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Background: The amount of intracranial blood is a strong predictor of poor outcome after subarachnoid hemorrhage (SAH). Here, we aimed to measure iron concentrations in the cerebral white matter, using the cerebral microdialysis (CMD) technique, and to associate iron levels with the local metabolic profile, complications, and functional outcome., Methods: For the observational cohort study, 36 patients with consecutive poor grade SAH (Hunt & Hess grade of 4 or 5, Glasgow Coma Scale Score ≤ 8) undergoing multimodal neuromonitoring were analyzed for brain metabolic changes, including CMD iron levels quantified by graphite furnace atomic absorption spectrometry. The study time encompassed 14 days after admission. Statistical analysis was performed using generalized estimating equations., Results: Patients were admitted in a poor clinical grade (n = 26, 72%) or deteriorated within 24 h (n = 10, 28%). The median blood volume in the subarachnoid space was high (SAH sum score = 26, interquartile range 20-28). Initial CMD iron was 44 µg/L (25-65 µg/L), which significantly decreased to a level of 25 µg/L (14-30 µg/L) at day 4 and then constantly increased over the remaining neuromonitoring days (p < 0.01). A higher intraventricular hemorrhage sum score (≥ 5) was associated with higher CMD iron levels (Wald-statistic = 4.1, df  = 1, p = 0.04) but not with the hemorrhage load in the subarachnoid space (p = 0.8). In patients developing vasospasm, the CMD iron load was higher, compared with patients without vasospasm (Wald-statistic = 4.1, degree of freedom = 1, p = 0.04), which was not true for delayed cerebral infarction (p = 0.4). Higher iron concentrations in the brain extracellular fluid (34 µg/L, 36-56 µg/L vs. 23 µg/L, 15-37 µg/L) were associated with mitochondrial dysfunction (CMD lactate to pyruvate ratio > 30 and CMD-pyruvate > 70 µM/L, p < 0.001). Brain extracellular iron load was not associated with functional outcome after 3 months (p > 0.5)., Conclusions: This study suggests that iron accumulates in the cerebral white matter in patients with poor grade SAH. These findings may support trials aiming to scavenger brain extracellular iron based on the hypothesis that iron-mediated neurotoxicity may contribute to acute and secondary brain injury following SAH., (© 2021. The Author(s).)

Background/objective: Monitoring of brain tissue oxygen tension (P bt O 2 ) provides insight into brain pathophysiology after intracerebral hemorrhage (ICH). Integration of probe location is recommended to optimize data interpretation. So far, little is known about the importance of P bt O 2 catheter location in ICH patients., Methods: We prospectively included 40 ICH patients after hematoma evacuation (HE) who required P bt O 2 -monitoring. P bt O 2 -probe location was evaluated in all head computed tomography (CT) scans within the first 6 days after HE and defined as location in the healthy brain tissue or perilesional when the catheter tip was located within 1 cm of a focal lesion (hypodense or hyperdense). Generalized estimating equations were used to investigate levels of P bt O 2 in relation to different probe locations., Results: Patients were 60 [51-66] years old and had a median ICH-volume of 47 [29-60] mL. Neuromonitoring probes remained for a median of 6 [2-11] days. P bt O 2 -probes were located in healthy brain tissue in 18/40 (45%) patients and in perilesional brain tissue in 22/40 (55%) patients. In the acute phase after HE (0-72 h), P bt O 2 levels were significantly lower (21 ± 12 mmHg vs. 29 ± 10 mmHg, p = 0.010) and brain tissue hypoxia (BTH) was more common in the perilesional area as compared to healthy brain tissue (46% vs. 19%, adjOR 4.0, 95% CI 1.54-10.58, p = 0.005). Episodes of BTH significantly decreased over time in patients with probes in perilesional location (p = 0.001) but remained stable in normal appearing area (p = 0.485). A significant association between BTH and poor functional outcome was only found when probes were located in the perilesional brain tissue (adjOR 6.6, 95% CI 1.3-33.8, p = 0.023)., Conclusions: In the acute phase, BTH was more common in the perilesional area compared to healthy brain tissue. The improvement of BTH in the perilesional area over time may be the result of targeted treatment interventions and tissue regeneration. Due to the localized measurement of invasive neuromonitoring devices, integration of probe location in the clinical management of ICH patients and in research protocols seems mandatory.

The impact of therapeutic hypothermia (TH) on long-term neurological outcome is still controversial. Data on the effects of TH on brain homeostasis are mostly derived from experimental research. Invasive multimodal neuromonitoring techniques may provide additional insight into pathophysiological changes associated with primary or secondary brain injury in humans. In this study we describe the principles of multimodal neuromonitoring and its potential in the clinical setting of TH. We call for more research using multimodal neuromonitoring techniques in patients undergoing TH to optimize cooling and rewarming strategies.

Traumatic brain injury (TBI) is an important cause of death and disability. Safety and pharmacodynamics of 4-amino-tetrahydrobiopterin (VAS203), a nitric oxide (NO)-synthase inhibitor, were assessed in TBI in an exploratory Phase IIa study (NOSynthase Inhibition in TRAumatic brain injury=NOSTRA). The study included 32 patients with TBI in six European centers. In a first open Cohort, eight patients received three 12-h intravenous infusions of VAS203 followed by a 12-h infusion-free interval over 3 days (total dose 15 mg/kg). Patients in Cohorts 2 and 3 (24) were randomized 2:1 to receive either VAS203 or placebo as an infusion for 48 or 72 h, respectively (total dose 20 and 30 mg/kg). Effects of VAS203 on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain metabolism using microdialysis, and the therapy intensity level (TIL) were end points. In addition, exploratory analysis of the extended Glasgow Outcome Score (eGOS) after 6 months was performed. Metabolites of VAS203 were detected in cerebral microdialysates. No significant differences between treatment and placebo groups were observed for ICP, CPP, and brain metabolism. TIL on day 6 was significantly decreased (p<0.04) in the VAS203 treated patients. The eGOS after 6 months was significantly higher in treated patients compared with placebo (p<0.01). VAS203 was not associated with hepatic, hematologic, or cardiac toxic effects. At the highest dose administered, four of eight patients receiving VAS203 showed transitory acute kidney injury (stage 2-3). In conclusion, the significant improvement in clinical outcome indicates VAS203-mediated neuroprotection after TBI. At the highest dose, VAS203 is associated with a risk of acute kidney injury.

Background: In a resource-poor environment such as rural East Africa, expensive medical devices such as computed tomographic (CT) scanners are rare. The CT scanner at the rural Haydom Lutheran Hospital (HLH) in Tanzania therefore offers a unique chance to observe possible differences with urban medical centers in the disease pattern of trauma-related cranial pathologies. The purpose of this study was to compare traumatic brain injuries (TBIs) between a rural and an urban area of Tanzania., Methods: HLH has 350 beds and one CT scanner. The urban Aga Khan Hospital is a private hospital with 80 beds and one CT scanner. This was a retrospective study. Data of 248 patients at HLH and of 432 patients at Aga Khan Hospital with TBI could be collected., Results: The prevalence of TBI was significantly higher in the rural area compared to the urban area (34.2% vs. 21.9%, P < 0.0001). TBI due to violence was noted to occur more frequently at HLH, whereas road traffic accidents were more frequent at the Aga Khan Hospital. The number of patients showing a normal CT result was significantly higher in the urban area (53.0% vs. 35.9%, P < 0.0001). Bone fractures (35.9% vs. 15.7%, P < 0.0001) and pneumocephalus (6.9% vs. 0.9%, P < 0.0001) were diagnosed significantly more frequently in the rural survey. Soft tissue swelling (11.6% vs. 1.2%, P < 0.0001) and frontal sinus injuries (7.4% vs. 0.4%, P < 0.0001) were observed significantly more often in the urban setting., Conclusions: This study documents the burden of TBI and the differences in TBI-related CT diagnoses and their incidence between urban and rural areas in Eastern Africa. These results are important as they demonstrate that patients with severe TBI are not a primarily urban concern. Management of TBI should be included in the training curricula for health personnel alike irrespective of whether their workplace is primarily urban or rural., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Daily interruption of sedation (IS) has been implemented in 30 to 40% of intensive care units worldwide and may improve outcome in medical intensive care patients. Little is known about the benefit of IS in acutely brain-injured patients., Methods: This prospective observational study was performed in a neuroscience intensive care unit in a tertiary-care academic center. Twenty consecutive severely brain-injured patients with multimodal neuromonitoring were analyzed for levels of brain lactate, pyruvate and glucose, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygen tension (PbtO2) during IS trials., Results: Of the 82 trial days, 54 IS-trials were performed as interruption of sedation and analgesics were not considered safe on 28 days (34%). An increase in the FOUR Score (Full Outline of UnResponsiveness score) was observed in 50% of IS-trials by a median of three (two to four) points. Detection of a new neurologic deficit occurred in one trial (2%), and in one-third of IS-trials the trial had to be stopped due to an ICP-crisis (> 20 mmHg), agitation or systemic desaturation. In IS-trials that had to be aborted, a significant increase in ICP and decrease in PbtO2 (P < 0.05), including 67% with critical values of PbtO2 < 20 mmHg, a tendency to brain metabolic distress (P < 0.07) was observed., Conclusions: Interruption of sedation revealed new relevant clinical information in only one trial and a large number of trials could not be performed or had to be stopped due to safety issues. Weighing pros and cons of IS-trials in patients with acute brain injury seems important as related side effects may overcome the clinical benefit.

Background: As brain temperature is reported to be extensively higher than core body temperature in traumatic brain injury (TBI) patients, posttraumatic hyperthermia is of particular relevance in the injured brain., Objective: To study the influence of prophylactic normothermia on brain temperature and the temperature gradient between brain and core body in patients with severe TBI using an intravascular cooling system and to assess the relationship between brain temperature and intracranial pressure (ICP) under endovascular temperature control., Methods: Prospective case series study conducted in the neurologic intensive care unit of a tertiary care university hospital. Seven patients with severe TBI with a Glasgow Coma Scale score of 8 or less were consecutively enrolled. Prophylactic normothermia, defined as a target temperature of 36.5°C, was maintained using an intravascular cooling system. Simultaneous measurements of brain and urinary bladder temperature and ICP were taken over a 72-hour period., Results: The mean bladder temperature in normothermic patients was 36.3 ± 0.4°C, and the mean brain temperature was determined as 36.4 ± 0.5°C. The mean temperature difference between brain and bladder was 0.1°C. We found a significant direct correlation between brain and bladder temperature (r = 0.95). In 52.4% of all measurements, brain temperature was higher than core body temperature. The mean ICP was 18 ± 8 mm Hg., Conclusion: Intravascular temperature management stabilizes both brain and body core temperature; prophylactic normothermia reduces the otherwise extreme increase of intracerebral temperature in patients with severe TBI. The intravascular cooling management proved to be an efficacious and feasible method to control brain temperature and to avoid hyperthermia in the injured brain. We could not find a statistically significant correlation between brain temperature and ICP.

The prevalence of spinal pathologies in sub-saharan Africa has received little attention so far. The aim of the survey was to investigate and compare the prevalence pattern of spinal lesions in two different populations of Tanzania, one coming from the urban and semi-urban catchment area of Aga Khan Hospital in Dar es Salaam and the other coming from the rural catchment area of Haydom Lutheran Hospital in Mbulu, northern Tanzania. At the Aga Khan Hospital a total number of 1163 patients were included in the survey. In 50 cases (4.3%) no radiological findings were available and 150 patients (12.9%) showed no pathological abnormality. 90.4% (n = 1051) of screened population were classified in the category of extradural-extramedullary pathologies. Intradural-extramedullary lesions were observed in only three cases (0.3%). Intramedullary pathologies accounted for 2.1% (n = 24). Mean age of the screened population was 46.6 years, male-female ratio 1.08:1. At the Haydom Lutheran Hospital 105 cases were included into the study. Twenty-six patients (24.8%) showed no pathological abnormalities. Extradural-extramedullary pathologies occurred in 72.4% (n = 76) of overall cases. However, intradural-extramedullary pathologies were not seen in Haydom. Intramedullary pathologies were diagnosed in two patients (1.9%). Mean age was with 39.8 years clearly younger compared to urban areas, male-female ratio being 1.21:1, only non-significantly higher than in the Aga Khan Hospital's population. Beside this, one of the main goals of this study was to assess the frequency of infections to the spinal cord and vertebral column in rural and urban Tanzania. Surprisingly there were only few radiological findings at the Aga Khan Hospital, which suggested diagnoses consistent with tropical diseases, a striking difference from rural Haydom Lutheran Hospital, where nearly 30% of all patients showed changes on radiograph consistent with infections/infestations.

The prevalence of neurological diseases and cranial pathologies in sub-Saharan Africa remains a very little investigated field. This study aims at providing an imaging-based overview of cranial pathologies in two Tanzanian hospitals and at identifying possible differences in the spectrum of diseases between rural and urban African populations. At rural Haydom Lutheran Hospital (Manyara region) the data of 726 patients were included in a retrospective survey. At urban Aga Khan Hospital (Dar es Salaam) the data of 1975 patients who had undergone Computed Tomography (CT) and of 537 Magnetic Resonance Imaging (MRI) patients were obtained. All three surveys showed a clear male preponderance within the populations. The median age of the patients was higher in the city (urban CT 48 years; range 0-95/MRI 39 years; 0.1-89; rural CT 32 years; 0-102). In the urban series stroke, extracranial infections, cerebral atrophy and tumours formed the main groups of diagnoses. Amongst rural patients traumatic pathologies, followed by stroke and cerebral infections/infestations were the most common diagnoses. The most striking differences were noticed with cases compatible with cerebral infections/infestations and hydrocephalus being reported more frequently in the rural population. On the other hand stroke and cerebral atrophy were more frequent amongst urban patients. In the rural catchment area the data of 51 HIV-positive CT patients could be obtained, showing a clear female preponderance. Within the urban HIV-positive subgroup of CT patients (n = 57), the gender distribution was almost equal. Furthermore, in both HIV-positive populations the proportion "compatible with cerebral infections/infestations" was higher than amongst the overall study populations. In conclusion, cranial pathologies seem to differ widely in rural and urban areas of Tanzania in particular with respect to cerebral infections and vascular disease.

Apoptosis plays an essential role in the cascade of CNS cell degeneration after traumatic brain injury. However, the underlying mechanisms are poorly understood. The authors examined the temporal profile and cell subtype distribution of the proapoptotic protein Bid from 6 hours to 7 days after cortical impact injury in the rat. Increased protein levels of tBid were seen in the cortex ipsilateral to the injury site from 6 hours to 3 days after trauma. Immunohistologic examinations revealed expression of tBid in neurons, astrocytes, and oligodendrocytes from 6 hours to 3 days after impact injury, and concurrent assessment of DNA damage using TUNEL identified tBid-immunopositive cells with apoptoticlike morphology in the traumatized cortex. Moreover, Bid cleavage and activation of caspase-8 and caspase-9 occurred at similar time points and in similar brain regions (i.e., cortical layers 2 to 5) after impact injury. In contrast, there was no evidence of caspase-8 or caspase-9 processing or Bid cleavage in the ipsilateral hippocampus, contralateral cortex, and hippocampus up to 7 days after the injury. The results provide the first evidence of Bid cleavage in the traumatized cortex after experimental traumatic brain injury in vivo, and demonstrate that tBid is expressed in neurons and glial cells. Further, findings indicate that cleavage of Bid may be associated with the activation of the initiator caspase-8 and caspase-9. Finally, these data support the hypothesis that cleavage of Bid contributes to the apoptotic degeneration of different CNS cells in the injured cortex.

Background: Traumatic brain injury is a leading cause of death and disability worldwide. The nitric oxide synthase inhibitor Ronopterin was shown to improve clinical outcome by enhancing neuroprotection in a phase IIa trial.Methods/design: The NOSTRA phase III trial (Ronopterin in traumatic brain injury) is a multi-centre, prospective, randomised, double-blinded, placebo-controlled, phase III trial in Europe. It aims at determining whether the administration of Ronopterin compared to placebo improves neurological outcome in patients with moderate or severe traumatic brain injury at 6 months after injury. The trial is designed to recruit patients between 18 and 60 years of age with moderate or severe traumatic brain injury (Glasgow Coma Scale score ≥ 3) and requiring insertion of an intracranial pressure probe. Trial patients will receive a 48-h intravenous infusion of either Ronopterin or placebo starting at the earliest 6 h and at the latest 18 h after injury. The primary outcome will be the extended Glasgow Outcome Score (eGOS) at 6 months. Secondary outcomes will include the Quality of Life Index (QOLIBRI) at 6 months after the injury and the eGOS at 3 months after the injury. Additionally, effects on mortality, intracranial pressure and cerebral perfusion pressure are evaluated.Discussion: The trial aims to provide evidence on the efficacy and safety of Ronopterin in patients with traumatic brain injury.Trial Registration: EudraCT, 2013-003368-29. Registered on 9 March 2016. ClinicalTrials.gov, NCT02794168. Registered on 8 June 2016. Protocol version 14.0 from 05 November 2018. [ABSTRACT FROM AUTHOR]

Objective: To review the published literature on the clinical application of cerebral microdialysis (CMD) in aneurysmal subarachnoid hemorrhage (SAH) patients and to summarize the evidence relating cerebral metabolism to pathophysiology, secondary brain injury, and outcome. Methods: Study selection: Two reviewers identified all manuscripts reporting on the clinical use of CMD in aneurysmal SAH patients from MEDLINE. All identified studies were grouped according to their focus on brain metabolic changes during the early and subacute phase after SAH, their association with mechanisms of secondary brain injury and outcome. Results: The review demonstrated: (1) limited literature is available in the very early phase before the aneurysm is secured. (2) Brain metabolic changes related to early and delayed secondary injury mechanisms may be used in addition to other neuromonitoring parameters in the critical care management of SAH patients. (3) CMD markers of ischemia may detect delayed cerebral ischemia early (up to 16 h before onset), underlining the importance of trend analysis. (4) Various CMD-derived parameters may be associated with patient outcome at 3-12 months, including CMD-lactate-to-pyruvate-ratio, CMD-glucose, and CMD-glutamate. Conclusion: The clinical use of CMD is an emerging area in the literature of aneurysmal SAH patients. Larger prospective multi-center studies on interventions based on CMD findings are needed. [ABSTRACT FROM AUTHOR]

The classification of epilepsy, which represents the commonest neurological disorder throughout the developing world, has been difficult due to lack of diagnostic tools. Adapted to the circumstances of an epilepsy clinic in northern Tanzania, we grouped people with epilepsy (PWE) according to an adjusted version of the International Classification of Epileptic Seizures with the main groups being: generalized types of seizures (206 PWE) divided into those starting within (147 PWE) and those starting outside (59 PWE) a specific age range (6-25 years); and partial types of seizures (102 PWE) with subgroups of generalized seizures with diffuse brain damage (41 PWE), those with predominantly focal signs (60 PWE) and complex partial seizures (1 PWE). Clinical implications are discussed. [ABSTRACT FROM AUTHOR]

After publication of our article [1] the authors have notified us that one of the names has been incorrectly spelled. [ABSTRACT FROM AUTHOR]

Background/Objectives: The prudent allocation of neurosurgical resources and training efforts requires an understanding of prevalence and clinical pattern of neurosurgical disorders in a particular region. The aim of our study was to assess the hospital-based prevalence of neurosurgical disease in the setting of rural sub-Saharan Africa. Methods: The study was conducted at Haydom Lutheran Hospital in northern Tanzania. Over a period of 8 months, all patients suspected of having neurologic or neurosurgical disorders were seen by a neurologist in consecutive order. Patients were assessed clinically and with plain radiographs, a computed tomography scanner was not available. Results: Of 8676 admissions, 151 patients (1.7%) were given a neurosurgical diagnosis. The most frequent diagnoses were traumatic brain injury (n=90), followed by tuberculosis of the spine (n=22), spina bifida (n=14), space-occupying cerebral lesion (n=13), and hydrocephalus (n=12). The overall mortality was 10.6%; it was especially high in patients with hydrocephalus (25%), space-occupying cerebral lesions (54%), and spina bifida (29%). Conclusions: Initial neurosurgical training and resource allocation in sub-Saharan Africa should focus on neurotrauma, spinal infections, congenital malformations, and hydrocephalus. [ABSTRACT FROM AUTHOR]