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Background: Obstructive sleep apnea syndrome (OSAS) is a common disorder that is accompanied by structural brain changes. This meta-analysis aimed to evaluate the effect of OSAS on the serum levels of astrocytic protein (S100B) and neuron-specific enolase (NSE) in observational studies., Methods: A comprehensive search was performed in the PubMed/Medline, Web of Science, Scopus, ScienceDirect, and Cochrane Library databases to assess the serum level of S100B and/or NSE in patients with OSAS and/or controls. The quality of the study was evaluated by the Newcastle-Ottawa Scale (NOS). A random-effects model was performed using RevMan 5.3 with the mean difference (MD) and 95% confidence intervals (CIs)., Results: Out of 63 studies found in the mentioned databases and one identified by a manual search, nine studies were included and analyzed in this meta-analysis (three cross-sectional and six case-control studies). The analysis showed that the S100B [MD = 53.58 pg/ml, 95%CI: 1.81, 105.35; P = 0.04] and NSE levels [MD = 3.78 ng/ml, 95%CI: 2.07, 5.48; P < 0.0001] were significantly higher in patients than the controls. However, there were no significant differences between the S100B [MD = -28.00 pg/ml, 95%CI: - 79.48, 23.47; P = 0.29] and NSE levels [MD = 0.49 ng/ml, 95%CI: - 0.82, 1.80; P = 0.46]., Conclusions: This meta-analysis found elevated serum S100B and NSE levels in OSAS patients compared to the controls, which suggests that these markers may be used as peripheral indicators of brain damage in OSAS.

Objectives- The prediction of patients at risk for poor clinical outcome after acute ischemic stroke remains challenging. An imbalance of coagulation factors may play an important role in progression and prognosis of these patients. In this systematic review, we assessed the current literature on hemostasis biomarkers and the association with poor clinical outcome in acute ischemic stroke. Approach and Results- A systematic search of Embase, Medline, Cochrane Library, Web of Science, and Google Scholar was performed on studies reporting on hemostasis biomarkers and clinical outcome after acute ischemic stroke. Studies were considered eligible if blood samples were collected within 72 hours after symptom onset. Additionally, clinical outcome should be assessed using a disability score (Barthel Index or modified Rankin scale). Methodological quality of included studies was assessed with an adapted version of the Quality Assessment of Diagnostic Accuracy Studies questionnaire. A total of 80 articles were read full text, and 41 studies were considered eligible for inclusion, reporting on 37 different hemostasis biomarkers. No single biomarker appeared to be effective in predicting poor clinical outcome in acute ischemic stroke patients. Conclusions- Based on current literature, no clear recommendations can be provided on which hemostasis biomarkers are a predictor of clinical outcome after acute ischemic stroke. However, some biomarkers show promising results and need to be further investigated and validated in large populations with clear defined study designs.

Objective: Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury., Methods: Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE., Results: Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1β levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1β and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1β, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1β or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17-393) of hippocampal T2 hyperintensity after FSE., Significance: Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE)., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Background and Purpose: Brain-derived neurotrophic factor (BDNF) plays important roles in brain plasticity and repair, and it influences stroke outcomes in animal models. Circulating BDNF concentrations are lowered in patients with traumatic brain injury, and low BDNF predicts poor recovery after this injury. We sought to investigate whether circulating concentrations of BDNF are altered in the acute phase of ischemic stroke and whether they are associated with short- or long-term functional outcome., Methods: Serum concentrations of BDNF were measured in the Sahlgrenska Academy Study on Ischemic Stroke. The main outcomes were modified Rankin Scale (mRS) good (mRS score of 0-2) versus poor (mRS score of 3-6) at 3 months and 2 years after stroke, and good (mRS score of 0-2) versus poor (mRS score of 3-5) at 7 years after stroke., Results: Acute concentrations of BDNF were significantly lower in ischemic stroke cases (n=491) compared with controls (n=513). BDNF concentrations were not significantly associated with 3-month outcome. However, patients with BDNF in the lowest tertile had an increased risk of experiencing a poor outcome both at 2-year and 7-year follow-up, and these associations were independent of vascular risk factors and stroke severity (odds ratio, 2.6; confidence intervals, 1.4-4.9; P=0.002 and odds ratio, 2.1; confidence intervals, 1.1-3.9; P=0.028, respectively)., Conclusions: Circulating concentrations of BDNF protein are lowered in the acute phase of ischemic stroke, and low levels are associated with poor long-term functional outcome. Further studies are necessary to confirm these associations and to determine the predictive value of BDNF in stroke outcomes., (© 2016 American Heart Association, Inc.)

The onset of hyperammonemia due to the flow of ammonia-rich portal vein blood through a portal-systemic shunt causes a type of encephalopathy known as chronic portal-systemic shunt encephalopathy (CPSE). We herein report two cases of CPSE that presented with opposite changes in the blood ammonia concentrations during hemodialysis. It is curious that the encephalopathy was ameliorated by hemodialysis in case 1, but not case 2. Therefore, it is necessary to recognize CPSE and assess the blood ammonia concentrations in dialysis patients who develop a disturbance of consciousness, even if the serum transaminase level is normal.

Objective: To evaluate if type 2 diabetes mellitus (DM) constitutes a prognostic factor for death and severe disability in patients with aneurysm clipping after subarachnoid hemorrhage (ASH), in an Intensive Care Unit (ICU)., Material and Methods: This is a cohort study in patients who were admitted to the ICU between December-2009 and June-2010; 20 with DM (exposed group) and 40 without DM (non-exposed group). Mortality was quantified during ICU stay. At ICU discharge, severe disability was measured through the Glasgow Outcome Scale (category 2); and Glasgow Coma Scale was used to estimate the difference in consciousness level between ICU arrival and discharge. Descriptive statistics and Kaplan Meier survival curves were performed., Results: Mean age was similar between groups (55.8 +/- 11 and 55.6 +/- 15 years, respectively, p = 0.40). A vegetative state was present in one patient without DM. The Glasgow Coma Scale score at ICU entry was 14.1 +/- 1.4 and at discharge, 12.0 +/- 3.6 in the exposed group (p = 0.01); and 13.9 +/- 2.0 us. 13.5 +/- 2.6, in the non-exposed group, respectively (p = 0.45). There were 3 deaths in patients with DM and 5, in patients without DM (p > 0.05); survival time was 12 (95%CI 7, 16) and 10 days (95%CI 7, 13), respectively. Mean glucose remained higher in patients who died at the ICU (p < 0.001). Hydrocephaly was present in 6 exposed patients and 2, non-exposed (p = 0.007). Additionally, 7 and 5 with and without DM, respectively registered a positive blood culture (p = 0.04)., Conclusions: DM was not associated with higher mortality in ICU patients, but hyperglycemia was; thus, it is essential that the intensive care provider watches closely the glycemic control.

Objectives: The aim of this study was to determine the added value of the serum biomarkers S100 and neuron-specific enolase to clinical characteristics for predicting outcome after out-of-hospital cardiac arrest., Background: Serum S100 beta (S100B) and neuron-specific enolase concentrations rise after brain injury., Methods: A prolective observational study was conducted among all adult survivors of nontraumatic out-of-hospital cardiac arrest admitted to 1 hospital (April 3, 2008 to April 3, 2011). Three blood samples (on arrival and on days 1 and 3) were drawn for biomarkers, contingent on survival. Follow-up continued until in-hospital death or discharge. Outcomes were defined as good (Cerebral Performance Category score 1 or 2) or poor (Cerebral performance category score 3 to 5)., Results: A total of 195 patients were included (65.6% men, mean age 73 ± 16 years), with presenting rhythms of asystole in 61.5% and ventricular tachycardia or ventricular fibrillation in 24.1%. Only 43 patients (22.0%) survived to hospital discharge, 26 (13.3%) with good outcomes. Patients with good outcomes had significantly lower S100B levels at all time points and lower neuron-specific enolase levels on days 1 and 3 compared with those with poor outcomes. Independent predictors at admission of a good outcome were younger age, a presenting rhythm of ventricular tachycardia or ventricular fibrillation, and lower S100B level. Predictors on day 3 were younger age and lower day 3 S100B level. The area under the receiver-operating characteristic curve of the admission-day model was 0.932 with and 0.880 without biomarker data (p = 0.027 for the difference)., Conclusions: Risk stratification after out-of-hospital cardiac arrest using both clinical and biomarker data is feasible. The biomarkers, although adding an ostensibly modest 5.2% to the area under the receiver-operating characteristic curve, substantially reduced the level of uncertainty in decision making. Nevertheless, current biomarkers cannot replace societal considerations in determining acceptable levels of uncertainty. (Protein S100 Beta as a Predictor of Resuscitation Outcome; NCT00814814)., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to investigate neuropeptides in patients presenting with symptoms of acute cerebrovascular disease., Background: The precursor neuropeptides proenkephalin A (PENK-A) and protachykinin (PTA) are markers of blood-brain barrier integrity and have been recently discussed in vascular dementia and neuroinflammatory disorders., Methods: In a prospective observational study, we measured plasma PENK-A and PTA concentrations in 189 consecutive patients who were admitted with symptoms of acute stroke. Plasma concentrations were determined by sandwich immunoassay; lower detection limits were 15.6 pmol/l (PENK-A) and 22 pmol/l (PTA). Clinical outcome was assessed at 3 months for mortality, major adverse cerebro/cardiovascular events, and functional outcome (modified Rankin scale)., Results: PENK-A was significantly elevated in patients with ischemic stroke (n = 124; 65.6%) compared to patients with transient ischemic attack (n = 16; 8.5%) and to patients with nonischemic events (n = 49; 25.9%): median (interquartile range), stroke 123.8 pmol/l (93 to 160.5); transient ischemic attack 114.5 pmol/l (85.3 to 138.8); and nonischemic event 102.8 pmol/l (76.4 to 137.6; both groups vs. stroke p < 0.05). High concentrations of PENK-A, but not PTA, were related to severity of stroke as assessed by National Institutes of Health Stroke Scale (NIHSS [r = 0.225; p = 0.002]) and to advanced functional disability (modified Rankin Scale score 3 to 6 vs. 0 to 2: 135.1 pmol/l [99.2 to 174.1] vs. 108.9 pmol/l [88.6 to 139.5]; p = 0.014). After adjusting for age, NIHSS, and brain lesion size (computed tomography), PENK-A predicted mortality (hazard ratio [HR] for log-10 PENK-A in pmol/l: 4.52; 95% confidence interval [CI]: 1.1 to 19.0; p < 0.05) and major adverse cerebro/cardiovascular events (HR: 6.65; 95% CI: 1.8 to 24.9; p < 0.05). Patients in the highest quartile of PENK-A (cutoff >153 pmol/l) had an increased risk of mortality (HR: 2.40; 95% CI: 1.02 to 5.40; p < 0.05) and of major adverse cerebro/cardiovascular events (HR: 2.23; 95% CI: 1.10 to 4.54; p < 0.05)., Conclusions: PENK-A is a prognostic biomarker in the acute phase of ischemic stroke. Elevated PENK-A concentrations are associated with ischemic stroke, severity of cerebral injury, and may have prognostic value for fatal and nonfatal events., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, and early predictors of neurological outcomes are of great clinical importance. Cell free DNA (CFD), a biomarker used for the diagnosis and monitoring of several diseases, has been implicated as a possible prognostic indicator after TBI. The purpose of this study was to determine the pattern and timing of CFD levels after TBI, and whether a relationship exists between the level of CFD and brain edema and neurological outcomes. Thirty-nine Sprague-Dawley rats were randomly assigned to two groups: rats in group 1 (sham group) were anesthetized and had a scalp incision without TBI, and rats in group 2 were anesthetized and had a scalp incision with TBI, which was induced by using a weight drop model that causes diffuse brain injury. A neurological severity score (NSS) was assessed at 1, 24, and 48 h after TBI. CFD was measured via blood samples drawn at t=0 (baseline), 12, 24, 48, 72, and 120 h after TBI. At 48 h after TBI, brain edema was determined in a subgroup of 11 rats by calculating the difference between rats' wet and dry brain weight. The significance of comparisons between and within groups (CFD levels, brain water content, and NSS) were determined using the Kruskal-Wallis, Mann-Whitney and Student t test. The correlation between CFD levels and the NSS, as well as between CFD levels and the extent of brain edema, was calculated using the Spearman and Pearson tests, respectively. Compared with baseline levels, the CFD levels in rats subjected to TBI were significantly increased at 24 and 48 h after TBI (p<0.01 and p<0.05, respectively). A positive correlation was demonstrated between CFD levels 24 h following TBI and the extent of brain edema (r=0.63, p<0.05), as well as between CFD levels and the NSS (r=0.79, p<0.005). In this study, we demonstrated an increase in CFD levels after TBI, as well as a correlation between CFD levels and brain edema and NSS. CFD levels may provide a quick, reliable, and simple prognostic indicator of neurological outcome in animals after TBI. Its role in humans has not been clearly elucidated, but has potentially significant clinical implications.

Levels of antibodies AB (AB) to S100B and S100B protein were studied in the blood serum of children with different severity and outcomes of traumatic brain injury (TBI) from the 1st to 15-75th days after TBI. Severity and outcomes were assessed using the Glasgow Coma Scale (GCS). Patients were stratified by outcomes into the following groups: complete recovery (group 1), moderate disability (group 2), high disability (group 3), vegetative state (group 4) and fatal outcome (group 5). In patients of groups 1-3, the changes of S100B in the blood serum didn't depend on the severity of brain's damage; the significant increase of S100B protein levels in the 1st day was accompanied by the decrease to the normal range in the following 2-3 days. On the contrary, the levels of nAB in these groups increased starting from 3-5 days corresponding to the severity of brain's damage. The development of vegetative state was accompanied by low S100B and high AB to S100B levels in the blood serum. The maximal level of S100B protein and increased levels of AB were observed in patients with fatal outcome. In most patients with combined TBI, the levels of both parameters were higher compared to those with separate TBI.

Effects of caffeic acid phenethyl ester (CAPE) on the serum S-100B levels were studied as an index for brain damage after permanent middle cerebral artery (MCA) occlusion in rabbits. Twenty rabbits were divided into four groups (n=5): control, sham, non-treatment and CAPE. The right MCA was occluded using a microsurgical procedure with bipolar coagulation and was then transected in non-treatment and CAPE groups. The rabbits in the sham group underwent a surgical procedure but the MCA was not occluded. No surgery was performed in the control group. CAPE was administered after MCA occlusion at the dose of 10 microg/kg, once a day intraperitoneally for 7 days in the CAPE group. Serum S-100B levels were determined on days 1, 2, 4 and 7. Serum S-100B level was significantly increased following permanent MCA occlusion. Posttreatment of CAPE significantly reduced the serum S-100B level. This study demonstrated that CAPE is capable of attenuating increased serum S-100B level induced by MCA occlusion in rabbits. CAPE may be useful as a neuroprotective agent.

Introduction: Oxygen is among the most frequently used therapies in neonates worldwide. Nevertheless, many times it is used unnecessarily. Neonatal practices have changed over the last several years; treatments originally believed to be beneficial have been discarded., Study Design: Oxygen utilized 'just in case' or 'prophylactically' can lead to great damage previously ignored and/or unseen by healthcare providers. It is imperative to improve education on neonatal oxygenation and saturation monitoring. It is also important not to depend on old assumptions, which were not based on evidences. The potential for unseen damage at the cellular and tissue levels cannot be ignored. Therapies that prove to be outdated or even dangerous must be eliminated while further research and confirmation of the best practices are determined. Freedom to choose can come at a price.

Objective: Studies have shown signs of brain damage caused by different mechanisms in cocaine users. The serum neuron specific enolase and S100B protein are considered specific biochemical markers of neuronal and glial cell injury. This study aimed at comparing blood levels of S100B and NSE in chronic cocaine users and in volunteers who did not use cocaine or other illicit drugs., Method: Twenty subjects dependent on cocaine but not on alcohol or marijuana, and 20 non-substance using controls were recruited. Subjects were selected by consecutive and non-probabilistic sampling. Neuron specific enolase and S100B levels were determined by luminescence assay., Results: Cocaine users had significantly higher scores than controls in all psychiatric dimensions of the SCL-90 and had cognitive deficits in the subtest cubes of WAIS and the word span. Mean serum S100B level was 0.09 +/- 0.04 microg/l among cocaine users and 0.08 +/- 0.04 microg/l among controls. Mean serum neuron specific enolase level was 9.7 +/- 3.5 ng/l among cocaine users and 8.3 +/- 2.6 ng/l among controls., Conclusions: In this first study using these specific brain damage markers in cocaine users, serum levels of S100B and neuron specific enolase were not statistically different between cocaine dependent subjects and controls.

Background and Purpose: Biochemical markers of acute neuronal injury may aid in the diagnosis and management of acute ischemic stroke. Serum samples from the National Institute for Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator Stroke Study were analyzed for the presence of 4 biochemical markers of neuronal, glial, and endothelial cell injury. These biochemical markers, myelin basic protein (MBP), neuron-specific enolase (NSE), S100beta, and soluble thrombomodulin, were studied for an association with initial stroke severity, infarct volume, and functional outcome., Methods: In the original NINDS study, serum samples were drawn from all patients on presentation to the Emergency Department and at approximately 2 and 24 hours after initiation of study therapy. In this analysis, stored serum samples were available for 359 patients; 107 patients had samples for all 3 time points. Serum marker concentrations were measured by ELISA techniques. We examined the relation between serum concentrations of each marker and the degree of baseline neurological deficit, functional outcome, and infarct size on computed tomography at 24 hours and the effect of fibrinolytic therapy., Results: Higher 24-hour peak concentrations of MBP, NSE, and S100beta were associated with higher National Institutes of Health Stroke Scale baseline scores (r=0.186, P<0.0001; r=0.117, P=0.032; and r=0.263, P<0.0001, respectively). Higher peak concentrations of MBP and S100beta (r=0.209, P<0.0001; r=0.239, P<0.0001) were associated with larger computed tomography lesion volumes. Patients with favorable outcomes had smaller changes in MBP and S100beta (P<0.05) concentrations in the first 24 hours. Soluble thrombomodulin was not associated with any severity or outcome measure., Conclusions: This study corroborates previous work demonstrating correlations of MBP, NSE, and S100beta with clinical and radiographic features in acute stroke. Despite significantly better outcomes in the tissue plasminogen activator-treated group, we found no difference in the early release of the 4 biomarkers between treatment groups. Further study will define the role of biomarkers in acute stroke management and prognostication.

Introduction: Elevated serum levels of S100beta, an astrocyte-derived protein, correlate with unfavourable neurological outcomes following cardiac surgery, neurotrauma, and resuscitation. This study evaluated whether pre-/postoperative serum S100beta levels correlate with unfavourable clinical and radiological findings in patients undergoing elective meningioma resection., Methods: In 52 consecutive patients admitted for meningioma surgery, serum S100beta levels were determined upon admission and immediately, 24 hours, and 48 hours after surgery. All patients underwent complete pre- and postoperative neurological examination and mini-mental state examination. Radiological evaluation included preoperative magnetic resonance imaging (MRI) and postoperative computed tomography. Tumour volume, brain edema, and bleeding volume were calculated using BrainSCAN software., Results: Preoperative S100beta levels did not correlate with the tumour characteristics demonstrated by preoperative MRI (for example, tumour volume, edema volume, ventricular asymmetry, and/or midline shift). Preoperative serum S100beta levels (0.065 +/- 0.040 microg/l) were significantly lower than the levels measured immediately (0.138 +/- 0.081 microg/l), 24 hours (0.142 +/- 0.084 microg/l), and 48 hours (0.155 +/- 0.119 microg/l) postoperatively (p < 0.0001). Significantly greater postcraniotomy S100beta levels were observed with prolonged surgery (p = 0.039), deterioration in the mini-mental state examination (p = 0.005, 0.011, and 0.036 for pre versus immediate, 24 hours, and 48 hours postsurgery, respectively), and with postoperative brain computed tomography evidence of brain injury; bleeding was associated with higher serum S100beta levels at 24 and 48 hours after surgery (p = 0.046, 95% confidence interval [CI] -0.095 to -0.001 and p = 0.034, 95% CI -0.142 to -0.006, respectively) as was the presence of midline shift (p = 0.005, 95% CI -0.136 to -0.025 and p = 0.006, 95% CI -0.186 to -0.032, respectively). Edema was associated with higher serum S100beta levels immediately (p = 0.022, 95% CI -0.092 to -0.007) and at 48 hours after surgery (p = 0.017, 95% CI -0.142 to -0.026). The degree of elevation in S100beta levels at 24 and 48 hours after surgery also correlated with the severity of midline shift and edema., Conclusion: In patients with meningioma, serum S100beta levels perform poorly as an indicator of tumour characteristics but may suggest ongoing postcraniotomy injury. Serum S100beta levels may serve as a potentially useful early marker of postcraniotomy brain damage in patients undergoing elective meningioma resection.

Neurologic disability is a feared outcome of resuscitation from cardiac arrest. The study by Rech and colleagues in the previous issue of Critical Care describes the use of neuron-specific enolase to inform an early prognosis in patients who survived in-hospital cardiac arrest. In their study 'none of the patients had a DNR order and there was no limitation of life support.' As a result, 10% of patients remained in a vegetative state at 6 months, a higher percentage than in other recent studies. The existence of a population of patients in which all are fully supported without withholding care or withdrawal of care may represent an important research opportunity. High neuron-specific enolase levels have been reported in patients that awoke and seem to occur in studies with a higher percentage of patients in a vegetative state at follow-up (more uniform support). If a comprehensive set of clinical, electrophysiological, biochemical and imaging measures could be obtained in a uniform manner in a cohort of patients without limitations in care, a more objective set of comprehensive prognostic indicators could be obtained. A focused international consortium is called for.

Background: Therapeutic hypothermia can improve survival after cardiopulmonary resuscitation (CPR). Coenzyme Q10 (CoQ10) has shown a protective effect in neurodegenerative disorders. We investigated whether combining mild hypothermia with CoQ10 after out-of-hospital cardiac arrest provides additional benefit., Methods and Results: Forty-nine patients were randomly assigned to either hypothermia plus CoQ10 or hypothermia plus placebo after CPR. Hypothermia with a core temperature of 35 degrees C was instituted for 24 hours. Liquid CoQ10 250 mg followed by 150 mg TID for 5 days or placebo was administered through nasogastric tube. Age, sex, premorbidity, cause of arrest, conditions of CPR, and degree of hypoxia were similar in both groups; no side effects of CoQ10 were identified. Three-month survival in the CoQ10 group was 68% (17 of 25) and 29% (7 of 24) in the placebo group (P=0.0413). Nine CoQ10 patients versus 5 placebo patients survived with a Glasgow Outcome Scale of 4 or 5. Mean serum S100 protein 24 hours after CPR was significantly lower in the CoQ10 group (0.47 versus 3.5 ng/mL)., Conclusions: Combining CoQ10 with mild hypothermia immediately after CPR appears to improve survival and may improve neurological outcome in survivors.

Aim: To study the protective effects of tumor necrosis factor alpha (TNFalpha) antibody on pancreatic encephalopathy in rats., Methods: One hundred and twenty SD rats were randomly divided into normal control group, acute necrotizing pancreatitis group and TNFalpha antibody treated group. Acute hemorrhage necrotizing pancreatitis model in rats was induced by retrograde injection of 50 g/L sodium taurocholate into the pancreatobiliary duct. Serum TNFalpha was detected and animals were killed 12 h after drug administration. Changes in content of brain water, MDA and SOD as well as leucocyte adhesion of brain microvessels were measured., Results: In TNFalpha antibody treated group, serum TNFalpha level was decreased. Content of brain water, MDA and SOD as well as leucocyte adhesion were decreased significantly in comparison with those of acute necrotizing pancreatitis group (P<0.05)., Conclusion: TNFalpha antibody can alleviate the brain damage of rats with acute hemorrhage necrotizing pancreatitis.

Background: One of the major concerns of a stroke victim is the threatening possibility of loosing all the functional achievements attained through prolonged rehabilitation effort, in case of a recurrent cerebrovascular event. Recently, elevated serum homocysteine (Hcy) level was found to be associated with an increased risk for atherosclerotic vascular disease. The aim of the present study was to assess the yield of screening stroke patients for hyperhomocysteinemia, as part of the measures taken to reduce the risk of stroke recurrence., Material/methods: Blood Hcy levels of stroke patients undergoing rehabilitation were compared to the Hcy levels of patients admitted for rehabilitation following brain damage of non-vascular etiologies., Results: The mean Hcy level was found to be significantly higher in the former group (10.21+/-7.81 micromol/L and 6.16+/-4.28 micromol/L in the stroke group and in the non-vascular group, respectively [p<0.003]). However, when analysis of variance was applied and the correlation with age was accounted for, the difference between the groups became insignificant., Conclusions: Considering the current high cost of blood Hcy tests, the above findings do not support adoption of an overall, non-selective screening policy for hyperhomocysteinemia in stroke patients. However, it may be justified to measure Hcy levels, as well as folic acid, vitamin B6 and vitamin B12 levels, in selected stroke cases. Further study is needed in order to set clear guidelines for the search after this possible risk factor of stroke, one of the major causes of morbidity and mortality in modern society.

Background: We used serial measurements of serum S-100B protein to evaluate the time course of serum S-100B protein concentration after cardiovascular surgery and to determine the clinical relevance of its concentration and cerebral damage., Methods: We assessed neurologic function in 149 patients undergoing cardiovascular surgery with cardiopulmonary bypass. The patients were classified into three groups according to their early postoperative outcome: those without complications (group A), those having unconsciousness or convulsion or both but no hemiplegia (group B), and those having unconsciousness and hemiplegia either with or without convulsion (group C). Serum S-100B protein concentrations were measured with a commercially available immunoluminometric assay, Sangtec 100 LIA, at seven time-points: before cardiopulmonary bypass, at the end of cardiopulmonary bypass, and at 5, 12, 24, 48, and 72 hours after cardiopulmonary bypass., Results: At 5 hours after cardiopulmonary bypass, the S-100B values in groups B and C were significantly higher than the value in group A. Although the S-100B level decreased in group C during the first 5 hours after cardiopulmonary bypass, it increased thereafter (12 through 24 hours) and continued at a high level until the final measurement at 72 hours. At 12 hours after cardiopulmonary bypass, S-100B was significantly higher in group C than in group B. This late increase in S-100B was associated with radiologically detected abnormalities and cerebral damage., Conclusions: Serial measurement of serum S-100B protein in the initial 12 hours after cardiopulmonary bypass can be used to predict early postoperative brain injury.

Of the approximately 130 million births worldwide each year, four million infants will suffer from birth asphyxia and, of these, one million will die and a similar number will develop serious sequelae. Before being able to develop effective interventions, a better understanding of the pathophysiological mechanisms leading to brain injury and an early identification of babies at high risk for brain injury are required. This study tests the predictivity of traditional and new markers of foetal oxidative stress in relation to neurodevelopmental outcome in 384 newborn infants. The results indicate plasma non protein bound iron as the best early predictive marker of neurodevelopmental outcome, with 100% sensitivity and 100% specificity for good neurodevelopmental outcome at 0-1.16 micro mol/l, and for poor neurodevelopmental outcome at values >15.2 micro mol/l. The number of children with values between 1.16 and 15.2 were 195. Common use of this predictive marker in neonatology units will improve the ability of clinicians to identify those newborn babies who will develop neurodisability.

This prospective clinical study was conducted to determine whether S 100 B is a reliable serum marker for traumatic brain injury (TBI) with and without multiple trauma. Fifty-five trauma patients (Injury Severity Score [ISS] > or = 24 and Glasgow Coma Score [GCS] < or = 8) were classified by radiography, computer tomography, ultrasound, and neurology as TBI without multiple trauma (n = 23), TBI with multiple trauma (n = 23), or multiple trauma without TBI (n = 9). S 100 B was measured initially after trauma and daily for a maximum of 21 days. Both survivors and nonsurvivors had markedly increased S 100 B initially. All survivors returned to normal or moderately increased S 100 B levels within the first 48 h after trauma. In contrast, all nonsurvivors of isolated TBI had S 100 B values that either increased consistently or dropped and then increased again 48 h after the initial increase after trauma. There was no relationship between localization, extent, or severity of TBI and S 100 B. According to receiver operating characteristic curve analysis and calculation of the area under the curve (AUC), S 100 B is equally accurate for mortality prediction at 24, 48, and 72 h after trauma and is most accurate >84 h after trauma. Sensitivity/specificity for mortality prediction are more accurate in TBI without multiple trauma (AUC 0.802-0.971) than in TBI with multiple trauma (AUC 0.693-0.783). Thus, though S 100 B may be a reliable marker of brain damage in TBI without multiple trauma 24 h after trauma and thereafter, it appears to be less reliable in TBI with multiple trauma.

Object: Hydrocephalus is characterised by elevated intracranial pressure (ICP) and gives rise to brain damage. The aim of this study was to investigate the significance of brain specific proteins as markers in the evaluation of brain damage in hydrocephalus. Therefore we determined the levels of four brain specific proteins in cerebrospinal fluid (CSF) and serum of symptomatic hydrocephalic patients., Methods: During 41 CSF shunt-operations (both primarily placed shunts and shunt-revisions) CSF and blood samples were obtained and analysed for neuron-specific enolase (NSE), S-100b, glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP). The results were compared with an age-matched control group. Patients with varying clinical symptoms, denoting different levels of increased intracranial pressure prior to surgery, were included in this study., Results: We observed significantly increased CSF-levels of S-100b and GFAP in the hydrocephalic patients, whereas NSE and MBP were markedly increased only in patients with very severe symptoms. Serum levels of all proteins were only minimally increased and did not correlate with CSF-levels. The slightly elevated levels of CSF-NSE in most of the patients suggest only subtle neuronal damage, which is not related to permanent neurological symptoms. The elevated levels of S-100b and GFAP are indicative of a reactive astrogliosis, which has also been demonstrated in histopathological studies. No demyelination seems to occur, according to the normal levels of MBP observed in this study., Conclusions: Although CSF levels of brain specific proteins are elevated in hydrocephalic patients, indicating brain damage due to hydrocephalus, neither CSF- nor serum-concentrations of brain specific proteins seem to be valuable tools in the clinical evaluation of the severity of hydrocephalus.

Background: Astrocyte protein S100beta is a potential serum marker for neurologic injury. The goals of this study were to determine whether elevated serum S100beta correlates with neurologic complications in patients requiring hypothermic circulatory arrest (HCA) during thoracic aortic repair, and to determine the impact of retrograde cerebral perfusion (RCP) on S100beta release in this setting., Methods: Thirty-nine consecutive patients underwent thoracic aortic repairs during HCA; RCP was used in 25 patients. Serum S100beta was measured preoperatively, after cardiopulmonary bypass, and 24 hours postoperatively., Results: Neurologic complications occurred in 3 patients (8%). These patients had higher postbypass S100beta levels (7.17 +/- 1.01 microg/L) than those without neurologic complications (3.63 +/- 2.31 microg/L, p = 0.013). Patients with S100beta levels of 6.0 microg/L or more had a higher incidence of neurologic complications (3 of 7, 43%) compared with those who had levels less than 6.0 microg/L (0 of 30, p = 0.005). Retrograde cerebral perfusion did not affect S100beta release., Conclusions: Serum S100beta levels of 6.0 microg/L or higher after HCA correlates with postoperative neurologic complications. Using serum S100beta as a marker for brain injury, RCP does not provide improved cerebral protection over HCA alone.

Background: Newborns undergoing cardiac operation may acquire some extent of neuronal damage. An early diagnosis is especially hard regarding neonates. In the past years, S-100 has been widely discussed as a marker revealing perioperative damage to the brain., Methods: Sequential blood samples from 33 neonates undergoing repair of congenital heart disease were taken perioperatively. Samples of 12 healthy neonates were taken at birth as a control group. The newborns were divided into four groups: cyanotic and acyanotic disease operated on in deep hypothermic circulatory arrest, operation without deep hypothermic cardiac arrest, and operation without extracorporeal circulation., Results: Even in healthy neonates, serum S-100 levels were at 10-fold values compared with adults. On admission, S-100 values in the operative groups were similar. During extracorporeal circulation, levels rose to a certain degree. Cyanotic newborns operated on in deep hypothermic cardiac arrest had significantly higher S-100 levels compared with acyanotic newborns also operated on in deep hypothermic cardiac arrest (p < 0.001). Two newborns who experienced seizures postoperatively had the highest absolute S-100 levels. One child with a poor neurologic outcome but no seizures did not have different values when compared with her group., Conclusions: In this study, S-100 seemed to be a possible marker for a certain degree of neurologic deficit after cardiac operation in neonates, especially regarding postoperative seizures. The missing peaks of this protein in one newborn with poor neurologic outcome show that it is not possible to exclude damage to the brain with normal postoperative values. These results suggest that the mechanism of cerebral damage and S-100 release into the blood in neonates with a developing central nervous system and blood-brain barrier is not fully understood.

Background: Cerebral injury is the most important complication of cardiac operations with cardiopulmonary bypass. Prolonged total circulatory arrest (TCA) can expose patients to an even greater risk of cerebral injury. We sought to detect the degree of cerebral injury in adults who had thoracic aortic operations with TCA by measuring S100B protein, which is released into the circulation after cerebral injury., Methods: Serial measurements of S100B protein, a highly specific serum marker of astroglial damage, were performed in 26 patients who had complex aortic operations, of whom 13 required cardiopulmonary bypass alone (for aortic root replacement), and in 13 patients who required an additional period of TCA (for type A aortic dissections and arch aneurysms). Blood samples were taken preoperatively, at skin closure, and 5 and 24 hours postoperatively., Results: There were significant increases in serum S100B concentrations in all patients, and peak levels occurred at skin closure. The magnitude of the increase in S100B was significantly greater at all postoperative time points and persisted longer in the TCA group. There was a significant correlation between the duration of the TCA and S100B concentration at 5 hours (r = 0.66, p = 0.01) and 24 hours (r = 0.63, p = 0.02) postoperatively., Conclusions: S100B levels were higher in all patients who had complex aortic operations and were significantly greater in patients requiring a period of TCA. The duration of the TCA period correlated with S100B levels 5 hours and at 24 hours postoperatively. Circumstantial evidence, in accordance with other studies, suggests that S100B protein is a marker for cerebral injury during cardiac operations.

Background and Purpose: The study aimed to investigate the predictive value of neurobiochemical markers of brain damage (protein S-100B and neuron-specific enolase [NSE]) with respect to early neurobehavioral outcome after stroke., Methods: We investigated 58 patients with completed stroke who were admitted to the stroke unit of the Department of Neurology at Magdeburg University. Serial venous blood samples were taken after admission and during the first 4 days, and protein S-100B and NSE were analyzed by the use of immunoluminometric assays. In all patients, lesion topography and vascular supply were analyzed and volume of infarcted brain areas was calculated. The neurological status was evaluated by a standardized neurological examination and the National Institutes of Health Stroke Scale (NIHSS) on admission, at days 1 and 4 on the stroke unit, at day 10, and at discharge from the hospital. Comprehensive neuropsychological examinations were performed in all patients with first-ever stroke event and supratentorial brain infarctions. Functional outcome was measured with the Barthel score at discharge from the hospital., Results: NSE and protein S-100B concentrations were significantly correlated with both volume of infarcted brain areas and NIHSS scores. Patients with an adverse neurological outcome had a significantly higher and significantly longer release of both markers. Neuropsychological impairment was associated with higher protein S-100B release, but this did not reach statistical significance., Conclusions: Serum concentrations and kinetics of protein S-100B and NSE have a high predictive value for early neurobehavioral outcome after acute stroke. Protein S-100B concentrations at days 2 to 4 after acute stroke may provide valuable information for both neurological status and functional impairment at discharge from the acute care hospital.

The intercellular adhesion molecule-1 (ICAM-1) expressed by endothelial cells is crucial in promoting adhesion and transmigration of circulating leukocytes across the blood-brain barrier (BBB). Migrated immunocompetent cells, in turn, release mediators that stimulate glial and endothelial cells to express ICAM-1 and release cytokines, possibly sustaining cerebral damage. Following activation, proteolytic cleavage of membrane-anchored ICAM-1 results in measurable levels of a soluble form, sICAM-1. The aims of this study were to investigate the changes of sICAM-1 levels in ventricular CSF and serum and to elucidate the influence of structural brain damage as estimated by computerized tomography (CT) as well as the extent of BBB dysfunction as calculated by the CSF/serum albumin ratio (QA) in patients with severe traumatic brain injury (TBI). All investigated parameters revealed two subgroups. Patients belonging to group A had sICAM-1 levels in CSF above normal range, presented marked cerebral damage and a disturbance of the BBB (range 0.6-24.7 ng/ml, n = 8). In contrast, patients belonging to group B had no elevation of sICAM-1 values in CSF (range 0.3-3.9 ng/ml, n = 5; p < 0.017) and showed minor cerebral damage with an intact BBB in most cases. In addition, overall analysis showed that sICAM-1 in CSF correlated with the extent of BBB damage as indicated by the QA (r = 0.76; p < 0.001). These results suggest that increased sICAM-1 levels in CSF might depict ongoing immunologic activation and that sICAM-1 correlates with the extent of tissue and BBB damage. The origin of soluble ICAM-1 in CSF and its pathophysiologic role after TBI remains to be clarified.

Aims: The objectives of this study were to determine the effect of brain trauma on the multiple pathways of metabolism of valproate and to evaluate the use of the urinary 6beta-hydroxycortisol to cortisol ratio in predicting changes in hepatic metabolism induced by brain injury., Methods: Fourteen patients with severe head injuries received a 15 mg kg(-1) loading dose and a maintenance dose of valproate to maintain therapeutic plasma concentrations. A minimum of one steady state trough blood sample and one dosage interval urine were collected during days 3-6 and during days 7-14 post-injury. Total and unbound valproate plasma concentrations were determined by gas chromatography-flame ionization detection (GC-FID) with and without ultrafiltration. Urinary valproate metabolites were measured by gas chromatography/mass spectrometry (GC-MS) (n = 10). Urinary 6beta-hydroxycortisol and cortisol concentrations were determined by high performance liquid chromatography (h.p.l.c.) (n = 14). Total intrinsic clearance (CL[int]) for valproate and individual formation clearances (CL[f]) to its major metabolites were calculated. Data obtained during baseline (days 3-6) were averaged for each patient and were compared with averaged data obtained from days 7 to 14 using a paired t-test., Results: Statistically significant increases in the CL(int), CL(f) of VPA glucuronide, 2-ene-VPA, and 4-OH-VPA pathways and the 6beta-hydroxycortisol to cortisol ratio were found. The percent change in the 6beta-hydroxycortisol to cortisol ratio correlated significantly with the changes in the CL(int) of valproate., Conclusions: Brain trauma results in induction of multiple pathways of valproate metabolism and increases in the 6beta-hydroxycortisol to cortisol ratio, suggesting a non-specific enzyme induction in response to head injury.

The objective of our study was to investigate the association between the initial levels of serum S-100B protein and neuron specific enolase and the severity of radiologically visible brain damage and outcome after severe head injury. Admission computed tomography (CT) scans of forty-four patients with severe head injury were analysed. Initial levels of S-100B protein and neuron specific enolase were compared between the different outcome groups at 6 month, the different categories of the Marshall classification, the presence of traumatic subarachnoid haemorrhage, the type of haematoma and the volume of contusion. Serum S-100B was significantly higher in patients with unfavourable outcome (1.1 micrograms/l versus 0.3 microgram/l, p < 0.005, Mann-Whitney U test). In diffuse injury, unfavourable outcome significantly increased with higher Marshall grades (p < 0.05). There was a significant correlation between the four grades of diffuse injury and initial serum S-100B protein (r = 0.48, p < 0.001). Patients with focal mass lesions and a favourable outcome after 6 month had significantly lower S-100B values than those who had an unfavourable outcome (0.51 microgram/l versus 1.3 micrograms/l, p < 0.05). A significant correlation was demonstrated between the volume of contusion visible on CT scans and serum S-100B (r = 0.58, p < 0.001). In our study, initial serum S-100B protein was a powerful predictor of outcome even within the same category of radiologically visible brain damage. Serum S-100B protein may provide independent information about the severity of primary brain damage after head injury.

To determine the influence of baseline paCO2 on the results of apnea testing in the diagnosis of brain death, we performed an open prospective study on 36 patients fulfilling all other criteria for the diagnosis of brain death according to the criteria proposed by the Advisory Board of the German Federal Chamber of Physicians. For testing of apnea, patients underwent hypoventilation with 100% oxygen supply until a baseline paCO2 of 40 torr (5.3 kPa, n = 24, group 1) or 60 torr (8.0 kPa, n = 12, group 2) was reached. Then, patients were disconnected from the ventilator and apneic oxygenation with insufflation of 61 O2/min into the tracheal cannula was performed for five minutes. Arterial blood gas samples were obtained every minute during the testing period. In parallel, patients were observed for signs of spontaneous breathing. All patients remained apneic during the five minute test period. No relevant hypoxia (paO2 < 80 torr [10.6 kPa]) was observed in either group. In group 1, a mean baseline paCO2 of 45 torr (6.0 kPa) was registered, mean end-paCO2 was 75 torr (10.0 kPa). In group 2, paCO2 values were 66 torr (8.8 kPa) and 90 torr (12 kPa), respectively. Baseline pH in group 1 (7.32) decreased to 7.18 at the end of testing and from 7.23 to 7.13 in group 2. Patients in group 2 were in possible danger of developing a CO2-induced narcosis mimicking apnea. Secondary organ damage due to severe respiratory acidosis could not be excluded in the patients of group 2. As no complications were observed in group 1 and apnea was evident in all these patients, we consider a baseline paCO2 of 40 torr (5.3 kPa) sufficient to establish apnea after five minutes of apneic oxygenation if an increase of baseline paCO2 of at least 20 mmHg is documented by arterial blood gas sampling. A higher baseline paCO2 may endanger patients without yielding more specific testing results.

Background and Purpose: Elevations of protein S-100 (S-100) in cerebrospinal fluid and serum have been reported after cerebral infarctions. The aim of our study was to evaluate the time course of serum S-100 concentrations after territorial middle cerebral artery (MCA) infarctions in correlation with clinical data and prognosis., Methods: S-100 serum levels were serially determined in 26 patients with an acute infarction in the territory of the MCA at day 0 (within 12 hours after onset of symptoms), day 1 (24 hours after stroke onset), and days 2, 3, 4, 5, 7 or 8, and 10 after stroke and in 26 age- and sex-matched control subjects. S-100 assays were performed using a two-site radioimmunoassay technique. The clinical status was documented using the Scandinavian Stroke Scale. The functional deficit 4 weeks after stroke onset was scored by use of the modified Rankin scale. A cranial computed tomography (CCT) was performed initially and at day 4 or 5., Results: Elevated concentrations of S-100 (> 0.2 microgram/L) were observed in 21 of 26 patients with MCA infarction but in none of the control subjects. S-100 levels peaked at days 2 and 3 after stroke. The S-100 concentrations in serum were significantly higher in patients with severe neurological deficits at admission, with extensive infarctions and a space-occupying effect of ischemic edema as compared with the rest of the population. S-100 values were not significantly correlated with the functional prognosis., Conclusions: Presence of S-100 in serum after ischemic stroke may be due to combined leakage out of necrotic glial cells and passage through an impaired brain-blood barrier, indicating severe ischemic cell injury. Therefore, S-100 in serum can be used as a peripheral marker of ischemic focal brain damage and may be helpful for therapeutic decisions in acute ischemic stroke.

Protein S-100 is a calcium binding protein, synthetized in astroglial cells in all parts of the central nervous system (CNS). We have previously reported high serum levels of protein S-100 in patients after minor head injury (MHI). A battery of conventional and computerized neuropsychological measures was administered to two groups of MHI patients. Neuropsychological outcome at 12 months postinjury was examined in a group of 7 patients with increased serum levels of protein S-100 after MHI and 7 age- and sex-matched controls without detectable S-100 in serum after MHI. Our results demonstrate no overall cognitive dysfunction in either of the two groups. Our findings indicate specific dysfunction on measures of reaction time, attention and speed of information processing for the S-100 group. Posttraumatic depression does not explain the neuropsychological differences between the groups. These findings support that increased serum levels of protein S-100 may be of predictive and prognostic value for longlasting neurocognitive abnormalities after minor head injury. Presence of S-100 in serum may indicate the presence of diffuse brain damage. Our results suggest that information processing measures in computerized neuropsychological assessment are more sensitive for detecting small signs of neurocognitive abnormalities after MHI than conventional test batteries.

Purpose: To identify a pattern of findings on CT or MR of the brain in glutaric acidemia type I typical enough to permit a correct diagnosis., Methods: Clinical history and findings and brain CT and MR results in 59 previously reported patients (MR in 12) and in 5 new patients (all examined with MR and 3 also with CT) were reviewed., Results: In half the patients macrocephaly was present, and in half the onset was acute, often following infection and mimicking encephalitis. Although brain atrophy or hypoplasia was found in 61% and white matter changes in 51% of the patients, open opercula (usually very widely open) and often also wide cerebrospinal fluid spaces anterior to the temporal lobes were seen in 93%. Basal ganglia lesions, presenting as volume loss and high T2 signal in the caudate head and often also the lentiform nucleus bilaterally, were found in 44% and extracerebral fluid collections in 7 of 64 patients., Conclusion: The finding of very widely open opercula suggests glutaric acidemia type I, and if combined with basal ganglia lesions is almost pathognomonic, especially in a child with macrocephaly.

Background and Purpose: The aim of this study was to characterize the response of the hypothalamic-pituitary-adrenal system in the first hours of ischemic stroke and to relate its extent to the occurrence of acute confusional state, volume of brain damage, and clinical outcome., Methods: The secretion of corticotropin (adrenocorticotropic hormone [ACTH]) and cortisol was studied in 23 patients by determinations at hours 4, 6, 8, 10, and 14 and days 1, 3, 5, and 7 after onset of symptoms. Acute confusional state (DSM-III-R criteria), extent of lesion (volumetry of computed tomographic scans), and neurological and functional outcome (Scandinavian Stroke Scale, Barthel Index scores) were assessed., Results: The massive neuroendocrine response observed consisted of an initial phase with concomitantly increased levels of ACTH and cortisol and a second phase with decreased levels of ACTH while high concentrations of cortisol persisted. Initial levels of ACTH but not cortisol were significantly increased in patients with acute confusional state and significantly correlated with volume of brain lesion and neurological and functional outcome., Conclusions: An early and persisting activation of the hypothalamic-pituitary-adrenal axis was observed in relation to severity of disease. Its characteristic biphasic pattern suggests an initial central stimulation of release of ACTH followed by feedback suppression concomitant with an increased susceptibility of the adrenal gland. Because these hormones are known to exacerbate hypoxic injury to neurons, their massive release in hyperacute stroke may increase the extent of brain damage.