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Elevated body temperature (T core ) is associated with poor outcome after subarachnoid hemorrhage (SAH). Brain temperature (T brain ) is usually higher than T core . However, the implication of this difference (T delta ) remains unclear. We aimed to study factors associated with higher T delta and its association with outcome. We included 46 SAH patients undergoing multimodal neuromonitoring, for a total of 7879 h of averaged data of T core , T brain , cerebral blood flow, cerebral perfusion pressure, intracranial pressure and cerebral metabolism (CMD). Three-months good functional outcome was defined as modified Rankin Scale ≤2. T brain was tightly correlated with T core (r = 0.948, p  < 0.01), and was higher in 73.7% of neuromonitoring time (T delta +0.18°C, IQR -0.01 - 0.37°C). A higher T delta was associated with better metabolic state, indicated by lower CMD-glutamate ( p  = 0.003) and CMD-lactate ( p  < 0.001), and lower risk of mitochondrial dysfunction (MD) (OR = 0.2, p  < 0.001). During MD, T delta was significantly lower (0°C, IQR -0.2 - 0.1; p  < 0.001). A higher T delta was associated with improved outcome (OR = 7.7, p  = 0.002). Our study suggests that T brain is associated with brain metabolic activity and exceeds T core when mitochondrial function is preserved. Further studies are needed to understand how T delta may serve as a surrogate marker for brain function and predict clinical course and outcome after SAH.

Background: There is no uniform definition for cerebral microdialysis (CMD) probe location with respect to focal brain lesions, and the impact of CMD-probe location on measured molecule concentrations is unclear., Methods: We retrospectively analyzed data of 51 consecutive subarachnoid hemorrhage patients with CMD-monitoring between 2010 and 2016 included in a prospective observational cohort study. Microdialysis probe location was assessed on all brain computed tomography (CT) scans performed during CMD-monitoring and defined as perilesional in the presence of a focal hypodense or hyperdense lesion within a 1-cm radius of the gold tip of the CMD-probe, or otherwise as normal-appearing brain tissue., Results: Probe location was detected in normal-appearing brain tissue on 53/143 (37%) and in perilesional location on 90/143 (63%) CT scans. In the perilesional area, CMD-glucose levels were lower (p = 0.003), whereas CMD-lactate (p = 0.002), CMD-lactate-to-pyruvate-ratio (LPR; p < 0.001), CMD-glutamate (p = 0.002), and CMD-glycerol levels (p < 0.001) were higher. Neuroglucopenia (CMD-glucose < 0.7 mmol/l, p = 0.002), metabolic distress (p = 0.002), and mitochondrial dysfunction (p = 0.005) were more common in perilesional compared to normal-appearing brain tissue. Development of new lesions in the proximity of the CMD-probe (n = 13) was associated with a decrease in CMD-glucose levels, evidence of neuroglucopenia, metabolic distress, as well as increasing CMD-glutamate and CMD-glycerol levels. Neuroglucopenia was associated with poor outcome independent of probe location, whereas elevated CMD-lactate, CMD-LPR, CMD-glutamate, and CMD-glycerol levels were only predictive of poor outcome in normal-appearing brain tissue., Conclusions: Focal brain lesions significantly impact on concentrations of brain metabolites assessed by CMD. With the exception of CMD-glucose, the prognostic value of CMD-derived parameters seems to be higher when assessed in normal-appearing brain tissue. CMD was sensitive to detect the development of new focal lesions in vicinity to the neuromonitoring probe. Probe location should be described in the research reporting brain metabolic changes measured by CMD and integrated in statistical models.

The amino-acids tryptophan, phenylalanine and tyrosine seem to play an important role in the pathophysiology of depressive disorders. We measured daily brain extracellular levels of these amino-acids using cerebral microdialysis (CMD) and high performance liquid chromatography in 26 consecutive subarachnoid hemorrhage (SAH) patients and associated them with the presence of depressive disorders. Patients were grouped as follows: medical history of depression (prior to SAH), antidepressant intake 12 months after SAH (but not before), or neither. CMD-tryptophan, CMD-phenylalanine and CMD-tyrosine levels were significantly lower in patients with preexisting depressive disorders compared to those without depression (p < 0.01). Disease severity and SAH-related complications were not associated with amino-acid concentrations. We found a positive correlation between nutritionally administered and brain interstitial levels of tryptophan and phenylalanine in non-depressed patients (R = 0.26 and R = 0.24, p < 0.05), which was not present in patients with preexisting depression (p > 0.1). In conclusion, brain interstitial levels of tryptophan, phenylalanine and tyrosine measured in the context of the clinical management of SAH were significantly decreased in patients with a medical history of depression. This study supports the hypothesis that the availability of these neurotransmitter precursor amino-acids in the human brain may play an important role in the pathophysiology of depressive disorders.

Objectives: Pressure reactivity index and oxygen reactivity index are used to assess cerebral autoregulation after acute brain injury. The value of autoregulation indices in the prediction of delayed cerebral ischemia and outcome in patients with subarachnoid hemorrhage is still inconclusive. In this study, we aimed to focus on the predictive value of the first 72 hours commonly referred to as "early brain injury" in comparison to the overall monitoring period., Design: Retrospective observational cohort study., Setting: Neurocritical care unit at a tertiary academic medical center., Patients: Forty-three consecutive poor-grade patients with nontraumatic subarachnoid hemorrhage admitted between 2012 and 2016 undergoing continuous high-frequency monitoring., Interventions: High-frequency monitoring includes arterial blood pressure, intracranial pressure, and brain tissue oxygen tension. Pressure reactivity index and oxygen reactivity index were evaluated as moving correlation coefficient between mean arterial pressure/intracranial pressure and cerebral perfusion pressure/brain tissue oxygen tension, respectively., Measurements and Main Results: Median autoregulation monitoring time was 188 ± 91 hours per patient. Initial pressure reactivity index was 0.31 ± 0.02 and decreased significantly to 0.01 ± 0.01 (p < 0.001) 3 days after admission with a second peak 10 days after admission (0.18 ± 0.14; p = 0.001). Admission oxygen reactivity index was high, 0.25 ± 0.03, and decreased to a minimum of 0.11 ± 0.02 eight days after admission (p = 0.008). Patients with delayed cerebral ischemia had significantly higher overall mean pressure reactivity index values (p < 0.04), which were more pronounced during the first 72 hours, reflecting early brain injury (p < 0.02). High pressure reactivity index during the first 72 hours was associated with poor functional outcome (p < 0.001). No association between oxygen reactivity index and delayed cerebral ischemia or clinical outcome was observed (p = 0.8/0.78)., Conclusions: High initial pressure reactivity index, presumably reflecting early brain injury, but not oxygen reactivity index, was associated with delayed cerebral ischemia and worse clinical outcome in poor-grade subarachnoid hemorrhage patients. Our data indicate that autoregulation indices should be interpreted cautiously when used in these patients and that timing is crucial when autoregulation indices are evaluated as predictor for delayed cerebral ischemia and outcome.

Spreading depolarizations (SDs) are highly active metabolic events, commonly occur in patients with intracerebral hemorrhage (ICH) and may be triggered by fever. We investigated the dynamics of brain-temperature (T brain ) and core-temperature (T core ) relative to the occurrence of SDs. Twenty consecutive comatose ICH patients with multimodal electrocorticograpy (ECoG) and T brain monitoring of the perihematomal area were prospectively enrolled. Clusters of SDs were defined as ≥2 SDs/h. Generalized estimating equations were used for statistical calculations. Data are presented as median and interquartile range. During 3097 h (173 h [81-223]/patient) of ECoG monitoring, 342 SDs were analyzed of which 51 (15%) occurred in clusters. Baseline T core and T brain was 37.3℃ (36.9-37.8) and 37.4℃ (36.7-37.9), respectively. T brain but not T core significantly increased 25 min preceding the onset of SDs by 0.2℃ (0.1-0.2; p < 0.001) and returned to baseline 35 min following SDs. During clusters, T brain increased to a higher level (+0.4℃ [0.1-0.4]; p = 0.006) when compared to single SDs. A higher probability (OR = 36.9; CI = 36.8-37.1; p < 0.001) of developing SDs was observed during episodes of T brain  ≥ 38.0℃ (23% probability), than during T brain  ≤ 36.6℃ (9% probability). Spreading depolarizations - and in particular clusters of SDs - may increase brain temperature following ICH.

Introduction: Animal data suggest an association between neuroinflammation and secondary brain injury including axonal injury after aneurysmal subarachnoid hemorrhage (aSAH). We sought to study the association between brain extracellular interleukin (IL)-6 and TAU-protein levels as a surrogate marker for neuroinflammation and axonal injury in patients with poor grade aSAH., Methods: Prospectively collected data from 26 consecutive poor-grade aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD) were retrospectively analyzed. IL-6 and TAU-protein levels were analyzed using ELISA from a single CMD-sample every 24 hours and correlated with brain metabolic and hemodynamic parameters. Patients were dichotomized to highgrade (N=10) or low-grade (N=16) neuroinflammation according to their median CMD-IL-6 levels. Data were analyzed using generalized estimating equations to account for multiple within-subject measurements., Results: Perilesional probe location (P=0.02) and aSAH related intracerebral hemorrhage (aICH) volume (P=0.003) at admission were associated with high-grade neuroinflammation. Brain extracellular TAU-protein levels (P=0.001), metabolic distress and delayed cerebral infarction (DCI; P=0.001) were linked to high-grade neuroinflammation. Relative or absolute phosphor-TAU levels were not correlated with CMD-IL-6 levels. High-grade neuroinflammation was a predictor for worse outcome three months after ictus, independently from probe location, initial Hunt&Hess grade and age (P=0.01)., Conclusion: Neuroinflammation after aSAH is associated with intraparenchymal bleeding, deranged cerebral metabolism and TAU-protein release. The impact of potential anti-inflammatory treatment strategies on secondary brain injury after aSAH has to be investigated in future studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define "definite", "probable" and "possible" diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A "definite" diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a "probable" diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A "possible" diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder., Competing Interests: Compliance with ethical standardsFundingThis study was partly supported by grants from Fundació Marató de TV3 to EG (grant no. 20141610), Fondo de Investigaciones Sanitarias, FEDER, (FIS 15/00377, FG), (FIS 14/00203, JD) and CIBERER (JD), Madrid, Spain, Fundació CELLEX (JD), and NIH RO1NS077851 (JD).DisclosuresJD receives royalties from licensing fees to Athena diagnostics for a patent for the use of Ma2 and autoantibody test, and from licensing fees to Euroimmun for patents for the use of NMDAR and GABAbR as autoantibody tests, and licensing fees for the use of DPPX, GABAaR, and IgLON5 antibodies as diagnostic tests. JD has received a research grant from Euroimmun. FG receives royalties from licensing fees to Euroimmun for the use of IgLON5 as a diagnostic test.Conflict of interestEG, RH, HL, JH, TD, MP, JP, BH, GR, JS, HB, TR, GK declare that they have no conflict of interest.

Background: Tick borne encephalitis (TBE) is an acute meningoencephalitis with or without myelitis caused by an RNA virus from the flavivirus family transmitted by Ixodes spp ticks. The neurotropic TBE virus infects preferentially large neurons in basal ganglia, anterior horns, medulla oblongata, Purkinje cells and thalamus. Brain metabolic changes related to radiologic and clinical findings have not been described so far., Methods: Here we describe the clinical course of 10 consecutive TBE patients with outcome assessment at discharge and after 12 month using a modified Rankin Scale. Patients underwent cerebral MRI after confirmation of diagnosis and before discharge. 18 F-FDG PET/CT scans were performed within day 5 to day 14 after TBE diagnosis. Extended analysis of coagulation parameters by thrombelastometry (ROTEM® InTEM, ExTEM, FibTEM) was performed every other day after confirmation of TBE diagnosis up to day 10 after hospital admission or discharge., Results: All patients presented with a meningoencephalitic course of disease. Cerebral MRI scans showed unspecific findings at predilection areas in 3 patients. 18 F-FDG PET/CT showed increased glucose utilization in one patient and decreased 18 F-FDG uptake in seven patients. Changes in coagulation measured by standard parameters and thrombelastometry were not found in any of the patients., Discussion: Glucose hypometabolism was present in 7 out of 10 TBE patients reflecting neuronal dysfunction in predilection areas of TBE virus infiltration responsible for development of clinical signs and symptoms., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Recent evidence suggests axonal injury after aneurysmal subarachnoid haemorrhage (aSAH). The microtubule-associated protein, tau, has been shown to be elevated in the cerebrospinal fluid after aSAH, however, brain extracellular tau levels and their relation to long-term neurological and cognitive outcomes have not been investigated., Methods: Serial cerebral microdialysis (CMD) samples were collected from 22 consecutive aSAH patients with multimodal neuromonitoring to determine CMD-total-tau by ELISA. CMD-total-tau was analysed considering other brain metabolic parameters, brain tissue oxygen tension (PbtO2), and functional and neuropsychological outcome at 12 months. All outcome models were analysed using generalised estimating equations with an autoregressive working correlation matrix to account for multiple measurements of brain extracellular proteins per subject., Results: CMD-total-tau levels positively correlated with brain extracellular fluid levels of lactate (r=0.40, p<0.001), glutamate (r=0.45, p<0.001), pyruvate (r=0.26, p<0.001), and the lactate-pyruvate ratio (r=0.26, p<0.001), and were higher in episodes of hypoxic (PbtO2<20 mm Hg) brain extracellular lactate elevation (>4 mmol/L) (p<0.01). More importantly, high CMD-total-tau levels were associated with poor functional outcome (modified Rankin Scale ≥4) 12 months after aSAH even after adjusting for disease severity and age (p=0.001). A similar association was found with 3/5 neuropsychological tests indicative of impairments in cognition, psychomotor speed, visual conceptualisation and frontal executive functions at 1 year after aSAH (p<0.01)., Conclusions: These results suggest that CMD-total tau may be an important biomarker for predicting long-term outcome in patients with severe aSAH. The value of axonal injury needs further confirmation in a larger patient cohort, preferably combined with advanced imaging techniques., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Introduction: Elevated brain potassium levels ([K+]) are associated with neuronal damage in experimental models. The role of brain extracellular [K+] in patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) and its association with hemorrhage load, metabolic dysfunction and outcome has not been studied so far., Methods: Cerebral microdialysis (CMD) samples from 28 poor grade aSAH patients were analyzed for CMD [K+] for 12 consecutive days after ictus, and time-matched to brain metabolic and hemodynamic parameters as well as corresponding plasma [K+]. Statistical analysis was performed using a generalized estimating equation with an autoregressive function to handle repeated observations of an individual patient., Results: CMD [K+] did not correlate with plasma [K+] (Spearman's ρ = 0.114, P = 0.109). Higher CMD [K+] was associated with the presence of intracerebral hematoma on admission head computed tomography, CMD lactate/pyruvate ratio >40 and CMD lactate >4 mmol/L (P < 0.05). In vitro retrodialysis data suggest that high CMD [K+] was of brain cellular origin. Higher CMD [K+] was significantly associated with poor 3-month outcome, even after adjusting for age and disease severity (P < 0.01)., Conclusions: The results of this pilot study suggest that brain extracellular [K+] may serve as a biomarker for brain tissue injury in poor-grade aSAH patients. Further studies are needed to elucidate the relevance of brain interstitial K+ levels in the pathophysiology of secondary brain injury after aSAH.

Introduction: Diclofenac, a nonsteroidal antiinflammatory drug, is commonly used as antipyretic therapy in intensive care. The purpose of this study was to investigate the effects of parenteral diclofenac infusion on brain homeostasis, including brain-tissue oxygen tension (PbtO2) and brain metabolism after aneurysmal subarachnoid hemorrhage (aSAH)., Methods: We conducted a prospective, observational study with retrospective analysis of 21 consecutive aSAH patients with multimodal neuromonitoring. Cerebral perfusion pressure (CPP), mean arterial pressure (MAP), intracranial pressure (ICP), body temperature, and PbtO2 were analyzed after parenteral diclofenac infusion administered over a 34-minute period (20 to 45 IQR). Data are given as mean ± standard error of mean and median with interquartile range (IQR), as appropriate. Time-series data were analyzed by using a general linear model extended by generalized estimation equations (GEEs)., Results: One-hundred twenty-three interventions were analyzed. Body temperature decreased from 38.3°C ± 0.05°C by 0.8°C ± 0.06°C (P < 0.001). A 10% decrease in MAP and CPP (P < 0.001) necessitated an increase of vasopressors in 26% (n = 32), colloids in 33% (n = 41), and crystalloids in 5% (n = 7) of interventions. PbtO2 decreased by 13% from a baseline value of 28.1 ± 2.2 mm Hg, resulting in brain-tissue hypoxia (PbtO2 <20 mm Hg) in 38% (n = 8) of patients and 35% (n = 43) of interventions. PbtO2 <30 mm Hg before intervention was associated with brain-tissue hypoxia after parenteral diclofenac infusion (likelihood ratio, 40; AUC, 93%; 95% confidence interval (CI), 87% to 99%; P < 0.001). Cerebral metabolism showed no significant changes after parenteral diclofenac infusion., Conclusions: Parenteral diclofenac infusion after aSAH effectively reduces body temperature, but may lead to CPP decrease and brain-tissue hypoxia, which were both associated with poor outcome after aSAH.

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: Vasospasm-related delayed cerebral ischemia (DCI) significantly impacts on outcome after aneurysmal subarachnoid hemorrhage (SAH). Erythropoietin (EPO) may reduce the severity of cerebral vasospasm and improve outcome, however, underlying mechanisms are incompletely understood. In this study, the authors aimed to investigate the effect of EPO on cerebral metabolism and brain tissue oxygen tension (PbtO2)., Methods: Seven consecutive poor grade SAH patients with multimodal neuromonitoring (MM) received systemic EPO therapy (30.000 IU per day for 3 consecutive days) for severe cerebral vasospasm. Cerebral perfusion pressure (CPP), mean arterial blood pressure (MAP), intracranial pressure (ICP), PbtO2 and brain metabolic changes were analyzed during the next 24 hours after each dose given. Statistical analysis was performed with a mixed effects model., Results: A total of 22 interventions were analyzed. Median age was 47 years (32-68) and 86 % were female. Three patients (38 %) developed DCI. MAP decreased 2 hours after intervention (P < 0.04) without significantly affecting CPP and ICP. PbtO2 significantly increased over time (P < 0.05) to a maximum of 7 ± 4 mmHg increase 16 hours after infusion. Brain metabolic parameters did not change over time., Conclusions: EPO increases PbtO2 in poor grade SAH patients with severe cerebral vasospasm. The effect on outcome needs further investigation.

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.

Cerebral malaria (CM) is associated with a high rate of transient or persistent neurological sequelae. Nogo-A, a protein that is highly expressed in the endoplasmic reticulum (ER) of the mammalian central nervous system (CNS), is involved in neuronal regeneration and synaptic plasticity in the injured CNS. The current study investigates the role of Nogo-A in the course of experimental CM. C57BL/6J mice were infected with Plasmodium berghei ANKA blood stages. Brain homogenates of mice with different clinical severity levels of CM, infected animals without CM and control animals were analyzed for Nogo-A up-regulation by Western blotting and immunohistochemistry. Brain regions with Nogo-A upregulation were evaluated by transmission electron microscopy. Densitometric analysis of Western blots yielded a statistically significant upregulation of Nogo-A in mice showing moderate to severe CM. The number of neurons and oligodendrocytes positive for Nogo-A did not differ significantly between the studied groups. However, mice with severe CM showed a significantly higher number of cells with intense Nogo-A staining in the brain stem. In this region ultrastructural alterations of the ER were regularly observed. Nogo-A is upregulated during the early course of experimental CM. In the brain stem of severely affected animals increased Nogo-A expression and ultrastructural changes of the ER were observed. These data indicate a role of Nogo-A in neuronal stress response during experimental CM.

Background: The patho-mechanisms leading to brain damage due to cerebral malaria (CM) are yet not fully understood. Immune-mediated and ischaemic mechanisms have been implicated. The role of complement factors C1q, C3 and C5 for the pathogenesis of CM were investigated in this study., Methods: C57BL/6J mice were infected with Plasmodium berghei ANKA blood stages. The clinical severity of the disease was assessed by a battery of 40 standardized tests for evaluating neurological functions in mice. Brain homogenates and sera of mice with CM, infected animals without CM and non-infected control animals were analyzed for C1q, C3 and C5 up-regulation by Western blotting., Results: Densitometric analysis of Western blots of brain homogenates yielded statistically significant differences in the levels of C1q and C5 in the analyzed groups. Correlation analysis showed a statistically significant association of C1q and C5 levels with the clinical severity of the disease. More severely affected animals showed higher levels of C1q and C5. No differences in complement levels were observed between frontal and caudal parts of the brain. Densitometric analysis of Western blot of sera yielded statistically lower levels of C1q in infected animals without CM compared to animals of the control group., Conclusion: The current study provides direct evidence for up-regulation of complement factors C1q and C5 in the brains of animals with CM. Local complement up-regulation is a possible mechanism for brain damage in experimental cerebral malaria.

Background: The mechanisms leading to death and functional impairments due to cerebral malaria (CM) are yet not fully understood. Most of the knowledge about the pathomechanisms of CM originates from studies in animal models. Though extensive histopathological studies of the murine brain during CM are existing, alterations have not been visualized by scanning electron microscopy (SEM) so far. The present study investigates the neuropathological features of murine CM by applying SEM., Methods: C57BL/6J mice were infected with Plasmodium berghei ANKA blood stages. When typical symptoms of CM developed perfused brains were processed for SEM or light microscopy, respectively., Results: Ultrastructural hallmarks were disruption of vessel walls, parenchymal haemorrhage, leukocyte sequestration to the endothelium, and diapedesis of macrophages and lymphocytes into the Virchow-Robin space. Villous appearance of observed lymphocytes were indicative of activated state. Cerebral oedema was evidenced by enlargement of perivascular spaces., Conclusion: The results of the present study corroborate the current understanding of CM pathophysiology, further support the prominent role of the local immune system in the neuropathology of CM and might expose new perspectives for further interventional studies.

Background: Brain autoimmunity has been reported in patients with preceding infection of the central nervous system by herpesviridae. It has been hypothesized that neuronal damage releasing antigens might trigger secondary immune response. The objective of the study was to investigate whether brain damage due to spontaneous subarachnoid haemorrhage (SAH) or intracerebral haemorrhage (ICH) induces reactivity against neuronal surface proteins.Methods: Patients with spontaneous SAH and ICH, who had cerebrospinal fluid (CSF) and serum sampling within 2 weeks after disease onset (baseline) and afterwards at least 10 days later (follow-up), were included. Antibodies against NMDA, GABA-B, AMPA-1/- 2 receptor, LGI1 and CASPR2 were determined by indirect immunofluorescence.Results: A total of 43 SAH and 11 ICH patients aged 62 (±12) years (65% females) had simultaneous CSF/ serum sampling median 5 and 26.5 days after disease onset. At baseline, all CSF samples were collected via ventricular drainage, at follow-up 20 (37.0%) patients had CSF collection by lumbar puncture because ventricular drain had been already removed. All CSF and serum samples at baseline and follow-up tested negative for antibodies against NMDA, GABA-B, AMPA-1/- 2 receptor, LGI1 and CASPR2.Conclusions: Immunoreactivity against common neuronal surface proteins was not observed within the early disease course of spontaneous SAH and ICH. [ABSTRACT FROM AUTHOR]

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 &y& Elsevier]