Investigating the relationship between high-dose norepinephrine administration and the incidence of delayed cerebral infarction in patients with aneurysmal subarachnoid hemorrhage: A single-center retrospective evaluation.

BACKGROUND: One of the longest-standing treatments to prevent delayed cerebral infarction (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) remains raising the blood pressure to a certain level of mean arterial pressure. This may require high doses of norepinephrine, which has been associated with severe end organ damage. With this study, we aimed to investigate the effects of norepinephrine on the incidence of DCI in a clinical setting. METHODS: We conducted a retrospective evaluation of patients with aSAH admitted to our institution between November 2018 and March 2021. Potential risk factors for DCI were analyzed and significant predictors were assessed by means of a logistic regression analysis to account for potential confounders. RESULTS: In this study, 104 patients were included. Hereof, 39 (38%) showed radiologic signs of DCI between day three and 14 post-intervention. These patients had more frequent vasospasms (n = 37 vs. 30, p = 0.022), a higher Hunt & Hess score (3 ± 2 vs. 2 ± 1, p = 0.004), a lower initial Glasgow Coma Scale score (9 ± 5 vs. 12 ± 4, p = 0.003) and received a higher median norepinephrine dose (20,356µg vs. 6,508µg, p < 0.001). A logistic regression analysis revealed that only high-dose norepinephrine administration (OR 2.84, CI 1.56-7.8) and vasospasm (OR 3.07, CI 1.2-7.84) appeared to be significant independent risk factors for DCI. CONCLUSION: Our results indicate a significant association between higher dose norepinephrine administration and the occurrence of DCI. Future research including greater sample sizes and a prospective setting will be necessary to further investigate the relationship.

Therapeutic hypercapnia for prevention of secondary ischemia after severe subarachnoid hemorrhage: physiological responses to continuous hypercapnia.

Temporary hypercapnia has been shown to increase cerebral blood flow (CBF) and might be used as a therapeutical tool in patients with severe subarachnoid hemorrhage (SAH). It was the aim of this study was to investigate the optimum duration of hypercapnia. This point is assumed to be the time at which buffer systems become active, cause an adaptation to changes of the arterial partial pressure of carbon dioxide (PaCO2) and annihilate a possible therapeutic effect. In this prospective interventional study in a neurosurgical ICU the arterial partial pressure of carbon dioxide (PaCO2) was increased to a target range of 55 mmHg for 120 min by modification of the respiratory minute volume (RMV) one time a day between day 4 and 14 in 12 mechanically ventilated poor-grade SAH-patients. Arterial blood gases were measured every 15 min. CBF and brain tissue oxygen saturation (StiO2) were the primary and secondary end points. Intracranial pressure (ICP) was controlled by an external ventricular drainage. Under continuous hypercapnia (PaCO2 of 53.17 ± 5.07), CBF was significantly elevated between 15 and 120 min after the start of hypercapnia. During the course of the trial intervention, cardiac output also increased significantly. To assess the direct effect of hypercapnia on brain perfusion, the increase of CBF was corrected by the parallel increase of cardiac output. The maximum direct CBF enhancing effect of hypercapnia of 32% was noted at 45 min after the start of hypercapnia. Thereafter, the CBF enhancing slowly declined. No relevant adverse effects were observed. CBF and StiO2 reproducibly increased by controlled hypercapnia in all patients. After 45 min, the curve of CBF enhancement showed an inflection point when corrected by cardiac output. It is concluded that 45 min might be the optimum duration for a therapeutic use and may provide an optimal balance between the benefits of hypercapnia and risks of a negative rebound effect after return to normal ventilation parameters.Trial registration: The study was approved by the institutional ethics committee (AZ 230/14) and registered at ClinicalTrials.gov (Trial-ID: NCT01799525). Registered 01/01/2015.

Amelioration of Cognitive and Behavioral Deficits after Traumatic Brain Injury in Coagulation Factor XII Deficient Mice.

Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII-/- mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII-/- mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII-/- mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII-/- mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII-/- mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.

Combined frameless stereotactical biopsy and intraoperative cerebral angiography by 3D-rotational fluoroscopy with intravenous contrast administration: a feasibility study.

BACKGROUND: Mobile 3-dimensional fluoroscopes are an integral part of modern neurosurgical operating theatres and can also be used in combination with free available image post processing to depict cerebral vessels. In preparation of stereotactic surgery, preoperative Computed Tomography (CT) may be required for image fusion. Contrast CT may be of further advantage for image fusion as it regards the vessel anatomy in trajectory planning. Time-consuming in-hospital transports are necessary for this purpose. Mobile 3D-fluoroscopes may be used to generate a CT equal preoperative data set without an in-hospital transport. This study was performed to determine the feasibility and image quality of intraoperative 3-dimensional fluoroscopy with intravenous contrast administration in combination with stereotactical procedures. METHODS: 6 patients were included in this feasibility study. After fixation in a radiolucent Mayfield clamp a rotational fluoroscopy scan was performed with 50 mL iodine contrast agent. The image data sets were merged with the existing MRI images at a planning station and visually evaluated by two observer. The operation times were compared between the frame-based and frameless systems ("skin-to-skin" and "OR entry to exit"). RESULTS: The procedure proves to be safe. The entire procedure from fluoroscope positioning to the transfer to the planning station took 5-6 min with an image acquisition time of 24 s. In 5 of 6 cases, the fused imaging was able to reproduce the vascular anatomy accurately and in good quality. Both time end-points were significantly shorter compared to frame-based interventions. CONCLUSION: The images could easily be transferred to the planning and navigation system and were successfully merged with the MRI data set. The procedure can be completely integrated into the surgical workflow. Preoperative CT imaging or transport under anaesthesia may even be replaced by this technique in the future. Furthermore, hemorrhages can be successfully visualized intraoperatively and might prevent time delays in emergencies.

Alloplastic or Autologous? Bone Chips versus PEEK Cage for Lumbar Interbody Fusion in Degenerative Spondylolisthesis.

INTRODUCTION: This study was conducted to compare bone-filled intervertebral cages with autologous bone chips for instrumented lumbar interbody fusion in patients with spinal stenosis and degenerative spondylolisthesis. METHODS: Surgery consisted of posterior instrumentation and decompression, diskectomy, and intervertebral fusion using a polyetheretherketone (PEEK) cage surrounded and filled with spongious bone chips (group 1, n = 57) or spongious bone chips alone (group 2, n = 37). The choice of method was left to the discretion of the surgeon. Postoperative results were prospectively evaluated using a standardized protocol. Radiological assessment included fusion rates and vertebral height, while clinical assessment included the visual analog scale (VAS) and Oswestry Disability Index (ODI). RESULTS: In group 1, a mean of 1.38 ± 0.64 segments were fused. In group 2, a mean of 1.58 ± 0.65 segments were fused. In both groups, the VAS for back pain and leg pain and the ODI improved without significant differences between the two groups. Osseous fusion was documented by computerized tomography in 73% in group 1 and 89% in group 2 after a mean of 18 months. The loss of height was 2.8 ± 4.0% in group 1 and 2.4 ± 5.2% in group 2. CONCLUSION: Regardless of whether a PEEK cage filled with spongious bone chips or spongious bone chips alone were used for lumbar interbody fusion, clinical parameters improved significantly after surgery. There were no significant differences in the rate of bony fusion and loss of height between the two groups. The results of this nonrandomized cohort study indicate that the implantation of autologous spongious bone chips harvested during the decompression procedure is a useful and cheap alternative to an intervertebral cage in patients with degenerative pseudospondylolisthesis.

Posttraumatic learning deficits correlate with initial trauma severity and chronic cellular reactions after closed head injury in male mice.

Traumatic brain injury (TBI) is often associated with sustained attention and memory deficits. As persisting neuroinflammation and neurodegeneration may contribute to posttraumatic psychomotor dysfunction, we studied the relationship of brain cellular reactions three months after a weight-drop closed head injury in male mice with posttraumatic learning and memory using automated home-cage monitoring of socially housed mice in IntelliCages as well as tests for locomotor activity, anxiety and forepaw fine motor skills. One month after TBI, deficits in place learning and cognitive flexibility in reverse learning were clearly detectable in IntelliCages and these memory deficits correlated with the initial trauma severity on the functional neuroscore. While sucrose preference or its extinction were not influenced by TBI, traumatized mice performed significantly worse in a complex episodic memory learning task. In consecutive locomotor and forepaw skilled use tests, posttraumatic hyperactivity and impairment of contralateral paw use were evident. Analysis of cellular reactions to TBI three months after injury in selected defined regions of interest in the immediate lesion, ipsi- and contralateral frontoparietal cortex and hippocampus revealed a persistent microgliosis and astrogliosis which were accompanied by iron-containing macrophages and myelin degradation in the lesion area as well as with axonal damage in the neighboring cortical regions. Microglial and astroglial reactions in cortex showed a positive correlation with the initial trauma severity and a negative correlation with the spatial and episodic memory indicating a role of brain inflammatory reactions in posttraumatic memory deficits.

Optimization of radiation settings for angiography using 3D fluoroscopy for imaging of intracranial aneurysms.

Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. We recently reported its use for imaging cerebral vascular malformations and aneurysms. This study was conducted to evaluate various radiation settings for the imaging of cerebral aneurysms before and after surgical occlusion. Eighteen patients with cerebral aneurysms with the indication for surgical clipping were included in this prospective analysis. Before surgery the patients were randomized into one of three different scan protocols according (default settings of the 3D fluoroscope): Group 1: 110 kV, 80 mA (enhanced cranial mode), group 2: 120 kV, 64 mA (lumbar spine mode), group 3: 120 kV, 25 mA (head/neck settings). Prior to surgery, a rotational fluoroscopy scan (duration 24 s) was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® MD 10.0 software. The procedure was repeated after clip placement. The image quality regarding preoperative aneurysm configuration and postoperative assessment of aneurysm occlusion and vessel patency was analyzed by 2 independent reviewers using a 6-grade scale. This technique quickly supplies images of adequate quality to depict intracranial aneurysms and distal vessel patency after aneurysm clipping. Regarding these features, a further optimization to our previous protocol seems possible lowering the voltage and increasing tube current. For quick intraoperative assessment, image subtraction seems not necessary. Thus, a native scan without a contrast agent is not necessary. Further optimization may be possible using a different contrast injection protocol.

Malignant "Angioglioma": Clinical, Radiologic, and Histopathologic Features.

BACKGROUND: Glioblastoma multiforme (GBM) is the most frequent malignant neoplasm in the adult brain. In contrast, arteriovenous malformations (AVMs) are presumably congenital lesions, usually presenting with hemorrhage. Hypervascular low-grade gliomas associated with AVMs were previously called "angioglioma." An association of AVMs and GBM was also described. STUDY AIMS: We discuss the data of the largest series of locally coincident GBM with AVM in a single institution so far. All analyses were explorative only. PATIENTS: We report a series of four patients presenting at our department from 2006 to 2014. All patients underwent surgery. The cases were analyzed regarding initial presentation, clinical findings, tumor localization, and histopathologic results. CONCLUSIONS: A local coincidence of cerebral AVM and GBM is rare. Only a few reports can be found in the literature. The radiologic as well as the clinical presentations are individual. Proangiogenic factors are discussed as involved in the appearance of both entities in the same location. However, the presence of pathologic vessels within malignant gliomas is well known to all neurosurgeons and proangiogenic activity has been proven. Therefore, it seems possible that tumor activity itself contributes to the pathogenesis of a vascular malformation.

Early Antiinflammatory Therapy Attenuates Brain Damage After Sah in Rats.

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.

Sensory profiles and immune-related expression patterns of patients with and without neuropathic pain after peripheral nerve lesion.

In this multicenter cross-sectional study, we determined sensory profiles of patients with (NL-1) and without neuropathic pain (NL-0) after nerve lesion and assessed immune-related systemic gene expression. Patients and matched healthy controls filled in questionnaires and underwent neurological examination, neurophysiological studies, quantitative sensory testing, and blood withdrawal. Neuropathic pain was present in 67/95 (71%) patients (NL-1). Tactile hyperalgesia was the most prominent clinical sign in NL-1 patients (P < 0.05). Questionnaires showed an association between neuropathic pain and the presence of depression, anxiety, and catastrophizing (P < 0.05 to P < 0.01). Neuropathic pain was frequently accompanied by other chronic pain (P < 0.05). Quantitative sensory testing showed ipsilateral signs of small and large fiber impairment compared to the respective contralateral side, with elevated thermal and mechanical detection thresholds (P < 0.001 to P < 0.05) and lowered pressure pain threshold (P < 0.05). Also, more loss of function was found in patients with NL-1 compared to NL-0. Pain intensity was associated with mechanical hyperalgesia (P < 0.05 to P < 0.01). However, quantitative sensory testing did not detect or predict neuropathic pain. Gene expression of peptidylglycine α-amidating monooxygenase was higher in NL patients compared with healthy controls (NL-1, P < 0.01; NL-0, P < 0.001). Also, gene expression of tumor necrosis factor-α was higher in NL-1 patients compared with NL-0 (P < 0.05), and interleukin-1ß was higher, but IL-10 was lower in NL-1 patients compared with healthy controls (P < 0.05 each). Our study reveals that nerve lesion presents with small and large nerve fiber dysfunction, which may contribute to the presence and intensity of neuropathic pain and which is associated with a systemic proinflammatory pattern.

How is the formation of microthrombi after traumatic brain injury linked to inflammation?

Traumatic brain injury (TBI) is characterized by mechanical disruption of brain tissue due to an external force and by subsequent secondary injury. Secondary brain injury events include inflammatory responses and the activation of coagulation resulting in microthrombi formation in the brain vasculature. Recent research suggests that these mechanisms do not work independently. There is strong evidence that FXII and platelet activation connects both, inflammation and the formation of microthrombi. This review summarizes the current knowledge on posttraumatic microthrombus formation and its link to inflammation.

Acute reaction of arterial blood vessels after experimental subarachnoid hemorrhage - An in vivo microscopic study.

Subarachnoid hemorrhage (SAH) results in a rapid decrease of cerebral perfusion. While cerebral perfusion pressure (CPP) may quickly recover, a sustained decrease of cerebral blood flow (CBF) has been observed. Acute vasospasm has been concluded from this mismatch. This study was conducted to visualize and investigate immediate vascular reactions during and after experimental SAH. Male Sprague-Dawley rats were subjected to SAH by the endovascular filament model (n = 7) or served as controls (n = 4). Videomicroscopy was performed via a cranial window. Regions of interest were defined in areas covered by videomicroscopy and arterial diameters measured at defined time-points from 15 min before until 3 h after SAH. Local CBF was monitored over the opposite hemisphere by laser-Doppler flowmetry. Local CBF showed a typical decrease immediately after vessel perforation followed by an incomplete recovery in the 3 h thereafter. Videomicroscopy demonstrated a sharp decrease of the arterial diameter in the first minutes after SAH. In some animals, SAH was followed by a complete disappearance of arterial vessel filling. In the following minutes, arterial filling reappeared or improved, respectively. All animals subjected to SAH showed significant vasospasm in subarachnoid arteries. This is the first study to visualize acute vascular reactions during and immediately after SAH. Although the cranial window technique only covers a part of the cerebral vasculature, it covers cerebral vessels rather distant from the site of endovascular perforation. Therefore, it is likely that acute vasospasm observed in the monitored areas reflects a global vascular reaction.

Magnesium Protects in Episodes of Critical Perfusion after Aneurysmal SAH.

BACKGROUND: To analyze whether magnesium has a neuroprotective effect during episodes that indicate a critical brain perfusion after aneurysmal subarachnoid hemorrhage (SAH). METHODS: 107 patients with aSAH were randomized to continuously receive intravenous magnesium sulfate with target serum levels of 2.0 - 2.5 mmol/l (n = 54) or isotonic saline (n = 53). Neurological examination and transcranial Doppler sonography (TCD) were performed daily, Perfusion-CT (PCT) was acquired in 3-day intervals, angiography in case of suspected vasospasm. The primary endpoint was the development of secondary infarction following episodes of delayed ischemic neurological deficit (DIND), elevated mean flow velocity (MFV) in TCD or pathological findings in PCT. RESULTS: In the magnesium group, 9 episodes of DIND were registered, none was followed by secondary infarction. In the control group, 23 episodes of DIND were registered, 9 were followed by secondary infarction (p < 0.05). In the magnesium group, 114 TCD-measurements showed an elevated MFV(> 140 cm/s). 7 were followed by new infarction. In control patients, 135 measurements showed elevated MFV, 32 were followed by new infarction (p < 0.05). 10 of 117 abnormal PCT-findings were followed by new infarction, compared to 30 of 122 in the control-group (p < 0.05). CONCLUSION: DIND, elevated MFV in TCD and abnormal PCT are findings which are associated with an increased risk to develop delayed secondary infarction. The results of this analysis suggest that magnesium-treatment may reduce the risk to develop infarction in a state of critical brain perfusion.

Imaging of Cerebral Arteriovenous Malformations and Arteriovenous Fistulas and Occlusion Control Using Intraoperative 3-Dimensional Rotational Fluoroscopy.

BACKGROUND: Intraoperative resection or occlusion control is indispensable in the surgery of vascular anomalies. This can be conducted using local vascular imaging modalities or angiographic techniques. This series was performed to assess whether cerebral arteriovenous malformations (AVMs) and dural arteriovenous fistulae (dAVFs) can be detected in a sufficient quality by intraoperative 3-dimensional (3D) fluoroscopy with intravenous contrast application. MATERIALS AND METHODS: Five patients were included in the analysis (2 AVMs, 3 dAVFs). All patients had preoperative digital subtraction angiography. The head was fixed in a carbon MAYFIELD clamp. After a 3D rotational fluoroscopy scan without contrast agent, a second scan with 50 mL of iodine contrast agent was performed. The Digital Imaging and Communications in Medicine data of both scans were subtracted and reconstructed using the OsiriX imaging software. In 2 patients with dAVF, occlusion control was performed after obliteration of the fistula. RESULTS: In the 2 patients with cerebral AVM, 3D fluoroscopy with intravenous contrast administration resulted in good image quality. Preoperative embolization with Onyx produces significant artifacts that can be largely removed by simple digital subtraction techniques. In dural AVF, occlusion control was well feasible after obliteration of the draining vein at its dural origin. CONCLUSIONS: This technique quickly supplies intraoperative images of adequate quality to locate cerebral AVM and dAVF. However, it does not produce dynamic images. Thus, early draining veins cannot be located unless anatomically identified based on the preoperative DSA. In this case, it can be used for intraoperative obliteration control.

Influence of Myelography and Postmyelographic CT on Therapeutic Decisions in Degenerative Diseases of the Cervical Spine.

STUDY DESIGN: A retrospective analysis of clinical records and radiologic imaging by 3 independent reviewers to assess the indication for surgical treatment with and without myelography and postmyelographic computed tomography (MCT). OBJECTIVE: To evaluate whether myelography and MCT obtained in addition to magnetic resonance imaging (MRI) influence therapeutic decisions in degenerative diseases of the cervical spine. SUMMARY OF BACKGROUND DATA: MRI has become the standard examination in spinal diseases. The role of myelography and MCT is not clearly defined in the modern diagnostic setup. In many departments, they are used if MRI leaves some diagnostic uncertainty. It has not been examined yet whether additional myelography and MCT change therapeutic strategies. MATERIALS AND METHODS: Three investigators independently reviewed the anonymized clinical data and image files of 105 patients who had all undergone MRI, myelography, and MCT. They determined their treatment decisions after each of 2 assessment rounds based on the following: (1) MRI and, if available, native CT, and plain radiographs. (2) Additional myelography and MCT. The intraobserver variability was the primary endpoint. RESULTS: Myelography and MCT had been performed in multilevel disease, recurrent complaints after surgery, or if MRI had not revealed a clear finding. The intraobserver variability was 26.3% and varied markedly between the 3 investigators (17%-41 %). It was the highest in cases of multilevel disease. If noninvasive imaging included native CT and plain radiographs, the intraobserver variability was significantly reduced to 10.3%. CONCLUSIONS: In unclear cases of degenerative disorders of the cervical spine, particularly multilevel stenosis, myelography and MCT add relevant information for therapeutic decisions in more than a quarter of the patients in comparison with MRI as the sole diagnostic modality, and changes therapeutic strategies. However, a significant part of the information drawn out of myelography and MCT can be obtained by a completion of noninvasive examinations (native CT and radiographs).

First Description of Reduced Pyruvate Dehydrogenase Enzyme Activity Following Subarachnoid Hemorrhage (SAH).

Object: Several previous studies reported metabolic derangements and an accumulation of metabolic products in the early phase of experimental subarachnoid hemorrhage (SAH), which may contribute to secondary brain damage. This may be a result of deranged oxygen utilization due to enzymatic dysfunction in aerobic glucose metabolism. This study was performed to investigate, if pyruvate dehydrogenase enzyme (PDH) is affected in its activity giving further hints for a derangement of oxidative metabolism. Methods: Eighteen male Sprague-Dawley rats were randomly assigned to one of two experimental groups (n = 9): (1) SAH induced by the endovascular filament model and (2) sham-operated controls. Mean arterial blood pressure (MABP), intracranial pressure (ICP), and local cerebral blood flow (LCBF; laser-Doppler flowmetry) were continuously monitored from 30 min before until 3 h after SAH. Thereafter, the animals were sacrificed and PDH activity was measured by ELISA. Results: PDH activity was significantly reduced in animals subjected to SAH compared to controls. Conclusion: The results of this study demonstrate for the first time a reduction of PDH activity following SAH, independent of supply of substrates and may be an independent factor contributing to a derangement of oxidative metabolism, failure of oxygen utilization, and secondary brain damage.

Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa.

BACKGROUND: Traumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI. METHODS: Using a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1ß by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings. RESULTS: We show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model. CONCLUSIONS: Stimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation.

Selective Brain Cooling after Traumatic Brain Injury: Effects of Three Different Cooling Methods-Case Report.

Background In experimental models of neuronal damage, therapeutic hypothermia proved to be a powerful neuroprotective method. In clinical studies of traumatic brain injury (TBI), this very distinct effect was not reproducible. Several meta-analyses draw different conclusions about whether therapeutic hypothermia can improve outcome after TBI. Adverse side effects of systemic hypothermia, such as severe pneumonia, have been held responsible by some authors to counteract the neuroprotective effect. Selective brain cooling (SBC) attempts to take advantage of the protective effects of therapeutic hypothermia without the adverse side effects of systemic hypothermia. Methods Three different methods of SBC were applied in a patient who had severe TBI with recurrent increases of intracranial pressure (ICP) refractory to conventional forms of treatment: (1) external cooling of the scalp and neck using ice packs prior to hemicraniectomy, (2) external cooling of the craniectomy defect using ice packs after hemicraniectomy, and (3) cooling by epidural irrigation with cold Ringer solution after hemicraniectomy. Results External scalp cooling before hemicraniectomy, external cooling of the craniectomy defect, and epidural irrigation with cold fluid resulted in temperature differences (brain temperature to body temperature) of - 0.2°, - 0.7°, and - 3.6°C, respectively. ICP declined with decreasing brain temperature. Conclusion Previous external cooling attempts for SBC faced the problem that brain temperature could not be lowered without a simultaneous decrease of systemic temperature. After hemicraniectomy, epidural irrigation with cold fluid may be a simple and effective way to lower ICP and apply one of the most powerful methods of cerebroprotection after severe TBI.

Combined [(18)F]DPA-714 micro-positron emission tomography and autoradiography imaging of microglia activation after closed head injury in mice.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry. METHODS: A weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo µPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [(18)F]DPA-714 was performed on day 1, 7, and 16 and [(18)F]FDG-µPET imaging for energy metabolism on days 2-5 after trauma using freshly synthesized radiotracers. Immediately after [(18)F]DPA-714-µPET imaging on days 7 and 16, cellular identity of the [(18)F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1. RESULTS: Functional outcome correlated with focal brain lesions, gliosis, and axonal injury. [(18)F]DPA-714-µPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [(18)F]FDG uptake on days 2-5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [(18)F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [(18)F]DPA-714 was not increased in autoradiography or in µPET imaging. CONCLUSIONS: [(18)F]DPA-714 uptake in µPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI.

Targeting coagulation factor XII as a novel therapeutic option in brain trauma.

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. Ann Neurol 2016;79:970-982.