Predictors of shunt insertion in patients with aneurysmal subarachnoid haemorrhage-a single-centre retrospective analysis.

BACKGROUND: No standard has been established regarding timing and choice of strategy for discontinuation of external ventricular drainage (EVD) in patients with aneurysmal subarachnoid haemorrhage (aSAH), and little is known about the importance of clinical variables. A proportion of the patients who initially pass their discontinuation attempt return with delayed hydrocephalus and the need of a permanent shunt. Early differentiation between patients who need a shunt and those who do not would facilitate care. We conducted a retrospective analysis on patients with aSAH and an EVD to search significant differences in treatment and clinical variables between patients who received a permanent shunt during initial hospitalization or after readmission, and those who never received a shunt. METHODS: We included 183 patients with aSAH who received an EVD over a 4-year period between 2015 and 2018 and divided them into three groups: those who received a shunt during primary admission, those who were readmitted for delayed hydrocephalus and received a shunt, and those who never needed a shunt. Between these groups, we compared selected clinical variables as well as outcome at discharge and after 6 months. Additionally, we assessed the ability of a shunt dependency score (SDASH) to predict the need for permanent drainage in the patients. RESULTS: Of 183 included patients, 108 (59%) ultimately received a ventriculoperitoneal (VP) shunt. Of these, 89 (82%) failed discontinuation during the primary admission and received a permanent shunt before discharge from the neurosurgical department. The remaining 19 (18%) were discharged after successful discontinuation, but subsequently developed delayed hydrocephalus and were admitted for shunt placement a median of 39 (range: 18-235) days after ictus. Ninety-four patients were discharged after successful discontinuation of the EVD, consisting of those who never developed the need for a permanent shunt and the 19 who were readmitted with delayed hydrocephalus, corresponding to a 20% (19/94) readmittance rate. Clinical variables such as drainage volume or discontinuation strategy did not differ across the three groups of patients. The SDASH score failed to provide any clinically useful information regarding prediction of shunt placement. CONCLUSION: In this study, clinical variables including use of the predictive score SDASH predicted neither the overall need for nor the timing of shunt placement after aSAH. The homogeneous distribution of data between the three different groups renders strong independent clinical predictive factors unlikely. Thus, attempts to predict a permanent shunt requirement from these variables may be futile in these patients.

Critical ICP thresholds in relation to outcome: Is 22 mmHg really the answer?

PURPOSE: Intensive care for patients with traumatic brain injury (TBI) aims, among other tasks, at avoiding high intracranial pressure (ICP), which is perceived to worsen motor and cognitive deficits and increase mortality. International recommendations for threshold values for ICP were increased from 20 to 22 mmHg in 2016 following the findings in a study by Sorrentino et al., which were based on an observational study of patients with TBI of averaged ICP values. We aimed to reproduce their approach and validate the findings in a separate cohort. METHODS: Three hundred thirty-one patients with TBI were included and categorised according to survival/death and favourable/unfavourable outcome at 6 months (based on Glasgow Outcome Score-Extended of 6-8 and 1-5, respectively). Repeated chi-square tests of survival and death (or favourable and unfavourable outcome) vs. high and low ICP were conducted with discrimination between high and low ICP sets at increasing values (integers) between 10 and 35 mmHg, using the average ICP for the entire monitoring period. The ICP limit returning the highest chi-square score was assumed to be the threshold with best discriminative ability. This approach was repeated after stratification by sex, age, and initial Glasgow Coma Score (GCS). RESULTS: An ICP limit of 18 mmHg was found for both mortality and unfavourable outcome for the entire cohort. The female and the low GCS subgroups both had threshold values of 18 mmHg; for all other subgroups, the threshold varied between 16 and 30 mmHg. According to a multiple logistic regression analysis, age, initial GCS, and average ICP are independently associated with mortality and outcome. CONCLUSIONS: Using identical methods and closely comparable cohorts, the critical thresholds for ICP found in the study by Sorrentino et al. could not be reproduced.

Protein kinase C-inhibition reduces critical weight loss and improves functional outcome after experimental subarachnoid haemorrhage.

OBJECTIVES: Subarachnoid haemorrhage (SAH) carries a high burden of morbidity and mortality. One in three patients develop vasospasm, which is associated with Delayed Cerebral Ischemia. The pathophysiology includes vasoconstrictor receptor upregulation in cerebral arteries. The protein kinase C - inhibitor RO-31-7549 reduces the expression of several vasoconstrictor receptors and normalizes cerebral blood flow in experimental SAH but functional and behavioural effects are unknown. This study was undertaken to analyse functional outcomes up to 14 days after experimental SAH. MATERIALS AND METHODS: 54 male rats were randomised to experimental SAH or sham, using the pre-chiasmatic, single injection model, and subsequent treatment or vehicle. 42 remained for final analysis. The animals were euthanized on day 14 or when reaching a humane endpoint. The primary endpoint was overall survival, defined as either spontaneous mortality or when reaching a predefined humane endpoint. The secondary outcomes were differences in the rotating pole test, weight, open field test, novel object recognition and qPCR of selected inflammatory markers. RESULTS: In the vehicle group 6/15 rats reached the humane endpoint of >20 % weight loss compared to 1/14 in the treatment group. This resulted in a significant reduced risk of early euthanasia due to >20 % weight loss of HR 0.15 (0.03-0.66, p = 0.04). Furthermore, the treatment group did significantly better on the rotating pole test, RR 0.64 (0.47-0.91, p = 0.02). CONCLUSION: RO-31-7549 improved outcomes in terms >20 % weight loss and rotating pole performance after experimental SAH and could be investigated.

The experience of living with malignant meningioma.

OBJECTIVES: Meningiomas are the most common, primary intracranial tumor and most are benign. Little is known of the rare patient group living with a malignant meningioma, comprising 1-3% of all meningiomas. Our aim was to explore how patients perceived quality of daily life after a malignant meningioma diagnosis. METHODS: This qualitative explorative study was composed of individual semi-structured interviews. Eligible patients (n = 12) were selected based on ability to participate in an interview, from a background population of 23 patients diagnosed with malignant meningioma at Rigshospitalet from 2000 to 2021. We performed an inductive thematic analysis following Braun and Clarke's guidelines. RESULTS: Eight patients were interviewed. The analysis revealed 4 overarching themes: (1) perceived illness and cause of symptoms, (2) identity, roles, and interaction, (3) threat and uncertainty of the future, and (4) belief in authority. The perceived quality of daily life is negatively impacted by the disease. Patients experience a shift in self-concept and close interactions, and some struggle with accepting a new everyday life. Patients have a high risk of discordant prognostic awareness in relation to health-care professionals. SIGNIFICANCE OF RESULTS: We provide a much-needed patient-centered perspective of living with malignant meningioma: quality of life was affected by perception of threat and an uncertainty of the future. Perception of illness and the interpretation of the cause of symptoms varied between subjects, but a common trait was that patients' identity, roles, and interactions were affected. Shared decision-making and a strengthened continuity during follow-up could aid this rare patient group.

Meningioma animal models: a systematic review and meta-analysis.

BACKGROUND: Animal models are widely used to study pathological processes and drug (side) effects in a controlled environment. There is a wide variety of methods available for establishing animal models depending on the research question. Commonly used methods in tumor research include xenografting cells (established/commercially available or primary patient-derived) or whole tumor pieces either orthotopically or heterotopically and the more recent genetically engineered models-each type with their own advantages and disadvantages. The current systematic review aimed to investigate the meningioma model types used, perform a meta-analysis on tumor take rate (TTR), and perform critical appraisal of the included studies. The study also aimed to assess reproducibility, reliability, means of validation and verification of models, alongside pros and cons and uses of the model types. METHODS: We searched Medline, Embase, and Web of Science for all in vivo meningioma models. The primary outcome was tumor take rate. Meta-analysis was performed on tumor take rate followed by subgroup analyses on the number of cells and duration of incubation. The validity of the tumor models was assessed qualitatively. We performed critical appraisal of the methodological quality and quality of reporting for all included studies. RESULTS: We included 114 unique records (78 using established cell line models (ECLM), 21 using primary patient-derived tumor models (PTM), 10 using genetically engineered models (GEM), and 11 using uncategorized models). TTRs for ECLM were 94% (95% CI 92-96) for orthotopic and 95% (93-96) for heterotopic. PTM showed lower TTRs [orthotopic 53% (33-72) and heterotopic 82% (73-89)] and finally GEM revealed a TTR of 34% (26-43). CONCLUSION: This systematic review shows high consistent TTRs in established cell line models and varying TTRs in primary patient-derived models and genetically engineered models. However, we identified several issues regarding the quality of reporting and the methodological approach that reduce the validity, transparency, and reproducibility of studies and suggest a high risk of publication bias. Finally, each tumor model type has specific roles in research based on their advantages (and disadvantages). SYSTEMATIC REVIEW REGISTRATION: PROSPERO-ID CRD42022308833.

Effect of controlled blood pressure increase on cerebral blood flow velocity and oxygenation in patients with subarachnoid haemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid haemorrhage (SAH) might have impaired cerebral autoregulation, that is, CBF - and thereby oxygen delivery - passively increase with an increase in CPP. This physiological study aimed to investigate the cerebral haemodynamic effects of controlled blood pressure increase in the early phase after SAH before any signs of delayed cerebral ischaemia (DCI) occurred. METHODS: The study was carried out within 5 days after ictus. Data were recorded at baseline and after 20 min of noradrenaline infusion to increase mean arterial blood pressure (MAP) by a maximum of 30 mmHg and to an absolute level of no more than 130 mmHg. The primary outcome was the difference in middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler (TCD), while differences in intracranial pressure (ICP), brain tissue oxygen tension (PbtO2 ), and microdialysis markers of cerebral oxidative metabolism and cell injury were assessed as exploratory outcomes. Data were analysed using Wilcoxon signed-rank test with correction for multiplicity for the exploratory outcomes using the Benjamini-Hochberg correction. RESULTS: Thirty-six participants underwent the intervention 4 (median, IQR: 3-4.75) days after ictus. MAP was increased from 82 (IQR: 76-85) to 95 (IQR: 88-98) mmHg (p-value: <.001). MCAv remained stable (baseline, median 57, IQR: 46-70 cm/s; controlled blood pressure increase, median: 55, IQR: 48-71 cm/s; p-value: .054), whereas PbtO2 increased significantly (baseline, median: 24, 95%CI: 19-31 mmHg; controlled blood pressure increase, median: 27, 95%CI: 24-33 mmHg; p-value <.001). The remaining exploratory outcomes were unchanged. CONCLUSION: In this study of patients with SAH, MCAv was not significantly affected by a brief course of controlled blood pressure increase; despite this, PbtO2 increased. This suggests that autoregulation might not be impaired in these patients or other mechanisms could mediate the increase in brain oxygenation. Alternatively, a CBF increase did occur that, in turn, increased cerebral oxygenation, but was not detected by TCD. TRIAL REGISTRATION: clinicaltrials.gov (NCT03987139; 14 June 2019).

Prompt closure versus gradual weaning of external ventricular drainage for hydrocephalus following aneurysmal subarachnoid haemorrhage: Protocol for the DRAIN randomised clinical trial.

BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) is a life-threatening disease caused by rupture of an intracranial aneurysm. A common complication following aSAH is hydrocephalus, for which placement of an external ventricular drain (EVD) is an important first-line treatment. Once the patient is clinically stable, the EVD is either removed or replaced by a ventriculoperitoneal shunt. The optimal strategy for cessation of EVD treatment is, however, unknown. Gradual weaning may increase the risk of EVD-related infection, whereas prompt closure carries a risk of acute hydrocephalus and redundant shunt implantations. We designed a randomised clinical trial comparing the two commonly used strategies for cessation of EVD treatment in patients with aSAH. METHODS: DRAIN is an international multi-centre randomised clinical trial with a parallel group design comparing gradual weaning versus prompt closure of EVD treatment in patients with aSAH. Participants are randomised to either gradual weaning which comprises a multi-step increase of resistance over days, or prompt closure of the EVD. The primary outcome is a composite outcome of VP-shunt implantation, all-cause mortality, or ventriculostomy-related infection. Secondary outcomes are serious adverse events excluding mortality, functional outcome (modified Rankin scale), health-related quality of life (EQ-5D) and Fatigue Severity Scale (FSS). Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, type I error 5%, power 80%), 122 patients are needed in each intervention group. Outcome assessment for the primary outcome, statistical analyses and conclusion drawing will be blinded. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03948256.

CSF hypersecretion versus impaired CSF absorption in posthemorrhagic hydrocephalus: a systematic review.

BACKGROUND: The molecular mechanisms underlying development of posthemorrhagic hydrocephalus (PHH) remain elusive. The aim of this systematic review was to evaluate existing literature on increased CSF secretion and impaired CSF absorption as pathogenic contributors to CSF accumulation in neonatal and adult PHH. METHODS: The systematic review was conducted in accordance with the PRISMA guidelines. Relevant studies published before March 11th, 2023, were identified from PubMed and reference lists. Studies were screened for eligibility using predefined inclusion and exclusion criteria. Data from eligible studies were extracted and potential sources of bias were evaluated. RESULTS: Nineteen studies quantified CSF production rates and/or CSF absorption capacity in human patients with PHH or animals with experimentally induced PHH. Increased CSF production was reported as early as 24 h and as late as 28 days post ictus in six out of eight studies quantifying CSF production rates in animals with experimentally induced PHH. Impaired CSF absorption was reported in all four studies quantifying CSF absorption capacity in human patients with PHH and in seven out of nine studies quantifying CSF absorption capacity in animals with experimentally induced PHH. Impaired CSF absorption was reported as early as 30 min and as late as 10 months post ictus. CONCLUSIONS: The pathological CSF accumulation in PHH likely arises from a combination of increased CSF secretion and impaired CSF absorption, which may manifest at different time scales following a hemorrhagic event. Emergent evidence on increased CSF secretion by the choroid plexus may herald a paradigm shift in our understanding of PHH.

Promotion of a neurosurgical academic journal on social media: a 1-year experience.

BACKGROUND: Social media (SoMe) use, in all of its forms, has seen massively increased throughout the past two decades, including academic publishing. Many journals have established a SoMe presence, yet the influence of promotion of scientific publications on their visibility and impact remains poorly studied. The European Journal of Neurosurgery «Acta Neurochirurgica¼ has established its SoMe presence in form of a Twitter account that regularly promotes its publications. We aim to analyze the impact of this initial SoMe campaign on various alternative metrics (altmetrics). METHODS: A retrospective analysis of all articles published in the journal Acta Neurochirurgica between May 1st, 2018, and April 30th, 2020, was performed. These articles were divided into a historical control group - containing the articles published between May 1st, 2018, and April 30th, 2019, when the SoMe campaign was not yet established - and into an intervention group. Several altmetrics were analyzed, along with website visits and PDF downloads per month. RESULTS: In total, 784 articles published during the study period, 128 (16.3%) were promoted via Twitter. During the promotion period, 29.7% of published articles were promoted. Overall, the published articles reached a mean of 31.3 ± 50.5 website visits and 17.5 ± 31.25 PDF downloads per month. Comparing the two study periods, no statistically significant differences in website visits (26.91 ± 32.87 vs. 34.90 ± 61.08, p = 0.189) and PDF downloads (17.52 ± 31.25 vs. 15.33 ± 16.07, p = 0.276) were detected. However, overall compared to non-promoted articles, promoted articles were visited (48.9 ± 95.0 vs. 29.0 ± 37.0, p = 0.005) and downloaded significantly more (25.7 ± 66.7 vs. 16.6 ± 18.0, p = 0.045) when compared to those who were not promoted during the promotion period. CONCLUSIONS: We report a 1-year initial experience with promotion of a general neurosurgical journal on Twitter. Our data suggest a clear benefit of promotion on article site visits and article downloads, although no single responsible element could be determined in terms of altmetrics. The impact of SoMe promotion on other metrics, including traditional bibliometrics such as citations and journal impact factor, remains to be determined.

Posthemorrhagic Hydrocephalus in Patients with Subarachnoid Hemorrhage Occurs Independently of CSF Osmolality.

The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.

Combined cone-beam CT imaging and microsurgical dissection of cadaver specimens to study cerebral venous anatomy: a technical note.

PURPOSE: Cadaver dissections and X-ray based 3D angiography are considered gold standards for studying neurovascular anatomy. We sought to develop a model that utilize the combination of both these techniques to improve current tools for anatomical research, teaching and preoperative surgical planning, particularly addressing the venous system of the brain. MATERIALS AND METHODS: Seven ethanol-fixed human cadaveric heads and one arm were injected with a latex-barium mixture into the internal jugular veins and the brachial artery. After the ethanol-based fixation, specimens were scanned by high-resolution cone-beam CT and images were post-processed on a 3D-workstation. Subsequent, microsurgical dissections were performed by an experienced neurosurgeon and venous anatomy was compared with relevant 3D venograms. RESULTS: Latex-barium mixtures resulted in a homogenous cast with filling of the cerebral venous structures down to 150 µm in diameter. The ethanol-based preparation of the cadaveric brains allowed for near-realistic microsurgical maneuverability during dissection. The model improves assessment of the venous system for anatomical education and hands-on surgical training. CONCLUSION: To our knowledge we describe the first preparation method which combines near-realistic microsurgical dissection of human heads with high-resolution 3D imaging of the cerebral venous system in the same specimens.

Implementation of TERT promoter mutations improve prognostication of the WHO classification in meningioma.

TERT promoter mutations have been associated with increased risk of recurrence in meningioma cohorts, thus a potential biomarker for aggressive phenotypes. A main purpose of refining tumour classification is better predictions on the patient level. We compiled data from previous published cohorts to investigate patient-level predictions of recurrence based on TERTp-mut status. Implementation of TERTp-mut into the WHO grading led to better patient prognostication by improved prediction of recurrence. Our results support implementation of TERTp-mut into diagnostics and classification of meningiomas.

Adjuvant radiotherapy and stereotactic radiosurgery in grade 3 meningiomas - a systematic review and meta-analysis.

Malignant meningioma is a rare, aggressive form of meningioma. Radiation is commonly included in treatment guidelines either as adjuvant radiotherapy (RT) or stereotactic radiosurgery (SRS). Nevertheless, the treatment recommendations are not supported by prospective comparative trials and systematical, critical evaluation of supportive evidence is lacking. For this systematic review, studies analyzing the effectiveness of adjuvant RT and SRS in grade 3 (gr. 3) meningioma were reviewed. Thirty studies met the inclusion criteria for qualitative synthesis, and 6 studies were assessed in quantitative analysis. In quantitative analysis, the weighted average of hazard ratios for adjuvant RT in univariate analyses of overall survival (OS) was 0.55 (CI: 0.41; 0.69). The median 5-year OS after adjuvant RT in gr. 3 meningiomas was 56.3%, and the median OS ranged from 24 to 80 months for patients treated with adjuvant RT versus 13 to 41.2 months in patients not treated. For SRS, the 3-year progression free survival was 0% in one study and 57% in another. The 2-year OS ranged from 25 to 75% in 2 studies. The quality of evidence was rated as "very low" in 14 studies analyzed, and considerable allocation bias was detected. Treatment toxicity was reported in 47% of the studies. The severity, according to the CTCAE, ranged from grades I-V and 5.3 to 100% of patients experienced complications. Adjuvant RT is usually considered standard of care for WHO grade 3 meningiomas, although supporting evidence was of low quality. Better evidence from registries and prospective trials can improve the evidence base for adjuvant fractionated RT in malignant meningiomas.

The role of systemic inflammatory cells in meningiomas.

The aim of this review is to describe the inflammatory systemic cell infiltrate and its role in pathophysiology and prognostic implications of meningiomas. Articles from PubMed describing inflammation and immune cells in meningioma were systematically selected and reviewed. Infiltrating inflammatory cells are common in meningiomas and correlate with tumor behavior and peritumoral edema. The immune cell infiltrate mainly comprised macrophages, CD4 + T cells of the Th1 and Th2 subtype, CD8 + cytotoxic T cells, mast cells, and to a lesser degree B cells. The polarization of macrophages to M1 or M2 states, as well as the differentiation of T-helper cells to Th1 or Th2 subsets, is of prognostic value, but whether or not the presence of macrophages is associated with the degree of malignancy of the tumor is controversial. The best documented immunosuppressive and tumor-promoting mechanism is the expression of programmed cell death protein 1 (PD-1/PD-1L) which is found on both tumor cells and tumor-infiltrating immune cells. The immune cell infiltration varies between different meningiomas. It contributes to a microenvironment with potential contradictory effects on tumor growth and edema. The immune mechanisms are potential therapeutic targets provided that their effects can be comprehensively understood.

The prognostic significance of biomarkers in cerebrospinal fluid following severe traumatic brain injury: a systematic review and meta-analysis.

After severe traumatic brain injury (sTBI) proteins, neurotrophic factors and inflammatory markers are released into the biofluids. This review and meta-analysis searched the literature for prognostic candidate cerebrospinal fluid markers and their relation to sTBI patient outcome. A systematic search of the literature was carried out across PubMed, EMBASE, PubMed Central (PMC), and Cochrane Central Library. Biomarker concentrations were related to the Glasgow Outcome Scale dichotomized into favorable and unfavorable outcomes. When a biomarker was reported in ≥ 3 studies, it was included in meta-analysis. The search returned 1527 articles. After full-text analysis, 54 articles were included, 34 from the search, and 20 from the reference lists. Of 9 biomarkers, 8 were significantly different compared to controls (IL-4, IL-6, IL-8, IL-10, TNFα, sFas, BDNF, and cortisol). Of these, 5 were significantly increased in sTBI patients with unfavorable outcome (IL-6, IL-8, IL-10, TNFα, and cortisol), compared to patients with favorable outcome. This review demonstrated a correlation between 5 biomarkers and clinical outcome in sTBI patients. The paucity of included studies, however, makes it difficult to extrapolate further on this finding.

Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data.

Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups.

Machine Learning and Ethics.

When new technology is introduced into healthcare, novel ethical dilemmas arise in the human-machine interface. As artificial intelligence (AI), machine learning (ML) and big data can exhaust human oversight and memory capacity, this will give rise to many of these new dilemmas.Technology has little if any ethical status but is inevitably interwoven with human activity and thus may serve to allow qualitative and quantitative disruption of human performance and interaction. We argue that personal integrity, justice of resource allocation and accountability of moral agency comprise three themes that characterize ethical dilemmas that arise with development and application of AI. These themes are important to address in parallel to further evolution of AI in health care for ethical practice of healthcare.

Mortality among patients treated for aneurysmal subarachnoid hemorrhage in Eastern Denmark 2017-2019.

OBJECTIVE: The aim of the study was to investigate (1) the 30-day, 3-month, and 12-month cumulative mortalities for patients who underwent aneurysm occlusion, and (2) the causes of death, and (3) the potential risk factors for death. METHODS: All patients who underwent surgical clipping or endovascular treatment of a ruptured aneurysm at Copenhagen University Hospital, during the period of January 1, 2017-December 31, 2019, were included and followed up for 12 months. Data regarding vital status, causes of death, comorbidities, treatment, and clinical presentations on admission was collected. The absolute mortality risk was estimated as a function of time with a 95% confidence interval. The associations between potential risk factors and death were estimated as odds ratios with 95% confidence intervals using logistic regression models. RESULTS: A total of 317 patients were included. The overall cumulative mortalities after 30 days, 3 months, and 12 months were 10.7%, 12.9%, and 16.1%, respectively. The most common cause of death was severe primary hemorrhage (52.9%), followed by infections (15.7%) and rebleeding (11.8%). WFNS score > 3 and Fisher score > 3 on admission, preprocedural hydrocephalus, and preprocedural rebleeding were found significantly associated with higher risk of death. CONCLUSIONS: Considerable mortality was seen. Possible preventable causes accounted for approximately 22% of the deaths. The occurrence of both pre- and postprocedural rebleeding's indicates an opportunity of further improvement of the mortality by (1) further reduction of time from aSAH to aneurysm occlusion and (2) continuous efforts in improving methods of aneurysm occlusion.

Proposal of a new grading system for meningioma resection: the Copenhagen Protocol.

INTRODUCTION: The extent of meningioma resection is the most fundamental risk factor for recurrence, and exact knowledge of extent of resection is necessary for prognostication and for planning of adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between "gross total removal" and "subtotal removal," while the latter comprises a five-tiered differentiation of the surgeon's impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging with 68Ga-DOTATOC allows more sensitive and specific imaging than MRI following surgery of meningiomas. OBJECTIVE: To develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy, and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance of 68Ga DOTATOC PET, we propose "Copenhagen Grading" for meningiomas. RESULTS: Copenhagen Grading was described for six pilot patients with examples of positive and negative findings on histopathology and DOTATOC PET scanning. The grading could be traceably implemented and parameters of grading appeared complementary. Copenhagen Grading is prospectively implemented as a clinical standard at Rigshospitalet, Copenhagen. CONCLUSION: Copenhagen Grading provided a comprehensive, logical, and reproducible definition of the extent of resection. It offers promise to be the most sensitive and specific imaging modality available for meningiomas. Clinical and cost-efficacy remain to be established during prospective implementation.

Three pitfalls of accountable healthcare rationing.

A pandemic may cause a sudden imbalance between available medical resources and medical needs where fundamental care to a patient cannot be delivered. Inability to fulfil a professional commitment to deliver care as needed can lead to distress among caregivers and patients. This distress is sometimes alleviated through mechanisms that hide the facts that care is rationed and not all medical needs are met. We have identified three mechanisms that jeopardise accountable and optimal allocation of resources: (1) hidden value judgements that allow rationing under the disguise of triage or prioritisation, (2) disguised conflict of interest between societal and individual patient's needs and (3) concealed biases in the application of medical tools. Under these three pitfalls decisions of resource allocation and who gets treated are handled as medical decisions: normative decisions are concealed and perceived as falling with the realm of medical judgement. Value judgements and moral agency are hidden to offer a 'false sense of medical judgement', while in fact there are several ethical judgements and biases at stake. The three pitfalls entail hidden normative deliberation and are inappropriate for sustainable healthcare delivery and resource allocation. We believe it is necessary to maintain transparency in decision making under conditions of insufficient resources to maintain trust in professional care givers and secure fair treatment allocation. Recognition of the pitfalls, by applying our recommendations, may help to ensure transparent and accountable distribution of care and contribute to public acceptance of the ethics behind rationing.