Dorothee Mielke

Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid

In multiple sclerosis, brain-reactive T cells invade the central nervous system (CNS) and induce a self-destructive inflammatory process. T-cell infiltrates are not only found within the parenchyma and the meninges, but also in the cerebrospinal fluid (CSF) that bathes the entire CNS tissue. How the T cells reach the CSF, their functionality, and whether they traffic between the CSF and other CNS compartments remains hypothetical. Here we show that effector T cells enter the CSF from the leptomeninges during Lewis rat experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. While moving through the three-dimensional leptomeningeal network of collagen fibres in a random Brownian walk, T cells were flushed from the surface by the flow of the CSF. The detached cells displayed significantly lower activation levels compared to T cells from the leptomeninges and CNS parenchyma. However, they did not represent a specialized non-pathogenic cellular sub-fraction, as their gene expression profile strongly resembled that of tissue-derived T cells and they fully retained their encephalitogenic potential. T-cell detachment from the leptomeninges was counteracted by integrins VLA-4 and LFA-1 binding to their respective ligands produced by resident macrophages. Chemokine signalling via CCR5/CXCR3 and antigenic stimulation of T cells in contact with the leptomeningeal macrophages enforced their adhesiveness. T cells floating in the CSF were able to reattach to the leptomeninges through steps reminiscent of vascular adhesion in CNS blood vessels, and invade the parenchyma. The molecular/cellular conditions for T-cell reattachment were the same as the requirements for detachment from the leptomeningeal milieu. Our data indicate that the leptomeninges represent a checkpoint at which activated T cells are licensed to enter the CNS parenchyma and non-activated T cells are preferentially released into the CSF, from where they can reach areas of antigen availability and tissue damage.

Concomitant and adjuvant temozolomide of newly diagnosed glioblastoma in elderly patients.

OBJECTIVE The effect of concomitant and adjuvant temozolomide in glioblastoma patients above the age of 65 years lacks evidence. However, after combined treatment became standard at our center all patients were considered for combined therapy. We retrospectively analyzed the effect of temozolomide focused on elderly patients. METHODS 293 patients with newly diagnosed glioblastoma treated single-centered between 1998 and 2010, by radiation alone or concomitant and adjuvant radiochemotherapy, were included. Treatment groups were analyzed by multi- and univariate analysis. Matched pairs for age, by a 5-year-caliper, extent of resection and general state was generated for all patients and elderly subgroups. RESULTS 103 patients received radiation only and 190 combined treatment. Multivariate and matched pair analysis revealed a benefit due to combined temozolomide (HR 1.895 and 1.752, respectively). For patients older than 65 years median survival was 3.6 (95% CI 3.2-4.7) and 8.7 months (6.3-11.8) for radiotherapy only and combined treatment (HR 3.097, p<0.0001, n=90). Over the age of 70 and 75 years median survival was 3.2 (2.3-4.2) vs. 7.5 (5.1-10.9, HR 4.453, p<0.0001, n=62) and 3.2 (1.4-3.9) vs. 9.2 months (4.7-13.5; HR 9.037, p<0.0001, n=24), respectively. In 8/56 (14%) patients over the age of 70 years temozolomide was terminated due to toxicity. CONCLUSION Retrospective matched pair analysis gives class 2b evidence for prolonged survival due to concomitant and adjuvant temozolomide in elderly glioblastoma patients. Until prospective data for combined radiochemotherapy in elderly patients will be available concomitant and adjuvant temozolomide therapy should not be withheld.

Cathodal transcranial direct current stimulation induces regional, long-lasting reductions of cortical blood flow in rats

Abstract Objective: Transcranial direct current stimulation (tDCS) induces polarity-specific changes of cerebral blood flow (CBF). To determine whether these changes are focally limited or if they incorporate large cortical regions and thus have the potential for a therapeutic application, we investigated the effects of cathodal tDCS on CBF in an established tDCS rat model with particular attention to the spatial extension in CBF changes using laser Doppler blood perfusion imaging (LDI). Methods: Twenty-one Sprague Dawley rats received a single 15-minute session of cathodal tDCS at current intensities of 200, 400, 600, or 700 μA applied over electrode contact areas (ECA) of 3·5, 7·0, 10·5, or 14·0 mm2. One animal died prior to the stimulation. Cerebral blood flow was measured prior and after tDCS with LDI in three defined regions of interest (ROI) over the stimulated left hemisphere (region anterior to ECA – ROI 1, ECA – ROI 2, region posterior to ECA – ROI 3). Results: A regional decrease in CBF was measured after cathodal tDCS, the extent of the decrease depending on the current density applied. The most effective and spatially limited reduction in CBF (up to 50%, lasting as long as 90 minutes) was found after the application of 600 μA over an ECA of 10·5 mm2. This significant reduction in CBF even lasted up to 90 minutes in distant cortical areas (ROI 1 and 3) that were not directly related to the ECA (ROI 2). Discussion: Cathodal tDCS induces a regional, long-lasting, reversible decrease in CBF that is not limited to the region to which tDCS is applied.

German Cranial Reconstruction Registry (GCRR): protocol for a prospective, multicentre, open registry

Introduction Owing to increasing numbers of decompressive craniectomies in patients with malignant middle cerebral artery infarction, cranioplastic surgery becomes more relevant. However, the current literature mainly consists of retrospective single-centre (evidence class III) studies. This leads to a wide variability of technical approaches and clinical outcomes. To improve our knowledge about the key elements of cranioplasty, which may help optimising clinical treatment and long-term outcome, a prospective multicentre registry across Germany, Austria and Switzerland will be established. Methods All patients undergoing cranioplastic surgery in participating centres will be invited to join the registry. Technical methods, materials, medical history, adverse events and clinical outcome measures, including modified Rankin scale and EQ-5D, will be assessed at several time points. Patients will be accessible to inclusion either at initial decompressive surgery or when cranioplasty is planned. Scheduled monitoring will be carried out at time of inclusion and subsequently at time of discharge, if any readmission is necessary, and at follow-up presentation. Cosmetic results and patient satisfaction will also be assessed. Collected data will be managed and statistically analysed by an independent biometric institute. The primary endpoint will be mortality, need for operative revision and neurological status at 3 months following cranioplasty. Ethics and dissemination Ethics approval was obtained at all participating centres. The registry will provide reliable prospective evidence on surgical techniques, used materials, adverse events and functional outcome, to optimise patient treatment. We expect this study to give new insights in the treatment of skull defects and to provide a basis for future evidence-based therapy regarding cranioplastic surgery. Trial registration number This trial is indexed in the German Clinical Trials Register (DRKS-ID: DRKS00007931). The Universal Trial Number (UTN) is U1111-1168-7425.

Paraplegia after contrast media application: a transient or devastating rare complication? Case report

The authors report the case of a 76-year-old man with a spinal dural arteriovenous fistula. The patient suffered from sudden repeated reversible paraplegia after spinal digital subtraction angiography as well as CT angiography. Neurotoxicity of contrast media (CM) is the most probable cause for this repeated short-lasting paraplegia. Intolerance to toxicity of CM to the vulnerable spinal cord is rare, and probably depends on the individual patient. This phenomenon is transient and can occur after both intraarterial and intravenous CM application.

Neuronavigated microvascular Doppler sonography for intraoperative monitoring of blood flow velocity changes during aneurysm surgery - a feasible monitoring technique.

INTRODUCTION AND AIM OF THE STUDY The intraoperative microvascular Doppler sonography (iMDS) is a well-established tool in vascular surgery for blood flow velocity (BFV) monitoring, capable of detecting vessel occlusion. However, identification of subtotal vessel compromise is more difficult, since the measured BFV may substantially vary with changing insonation angles and insonated vessel segments. To keep these parameters constant we combined neuronavigation with iMDS (niMDS). The question was if niMDS allows the detection of subtotal vessel compromise in aneurysm surgery. METHODS During surgery, the 3-dimensional reconstruction of the CT-angiography, which was obtained routinely prior to surgery, was displayed by the neuronavigational system. Prior to clipping, neuronavigation was used to define target point and trajectory, which, by coupling the neuronavigational pointer with the Doppler probe, correspond to the insonated vessel segment and the insonation angle. After clipping, for each vessel segment, the same trajectory was used for all consecutive measurements. The mean BFVs pre- and post-clipping were documented. RESULTS We performed 82 BFV-measurements in 39 aneurysm surgeries. Mean deviation between pre- and post-clipping BFV values was 2.12cm/s. There was a significant correlation between the mean BFV values before and after clipping (r=0.45 [95% CI 17-66%]; p=0.002). One patient experienced new neurological deficits due to occlusion of a perforating vessel that was not insonated. CONCLUSION The study could not answer the question if niMDS can detect BFV changes after clipping indicating vessel compromise, as no subtotal vessel occlusion occurred in the 39 operations. However, we proofed that niMDS-measured BFVs only varied minimally in uncompromised vessels pre- and post-clipping, suggesting that vessel compromises might be easily detected during aneurysm surgery.

Intermittent visual field defects caused by a dilated Virchow–Robin space close to the optic radiation: Therapeutic and pathomechanical considerations

Abstract Objective. Virchow–Robin spaces (VRSs) are extensions of subarachnoid spaces that accompany vessels entering the brain. T2-weighted magnetic resonance imaging detects VRS in about 95 percent of patients in a recent study. VRSs are considered a normal variant with benign prognosis.1 Occasionally, VRS might become symptomatic causing neurological deficits depending on their location.2 Case description. We report the case of a 55-year-old female patient with dilated VRS presenting with visual field disturbances and cognitive deficits. The patient underwent endoscopic fenestration of a large periventricular VRS located next to the visual radiation into the posterior horn of the right lateral ventricle. During the postoperative course, visual field disturbances were resolved but cognitive deficits remained unchanged. Conclusion. Dilated VRSs can cause a variety of neurological deficits depending on their size and location. Therefore, patients harboring dilated VRS should undergo early close inspection and in case of progressive neurological deficits, an operative therapy should be done; as valve mechanisms can cause a reduction of size when brain scans are conducted and later lead to occurrence of severe neurological deficits during phase of dilation.

Bilateral spinal canal decompression via hemilaminectomy in cervical spondylotic myelopathy

BackgroundIn cervical spondylotic myelopathy (CSM), laminoplasty (LP) or laminectomy plus fusion (LF) are accepted operative options and alternatives to anterior approaches. Both LP and LF have distinctive disadvantages, which might be avoided by unilateral hemilaminectomy and bilateral decompression of the spinal cord.MethodsDescription of the surgical technique, indications, and limitations. The potential advantages in comparison to LP and LF are discussed.ConclusionsUnilateral hemilaminectomy allows bilateral decompression of the whole dorsal circumference of spinal cord from nerve root to nerve root. The potential major advantages are a reduction of invasiveness by only unilateral muscle detachment, avoidance of implants, and shorter operation times.

Study of Radial Nerve Injury Caused By Gunshot Wounds and Explosive Injuries among Iraqi Soldiers

BACKGROUND: Gunshot wounds and blast injuries to the upper limbs produce complex wounds requiring management by multiple surgical specialities. AIM: We sought to determine the pattern of peripheral nerve injuries among Iraqi soldiers in the war. METHODS: We performed a 3 year retrospective cohort analysis based on medical records of patients with sustaining gunshot wounds and blast injuries to the upper limbs. Ethical approval was obtained from the institutional review board. The patients included were male, serving military personnel of all age groups and ranks presenting with weakness or sensory loss of radial nerve. Three hundred eighteen patients aged 24 years or older with a high-energy, diaphyseal fracture of the humerus and complete motor and sensory radial nerve palsy were reviewed retrospectively. In these patients, the physical examination and electrodiagnostic study were carried out by experienced neurologists. Seddon’s classification system was used to assess the severity of the injury. The data related to the types of fracture, the type of damage, the factors causing damage and the failure of treatment were entered into the IBM SPSS 23 software after extraction of files. Based on mid-range indicators and data distribution, traumatic injuries among Iraqi soldiers in the war against ISIL were then investigated. RESULTS: A group of 318 patients with mean age of 25.41 ± 6 years were enrolled in the study, of which 127 patients were included with an open fracture and 191 patients with closed lesions. All 127 patients with a transected radial nerve had an open humerus fracture and were part of a complex upper-extremity injury. 113 of 127 subjects had primary repair of the radial nerve and recovered well. 14 of 127 subjects were not recovered. 3 of them had iatrogenic radial nerve injury due to the internal fixation device. Furthermore, all 191 patients with closed injuries recovered well. The average time to initial signs of recovery was 8 weeks (range, 1–27 weeks). Axonotmesis and Neurotmesis were found in 283 (89%) subjects. The average time to full recovery was determined to be 6 months (range, 1–22 months). The blast was found to be the main cause of nerve injury in 236 (74.2%) cases, followed by gunshot damage (21.4%, 68 subjects), falling from height and motor vehicle accidents (4.4%, 14 subjects) and multiple injuries (17%, 54 cases). CONCLUSIONS: Trauma caused by factors such as explosions and gunshot worsens the condition of the injuries and presents the treatment conditions with many challenges. However, the success rate in post-surgical recovery of humerus fracture and injured radial nerve can be remarkably higher in young people as compared to other age groups.

Does the subspecialty of an intensive care unit (ICU) has an impact on outcome in patients suffering from aneurysmal subarachnoid hemorrhage

We retrospectively compared the outcome of aneurysmal subarachnoid hemorrhage (aSAH) patients treated in a neurosurgical ICU (nICU) between 1990 and 2005 with that of patients treated in a general ICU (gICU) between 2005 and 2013 with almost identical treatment strategies. Among other parameters, we registered the initial Hunt and Hess grade, Fisher score, the incidence of vasospasm, and outcome. A multivariate analysis (logistic regression model) was performed to adjust for different variables. In total, 755 patients were included in this study with 456 patients assigned to the nICU and 299 patients to the gICU. Multivariate logistic regression analysis revealed no significant difference between the patient outcome treated in a nICU versus gICU after adjusting for different variables. The outcome of patients after aSAH is not influenced by the type of ICU (gICU versus nICU). The data do not allow claiming that aSAH patients need to be treated in a specialized ICU for obtaining better results. Parameters which might differ from hospital to hospital, especially warranty of neurosurgical expertise on gICU, have the potential to influence the results.