Publications by authors named "Peter J Hutchinson"

293 Publications

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

Nat Genet 2021 Jun 3;53(6):861-868. Epub 2021 Jun 3.

Division of Neurosurgery, Department of Clinical Neurosciences, Cambridge University Hospitals, Cambridge, UK.

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.
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http://dx.doi.org/10.1038/s41588-021-00875-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610960PMC
June 2021

CovidNeuroOnc: A UK multicenter, prospective cohort study of the impact of the COVID-19 pandemic on the neuro-oncology service.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab014. Epub 2021 Jan 28.

Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, UK.

Background: The COVID-19 pandemic has profoundly affected cancer services. Our objective was to determine the effect of the COVID-19 pandemic on decision making and the resulting outcomes for patients with newly diagnosed or recurrent intracranial tumors.

Methods: We performed a multicenter prospective study of all adult patients discussed in weekly neuro-oncology and skull base multidisciplinary team meetings who had a newly diagnosed or recurrent intracranial (excluding pituitary) tumor between 01 April and 31 May 2020. All patients had at least 30-day follow-up data. Descriptive statistical reporting was used.

Results: There were 1357 referrals for newly diagnosed or recurrent intracranial tumors across 15 neuro-oncology centers. Of centers with all intracranial tumors, a change in initial management was reported in 8.6% of cases ( = 104/1210). Decisions to change the management plan reduced over time from a peak of 19% referrals at the start of the study to 0% by the end of the study period. Changes in management were reported in 16% ( = 75/466) of cases previously recommended for surgery and 28% of cases previously recommended for chemotherapy ( = 20/72). The reported SARS-CoV-2 infection rate was similar in surgical and non-surgical patients (2.6% vs. 2.4%, > .9).

Conclusions: Disruption to neuro-oncology services in the UK caused by the COVID-19 pandemic was most marked in the first month, affecting all diagnoses. Patients considered for chemotherapy were most affected. In those recommended surgical treatment this was successfully completed. Longer-term outcome data will evaluate oncological treatments received by these patients and overall survival.
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http://dx.doi.org/10.1093/noajnl/vdab014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928638PMC
January 2021

Improving Neurosurgery Education Using Social Media Case-Based Discussions: A Pilot Study.

World Neurosurg X 2021 Jul 31;11:100103. Epub 2021 Mar 31.

Department of Neurosurgery, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.

Background: The increasing shift toward a more generalized medical undergraduate curriculum has led to limited exposure to subspecialties, including neurosurgery. The lack of standardized teaching may result in insufficient coverage of core learning outcomes. Social media (SoMe) in medical education are becoming an increasingly accepted and popular way for students to meet learning objectives outside formal medical school teaching. We delivered a series of case-based discussions (CbDs) over SoMe to attempt to meet core learning needs in neurosurgery and determine whether SoMe-based CbDs were an acceptable method of education.

Methods: Twitter was used as a medium to host 9 CbDs pertaining to common neurosurgical conditions in practice. A sequence of informative and interactive tweets were formulated before live CbDs and tweeted in progressive order. Demographic data and participant feedback were collected.

Results: A total of 277 participants were recorded across 9 CbDs, with 654,584 impressions generated. Feedback responses were received from 135 participants (48.7%). Participants indicated an increase of 77% in their level of knowledge after participating. Of participants, 57% ( = 77) had previous CbD experience as part of traditional medical education, with 62% ( = 84) receiving a form of medical education previously through SoMe. All participants believed that the CbDs objectives were met and would attend future sessions. Of participants, 99% ( = 134) indicated that their expectations were met.

Conclusions: SoMe has been shown to be a favorable and feasible medium to host live, text-based interactive CbDs. SoMe is a useful tool for teaching undergraduate neurosurgery and is easily translatable to all domains of medicine and surgery.
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http://dx.doi.org/10.1016/j.wnsx.2021.100103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095172PMC
July 2021

Surgical microdiscectomy versus transforaminal epidural steroid injection in patients with sciatica secondary to herniated lumbar disc (NERVES): a phase 3, multicentre, open-label, randomised controlled trial and economic evaluation.

Lancet Rheumatol 2021 May 18;3(5):e347-e356. Epub 2021 Mar 18.

Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, UK.

Background: The optimal invasive treatment for sciatica secondary to herniated lumbar disc remains controversial, with a paucity of evidence for use of non-surgical treatments such as transforaminal epidural steroid injection (TFESI) over surgical microdiscectomy. We aimed to investigate the clinical and cost-effectiveness of these options for management of radicular pain secondary to herniated lumbar disc.

Methods: We did a pragmatic, multicentre, phase 3, open-label, randomised controlled trial at 11 spinal units across the UK. Eligible patients were aged 16-65 years, had MRI-confirmed non-emergency sciatica secondary to herniated lumbar disc with symptom duration between 6 weeks and 12 months, and had leg pain that was not responsive to non-invasive management. Participants were randomly assigned (1:1) to receive either TFESI or surgical microdiscectomy by an online randomisation system that was stratified by centre with random permuted blocks. The primary outcome was Oswestry Disability Questionnaire (ODQ) score at 18 weeks. All randomly assigned participants who completed a valid ODQ at baseline and at 18 weeks were included in the analysis. Safety analysis included all treated participants. Cost-effectiveness was estimated from the EuroQol-5D-5L, Hospital Episode Statistics, medication usage, and self-reported resource-use data. This trial was registered with ISRCTN, number ISRCTN04820368, and EudraCT, number 2014-002751-25.

Findings: Between March 6, 2015, and Dec 21, 2017, 163 (15%) of 1055 screened patients were enrolled, with 80 participants (49%) randomly assigned to the TFESI group and 83 participants (51%) to the surgery group. At week 18, ODQ scores were 30·02 (SD 24·38) for 63 assessed patients in the TFESI group and 22·30 (19·83) for 61 assessed patients in the surgery group. Mean improvement was 24·52 points (18·89) for the TFESI group and 26·74 points (21·35) for the surgery group, with an estimated treatment difference of -4·25 (95% CI -11·09 to 2·59; p=0·22). There were four serious adverse events in four participants associated with surgery, and none with TFESI. Compared with TFESI, surgery had an incremental cost-effectiveness ratio of £38 737 per quality-adjusted life-year gained, and a 0·17 probability of being cost-effective at a willingness-to-pay threshold of £20 000 per quality-adjusted life-year.

Interpretation: For patients with sciatica secondary to herniated lumbar disc, with symptom duration of up to 12 months, TFESI should be considered as a first invasive treatment option. Surgery is unlikely to be a cost-effective alternative to TFESI.

Funding: Health Technology Assessment programme of the National Institute for Health Research (NIHR), UK.
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http://dx.doi.org/10.1016/S2665-9913(21)00036-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080892PMC
May 2021

Chest Computed Tomography for the Diagnosis of COVID-19 in Emergency Trauma Surgery Patients Who Require Urgent Care During the Pandemic: Protocol for an Umbrella Review.

JMIR Res Protoc 2021 May 6;10(5):e25207. Epub 2021 May 6.

National Institute of Health Research Global Health Research Group on Neurotrauma, University of Cambridge, Cambridge, United Kingdom.

Background: Many health care facilities in low- and middle-income countries are inadequately resourced. COVID-19 has the potential to decimate surgical health care services unless health systems take stringent measures to protect health care workers from viral exposure and ensure the continuity of specialized care for patients. Among these measures, the timely diagnosis of COVID-19 is paramount to ensure the use of protective measures and isolation of patients to prevent transmission to health care personnel caring for patients with an unknown COVID-19 status or contact during the pandemic. Besides molecular and antibody tests, chest computed tomography (CT) has been assessed as a potential tool to aid in the screening or diagnosis of COVID-19 and could be valuable in the emergency care setting.

Objective: This paper presents the protocol for an umbrella review that aims to identify and summarize the available literature on the diagnostic accuracy of chest CT for COVID-19 in trauma surgery patients requiring urgent care. The objective is to inform future recommendations on emergency care for this category of patients.

Methods: We will conduct several searches in the L·OVE (Living Overview of Evidence) platform for COVID-19, a system that performs automated regular searches in PubMed, Embase, Cochrane Central Register of Controlled Trials, and over 30 other sources. The search results will be presented according to PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis). This review will preferentially consider systematic reviews of diagnostic test accuracy studies, as well as individual studies of such design, if not included in the systematic reviews, that assessed the sensitivity and specificity of chest CT in emergency trauma surgery patients. Critical appraisal of the included studies for risk of bias will be conducted. Data will be extracted using a standardized data extraction tool. Findings will be summarized narratively, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach will be used to grade the certainty of evidence.

Results: Ethics approval is not required for this systematic review, as there will be no patient involvement. The search for this systematic review commenced in October 2020, and we expect to publish the findings in early 2021. The plan for dissemination is to publish the findings in a peer-reviewed journal and present our results at conferences that engage the most pertinent stakeholders.

Conclusions: During the COVID-19 pandemic, protecting health care workers from infection is essential. Up-to-date information on the efficacy of diagnostic tests for detecting COVID-19 is essential. This review will serve an important role as a thorough summary to inform evidence-based recommendations on establishing effective policy and clinical guideline recommendations.

Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42020198267; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=198267.

International Registered Report Identifier (irrid): PRR1-10.2196/25207.
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http://dx.doi.org/10.2196/25207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104001PMC
May 2021

Current surgical practice for multi-level degenerative cervical myelopathy: Findings from an international survey of spinal surgeons.

J Clin Neurosci 2021 May 17;87:84-88. Epub 2021 Mar 17.

Division of Neurosurgery, Addenbrooke's Hospital and University of Cambridge, Cambridge, United Kingdom; Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield, United Kingdom.

Degenerative cervical myelopathy (DCM) results from compression of the cervical spine cord as a result of age related changes in the cervical spine, and affects up to 2% of adults, leading to progressive disability. Surgical decompression is the mainstay of treatment, but there remains significant variation in surgical approaches used. This survey was conducted in order to define current practice amongst spine surgeons worldwide, as a possible prelude to further studies comparing surgical approaches.

Methods: An electronic survey was developed and piloted by the investigators using SurveyMonkey. Collected data was categorical and is presented using summary statistics. Where applicable, statistical comparisons were made using a Chi-Squared test. The level of significance for all statistical analyses was defined as p < 0.05. All analysis, including graphs was performed using R (R Studio).

Results: 127 surgeons, from 30 countries completed the survey; principally UK (66, 52%) and North America (15, 12%). Respondents were predominantly Neurosurgeons by training (108, 85%) of whom 84 (75%) reported Spinal Surgery as the principal part of their practice. The majority indicated they selected their surgical procedure for multi-level DCM on a case by case basis (62, 49%). Overall, a posterior approach was more popular for multi-level DCM (74, 58%). Region, speciality or annual multi-level case load did not influence this significantly. However, there was a trend for North American surgeons to be more likely to favour a posterior approach.

Conclusions: A posterior approach was favoured and more commonly used to treat multi-level DCM, in an international cohort of surgeons. Posterior techniques including laminectomy, laminectomy and fusion or laminoplasty appeared to be equally popular.
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http://dx.doi.org/10.1016/j.jocn.2021.01.049DOI Listing
May 2021

Microdiscectomy compared with transforaminal epidural steroid injection for persistent radicular pain caused by prolapsed intervertebral disc: the NERVES RCT.

Health Technol Assess 2021 Apr;25(24):1-86

Liverpool Clinical Trials Centre, University of Liverpool (member of Liverpool Health Partners), Liverpool, UK.

Background: Sciatica is a common condition reported to affect > 3% of the UK population at any time and is most often caused by a prolapsed intervertebral disc. Currently, there is no uniformly adopted treatment strategy. Invasive treatments, such as surgery (i.e. microdiscectomy) and transforaminal epidural steroid injection, are often reserved for failed conservative treatment.

Objective: To compare the clinical effectiveness and cost-effectiveness of microdiscectomy with transforaminal epidural steroid injection for the management of radicular pain secondary to lumbar prolapsed intervertebral disc for non-emergency presentation of sciatica of < 12 months' duration.

Interventions: Patients were randomised to either (1) microdiscectomy or (2) transforaminal epidural steroid injection.

Design: A pragmatic, multicentre, randomised prospective trial comparing microdiscectomy with transforaminal epidural steroid injection for sciatica due to prolapsed intervertebral disc with < 1 year symptom duration.

Setting: NHS services providing secondary spinal surgical care within the UK.

Participants: A total of 163 participants (aged 16-65 years) were recruited from 11 UK NHS outpatient clinics.

Main Outcome Measures: The primary outcome was participant-completed Oswestry Disability Questionnaire score at 18 weeks post randomisation. Secondary outcomes were visual analogue scores for leg pain and back pain; modified Roland-Morris score (for sciatica), Core Outcome Measures Index score and participant satisfaction at 12-weekly intervals. Cost-effectiveness and quality of life were assessed using the EuroQol-5 Dimensions, five-level version; Hospital Episode Statistics data; medication usage; and self-reported cost data at 12-weekly intervals. Adverse event data were collected. The economic outcome was incremental cost per quality-adjusted life-year gained from the perspective of the NHS in England.

Results: Eighty-three participants were allocated to transforaminal epidural steroid injection and 80 participants were allocated to microdiscectomy, using an online randomisation system. At week 18, Oswestry Disability Questionnaire scores had decreased, relative to baseline, by 26.7 points in the microdiscectomy group and by 24.5 points in the transforaminal epidural steroid injection. The difference between the treatments was not statistically significant (estimated treatment effect -4.25 points, 95% confidence interval -11.09 to 2.59 points). Nor were there significant differences between treatments in any of the secondary outcomes: Oswestry Disability Questionnaire scores, visual analogue scores for leg pain and back pain, modified Roland-Morris score and Core Outcome Measures Index score up to 54 weeks. There were four (3.8%) serious adverse events in the microdiscectomy group, including one nerve palsy (foot drop), and none in the transforaminal epidural steroid injection group. Compared with transforaminal epidural steroid injection, microdiscectomy had an incremental cost-effectiveness ratio of £38,737 per quality-adjusted life-year gained and a probability of 0.17 of being cost-effective at a willingness to pay threshold of £20,000 per quality-adjusted life-year.

Limitations: Primary outcome data was invalid or incomplete for 24% of participants. Sensitivity analyses demonstrated robustness to assumptions made regarding missing data. Eighteen per cent of participants in the transforaminal epidural steroid injection group subsequently received microdiscectomy prior to their primary outcome assessment.

Conclusions: To the best of our knowledge, the NErve Root Block VErsus Surgery trial is the first trial to evaluate the comparative clinical effectiveness and cost-effectiveness of microdiscectomy and transforaminal epidural steroid injection. No statistically significant difference was found between the two treatments for the primary outcome. It is unlikely that microdiscectomy is cost-effective compared with transforaminal epidural steroid injection at a threshold of £20,000 per quality-adjusted life-year for sciatica secondary to prolapsed intervertebral disc.

Future Work: These results will lead to further studies in the streamlining and earlier management of discogenic sciatica.

Trial Registration: Current Controlled Trials ISRCTN04820368 and EudraCT 2014-002751-25.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 24. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072519PMC
April 2021

Differences in Cerebrospinal Fluid Dynamics in Posttraumatic Hydrocephalus Versus Atrophy, Including Effect of Decompression and Cranioplasty.

Acta Neurochir Suppl 2021 ;131:343-347

Division of Neurosurgery, Department of Clinical Neuroscience, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Introduction: Challenges in diagnosing post-traumatic hydrocephalus (PTH) have created a need for an accurate diagnostic tool. We aim to report CSF dynamics in PTH and atrophy, along with differences before and after cranioplasty.

Methods: We retrospectively analyzed traumatic brain injury patients with ventriculomegaly who had infusion studies. We divided patients depending on CSF dynamics into two groups: 'likely PTH' (A) and 'likely atrophy' (B). A group of idiopathic normal pressure hydrocephalus shunt-responsive patients was used for comparison (C).

Results: Group A consisted of 36 patients who were non-decompressed or had a cranioplasty in situ for over 1 month. Group B included 16 patients with low Rout, AMP, and dAMP, 9 of whom were decompressed. Rout and dAMP were significantly higher in Group A than B, but significantly lower than Group C (45 iNPH patients). RAP change during infusion in group A indicated depleted compensatory reserve compared to ample reserve in group B. Repeat studies in five decompressed patients post-cranioplasty showed all parameters increased.

Conclusions: Infusion tests are not useful in decompressed patients, whilst cranioplasty allowed differentiation between possible PTH and atrophy. Rout and AMP were significantly lower in PTH compared to iNPH and did not always reflect the degree of hydrocephalus reported on imaging.
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http://dx.doi.org/10.1007/978-3-030-59436-7_66DOI Listing
June 2021

Single Center Experience in Cerebrospinal Fluid Dynamics Testing.

Acta Neurochir Suppl 2021 ;131:311-313

Division of Neurosurgery, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Normal pressure hydrocephalus is more complex than a simple disturbance of the cerebrospinal fluid (CSF) circulation. Nevertheless, an assessment of CSF dynamics is key to making decisions about shunt insertion, shunt malfunction, and for further management if a patient fails to improve. We summarize our 25 years of single center experience in CSF dynamics assessment using pressure measurement and analysis. 4473 computerized infusion tests have been performed. We have shown that CSF infusion studies are safe, with incidence of infection at less than 1%. Raised resistance to CSF outflow positively correlates (p < 0.014) with improvement after shunting and is associated with disturbance of cerebral blood flow and its autoregulation (p < 0.02). CSF infusion studies are valuable in assessing possible shunt malfunction in vivo and for avoiding unnecessary revisions. Infusion tests are safe and provide useful information for clinical decision-making for the management of patients suffering from hydrocephalus.
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http://dx.doi.org/10.1007/978-3-030-59436-7_58DOI Listing
June 2021

An Update on the COGiTATE Phase II Study: Feasibility and Safety of Targeting an Optimal Cerebral Perfusion Pressure as a Patient-Tailored Therapy in Severe Traumatic Brain Injury.

Acta Neurochir Suppl 2021 ;131:143-147

Department of Intensive Care Medicine, University of Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.

Introduction: Monitoring of cerebral autoregulation (CA) in patients with a traumatic brain injury (TBI) can provide an individual 'optimal' cerebral perfusion pressure (CPP) target (CPPopt) at which CA is best preserved. This potentially offers an individualized precision medicine approach. Retrospective data suggest that deviation of CPP from CPPopt is associated with poor outcomes. We are prospectively assessing the feasibility and safety of this approach in the COGiTATE [CPPopt Guided Therapy: Assessment of Target Effectiveness] study. Its primary objective is to demonstrate the feasibility of individualizing CPP at CPPopt in TBI patients. The secondary objectives are to investigate the safety and physiological effects of this strategy.

Methods: The COGiTATE study has included patients in four European hospitals in Cambridge, Leuven, Nijmegen, and Maastricht (coordinating centre). Patients with severe TBI requiring intracranial pressure (ICP)-directed therapy are allocated into one of two groups. In the intervention group, CPPopt is calculated using a published (modified) algorithm. In the control group, the CPP target recommended in the Brain Trauma Foundation guidelines (CPP 60-70 mmHg) is used.

Results: Patient recruitment started in February 2018 and will continue until 60 patients have been studied. Fifty-one patients (85% of the intended total) have been recruited in October 2019. The first results are expected early 2021.

Conclusion: This prospective evaluation of the feasibility, safety and physiological implications of autoregulation-guided CPP management is providing evidence that will be useful in the design of a future phase III study in severe TBI patients.
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http://dx.doi.org/10.1007/978-3-030-59436-7_29DOI Listing
June 2021

Variability of the Optic Nerve Sheath Diameter on the Basis of Sex and Age in a Cohort of Healthy Volunteers.

Acta Neurochir Suppl 2021 ;131:121-124

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Many studies have demonstrated that the optic nerve sheath diameter (ONSD) is a good indicator of intracranial pressure (ICP). There are uncertainties regarding the optimal ONSD threshold, considering age and sex differences in the healthy population, and these differences could lead to uncertainties in evaluation of ONSD in pathological conditions.The aim of this prospective observational study was to investigate if age and sex could influence ONSD in a cohort of healthy Italian volunteers recruited during preanesthetic assessment for low-risk surgical procedures.The population was stratified for sex (males versus females) and for age (18-44 years, 45-64 years, and ≥65 years). The axial and longitudinal ONSD diameters were measured by two trained investigators.A significant difference in ONSD between males and females was found (median 4.2 (interquartile range 3.9-4.6) versus 4.1 (interquartile range 3.6-4.2) mm, P = 0.01), and a positive correlation between ONSD and age was found (R = 0.50, P < 0.0001).It was concluded that ONSD increases with age and is significantly larger in the healthy male population. These discrepancies should be taken into consideration when ONSD measurement is performed.
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http://dx.doi.org/10.1007/978-3-030-59436-7_25DOI Listing
June 2021

Cerebrovascular Consequences of Elevated Intracranial Pressure After Traumatic Brain Injury.

Acta Neurochir Suppl 2021 ;131:43-48

Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

We compared various descriptors of cerebral hemodynamics in 517 patients with traumatic brain injury (TBI) who had, on average, elevated (>23 mmHg) or normal (<15 mmHg) intracranial pressure (ICP). In a subsample of 193 of those patients, transcranial Doppler ultrasound (TCD) recordings were made. Arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), cerebral autoregulation indices based on TCD (the mean flow index (Mx; the coefficient of correlation between the the cerebral perfusion pressure CPP and flow velocity) and the autoregulation index (ARI)), and the pressure reactivity index (PRx) were compared between groups. We also analyzed the TCD-based cerebral blood flow (CBF) index (diastolic CBFV/mean CBFV), the spectral pulsatility index (sPI), and the critical closing pressure (CrCP). Finally, we also looked at brain tissue oxygenation (cerebral oxygen partial tension (PbtO)) in 109 patients. The mean cerebral perfusion pressure (CPP) was lower in the group with elevated ICP (p < 0.01), despite a higher mean arterial pressure (MAP) (p < 0.005) and worse autoregulation (as assessed with the Mx, ARI, and PRx indices), greater CrCP, a lower CBF index, and a higher sPI (all with p values of <0.001). Neither the mean CBFV nor PbtO reached significant differences between groups. Mortality in the group with elevated ICP was almost three times greater than that in the group with normal ICP (45% versus 17%). Elevated ICP affects cerebral autoregulation. When autoregulation is not working properly, the brain is exposed to ischemic insults whenever CPP falls.
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http://dx.doi.org/10.1007/978-3-030-59436-7_10DOI Listing
June 2021

External Hydrocephalus After Traumatic Brain Injury: Retrospective Study of 102 Patients.

Acta Neurochir Suppl 2021 ;131:35-38

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neuroscience, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Introduction: External hydrocephalus (EH) refers to impairment of extra-axial cerebrospinal fluid flow with enlargement of the subarachnoid space (SAS) and concomitant raised intracranial pressure (ICP). It is often confused with a subdural hygroma and overlooked, particularly when there is no ventricular enlargement. In this study, we aimed to describe the epidemiology of EH in a large population of adults with traumatic brain injury (TBI).

Methods: This observational, retrospective cohort study was conducted in adult patients who were admitted with TBI to the Department of Clinical Neuroscience at Addenbrooke's Hospital (Cambridge, UK) over a period of 3 years (2014-2017). Patients were included in the study if they had ICP monitoring and at least three CT scans within the first 21 days to assess SAS evolution. Patients who underwent a decompressive craniectomy were excluded. SAS was assessed individually on each CT scan by two independent investigators. ICP data were analysed with ICM+ software (Cambridge Enterprise Ltd., Cambridge, UK). Short-term and 6-month outcomes were examined. The groups of patients with and without EH were compared.

Results: Of the 102 patients included in the study, 30.4% developed EH after a delay of 2.98 ± 2.4 days. The initial Glasgow Coma Scale (GCS) scores did not differ between patients with and without EH. Subarachnoid haemorrhage was found to be the main risk factor for EH. Patients with EH required a significantly longer period of mechanical ventilation (+6.9 days), were more likely to have a tracheostomy (55% versus 33%), and had a longer stay in the intensive care unit (+8.5 days). ICP was higher during the 48 h after diagnosis of EH than during the previous 48 h. EH survivors had a lower mean Glasgow Outcome Scale Extended (GOS-E) score (4.6 versus 5.9, P = 0.031) and were more likely to receive a permanent shunt for secondary hydrocephalus (17.4% versus 1.8%, odds ratio 7.1).

Conclusion: In adults with TBI, EH remains insufficiently understood and probably underdiagnosed. This study showed that it is a frequent complication of TBI, with significant clinical consequences.
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http://dx.doi.org/10.1007/978-3-030-59436-7_8DOI Listing
June 2021

Analysis of the Association Between Lung Function and Brain Tissue Oxygen Tension in Severe Traumatic Brain Injury.

Acta Neurochir Suppl 2021 ;131:27-30

Neurosciences Critical Care, University of Cambridge, Cambridge, UK.

Introduction: Low brain tissue oxygen tension (PbtO) has been shown to be an independent factor associated with unfavourable outcomes in traumatic brain injury (TBI). Although PbtO provides clinicians with an understanding of ischaemic and non-ischaemic derangements of brain physiology, the value alone can be the result of several factors, including partial arterial oxygenation pressure (PaO), haemoglobin levels (Hb) and cerebral perfusion pressure (CPP).

Methods: This chapter presents a single-centre, retrospective cohort study of 70 adult patients with severe TBI who were admitted to the Neurocritical Care Unit (NCCU) at Addenbrooke's Hospital (Cambridge, UK) between October 2014 and December 2017. A total of 303 simultaneous measurements of different variables that included (but were not limited to) intracranial pressure (ICP), PaO, PbtO, CPP and the fraction of inspired oxygen (FiO) were considered in this work. We conducted a correlation analysis between all of the variables. We also implemented a longitudinal data analysis of the PbtO and PaO/FiO ratio (PF ratio).

Results: There were strong and independent correlations between PbtO and the PF ratio, and between PbtO and PaO, with adjusted p values of <0.001 for both correlations. After adjustment for ICP, age, sex and the Glasgow Coma Scale (GCS) score, a PF ≤ 330 was shown to be an independent risk factor for a compromised PbtO value of <20, with an adjusted odds ratio of 1.94 (95% confidence interval 1.12-3.34) and a p value of 0.02.

Conclusion: Brain and lung interactions in patients with TBI patients have complex interrelationships. Our results confirm the importance of employing lung-protective strategies to prevent brain hypoxia in patients with TBI.
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http://dx.doi.org/10.1007/978-3-030-59436-7_6DOI Listing
June 2021

An exploratory qualitative study of the prevention of road traffic collisions and neurotrauma in India: perspectives from key informants in an Indian industrial city (Visakhapatnam).

BMC Public Health 2021 03 30;21(1):618. Epub 2021 Mar 30.

NIHR Global Health Research Group on Neurotrauma, University of Cambridge, Cambridge, UK.

Background: Despite current preventative strategies, road traffic collisions (RTCs) and resultant neurotrauma remain a major problem in India. This study seeks to explore local perspectives in the context within which RTCs take place and identify potential suggestions for improving the current status.

Methods: Ten semi-structured interviews were carried out with purposively selected key informants from the city of Visakhapatnam, Andhra Pradesh. Participants were from one of the following categories: commissioning stakeholders; service providers; community or local patient group/advocacy group representatives. Transcripts from these interviews were analysed qualitatively using the Framework Method.

Results: Participants felt RTCs are a serious problem in India and a leading cause of neurotrauma. Major risk factors identified related to user behaviour such as speeding and not using personal safety equipment, and the user state, namely drink driving and underage driving. Other reported risk factors included poor infrastructure, moving obstacles on the road such as other vehicles, pedestrians and animals, overloaded vehicles and substandard safety equipment. Participants discussed how RTCs affect not only the health of the casualty, but are also a burden to the healthcare system, families, and the national economy. Although there are ongoing preventative strategies being carried out by both the government and the community, challenges to successful prevention emerged from the interviews which included resource deficiencies, inconsistent implementation, lack of appropriate action, poor governance, lack of knowledge and the mindset of the community and entities involved in prevention. Recommendations were given on how prevention of RTCs and neurotrauma might be improved, addressing the areas of education and awareness, research, the pre-hospital and trauma systems, enforcement and legislation, and road engineering, in addition to building collaborations and changing mindsets.

Conclusions: RTCs remain a major problem in India and a significant cause of neurotrauma. Addressing the identified gaps and shortfalls in current approaches and reinforcing collective responsibility towards road safety would be the way forward in improving prevention and reducing the burden.
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http://dx.doi.org/10.1186/s12889-021-10686-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008519PMC
March 2021

Prevention of road traffic collisions and associated neurotrauma in Colombia: An exploratory qualitative study.

PLoS One 2021 25;16(3):e0249004. Epub 2021 Mar 25.

NIHR Global Health Research Group on Neurotrauma, University of Cambridge, Cambridge, United Kingdom.

Introduction: Neurotrauma is an important but preventable cause of death and disability worldwide, with the majority being associated with road traffic collisions (RTCs). The greatest burden is seen in low -and middle- income countries (LMICs) where variations in the environment, infrastructure, population and habits can challenge the success of conventional preventative approaches. It is therefore necessary to understand local perspectives to allow for the development and implementation of context-specific strategies which are effective and sustainable.

Methods: This study took place in Colombia where qualitative data collection was carried out with ten key informants between October and November 2019. Semi-structured interviews were conducted and explored perceptions on RTCs and neurotrauma, preventative strategies and interventions, and the role of research in prevention. Interview transcripts were analysed by thematic analysis using a framework approach.

Results: Participants' confirmed that RTCs are a significant problem in Colombia with neurotrauma as an important outcome. Human and organisational factors were identified as key causes of the high rates of RTCs. Participants described the current local preventative strategies, but were quick to discuss limitations and challenges to their success. Key barriers reported were poor attitudes and knowledge, particularly in the community. Suggestions were provided on ways to improve prevention through better education and awareness, stricter enforcement and new policies on prevention, proper budgeting and resource allocation, as well as through collaboration and changes in attitudes and leadership. Participants identified four key research areas they felt would influence prevention of RTCs and associated neurotrauma: causes of RTCs; consequences and impact of RTCs; public involvement in research; improving prevention.

Conclusion: RTCs are a major problem in Colombia despite the current preventative strategies and interventions. Findings from this study have a potential to influence policy, practice and research by illustrating different solutions to the challenges surrounding prevention and by highlighting areas for further research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249004PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993809PMC
March 2021

Management of traumatic brain injury (TBI): a clinical neuroscience-led pathway for the NHS.

Clin Med (Lond) 2021 03;21(2):e198-e205

National Hospital for Neurology and Neurosurgery, London, UK and Homerton University Hospital NHS Foundation Trust, London, UK

Following hyperacute management after traumatic brain injury (TBI), most patients receive treatment which is inadequate or inappropriate, and delayed. This results in suboptimal rehabilitation outcome and avoidable detrimental chronic effects on patients' recovery. This worsens long-term disability, and magnifies costs to the individual and society. We believe that accurate diagnosis (at the level of pathology, impairment and function) of the causes of disability is a prerequisite for appropriate care and for accessing effective rehabilitation. An expert-led, integrated care pathway is needed to deliver accurate and timely diagnosis and optimal treatment at all stages during a TBI patient's care.We propose the introduction of a specialist interdisciplinary traumatic brain injury team, led by a neurosciences-trained brain injury consultant. This team would engage acutely and for a longer term after TBI to provide accurate diagnoses, which guides subsequent management and rehabilitation. This approach would also encourage more efficient collaboration between research and the clinic. We propose that the current major trauma network is leveraged to introduce and evaluate this proposal. Improvements to patient outcomes through this approach would lead to reduced personal, societal and economic impact of TBI.
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http://dx.doi.org/10.7861/clinmed.2020-0336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002793PMC
March 2021

Decompressive craniotomy: an international survey of practice.

Acta Neurochir (Wien) 2021 05 18;163(5):1415-1422. Epub 2021 Mar 18.

NIHR Global Health Research Group on Neurotrauma, University of Cambridge, Cambridge, UK.

Background: Traumatic brain injury (TBI) and stroke have devastating consequences and are major global public health issues. For patients that require a cerebral decompression after suffering a TBI or stroke, a decompressive craniectomy (DC) is the most commonly performed operation. However, retrospective non-randomized studies suggest that a decompressive craniotomy (DCO; also known as hinge or floating craniotomy), where a bone flap is replaced but not rigidly fixed, has comparable outcomes to DC. The primary aim of this project was to understand the current extent of usage of DC and DCO for TBI and stroke worldwide.

Method: A questionnaire was designed and disseminated globally via emailing lists and social media to practicing neurosurgeons between June and November 2019.

Results: We received 208 responses from 60 countries [40 low- and middle-income countries (LMICs)]. DC is used more frequently than DCO, however, about one-quarter of respondents are using a DCO in more than 25% of their patients. The three top indications for a DCO were an acute subdural hematoma (ASDH) and a GCS of 9-12, ASDH with contusions and a GCS of 3-8, and ASDH with contusions and a GCS of 9-12. There were 8 DCO techniques used with the majority (60/125) loosely tying sutures to the bone flap. The majority (82%) stated that they were interested in collaborating on a randomized trial of DCO vs. DC.

Conclusion: Our results show that DCO is a procedure carried out for TBI and stroke, especially in LMICs, and most commonly for an ASDH. The majority of the respondents were interested in collaborating on a is a future randomized trial.
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http://dx.doi.org/10.1007/s00701-021-04783-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053664PMC
May 2021

Personal protective equipment for reducing the risk of COVID-19 infection among healthcare workers involved in emergency trauma surgery during the pandemic: an umbrella review protocol.

BMJ Open 2021 03 2;11(3):e045598. Epub 2021 Mar 2.

Neuroscience Institute, INUB-MEDITECH Research Group, El Bosque University, Bogotá, Colombia

Introduction: Many healthcare facilities in low-income and middle-income countries are inadequately resourced and may lack optimal organisation and governance, especially concerning surgical health systems. COVID-19 has the potential to decimate these already strained surgical healthcare services unless health systems take stringent measures to protect healthcare workers (HCWs) from viral exposure and ensure the continuity of specialised care for patients. The objective of this broad evidence synthesis is to identify and summarise the available literature regarding the efficacy of different personal protective equipment (PPE) in reducing the risk of COVID-19 infection in health personnel caring for patients undergoing trauma surgery in low-resource environments.

Methods: We will conduct several searches in the L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs automated regular searches in PubMed, Embase, Cochrane Central Register of Controlled Trials and over 30 other sources. The search results will be presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. This review will preferentially consider systematic reviews of experimental and quasi-experimental studies, as well as individual studies of such designs, evaluating the effect of different PPE on the risk of COVID-19 infection in HCWs involved in emergency trauma surgery. Critical appraisal of eligible studies for methodological quality will be conducted. Data will be extracted using the standardised data extraction tool in Covidence. Studies will, when possible, be pooled in a statistical meta-analysis using JBI SUMARI. The Grading of Recommendations, Assessment, Development and Evaluation approach for grading the certainty of evidence will be followed and a summary of findings will be created.

Ethics And Dissemination: Ethical approval is not required for this review. The plan for dissemination is to publish review findings in a peer-reviewed journal and present findings at high-level conferences that engage the most pertinent stakeholders.

Prospero Registration Number: CRD42020198267.
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http://dx.doi.org/10.1136/bmjopen-2020-045598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929636PMC
March 2021

Research Evaluating Sports ConcUssion Events-Rapid Assessment of Concussion and Evidence for Return (RESCUE-RACER): a two-year longitudinal observational study of concussion in motorsport.

BMJ Open Sport Exerc Med 2021 13;7(1):e000879. Epub 2021 Jan 13.

Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Introduction: Concussion is a clinical diagnosis, based on self-reported patient symptoms supported by clinical assessments across many domains including postural control, ocular/vestibular dysfunction, and neurocognition. Concussion incidence may be rising in motorsport which, combined with unresolved challenges to accurate diagnosis and lack of guidance on the optimal return-to-race timeframe, creates a difficult environment for healthcare practitioners.

Methods And Analysis: Research Evaluating Sports ConcUssion Events-Rapid Assessment of Concussion and Evidence for Return (RESCUE-RACER) evaluates motorsports competitors at baseline (Competitor Assessment at Baseline; Ocular, Neuroscientific (CArBON) study) and post-injury (Concussion Assessment and Return to motorSport (CARS) study), including longitudinal data. CArBON collects pre-injury neuroscientific data; CARS repeats the CArBON battery sequentially during recovery for competitors involved in a potentially concussive event. As its primary outcome, RESCUE-RACER will develop the evidence base for an accurate trackside diagnostic tool. Baseline objective clinical scoring (Sport Concussion Assessment Tool-5th edition (SCAT5)) and neurocognitive data (Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT)) will be assessed for specificity to motorsport and relationship to existing examinations. Changes to SCAT5 and ocular, vestibular, and reaction time function (Dx 100) will be estimated by the reliability change index as a practical tool for trackside diagnosis. Neuropsychological (Cambridge Neuropsychological Test Automated Battery (CANTAB)) assessments, brain MRI (7 Tesla) and salivary biomarkers will be compared with the new tool to establish utility in diagnosing and monitoring concussive injuries.

Ethics And Dissemination: Ethical approval was received from East of England-Cambridge Central Research Ethics Committee (18/EE/0141). Participants will be notified of study outcomes via publications (to administrators) and summary reports (funder communications). Ideally, all publications will be open access.

Trial Registration Number: February 2019 nationally (Central Portfolio Management System 38259) and internationally (ClinicalTrials.gov NCT03844282).
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http://dx.doi.org/10.1136/bmjsem-2020-000879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812087PMC
January 2021

Personal protective equipment for reducing the risk of COVID-19 infection among health care workers involved in emergency trauma surgery during the pandemic: An umbrella review.

J Trauma Acute Care Surg 2021 04;90(4):e72-e80

From the NIHR Global Health Research Group on Neurotrauma (D.P.G., A.K., P.J.H., A.M.R.), University of Cambridge; Division of Neurosurgery (D.P.G., A.K., P.J.H.), Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Clinical Research Center (A.G.), Fundación Valle del Lili, Cali; Neuroscience Institute (A.M.R.), INUB-MEDITECH Research Group, El Bosque University, Bogotá; and Neurological Surgery Service (A.M.R.), Vallesalud Clinic, Cali, Colombia.

Background: Health care facilities in low- and middle-income countries are inadequately resourced to adhere to current COVID-19 prevention recommendations. Recommendations for surgical emergency trauma care measures need to be adequately informed by available evidence and adapt to particular settings. To inform future recommendations, we set to summarize the effects of different personal protective equipment (PPE) on the risk of COVID-19 infection in health personnel caring for trauma surgery patients.

Methods: We conducted an umbrella review using Living Overview of Evidence platform for COVID-19, which performs regular automated searches in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and more than 30 other sources. Systematic reviews of experimental and observational studies assessing the efficacy of PPE were included. Indirect evidence from other health care settings was also considered. Risk of bias was assessed with the AMSTAR II tool (Assessing the Methodological Quality of Systematic Reviews, Ottawa, ON, Canada), and the Grading of Recommendations, Assessment, Development, and Evaluation approach for grading the certainty of the evidence is reported (registered in International Prospective Register of Systematic Reviews, CRD42020198267).

Results: Eighteen studies that fulfilled the selection criteria were included. There is high certainty that the use of N95 respirators and surgical masks is associated with a reduced risk of COVID-19 when compared with no mask use. In moderate- to high-risk environments, N95 respirators are associated with a further reduction in risk of COVID-19 infection compared with surgical masks. Eye protection also reduces the risk of contagion in this setting. Decontamination of masks and respirators with ultraviolet germicidal irradiation, vaporous hydrogen peroxide, or dry heat is effective and does not affect PPE performance or fit.

Conclusion: The use of PPE drastically reduces the risk of COVID-19 compared with no mask use in health care workers. N95 and equivalent respirators provide more protection than surgical masks. Decontamination and reuse appear feasible to overcome PPE shortages and enhance the allocation of limited resources. These effects are applicable to emergency trauma care and should inform future recommendations.

Level Of Evidence: Review, level II.
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http://dx.doi.org/10.1097/TA.0000000000003073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996059PMC
April 2021

Trial of Dexamethasone for Chronic Subdural Hematoma.

N Engl J Med 2020 12 16;383(27):2616-2627. Epub 2020 Dec 16.

From the Divisions of Neurosurgery (P.J.H., E.E., E.P.T., S. Tarantino, K.C., H.M., T.S., C.T., A.G.K.) and Neurology (E.A.W.), Department of Clinical Neurosciences, and the Division of Experimental Medicine and Immunotherapeutics (I.W.), Addenbrooke's Hospital, University of Cambridge, and the Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust (A.A., B.P., C.D.-W., I.W., S.B.), Cambridge, the Faculty of Health: Medicine, Dentistry and Human Sciences, University of Plymouth (E.E.), and the South West Neurosurgical Centre, Derriford Hospital (E.E., P.C.W., M.G.), Plymouth, Wessex Neurological Unit, University Hospital Southampton, Southampton (D.B., A.Z., P.H.), the Department of Neurosurgery, Queen Elizabeth University Hospital, Glasgow (N.S., K.A.), the Department of Neurosurgery, Leeds General Infirmary, Leeds (S. Thomson, I.A.A.), the Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield (Y.Z.A.-T., D.H.), Translational Neurosurgery, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh (P.M.B.), Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich (G.B.), the Department of Neurosurgery, Great Ormond Street Hospital and Institute of Child Health, University College London (A.C.), and the National Hospital for Neurology and Neurosurgery (H.J.M.), London, the Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Salford Royal Hospital, Manchester Academic Health Science Centre, Manchester (A.T.K.), the National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre and Institute of Inflammation and Ageing, University of Birmingham, Birmingham (A.B.), and the Ageing Clinical and Experimental Research Group, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen (P.K.M.) - all in the United Kingdom; and the Department of Neurology, Karolinska University Hospital, Stockholm (E.P.T.).

Background: Chronic subdural hematoma is a common neurologic disorder that is especially prevalent among older people. The effect of dexamethasone on outcomes in patients with chronic subdural hematoma has not been well studied.

Methods: We conducted a multicenter, randomized trial in the United Kingdom that enrolled adult patients with symptomatic chronic subdural hematoma. The patients were assigned in a 1:1 ratio to receive a 2-week tapering course of oral dexamethasone, starting at 8 mg twice daily, or placebo. The decision to surgically evacuate the hematoma was made by the treating clinician. The primary outcome was a score of 0 to 3, representing a favorable outcome, on the modified Rankin scale at 6 months after randomization; scores range from 0 (no symptoms) to 6 (death).

Results: From August 2015 through November 2019, a total of 748 patients were included in the trial after randomization - 375 were assigned to the dexamethasone group and 373 to the placebo group. The mean age of the patients was 74 years, and 94% underwent surgery to evacuate their hematomas during the index admission; 60% in both groups had a score of 1 to 3 on the modified Rankin scale at admission. In a modified intention-to-treat analysis that excluded the patients who withdrew consent for participation in the trial or who were lost to follow-up, leaving a total of 680 patients, a favorable outcome was reported in 286 of 341 patients (83.9%) in the dexamethasone group and in 306 of 339 patients (90.3%) in the placebo group (difference, -6.4 percentage points [95% confidence interval, -11.4 to -1.4] in favor of the placebo group; P = 0.01). Among the patients with available data, repeat surgery for recurrence of the hematoma was performed in 6 of 349 patients (1.7%) in the dexamethasone group and in 25 of 350 patients (7.1%) in the placebo group. More adverse events occurred in the dexamethasone group than in the placebo group.

Conclusions: Among adults with symptomatic chronic subdural hematoma, most of whom had undergone surgery to remove their hematomas during the index admission, treatment with dexamethasone resulted in fewer favorable outcomes and more adverse events than placebo at 6 months, but fewer repeat operations were performed in the dexamethasone group. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Dex-CSDH ISRCTN number, ISRCTN80782810.).
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http://dx.doi.org/10.1056/NEJMoa2020473DOI Listing
December 2020

Robotic Semi-Automated Transcranial Doppler Assessment of Cerebrovascular Autoregulation in Post-Concussion Syndrome: Methodological Considerations.

Neurotrauma Rep 2020 25;1(1):218-231. Epub 2020 Nov 25.

Division of Neurosurgery, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.

Post-concussion syndrome (PCS) refers to a constellation of physical, cognitive, and emotional symptoms after traumatic brain injury (TBI). Despite its incidence and impact, the underlying mechanisms of PCS are unclear. We hypothesized that impaired cerebral autoregulation (CA) is a contributor. In this article, we present our protocol for non-invasively assessing CA in patients with TBI and PCS in a real-world clinical setting. A prospective, observational study was integrated into outpatient clinics at a tertiary neurosurgical center. Data points included: demographics, symptom profile (Post-Concussion Symptom Scale [PCSS]) and neuropsychological assessment (Cambridge Neuropsychological Test Automated-Battery [CANTAB]). Cerebrovascular metrics (nMxa co-efficient and the transient hyperaemic-response ratio [THRR]) were collected using transcranial Doppler (TCD), finger plethysmography, and bespoke software (ICM+). Twelve participants were initially recruited but 2 were excluded after unsuccessful insonation of the middle cerebral artery (MCA); 10 participants (5 patients with TBI, 5 healthy controls) were included in the analysis (median age 26.5 years, male to female ratio: 7:3). Median PCSS scores were 6/126 for the TBI patient sub-groups. Median CANTAB percentiles were 78 (healthy controls) and 25 (TBI). nMxa was calculated for 90% of included patients, whereas THRR was calculated for 50%. Median study time was 127.5 min and feedback ( = 6) highlighted the perceived acceptability of the study. This pilot study has demonstrated a reproducible assessment of PCS and CA metrics (non-invasively) in a real-world setting. This protocol is feasible and is acceptable to participants. By scaling this methodology, we hope to test whether CA changes are correlated with symptomatic PCS in patients post-TBI.
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http://dx.doi.org/10.1089/neur.2020.0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703686PMC
November 2020

Admission Levels of Interleukin 10 and Amyloid β 1-40 Improve the Outcome Prediction Performance of the Helsinki Computed Tomography Score in Traumatic Brain Injury.

Front Neurol 2020 30;11:549527. Epub 2020 Oct 30.

Department of Specialities of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Blood biomarkers may enhance outcome prediction performance of head computed tomography scores in traumatic brain injury (TBI). To investigate whether admission levels of eight different protein biomarkers can improve the outcome prediction performance of the Helsinki computed tomography score (HCTS) without clinical covariates in TBI. Eighty-two patients with computed tomography positive TBIs were included in this study. Plasma levels of β-amyloid isoforms 1-40 (Aβ40) and 1-42 (Aβ42), glial fibrillary acidic protein, heart fatty acid-binding protein, interleukin 10 (IL-10), neurofilament light, S100 calcium-binding protein B, and total tau were measured within 24 h from admission. The patients were divided into favorable (Glasgow Outcome Scale-Extended 5-8, = 49) and unfavorable (Glasgow Outcome Scale-Extended 1-4, = 33) groups. The outcome was assessed 6-12 months after injury. An optimal predictive panel was investigated with the sensitivity set at 90-100%. The HCTS alone yielded a sensitivity of 97.0% (95% CI: 90.9-100) and specificity of 22.4% (95% CI: 10.2-32.7) and partial area under the curve of the receiver operating characteristic of 2.5% (95% CI: 1.1-4.7), in discriminating patients with favorable and unfavorable outcomes. The threshold to detect a patient with unfavorable outcome was an HCTS > 1. The three best individually performing biomarkers in outcome prediction were Aβ40, Aβ42, and neurofilament light. The optimal panel included IL-10, Aβ40, and the HCTS reaching a partial area under the curve of the receiver operating characteristic of 3.4% (95% CI: 1.7-6.2) with a sensitivity of 90.9% (95% CI: 81.8-100) and specificity of 59.2% (95% CI: 40.8-69.4). Admission plasma levels of IL-10 and Aβ40 significantly improve the prognostication ability of the HCTS after TBI.
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http://dx.doi.org/10.3389/fneur.2020.549527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661930PMC
October 2020

Descriptive analysis of low versus elevated intracranial pressure on cerebral physiology in adult traumatic brain injury: a CENTER-TBI exploratory study.

Acta Neurochir (Wien) 2020 11 4;162(11):2695-2706. Epub 2020 Sep 4.

Brain Physics Lab, Division of Neurosurgery, Dept of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Background: To date, the cerebral physiologic consequences of persistently elevated intracranial pressure (ICP) have been based on either low-resolution physiologic data or retrospective high-frequency data from single centers. The goal of this study was to provide a descriptive multi-center analysis of the cerebral physiologic consequences of ICP, comparing those with normal ICP to those with elevated ICP.

Methods: The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) High-Resolution Intensive Care Unit (HR-ICU) sub-study cohort was utilized. The first 3 days of physiologic recording were analyzed, evaluating and comparing those patients with mean ICP < 15 mmHg versus those with mean ICP > 20 mmHg. Various cerebral physiologic parameters were derived and evaluated, including ICP, brain tissue oxygen (PbtO), cerebral perfusion pressure (CPP), pulse amplitude of ICP (AMP), cerebrovascular reactivity, and cerebral compensatory reserve. The percentage time and dose above/below thresholds were also assessed. Basic descriptive statistics were employed in comparing the two cohorts.

Results: 185 patients were included, with 157 displaying a mean ICP below 15 mmHg and 28 having a mean ICP above 20 mmHg. For admission demographics, only admission Marshall and Rotterdam CT scores were statistically different between groups (p = 0.017 and p = 0.030, respectively). The high ICP group displayed statistically worse CPP, PbtO, cerebrovascular reactivity, and compensatory reserve. The high ICP group displayed worse 6-month mortality (p < 0.0001) and poor outcome (p = 0.014), based on the Extended Glasgow Outcome Score.

Conclusions: Low versus high ICP during the first 72 h after moderate/severe TBI is associated with significant disparities in CPP, AMP, cerebrovascular reactivity, cerebral compensatory reserve, and brain tissue oxygenation metrics. Such ICP extremes appear to be strongly related to 6-month patient outcomes, in keeping with previous literature. This work provides multi-center validation for previously described single-center retrospective results.
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http://dx.doi.org/10.1007/s00701-020-04485-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550280PMC
November 2020

Lung Injury Is a Predictor of Cerebral Hypoxia and Mortality in Traumatic Brain Injury.

Front Neurol 2020 7;11:771. Epub 2020 Aug 7.

Neurocritical Care Unit, Addenbrooke's Hospital, Cambridge, United Kingdom.

A major contributor to unfavorable outcome after traumatic brain injury (TBI) is secondary brain injury. Low brain tissue oxygen tension (PbtO2) has shown to be an independent predictor of unfavorable outcome. Although PbtO2 provides clinicians with an understanding of the ischemic and non-ischemic derangements of brain physiology, its value does not take into consideration systemic oxygenation that can influence patients' outcomes. This study analyses brain and systemic oxygenation and a number of related indices in TBI patients: PbtO2, partial arterial oxygenation pressure (PaO2), PbtO2/PaO2, ratio of PbtO2 to fraction of inspired oxygen (FiO2), and PaO2/FiO2. The primary aim of this study was to identify independent risk factors for cerebral hypoxia. Secondary goal was to determine whether any of these indices are predictors of mortality outcome in TBI patients. A single-centre retrospective cohort study of 70 TBI patients admitted to the Neurocritical Care Unit (NCCU) at Cambridge University Hospital in 2014-2018 and undergoing advanced neuromonitoring including invasive PbtO2 was conducted. Three hundred and three simultaneous measurements of PbtO2, PaO2, PbtO2/PaO2, PbtO2/FiO2, PaO2/FiO2 were collected and mortality at discharge from NCCU was considered as outcome. Generalized estimating equations were used to analyse the longitudinal data. Our results showed PbtO2 of 28 mmHg as threshold to define cerebral hypoxia. PaO2/FiO2 found to be a strong and independent risk factor for cerebral hypoxia when adjusting for confounding factor of intracranial pressure (ICP) with adjusted odds ratio of 1.78, 95% confidence interval of (1.10-2.87) and -value = 0.019. With respect to TBI outcome, compromised values of PbtO2, PbtO2/PaO2, PbtO2/FiO2, and PaO2/FiO2 were all independent predictors of mortality while considered individually and adjusting for confounding factors of ICP, age, gender, and cerebral perfusion pressure (CPP). However, when considering all the compromised values together, only PaO2/FiO2 became an independent predictor of mortality with adjusted odds ratio of 3.47 (1.20-10.04) and -value = 0.022. Brain and Lung interaction in TBI patients is a complex interrelationship. PaO2/FiO2 seems to be a major determinant of cerebral hypoxia and mortality. These results confirm the importance of employing ventilator strategies to prevent cerebral hypoxia and improve the outcome in TBI patients.
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http://dx.doi.org/10.3389/fneur.2020.00771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426476PMC
August 2020

Effects of Age and Sex on Optic Nerve Sheath Diameter in Healthy Volunteers and Patients With Traumatic Brain Injury.

Front Neurol 2020 7;11:764. Epub 2020 Aug 7.

Brain Physics Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

The measurement of optic nerve sheath diameter (ONSD) has been reported as a non-invasive marker for intracranial pressure (ICP). Nevertheless, it is uncertain whether possible ONSD differences occur with age and sex in healthy and brain-injured populations. The aim of this study was to investigate the effects of sex and age on ONSD in healthy volunteers and patients with traumatic brain injury. We prospectively included 122 healthy adult volunteers (Galliera Hospital, Genova, Italy), and compared age/sex dependence of ONSD to 95 adult patients (Addenbrooke's Hospital, Cambridge, UK) with severe traumatic brain injury (TBI) requiring intubation and invasive ICP monitoring. The two groups were stratified for sex and age. Age was divided into 3 subgroups: (1) young adults: 18-44 years; (2) middle-aged adults: 45-64 years; (3) old adults: >65 years. In healthy volunteers, ONSD was significantly different between males and females [median (interquartile range): 4.2 (3.9-4.6) mm vs. 4.1 (3.6-4.2) mm ( = 0.01), respectively] and was correlated with age (R = 0.50, < 0.0001). ONSD was significantly increased in group 3 compared to groups 2 and 1, indicating that ONSD values are higher in elderly subjects. In TBI patients, no differences in ONSD were found for sex and the correlation between ONSD and age was non-significant (R = 0.13, = 0.20). ONSD increases with age and is significantly larger for males in healthy volunteers but not in TBI patients. Different ONSD cut-off values need not be age- or sex-adjusted for the assessment of increased ICP in TBI patients.
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http://dx.doi.org/10.3389/fneur.2020.00764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426488PMC
August 2020

Association between Physiological Signal Complexity and Outcomes in Moderate and Severe Traumatic Brain Injury: A CENTER-TBI Exploratory Analysis of Multi-Scale Entropy.

J Neurotrauma 2021 01 23;38(2):272-282. Epub 2020 Sep 23.

Brain Physics Laboratory, Division of Neurosurgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

In traumatic brain injury (TBI), preliminary retrospective work on signal entropy suggests an association with global outcome. The goal of this study was to provide multi-center validation of the association between multi-scale entropy (MSE) of cardiovascular and cerebral physiological signals, with six-month outcome. Using the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit (ICU) cohort, we selected patients with a minimum of 72 h of physiological recordings and a documented six-month Glasgow Outcome Scale Extended (GOSE) score. The 10-sec summary data for heart rate (HR), mean arterial pressure (MAP), intracranial pressure (ICP), and pulse amplitude of ICP (AMP) were derived across the first 72 h of data. The MSE complexity index (MSE-Ci) was determined for HR, MAP, ICP, and AMP, with the association between MSE and dichotomized six-month outcomes assessed using Mann-Whitney testing and logistic regression analysis. A total of 160 patients had a minimum of 72 h of recording and a documented outcome. Decreased HR MSE-Ci (7.3 [interquartile range (IQR) 5.4 to 10.2] vs. 5.1 [IQR 3.1 to 7.0];  = 0.002), lower ICP MSE-Ci (11.2 [IQR 7.5 to 14.2] vs. 7.3 [IQR 6.1 to 11.0];  = 0.009), and lower AMP MSE-Ci (10.9 [IQR 8.0 to 13.7] vs. 8.7 [IQR 6.6 to 11.0];  = 0.022), were associated with death. Similarly, lower HR MSE-Ci (8.0 [IQR 6.2 to 10.9] vs. 6.2 [IQR 3.9 to 8.7];  = 0.003) and lower ICP MSE-Ci (11.4 [IQR 8.6 to 14.4)] vs. 9.2 [IQR 6.0 to 13.5]), were associated with unfavorable outcome. Logistic regression analysis confirmed that lower HR MSE-Ci and ICP MSE-Ci were associated with death and unfavorable outcome at six months. These findings suggest that a reduction in cardiovascular and cerebrovascular system entropy is associated with worse outcomes. Further work in the field of signal complexity in TBI multi-modal monitoring is required.
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http://dx.doi.org/10.1089/neu.2020.7249DOI Listing
January 2021

Bedside EEG predicts longitudinal behavioural changes in disorders of consciousness.

Neuroimage Clin 2020 5;28:102372. Epub 2020 Aug 5.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; School of Computing, University of Kent, Canterbury, United Kingdom.

Providing an accurate prognosis for prolonged disorder of consciousness (pDOC) patients remains a clinical challenge. Large cross-sectional studies have demonstrated the diagnostic and prognostic value of functional brain networks measured using high-density electroencephalography (hdEEG). Nonetheless, the prognostic value of these neural measures has yet to be assessed by longitudinal follow-up. We address this gap by assessing the utility of hdEEG to prognosticate long-term behavioural outcome, employing longitudinal data collected from a cohort of patients assessed systematically with resting hdEEG and the Coma Recovery Scale-Revised (CRS-R) at the bedside over a period of two years. We used canonical correlation analysis to relate clinical (including CRS-R scores combined with demographic variables) and hdEEG variables to each other. This analysis revealed that the patient's age, and the hdEEG theta band power and alpha band connectivity, contributed most significantly to the relationship between hdEEG and clinical variables. Further, we found that hdEEG measures recorded at the time of assessment augmented clinical measures in predicting CRS-R scores at the next assessment. Moreover, the rate of hdEEG change not only predicted later changes in CRS-R scores, but also outperformed clinical measures in terms of prognostic power. Together, these findings suggest that improvements in functional brain networks precede changes in behavioural awareness in pDOC. We demonstrate here that bedside hdEEG assessments conducted at specialist nursing homes are feasible, have clinical utility, and can complement clinical knowledge and systematic behavioural assessments to inform prognosis and care.
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http://dx.doi.org/10.1016/j.nicl.2020.102372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426558PMC
August 2020

Neurosurgeons' experiences of conducting and disseminating clinical research in low- and middle-income countries: a qualitative study protocol.

BMJ Open 2020 08 13;10(8):e038939. Epub 2020 Aug 13.

Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK.

Introduction: Low-income and middle-income countries (LMICs) face the greatest burden of neurotrauma. However, most of the research published in scientific journals originates from high-income countries, suggesting those in LMICs are either not engaging in research or are not publishing it. Evidence originating in high-income countries may not be generalisable to LMICs; therefore, it is important to nurture research capacity in LMICs so that a relevant evidence base can be developed. However, little is published about specific challenges or contextual issues relevant to increasing research activity of neurosurgeons in LMICs. Therefore, the aim of this study was to understand neurosurgeons' experiences of, aspirations for and ability to conduct and disseminate clinical research in LMICs.

Methods And Analysis: This is a pragmatic qualitative study situated within the naturalistic paradigm using focus groups and interviews with a purposive sample of neurosurgeons from LMICs. First, we will conduct asynchronous online focus groups with 36 neurosurgeons to broadly explore issues relevant to the study aim. Second, we will select 20 participants for follow-up semistructured interviews to explore concepts in more depth and detail than could be achieved in the focus group. Interviews will be audio-recorded and transcribed verbatim. A thematic analysis will be conducted following Braun and Clarke's six stages and will be supported by NVIVO software.

Ethics And Dissemination: The University of Cambridge Psychology Research Ethics Committee reviewed this study and provided a favourable opinion in January 2020 (REF PRE.2020.006). Participants will provide informed consent, be able to withdraw at any time and will have their contributions kept confidential. The findings of the study will be shared with relevant stakeholders and disseminated in conference presentations and journal publications.
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http://dx.doi.org/10.1136/bmjopen-2020-038939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430326PMC
August 2020