Neurochirurgische Klinik und Poliklinik
Refine
Year of publication
Document Type
- Journal article (98)
- Doctoral Thesis (40)
- Report (2)
- Review (1)
Keywords
- Neurobiologie (41)
- Medizin (9)
- Glioblastom (6)
- Durchblutung (4)
- Gehirn (4)
- glioma (4)
- rats (4)
- Astrozytom (3)
- Glioblastoma (3)
- Gliom (3)
Institute
- Neurochirurgische Klinik und Poliklinik (141)
- Neurologische Klinik und Poliklinik (11)
- Pathologisches Institut (8)
- Klinik und Poliklinik für Nuklearmedizin (4)
- Frauenklinik und Poliklinik (2)
- Kinderklinik und Poliklinik (2)
- Physiologisches Institut (2)
- Rudolf-Virchow-Zentrum (2)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (1)
- Institut für Medizinische Strahlenkunde und Zellforschung (1)
Trotz jahrelanger, intensiver Forschung ist es bisher nicht gelungen, die Morbidität und
Mortalität der aneurysmatischen Subarachnoidalblutung (SAB) signifikant zu senken. Der Fokus dieser Bemühungen lag in den letzten Jahrzehnten vor allem auf der frühen Erkennung und Behandlung des verzögert, typischerweise zwischen Tag 4 und 14 auftretenden, symptomatischen Vasospasmus´ und somit einer zerebralen Ischämie, die mit einer höheren Rate an klinischen Komplikationen, reduzierter Alltagsaktivität, schlechterer kognitiver Leistungsfähigkeit und einer insgesamt höheren Mortalität einhergeht sowie mit einem insgesamt schlechteren neurologischen Outcome assoziiert ist.
Diese Arbeit beschäftigt sich per Tierexperiment mit der Akutphase der SAB und zweier möglicher Therapiestrategien (Hyper-HES und Hypothermie), die möglichst früh im Verlauf angewendet werden und für eine histologisch sowie neurologisch nachweisbare Verbesserung im Gesamtergebnis sorgen können.
Insgesamt entsprechen sowohl die osmotischwirksame Therapie mit Hydroxyethylstärke als auch die hypotherme Therapie nach unseren Resultaten der primären Zielsetzung der Studie. Die Möglichkeit einer prinzipiell überall verfügbaren, kostengünstigen und gut steuerbaren Frühphasentherapie nach SAB ohne Kompromittierung der initialen Diagnostik und der klinischen Differentialdiagnosen
scheint hier jeweils gegeben zu sein.
Frühe entzündliche Vorgänge scheinen eine große Rolle in der Entstehung der globalen Hirnschädigung in der Frühphase nach einer Subarachnoidalblutung (SAB) zu spielen.
Ziel der vorliegenden Arbeit war es den Effekt der anti-inflammatorischen Medikamente Methylprednisolon und Minozyklin auf die Gehirndurchblutung und frühe Hirnschädigung nach SAB zu untersuchen.
Hierzu wurde ein randomisiertes und kontrolliertes Tierexperiment durchgeführt. Mit Hilfe des endovaskulären Perforationsmodells wurde bei männlichen Sprague-Dawley-Ratten eine SAB ausgelöst. Den Tieren wurde 30 Minuten nach Auftreten der SAB Methylprednisolon, Minozyklin oder Kochsalzlösung intraperitoneal verabreicht.
Sowohl Methylprednisolon als auch Minozyklin verminderten den Anteil Caspase 3 positiver Zellen in immunhistochemischen Färbungen der Hippocampie der Versuchstiere signifikant. In Bezug auf die klinische Untersuchung, den intrakraniellen Druck und die Hirndurchblutung der Ratten ergaben sich keine signifikanten Unterschiede zwischen den Versuchsgruppen. Die Ergebnisse suggerieren, dass Methylprednisolon und Minozyklin den akuten Zellschaden nach SAB reduzieren. Daher könnten sich beide Mittel als geeignet für die Therapie der „Early Brain Injury“ nach SAB erweisen. Weitere Studien zum besseren Verständnis der zugrunde liegenden Wirkmechanismen von Methylprednisolon und Minozyklin auf die Frühphase der SAB sind nötig.
Introduction
A novel neurostimulation system allows steering current in horizontal directions by combining segmented leads and multiple independent current control. The aim of this study was to evaluate directional DBS effects on parkinsonian motor features and adverse effects of subthalamic neurostimulation.
Methods
Seven PD patients implanted with the novel directional DBS system for bilateral subthalamic DBS underwent an extended monopolar review session during the first postoperative week, in which current thresholds were determined for rigidity control and stimulation-induced adverse effects using either directional or ring-mode settings.
Results
Effect or adverse effect thresholds were modified by directional settings for each of the 14 STN leads. Magnitude of change varied markedly between leads, as did orientation of optimal horizontal current steering.
Conclusion
Directional current steering through chronically implanted segmented electrodes is feasible, alters adverse effect and efficacy thresholds in a highly individual manner, and expands the therapeutic window in a monopolar review as compared to ring-mode DBS.
Die zunehmende Bedeutung der Molekularbiologie zeigt sich in der neuen WHO-Klassifikation von 2016 für ZNS-Tumoren und insbesondere astrozytäre Tumoren. Dabei gehört das Glioblastoma multiforme (GBM) mit einer äußerst ungünstigen Prognose zu den hoch-malignen Astrozytomen (WHO °IV) und ist durch eine ausgeprägte chromosomale Instabilität (CIN) gekennzeichnet. Der mitotische Spindelkontrollpunkt (SAC) und die zeitlich korrekte Auflösung der Schwesterchromatidkohäsion sorgen normalerweise für den fehlerfreien Ablauf der Mitose. Um der Ursache der CIN nachzugehen, wurden die Regulatorproteine des SAC Mad2A und Mad2B sowie der Schwesterchromatidkohäsion Pds5A und Pds5B in einem Patientenpanel immunhistochemisch untersucht. Alle vier Proteine wiesen eine hohe Expression in Proliferationszentren auf, die durch Ki67-Expression definiert wurden. Zusätzlich wurden Unterschiede in der Expressionsstärke bzw. der subzellulären Lokalisation detektiert. Pds5A könnte für die Ausbildung von Rezidiven niedriggradiger Astrozytome (low-grade astrozytoma, LGA) °II bzw. von sekundären GBM wichtig sein. Sein Ortholog war in allen Tumorentitäten gleichmäßig hoch exprimiert. Eine starke Mad2A-Expression war in allen GBM im Vergleich zu allen LGA °II signifikant vermindert und könnte durch den in GBM häufig vorkommenden Verlust von Chromosomenarm 4q bedingt sein, der das Mad2A-Gen enthält. Für sein Homolog Mad2B konnte ein signifikanter Anstieg in der Gesamt- bzw. Zytoplasmaexpression mit steigendem WHO-Grad ermittelt werden. Eine niedrige Gesamtexpression von Mad2A bzw. von Mad2B in Kern- und Zytoplasma könnte mit einem Überlebensvorteil für GBM-Patienten verbunden sein. Je nach Entität, Expressionsstärke und Expressionslokalisation gab es Korrelationen zwischen der Expression von Ki67, Pds5A, Pds5B, Mad2A und Mad2B.
Die Expressionswerte dieser mitotischen Regulatorproteine könnten einerseits der Grund für, andererseits aber auch eine Konsequenz von CIN sein und eine Anpassung der Tumorzellen zur Ausbalancierung der Vor- und Nachteile genetischer Veränderungen darstellen, die ihr Überleben sichert (Rimkus et al., 2007).
Damit könnten diese Regulatorproteine als neue Angriffspunkte einer noch spezifischeren Therapie in der Behandlung von astrozytären Tumoren und für die Prognose von Patienten Bedeutung erlangen.
Objective:
To assess the therapy-related risk of malignancies in mitoxantrone-treated patients with multiple sclerosis.
Methods:
This retrospective observational cohort study included all mitoxantrone-treated patients with multiple sclerosis seen at our department between 1994 and 2007. We collected follow-up information on medically confirmed malignancies, life status, and cause of death, as of 2010. Malignancy rates were compared to the German national cancer registry matched for sex, age, and year of occurrence.
Results:
Follow-up was completed in 676 of 677 identified patients. Median follow-up time was 8.7 years (interquartile range 6.8-11.2), corresponding to 6,220 person-years. Median cumulative mitoxantrone dose was 79.0 mg/m(2) (interquartile range 50.8-102.4). Thirty-seven patients (5.5%) were diagnosed with a malignancy after mitoxantrone initiation, revealing a standardized incidence ratio of 1.50 (95% confidence interval CI] 1.05-2.08). Entities included breast cancer (n = 9), colorectal cancer (n = 7), acute myeloid leukemia (n = 4, 0.6%), and others (each entity n = 1 or 2). The standardized incidence ratio of colorectal cancer was 2.98 (95% CI 1.20-6.14) and of acute myeloid leukemia 10.44 (95% CI 3.39-24.36). It was not increased for other entities including breast cancer. Multivariate Cox regression identified higher age at treatment initiation but neither cumulative mitoxantrone dose (>75 vs 75 mg/m(2)) nor treatment with other immunosuppressive drugs or sex as a risk factor. Fifty-five patients had died, among them 12 of a malignancy and 43 reportedly of other causes.
Conclusions:
While the overall incidence of malignancies was only mildly increased, the risk of leukemia and colorectal cancer was heightened. If confirmed, posttherapy colonoscopy could become advisable.
Objective:
Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.
Methods:
We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.
Results:
Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.
Interpretation:
The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.
Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of similar to 20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a \(^{15}\)N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated \(^{15}\)N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration.
Background
Early inflammatory processes may play an important role in the development of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Experimental studies suggest that anti-inflammatory and membrane-stabilizing drugs might have beneficial effects, although the underlying mechanisms are not fully understood. The aim of this study was to investigate the effect of early treatment with methylprednisolone and minocycline on cerebral perfusion and EBI after experimental SAH.
Methods
Male Sprague-Dawley rats were subjected to SAH using the endovascular filament model. 30 minutes after SAH, they were randomly assigned to receive an intravenous injection of methylprednisolone (16mg/kg body weight, n=10), minocycline (45mg/kg body weight, n=10) or saline (n=11). Mean arterial blood pressure (MABP), intracranial pressure (ICP) and local cerebral blood flow (LCBF) over both hemispheres were recorded continuously for three hours following SAH. Neurological assessment was performed after 24 hours. Hippocampal damage was analyzed by immunohistochemical staining (caspase 3).
Results
Treatment with methylprednisolone or minocycline did not result in a significant improvement of MABP, ICP or LCBF. Animals of both treatment groups showed a non-significant trend to better neurological recovery compared to animals of the control group. Mortality was reduced and hippocampal damage significantly attenuated in both methylprednisolone and minocycline treated animals.
Conclusion
The results of this study suggest that inflammatory processes may play an important role in the pathophysiology of EBI after SAH. Early treatment with the anti-inflammatory drugs methylprednisolone or minocycline in the acute phase of SAH has the potential to reduce brain damage and exert a neuroprotective effect.
We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor.
Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients.
Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors.
Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression.
Introduction: Striatal dopamine depletion disrupts basal ganglia function and causes Parkinson’s disease (PD). The pathophysiology of the dopamine-dependent relationship between basal ganglia signaling and motor control, however, is not fully understood. We obtained simultaneous recordings of local field potentials (LFPs) from the subthalamic nucleus (STN) and electromyograms (EMGs) in patients with PD to investigate the impact of dopaminergic state and movement on long-range beta functional connectivity between basal ganglia and lower motor neurons.
Methods: Eight PD patients were investigated 3 months after implantation of a deep brain stimulation (DBS)-system capable of recording LFPs via chronically-implanted leads (Medtronic, ACTIVA PC+S®). We analyzed STN spectral power and its coherence with EMG in the context of two different movement paradigms (tonic wrist extension vs. alternating wrist extension and flexion) and the effect of levodopa (L-Dopa) intake using an unbiased data-driven approach to determine regions of interest (ROI).
Results: Two ROIs capturing prominent coherence within a grand average coherogram were identified. A trend of a dopamine effect was observed for the first ROI (50–150 ms after movement start) with higher STN-EMG coherence in medicated patients. Concerning the second ROI (300–500 ms after movement start), an interaction effect of L-Dopa medication and movement task was observed with higher coherence in the isometric contraction task compared to alternating movements in the medication ON state, a pattern which was reversed in L-Dopa OFF.
Discussion: L-Dopa medication may normalize functional connectivity between remote structures of the motor system with increased upper beta coherence reflecting a physiological restriction of the amount of information conveyed between remote structures. This may be necessary to maintain simple movements like isometric contraction. Our study adds dynamic properties to the complex interplay between STN spectral beta power and the nucleus’ functional connectivity to remote structures of the motor system as a function of movement and dopaminergic state. This may help to identify markers of neuronal activity relevant for more individualized programming of DBS therapy.
