Time-Dependent Changes in the Biofluid Levels of Neural Injury Markers in Severe Traumatic Brain Injury Patients-Cerebrospinal Fluid and Cerebral Microdialysates: A Longitudinal Prospective Pilot Study.

Monitoring protein biomarker levels in the cerebrospinal fluid (CSF) can help assess injury severity and outcome after traumatic brain injury (TBI). Determining injury-induced changes in the proteome of brain extracellular fluid (bECF) can more closely reflect changes in the brain parenchyma, but bECF is not routinely available. The aim of this pilot study was to compare time-dependent changes of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), total Tau, and phosphorylated Tau (p-Tau) levels in matching CSF and bECF samples collected at 1, 3, and 5 days post-injury from severe TBI patients (n = 7; GCS 3-8) using microcapillary-based western analysis. We found that time-dependent changes in CSF and bECF levels were most pronounced for S100B and NSE, but there was substantial patient-to-patient variability. Importantly, the temporal pattern of biomarker changes in CSF and bECF samples showed similar trends. We also detected two different immunoreactive forms of S100B in both CSF and bECF samples, but the contribution of the different immunoreactive forms to total immunoreactivity varied from patient to patient and time point to time point. Our study is limited, but it illustrates the value of both quantitative and qualitative analysis of protein biomarkers and the importance of serial sampling for biofluid analysis after severe TBI.

Bringing rehabilitation home with an e-health platform to treat stroke patients: study protocol of a randomized clinical trial (RGS@home).

BACKGROUND: There is a pressing need for scalable healthcare solutions and a shift in the rehabilitation paradigm from hospitals to homes to tackle the increase in stroke incidence while reducing the practical and economic burden for patients, hospitals, and society. Digital health technologies can contribute to addressing this challenge; however, little is known about their effectiveness in at-home settings. In response, we have designed the RGS@home study to investigate the effectiveness, acceptance, and cost of a deep tech solution called the Rehabilitation Gaming System (RGS). RGS is a cloud-based system for delivering AI-enhanced rehabilitation using virtual reality, motion capture, and wearables that can be used in the hospital and at home. The core principles of the brain theory-based RGS intervention are to deliver rehabilitation exercises in the form of embodied, goal-oriented, and task-specific action. METHODS: The RGS@home study is a randomized longitudinal clinical trial designed to assess whether the combination of the RGS intervention with standard care is superior to standard care alone for the functional recovery of stroke patients at the hospital and at home. The study is conducted in collaboration with hospitals in Spain, Sweden, and France and includes inpatients and outpatients at subacute and chronic stages post-stroke. The intervention duration is 3 months with assessment at baseline and after 3, 6, and 12 months. The impact of RGS is evaluated in terms of quality of life measurements, usability, and acceptance using standardized clinical scales, together with health economic analysis. So far, one-third of the patients expected to participate in the study have been recruited (N = 90, mean age 60, days after stroke ≥ 30 days). The trial will end in July 2023. DISCUSSION: We predict an improvement in the patients' recovery, high acceptance, and reduced costs due to a soft landing from the clinic to home rehabilitation. In addition, the data provided will allow us to assess whether the prescription of therapy at home can counteract deterioration and improve quality of life while also identifying new standards for online and remote assessment, diagnostics, and intervention across European hospitals. TRIAL REGISTRATION: C linicalTrials.gov NCT04620707. Registered on November 3, 2020.

Influence of Blood-Brain Barrier Integrity on Brain Protein Biomarker Clearance in Severe Traumatic Brain Injury: A Longitudinal Prospective Study.

Brain protein biomarker clearance to blood in traumatic brain injury (TBI) is not fully understood. The aim of this study was to analyze the effect that a disrupted blood-brain barrier (BBB) had on biomarker clearance. Seventeen severe TBI patients admitted to Karolinska University Hospital were prospectively included. Cerebrospinal fluid (CSF) and blood concentrations of S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) were analyzed every 6-12 h for ∼1 week. Blood and CSF albumin were analyzed every 12-24 h, and BBB integrity was assessed using the CSF:blood albumin quotient (QA). We found that time-dependent changes in the CSF and blood levels of the two biomarkers were similar, but that the correlation between the biomarkers and QA was lower for NSE (ρ = 0.444) than for S100B (ρ = 0.668). Because data were longitudinal, we also conducted cross correlation analyses, which indicated a directional flow and lag-time of biomarkers from CSF to blood. For S100B, this lag-time could be ascribed to BBB integrity, whereas for NSE it could not. Upon inferential modelling, using generalized least square estimation (S100B) or linear mixed models (NSE), QA (p = 0.045), time from trauma (p < 0.001), time from trauma2 (p = 0.023), and CSF biomarker levels (p = 0.008) were independent predictors of S100B in blood. In contrast, for NSE, only time from trauma was significant (p < 0.001). These findings are novel and important, but must be carefully interpreted because of different characteristics between the two proteins. Nonetheless, we present the first data that indicate that S100B and NSE are cleared differently from the central nervous system, and that both the disrupted BBB and additional alternative pathways, such as the recently described glymphatic system, may play a role. This is of importance both for clinicians aiming to utilize these biomarkers and for the pathophysiological understanding of brain protein clearance, but warrants further examination.

Neuron-Specific Enolase Is Correlated to Compromised Cerebral Metabolism in Patients Suffering from Acute Bacterial Meningitis; An Observational Cohort Study.

INTRODUCTION: Patients suffering from acute bacterial meningitis (ABM) with a decreased level of consciousness have been shown to have an improved clinical outcome if treated with an intracranial pressure (ICP) guided therapy. By using intracranial microdialysis (MD) to monitor cerebral metabolism in combination with serum samples of biomarkers indicating brain tissue injury, S100B and Neuron Specific Enolase (NSE), additional information might be provided. The aim of this study was to evaluate biomarkers in serum and MD parameters in patients with ABM. METHODS: From a prior study on patients (n = 52) with a confirmed ABM and impaired consciousness (GCS ≤ 9, or GCS = 10 combined with lumbar spinal opening pressure > 400 mmH2O), a subgroup of patients (n = 21) monitored with intracerebral MD and biomarkers was included in the present study. All patients were treated in the NICU with intracranial pressure (ICP) guided therapy. Serum biomarkers were obtained at admission and every 12 hours. The MD parameters glucose, lactate, pyruvate and glycerol were analyzed. Outcome was assessed at 12-55 months after discharge from hospital. Mann-Whitney U-Test and Wilcoxon matched-pairs signed rank test were applied. RESULTS: The included patients had a mean GCS of 8 (range, 3-10) on admission and increased ICP (>20 mmHg) was observed in 62% (n = 13/21) of the patients. Patients with a lactate:pyruvate ratio (LPR) >40 (n = 9/21, 43%) had significantly higher peak levels of serum NSE (p = 0.03), with similar, although non-significant observations made in patients with high levels of glycerol (>500 µmol/L, p = 0.11) and those with a metabolic crisis (Glucose <0.8 mmol/L, LPR >25, p = 0.09). No associations between serum S100B and MD parameters were found. Furthermore, median MD glucose levels decreased significantly between day 1 (0-24 h) and day 3 (48-72 h) after admission to the NICU (p = 0.0001). No correlation between MD parameters or biomarkers and outcome was found. CONCLUSION: In this observational cohort study, we were able to show that cerebral metabolism is frequently affected in patients with ABM. Furthermore, patients with high LPR (LPR>40) had significantly higher levels of NSE, suggesting ongoing deterioration in compromised cerebral tissue. However, the potential clinical impact of MD and biomarker monitoring in ABM patients will need to be further elaborated in larger clinical trials.

Sensitization to omeprazole in the occupational setting.

BACKGROUND: Omeprazole is a proton pump inhibitor for the treatment of gastric acid-related disorders. In recent years, reports of dermatitis upon exposure to omeprazole during manufacture have been noted. OBJECTIVE: To present diagnostic findings in workers who reported suspected hypersensitivity reactions resulting from occupational exposure to omeprazole. METHODS: Ninety-six workers exposed to omeprazole during the manufacturing process underwent investigation by the AstraZeneca Occupational Health Centre (Södertälje, Sweden) for suspected allergy. All subjects underwent a lymphocyte transformation test (LTT) and a skin test within 6 months of the clinical reaction. Predictive tests on guinea-pigs were conducted to establish omeprazole's sensitizing potential. RESULTS: Thirty-one subjects with clinical symptoms had a positive LTT result. Twenty-eight subjects had positive patch test results; of these, 23 also had a positive LTT result (sensitivity of the LTT: 82%). Fifty-six subjects had negative patch test results; 46 of these had a negative LTT result (specificity: 82%). All subjects who underwent prick testing (n = 18) had negative results. Delayed contact hypersensitivity was observed in 18 of 20 test animals. CONCLUSIONS: These findings confirm the risk of sensitization to omeprazole from occupational exposure. They are of importance for the development of new formulations of omeprazole, or its enantiomers, in light of the potential for inducing skin allergy.

Microdialysis Monitoring of CSF Parameters in Severe Traumatic Brain Injury Patients: A Novel Approach.

BACKGROUND: Neuro-intensive care following traumatic brain injury (TBI) is focused on preventing secondary insults that may lead to irreversible brain damage. Microdialysis (MD) is used to detect deranged cerebral metabolism. The clinical usefulness of the MD is dependent on the regional localization of the MD catheter. The aim of this study was to analyze a new method of continuous cerebrospinal fluid (CSF) monitoring using the MD technique. The method was validated using conventional laboratory analysis of CSF samples. MD-CSF and regional MD-Brain samples were correlated to patient outcome. MATERIALS AND METHODS: A total of 14 patients suffering from severe TBI were analyzed. They were monitored using (1) a MD catheter (CMA64-iView, n = 7448 MD samples) located in a CSF-pump connected to the ventricular drain and (2) an intraparenchymal MD catheter (CMA70, n = 8358 MD samples). CSF-lactate and CSF-glucose levels were monitored and were compared to MD-CSF samples. MD-CSF and MD-Brain parameters were correlated to favorable (Glasgow Outcome Score extended, GOSe 6-8) and unfavorable (GOSe 1-5) outcome. RESULTS: Levels of glucose and lactate acquired with the CSF-MD technique could be correlated to conventional levels. The median MD recovery using the CMA64 catheter in CSF was 0.98 and 0.97 for glucose and lactate, respectively. Median MD-CSF (CMA 64) lactate (p = 0.0057) and pyruvate (p = 0.0011) levels were significantly lower in the favorable outcome group compared to the unfavorable group. No significant difference in outcome was found using the lactate:pyruvate ratio (LPR), or any of the regional MD-Brain monitoring in our analyzed cohort. CONCLUSION: This new technique of global MD-CSF monitoring correlates with conventional CSF levels of glucose and lactate, and the MD recovery is higher than previously described. Increase in lactate and pyruvate, without any effect on the LPR, correlates to unfavorable outcome, perhaps related to the presence of erythrocytes in the CSF.

Neuro-intensive treatment targeting intracranial hypertension improves outcome in severe bacterial meningitis: an intervention-control study.

OBJECTIVE: To evaluate the efficacy of early intracranial pressure (ICP)-targeted treatment, compared to standard intensive care, in adults with community acquired acute bacterial meningitis (ABM) and severely impaired consciousness. DESIGN: A prospectively designed intervention-control comparison study of adult cases from September 2004 to January 2012. PATIENTS: Included patients were confirmed ABM-cases, aged 16-75 years, with severely impaired mental status on admission. Fifty-two patients, given ICP-targeted treatment at the neuro-intensive care unit, and 53 control cases, treated with conventional intensive care, were included. All the patients received intensive care with mechanical ventilation, sedation, antibiotics and corticosteroids according to current guidelines. Additional ICP-treatment in the intervention group included cerebrospinal fluid drainage using external ventricular catheters (n = 48), osmotherapy (n = 21), hyperventilation (n = 13), external cooling (n = 9), gram-doses of methylprednisolone (n = 3) and deep barbiturate sedation (n = 2) aiming at ICP <20 mmHg and a cerebral perfusion pressure of >50 mmHg. MEASUREMENTS: The primary endpoint was mortality at two months and secondary endpoint was Glasgow outcome score and hearing ability at follow-up at 2-6 months. OUTCOMES: The mortality was significantly lower in the intervention group compared to controls, 5/52 (10%) versus 16/53 (30%; relative risk reduction 68%; p<0.05). Furthermore, only 17 patients (32%) in the control group fully recovered compared to 28 (54%) in the intervention group (relative risk reduction 40%; p<0.05). CONCLUSIONS: Early neuro-intensive care using ICP-targeted therapy, mainly cerebrospinal fluid drainage, reduces mortality and improves the overall outcome in adult patients with ABM and severely impaired mental status on admission.

Secondary insults following traumatic brain injury enhance complement activation in the human brain and release of the tissue damage marker S100B.

OBJECT: Complement activation has been suggested to play a role in the development of secondary injuries following traumatic brain injury (TBI). The present study was initiated in order to analyze complement activation in relation to the primary brain injury and to secondary insults, frequently occurring following TBI. METHODS: Twenty patients suffering from severe TBI (Glasgow coma score ≤ 8) were included in the study. The "membrane attack complex," C5b9, which is the cytolytic end product of the complement system was analyzed in cerebrospinal fluid (CSF). The degree of brain tissue damage was assessed using the release of S100B and neuron-specific enolase (NSE) to the CSF and blood. The blood-brain barrier was assessed using the CSF/serum quotient of albumin (Q (A)). RESULTS: Following impact, initial peaks (0-48 h) of C5b9, S100B, and NSE with a concomitant loss of integrity of the blood-brain barrier were observed. Secondary insults at the intensive care unit were monitored. Severe secondary insults were paralleled by a more pronounced complement activation (C5b9 in CSF) as well as increased levels of S100B (measured in CSF), but not with NSE. CONCLUSION: This human study indicates that complement activation in the brain is triggered not only by the impact of trauma per se but also by the amount of secondary insults that frequently occur at the scene of accident as well as during treatment in the neurointensive care unit. Complement activation and in particular the end product C5b9 may in turn contribute to additional secondary brain injuries by its membrane destructive properties.

Suppressed neuroendocrine stress response in depressed women on job-stress-related long-term sick leave: a stable marker potentially suggestive of preexisting vulnerability.

BACKGROUND: We recently reported marked hyporeactivity of the hypothalamo-pituitary-adrenal (HPA) axis in depressed women on job-stress-related long-term sick leave (LTSL). This unexpected finding prompted the question of whether HPA axis hypofunction in this group results from stress exposure or reflects preexisting vulnerability. Here, as a first step toward addressing this question, we assessed temporal stability of HPA axis reactivity in these subjects. METHOD: We used the combined dexamethasone/corticotropin-releasing hormone (DEX-CRH) test to retest HPA axis reactivity in 29 patients and 27 control subjects after 12 months of follow-up. Clinical status and cognitive performance was also retested. RESULTS: Despite marked clinical improvement and normalization of initially observed impairments in attention and working memory, marked HPA axis hyporeactivity persisted in patients. A high test-retest correlation was found both at the level of corticotropin (R = .85, p < .001) and cortisol (R = .76, p < .001) responses. CONCLUSIONS: Hyporeactivity of the HPA was stable over 12 months in LTSL subjects, independent of clinical improvement and normalized cognitive function. The stability of this response over time suggests that decreased DEX-CRH responses in this group may be a trait rather than a state marker. This finding is compatible with a hypothesis that HPA axis hyporeactivity may reflect a preexisting vulnerability in these subjects.

Neuroendocrine, cognitive and structural imaging characteristics of women on longterm sickleave with job stress-induced depression.

BACKGROUND: A recent increase in long-term sick leave (LTSL) in Sweden affects mostly women in the public sector. Depression-related diagnoses account for most of the increase, and work-related stress has been implicated. METHODS: We examined dexamethasone/corticotropin-releasing hormone (dex/CRH) test responses, magnetic resonance imaging measures of prefrontocortical and hippocampal volumes, and cognitive performance in 29 female subjects fulfilling three core criteria: 1) LTSL > 90 days; 2) unipolar depression or maladaptive stress reaction with depressed mood; 3) job-related stress given as a reason for disability. This group was compared with 28 healthy matched controls. RESULTS: The cortisol response to CRH differed markedly between the two groups (p = .002), with a dampened response in patients. This difference remained after removing subjects on antidepressant drugs (p = .006) or smokers (p = .003). Neither hippocampal nor prefrontocortical volumes differed. Performance on hippocampus-dependent declarative memory tests did not differ between groups, but the LTSL group had impaired working memory. CONCLUSIONS: Our most salient finding is an attenuated dex-CRH response in patients on LTSL due to job-stress related depression. This is opposite to what has been described in major depression. It remains to be established whether this impairment is the end result of prolonged stress exposure, or a pre-existing susceptibility factor.