Reduced temporal muscle thickness predicts shorter survival in patients undergoing chronic subdural haematoma drainage.

BACKGROUND: Chronic subdural haematoma (CSDH) drainage is a common neurosurgical procedure. CSDHs cause excess mortality, which is exacerbated by frailty. Sarcopenia contributes to frailty - its key component, low muscle mass, can be assessed using cross-sectional imaging. We aimed to examine the prognostic role of temporal muscle thickness (TMT) measured from preoperative computed tomography head scans among patients undergoing surgical CSDH drainage. METHODS: We retrospectively identified all patients who underwent CSDH drainage within 1 year of February 2019. We measured their mean TMT from preoperative computed tomography scans, tested the reliability of these measurements, and evaluated their prognostic value for postoperative survival. RESULTS: One hundred and eighty-eight (122, 65% males) patients (median age 78 years, IQR 70-85 years) were included. Thirty-four (18%) patients died within 2 years, and 51 (27%) died at a median follow-up of 39 months (IQR 34-42 months). Intra- and inter-observer reliability of TMT measurements was good-to-excellent (ICC 0.85-0.97, P < 0.05). TMT decreased with age (Pearson's r = -0.38, P < 0.001). Females had lower TMT than males (P < 0.001). The optimal TMT cut-off values for predicting two-year survival were 4.475 mm for males and 3.125 mm for females. TMT below these cut-offs was associated with shorter survival in both univariate (HR 3.24, 95% CI 1.85-5.67) and multivariate (HR 1.86, 95% CI 1.02-3.36) analyses adjusted for age, ASA grade and bleed size. The effect of TMT on mortality was not mediated by age. CONCLUSIONS: In patients with CSDH, TMT measurements from preoperative imaging were reliable and contained prognostic information supplemental to previously known predictors of poor outcomes.

Visualization of Cerebral Pressure Autoregulatory Insults in Traumatic Brain Injury.

OBJECTIVES: The first aim was to investigate the combined effect of insult intensity and duration of the pressure reactivity index (PRx) and deviation from the autoregulatory cerebral perfusion pressure target (∆CPPopt = actual CPP - optimal CPP [CPPopt]) on outcome in traumatic brain injury. The second aim was to determine if PRx influenced the association between intracranial pressure (ICP), CPP, and ∆CPPopt with outcome. DESIGN: Observational cohort study. SETTING: Neurocritical care unit, Cambridge, United Kingdom. PATIENTS: Five hundred fifty-three traumatic brain injury patients with ICP and arterial blood pressure monitoring and 6-month outcome data (Glasgow Outcome Scale [GOS]). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The insult intensity (mm Hg or PRx coefficient) and duration (minutes) of ICP, PRx, CPP, and ∆CPPopt were correlated with GOS and visualized in heatmaps. In these plots, there was a transition from favorable to unfavorable outcome when PRx remained positive for 30 minutes and this was also the case for shorter durations when the intensity was higher. In a similar plot of ∆CPPopt, there was a gradual transition from favorable to unfavorable outcome when ∆CPPopt went below -5 mm Hg for 30-minute episodes of time and for shorter durations for more negative ∆CPPopt. Furthermore, the percentage of monitoring time with certain combinations of PRx with ICP, CPP, and ∆CPPopt were correlated with GOS and visualized in heatmaps. In the combined PRx/ICP heatmap, ICP above 20 mm Hg together with PRx above 0 correlated with unfavorable outcome. In a PRx/CPP heatmap, CPP below 70 mm Hg together with PRx above 0.2-0.4 correlated with unfavorable outcome. In the PRx-/∆CPPopt heatmap, ∆CPPopt below 0 together with PRx above 0.2-0.4 correlated with unfavorable outcome. CONCLUSIONS: Higher intensities for longer durations of positive PRx and negative ∆CPPopt correlated with worse outcome. Elevated ICP, low CPP, and negative ∆CPPopt were particularly associated with worse outcomes when the cerebral pressure autoregulation was concurrently impaired.

Technical considerations and long-term results of endovascular venous stenting to control venous hypertension from meningiomas invading intracranial venous sinuses.

OBJECTIVE: Meningiomas invading the intracranial venous sinuses may cause intracranial venous hypertension, papilledema, and visual compromise. Sinus resection and graft reconstructions, however, add significant complexity to tumor surgery, with the potential for increased morbidity. In this study, the authors explored whether venous sinus stenting might provide an alternative means of controlling venous hypertension that would be sustainable over the long term. METHODS: The authors performed a retrospective review of all 16 patients with intracranial meningiomas who underwent stenting at their institution for venous sinus compromise. At presentation, all had headache and 9 had papilledema. Thirteen patients had 1 meningioma and 3 had 2 or more. Three patients had had previous tumor resection and radiotherapy. One patient had been treated with a lumboperitoneal shunt and radiotherapy. The median length of clinical follow-up was 8 years (range 4 months-18 years). RESULTS: Venous sinus narrowing was often not confined to the site of meningioma, and bilateral transverse sinus narrowing, reminiscent of that seen in idiopathic intracranial hypertension, was present in 7 patients with sagittal sinus meningiomas. Eleven patients had stents placed solely across sinus narrowing caused by meningioma. Five patients had additional stents placed at other sites of venous narrowing at the same time: in one of these patients, a stent was placed across a defect in the sagittal sinus caused by previous surgery, and in the 4 other patients, stents were placed across nontumor narrowings of the transverse sinuses. In 1 patient, the jugular vein was also stented. Nine patients developed symptomatic in-stent restenosis at the meningioma site. Eight had further stenting procedures with variable success in restoring the in-stent lumen. The remaining patient, with a late partial relapse, is being reinvestigated. Papilledema resolved in all patients after stenting. Six patients experienced prolonged and very substantial relief of all symptoms. Five patients had persistent headache despite restoration of the sinus lumen. Five had persistent symptoms associated with resistant in-stent stenosis. There were no significant complications from any of the diagnostic or therapeutic procedures. CONCLUSIONS: In patients who are symptomatic with meningiomas obstructing the venous sinuses, successful stenting of the affected segment can give a good outcome, especially in terms of relieving papilledema. However, further procedures are often necessary to maintain stent patency, other areas of venous compromise frequently coexist, and some patients remain symptomatic despite apparently successful treatment of the index lesion. Long-term surveillance is a requirement.

Brain tissue oxygen monitoring in traumatic brain injury-part II: isolated and combined insults in relation to outcome.

BACKGROUND: The primary aim was to explore the concept of isolated and combined threshold-insults for brain tissue oxygenation (pbtO2) in relation to outcome in traumatic brain injury (TBI). METHODS: A total of 239 TBI patients with data on clinical outcome (GOS) and intracranial pressure (ICP) and pbtO2 monitoring for at least 12 h, who had been treated at the neurocritical care unit, Addenbrooke's Hospital, Cambridge, UK, between 2002 and 2022 were included. Outcome was dichotomised into favourable/unfavourable (GOS 4-5/1-3) and survival/mortality (GOS 2-5/1). PbtO2 was studied over the entire monitoring period. Thresholds were analysed in relation to outcome based on median and mean values, percentage of time and dose per hour below critical values and visualised as the combined insult intensity and duration. RESULTS: Median pbtO2 was slightly, but not significantly, associated with outcome. A pbtO2 threshold at 25 and 20 mmHg, respectively, yielded the highest x2 when dichotomised for favourable/unfavourable outcome and mortality/survival in chi-square analyses. A higher dose and higher percentage of time spent with pbtO2 below 25 mmHg as well as lower thresholds were associated with unfavourable outcome, but not mortality. In a combined insult intensity and duration analysis, there was a transition from favourable towards unfavourable outcome when pbtO2 went below 25-30 mmHg for 30 min and similar transitions occurred for shorter durations when the intensity was higher. Although these insults were rare, pbtO2 under 15 mmHg was more strongly associated with unfavourable outcome if, concurrently, ICP was above 20 mmHg, cerebral perfusion pressure below 60 mmHg, or pressure reactivity index above 0.30 than if these variables were not deranged. In a multiple logistic regression, a higher percentage of monitoring time with pbtO2 < 15 mmHg was associated with a higher rate of unfavourable outcome. CONCLUSIONS: Low pbtO2, under 25 mmHg and particularly below 15 mmHg, for longer durations and in combination with disturbances in global cerebral physiological variables were associated with poor outcome and may indicate detrimental ischaemic hypoxia. Prospective trials are needed to determine if pbtO2-directed therapy is beneficial, at what individualised pbtO2 threshold therapies are warranted, and how this may depend on the presence/absence of concurrent cerebral physiological disturbances.

Results of Surgical Treatment of Aneurysmal Subarachnoid Hemorrhage in a Single Institution Over 12 Years.

OBJECTIVE: For patients with aneurysmal subarachnoid hemorrhage (aSAH) in whom endovascular treatment is not the optimal treatment strategy, microsurgical clipping remains a viable option. We examined changes in morbidity and outcome over time in patients treated surgically and in relation to surgeon volume and experience. METHODS: All patients who underwent microsurgery for aSAH from 2007 to 2019 at our institution were included. We compared technical complication rates and surgical outcomes between experienced (≥50 independent cases) and inexperienced (<50 independent cases) surgeons and between high-volume (≥20 cases/year) and low-volume (<20 cases/year) surgeons. RESULTS: Most of the 1,003 aneurysms (970 patients, median age 56 years) were in the middle cerebral (41.4%), anterior communicating (27.6%), and posterior communicating (17.5%) arteries; 46.5% were <7 mm. The technical complication rate was 7%, resulting in postoperative infarct in 4.9% of patients. Nineteen patients (2%) died within 30 days of admission. There were no significant changes in rates of technical complication, postoperative infarct, or mortality over the study period. There were no differences in postoperative infarction and technical complication rates between experienced and inexperienced surgeons (P = 0.28 and P = 0.05, respectively), but there were differences when comparing high-volume and low-volume surgeons (P = 0.03 and P < 0.001, respectively). The independent predictors of postoperative infarctions were aneurysm size (P = 0.001), intraoperative large-vessel injury (P < 0.001), and low surgeon volume (P = 0.03). CONCLUSIONS: We present real-world data on surgical morbidity and outcomes after aSAH. We demonstrated a relationship between surgeon volume and outcome for surgical treatment of aSAH, which supports the benefit of subspecialization in cerebrovascular surgery.

Brain tissue oxygen monitoring in traumatic brain injury: part I-To what extent does PbtO2 reflect global cerebral physiology?

BACKGROUND: The primary aim was to explore the association of global cerebral physiological variables including intracranial pressure (ICP), cerebrovascular reactivity (PRx), cerebral perfusion pressure (CPP), and deviation from the PRx-based optimal CPP value (∆CPPopt; actual CPP-CPPopt) in relation to brain tissue oxygenation (pbtO2) in traumatic brain injury (TBI). METHODS: A total of 425 TBI patients with ICP- and pbtO2 monitoring for at least 12 h, who had been treated at the neurocritical care unit, Addenbrooke's Hospital, Cambridge, UK, between 2002 and 2022 were included. Generalized additive models (GAMs) and linear mixed effect models were used to explore the association of ICP, PRx, CPP, and CPPopt in relation to pbtO2. PbtO2 < 20 mmHg, ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, and ∆CPPopt < - 5 mmHg were considered as cerebral insults. RESULTS: PbtO2 < 20 mmHg occurred in median during 17% of the monitoring time and in less than 5% in combination with ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, or ∆CPPopt < - 5 mmHg. In GAM analyses, pbtO2 remained around 25 mmHg over a large range of ICP ([0;50] mmHg) and PRx [- 1;1], but deteriorated below 20 mmHg for extremely low CPP below 30 mmHg and ∆CPPopt below - 30 mmHg. In linear mixed effect models, ICP, CPP, PRx, and ∆CPPopt were significantly associated with pbtO2, but the fixed effects could only explain a very small extent of the pbtO2 variation. CONCLUSIONS: PbtO2 below 20 mmHg was relatively frequent and often occurred in the absence of disturbances in ICP, PRx, CPP, and ∆CPPopt. There were significant, but weak associations between the global cerebral physiological variables and pbtO2, suggesting that hypoxic pbtO2 is often a complex and independent pathophysiological event. Thus, other variables may be more crucial to explain pbtO2 and, likewise, pbtO2 may not be a suitable outcome measure to determine whether global cerebral blood flow optimization such as CPPopt therapy is successful.

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.

Microdialysis-Based Classifications of Abnormal Metabolic States after Traumatic Brain Injury: A Systematic Review of the Literature.

After traumatic brain injury (TBI), cerebral metabolism can become deranged, contributing to secondary injury. Cerebral microdialysis (CMD) allows cerebral metabolism assessment and is often used with other neuro-monitoring modalities. CMD-derived parameters such as the lactate/pyruvate ratio (LPR) show a failure of oxidative energy generation. CMD-based abnormal metabolic states can be described following TBI, informing the etiology of physiological derangements. This systematic review summarizes the published literature on microdialysis-based abnormal metabolic classifications following TBI. Original research studies in which the populations were patients with TBI were included. Studies that described CMD-based classifications of metabolic abnormalities were included in the synthesis of the narrative results. A total of 825 studies underwent two-step screening after duplicates were removed. Fifty-three articles that used CMD in TBI patients were included. Of these, 14 described abnormal metabolic states based on CMD parameters. Classifications were heterogeneous between studies. LPR was the most frequently used parameter in the classifications; high LPR values were described as metabolic crisis. Ischemia was consistently defined as high LPR with low CMD substrate levels (glucose or pyruvate). Mitochondrial dysfunction, describing inability to use energy substrate despite availability, was identified based on raised LPR with near-normal levels of pyruvate. This is the first systematic review summarizing the published literature on microdialysis-based abnormal metabolic states following TBI. Although variability exists among individual classifications, there is broad agreement about broad definitions of metabolic crisis, ischemia, and mitochondrial dysfunction. Identifying the etiology of deranged cerebral metabolism after TBI is important for targeting therapeutic interventions.

Comparison of health-related quality of life in patients with traumatic brain injury, subarachnoid haemorrhage and cervical spine disease.

PURPOSE: The degree of disability that is acceptable to patients following traumatic brain injury (TBI) continues to be debated. While the dichotomization of outcome on the Glasgow Outcome Score (GOSE) into 'favourable' and 'unfavourable' continues to guide clinical decisions, this may not reflect an individual's subjective experience. The aim of this study is to assess how patients' self-reported quality of life (QoL) relates to objective outcome assessments and how it compares to other debilitating neurosurgical pathologies, including subarachnoid haemorrhage (SAH) and cervical myelopathy. METHOD: A retrospective analysis of over 1300 patients seen in Addenbrooke's Hospital, Cambridge, UK with TBI, SAH and patients pre- and post- cervical surgery was performed. QoL was assessed using the SF-36 questionnaire. Kruskal-Wallis test was used to analyse the difference in SF-36 domain scores between the four unpaired patient groups. To determine how the point of dichotomization of GOSE into 'favourable' and 'unfavourable' outcome affected QOL, SF-36 scores were compared between GOSE and mRS. RESULTS: There was a statistically significant difference in the median Physical Component Score (PCS) and Mental Component Score (MCS) of SF-36 between the three neurosurgical pathologies. Patients with TBI and SAH scored higher on most SF-36 domains when compared with cervical myelopathy patients in the severe category. While patients with Upper Severe Disability on GOSE showed significantly higher PC and MC scores compared to GOSE 3, there was a significant degree of variability in individual responses across the groups. CONCLUSION: A significant number of patients following TBI and SAH have better self-reported QOL than cervical spine patients and patients' subjective perception and expectations following injury do not always correspond to objective disability. These results can guide discussion of treatment and outcomes with patients and families.

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.

Characterising the dynamics of cerebral metabolic dysfunction following traumatic brain injury: A microdialysis study in 619 patients.

Traumatic brain injury (TBI) is a major cause of death and disability, particularly amongst young people. Current intensive care management of TBI patients is targeted at maintaining normal brain physiology and preventing secondary injury. Microdialysis is an invasive monitor that permits real-time assessment of derangements in cerebral metabolism and responses to treatment. We examined the prognostic value of microdialysis parameters, and the inter-relationships with other neuromonitoring modalities to identify interventions that improve metabolism. This was an analysis of prospective data in 619 adult TBI patients requiring intensive care treatment and invasive neuromonitoring at a tertiary UK neurosciences unit. Patients had continuous measurement of intracranial pressure (ICP), arterial blood pressure (ABP), brain tissue oxygenation (PbtO2), and cerebral metabolism and were managed according to a standardized therapeutic protocol. Microdialysate was assayed hourly for metabolites including glucose, pyruvate, and lactate. Cerebral perfusion pressure (CPP) and cerebral autoregulation (PRx) were derived from the ICP and ABP. Outcome was assessed with the Glasgow Outcome Score (GOS) at 6 months. Relationships between monitoring variables was examined with generalized additive mixed models (GAMM). Lactate/Pyruvate Ratio (LPR) over the first 3 to 7 days following injury was elevated amongst patients with poor outcome and was an independent predictor of ordinal GOS (p<0.05). Significant non-linear associations were observed between LPR and cerebral glucose, CPP, and PRx (p<0.001 to p<0.05). GAMM models suggested improved cerebral metabolism (i.e. reduced LPR with CPP >70mmHg, PRx <0.1, PbtO2 >18mmHg, and brain glucose >1mM. Deranged cerebral metabolism is an important determinant of patient outcome following TBI. Variations in cerebral perfusion, oxygenation and glucose supply are associated with changes in cerebral LPR and suggest therapeutic interventions to improve cerebral metabolism. Future prospective studies are required to determine the efficacy of these strategies.

Systemic inflammation alters the neuroinflammatory response: a prospective clinical trial in traumatic brain injury.

BACKGROUND: Neuroinflammation following traumatic brain injury (TBI) has been shown to be associated with secondary injury development; however, how systemic inflammatory mediators affect this is not fully understood. The aim of this study was to see how systemic inflammation affects markers of neuroinflammation, if this inflammatory response had a temporal correlation between compartments and how different compartments differ in cytokine composition. METHODS: TBI patients recruited to a previous randomised controlled trial studying the effects of the drug anakinra (Kineret®), a human recombinant interleukin-1 receptor antagonist (rhIL1ra), were used (n = 10 treatment arm, n = 10 control arm). Cytokine concentrations were measured in arterial and jugular venous samples twice a day, as well as in microdialysis-extracted brain extracellular fluid (ECF) following pooling every 6 h. C-reactive protein level (CRP), white blood cell count (WBC), temperature and confirmed systemic clinical infection were used as systemic markers of inflammation. Principal component analyses, linear mixed-effect models, cross-correlations and multiple factor analyses were used. RESULTS: Jugular and arterial blood held similar cytokine information content, but brain-ECF was markedly different. No clear arterial to jugular gradient could be seen. No substantial delayed temporal associations between blood and brain compartments were detected. The development of a systemic clinical infection resulted in a significant decrease of IL1-ra, G-CSF, PDGF-ABBB, MIP-1b and RANTES (p < 0.05, respectively) in brain-ECF, even if adjusting for injury severity and demographic factors, while an increase in several cytokines could be seen in arterial blood. CONCLUSIONS: Systemic inflammation, and infection in particular, alters cytokine levels with different patterns seen in brain and in blood. Cerebral inflammatory monitoring provides independent information from arterial and jugular samples, which both demonstrate similar information content. These findings could present potential new treatment options in severe TBI patients, but novel prospective trials are warranted to confirm these associations.

Longitudinal Changes in Size of Conservatively Managed Flow-Related Aneurysms Associated with Brain Arteriovenous Malformations.

BACKGROUND: Flow aneurysms (FAs) associated with brain arteriovenous malformations (AVMs) are thought to arise from increased hemodynamic stress due to high-flow shunting. This study aims to describe the changes in conservatively managed FAs after successful AVM treatment. METHODS: Patients with symptomatic AVMs and associated FAs who underwent successful treatment of the AVM between 2008 and 2017 were included. FA dimensions were measured on surveillance angiography to assess longitudinal changes. RESULTS: Thirty-two patients were identified with 48 FAs. Sixteen (33%) FAs were treated endovascularly; 18 (38%) FAs were treated surgically; and 14 (29%) FAs (11 patients) were monitored. FAs demonstrated a decrease in size from 5.0 mm to 3.8 mm (24%; P = 0.016) and 4.9 mm to 3.6 mm (27%; P = 0.013) in height and width, respectively, over a median 35 months. However, on subgroup analysis, only class IIb aneurysms demonstrated a significant decrease in size (51% reduction in largest diameter, P = 0.046) and only 3 FAs (21%) resolved. There were no hemorrhages observed during follow-up. CONCLUSIONS: While conservatively managed FAs demonstrated a reduction in size after the culprit AVM was treated, this was only significant in FAs located close to an AVM nidus (class IIb). There were no hemorrhages during the median 35 months' follow-up; however, long-term data are lacking. Our data support close observation of all conservatively managed aneurysms and a tailored approach based on the proximity to the nidus and observed changes in size.

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.

Phosphorus spectroscopy in acute TBI demonstrates metabolic changes that relate to outcome in the presence of normal structural MRI.

Metabolic dysfunction is a key pathophysiological process in the acute phase of traumatic brain injury (TBI). Although changes in brain glucose metabolism and extracellular lactate/pyruvate ratio are well known, it was hitherto unknown whether these translate to downstream changes in ATP metabolism and intracellular pH. We have performed the first clinical voxel-based in vivo phosphorus magnetic resonance spectroscopy (31P MRS) in 13 acute-phase major TBI patients versus 10 healthy controls (HCs), at 3T, focusing on eight central 2.5 × 2.5 × 2.5 cm3 voxels per subject. PCr/γATP ratio (a measure of energy status) in TBI patients was significantly higher (median = 1.09) than that of HCs (median = 0.93) (p < 0.0001), due to changes in both PCr and ATP. There was no significant difference in PCr/γATP between TBI patients with favourable and unfavourable outcome. Cerebral intracellular pH of TBI patients was significantly higher (median = 7.04) than that of HCs (median = 7.00) (p = 0.04). Alkalosis was limited to patients with unfavourable outcome (median = 7.07) (p < 0.0001). These changes persisted after excluding voxels with > 5% radiologically visible injury. This is the first clinical demonstration of brain alkalosis and elevated PCr/γATP ratio acutely after major TBI. 31P MRS has potential for non-invasively assessing brain injury in the absence of structural injury, predicting outcome and monitoring therapy response.

Thresholds for identifying pathological intracranial pressure in paediatric traumatic brain injury.

Intracranial pressure (ICP) monitoring forms an integral part of the management of severe traumatic brain injury (TBI) in children. The prediction of elevated ICP from imaging is important when deciding on whether to implement invasive ICP monitoring for a patient. However, the radiological markers of pathologically elevated ICP have not been specifically validated in paediatric studies. Here in, we describe an objective, non-invasive, quantitative method of stratifying which patients are likely to require invasive monitoring. A retrospective review of patients admitted to Cambridge University Hospital's Paediatric Intensive Care Unit between January 2009 and December 2016 with a TBI requiring invasive neurosurgical monitoring was performed. Radiological biomarkers of TBI (basal cistern volume, ventricular volume, volume of extra-axial haematomas) from CT scans were measured and correlated with epochs of continuous high frequency variables of pressure monitoring around the time of imaging. 38 patients were identified. Basal cistern volume was found to correlate significantly with opening ICP (r = -0.53, p < 0.001). The optimal threshold of basal cistern volume for predicting high ICP ([Formula: see text]20 mmHg) was a relative volume of 0.0055 (sensitivity 79%, specificity 80%). Ventricular volume and extra-axial haematoma volume did not correlate significantly with opening ICP. Our results show that the features of pathologically elevated ICP in children may differ considerably from those validated in adults. The development of quantitative parameters can help to predict which patients would most benefit from invasive neurosurgical monitoring and we present a novel radiological threshold for this.

Predictors of early progression of surgically treated atypical meningiomas.

BACKGROUND: Clinical behaviour of atypical meningiomas is not uniform. While, as a group, they exhibit a high recurrence rate, some pursue a more benign course, whereas others progress early. We aim to investigate the imaging and pathological factors that predict risk of early tumour progression and to determine whether early progression is related to outcome. METHODS: Adult patients with WHO grade II meningioma treated in three regional referral centres between 2007 and 2014 were included. MRI and pathology characteristics were assessed. Gross total resection (GTR) was defined as Simpson 1-3. Recurrence was classified into early and late (≤ 24 vs. > 24 months). RESULTS: Among the 220 cases, 37 (16.8%) patients progressed within 24 months of operation. Independent predictors of early progression were subtotal resection (STR) (p = 0.005), parafalcine/parasagittal location (p = 0.015), peritumoural oedema (p = 0.027) and mitotic index (MI) > 7 (p = 0.007). Adjuvant radiotherapy was negatively associated with early recurrence (p = 0.046). Thirty-two per cent of patients with residual tumour and 26% after GTR received adjuvant radiotherapy. There was a significantly lower proportion of favourable outcomes at last follow-up (mRS 0-1) in patients with early recurrence (p = 0.001). CONCLUSIONS: Atypical meningiomas are a heterogeneous group of tumours with 16.8% patients having recurrence within 24 months of surgery. Residual tumour, parafalcine/parasagittal location, peritumoural oedema and a MI > 7 were all independently associated with early recurrence. As administration of adjuvant radiotherapy was not protocolised in this cohort, any conclusions about benefits of irradiation of WHO grade II meningiomas should be viewed with caution. Patients with early recurrence had worse neurological outcome. While histological and imaging characteristics provide some prognostic value, further molecular characterisation of atypical meningiomas is warranted to aid clinical decision making.

The effect of succinate on brain NADH/NAD+ redox state and high energy phosphate metabolism in acute traumatic brain injury.

A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31P MRS at 3T, and tissue NADH/NAD+ redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days). Succinate perfusion was associated with increased extracellular pyruvate (+26%, p < 0.0001) and decreased L/P ratio (-13%, p < 0.0001) in patients overall (baseline-vs-supplementation over time), but no clear-cut change in 31P MRS PCr/ATP existed in our cohort (p > 0.4, supplemented-voxel-vs-contralateral voxel). However, the percentage decrease in L/P ratio for each patient following succinate perfusion correlated significantly with their percentage increase in PCr/ATP ratio (Spearman's rank correlation, r = -0.86, p = 0.024). Our findings support the interpretation that L/P ratio is linked to brain energy state, and that succinate may support brain energy metabolism in select TBI patients suffering from mitochondrial dysfunction.

Pre-hospital Predictors of Impaired ICP Trends in Continuous Monitoring of Paediatric Traumatic Brain Injury Patients.

OBJECTIVE: Although secondary insults such as raised intracranial pressure (ICP) or cardiovascular compromise strongly contribute to morbidity, a growing interest can be noticed in how the pre-hospital management can affect outcomes after traumatic brain injury (TBI). The objective of this study was to determine whether pre-hospital co-morbidity has influence on patterns of continuously measured waveforms of intracranial physiology after paediatric TBI. MATERIALS AND METHODS: Thirty-nine patients (mean age, 10 years; range, 0.5-15) admitted between 2002 and 2015 were used for the current analysis. Pre-hospital motor score, pupil reactivity, pre-hospital hypoxia (SpO2 < 90%) and hypotension (mean arterial pressure < 70 mmHg) were documented. ICP and arterial blood pressure (ABP) were monitored continuously with an intraparenchymal microtransducer and an indwelling arterial line. Pressure monitors were connected to bedside computers running ICM+ software. Pressure reactivity was determined as the moving correlation between 30 10-s averages of ABP and ICP (PRx). The mean ICP and PRx were calculated for the whole monitoring period for each patient. RESULTS: Those with pre-hospital hypotension were susceptible to higher ICP [20 (IQR 8) vs 13 (IQR 6) mmHg; p = 0.01] and more frequent ICP plateau waves [median = 0 (IQR 1), median = 4 (IQR 9); p = 0.001], despite having similar MAP, CPP and PRx during monitoring. Those with unreactive pupils tended to have higher ICP than those with reactive pupils (18 vs 14 mmHg, p = 0.08). Pre-hospital hypoxia, motor score and pupillary reactivity were not related to subsequent monitored intracranial or systemic physiology. CONCLUSION: In paediatric TBI, pre-hospital hypotension is associated with increased ICP in the intensive care unit.

Computed Tomography Indicators of Deranged Intracranial Physiology in Paediatric Traumatic Brain Injury.

OBJECTIVE: Computed tomography (CT) of the brain can allow rapid assessment of intracranial pathology after traumatic brain injury (TBI). Frequently in paediatric TBI, CT imaging can fail to display the classical features of severe brain injury with raised intracranial pressure. The objective of this study was to determine early CT brain features that influence intracranial or systemic physiological trends following paediatric TBI. MATERIALS AND METHODS: Thirty-three patients (mean age, 10 years; range, 0.5-16) admitted between 2002 and 2015 were used for the current analysis. Presence of petechial haemorrhages, basal cistern compression, subarachnoid blood, midline shift and extra-axial masses on the initial trauma CT head were assessed. ICP and arterial blood pressure (ABP) were then monitored continuously with an intraparenchymal microtransducer and an indwelling arterial line. Pressure monitors were connected to bedside computers running ICM+ software. Pressure reactivity was determined as the moving correlation between 30, 10-s averages of ABP and ICP (PRx). The mean ICP, ABP, cerebral perfusion pressure (CPP; ABP minus ICP) and PRx were calculated for the whole monitoring period for each patient. RESULTS: The presence of subarachnoid blood was related to higher ICP, higher ABP and a trend toward higher PRx. Smaller basal cisterns were related to increased ICP (R = -0.42, p = 0.02), impaired PRx (R = -0.5, p = 0.003). The presence of an extra-axial mass was associated with deranged PRx (-0.02 vs. 0.41, p = 0.003) and a trend toward higher ICP (14 vs. 40, p = 0.07). Interestingly the degree of midline shift was not related to ICP or PRx. CONCLUSIONS: The size of the basal cisterns, the presence of subarachnoid blood or an extra-axial mass are all related to disturbed ICP and pressure reactivity in this paediatric TBI cohort. Patients with these features are ideal candidates for invasive multimodal monitoring.