein Therapieansprechen bei Multipler Sklerose (MS) eignet.Bei 11 MS-PatientInnen wurde vor Therapiebeginn und nach 4, 8 und 12 Wochen die Natalizumab-Sättigung von T-Zellen (CD3+) und wichtigen T-Zell Subpopulationen (naive (CD45RA+)/memory (CD45R0+) CD4+ und CD8+) mittels Durchflusszytometrie untersucht.Jeweils vier Wochen nach den ersten drei Infusionen war der mittlere Natalizumab-Sättigungsgrad (n=9) von T-Zellen jeweils knapp unter 80%. Eine Patientin mit neutralisierenden Antikörpern (NAB) gegen Natalizumab und ein Patient mit zu langen Infusionsintervallen wurden aufgrund von Auffälligkeiten im Natalizumab-Sättigungsgrad der Immunzellen identifiziert. Die unterschiedlich hohen alpha-4 Expressionswerte der einzelnen T-Zellsubpopulationen hatten keinen Einfluss auf den Sättigungsgrad mit Natalizumab.Wir konnten zeigen, dass ein Monitoring der Natalizumab-Sättigung von T-Lymphozyten mittels Durchflusszytometrie eine Routine-taugliche Methode ist, um PatientInnen mit einem möglichen suboptimalen Therapieerfolg aufgrund von NAB oder unregelmäßigen Infusionsintervallen zu identifizieren. Weiterführende Studien zur Bestimmung eines Schwellenwertes für eine unzureichende Nalizumab-Sättigung eröffnen die Möglichkeit für individualisierte Therapieschemata. Dies ist im Hinblick auf das Risiko opportunistischer Infektionen wichtig, um die Sicherheit dieses so hochwirksamen Therapeutikums für die Langzeitbehandlung in der MS zu erhöhen.

ZusammenfassungIn den letzten Jahren wurde die Therapie der Multiplen Sklerose (MS) durch neue, immunologisch selektivere und wirksamere Medikamente erweitert. Untersuchungen des Liquors cerebrospinalis (CSF) zeigten, dass diese Medikamente auch einschneidende immunologische Veränderungen hinter der Blut-CSF-Schranke induzieren. Dadurch kann einerseits die gute Wirksamkeit erklärt werden, andererseits wird aber auch das Risiko opportunistischer Infektionen im ZNS, wie z.B. das Auftreten einer progressiven multifokalen Leukenzephalopathie (PML), begünstigt. In dieser Übersichtsarbeit wird auf die bis jetzt bekannten immunologischen Veränderungen, die durch die beiden in der Behandlung der hochaktiven MS zugelassenen Medikamente-Natalizumab und Fingolimod-ausgelöst werden, eingegangen. Die Untersuchung des CSF bietet ein sehr interessantes Forschungsfeld, um zukünftig mehr über die immunologischen Veränderungen bei MS hinter der Blut-Hirn-Schranke unter Therapie herauszufinden.

ZusammenfassungDie Einführung mehrerer neuer Therapien zur Behandlung der Multiplen Sklerose (MS) hat in den vergangenen Jahren die Situation vieler Betroffenen deutlich verbessert. Allerdings hat sich durch die neuen Medikamente auch das Spektrum von potenziellen Nebenwirkungen deutlich verbreitert. Dies führte zur Entwicklung neuer, mittlerweile gut etablierter und in der Routinediagnostik eingesetzter Laborparameter mit dem Ziel, die Qualität einer Immunbehandlung in Bezug auf die Wirksamkeit und vor allem die Nebenwirkungen zu verbessern. Es wird zunächst ein Überblick über wesentliche Aspekte der Pathogenese und der Therapie der MS gegeben. Im Weiteren werden die zum Teil neu etablierten Therapie-spezifischen Laborparameter der wichtigsten krankheitsmodifizierenden Medikamente vorgestellt, die im Alltag leicht verwechselt werden können und somit zu Irritationen und ungenügenden Aussagen führen. Daher ist der adäquate Einsatz der vorgestellten Biomarker essentiell und führt zu einer zusätzlichen Sicherheit im Umgang mit den MS-spezifischen Medikamenten.

Background The diagnosis of the isolated leptomeningeal involvement of a primary central nervous system B-cell lymphoma without parenchyma lesions may be difficult. Patients with leptomeningeal meningeosis lymphomatosa can present with various neurologic deficits. Aims of the study To demonstrate the impact of cerebrospinal fluid (CSF) flow cytometry in the diagnosis of an isolated leptomeningeal manifestation of B-cell lymphoma by presenting an interesting case report. Methods Flow cytometric analysis of B-cell monoclonality of the CSF was performed as complementary diagnostic procedure in addition to CSF cytology. Final diagnosis was confirmed by necropsy. Results We suspected isolated leptomeningeal manifestation of B-cell lymphoma with palsy of the VI and VII cranial nerves in a 79-year-old male, because of mononuclear pleocytosis in CSF. Interestingly, the decisive diagnostic hint was given by implementation of flow cytometry of the CSF. Diagnosis was confirmed by postmortem autopsy. Conclusion Our case shows that flow cytometry of the CSF in addition to conventional CSF cytology has the potential to accelerate diagnosis of lymphomeningeal infiltration of B-cell lymphoma.

Natalizumab is a humanized monoclonal antibody directed against the alpha-4 integrin subunit of very late activation antigen-4 (VLA-4). Natalizumab neutralizing antibodies (NAB) have been found to significantly reduce beneficial effects of natalizumab treatment in multiple sclerosis. We investigated interactions of NAB with natalizumab by serial measurements of alpha-4 integrin levels on peripheral blood mononuclear cells using flow cytometry. In addition, serum concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1), the endothelial ligand of VLA-4, and serum NAB were serially determined. Natalizumab infusion led to a transient reduction in alpha-4 integrin levels on immune cells and serum sVCAM-1 levels along with serum negativity of NAB lasting for a few days post-infusion. Apparently, the high-dose effect of freshly infused natalizumab resulted in a transient neutralization of NAB possibly involving a transient therapeutic effectiveness.

Stroke is the third leading cause of death with an increasing prevalence. In previous years many important achievements and new therapeutic strategies have been established. This article provides an overview on recent developments and is an update to the article of Green et al. that was published in 2004. As this article is a comprehensive review we divided it in two parts. In this Part A of our review, recent developments in acute stroke treatment and in stroke prevention are described. In Part B we will reflect on neuroprotection.

Spinal subdural hematoma (SSDH) with no underlying pathology is a very rare condition and has been rarely reported. Our patient presented with severe occipital headache as isolated symptom during the first 4 days. SSDH slowly enlarges with time, and first determines tension of the pain-sensitive dural membrane, resulting in cervicogenic-like headache. Therefore, spontaneous SSDH should be considered in the differential diagnosis of recent occipital headache.

A 43 year old female presented with a facial palsy on the right ide as initial symptom. Her medical history included a prolactioma (649.6 U/ml) treated with Cabergolin and a strabismus nown since childhood. The initial cranial CT scan, cerebrospinal uid analysis and laboratory findings were normal (Table 1). An diopathic facial palsy was assumed and the patient was discharged ith 40 mg methylprednisolone. With this treatment the patient ompletely recovered. Two weeks later, after reducing the corticosteroid dose, the atient presented with diplopia which was marked when look

The specific neurochemical substrate underlying the amnesia in patients with Wernicke–Korsakoff syndrome (WKS) is still poorly defined. Memory impairment has been linked to dysfunction of neurons in the cholinergic system. A transcranial magnetic stimulation (TMS) protocol, the short latency afferent inhibition (SAI), may give direct information about the function of some cholinergic pathways in the human motor cortex. In the present study, we measured SAI in eight alcoholics with WKS and compared the data with those from a group of age-matched healthy individuals; furthermore, we correlated the individual SAI values of the WKS patients with memory and other cognitive functions. Mean SAI was significantly reduced in WKS patients when compared with the controls. SAI was increased after administration of a single dose of donezepil in a subgroup of four patients. The low score obtained in the Rey Complex Figure delayed recall test, the Digit Span subtest of the Wechsler Adult Intelligence Scale—Revised (WAIS-R) and the Corsi’s Block Span subtest of the WAIS-R documented a severe impairment in the anterograde memory and short-term memory. None of the correlations between SAI values and these neuropsychological tests reached significance. We provide physiological evidence of cholinergic involvement in WKS. However, this putative marker of central cholinergic activity did not significantly correlate with the memory deficit in our patients. These findings suggest that the cholinergic dysfunction does not account for the memory disorder and that damage to the cholinergic system is not sufficient to cause a persisting amnesic syndrome in WKS.

Objective We report on a patient who presented with complete ophthalmoplegia as a first symptom of fatal invasive aspergillosis. Case report We present the clinical course of an immunocompromised 68-year-old man with unclear painless loss of vision, ptosis and ophthalmoplegia of the right eye lasting for 10 days which was referred from an ophthalmological outpatient clinic. He had a history of kidney transplantation after renal failure, diabetes mellitus II, and coronary heart disease. He was on immunsuppressive therapy with tacrolimus, mycophenolate and prednisolone since renal transplantation. The initial cranial magnetic resonance imaging (MRI) was unremarkable. The additional thin section computed tomography (CT) of the paranasal sinuses was suspicious for bone erosion of the superior wall of the right sphenoidal sinus. Initial laboratory testing and cerebrospinal fluid were without pathological findings. When the patient showed signs of generalised sepsis he was transferred to the intensive care unit. Due to fulminant sepsis it was not possible to perform the planned biopsy. The patient died a few days later of cardio-respiratory insufficiency. The consecutive autopsy revealed invasive aspergillosis of paranasal sinuses with infiltration into the orbita and intracranial spreading into sinus cavernosus. Autopsy also showed aspergillus pneumonia. Discussion Invasive aspergillosis of the paranasal sinuses and the skull base is most often a lethal condition in immunocompromised patients. Therefore, rapid diagnostics applying radiological (CT and MRI) and surgical procedures (biopsy) and immediate ignition of antimycotic treatment can be life-saving.

BACKGROUND Although there exists a large body of knowledge on the regulation of arterial cerebral hemodynamics, little is known about the cerebral venous outflow (CVO). METHODS In 19 healthy volunteers, the middle cerebral artery and the straight sinus were examined using transcranial Doppler sonography. Arterial and venous mean flow velocities (aFV(mean), vFV(mean), respectively) were registered continuously while applying lower body positive (LBPP) or negative (LBNP) pressure of 30 mmHg and performing head-down (-20 degrees , HDT) and -up (+30 degrees , HUT) tilt manoeuvres. The arterial blood pressure was registered simultaneously with a noninvasive finger blood pressure monitor. Relative changes in parameters compared to the proceeding no-pressure, no-tilt baseline were used for analysis. RESULTS While aFV(mean) did not change significantly, vFV(mean) inc reased during LBPP by 10.5 +/- 2.9% and decreased during LBNP by 15.1 +/- 3.5% (mean +/- standard error of mean [SEM], P < .01). HUT resulted in a decrease in vFV(mean) by 25.5 +/- 3.3% and HDT, in an increase by 7.8 +/- 3.2% (P < .01) without alteration in aFV(mean). This may imply a decrease of cerebral blood volume (CBV) during LBPP and HDT and an increase during LBNP and HUT. CONCLUSIONS CVO cannot be neglected when studying cerebral hemodynamics because it might affect the CBV.

In the mid-1990s, the implementation of the immunomodulatory drugs interferon-beta and glatiramer acetate offered the first evidence-based treatment option for multiple sclerosis (MS). These new drugs were beneficial in a huge number of MS patients worldwide, leading to a delay in disease-related disability. Moreover, MS was suddenly the focus not only of patients and their physicians but also of pharmaceutical companies, with a tremendous increase in interest by scientists. As a result of these efforts the first monoclonal antibody treatment has recently been implemented in MS. It will presumably be followed by several other more specific, more effective and more comfortable therapies within the next few years. Here, we will show the current MS treatment options as well as recent progress in the field, and we will introduce the potential new treatment options for future MS therapy.

Einleitung: Die Differenzialdiagnose zwischen akutem ischamischen Hirninsult und prolongierter Aura bei Migrane kann diagnostische Schwierigkeiten bereiten. Insbesondere im Zeitalter der systemischen Lyse des Hirninfarkts ist diese Differenzialdiagnose entsprechend des „time is brain“-Konzepts fur die Patienten von entscheidender Bedeutung. Wir berichten uber zwei Patienten, bei denen die Durchfuhrung eines cMRT wegweisend fur die Diagnosestellung eine Migrane mit prolongierter Aura war. Fallberichte: Bei einem 31-jahrigen Patienten kam es akut wahrend einer Busfahrt zu einer Sprachstorung. Der hinzugerufene Notarzt brachte den Patienten unter der Verdachtsdiagnose eines Schlaganfalls zur systemischen Lyse in unsere Klinik. Die klinisch-neurologische Untersuchung ergab eine motorisch betonte globale Aphasie, eine Hemianopsie nach rechts sowie eine leichtgradige Hemiparese rechts. Mittels MRT-Diffusionswichtung konnte ein frischer Infarkt ausgeschlossen werden, allerdings stellte sich eine Minderperfusion im hinteren Media-Posteriorgrenzstromgebiet dar. Nach vier Stunden bildete sich die Symptomatik komplett zuruck und es kam zu halbseitigen Kopfschmerzen, woraufhin der Patient berichtete, dass bei ihm seit vielen Jahren eine Migrane mit Aura und bisher dreimalig ahnlichen Attacken besteht. Bei einem 26-jahrigen Patienten trat akut eine motorische Aphasie sowie eine leichtgradige Hemiparese rechts auf. Auch bei ihm zeigte sich im Perfusions-MRT eine Minderperfusion im linken temporooccipitalen Mediastromgebiet ohne Darstellung eines Infarktareals in der Diffusionswichtung. Im Weiteren bildete sich die Symptomatik komplett zuruck und es kam zu einseitigen pulsierenden Kopfschmerzen mit Ubelkeit und Erbrechen. Weiters ergab die daraufhin erhebbare Anamnese, dass der Patient in der Adoleszenz an Migrane mit Aura litt. Diskussion: Eine kontralaterale Minderperfusion im MRT wurde bisher in der Literatur bei wenigen Patienten mit Migrane mit prolongierter Aura beschrieben. Unsere beiden Fallberichte unterstreichen eindrucksvoll, dass die Durchfuhrung eines MRT in der Akutphase, insbesondere wenn es um die Frage einer Lysetherapie geht, entscheidend zur Diagnosestellung beitragt.

Background and Purpose: Although sleep apnea (SA) is a risk factor for ischemic stroke and an important prognosticator in affected patients, the exact pathophysiological link between SA and stroke remains to be established. We investigated whether levels of C-reactive protein (CRP) and fibrinogen are increased in patients with acute stroke and SA compared with stroke patients without SA. Patients and Methods: 117 consecutive patients with ischemic stroke admitted to our stroke unit within 12 h after stroke onset were included in this study. On admission, CRP and fibrinogen levels were determined. All patients received cardiorespiratory polygraphy during the first 72 h of their hospital stay. In all patients, demographic data, National Institutes of Health Stroke Scale score and cerebrovascular risk factors were assessed. Results: SA defined by an apnea-hypopnea index (AHI) of ≧10/h was found in 64 (55%) patients. Elevated CRP and fibrinogen levels were seen twice as often in patients with SA than in patients without (CRP: 52 vs. 26%; fibrinogen: 72 vs. 37%). After multivariate logistic regression analysis, an AHI of ≧10/h was independently correlated with raised levels of both of these parameters. Conclusion: SA is independently associated with raised levels of CRP and fibrinogen in patients with acute ischemic stroke. We assume that both proteins are part of the pathophysiological pathway linking SA to stroke.

Andreas Rogalewski1, Jörg Kraus3, Martin Hasselblatt2, Christoffer Kraemer1, Wolf-Rüdiger Schäbitz11Department of Neurology; 2Institute of Neuropathology, University of Muenster, Germany, 3Paracelsus Private Medical University and Salzburger Landesklinken, Christian-Doppler-Klinik, Department of Neurology, Salzburg, AustriaAbstract: We report a case of acute demyelinating encephalitis that occurred after viral vaccination against hepatitis A-, hepatitis B-, and poliovirus and vaccination against bacterial toxins of diphtheria and tetanus. After different diagnosis had been excluded, we diagnosed postvaccinal demyelinating encephalitis and started treatment with high dose intravenous methylprednisolone, followed by peroral application in decreasing dosages for three weeks. A few days after the treatment with methylprednisolone had been finished, the patient’s medical condition deteriorated again. Thus, we initiated plasma exchange at an advanced state of illness, which led to significant continuous improvement. The role of plasma exchange is discussed controversially, in particular the issue of timing. We report a case that shows improvement due to plasmapheresis several weeks after symptom onset.Keywords: ADEM, vaccination, encephalitis, plasmapheresis, demyelination, plasma exchange

Background We prospectively reviewed response rates, local control, and side effects after non-fractionated stereotactic high single-dose body radiation therapy for lung tumors. Methods Fifty-eight patients underwent radiosurgery involving single-dose irradiation. With 25 patients, 31 metastases in the lungs were irradiated; with each of 33 patients, stage I non-small cell lung cancer (NSCLC) was subject to irradiation. The standard dose prescribed to the isocenter was 30 Gy with an axial safety margin of 10 mm and a longitudinal safety margin of 15 mm. The planning target volume (PTV) was defined using three CT scans with reference to the phases of respiration so that the movement span of the clinical target volume (CTV) was enclosed. Results The volume of the metastases (CTV) varied from 2.8 to 55.8 cm3 (median: 6.0 cm3) and the PTV varied from 12.2 to 184.0 cm3 (median: 45.0 cm3). The metastases ranged from 0.7 to 4.5 cm in largest diameter. The volume of the bronchial carcinomas varied from 4.2 to 125.4 cm3(median: 17.5 cm3) and the PTV from 15.6 to 387.3 cm3 (median: 99.8 cm3). The bronchial carcinomas ranged from 1.7 to 10 cm in largest diameter. Follow-up periods varied from 6.8 to 63 months (median: 22 months for metastases and 18 months for NSCLC). Local control was achieved with 94% of NSCLC and 87% of metastases. No serious symptomatic side effects were observed. According to the Kaplan-Meier method the overall survival probability rates of patients with lung metastases were as follows: 1 year: 97%, 2 years: 73%, 3 years: 42%, 4 years: 42%, 5 years: 42% (median survival: 26 months); of those with NSCLC: 1 year: 83%, 2 years: 63%, 3 years: 53%, 4 years: 39%: (median survival: 20.4 months). Conclusion Non-fractionated single-dose irradiation of metastases in the lungs or of small, peripheral bronchial carcinomas is an effective and safe form of local treatment and might become a viable alternative to invasive techniques.

We reviewed response rates, local control, survival and side effects after non-fractionated stereotactic high single-dose body radiation therapy for lung tumors. Forty patients with stage I non-small cell lung cancer (NSCLC) underwent radiosurgery involving single-dose irradiation. The standard dose prescribed to the isocenter was 30Gy with an axial safety margin of 10mm and a longitudinal safety margin of 15mm. The planning target volume (PTV) was defined using three CT scans with reference to the phases of respiration so that the movement span of the clinical target volume (CTV) was enclosed. The volume of the bronchial carcinomas varied from 4.2 to 130cm(3) (median: 19.5cm(3)), and the PTV derived from four-dimensional CT (4D-CT) scans using image fusion ranged from 15.6 to 390.5cm(3) (median: 101cm(3)). Tumor size ranged from 1.7 to 10cm at largest focuses. Follow-up periods varied from 6.0 to 61.5 months (median: 20 months). We observed three local tumor recurrences, resulting in an actuarial local tumor control of 81% at 3 years. With the exception of two rib fractures, no serious late toxicity was observed. The overall survival probability rates were: 2 years: 66%, 3 years: 53% (median overall survival: 37 months). Cancer-specific survival probability was: 2 years: 71%, 3 years: 57%. Non-fractionated high single-dose SBRT for NSCLC is more convenient for the patient and less time-consuming than hypofractionated SBRT, but data dealing with this method are still scanty. This alternative treatment results in favourable local control and acceptable toxicity.

With reference to radiosurgery of the liver, we describe techniques designed to solve the methodological problem of striking targets subject to respiratory motion with the necessary precision. Implanting a gold marker in the vicinity of the liver tumor was the first step in ensuring the reproducibility of the isocenter's position. An 18-karat gold rod measuring 1.9 × 3 mm was implanted approximately 2 cm from the edge of the tumor as this was displayed in the spiral, thin-slice CT with contrast media. Both the implantation of the marker and the required, CT-controlled biopsy of the liver tumor can be achieved simultaneously with the same puncture needle. The efficiency of high-frequency jet ventilation (HFJV) in neutralizing the targeted organ's respiratory motion during stereotactic single-dose irradiation was evaluated. The procedure was carried out on ten patients without any complications. In the time between treatment planning and irradiation (3 days), no significant marker migration was observable. In all cases, the gold marker (volume: 7.5 mm3) was readily observable in the treatment beam using portal imaging. HFJV provided reliable immobilization. The liver motion in each anesthetized patient was limited to under 3.0 mm in all directions. Thus, the correct field settings and target reproducibility were able to be analyzed and documented during the irradiation. The combination of marker and HFJV enables the determination of stereotactic coordinates directly related to the liver itself and, in this way, stereotactic radiation treatment of liver tumors is freed from the uncertainties involved in orientation to bony landmarks, in respiratory motion, and in changes of position in the stereotactic body frame. The method is feasible and can improve the accuracy of stereotactic body radiation therapy.

WCN 2013 No: 2028 Topic: 6 — MS & Demyelinating Diseases Reduced intrathecal IgG synthesis in the cerebrospinal fluid from natalizumab-treated patients with active multiple sclerosis A. Harrer, G. Pilz, P. Wipfler, K. Oppermann, B. Holl, W. Hitzl, S. Afazel, E. Haschke-Becher, E. Trinka, J. Kraus. Department of Neurology, Paracelsus Medical University, Christian-Doppler-Klinik, Salzburg, Austria; Research Office, Biostatistics, Paracelsus Medical University, Salzburg, Austria; Central Laboratory, Paracelsus Medical University, Christian-Doppler-Klinik, Salzburg, Austria Oligoclonal bands (OCB) have been reported to disappear from the cerebrospinal fluid (CSF) in natalizumab (NZB)-treated patients with multiple sclerosis (MS) although OCB are considered to persist in MS. Detection of OCB is qualitative evidence of intrathecally produced IgG. We investigated if this NZB-effect on intrathecal IgG synthesis can be quantitatively assessed by analyzing the fraction of intrathecally produced IgG (IgGIF). We included 31 MS patients, 17 were untreated (first diagnosis) and from 14 patients CSF was collected to rule out progressive multifocal leukoencephalopathy (PML) during NZB treatment. From 6 of the 14 NZB-treated patients CSF data from the first diagnosis were also available. IgG and albumin concentrations of CSF and serum samples were measured by immunonephelometry and used to calculate the CSF/serum quotients and IgGIF (in %) according to Reiber (1998). Quantification of intrathecal IgG synthesis showed a reduced IgGIF in NZB-treated patients compared to untreatedMS patients (p= 0.0026). Intraindividual comparisons of baseline and follow-up data in the NZBtreated group of 6 showed disappearance of intrathecal IgG production in 2 and an overall reduction of the IgGIF (p= 0.018). Quantifying intrathecal IgG synthesis revealed a pronouncedly reduced IgGIF in NZB-treated MS patients. This corroborates previous reports about disappearing OCB and suggests effectiveness of NZB therapy on intrathecal IgG production. Since lumbar punctures were performed to rule out PML this observation is limited to NZB-treated patients with active disease. Clarification of the underlying mechanisms will provide important knowledge about the clinical relevance of this finding and the pathogenesis of NZB-associated PML. doi:10.1016/j.jns.2013.07.1410 Abstract — WCN 2013 No: 2004 Topic: 6 — MS & Demyelinating Diseases Incidence of multiple sclerosis in the region of Sarajevo before and after the war events WCN 2013 No: 2004 Topic: 6 — MS & Demyelinating Diseases Incidence of multiple sclerosis in the region of Sarajevo before and after the war events J. Djelilovic-Vranic, A. Alajbegovic, M. Tiric-Campara, S. Salcic, E. Djozic, E. Eljubovic. Neurology Clinic, Clinical Center of Sarajevo University, Sarajevo, Bosnia and Herzegovina Introduction: Multiple sclerosis is an autoimmune demyelinating disease and degeneration of axons, in the appearance of which stress has an important role. The goal is to determine the incidence of multiple sclerosis in the region of Sarajevo in the period before and after the war (1986–2012). Material andmethods:We analyzed all new cases of multiple sclerosis in the region of Sarajevo in the period January 1986–December 2012. Diagnostic criteria included anamnesis, clinical presentation, MRI findings and evaluation of the spine, evoked potentials-visual and cerebrospinal fluid examination. Results:During the period 1986–1990, therewere 45 new cases ofMS, in the period 1991–1995, there were 27 new MS cases, from 1996 to 2000 107 new cases were registered of MS, and from 2001–2005 there were 150 new cases ofMS. In the period 2006–2010, therewere 174 new cases of MS. In 2011 there were 34 new cases of MS and during the 2012, 41 new cases. Stress as provoking factor was present in the first five-year period at 11.1% in the second at 18.5%, in the third with 19.6%, in the fourth five-year period at 36.5% of cases and in the final at 43.8% of cases. Conclusions: In the period after the war, the MS in the region of Sarajevo has increased in incidence. Multiple sclerosis in the region of Sarajevo is more frequent in women than in men, most frequently in the age 20–40 years. But it also tends to occur in a relatively advanced age, after 50 years. doi:10.1016/j.jns.2013.07.1411 Abstract — WCN 2013 No: 1996 Topic: 6 — MS & Demyelinating Diseases Multiple sclerosis prevalence study: The comparison of two coastal cities, located in the Black Sea and the Mediterranean Sea in Turkey WCN 2013 No: 1996 Topic: 6 — MS & Demyelinating Diseases Multiple sclerosis prevalence study: The comparison of two coastal cities, located in the Black Sea and the Mediterranean Sea in Turkey U. Turk Boru, A. Duman, A.S. Kulualp, N. Guler, M. Tasdemir. Neurology, Dr. Lutfi Kirdar Kartal Training and Research Hospital, Istanbul, Turkey; Neurology, Artvin State Hospital, Marmara University, Istanbul, Turkey; Public Health, Marmara University, Istanbul, Turkey Background: The studies about Multiple Sclerosis (MS) epidemiology have increased in the last years. The studies, we conducted in Turkey, which have been compared with new studies were made in Turkey. These studies show that there are also distinct variations between the same geographical areas. Objective: We carried out this study in order to determine the prevalence and to compare the difference between Mediterranean and Black Sea regions. Patients and metods: This descriptive, cross-sectional, door-to-door survey was carried out in the Mediterranean coastal city Gazipasa and the Black Sea coastal city Artvin in 2012. All people, who live in the city, were visited and interviewed in their houses. The center town of Artvin andGazipasa had been screened by door to door. A population of 16.116 people was screened in Artvin and 13.451 of the people were screened in Gazipasa. Poser criteria were used as diagnostic criteria in the study. Results: Seven patients were diagnosed as clinically definitive MS with the definitive anamnesis and MR investigation. Female to male ratio was 1.33. The prevalence of MS was found to be 52.0/100.000 in Gazipasa. Three female patients were diagnosed as clinically definitive MS. The prevalence of MS was found to be 18.6/100.000 in Artvin. Conclusion: According to the results, the countries in the Mediterranean area is also now in the high MS prevalence zone. More than 2 times of the difference was found between prevalences of Artvin and Gazipasa. Our recent studies, conducted in Turkey, provide evidence that the latitude gradient in the distribution of MS is disappearing. doi:10.1016/j.jns.2013.07.1412 Abstract — WCN 2013 No: 2019 Topic: 6 — MS & Demyelinating Diseases Flow-cytometry and the detection of anti-natalizumab NAB in multiple sclerosis WCN 2013 No: 2019 Topic: 6 — MS & Demyelinating Diseases Flow-cytometry and the detection of anti-natalizumab NAB in multiple sclerosis K. Oppermann, A. Harrer, G. Pilz, P. Wipfler, B. Holl, F. Deisenhammer, S. Afazel, E. Haschke-Becher, E. Trinka, J. Kraus. Abstracts / Journal of the Neurological Sciences 333 (2013) e358–e421 e389

Objectives– Multiple sclerosis (MS) is believed to be an autoimmune disease of the human central nervous system mediated by autoreactive T cells. Interferon-β1b (IFN-β1b) has been shown to be effective in reducing disease activity defined by clinical and magnetic resonance imaging (MRI) criteria in relapsing–remitting MS (RRMS). Yet, the exact mechanisms by which these benefits are achieved remain unknown. CD45RA is a marker for naive T lymphocytes and intercellular adhesion molecule-3 (ICAM-3) is expressed on resting lymphocytes. Material and methods– Forty-eight patients with RRMS, 24 of them treated with recombinant IFN-β1b and 24 untreated, were enrolled in this prospective study over 18 months. We investigated the percentage of CD45RA+ ICAM-3+ cells within the total lymphocyte subset in the peripheral blood serially every 3 months and in CSF once at baseline. Detailed clinical examination including Expanded Disability Status Scale (EDSS) score was performed every 3 months and cranial MRI scans were assessed every 6 months. Results– We found a temporary increase in the CD45RA+ ICAM-3+ lymphocyte ratio in peripheral blood of both untreated and IFN-β1b-treated RRMS patients. Moreover, we determined a significant negative correlation (r = −0.5874; P

International audience; In the central nervous system (CNS) complex endothelial tight junctions (TJs) form a restrictive paracellular diffusion barrier, the blood-brain barrier (BBB). Pathogenic changes within the CNS are frequently accompanied by the loss of BBB properties, resulting in brain edema. In order to investigate whether BBB leakiness can be monitored by a loss of TJ proteins from cellular borders, we used an in vitro BBB model where brain endothelial cells in co-culture with astrocytes form a tight permeability barrier for 3H-inulin and 14C-sucrose. Removal of astrocytes from the co-culture resulted in an increased permeability to small tracers across the brain endothelial cell monolayer and an opening of the TJs to horseradish peroxidase as detected by electron microscopy. Strikingly, opening of the endothelial TJs was not accompanied by any visible change in the molecular composition of endothelial TJs as junctional localization of the TJ-associated proteins claudin-3, claudin-5, occludin, ZO-1 or ZO-2 or the adherens junction-associated proteins β-catenin or p120cas did not change. Thus, opening of BBB TJs is not readily accompanied by the complete loss of the junctional localization of TJ proteins.

Paraneoplastic opsoclonus-myoclonus syndrome (OMS) is a rare complication of cancer characterised by chaotic, synchronous eye movements (opsoclonus), spontaneous muscle jerks (myoclonus), and ataxia. In children OMS is almost exclusively associated with neuroblastoma, whereas in adults small cell lung cancer (SCLC) and breast cancer are the most frequent tumours associated with OMS.1,2 Some breast cancer patients with OMS have an antineuronal antibody called anti-Ri in the serum and CSF.1,2 In most patients with SCLC-associated OMS, antineuronal antibodies are not detected.1 Here we report the first case of SCLC-associated OMS with high titre antimitochondrial antibodies (AMA) in serum and CSF. A 58 year old Caucasian woman developed a flu like syndrome, followed by eye movement disturbances three days later. On admission to our hospital, physical examination revealed disorientation, opsoclonus, myoclonus predominantly of the upper limbs, and severe limb and trunk ataxia. The deep tendon reflexes were normal and no paresis or sensory deficit could be found. Cranial CT and MRI scans and routine laboratory tests were normal. CSF examination revealed lymphocytic pleiocytosis, normal total …

Thrombocyte activation and subsequent aggregate formation play a pivotal role in arterio-arterial embolism in high grade carotid artery stenosis. The aim of this study was to test the hypothesis that the amount of activated thrombocytes would differ with the degree of stenosis. In 19 patients with asymptomatic carotid artery stenosis > 70%, 11 patients with low grade carotid disease and a luminal narrowing of < 70%, and 13 healthy controls in vivo thrombocyte activation was determined by the surface thrombocyte expression of P-selectin before and after thrombin stimulation by whole blood flow cytometry. Soluble P (sP)-selectin in serum was measured by ELISA. We found that thrombocyte activation significantly increased with the degree of stenosis in a multiple correlation analysis corrected for age, sex, and cardiovascular risk factors. Only thrombocyte P-selectin expression and sP-selectin serum concentrations were able to discriminate the patient groups in a multivariate analysis, however, only thrombocyte P-selectin expression was an independent variable. In vivo thrombocyte activation, then, increases with the degree of carotid stenosis. Flow cytometry is especially useful in the evaluation of the thrombocyte activation state in patients with cerebrovascular disease.

Objective: To investigate if high-dose intravenous interferon-beta (IFNb) in high-titer neutralizing antibody-(NAb)-positive multiple sclerosis (MS) patients reduces NAb titers to less than 100 neutralizing units (NU) - presumably by induction of immune tolerance (IT) - and restores IFNb bioavailability measured by myxovirus protein A (MxA) concentrations. Background IFNb is associated with the generation of NAbs affecting treatment efficacy. Successful IT induction has been shown for hemophilia patients with NAbs against recombinant factor-VIII by high-dose intravenous administration of factor-VIII. Design/Methods: 9 MS patients, with a NAb titer of >=500 NU, received 48 MIU IFNb-1b intravenously once weekly over 3 months. Blood samples were collected at screening, monthly before and 4 hours after infusions, and at follow-up after 6 months for NAb and MxA measurement. Disease activity was monitored by brain MRI and EDSS assessments. Results: Median NAb titer at baseline was 1429 NU. Titers determined before each infusion did not change over the treatment period. There was a significant decrease of titers four hours after each infusion. NAb titers at follow-up did not significantly differ compared to titers at screening. Comparing NAb titers after 3 months to baseline, 4 patients showed increased titers by 654 NU and 5 decreased titers by 235 NU indicating a possible responder group. MxA levels were significantly elevated after all IFNb infusions reaching a median value of 206. MRI data are currently being analyzed. Conclusions: Weekly intravenous IFNb induced short-term bioactivity in patients with high NAb titers but failed to induce long-term reversion of NAb although in some patients a trend towards reversion was observed. Supported by: Bayer Schering Pharma. Disclosure: Dr. Hegen has received personal compensation for activities with Bayer PHarmaceuticals Corporation, Schering-Plough Corporation, Biogen Idec, Merck Serono as speaker. Dr. Guger has nothing to disclose. Dr. Harrer has nothing to disclose. Dr. Hoelzl has nothing to disclose. Dr. Kraus has received personal compensation for activities with Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck-Serono, Novartis, Genzyme Corporation as a consultant. Dr. Kraus has received research support from Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck Serono, Novartis, Genzyme Corporation. Dr. Skrobal has nothing to disclose. Dr. Schautzer has nothing to disclose. Dr. Schmidegg has nothing to disclose. Dr. Deisenhammer has received personal compensation for activities with Biogen Idec, Merck Serono, Bayer and Sanofi. Dr. Deisenhammer has received research support from Bayer HealthCare.

Objective: To obtain a better understanding of potential additional effector mechanisms of natalizumab we analyzed the influence of short and long-term treatment on soluble adhesion molecules (sAMs) in peripheral blood of MS patients. Background Natalizumab (Tysabri) is a humanized monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis (MS). It directly binds to the alpha4-integrin subunit of very late activation antigen-4 (VLA-4) and results in decreased detectability of unblocked alpha-4 leading to an inhibition of immune cell extravasation across the blood-brain-barrier. The impressive therapeutic effect of natalizumab is overshadowed by rare but potentially serious side effects such as progressive multifocal leukoencephalopathy. Design/Methods: Serum levels of fibronectin (FN) and 4 different sAMs (soluble intercellular adhesion molecule-1,-2,-3 (sICAM-1,-2,-3) and vascular cell adhesion molecule-1 (sVCAM-1)) were analyzed before (baseline, n=16), 3 months after (short-term, n=16) and 24 months after (long-term, n=14) onset of Natalizumab treatment by fluorescent bead immunoassay and enzyme-linked immunosorbent assay. Results: A significant and sustained decrease in serum concentrations of FN, sICAM-3 and sVCAM-1 was observed during the first 3 months (FN p Conclusions: The observed decreases in serum levels highlight sICAM-3, sVCAM-1, and FN to be affected by natalizumab therapy. Decreases in sVCAM-1 serum levels have already been previously reported. We add sICAM-3 and the soluble form of the extracellular matrix protein FN. Both, sVCAM-1 and FN have been shown to be directly engaged in VLA-4-mediated extravasation of immune cells and sICAM-3 is important in the initiation of immune responses. Decreased serum levels indicate potential therapy-induced interference with fine-tuning and/or feedback mechanisms between endothelium and immune cells with yet unresolved consequences. Supported by: Biogen-Idec Austria. Disclosure: Dr. Kraus has received personal compensation for activities with Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck-Serono, Novartis, Genzyme Corporation as a consultant. Dr. Kraus has received research support from Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck Serono, Novartis, Genzyme Corporation. Dr. Oppermann has nothing to disclose. Dr. Pilz has nothing to disclose. Dr. Wipfler has nothing to disclose. Dr. Afazel has nothing to disclose. Dr. Haschke-Becher has nothing to disclose. Dr. Trinka has received personal compensation for activities with UCB Pharma, Eisai Inc., Sunovion, Medtronic, Pfizer Inc, Ever-Neuropharma and GlaxoSmithKline, Inc. as a consultant and/or speaker. Dr. Trinka has received research support from UCB Pharma, Ever-Neuropharma, Medtronic and GlaxoSmithKline, Inc. Dr. Harrer has nothing to disclose.

Eine gute Geschaftsidee haben viele, doch die Umsetzung wird nur von wenigen gewagt. Der Umsetzung stehen zum Teil reale, zum Teil nur vermutete Risiken entgegen. Um die wirtschaftlichen Potentiate der eigenen Geschaftsideen auf einer solideren Grundlage auszuarbeiten und prufen zu konnen, bietet die gemeinsame Akademie fur Weiterbildung der Universitaten Heidelberg und Mannheim zusammen mit Chemie- und Pharmaunternehmen der Region Rhein-Neckar-Dreieck das Existenzgrunderprogramm Post-Graduate BioBusiness an.