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Children who have sustained severe traumatic brain injuries (TBIs) demonstrate a range of post-injury neurocognitive and behavioral sequelae, which may have adverse effects on their academic and behavioral outcomes and interfere with school re-entry, educational progress, and quality of life. These post-TBI sequelae are exacerbated within the context of a resource-poor country like South Africa (SA) where the education system is in a somewhat precarious state especially for those from disadvantaged backgrounds. To describe behavioral and academic outcomes of a group of school-aged SA children following severe TBI. The sample included 27 school-age children who were admitted to the Red Cross War Memorial Children's Hospital (RXH), SA, between 2006 and 2011 for closed severe TBI and who received intracranial monitoring. We collected behavioral data using the Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function (BRIEF) and academic information sourced from the BRIEF, CBCL, medical folders, and caregivers. Analyses include descriptive statistics and bivariate correlation matrices. The descriptive results show that (1) more than half of the participants experienced clinically-significant behavioral problems across the CBCL scales, (2) the working memory BRIEF subscale appeared to be the most problematic subdomain, (3) two thirds of the sample were receiving some form of, or were in the process of being placed in, special needs education, (4) there was a three-fold increase in the use of special education services from pre- to post-injury, and (5) more than half ( = 16) of the sample repeated at least one grade after returning to school post-injury. Correlation analyses results suggest that children with increased externalizing behavioral problems and executive dysfunction are more likely to repeat a grade post-injury; and that children with executive dysfunction post-TBI are more likely to require some form of special educational services. While there is a vast amount of literature on pediatric TBI (pTBI) academic and behavioral outcomes, little literature exists on the pTBI population from the developing world and SA specifically. This is important to address given unique challenges that face the country and its educational system, and its implications for the management and care of children post-TBI.

Background. Tuberculous meningitis (TBM) leads to death or disability in half the affected individuals. Tools to assess severity and predict outcome are lacking. Neurospecific biomarkers could serve as markers of the severity and evolution of brain injury, but have not been widely explored in TBM. We examined biomarkers of neurological injury (neuromarkers) and inflammation in pediatric TBM and their association with outcome. Methods. Blood and cerebrospinal fluid (CSF) of children with TBM and hydrocephalus taken on admission and over 3 weeks were analyzed for the neuromarkers S100B, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), in addition to multiple inflammatory markers. Results were compared with 2 control groups: patients with (1) a fatty filum (abnormal filum terminale of the spinal cord); and (2) pulmonary tuberculosis (PTB). Imaging was conducted on admission and at 3 weeks. Outcome was assessed at 6 months. Results. Data were collected from 44 patients with TBM (cases; median age, 3.3 [min–max 0.3–13.1] years), 11 fatty filum controls (median age, 2.8 [min–max 0.8–8] years) and 9 PTB controls (median age, 3.7 [min–max 1.3–11.8] years). Seven cases (16%) died and 16 (36%) had disabilities. Neuromarkers and inflammatory markers were elevated in CSF on admission and for up to 3 weeks, but not in serum. Initial and highest concentrations in week 1 of S100B and NSE were associated with poor outcome, as were highest concentration overall and an increasing profile over time in S100B, NSE, and GFAP. Combined neuromarker concentrations increased over time in patients who died, whereas inflammatory markers decreased. Cerebral infarcts were associated with highest overall neuromarker concentrations and an increasing profile over time. Tuberculomas were associated with elevated interleukin (IL) 12p40, interferon-inducible protein 10, and monocyte chemoattractant protein 1 concentrations, whereas infarcts were associated with elevated tumor necrosis factor α, macrophage inflammatory protein 1α, IL-6, and IL-8. Conclusions. CSF neuromarkers are promising biomarkers of injury severity and are predictive of mortality. An increasing trend suggested ongoing brain injury, even though markers of inflammation declined with treatment. These findings could offer novel insight into the pathophysiology of TBM.

Tuberculous meningitis causes death or disability in approximately 50% of affected individuals and kills approximately 78 200 adults every year. Antimicrobial treatment is based on regimens used for pulmonary tuberculosis, which overlooks important differences between lung and brain drug distributions. Tuberculous meningitis has a profound inflammatory component, yet only adjunctive corticosteroids have shown clear benefit. There is an active pipeline of new antitubercular drugs, and the advent of biological agents targeted at specific inflammatory pathways promises a new era of improved tuberculous meningitis treatment and outcomes. Yet, to date, tuberculous meningitis trials have been small, underpowered, heterogeneous, poorly generalisable, and have had little effect on policy and practice. Progress is slow, and a new approach is required. In this Personal View, a global consortium of tuberculous meningitis researchers articulate a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes for this life-threatening infection.

Central nervous system (CNS) infections present a major burden of disease worldwide and are associated with high rates of mortality and morbidity. Swift diagnosis and initiation of appropriate treatment are vital to minimize the risk of poor outcome; however, tools are lacking to accurately diagnose infection, assess injury severity, and predict outcome. Biomarkers of structural neurological injury could provide valuable information in addressing some of these challenges. In this review, we summarize experimental and clinical research on biomarkers of neurological injury in a range of CNS infectious diseases. Data suggest that in both adults and children, the biomarkers S100B and neuron-specific enlose (NSE), among others, can provide insight into the pathophysiology of CNS infection and injury severity, evolution, and response to treatment. Research into the added utility of combining a panel of biomarkers and in assessing biomarker association with clinical and radiological outcomes warrants further work. Various factors, including age, the establishment of normative values, and comparison of biomarker concentrations across different testing platforms still present challenges in biomarker application. Research regarding the value of biomarkers in CNS infections is still in its infancy. However, early evidence supports their utility in diagnosis and prognosis, and potentially as effective surrogate end points in the assessment of novel interventions.

The assessment and management of tuberculous meningitis (TBM) is often complex, yet no standardised approach exists, and evidence for the clinical care of patients, including those with critical illness, is limited. The roles of proformas and checklists are increasing in medicine; proformas provide a framework for a thorough approach to patient care, whereas checklists offer a priority-based approach that may be applied to deteriorating patients in time-critical situations. We aimed to develop a comprehensive assessment proforma and an accompanying ‘priorities’ checklist for patients with TBM, with the overriding goal being to improve patient outcomes. The proforma outlines what should be asked, checked, or tested at initial evaluation and daily inpatient review to assist supportive clinical care for patients, with an adapted list for patients in critical care. It is accompanied by a supporting document describing why these points are relevant to TBM. Our priorities checklist offers a useful and easy reminder of important issues to review during a time-critical period of acute patient deterioration. The benefit of these documents to patient outcomes would require investigation; however, we hope they will promote standardisation of patient assessment and care, particularly of critically unwell individuals, in whom morbidity and mortality remains unacceptably high.

Evidence-based analgosedation in severe pediatric traumatic brain injury (pTBI) management is lacking, and improved pharmacological understanding is needed. This starts with increased knowledge of factors controlling the pharmacokinetics (PK) of unbound drug at the target site (brain) and related drug effect(s). This prospective, descriptive study tested a pediatric physiology-based pharmacokinetic software model by comparing actual plasma and brain extracellular fluid (brainECF) morphine concentrations with predicted concentration-time profiles in severe pTBI patients (Glasgow Coma Scale [GCS], ≤8). Plasma and brainECF samples were obtained after legal guardian written consent and were collected from 8 pTBI patients (75% male; median age, 96 months [34.0–155.5]; median weight, 24 kg [14.5–55.0]) with a need for intracranial pressure monitoring (GCS, ≤8) and receiving continuous morphine infusion (10–40 μg/kg/h). BrainECF samples were obtained by microdialysis. BrainECF samples were taken from “injured” and “uninjured” regions as determined by microdialysis catheter location on computed head tomography. A previously developed physiology-based software model to predict morphine concentrations in the brain was adapted to children using pediatric physiological properties. The model predicted plasma morphine concentrations well for individual patients (97% of data points within the 90% prediction interval). In addition, predicted brainECF concentration-time profiles fell within a 90% prediction interval of microdialysis brainECF drug concentrations when sampled from an uninjured area. Prediction was less accurate in injured areas. This approach of translational physiology-based PK modeling allows prediction of morphine concentration-time profiles in uninjured brain of individual patients and opens promising avenues towards evidence-based pharmacotherapies in pTBI.

Abstract BACKGROUND: Intracranial pressure (ICP) monitoring is a cornerstone of care for severe traumatic brain injury (TBI). Management of ICP can help ensure adequate cerebral blood flow and oxygenation. However, studies indicate that brain hypoxia may occur despite normal ICP and the relationship between ICP and brain oxygenation is poorly defined. This is particularly important for children in whom less is known about intracranial dynamics. OBJECTIVE: To examine the relationship between ICP and partial pressure of brain tissue oxygen (PbtO2) in children with severe TBI (Glasgow Coma Scale score ⩽8) admitted to Red Cross War Memorial Children's Hospital, Cape Town. METHODS: The relationship between time-linked hourly and high-frequency ICP and PbtO2 data was examined using correlation, regression, and generalized estimating equations. Thresholds for ICP were examined against reduced PbtO2 using age bands and receiver-operating characteristic curves. RESULTS: Analysis using more than 8300 hourly (n = 75) and 1 million high-frequency data points (n = 30) demonstrated a weak relationship between ICP and PbtO2 (r = 0.05 and r = 0.04, respectively). No critical ICP threshold for low PbtO2 was identified. Individual patients revealed a strong relationship between ICP and PbtO2 at specific times, but different relationships were evident over longer periods. CONCLUSION: The relationship between ICP and PbtO2 appears complex, and several factors likely influence both variables separately and in combination. Although very high ICP is associated with reduced PbtO2, in general, absolute ICP has a poor relationship with PbtO2. Because reduced PbtO2 is independently associated with poor outcome, a better understanding of ICP and PbtO2 management in pediatric TBI seems to be needed.

Background This study examines the effect of an increase in the inspired fraction of oxygen (FiO 2 ) on brain tissue oxygen (PbO 2 ) in children with severe traumatic brain injury (TBI). Methods A prospective observational study of patients who underwent PbO 2 monitoring and an oxygen challenge test (temporary increase of FiO 2 for 15 min) was undertaken. Pre- and post-test values for arterial partial pressure of oxygen (PaO 2 ), PbO 2 , and arterial oxygen content (CaO 2 ) were examined while controlling for any changes in arterial carbon dioxide tension and cerebral perfusion pressure during the test. Baseline transcranial Doppler studies were done. Outcome was assessed at 6 months. Results A total of 43 tests were performed in 28 patients. In 35 tests in 24 patients, the PbO 2 monitor was in normal-appearing white matter and in eight tests in four patients, the monitor was in a pericontusional location. When catheters were pericontusional or in normal white matter the baseline PbO 2 /PaO 2 ratio was similar. PaO 2 ( P  < 0.0001) and PbO 2 ( P  < 0.0001) significantly increased when FiO 2 was increased. The magnitude of the PbO 2 response (∆PbO 2 ) was correlated with ∆PaO 2 ( P  < 0.0001, R 2  = 0.37) and ∆CaO 2 ( P  = 0.001, R 2  = 0.23). The ∆PbO 2 /∆PaO 2 ratio (oxygen reactivity) varied between patients, was related to the baseline PbO 2 ( P  = 0.001, r  = 0.54) and was inversely related to outcome ( P  = 0.02, confidence interval 0.03–0.78). Conclusion Normobaric hyperoxia increases PbO 2 in children with severe TBI, but the response is variable. The magnitude of this response is related to the change in PaO 2 and the baseline PbO 2 . A greater response appears to be associated with worse outcome.

Most physicians rely on conventional treatment targets for intracranial pressure, cerebral perfusion pressure, systemic oxygenation, and hemoglobin to direct management of traumatic brain injury (TBI) in children. In this study, we used brain tissue oxygen tension (PbtO2) monitoring to examine the association between PbtO2 values and outcome in pediatric severe TBI and to determine the incidence of compromised PbtO2 in patients for whom acceptable treatment targets had been achieved. In this prospective observational study, 26 children with severe TBI and a median postresuscitation Glasgow Coma Scale score of 5 were managed with continuous PbtO2 monitoring. The relationships between outcome and the 6-hour period of lowest PbtO2 values and the length of time that PbtO2 was less than 20, 15, 10, and 5 mmHg were examined. The incidence of reduced PbtO2 for each threshold was evaluated where the following targets were met: intracranial pressure less than 20 mmHg, cerebral perfusion pressure greater than 50 mmHg, arterial oxygen tension greater than 60 mmHg (and peripheral oxygen saturation > 90%), and hemoglobin greater than 8 g/dl. There was a significant association between poor outcome and the 6-hour period of lowest PbtO2 and length of time that PbtO2 was less than 15 and 10 mmHg. Multiple logistic regression analysis showed that low PbtO2 had an independent association with poor outcome. Despite achieving the management targets described above, 80% of patients experienced one or more episodes of compromised PbtO2 (< 20 mmHg), and almost one-third experienced episodes of brain hypoxia (PbtO2 < 10 mmHg). Reduced PbtO2 is associated with poor outcome in pediatric severe TBI. In addition, many patients experience episodes of compromised PbtO2 despite achieving acceptable treatment targets.

Background Diagnosing brain death in children is challenging. Guidelines recommend using confirmatory testing to provide ancillary information to support the diagnosis. Brain tissue oxygenation (PbtO 2 ) is being increasingly used in the adult neurocritical care for continuous monitoring of the adequacy of brain oxygenation; however, data in pediatrics is limited. Evidence from adult studies suggests that persistent PbtO 2 of 0 mmHg is associated with brain death, but this relationship has not yet been demonstrated in children; therefore, we examined our experience with PbtO 2 monitoring and brain death in children with acute neurological pathology. Methods We retrospectively reviewed patient records from a prospectively maintained database of 85 children who were ventilated for coma due to acute neurological injury and who received intracerebral monitoring. Results We identified five children who had suffered brain death while being monitored. PbtO 2 had decreased to 0 mmHg in all five children at the time of brain death diagnosis. In contrast, PbtO 2 in patients, who did not develop brain death, never decreased to 0 mmHg. We review the benefits and drawbacks of using brain tissue oxygenation as ancillary information in diagnosing brain death in children. Conclusions Preliminary data from this study suggest that PbtO 2 decreases to 0 mmHg when brain death occurs in children. Further study is needed to determine the limitations, and the sensitivity and specificity of this finding in a larger group of children.