Rifampicin and protein concentrations in paired spinal versus ventricular cerebrospinal fluid samples of children with tuberculous meningitis.

BACKGROUND: Tuberculous meningitis (TBM) is the most lethal form of TB. To study the disease, drug concentrations in samples obtained from the spinal CSF are usually used to reflect brain concentrations. Emerging data suggest that transport of substances across capillaries in the brain (ventricular CSF) and spinal cord may differ. METHODS: We examined paired, time-linked samples of ventricular CSF (VCSF) and lumbar CSF (LCSF) of 28 patients with TBM and analysed these for rifampicin and total protein concentrations. Clinically indicated samples from procedures to determine the level of CSF block were collected from children being treated for TBM and hydrocephalus. Total protein concentrations were determined using the bicinchoninic acid (BCA) or turbidimetry assay, and rifampicin concentrations were determined using a validated LC coupled with tandem MS method. A paired Wilcoxon signed-rank test was used to determine significance. RESULTS: TBM was confirmed in 19 cases (68%) using TB culture or GeneXpert Mtb/Rifampicin assay. All other cases were classified as probable. The median total protein concentration in LCSF was 6.0 g/L and in VCSF was 1.3 g/L. The median rifampicin concentration in LCSF was 299 ng/mL and 133 ng/mL in VCSF. The median ratio of LCSF/VSCF for protein was 4.23 and 1.57 for rifampicin. CONCLUSIONS: Total protein and rifampicin concentrations differed significantly between the two compartments, both being higher in LCSF than in VCSF samples (P < 0.0001 for total protein and P = 0.0046 for rifampicin). Further studies are required to explore the causative reasons for the observed differences.

Population Pharmacokinetic Analysis of Rifampicin in Plasma, Cerebrospinal Fluid, and Brain Extracellular Fluid in South African Children with Tuberculous Meningitis.

Limited knowledge is available on the pharmacokinetics of rifampicin in children with tuberculous meningitis (TBM) and its penetration into brain tissue, which is the site of infection. In this analysis, we characterize the distribution of rifampicin in cerebrospinal fluid (CSF), lumbar (LCSF) and ventricular (VCSF), and brain extracellular fluid (ECF). Children with TBM were included in this pharmacokinetic analysis. Sparse plasma, LCSF, and VCSF samples were collected opportunistically, as clinically indicated. Brain ECF was sampled using microdialysis (MD). Rifampicin was quantified with liquid chromatography with tandem mass spectrometry in all samples, and 25-desacetyl rifampicin in the plasma samples. The data were interpreted with nonlinear mixed-effects modeling, with the CSF and brain ECF modeled as "effect compartments." Data were available from 61 children, with median (min-max) age of 2 (0.3 to 10) years and weight of 11.0 (4.8 to 49.0) kg. A one-compartment model for parent and metabolite with first-order absorption and elimination via saturable hepatic clearance described the data well. Allometric scaling, maturation, and auto-induction of clearance were included. The pseudopartition coefficient between plasma and LCSF/VCSF was ~5%, while the value for ECF was only ~0.5%, possibly reflecting low recovery of rifampicin using MD. The equilibration half-life between plasma and LCSF/VCSF was ~4 h and between plasma and ECF ~2 h. Our study confirms previous reports showing that rifampicin concentrations in the LCSF are lower than in plasma and provides novel knowledge about rifampicin in the VCSF and the brain tissue. Despite MD being semiquantitative because the relative recovery cannot be quantified, our study presents a proof-of-concept that rifampicin reaches the brain tissue and that MD is an attractive technique to study site-of-disease pharmacokinetics in TBM.

Cerebrovascular Pressure Reactivity Has a Strong and Independent Association With Outcome in Children With Severe Traumatic Brain Injury.

OBJECTIVES: To examine cerebrovascular pressure reactivity index (PRx) in a large cohort of children with severe traumatic brain injury (sTBI) in association with physiologic variables and outcome. DESIGN: Retrospective observational cohort study. SETTING: Red Cross War Memorial Children's Hospital in Cape Town, South Africa. PATIENTS: Pediatric (≤ 14 yr old) sTBI patients with intracranial pressure (ICP) monitoring (postresuscitation Glasgow Coma Score [Glasgow Coma Scale (GCS)] of ≤ 8). MEASUREMENTS AND MAIN RESULTS: Data were analyzed from ICM+ files sampled at 100Hz. PRx (a mathematical indicator of pressure reactivity) was calculated as a moving correlation coefficient between ICP and mean arterial pressure (MAP) as previously described. Associations between PRx, age, GCS, ICP, MAP, and cerebral perfusion pressure (CPP) were examined with summary measures and correlation analysis using high-frequency data. Associations between PRx and mortality/outcome were examined with multivariable logistic regression analysis and the prognostic ability of PRx with receiver operating characteristic (ROCs) curves. The dataset included over 1.7 million minutes (28,634 hr) of MAP and ICP data in 196 children. The series mortality was 10.7% (21/196), and unfavorable outcome 29.6% (58/196). PRx had a moderate positive correlation with ICP ( r = 0.44; p < 0.001), a moderate negative correlation with CPP ( r = -0.43; p < 0.001), and a weak negative correlation with MAP ( r = -0.21; p = 0.004). PRx was consistently higher in patients with poor outcome and had a strong, independent association with mortality (ROC area under the curve = 0.91). A PRx threshold of 0.25 showed the best predictive ability for mortality. CONCLUSIONS: This is the largest cohort of children with PRx analysis of cerebrovascular reactivity to date. PRx had a strong association with outcome that was independent of ICP, CPP, GCS, and age. The data suggest that impaired autoregulation is an independent factor associated with poor outcome and may be useful in directing clinical care.

SIOP PODC-adapted treatment guidelines for craniopharyngioma in low- and middle-income settings.

Pediatric craniopharyngioma is a rare tumor with excellent survival but significant long-term morbidities due to the loco-regional tumor growth or secondary to its treatment. Visual impairment, panhypopituitarism, hypothalamic damage, and behavioral changes are among the main challenges. This tumor should be managed under the care of a multidisciplinary team to determine the optimum treatment within the available resources. This is particularly important for low middle-income countries where resources are variable. This report provides risk-stratified management guidelines for children diagnosed with craniopharyngioma in a resource-limited setting.

An update on pediatric traumatic brain injury.

INTRODUCTION: Traumatic brain injury (TBI) remains the commonest neurological and neurosurgical cause of death and survivor disability among children and young adults. This review summarizes some of the important recent publications that have added to our understanding of the condition and advanced clinical practice. METHODS: Targeted review of the literature on various aspects of paediatric TBI over the last 5 years. RESULTS: Recent literature has provided new insights into the burden of paediatric TBI and patient outcome across geographical divides and the severity spectrum. Although CT scans remain a standard, rapid sequence MRI without sedation has been increasingly used in the frontline. Advanced MRI sequences are also being used to better understand pathology and to improve prognostication. Various initiatives in paediatric and adult TBI have contributed regionally and internationally to harmonising research efforts in mild and severe TBI. Emerging data on advanced brain monitoring from paediatric studies and extrapolated from adult studies continues to slowly advance our understanding of its role. There has been growing interest in non-invasive monitoring, although the clinical applications remain somewhat unclear. Contributions of the first large scale comparative effectiveness trial have advanced knowledge, especially for the use of hyperosmolar therapies and cerebrospinal fluid drainage in severe paediatric TBI. Finally, the growth of large and even global networks is a welcome development that addresses the limitations of small sample size and generalizability typical of single-centre studies. CONCLUSION: Publications in recent years have contributed iteratively to progress in understanding paediatric TBI and how best to manage patients.

Intracranial pressure management: moving beyond guidelines.

PURPOSE OF REVIEW: The aim of this study was to provide an overview on advances in intracranial pressure (ICP) protocols for care, moving from traditional to more recent concepts. RECENT FINDINGS: Deep understanding of mechanics and dynamics of fluids and solids have been introduced for intracranial physiology. The amplitude or the harmonics of the cerebral-spinal fluid and the cerebral blood waves shows more information about ICP than just a numeric threshold. When the ICP overcome the compensatory mechanisms that maintain the compliance within the skull, an intracranial compartment syndrome (ICCS) is defined. Autoregulation monitoring emerge as critical tool to recognize CPP management. Measurement of brain tissue oxygen will be a critical intervention for diagnosing an ICCS. Surgical procedures focused on increasing the physiological compliance and increasing the volume of the compartments of the skull. SUMMARY: ICP management is a complex task, moving far than numeric thresholds for activation of interventions. The interactions of intracranial elements requires new interpretations moving beyond classical theories. Most of the traditional clinical studies supporting ICP management are not generating high class evidence. Recommendations for ICP management requires better designed clinical studies using new concepts to generate interventions according to the new era of personalized medicine.

Brain interstitial glycerol correlates with evolving brain injury in paediatric traumatic brain injury.

PURPOSE: A better understanding of the complex pathophysiology of traumatic brain injury (TBI) is needed to improve our current therapies. Cerebral microdialysis (CMD) is an advanced method to monitor the brain, but little is known about its parameters in children. Brain glycerol, one of the CMD variables, is an essential component of the phospholipid bilayer cell membrane and is considered a useful marker of tissue hypoxia in adults. This study examined the time course of glycerol and its associations in paediatric TBI. METHODS: In this retrospective cohort study, we collected data on children (< 13years) with severe TBI who underwent CMD monitoring. The relationship of glycerol was examined with respect to physiological, radiological variables, and clinical outcome. RESULTS: Twenty-eight children underwent CMD monitoring and had evaluable data. Lesion progression on head computed tomography (CT) demonstrated a strong relationship with glycerol (median glycerol, maximum and initial-to-maximum) when lesion size increased by > 30% (p=0.01, p=0.04 and p=0.004). Absolute glycerol values had a weak but statistically significant association with intracranial pressure and brain oxygenation. We did not find an association with clinical outcome. CONCLUSION: This is the first study to provide data on brain interstitial glycerol in children. CMD glycerol, particularly an increase from baseline, is associated with other markers of injury and with a significant increase in lesion size on repeat head CT. As such, it may represent a useful monitorable marker for evolving injury in paediatric TBI.

Consensus statement from the International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury : Consensus statement.

BACKGROUND: Two randomised trials assessing the effectiveness of decompressive craniectomy (DC) following traumatic brain injury (TBI) were published in recent years: DECRA in 2011 and RESCUEicp in 2016. As the results have generated debate amongst clinicians and researchers working in the field of TBI worldwide, it was felt necessary to provide general guidance on the use of DC following TBI and identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The International Consensus Meeting on the Role of Decompressive Craniectomy in the Management of Traumatic Brain Injury took place in Cambridge, UK, on the 28th and 29th September 2017. The meeting was jointly organised by the World Federation of Neurosurgical Societies (WFNS), AO/Global Neuro and the NIHR Global Health Research Group on Neurotrauma. Discussions and voting were organised around six pre-specified themes: (1) primary DC for mass lesions, (2) secondary DC for intracranial hypertension, (3) peri-operative care, (4) surgical technique, (5) cranial reconstruction and (6) DC in low- and middle-income countries. RESULTS: The invited participants discussed existing published evidence and proposed consensus statements. Statements required an agreement threshold of more than 70% by blinded voting for approval. CONCLUSIONS: In this manuscript, we present the final consensus-based recommendations. We have also identified areas of uncertainty, where further research is required, including the role of primary DC, the role of hinge craniotomy and the optimal timing and material for skull reconstruction.

Neuroendoscopy for post-infective hydrocephalus in children.

The treatment of hydrocephalus has changed in recent years with better imaging and introduction of endoscopic procedures as well as enhanced shunts. Indications of endoscopic third ventriculostomy (ETV) are now more refined with better quantification of outcome. This article reviews the current state of neuroendoscopy for infective hydrocephalus in children. The roles of third ventriculostomy as a primary procedure or after shunt malfunction, endoscopic interventions in multiloculated hydrocephalus and introduction of intraventricular lavage to salvage severely infected children are evaluated.

Biomarkers of Cerebral Injury and Inflammation in Pediatric Tuberculous Meningitis.

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.

Standardized Methods for Enhanced Quality and Comparability of Tuberculous Meningitis Studies.

Tuberculous meningitis (TBM) remains a major cause of death and disability in tuberculosis-endemic areas, especially in young children and immunocompromised adults. Research aimed at improving outcomes is hampered by poor standardization, which limits study comparison and the generalizability of results. We propose standardized methods for the conduct of TBM clinical research that were drafted at an international tuberculous meningitis research meeting organized by the Oxford University Clinical Research Unit in Vietnam. We propose a core dataset including demographic and clinical information to be collected at study enrollment, important aspects related to patient management and monitoring, and standardized reporting of patient outcomes. The criteria proposed for the conduct of observational and intervention TBM studies should improve the quality of future research outputs, can facilitate multicenter studies and meta-analyses of pooled data, and could provide the foundation for a global TBM data repository.

SIOP PODC Adapted treatment guidelines for low grade gliomas in low and middle income settings.

Effective treatment of children with low grade glioma (LGG) requires a functioning multi-disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition, the treating centre should have the capacity to manage a variety of LGG and treatment-associated complications. These requirements have made it difficult for many centers in low and middle-income countries (LMIC) to offer effective treatment and follow up. This article provides management recommendations for children with LGG according to the level of facilities available.

Targeted treatment in severe traumatic brain injury in the age of precision medicine.

In recent years, much progress has been made in our understanding of traumatic brain injury (TBI). Clinical outcomes have progressively improved, but evidence-based guidelines for how we manage patients remain surprisingly weak. The problem is that the many interventions and strategies that have been investigated in randomized controlled trials have all disappointed. These include many concepts that had become standard care in TBI. And that is just for adult TBI; in children, the situation is even worse. Not only is pediatric care more difficult than adult care because physiological norms change with age, but also there is less evidence for clinical practice. In this article, we discuss the heterogeneity inherent in TBI and why so many clinical trials have failed. We submit that a key goal for the future is to appreciate important clinical differences between patients in their pathophysiology and their responses to treatment. The challenge that faces us is how to rationally apply therapies based on the specific needs of an individual patient. In doing so, we may be able to apply the principles of precision medicine approaches to the patients we treat.

Clinical characteristics and neurodevelopmental outcomes of children with tuberculous meningitis and hydrocephalus.

AIM: Tuberculous meningitis (TBM) is a lethal and commonly occurring form of extra-pulmonary tuberculosis in children, often complicated by hydrocephalus which worsens outcome. Despite high mortality and morbidity, little data on the impact on neurodevelopment exists. We examined the clinical characteristics, and clinical and neurodevelopmental outcomes of TBM and hydrocephalus. METHOD: Demographic and clinical data (laboratory and radiological findings) were prospectively collected on children treated for probable and definite TBM with hydrocephalus. At 6 months, clinical outcome was assessed using the Paediatric Cerebral Performance Category Scale and neurodevelopmental outcome was assessed with the Griffiths Mental Development Scale - Extended Version. RESULTS: Forty-four patients (median age 3y 3mo, range 3mo-13y 1mo, [SD 3y 5mo]) were enrolled. The mortality rate was 16%, three patients (6.8%) were in a persistent vegetative state, two were severely disabled (4.5%), and 11 (25%) suffered mild-moderate disability. All cases demonstrated neurodevelopmental deficits relative to controls. Multiple or large infarcts were prognostic of poor outcome. INTERPRETATION: Neurological and neurodevelopmental deficits are common after paediatric TBM with hydrocephalus, and appear to be related to ongoing cerebral ischaemia and consequent infarction. The impact of TBM on these children is multidimensional and presents short- and long-term challenges.

Change in optic nerve sheath diameter as a radiological marker of outcome from endoscopic third ventriculostomy in children.

PURPOSE: The purpose of this study was to investigate the value of the change in optic nerve sheath diameter (ONSD) as a radiological marker of endoscopic third ventriculostomy (ETV) outcome in children. METHODS: Magnetic resonance imaging (MRI) scans of patients on whom ETVs were performed between the periods of January 2009 and June 2013 were reviewed. ONSD measurements on pre- and post-operative images were performed by two blinded observers, and the relationship between the change in these measurements and outcome from ETV were investigated. These findings were then also compared to conventional imaging features associated with ETV outcome. RESULTS: MRI scans of 24 patients were adequate to measure the ONSD pre- and post-operatively. In patients with successful ETV (n = 19), the mean change in ONSD was 0.73 mm and in patients with a failed ETV (n = 5), the mean change in ONSD was 0.18 mm (p = 0.0007). A change in ONSD of 7.5 % of the initial measurement demonstrated a sensitivity of 92.9 % and a sensitivity of 85.7 % for ETV outcome (area under the receiver operating characteristic curve (AUROC) = 0.96). CONCLUSION: Change in ONSD is a useful radiological marker of ETV outcome and may be used in combination with conventional radiological parameters to aid decision-making in this difficult group of patients.

Emergency Neurological Life Support: Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a neurological emergency because it may lead to sudden neurological decline and death and, depending on the cause, has treatment options that can return a patient to normal. Because there are interventions that can be life-saving in the first hour of onset, SAH was chosen as an Emergency Neurological Life Support protocol.

Biomarkers of brain injury in cerebral infections.

BACKGROUND: 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. CONTENT: 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. SUMMARY: 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.

Multimodality monitoring consensus statement: monitoring in emerging economies.

The burden of disease and so the need for care is often greater at hospitals in emerging economies. This is compounded by frequent restrictions in the delivery of good quality clinical care due to resource limitations. However, there is substantial heterogeneity in this economically defined group, such that advanced brain monitoring is routinely practiced at certain centers that have an interest in neurocritical care. It also must be recognized that significant heterogeneity in the delivery of neurocritical care exists even within individual high-income countries (HICs), determined by costs and level of interest. Direct comparisons of data between HICs and the group of low- and middle-income countries (LAMICs) are made difficult by differences in patient demographics, selection for ICU admission, therapies administered, and outcome assessment. Evidence suggests that potential benefits of multimodality monitoring depend on an appropriate environment and clinical expertise. There is no evidence to suggest that patients in LAMICs where such resources exist should be treated any differently to patients from HICs. The potential for outcome benefits in LAMICs is arguably greater in absolute terms because of the large burden of disease; however, the relative cost/benefit ratio of such monitoring in this setting must be viewed in context of the overall priorities in delivering health care at individual institutions.