Neuromonitoring in Children with Traumatic Brain Injury.

Traumatic brain injury remains a major cause of mortality and morbidity in children across the world. Current management based on international guidelines focuses on a fixed therapeutic target of less than 20 mm Hg for managing intracranial pressure and 40-50 mm Hg for cerebral perfusion pressure across the pediatric age group. To improve outcome from this complex disease, it is essential to understand the pathophysiological mechanisms responsible for disease evolution by using different monitoring tools. In this narrative review, we discuss the neuromonitoring tools available for use to help guide management of severe traumatic brain injury in children and some of the techniques that can in future help with individualizing treatment targets based on advanced cerebral physiology monitoring.

Evaluating the efficacy and safety of single-agent etoposide intra-CSF chemotherapy in children and young people with relapsed/refractory central nervous system tumours.

PURPOSE: The aim of the project was to evaluate intra-CSF etoposide administration in a palliative setting for children and young people with relapsed/refractory central nervous system (CNS) tumours, with the primary endpoints being overall survival and progression-free survival time. A safety endpoint was to assess the side effect profile and complications of intra-CSF etoposide. METHODS: Thirty-five patients under the age of 30 years (median age: 5.33 years) were enrolled onto the project. The cross-centre study was a service evaluation, with a data collection spreadsheet designed in Nottingham and completed by both Nottingham and Oxford centres. Data was analysed using SPSS, assessing the overall survival and progression-free survival times, as well as the 6-month and 1-year survival rates. RESULTS: The median overall survival and progression-free survival times were 10.97 and 5.91 months, respectively. The 6-month and 1-year overall survival rates were 67% and 48%, and the progression-free survival rates were 50% and 22%. Age at the start of intra-CSF therapy was significantly associated with overall survival (P = 0.046), with the 6 + age group having improved overall survival. Treatment type was significantly associated with overall survival (P = 0.012), with etoposide intra-CSF treatment being associated with improved overall survival. Treatment duration was significantly associated with both overall survival (P < 0.001) and progression-free survival (P < 0.001). CONCLUSION: Intra-CSF etoposide treatment has shown to increase both overall and progression-free survival significantly, whilst having few side effects and maintaining a good quality of life for patients, reflecting it as a beneficial therapy in the palliative setting.

Modelling success after perinatal post-haemorrhagic hydrocephalus: a single-centre study.

INTRODUCTION: Post-haemorrhagic hydrocephalus is common amongst premature infants and one of the leading indications for paediatric cerebrospinal fluid (CSF) diversion. Permanent CSF diversion is often delayed until the infant is older but there is no clear consensus on the timing for this. The outcomes for permanent shunting in this patient group are poor, with higher rates of failure and infection compared to other aetiologies of hydrocephalus. METHODS: We conduct a single-centre retrospective review of infants with post-haemorrhagic hydrocephalus requiring a permanent shunt insertion over a 5-year period. Demographic and clinical data from time of shunt insertion were collected and used to generate generalised linear models (GLMs) to predict shunt success at 12 months after insertion. RESULTS: Twenty-six infants underwent permanent shunting in this period for post-haemorrhagic hydrocephalus, with 10 suffering shunt failure within the first 12 months. The best-performing GLM was able to predict shunt success with a sensitivity of 1 and specificity of 0.90, with head circumference, weight, and corrected age at the time of shunt insertion being the most significantly associated variables for shunt success in this model. CONCLUSION: Our proof-of-principle study suggests that highly accurate prediction of shunt success for infants with post-haemorrhagic hydrocephalus is possible using routinely available clinical variables. Further work is required to test this model in larger cohorts and validate whether pre-operative use can improve outcomes for this patient group.

Feasibility of awake craniotomy in the pediatric population.

BACKGROUND: Awake craniotomy with direct cortical stimulation and mapping is the gold standard for resection of lesions near eloquent brain areas, as it can maximize the extent of resection while minimizing the risk of neurological damage. In contrast to the adult population, only small series of awake craniotomies have been reported in children. AIMS: The aim of our study is to establish the feasibility of awake craniotomy in the pediatric population. METHODS: We performed a retrospective observational study of children undergoing a supratentorial awake craniotomy between January 2009 and April 2019 in a pediatric tertiary care center. Our primary outcome was feasibility of awake craniotomy, defined as the ability to complete the procedure without conversion to general anesthesia. Our secondary outcomes were the incidence of serious intraoperative complications and the mapping completion rate. RESULTS: Thirty procedures were performed in 28 children: 12 females and 16 males. The median age was 14 years (range 7-17). The primary diagnosis was tumor (83.3%), epilepsy (13.3%), and arterio-venous malformation (3.3%). The anesthetic techniques were asleep-awake-asleep (96.7%) and conscious sedation (3.3%), all cases supplemented with scalp block and pin-site infiltration. Awake craniotomy was feasible in 29 cases (96.7%), one patient converted to general anesthesia due to agitation. Serious complications occurred in six patients: agitation (6.7%), seizures (3.3%), increased intracranial pressure (3.3%), respiratory depression (3.3%), and bradycardia (3.3%). All complications were quickly resolved and without major consequences. Cortical mapping was completed in 96.6% cases. New neurological deficits occurred in six patients (20%)-moderate in one case and mild in 5-being all absent at 6 months of follow-up. CONCLUSION: Awake craniotomy with intraoperative mapping can be successfully performed in children. Adequate patient selection and close cooperation between neurosurgeons, anesthesiologists, neuropsychologists, and neurophysiologists is paramount. Further studies are needed to determine the best anesthetic technique in this population group.

Correction: Modelling outcomes after paediatric brain injury with admission laboratory values: a machine-learning approach.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Modelling outcomes after paediatric brain injury with admission laboratory values: a machine-learning approach.

BACKGROUND: Severe traumatic brain injury (TBI) is a leading cause of mortality in children, but the accurate prediction of outcomes at the point of admission remains very challenging. Admission laboratory results are a promising potential source of prognostic data, but have not been widely explored in paediatric cohorts. Herein, we use machine-learning methods to analyse 14 different serum parameters together and develop a prognostic model to predict 6-month outcomes in children with severe TBI. METHODS: A retrospective review of patients admitted to Cambridge University Hospital's Paediatric Intensive Care Unit between 2009 and 2013 with a TBI. The data for 14 admission serum parameters were recorded. Logistic regression and a support vector machine (SVM) were trained with these data against dichotimised outcomes from the recorded 6-month Glasgow Outcome Scale. RESULTS: Ninety-four patients were identified. Admission levels of lactate, H+, and glucose were identified as being the most informative of 6-month outcomes. Four different models were produced. The SVM using just the three most informative parameters was the best able to predict favourable outcomes at 6 months (sensitivity = 80%, specificity = 99%). CONCLUSIONS: Our results demonstrate the potential for highly accurate outcome prediction after severe paediatric TBI using admission laboratory data.

The role of surgery in refractory epilepsy secondary to polymicrogyria in the pediatric population.

OBJECTIVE: Polymicrogyria (PMG) is a common malformation of cortical development. Many patients with PMG will have medically refractory epilepsy but the role of epilepsy surgery is unclear. The objective of this study was to assess the efficacy of surgical resection/disconnection in achieving seizure control in pediatric patients with PMG. METHODS: A retrospective review of children undergoing epilepsy surgery for PMG between 2002 and 2017 at The Hospital for Sick Children in Toronto, Canada, was performed. RESULTS: A total of 12 children aged 6 months to 17.8 years (median 8.8 years) underwent resective surgery (7 children) or functional hemispherectomy (5 children). Gross total resection or complete disconnection of PMG was carried out in 7 of 12 children. Follow-up duration was between 1 and 9 years (median 2.1 years). Nine children remained seizure-free at last follow-up. Complete resection or disconnection of PMG led to seizure freedom in 6 of 7 patients (86%), whereas subtotal resection produced seizure freedom in 3 of 5 patients (60%). SIGNIFICANCE: We present one of the largest surgical series of pediatric PMG patients. Seizure outcomes were best with complete resection/disconnection of PMG. However, tailored resections based on electroclinical and neuroradiologic data can produce good outcomes and remain an appropriate strategy for patients with extensive PMG.

A cracking shot! depressed skull fracture sustained from a golf ball in a 16-year old.

Depressed skull fractures sustained from golf balls are quite rare. We report such a case in a 16-year old, and demonstrate its appearance in a 3D CT reconstruction.

Glucose metabolism following human traumatic brain injury: methods of assessment and pathophysiological findings.

The pathophysiology of traumatic brain (TBI) injury involves changes to glucose uptake into the brain and its subsequent metabolism. We review the methods used to study cerebral glucose metabolism with a focus on those used in clinical TBI studies. Arterio-venous measurements provide a global measure of glucose uptake into the brain. Microdialysis allows the in vivo sampling of brain extracellular fluid and is well suited to the longitudinal assessment of metabolism after TBI in the clinical setting. A recent novel development is the use of microdialysis to deliver glucose and other energy substrates labelled with carbon-13, which allows the metabolism of glucose and other substrates to be tracked. Positron emission tomography and magnetic resonance spectroscopy allow regional differences in metabolism to be assessed. We summarise the data published from these techniques and review their potential uses in the clinical setting.

Increased blood glucose is related to disturbed cerebrovascular pressure reactivity after traumatic brain injury.

BACKGROUND: Increased blood glucose and impaired pressure reactivity (PRx) after traumatic brain injury (TBI) are both known to correlate with unfavorable patient outcome. However, the relationship between these two variables is unknown. METHODS: To test the hypothesis that increased blood glucose leads to increased PRx, we retrospectively analyzed data from 86 traumatic brain injured patients admitted to the Neurocritical Care Unit. Data analyzed included arterial glucose concentration, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and end-tidal CO2. PRx was calculated as the moving correlation coefficient between averaged (10 seconds) arterial blood pressure and ICP. One arterial glucose concentration and one time-aligned PRx value were obtained for each patient, during each day until the fifth day after ictus. RESULTS: Mean arterial glucose concentrations during the first 5 days since ictus were positively correlated with mean PRx (Pearson correlation coefficient = 0.25, p = 0.02). The correlation was strongest on the first day after injury (Pearson correlation coefficient = 0.47, p = 0.008). CONCLUSION: Our preliminary findings indicate that increased blood glucose may impair cerebrovascular reactivity, potentially contributing to a mechanistic link between increased blood glucose and poorer outcome after TBI.

Giant intracranial hemangioma in a neonate.

In this report we detail the case of an infant presenting with a giant intracranial congenital hemangioma and describe the clinical features and surgical management. Congenital hemangiomas are benign vascular tumors that typically present as skin lesions in neonates and infants. On rare occasions they present as intracranial tumors. The possibility that these tumors may undergo spontaneous regression poses a treatment dilemma.

Measurement of Head Circumference Using a Smartphone: Feasibility Cohort Study.

BACKGROUND: Accurate head circumference (HC) measurement is essential when assessing neonates and infants. Tape measure HC measurements are prone to errors, particularly when performed by parents/guardians, due to individual differences in head shape, hair style and texture, subject cooperation, and examiner techniques, including tape measure placement and tautness. There is, therefore, the need for a more reliable method. OBJECTIVE: The primary objective of this study was to evaluate the validity, reliability, and consistency of HC app measurement compared to the current standard of practice, serving as a proof-of-concept for use by health care professionals. METHODS: We recruited infants attending the neurosurgery clinic, and parents/guardians were approached and consented to participate in the study. Along with the standard head circumference measurement, measurements were taken with the head circumference app (HC app) developed in-house, and we also collected baseline medical history and characteristics. For the statistical analysis, we used RStudio (version 4.1.1). In summary, we analyzed covariance and intraclass correlation coefficient (ICC) to compare the measurement's within-rater and interrater reliability. The F test was used to analyze the variance between measurements and the Bland-Altman agreement, t test, and correlation coefficients were used to compare the tape measurement to the measures taken by the HC app. We also used nonvalidated questionnaires to explore parental or guardians' experiences, assess their views on app utility, and collect feedback. RESULTS: The total number of recruited patients was 37. Comparison between the app measurements and the measurements with a tape measure showed poor reliability (ICC=0.177) and wide within-app variations (ICC=0.341). The agreement between the measurements done by parents/guardians and the tape measurements done by the researcher was good (ICC=0.901). Parental/guardian feedback was overall very positive, with most of the parents/guardians reporting that the app was easy to use (n=31, 84%) and that they are happy to use the app in an unsupervised setting, provided that they are assured of the measurement quality. CONCLUSIONS: We developed this project as a proof-of-concept study, and as such, the app has shown great potential to be used both in a clinical setting and by parents/guardians in their own homes.

Characterizing Diffusion from Microdialysis Catheters in the Human Brain: A Magnetic Resonance Imaging Study With Gadobutrol.

Cerebral microdialysis (CMD) catheters allow continuous monitoring of patients' cerebral metabolism in severe traumatic brain injury (TBI). The catheters consist of a terminal semi-permeable membrane that is inserted into the brain's interstitium to allow perfusion fluid to equalize with the surrounding cerebral extracellular environment before being recovered through a central non-porous channel. However, it is unclear how far recovered fluid and suspended metabolites have diffused from within the brain, and therefore what volume or region of brain tissue the analyses of metabolism represent. We assessed diffusion of the small magnetic resonance (MR)-detectible molecule gadobutrol from microdialysis catheters in six subjects (complete data five subjects, incomplete data one subject) who had sustained a severe TBI. Diffusion pattern and distance in cerebral white matter were assessed using T1 (time for MR spin-lattice relaxation) maps at 1 mm isotropic resolution in a 3 Tesla MR scanner. Gadobutrol at 10 mmol/L diffused from cerebral microdialysis catheters in a uniform spheroidal (ellipsoid of revolution) pattern around the catheters' semipermeable membranes, and across gray matter-white matter boundaries. Evidence of gadobutrol diffusion was found up to a mean of 13.4 ± 0.5 mm (mean ± standard deviation [SD]) from catheters, but with a steep concentration drop off so that ≤50% of maximum concentration was achieved at ∼4 mm, and ≤10% of maximum was found beyond ∼7 mm from the catheters. There was little variation between subjects. The relaxivity of gadobutrol in human cerebral white matter was estimated to be 1.61 ± 0.38 L.mmol-1sec-1 (mean ± SD); assuming gadobutrol remained extracellular thereby occupying 20% of total tissue volume (interstitium), and concentration equilibrium with perfusion fluid was achieved immediately adjacent to catheters after 24 h of perfusion. No statistically significant change was found in the concentration of the extracellular metabolites glucose, lactate, pyruvate, nor the lactate/pyruvate ratio during gadobutrol perfusion when compared with period of baseline microdialysis perfusion. Cerebral microdialysis allows continuous monitoring of regional cerebral metabolism-the volume of which is now clearer from this study. It also has the potential to deliver small molecule therapies to focal pathologies of the human brain. This study provides a platform for future development of new catheters optimally designed to treat such conditions.

An overview of clinical cerebral microdialysis in acute brain injury.

Cerebral microdialysis may be used in patients with severe brain injury to monitor their cerebral physiology. In this article we provide a concise synopsis with illustrations and original images of catheter types, their structure, and how they function. Where and how catheters are inserted, their identification on imaging modalities (CT and MRI), together with the roles of glucose, lactate/pyruvate ratio, glutamate, glycerol and urea are summarized in acute brain injury. The research applications of microdialysis including pharmacokinetic studies, retromicrodialysis, and its use as a biomarker for efficacy of potential therapies are outlined. Finally, we explore limitations and pitfalls of the technique, as well as potential improvements and future work that is needed to progress and expand the use of this technology.

High-physiological and supra-physiological 1,2-13C2 glucose focal supplementation to the traumatised human brain.

How to optimise glucose metabolism in the traumatised human brain remains unclear, including whether injured brain can metabolise additional glucose when supplied. We studied the effect of microdialysis-delivered 1,2-13C2 glucose at 4 and 8 mmol/L on brain extracellular chemistry using bedside ISCUSflex, and the fate of the 13C label in the 8 mmol/L group using high-resolution NMR of recovered microdialysates, in 20 patients. Compared with unsupplemented perfusion, 4 mmol/L glucose increased extracellular concentrations of pyruvate (17%, p = 0.04) and lactate (19%, p = 0.01), with a small increase in lactate/pyruvate ratio (5%, p = 0.007). Perfusion with 8 mmol/L glucose did not significantly influence extracellular chemistry measured with ISCUSflex, compared to unsupplemented perfusion. These extracellular chemistry changes appeared influenced by the underlying metabolic states of patients' traumatised brains, and the presence of relative neuroglycopaenia. Despite abundant 13C glucose supplementation, NMR revealed only 16.7% 13C enrichment of recovered extracellular lactate; the majority being glycolytic in origin. Furthermore, no 13C enrichment of TCA cycle-derived extracellular glutamine was detected. These findings indicate that a large proportion of extracellular lactate does not originate from local glucose metabolism, and taken together with our earlier studies, suggest that extracellular lactate is an important transitional step in the brain's production of glutamine.

Focally administered succinate improves cerebral metabolism in traumatic brain injury patients with mitochondrial dysfunction.

Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.

Use of drains versus no drains after burr-hole evacuation of chronic subdural haematoma: a randomised controlled trial.

BACKGROUND: Chronic subdural haematoma causes serious morbidity and mortality. It recurs after surgical evacuation in 5-30% of patients. Drains might reduce recurrence but are not used routinely. Our aim was to investigate the effect of drains on recurrence rates and clinical outcomes. METHODS: We did a randomised controlled trial at one UK centre between November, 2004, and November, 2007. 269 patients aged 18 years and older with a chronic subdural haematoma for burr-hole drainage were assessed for eligibility. 108 were randomly assigned by block randomisation to receive a drain inserted into the subdural space and 107 to no drain after evacuation. The primary endpoint was recurrence needing redrainage. The trial was stopped early because of a significant benefit in reduction of recurrence. Analyses were done on an intention-to-treat basis. This study is registered with the International Standard Randomised Controlled Trial Register (ISRCTN 97314294). FINDINGS: Recurrence occurred in ten of 108 (9.3%) people with a drain, and 26 of 107 (24%) without (p=0.003; 95% CI 0.14-0.70). At 6 months mortality was nine of 105 (8.6%) and 19 of 105 (18.1%), respectively (p=0.042; 95% CI 0.1-0.99). Medical and surgical complications were much the same between the study groups. INTERPRETATION: Use of a drain after burr-hole drainage of chronic subdural haematoma is safe and associated with reduced recurrence and mortality at 6 months. FUNDING: Academy of Medical Sciences, Health Foundation, and NIHR Biomedical Research Centre (Neurosciences Theme).