Addressing barriers and identifying facilitators to support informed consent and recruitment in the Cavernous malformations A Randomised Effectiveness (CARE) pilot phase trial: insights from the integrated QuinteT recruitment intervention (QRI).

Background: It was anticipated that recruitment to the Cavernous malformations: A Randomised Effectiveness (CARE) pilot randomised trial would be challenging. The trial compared medical management and surgery (neurosurgical resection or stereotactic radiosurgery) with medical management alone, for people with symptomatic cerebral cavernous malformation (ISRCTN41647111). Previous trials comparing surgical and medical management for intracranial vascular malformations failed to recruit to target. A QuinteT Recruitment Intervention was integrated during trial accrual, September 2021-April 2023 inclusive, to improve informed consent and recruitment. Methods: The QuinteT Recruitment Intervention combined iterative collection and analysis of quantitative data (28 trial site screening logs recording numbers/proportions screened, eligible, approached and randomised) and qualitative data (79 audio-recorded recruitment discussions, 19 interviews with healthcare professionals, 11 interviews with patients, 2 investigator workshops, and observations of study meetings, all subject to thematic, content or conversation analysis). We triangulated quantitative and qualitative data to identify barriers and facilitators to recruitment and how and why these arose. Working with the chief investigators and trial management group, we addressed barriers and facilitators with corresponding actions to improve informed consent and recruitment. Findings: Barriers identified included how usual care practices made equipoise challenging, multi-disciplinary teams sometimes overrode recruiter equipoise and logistical issues rendered symptomatic cavernoma diagnosis and assessment for stereotactic radiosurgery challenging. Facilitators identified included the preparedness of some neurosurgeons' to offer surgery to people otherwise offered medical management alone, multi-disciplinary team equipoise, and effective information provision presenting participation as a solution to equipoise regarding management. Actions, before and during recruitment, to improve inclusivity of site screening, approach and effectiveness of information provision resulted in 72 participants recruited following a 5-month extension, exceeding the target of 60 participants. Interpretation: QuinteT Recruitment Intervention insights revealed barriers and facilitators, enabling identification of remedial actions. Recruitment to a definitive trial would benefit from further training/support to encourage clinicians to be comfortable approaching patients to whom medical management is usually offered, and broadening the pool of neurosurgeons and multi-disciplinary team members prepared to offer surgery, particularly stereotactic radiosurgery. Funding: National Institute for Health and Care Research.

The incidence and impact of 'Tandem Neurotrauma'.

Introduction: The epidemiology and prognosis of the isolated traumatic brain injury (TBI) and spinal cord injury (SCI) are well studied. However, the knowledge of the impact of concurrent neurotrauma is very limited. Research questions: To characterize the longitudinal incidence of concurrent TBI and SCI and to investigate their combined impact on clinical care and outcomes, compared to a comparative but isolated SCI or TBI. Materials and methods: Data from 167,793 patients in the Trauma Audit and Research Network (TARN) registry collected in England and Wales between 2008 and 2018 were analysed. Tandem neurotrauma was defined as patients with concurrent TBI and SCI. The patient with isolated TBI or SCI was matched to the patient with tandem neurotrauma using propensity scores. Results: The incidence of tandem neurotrauma increased tenfold between 2008 and 2018, from 0.21 to 2.21 per 100,000 person-years. Patients in the tandem neurotrauma group were more likely to require multiple surgeries, ICU admission, longer ICU and hospital LOS, higher 30-day mortality, and were more likely to be transferred to acute hospitals and rehabilitation or suffer death at discharge, compared to patients with isolated TBI. Likewise, individuals with tandem neurotrauma compared to those with isolated SCI had a higher tendency to receive more than one surgery, ICU admission, longer LOS for ICU and higher mortality either at 30-day follow-up or at discharge. Discussion and conclusions: The incidence of tandem neurotrauma has increased steadily during the past decade. Its occurrence leads to greater mortality and care requirements, particularly when compared to TBI alone. Further investigations are warranted to improve outcomes in tandem neurotrauma.

Comparative effectiveness of decompressive craniectomy versus craniotomy for traumatic acute subdural hematoma (CENTER-TBI): an observational cohort study.

Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014-2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12-26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% [IQR increase] more DC in a centre = 0.9 [95% CI 0.7-1.1], n = 200). Primary DC was associated with more follow-on surgeries and complications [secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%]; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 [95% CI (1.0-3.4), n = 200]). Interpretation: We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling. Funding: Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.

Early management of isolated severe traumatic brain injury patients in a hospital without neurosurgical capabilities: a consensus and clinical recommendations of the World Society of Emergency Surgery (WSES).

BACKGROUND: Severe traumatic brain-injured (TBI) patients should be primarily admitted to a hub trauma center (hospital with neurosurgical capabilities) to allow immediate delivery of appropriate care in a specialized environment. Sometimes, severe TBI patients are admitted to a spoke hospital (hospital without neurosurgical capabilities), and scarce data are available regarding the optimal management of severe isolated TBI patients who do not have immediate access to neurosurgical care. METHODS: A multidisciplinary consensus panel composed of 41 physicians selected for their established clinical and scientific expertise in the acute management of TBI patients with different specializations (anesthesia/intensive care, neurocritical care, acute care surgery, neurosurgery and neuroradiology) was established. The consensus was endorsed by the World Society of Emergency Surgery, and a modified Delphi approach was adopted. RESULTS: A total of 28 statements were proposed and discussed. Consensus was reached on 22 strong recommendations and 3 weak recommendations. In three cases, where consensus was not reached, no recommendation was provided. CONCLUSIONS: This consensus provides practical recommendations to support clinician's decision making in the management of isolated severe TBI patients in centers without neurosurgical capabilities and during transfer to a hub center.

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.

Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and malignant human neural progenitor cells.

Zika virus (ZIKV) can infect human developing brain (HDB) progenitors resulting in epidemic microcephaly, whereas analogous cellular tropism offers treatment potential for the adult brain cancer, glioblastoma (GBM). We compared productive ZIKV infection in HDB and GBM primary tissue explants that both contain SOX2+ neural progenitors. Strikingly, although the HDB proved uniformly vulnerable to ZIKV infection, GBM was more refractory, and this correlated with an innate immune expression signature. Indeed, GBM-derived CD11b+ microglia/macrophages were necessary and sufficient to protect progenitors against ZIKV infection in a non-cell autonomous manner. Using SOX2+ GBM cell lines, we found that CD11b+-conditioned medium containing type 1 interferon beta (IFNß) promoted progenitor resistance to ZIKV, whereas inhibition of JAK1/2 signaling restored productive infection. Additionally, CD11b+ conditioned medium, and IFNß treatment rendered HDB progenitor lines and explants refractory to ZIKV. These findings provide insight into neuroprotection for HDB progenitors as well as enhanced GBM oncolytic therapies.

Dex-CSDH randomised, placebo-controlled trial of dexamethasone for chronic subdural haematoma: report of the internal pilot phase.

The Dex-CSDH trial is a randomised, double-blind, placebo-controlled trial of dexamethasone for patients with a symptomatic chronic subdural haematoma. The trial commenced with an internal pilot, whose primary objective was to assess the feasibility of multi-centre recruitment. Primary outcome data collection and safety were also assessed, whilst maintaining blinding. We aimed to recruit 100 patients from United Kingdom Neurosurgical Units within 12 months. Trial participants were randomised to a 2-week course of dexamethasone or placebo in addition to receiving standard care (which could include surgery). The primary outcome measure of the trial is the modified Rankin Scale at 6 months. This pilot recruited ahead of target; 100 patients were recruited within nine months of commencement. 47% of screened patients consented to recruitment. The primary outcome measure was collected in 98% of patients. No safety concerns were raised by the independent data monitoring and ethics committee and only five patients were withdrawn from drug treatment. Pilot trial data can inform on the design and resource provision for substantive trials. This internal pilot was successful in determining recruitment feasibility. Excellent follow-up rates were achieved and exploratory outcome measures were added to increase the scientific value of the trial.

Optimal Cerebral Perfusion Pressure in Centers With Different Treatment Protocols.

OBJECTIVES: The three centers in this study have different policies regarding cerebral perfusion pressure targets and use of vasopressors in traumatic brain injury patients. The aim was to determine if the different policies affected the estimation of cerebral perfusion pressure which optimizes the strength of cerebral autoregulation, termed "optimal cerebral perfusion pressure." DESIGN: Retrospective analysis of prospectively collected data. SETTING: Three neurocritical care units at university hospitals in Cambridge, United Kingdom, Groningen, the Netherlands, and Uppsala, Sweden. PATIENTS: A total of 104 traumatic brain injury patients were included: 35 each from Cambridge and Groningen, and 34 from Uppsala. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In Groningen, the cerebral perfusion pressure target was greater than or equal to 50 and less than 70 mm Hg, in Uppsala greater than or equal to 60, and in Cambridge greater than or equal to 60 or preferably greater than or equal to 70. Despite protocol differences, median cerebral perfusion pressure for each center was above 70 mm Hg. Optimal cerebral perfusion pressure was calculated as previously published and implemented in the Intensive Care Monitoring+ software by the Cambridge group, now replicated in the Odin software in Uppsala. Periods with cerebral perfusion pressure above and below optimal cerebral perfusion pressure were analyzed, as were absolute difference between cerebral perfusion pressure and optimal cerebral perfusion pressure and percentage of monitoring time with a valid optimal cerebral perfusion pressure. Uppsala had the highest cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Uppsala patients were older than the other centers, and age is positively correlated with cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Optimal cerebral perfusion pressure was significantly lower in Groningen than in Cambridge. There were no significant differences in percentage of monitoring time with valid optimal cerebral perfusion pressure. Summary optimal cerebral perfusion pressure curves were generated for the combined patient data for each center. These summary curves could be generated for Groningen and Cambridge, but not Uppsala. The older age of the Uppsala patient cohort may explain the absence of a summary curve. CONCLUSIONS: Differences in optimal cerebral perfusion pressure calculation were found between centers due to demographics (age) and treatment (cerebral perfusion pressure targets). These factors should be considered in the design of trials to determine the efficacy of autoregulation-guided treatment.

Assessing Metabolism and Injury in Acute Human Traumatic Brain Injury with Magnetic Resonance Spectroscopy: Current and Future Applications.

Traumatic brain injury (TBI) triggers a series of complex pathophysiological processes. These include abnormalities in brain energy metabolism; consequent to reduced tissue pO2 arising from ischemia or abnormal tissue oxygen diffusion, or due to a failure of mitochondrial function. In vivo magnetic resonance spectroscopy (MRS) allows non-invasive interrogation of brain tissue metabolism in patients with acute brain injury. Nuclei with "spin," e.g., 1H, 31P, and 13C, are detectable using MRS and are found in metabolites at various stages of energy metabolism, possessing unique signatures due to their chemical shift or spin-spin interactions (J-coupling). The most commonly used clinical MRS technique, 1H MRS, uses the great abundance of hydrogen atoms within molecules in brain tissue. Spectra acquired with longer echo-times include N-acetylaspartate (NAA), creatine, and choline. NAA, a marker of neuronal mitochondrial activity related to adenosine triphosphate (ATP), is reported to be lower in patients with TBI than healthy controls, and the ratio of NAA/creatine at early time points may correlate with clinical outcome. 1H MRS acquired with shorter echo times produces a more complex spectrum, allowing detection of a wider range of metabolites.31 P MRS detects high-energy phosphate species, which are the end products of cellular respiration: ATP and phosphocreatine (PCr). ATP is the principal form of chemical energy in living organisms, and PCr is regarded as a readily mobilized reserve for its replenishment during periods of high utilization. The ratios of high-energy phosphates are thought to represent a balance between energy generation, reserve and use in the brain. In addition, the chemical shift difference between inorganic phosphate and PCr enables calculation of intracellular pH.13 C MRS detects the 13C isotope of carbon in brain metabolites. As the natural abundance of 13C is low (1.1%), 13C MRS is typically performed following administration of 13C-enriched substrates, which permits tracking of the metabolic fate of the infused 13C in the brain over time, and calculation of metabolic rates in a range of biochemical pathways, including glycolysis, the tricarboxylic acid cycle, and glutamate-glutamine cycling. The advent of new hyperpolarization techniques to transiently boost signal in 13C-enriched MRS in vivo studies shows promise in this field, and further developments are expected.

The reporting of study and population characteristics in degenerative cervical myelopathy: A systematic review.

OBJECT: Degenerative cervical myelopathy [DCM] is a disabling and increasingly prevalent condition. Variable reporting in interventional trials of study design and sample characteristics limits the interpretation of pooled outcomes. This is pertinent in DCM where baseline characteristics are known to influence outcome. The present study aims to assess the reporting of the study design and baseline characteristics in DCM as the premise for the development of a standardised reporting set. METHODS: A systematic review of MEDLINE and EMBASE databases, registered with PROSPERO (CRD42015025497) was conducted in accordance with PRISMA guidelines. Full text articles in English, with >50 patients (prospective) or >200 patients (retrospective), reporting outcomes of DCM were deemed to be eligible. RESULTS: A total of 108 studies involving 23,876 patients, conducted world-wide, were identified. 33 (31%) specified a clear primary objective. Study populations often included radiculopathy (51, 47%) but excluded patients who had undergone previous surgery (42, 39%). Diagnositic criteria for myelopathy were often uncertain; MRI assessment was specified in only 67 (62%) of studies. Patient comorbidities were referenced by 37 (34%) studies. Symptom duration was reported by 46 (43%) studies. Multivariate analysis was used to control for baseline characteristics in 33 (31%) of studies. CONCLUSIONS: The reporting of study design and sample characteristics is variable. The development of a consensus minimum dataset for (CODE-DCM) will facilitate future research synthesis in the future.

Improved long-term survival with subdural drains following evacuation of chronic subdural haematoma.

BACKGROUND: Chronic subdural haematoma (CSDH) is a common condition that is effectively managed by burrhole drainage but requires repeat surgery in a significant minority of patients. The Cambridge Chronic Subdural Haematoma Trial (CCSHT) was a randomised controlled study that showed placement of subdural drains for 48 h following burrhole evacuation significantly reduces the incidence of reoperation and improves survival at 6 months. The present study examined the long-term survival of the patients in the trial. METHODS: In the original trial patients at a single neurosurgical centre from 2004-2007 were randomly assigned to receive a drain (n = 108) or no drain (n = 107) following burrhole drainage of CSDH. We ascertained whether the trial patients were alive in February 2016-a minimum of 8 years following enrollment-via the UK NHS tracing service. Survival was compared between the trial groups and against expected survival for the UK general population matched for age and sex. RESULTS: At 5 years following surgery the drain group continued to have significantly better survival than the no drain patients (p = 0.027), but this was no longer apparent at 10 years. Survival of patients in the drain group did not differ significantly from that of the general population whereas patients who did not receive a drain had significantly lower survival than expected (p = 0.0006). CONCLUSION: Subdural drains following CSDH evacuation are associated with improved long-term survival, which appears similar to that expected for the general population of the same age and sex. All patients having burrhole CSDH evacuation should receive a drain as standard practice unless specifically contraindicated.

Regional scalp block for postcraniotomy analgesia: a systematic review and meta-analysis.

BACKGROUND: Up to two-thirds of patients report moderate to severe surgical site pain after craniotomy procedures, and there is understandable reluctance to manage these symptoms with systemic opioids that may impair neurological assessment. Furthermore, there is a lack of consensus and evidence concerning alternative analgesia strategies for cranial neurosurgery. Regional scalp block (RSB) is an established technique that involves infiltration of local anesthetic (LA) at well-defined anatomical sites targeting the major sensory innervation of the scalp. However, the efficacy of RSB in reducing postoperative pain remains unclear. In this study, we sought to systematically identify and review randomized controlled trials (RCTs) of RSB and synthesize an overall estimate of efficacy in a quantitative meta-analysis. METHODS: Medline, EMBASE, and the Cochrane Central Register of Controlled Trials databases were searched for all RCTs evaluating the effect of RSB on postoperative pain after craniotomy. Titles, abstracts, and papers were reviewed independently by 2 authors against predefined inclusion criteria. Two authors independently assessed the quality of included studies and extracted data on patient-reported pain scores, other analgesia requirements, and complications of RSB. Pain scores were scaled to a common 0 to 10 interval with higher scores indicating more severe pain. Meta-analysis of the pooled treatment effect was performed with a random-effects inverse-variance weighted model; heterogeneity was quantified with the I(2) statistic. RESULTS: The literature search identified 138 unique citations, from which 7 RCTs with a total recruitment of 320 patients met the inclusion criteria. All studies used standard LA drugs (lidocaine, bupivacaine, or ropivacaine); in 3 studies, LA was combined with epinephrine. In 3 studies, RSB was performed preoperatively; in the other 4 studies, it was administered postoperatively after wound closure. No complications attributable to RSB were reported. Meta-analysis found a pooled reduction in pain score at 1 hour postoperatively (N = 5 studies; mean difference, -1.61; 95% confidence interval, -2.06 to -1.15; P < 0.001; I(2) = 0%). Subgroup analysis of preoperative RSB showed significant reduction in pain scores at 2, 4, and 6 to 8 hours after surgery whereas postoperative RSB was associated with significant reduction in pain scores at 2, 4, 6 to 8 and 12 hours assessments. There was also an overall reduction in the opioid requirements over the first 24 hours postoperatively, although with significant heterogeneity among the studies (N = 6 studies; standardized mean difference, -0.79; 95% confidence interval, -1.55 to -0.03; P = 0.04; I(2) = 86%). CONCLUSION: Published RCTs of RSB are small and of limited methodological quality but meta-analysis shows a consistent finding of reduced postoperative pain. This evidence supports the use of RSB for patients undergoing craniotomy.

The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production.

The role of neuroinflammation is increasingly being recognised in a diverse range of cerebral pathologies, including traumatic brain injury (TBI). We used cerebral microdialysis and paired arterial and jugular bulb plasma sampling to characterise the production of 42 cytokines after severe TBI in 12 patients over 5 days. We compared two microdialysis perfusates in six patients: central nervous system perfusion fluid and 3.5% human albumin solution (HAS); 3.5% HAS has a superior fluid recovery (95.8 versus 83.3%), a superior relative recovery in 18 of 42 cytokines (versus 8 of 42), and a qualitatively superior recovery profile. All 42 cytokines were recovered from the human brain. Sixteen cytokines showed a stereotyped temporal peak, at least twice the median value for that cytokine over the monitoring period; day 1: tumour necrosis factor, interleukin (IL)7, IL8, macrophage inflammatory protein (MIP)1α, soluble CD40 ligand, GRO, IL1ß, platelet derived growth factor (PDGF)-AA, MIP1ß, RANTES; day 2: IL1 receptor antagonist (ra). IL6, granulocyte-colony stimulating factor (G-CSF), chemokine CXC motif ligand 10 (IP10); days 4 to 5: IL12p70, IL10. Brain extracellular fluid concentrations were significantly higher than plasma concentrations for 19 cytokines: basic fibroblast growth factor (FGF2), G-CSF, IL1α, IL1ß, IL1ra, IL3, IL6, IL8, IL10, IL12p40, IL12p70, IP10, monocyte chemotactic protein (MCP)1, MCP3, MIP1α, MIP1ß, PDGF-AA, transforming growth factor (TGF)α and vascular endothelial growth factor. No clear arterio-jugular venous gradients were apparent. These data provide evidence for the cerebral production of these cytokines and show a stereotyped temporal pattern after TBI.