The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. METHODS: The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. RESULTS: The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). CONCLUSION: GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. TRIAL REGISTRATION: EudraCT-Nr. 2005-003201-81.

Clinical Trial Results Summary for Laypersons: A User Testing Study.

OBJECTIVE: To apply "user testing" to maximize readability and acceptability of a Clinical Trial Results Laypersons Summary-a new European requirement. METHODS: "User testing" (using questionnaire and semistructured interview) assessed whether people could find and understand key points. Findings were used to improve content and design, prior to retesting. Participants had a range of levels of health literacy and there was a higher education group. Participants accessed the summary on screen. In round 1 we tested 12 points of information. In round 2 a revised summary addressing round 1 findings was tested, leading to a third final version. RESULTS: In round 1, 2 of 12 points of information did not reach the target and interviews raised further format and content issues (some distracting technical explanations and inability to find or understand the 2 main study purposes). These findings informed revisions for the version tested in round 2, with 2 different points not reaching the target (inclusion criteria relating to duration of seasonal allergies and how researchers found out about participants' symptoms). Identified problems in both rounds were addressed and reflected in the final version. Despite improvements, participants did not consistently understand that summaries were intended for the public, or to only interpret results of single trials in the context of additional trials. All readers, including those with higher education, found the clear and straightforward language acceptable. CONCLUSIONS: Applying "user testing" resulted in a largely health-literate summary suitable for people across a range of backgrounds.

[Mission (im)possible : Setting up a neurological center 12,000 km away with telemedicine]. / "Mission (im)possible" : Aufbau eines neurologischen Zentrums 12.000 km entfernt mittels Telemedizin.

BACKGROUND: Specialized neurological treatment decreases the mortality and morbidity of stroke patients. In many regions of the world an extensive coverage is not available. The cooperation between the Krankenhaus Nordwest (KHNW, Frankfurt, Germany) and the Government of Brunei Darussalam describes the set-up process of a specialized neurological center, including stroke unit, science and rehabilitation center. AIM: The aim of this project called to teach to treat - to treat to teach was to set up a center of excellence in neurology in Brunei Darussalam over a distance of 12,000 km. Treatment options were elucidated by teaching and taught by case examples. MATERIAL AND METHODS: The construction of the Brunei Neuroscience Stroke and Rehabilitation Center (BNSRC) began in July 2010. To overcome the large distance between the department of neurology and neuroradiology at the KHNW and the BNSRC, a telemedical network was established. We provided daily teleteaching for all professions involved in patient care as well as 24/7 availability of teleneurological services from Germany to support the local team on site. RESULTS: In the BNSRC unit over 1000 patients with ischemic and hemorrhagic stroke and all the various acute neurological conditions were treated from July 2010 until July 2016 as inpatients and over 5000 were treated as outpatients. Since 2010, a total of 52 patients with stroke were treated by thrombolysis within the thrombolytic window and 81 hemicraniectomies were performed. CONCLUSION: The project has shown that it is possible to convey specialized neurological knowledge over large distances to provide significant benefits for patients and caregivers.

Setting up a Neuroscience Stroke and Rehabilitation Centre in Brunei Darussalam by a transcontinental on-site and telemedical cooperation.

Due to the world-wide aging population, there is a need for specialist neurological knowledge, treatment and care. Stroke treatment is effective in reducing mortality and disability, but it is still not available in many areas of the world. We describe the set-up process of a specialized Neuroscience, Stroke and Rehabilitation Centre in Brunei Darussalam (BNSRC) in cooperation with a German hospital. This study details the setup of a stroke-, neurological intensive care- and neurorehabilitation unit, laboratories and a telemedical network to perform all evidence-based stroke treatments. All neurological on-site services and the telemedical network were successfully established within a short time. After setup, 1386 inpatients and 1803 outpatients with stroke and stroke mimics were treated. All evidence-based stroke treatments including thrombolysis and hemicraniectomy could be performed. It is possible to establish evidence-based modern stroke treatment within a short time period by a transcontinental on-site and telemedical cooperation.

CO oxidation on Pt(111) at near ambient pressures.

The oxidation of CO on Pt(111) was investigated simultaneously by near ambient pressure X-ray photoelectron spectroscopy and online gas analysis. Different CO:O2 reaction mixtures at total pressures of up to 1 mbar were used in continuous flow mode to obtain an understanding of the surface chemistry. By temperature-programmed and by isothermal measurements, the onset temperature of the reaction was determined for the different reactant mixtures. Highest turnover frequencies were found for the stoichiometric mixture. At elevated temperatures, the reaction becomes diffusion-limited in both temperature-programmed and isothermal measurements. In the highly active regime, no adsorbates were detected on the surface; it is therefore concluded that the catalyst surface is in a metallic state, within the detection limits of the experiment, under the applied conditions. Minor bulk impurities such as silicon were observed to influence the reaction up to total inhibition by formation of non-platinum oxides.

Global storm time depletion of the outer electron belt.

The outer radiation belt consists of relativistic (>0.5 MeV) electrons trapped on closed trajectories around Earth where the magnetic field is nearly dipolar. During increased geomagnetic activity, electron intensities in the belt can vary by orders of magnitude at different spatial and temporal scales. The main phase of geomagnetic storms often produces deep depletions of electron intensities over broad regions of the outer belt. Previous studies identified three possible processes that can contribute to the main-phase depletions: adiabatic inflation of electron drift orbits caused by the ring current growth, electron loss into the atmosphere, and electron escape through the magnetopause boundary. In this paper we investigate the relative importance of the adiabatic effect and magnetopause loss to the rapid depletion of the outer belt observed at the Van Allen Probes spacecraft during the main phase of 17 March 2013 storm. The intensities of >1 MeV electrons were depleted by more than an order of magnitude over the entire radial extent of the belt in less than 6 h after the sudden storm commencement. For the analysis we used three-dimensional test particle simulations of global evolution of the outer belt in the Tsyganenko-Sitnov (TS07D) magnetic field model with an inductive electric field. Comparison of the simulation results with electron measurements from the Magnetic Electron Ion Spectrometer experiment shows that magnetopause loss accounts for most of the observed depletion at L>5, while at lower L shells the depletion is adiabatic. Both magnetopause loss and the adiabatic effect are controlled by the change in global configuration of the magnetic field due to storm time development of the ring current; a simulation of electron evolution without a ring current produces a much weaker depletion.

White matter astrocytes in health and disease.

Myelination by oligodendrocytes is a highly specialized process that relies on intimate interactions between the axon and the oligodendrocytes. Astrocytes have an important part in facilitating myelination in the CNS, however, comparatively less is known about how they affect myelination. This review therefore summarizes the literature and explores lingering questions surrounding differences between white matter and gray matter astrocytes, how astrocytes support myelination, how their dysfunction in pathological states contributes to myelin pathologies and how astrocytes may facilitate remyelination. We discuss how astrocytes in the white matter are specialized to promote myelination and myelin maintenance by clearance of extracellular ions and neurotransmitters and by secretion of pro-myelinating factors. Additionally, astrocyte-oligodendrocyte coupling via gap junctions is crucial for both myelin formation and maintenance, due to K(+) buffering and possibly metabolic support for oligodendrocytes via the panglial syncytium. Dysfunctional astrocytes aberrantly affect oligodendrocytes, as exemplified by a number of leukodystrophies in which astrocytic pathology is known as the direct cause of myelin pathology. Conversely, in primary demyelinating diseases, such as multiple sclerosis, astrocytes may facilitate remyelination. We suggest that specific manipulation of astrocytes could help prevent myelin pathologies and successfully restore myelin sheaths after demyelination.

Enhanced radial transport and energization of radiation belt electrons due to drift orbit bifurcations.

[1]Relativistic electron intensities in Earth's outer radiation belt can vary by multiple orders of magnitude on the time scales ranging from minutes to days. One fundamental process contributing to dynamic variability of radiation belt intensities is the radial transport of relativistic electrons across their drift shells. In this paper we analyze the properties of three-dimensional radial transport in a global magnetic field model driven by variations in the solar wind dynamic pressure. We use a test particle approach which captures anomalous effects such as drift orbit bifurcations. We show that the bifurcations lead to an order of magnitude increase in radial transport rates and enhance the energization at large equatorial pitch angles. Even at quiet time fluctuations in dynamic pressure, radial transport at large pitch angles exhibits strong deviations from the diffusion approximation. The radial transport rates are much lower at small pitch angle values which results in a better agreement with the diffusion approximation.

Improved axonal regeneration after spinal cord injury in mice with conditional deletion of ephrin B2 under the GFAP promoter.

Spinal cord injury (SCI) initiates a cascade of processes that ultimately form a nonpermissive environment for axonal regeneration. Emerging evidence suggests that regenerative failure may be due in part to inhibitory factors expressed by reactive spinal cord glial cells and meningeal fibroblasts, such as the Eph receptor protein-tyrosine kinases and their corresponding ligands (ephrins). Here we sought to assess the role of ephrin B2, an inhibitory axonal guidance molecule, as an inhibitor of the recovery process following SCI. To determine the extent of ephrin B2 involvement in axonal regenerative failure, a SCI model was performed on a conditional ephrin B2 knockout mouse strain (ephrin B2(-/-)), in which the ephrin B2 gene was deleted under the GFAP promoter . The expression of ephrin B2 was significantly decreased in astrocytes of injured and uninjured ephrin B2(-/-) mice compared to wild-type mice. Notably, in the ephrin B2(-/-) mice, the deletion of ephrin B2 reduced astrogliosis, and accelerated motor function recovery after SCI. Anterograde axonal tracing on a hemisection model of SCI further showed that ephrin B2(-/-) mice exhibited increased regeneration of injured corticospinal axons and a reduced glial scar, when compared to littermate controls exposed to similar injury. These results were confirmed by an in vitro neurite outgrowth assay and ephrin B2 functional blockage, which showed that ephrin B2 expressed on astrocytes inhibited axonal growth. Combined these findings suggest that ephrin B2 ligands expressed by reactive astrocytes impede the recovery process following SCI.

Neuropathic pain resulting from implant placement: case report and diagnostic conclusions.

Temporary or persisting dysesthesia of the nervus alveolaris inferior has often been described as a complication of implant surgery of the lower mandible. In most cases, lesion of the nerve results in anaesthesia of the innervated region, a symptom clearly indicative of correct diagnosis. In our case report, however, a minor perforation of the roof of the mandibular canal during implant placement apparently provoked discrete irritation of the nerve, resulting in persistent neuropathic pain without concomitant hypesthesia or dysesthesia. Because the canal could not be detected in conventional dental radiographs, this uncharacteristic situation made correct diagnosis difficult and led to unnecessary surgical procedures including extraction of adjacent teeth. Medical imaging [computed tomography (CT)] finally revealed the close proximity of the apex of the implant and the bony structure of the mandibular canal. The effect on the nervus alveolaris inferior was also demonstrated using an innovative high-resolution dental magnetic-resonance-imaging technique reflecting vascular reactions of the neurovascular bundle after potentially damaging surgical intervention. After removal of the causative implant, the pain gradually faded over a period of a year.

Intraoperative computed tomography and automated registration for image-guided cranial surgery.

OBJECTIVES: Two key problems for the use of navigation systems in image-guided surgery are accurate patient-to-image registration and the fact that with ongoing surgery the patient's anatomy is altered while the image data remains unchanged. A system for intraoperative CT imaging and fully automated registration of this image addresses both problems. It had been evaluated successfully in phantom studies. In this clinical study, we assessed the impact of the system on intraoperative workflow and registration accuracy in everyday patient care. METHODS: In ten patients who underwent image-guided surgery, CT image data were acquired intraoperatively and were automatically registered in the navigation system. Registration accuracy and surgical outcome were assessed clinically. In six of these patients, a maxillary splint with markers had been inserted to cross-check registration accuracy. The target registration error of these markers was measured. RESULTS: In all cases, registration accuracy was clinically sufficient and the surgical task could be performed successfully. In those cases where a maxillary template with target markers was attached for additional control of the registration accuracy, the target registration error was always better than 2 mm. Automated registration reduced the intraoperative registration time considerably and partially compensated for the time needed to perform the image data acquisition. CONCLUSIONS: Intraoperative CT imaging and automated registration successfully address the two key problems of image-guided surgery. The method is robust and accurate and proved its usability in everyday patient care.

Automated registration of intraoperative CT image data for navigated skull base surgery.

OBJECTIVES: With a new intraoperative computed tomography (CT) imaging system, patient-to-image registration without any invasive registration markers is possible. Furthermore, registration can be performed fully automatically. The accuracy of this method for skull base surgery was investigated in this study. METHODS: We employed a phantom study design. A phantom skull was equipped with 33 target markers in the regions of the anterior and lateral skull base. CT image data were acquired with an intraoperative CT suite. Image data were transferred as DICOM data to the navigation system, and registration was performed automatically. For registration, the position of the patient and the position of the CT gantry were monitored in the imaging process, using the infrared camera of a navigation system. Using the pointing device of the navigation system, the target markers were identified. The accuracy was measured as the spatial difference of the target markers in image space and on the phantom. RESULTS: Accuracy was always sufficient for image-guided surgery of any region of the skull base, with an average target registration error of below 1.2 mm. In contrast to traditional non-invasive registration methods, there was no difference in registration accuracy between the anterior skull base and the lateral skull base. CONCLUSIONS: Fully automated registration based on a tracked CT gantry is a robust and accurate registration method for skull base surgery.

Loss of anisotropy in trigeminal neuralgia revealed by diffusion tensor imaging.

We studied the trigeminal nerve in seven healthy volunteers and six patients with trigeminal neuralgia using the diffusion tensor imaging derived parameter fractional anisotropy (FA). While controls did not show a difference between both sides, there was a reduction of FA in the affected nerve in three of six patients with accompanying nerve-vessel conflict and atrophy. Reversibility of abnormally low FA values was demonstrated in one patient successfully treated with microvascular decompression.

[Injury of craniocervical arteries: imaging findings and therapy]. / Kraniale und zervikale arterielle Gefässverletzungen: Bildgebung und Therapie.

Direct or indirect injury of craniocervical vessels may be the consequence of an accident, may result from tumor arrosion, or may even occur spontaneously. Many of these vascular lesions can be detected using modern non-invasive vascular imaging techniques such as CT angiography and MR angiography. These traumatic vascular lesions can usually be treated using endovascular techniques. This overview describes neuroradiological findings for traumatic lesions of cervical and cranial vessels as well as endovascular treatment options.

Subarachnoid hemorrhage due to Borrelia burgdorferi-associated vasculitis.

We report the case history of a patient who suffered a subarachnoid hemorrhage (SAH) in association with early Lyme neuroborreliosis. After a tick bite, this patient developed erythema chronicum migrans and complained of stinging radicular pain in both legs. A computed tomography (CT) scan was performed because of acute headache and nuchal rigidity, which revealed an occipital SAH. Cerebrospinal fluid analysis provided further evidence of acute neuroborreliosis. Digital substraction angiography showed irregularities in the right posterior cerebral artery, which might be due to vasculitis, but no aneurysms.

Repeated digital substraction angiography after perimesencephalic subarachnoid hemorrhage?

BACKGROUND AND PURPOSE: In patients with perimesencephalic subarachnoid hemorrhage (pSAH) DSA is recommended to exclude aneurysms to due false negative findings in CT-angiography. However, whether a second DSA is indicated during the clinical course to exclude--in addition to aneurysms--fistulas, too, is still under debate. We aimed to evaluate the benefit of repeated DSA in patients with pSAH. METHODS: The source of data was a prospective database set up at the neurological, neurosurgical and neuroradiological departments in our institution. A total of 69 patients with pSAH were enrolled and analyzed by reviewing the medical records and neuroradiological findings. RESULTS: 68 patients presented with Hunt & Hess Grade I-II and one patient with Hunt & Hess Grade III. Median in-hospital stay was 8 days (3-22). In 2 patients mild vasospasm were diagnosed. DSA was performed in all patients at least once. DSA was repeated in 38 patients (55%) after a median of 7 (3-21) days. None of the repeated DSA did show any additional distinctive features with respect to the first DSA. CONCLUSIONS: In our opinion the procedure of repeating DSA in patients with pSAH is likely to become obsolete. One DSA should be performed prior to discharge--and subsequent to possible vasospasm--to exclude hemorrhage caused by aneurysms of the posterior circulation mimicking a perimesencephalic SAH pattern.

[Trigeminal neuralgia: how often are trigeminal nerve-vessel contacts found by MRI in normal volunteers]. / Trigeminusneuralgie: Wie häufig gibt es einen Gefäss-Nerven-Kontakt bei schmerzfreien Probanden?

PURPOSE: To assess prospectively how often contacts are found between the trigeminal nerve and arteries or veins in the perimesencephalic cistern via MRI in normal volunteers. MATERIALS AND METHODS: 48 volunteers without a history of trigeminal neuralgia were examined prospectively (MRI at 1.5 T; T2-CISS sequence, coronal orientation, 0.9 mm slice thickness). Two radiologists decided by consensus whether there was a nerve-vessel contact in the perimesencephalic cistern. RESULTS: In 27 % of the volunteers, no contact was found between the trigeminal nerve and regional vessels, while in 73 %, such a contact was present. In 61 % of the cases, the offending vessel was an artery, in 39 %, it was a vein. In 2 volunteers, a deformation of the nerve was noted. CONCLUSION: Contrary to what has been suggested by retrospective studies, the majority of normal volunteers, if studied prospectively, do show a contact between the trigeminal nerve and local vessels. A close proximity between the nerve and regional vessels is thus normal and is not necessarily proof of a pathological nerve-vessel conflict.

[Infectious diseases of brain parenchyma in adults: imaging and differential diagnosis aspects]. / Infektiöse Erkrankungen des Hirnparenchyms bei Erwachsenen: Bildgebung und differenzialdiagnostische Aspekte.

Infectious diseases of the central nervous system have often to be considered in differential diagnosis, particularly in immunocompromised persons. Neuroimaging, specifically advanced techniques such as diffusion-weighted MRI and perfusion MRI contribute much to the differentiation of various brain infections and to delineation of brain infections from other, for instance, neoplastic diseases. In this review we present the imaging criteria for the most important brain infections in adults and discuss in detail differential diagnostic aspects.