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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.

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 ISCUS flex, 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 ISCUS flex, 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.

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.

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.

In recent years, there is a tendency to reduce greenhouse gas emissions internationally in consideration of environmental problems. In the field of electric power systems, the introduction of renewable energy power generation facilities centered on photovoltaic power generation is being promoted in order to reduce greenhouse gas emissions. However, if these power generation facilities are introduced excessively, a duck curve phenomenon occurs in which the operating efficiency of the thermal power generator is poor. Currently, we are reducing the output of photovoltaic power generation equipment to avoid the duck curve phenomenon. In order to suppress the output, it is not possible to further install renewable energy power generation equipment, and the limit of introduction comes with a fixed amount. Therefore, this paper proposes a new load demand control method that improves the duck curve phenomenon without hindering the introduction of renewable energy power generation equipment. In addition, in order to make the proposed method more active, the usual unit commitment has a time interval of 1 hour, but at the same time, we also devised a time interval of 30 minutes. We show that by performing a short-term unit commitment using the proposed method, the optimal operation can be performed even when a large amount of renewable energy power generation is introduced.

Background The current biomarkers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) have limited sensitivity/specificity for diagnosing malignant germ cell tumors (GCTs) and “marker-negative” patients require histological confirmation for diagnosis. However, GCTs at intracranial sites are surgically relatively inaccessible and biopsy carries risks. MicroRNAs from the miR-371~373 and miR-302/367 clusters are over-expressed in all malignant GCTs and, in particular, miR-371a-3p shows elevated serum levels at diagnosis for testicular disease. Methods Using our robust preamplified qRT-PCR methodology, we quantified miR-371a-3p levels in serum and cerebrospinal fluid (CSF) in a series of 4 representative clinical cases, 3 with intracranial malignant GCT and 1 with Langerhans cell histiocytosis (LCH), compared with appropriate control cases. Results Serum and/or CSF miR-371a-3p levels distinguished those with intracranial malignant GCTs from LCH and, if known in real time, could have helped clinical management. The benefits would have included (1) the only confirmatory evidence of an intracranial malignant GCT in 1 case, supporting clinical decision making; (2) early detection of intracranial malignant GCT in another, where an elevated CSF miR-371a-3p level preceded the histologically confirmed diagnosis by 2 years; and (3) confirmation of an intracranial malignant GCT relapse with an elevated serum miR-371a-3p level, where serum and CSF AFP and HCG levels were below thresholds for such a diagnosis. Conclusions This series highlights the potential for microRNA quantification to assist the noninvasive diagnosis, prognostication, and management for patients with intracranial malignant GCTs. Serum and CSF should be collected routinely as part of future studies to facilitate the extension of these findings to larger patient cohorts.

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.

Microglia, the tissue resident macrophages of the CNS, are implicated in a broad range of neurological pathologies, from acute brain injury to dementia. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single cell and bulk RNA sequencing, we defined distinct cellular populations of acutelyin vivo-activated microglia, and characterised a dramatic switch in microglial population composition in patients suffering from acute brain injury. We mapped expression quantitative trait loci (eQTLs) in human microglia and show that many disease-associated eQTLs in microglia replicate well in a human induced pluripotent stem cell (hIPSC) derived macrophage model system. Using ATAC-seq from 95 individuals in this hIPSC model we fine-map candidate causal variants at risk loci for Alzheimer’s disease, the most prevalent neurodegenerative condition in acute brain injury patients. Our study provides the first population-scale transcriptional map of a critically important cell for neurodegenerative disorders.

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.

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.

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.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.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%).Our results demonstrate the potential for highly accurate outcome prediction after severe paediatric TBI using admission laboratory data.

Increased ‘anaerobic’ glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-13C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. 13C enrichment for glycolytic 2,3-13C2 lactate was the median 5.4% (interquartile range (IQR) 4.6–7.5%) in TBI brain and 4.2% (2.4–4.4%) in ‘normal’ brain ( P13C lactate to glycolytic 2,3-13C2 lactate was median 4.9% (3.6–8.2%) in TBI brain and 6.7% (6.3–8.9%) in ‘normal’ brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 ( r=−0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than ‘normal’ brain. Several TBI patients exhibited PPP—lactate elevation above the ‘normal’ range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain.

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.

BACKGROUND: Correctly distinguishing gliomas as low or high grade (LGG or HGG) during surgery can influence the surgical procedure, enhancing resection and improving survival. The UK NCRI GALA-BIDD study was designed to prospectively investigate whether the presence of visible fluorescence is a pragmatic intra-operative diagnostic surgical biomarker of high-grade disease within a tumour mass in real time during surgery. METHODS: Patients with suspected intrinsic glioma discussed at neuro-oncology Multidisciplinary Team meetings and suitable for fluorescence guided cytoreductive surgery were eligible. 5-aminolevulinic acid (5-ALA) was used to generate visible fluorescence. Samples of fluorescent tissue were sent for peri-operative histopathological analysis to establish an intra-operative diagnosis of LGG or HGG. These data were compared with the final central pathological diagnosis. RESULTS: From Feb 2015 to March 2017 in the UK, 106 patients were recruited: median age 59 (range 23–77); 59% male; 25% WHO radiological grade II transforming to a higher grade and 55% grade IV. 5-ALA were given for 103 patients with a median dose of 1500mg (range 960-2200mg). 67% of patients classified as HGG at local peri-operative diagnosis were confirmed by the central review (weighted Kappa 0.37 (95%CI=0.21–0.54)). 88 patients were evaluable for the primary endpoint: 81 had visible fluorescence of the tumour with central histopathology diagnosis as 1 LGG, 78 HGG (a 99% concordance in HGG classification with the 99%CI=91%-99.9%) and 2 not assessed; 7 patients had no visible fluorescence and were diagnosed as 6 LGG and 1 HGG. CONCLUSION: There is an urgent need to improve the local peri-operative diagnosis. The presence of visible fluorescence can be used as an additional pragmatic intra-operative diagnostic surgical biomarker of high-grade disease within a tumour mass. Use for assessment of low-grade disease needs further investigation.

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.

N-acetylaspartate (NAA) is an amino acid derivative primarily located in the neurons of the adult brain. The function of NAA is incompletely understood. Decrease in brain tissue NAA is presently considered symptomatic and a potential biomarker of acute and chronic neuropathological conditions. The aim of this study was to use microdialysis to investigate the behavior of extracellular NAA (eNAA) levels after traumatic brain injury (TBI). Sampling for this study was performed using cerebral microdialysis catheters (M Dialysis 71) perfused at 0.3 μL/min. Extracellular NAA was measured in microdialysates by high-performance liquid chromatography in 30 patients with severe TBI and for comparison, in radiographically “normal” areas of brain in six non-TBI neurosurgical patients. We established a detailed temporal eNAA profile in eight of the severe TBI patients. Microdialysate concentrations of glucose, lactate, pyruvate, glutamate, and glycerol were measured on an ISCUS clinical microdialysis analyzer. Here, we show that the temporal profile of microdialysate eNAA was characterized by highest levels in the earliest time-points post-injury, followed by a steady decline; beyond 70 h post-injury, average levels were 40% lower than those measured in non-TBI patients. There was a significant inverse correlation between concentrations of eNAA and pyruvate; eNAA showed significant positive correlations with glycerol and the lactate/pyruvate (L/P) ratio measured in microdialysates. The results of this on-going study suggest that changes in eNAA after TBI relate to the release of intracellular components, possibly due to neuronal death or injury, as well as to adverse brain energy metabolism.

Much progress has been made over the past two decades in the treatment of severe acute brain injury, including traumatic brain injury and subarachnoid hemorrhage, resulting in a higher proportion of patients surviving with better outcomes. This has arisen from a combination of factors. These include improvements in procedures at the scene (pre-hospital) and in the hospital emergency department, advances in neuromonitoring in the intensive care unit, both continuously at the bedside and intermittently in scans, evolution and refinement of protocol-driven therapy for better management of patients, and advances in surgical procedures and rehabilitation. Nevertheless, many patients still experience varying degrees of long-term disabilities post-injury with consequent demands on carers and resources, and there is room for improvement. Biomarkers are a key aspect of neuromonitoring. A broad definition of a biomarker is any observable feature that can be used to inform on the state of the patient, e.g., a molecular species, a feature on a scan, or a monitoring characteristic, e.g., cerebrovascular pressure reactivity index. Biomarkers are usually quantitative measures, which can be utilized in diagnosis and monitoring of response to treatment. They are thus crucial to the development of therapies and may be utilized as surrogate endpoints in Phase II clinical trials. To date, there is no specific drug treatment for acute brain injury, and many seemingly promising agents emerging from pre-clinical animal models have failed in clinical trials. Large Phase III studies of clinical outcomes are costly, consuming time and resources. It is therefore important that adequate Phase II clinical studies with informative surrogate endpoints are performed employing appropriate biomarkers. In this article, we review some of the available systemic, local, and imaging biomarkers and technologies relevant in acute brain injury patients, and highlight gaps in the current state of knowledge.

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. 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. 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). 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.

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.

Background Herpes simplex is a common human pathogen that has rare but severe manifestations including encephalitis. Case Description A 44-year-old man underwent uneventful resection of an acoustic neuroma. Postoperatively, he developed swinging pyrexia, vomiting, and episodic confusion. Analysis of cerebrospinal fluid showed a lymphocytosis, and polymerase chain reaction revealed herpes simplex DNA. After treatment of herpes encephalitis with acyclovir, the patient made a good recovery. Conclusion Herpes encephalitis is a rare complication of neurosurgical procedures, and the most likely etiology is reactivation of latent infection from manipulation of cranial nerves.

Summary Background: Preoperative smoking cessation has been shown to improve postoperative outcomes. Methods: A total of 120 anonymous questionnaires were distributed to non-vascular surgeons practising in four centres in the UK asking about their smoking cessation advice practices, and whether they appreciated both the benefits of preoperative smoking cessation, and the efficacy of smoking cessation interventions. Results: Eighty-three questionnaires were returned (response rate 69%). Twenty-three gastrointestinal surgeons, 11 orthopaedic surgeons, 9 breast surgeons, 12 plastic surgeons, 13 neurosurgeons and 15 urologists took part in this study. Eighty-eight per cent of respondents had not referred any elective patients to smoking cessation services in the previous month. Most non-vascular surgeons underestimated both the benefits of preoperative smoking cessation on outcome, and the efficacy of smoking cessation interventions. Conclusions: This survey demonstrates that non-vascular surgeons underestimate the fact that preoperative smoking cessation can improve postoperative outcome, and that smoking cessation interventions are successful in helping patients to quit smoking. They largely do not refer patients to smoking cessation services. In order for patients to benefit postoperatively from this intervention it would be necessary to educate surgeons about the scale of the benefit, and the efficacy of smoking cessation interventions or to set up systematic frameworks to offer smoking cessation advice to preoperative patients who smoke.

Lactate has been regarded as a waste product of anaerobic metabolism of glucose. Evidence also suggests, however, that the brain may use lactate as an alternative fuel. Our aim was to determine the extent of lactate uptake from the circulation into the brain after traumatic brain injury (TBI) and to compare it with levels of lactate in the brain extracellular fluid. We recruited 19 patients with diffuse TBI, monitored with cerebral microdialysis and jugular bulb catheters. Serial arteriovenous (AV) concentration differences of glucose and lactate were calculated from arterial and jugular blood samples, providing a measure of net uptake or export by the brain. Microdialysis was used to measure brain extracellular glucose and lactate. In 17/19 patients studied for 5 days post-injury, there were periods of net lactate uptake into the brain, most frequently on day 3 after injury. Brain microdialysate lactate had a median (interquartile range [IQR]) concentration of 2.5 (1.5–3.2) mmol/L during lactate uptake and 2.2 (1.7–3.0) mmol/L during lactate export. Lactate uptake into the brain occurred at a median (IQR) arterial lactate concentration of 1.6 (1.0–2.2) mmol/L. Lactate uptake was associated with significantly higher AV difference in glucose values with a median (IQR) of 0.4 (0.03–0.7) mmol/L during uptake and 0.1 (−0.2–0.3) mmol/L during lactate export (Mann-Whitney U p=0.003). Despite relatively high brain lactate compared with arterial lactate concentrations, the brain appears to up-regulate lactate transport into the brain after TBI. This may serve to satisfy greater demands for energy substrate from the brain after TBI.

Background: Ebola Virus Disease (EVD) has ravaged three countries in West Africa. The mortality rate is extremely high, and it is perceived not only as threat to all of Africa but to the entire world. There is no known treatment to date other than administration of convalescent blood or experimental monoclonal antibodies, which both often fail. Ozone therapy (OT) has been in clinical use for decades and has been found to have physiological effects, which should directly inactivate the virus itself, as well as modulate its damaging effects. We present the scientific background and the possibility of ozone therapy as a cure or prevention for EVD in five consecutive patients.Materials and Methods: Ozone therapy administration by a combination of direct intravenous gas administration, rectal gas administration and ozonized water was administered to three patients with known acute EVD, one with apparent acute infection, and one case of extremely high risk. Treatment was carried out for up to ten days despite fast total remission of symptoms. Vitamin C and glutathione supporting supplements were administered.Results: Four symptomatic patients, three with test positive EVD confirmation and one (who suffered Ebola contaminated needle stick contamination three days earlier) without lab confirmation all remitted symptoms within 2-4 days and fully recovered. All four ill cases had an immediate recovery course upon initiation of therapy. The single case of non-symptomatic high-risk exposure treated preventively did not develop symptoms.Conclusion: Ebola virus may have a very narrow window of redox infectivity capacity, which can be easily exploited with OT. OT may be a useful modality in EVD and other viral diseases and should be immediately studied to save lives that might otherwise be lost.Key words: Ebola, Hemorrhagic Fever, ozone therapy, oxidation, virus, antiviral therapy

Introduction Status dystonicus is a rare but life-threatening disorder characterized by increasingly frequent and severe episodes of generalized dystonia that may occur in patients with primary or secondary dystonia. Painful and repetitive spasms interfere with respiration and may cause metabolic disturbances such as hyperpyrexia, dehydration, respiratory insufficiency, and acute renal failure secondary to rhabdomyolysis. Intrathecally administered baclofen, delivered by an implantable pump system, is widely used for the treatment of refractory spasticity. Abrupt cessation of intrathecal baclofen infusion has been associated with a severe withdrawal syndrome comprised of dystonia, autonomic dysfunction, hyperthermia, end-organ failure and sometimes death. The aetiology of this syndrome is not well understood. Status dystonicus describes the episodes of acute and life-threatening generalized dystonia, which occasionally manifest themselves in patients with dystonic syndromes. Case presentation We present the case of a nine-year-old Caucasian boy who experienced a severe episode of status dystonicus with no known cause and clinical features resembling those described in intrathecal baclofen withdrawal. Our patient subsequently underwent the placement of an intrathecal baclofen pump without incident. Conclusion The similarity between the clinical features of the case we present and those reported in connection to abrupt withdrawal of intrathecal baclofen is emphasized. Several drugs, although not intrathecal baclofen withdrawal, have previously been associated with status dystonicus. The similarity between the life-threatening dystonic episode experienced by our patient, and those reported in intrathecal baclofen withdrawal, highlights the possibility that, rather than representing a true physiological withdrawal syndrome, abrupt withdrawal of intrathecal baclofen may simply precipitate an episode of status dystonicus in susceptible individuals. The clinical similarities between the intrathecal baclofen withdrawal syndrome and status dystonicus have not previously been highlighted.

Summary 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).

We describe the case of a patient with known Wegener's Granulomatosis who developed a spontaneous intradural haematoma in the thoracic spine against a background of a recent relapse in her vasculitis. Decompression resulted in a rapid recovery of lower limb function. We propose involvement of the spinal meninges in the systemic vasculitis as the cause of haemorrhage.

Objective: To identify reasons for delay in management of patients with cauda equina syndrome (CES) and to determine commonly presented features of CES. Methods: Retrospectively, the presenting features and management of patients treated for CES over a 4-year period were reviewed. Results: Reasons for delay in treatment were identified in over half of the patients. Discussion: Most patients do not present with all the characteristic features of CES. Sacral sensory loss is a sensitive and relatively specific sign for diagnosing CES.

A 50 year old right handed woman presented to the emergency department with her first generalised tonic clonic seizure, followed by a severe unremitting headache and neck stiffness. The seizure was preceded by a three week history of pain around the left ear and nausea, which her general practitioner had diagnosed as otitis media and had treated with a course of amoxicillin. She had no history of trauma and her medical history was otherwise unremarkable. On examination the patient had a low grade fever but her pulse rate, blood pressure, respiratory rate, and oxygen saturation on air were all normal. She had also developed a global dysphasia and a right sided homonymous hemianopia. The patient’s head computed tomogram⇓ and digital subtraction angiogram⇓ are shown in the two images. Fig 1 The patient’s head computed tomogram Fig 2 The patient’s digital subtraction angiogram ### Short answers ### Long answers #### 1 Diagnosis of subarachnoid haemorrhage Unenhanced computed tomography of the brain is the investigation of choice for the assessment of acute haemorrhage and bony injury. A good quality non-contrast high resolution computed tomogram can …

Chronic subdural hematoma (CSDH) is a cause of significant morbidity and mortality which is often amenable to surgical drainage. The majority of patients recover rapidly after surgical intervention, but 5% to 30% experience recurrence. Although the use of drains after burr hole evacuation may lower recurrence, they are not used routinely because of a lack of evidence showing efficacy and a concern for increasing surgical morbidity. The aim of this study was to investigate the use of drains in reducing recurrence rates, and their influence on clinical outcome for those presenting with a CSDH.

Graphical abstract, Human brain chemistry is incompletely understood and better methodologies are needed. Traumatic brain injury (TBI) causes metabolic perturbations, one result of which includes increased brain lactate levels. Attention has largely focussed on glycolysis, whereby glucose is converted to pyruvate and lactate, and is proposed to act as an energy source by feeding into neurons’ tricarboxylic acid (TCA) cycle, generating ATP. Also reportedly upregulated by TBI is the pentose phosphate pathway (PPP) that does not generate ATP but produces various molecules that are putatively neuroprotective, antioxidant and reparative, in addition to lactate among the end products. We have developed a novel combination of 13C-labelled cerebral microdialysis both to deliver 13C-labelled substrates into brains of TBI patients and recover the 13C-labelled metabolites, with high-resolution 13C NMR analysis of the microdialysates. This methodology has enabled us to achieve the first direct demonstration in humans that the brain can utilise lactate via the TCA cycle. We are currently using this methodology to make the first direct comparison of glycolysis and the PPP in human brain. In this article, we consider the application of 13C-labelled cerebral microdialysis for studying brain energy metabolism in patients. We set this methodology within the context of metabolic pathways in the brain, and 13C research modalities addressing them.