Tranexamic acid to prevent operation in chronic subdural haematoma (TORCH): study protocol for a randomised placebo-controlled clinical trial

Background: Chronic subdural haematoma (cSDH) occurs mainly in the elderly. Surgical evacuation is effective, but in these old, often frail, patients with multi-comorbidity, surgery carries significant risks for future cognitive functioning and loss of independency. Therefore, a growing interest is noted for a non-surgical treatment with medication such as tranexamic acid (TXA). In five small retrospective series, this antifibrinolytic drug showed a beneficial effect on the spontaneous resolution of the haematoma, and with that, the necessity for surgery. Methods: For this randomised, placebo-controlled clinical multicentre trial, all cSDH patients, over 50 years old with mild symptoms (Glasgow Coma Score (GCS) ≥ 14, modified National Institutes of Health Stroke Scale (mNIHSS) ≤ 4), a midline shift of ≤ 10 mm and in whom a primary conservative treatment is chosen, are eligible for study participation. After informed consent, 140 patients will be randomised to receive either TXA 500 mg or placebo two times daily for 28 days. The primary outcome is the necessity for surgery within 12 weeks; secondary outcomes are cSDH volume, neurological impairment (mNIHSS), falling incidents, cognitive functioning (Montreal Cognitive Assessment (MOCA)), performance in activities of daily living (Barthel and Lawton score), functional outcome (modified Rankin Scale (mRS)), quality of life (Short Form Health Survey (SF-36) and EuroQol 5-Dimension Health Survey (EQ-5D)), mortality and the use of care and health-related costs (Medical Consumption Questionnaire (iMCQ) and Productivity Cost Questionnaire (iPCQ)) at 12 weeks and 6 months. Discussion: This phase III trial investigating the efficacy of TXA to prevent surgery for cSDH is the first in including patients using anticoagulants and mentally incompetent patients, since these comprise a significant part of the target population. Also, this study is one of the first to prospectively measure functional outcome and quality of life in cSDH patients. Final results of this study are expected in 2024. Trial registration: Dutch Trial Registry (Nederlands Trial Register) NL6584. Registered on 11 November 2017 ClinicalTrials.govNCT03582293. Registered on 11 July 2018 EU Clinical Trials Register 2017-004311-40. Registered on 29 March 201

Subjecting acute ischemic stroke patients to continuous tube feeding and an intensive computerized protocol establishes tight glycemic control

Introduction: Tight glycemic control (TGC) after ischemic stroke may improve clinical outcome but previous studies failed to establish TGC, principally because of postprandial glucose surges. The aim of the present study was to investigate if safe, effective and feasible TGC can be achieved with continuous tube feeding and a computerized treatment protocol. Methods: We subjected ten acute ischemic stroke patients with admission hyperglycemia (glucose >7.0 mmol/l (126.0 mg/dl)) to continuous tube feeding and a computerized intensive protocol with insulin adjustments every 1-2 h. Two groups of regularly fed patients from a previous study with a similar design served as controls. These groups comprised hyperglycemic patients treated according to an intermediate protocol with insulin adjustments at standard intervals (N = 13), and normoglycemic controls treated according to standard care (N = 15). The primary outcome was the percentage of time within target (4.4-6.1 mmol/l (79.2-109.8 mg/dl)). Secondary outcome was the number of patients with hypoglycemic episodes (glucose <3.0 mmol/l (54.0 mg/dl)). Results: Median time within target was 55% in the continuously fed intensive group compared to 19% in the regularly fed intermediate group, and 58% in normoglycemic controls. Hypoglycemic episodes occurred in 20% of patients in the continuously fed group-lowest glucose level 2.4 mmol/l (43.2 mg/dl). In contrast, in the regularly fed group, this was 31%-lowest glucose level 1.6 mmol/l (28.8 mg/dl). Conclusions: TGC after acute ischemic stroke is feasible with continuous tube feeding and a computerized intensive treatment protocol. Although glycemic control is associated with hypoglycemia, no severe hypoglycemia occurred in the continuous tube feeding group

Association of quantified location-specific blood volumes with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

BACKGROUND AND PURPOSE: Delayed cerebral ischemia is a severe complication of aneurysmal SAH and is associated with a high case morbidity and fatality. The total blood volume and the presence of intraventricular blood on CT after aneurysmal SAH are associated with delayed cerebral ischemia. Whether quantified location-specific (cisternal, intraventricular, parenchymal, and subdural) blood volumes are associated with delayed cerebral ischemia has been infrequently researched. This study aimed to associate quantified location-specific blood volumes with delayed cerebral ischemia. MATERIALS AND METHODS: Clinical and radiologic data were collected retrospectively from consecutive patients with aneurysmal SAH with available CT scans within 24 hours after ictus admitted to 2 academic centers between January 2009 and December 2011. Total blood volume was quantified using an automatic hemorrhage-segmentation algorithm. Segmented blood was manually classified as cisternal, intraventricular, intraparenchymal, or subdural. Adjusted ORs with 95% confidence intervals for delayed cerebral ischemia per milliliter of location-specific blood were calculated using multivariable logistic regression analysis. RESULTS: We included 282 patients. Per milliliter increase in blood volume, the adjusted OR for delayed cerebral ischemia was 1.02 (95% CI, 1.01–1.04) for cisternal, 1.02 (95% CI, 1.00 –1.04) for intraventricular, 0.99 (95% CI, 0.97–1.02) for intraparenchymal, and 0.96 (95% CI, 0.86 –1.07) for subdural blood. CONCLUSIONS: Our findings suggest that in patients with aneurysmal subarachnoid hemorrhage, the cisternal blood volume has a stronger relation with delayed cerebral ischemia than the blood volumes at other locations in the brain

Association of hyperglycemia and computed tomographic perfusion deficits in patients who underwent endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion: A subgroup analysis of a randomized phase 3 trial (MR CLEAN)

Introduction: Hyperglycemia is highly prevalent in patients with acute ischemic stroke and is associated with increased risk of symptomatic intracranial hemorrhage, larger infarct size and unfavorable outcome. Furthermore, glucose may modify the effect of endovascular treatment (EVT) in patients with ischemic stroke. Hyperglycemia might lead to accelerated conversion of penumbra into infarct core. However, it remains uncertain whether hyperglycemia on admission is associated with the size of penumbra or infarct core in acute ischemic stroke. In this study, we aimed to assess the association between hyperglycemia and Computed Tomographic Perfusion (CTP) derived parameters in patients who underwent EVT for acute ischemic stroke. Methods: We used data from the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Hyperglycemia was defined as admission serum glucose of >7.8 mmol/L. Dichotomized and quantiles of glucose levels were related to size of core, penumbra and core penumbra ratio. Hypoperfused area is mean transient time 45% higher than that of the contralateral hemisphere. Core is the area with cerebral blood volume of 2 mL/100 g. Core-penumbra ratio is the ischemic core divided by the total volume of hypoperfused tissue (core plus penumbra) multiplied by 100. Adjustments were made for age, sex, NIHSS on admission, onset-imaging time and diabetes mellitus. Results: Hundred seventy-three patients were included. Median glucose level on admission was 6.5 mmol/L (IQR 5.8–7.5 mmol/L) and thirty-five patients (20%) were hyperglycemic. Median core volume was 33.3 mL (IQR 13.6–62.4 mL), median penumbra volume was 80.2 mL (IQR 36.3–123.5 mL) and median core-penumbra ratio was 28.5% (IQR 18.6–45.8%). Patients with hyperglycemia on admission had larger core volumes and core penumbra ratio than normoglycemic patients with a regression coefficient of 15.1 (95% confidence interval (CI), 1.8 to 28.3) and 11.5 (95% confidence interval (CI), 3.4 to 19.7) respectively. Conclusion: Hyperglycemia on admission was associated with larger ischemic core volume and larger core-penumbra ratio in patients with acute ischemic stroke who underwent endovascular treatment

Association of hyperglycemia and computed tomographic perfusion deficits in patients who underwent endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion:A subgroup analysis of a randomized phase 3 trial (MR CLEAN)

Introduction: Hyperglycemia is highly prevalent in patients with acute ischemic stroke and is associated with increased risk of symptomatic intracranial hemorrhage, larger infarct size and unfavorable outcome. Furthermore, glucose may modify the effect of endovascular treatment (EVT) in patients with ischemic stroke. Hyperglycemia might lead to accelerated conversion of penumbra into infarct core. However, it remains uncertain whether hyperglycemia on admission is associated with the size of penumbra or infarct core in acute ischemic stroke. In this study, we aimed to assess the association between hyperglycemia and Computed Tomographic Perfusion (CTP) derived parameters in patients who underwent EVT for acute ischemic stroke. Methods: We used data from the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Hyperglycemia was defined as admission serum glucose of >7.8 mmol/L. Dichotomized and quantiles of glucose levels were related to size of core, penumbra and core penumbra ratio. Hypoperfused area is mean transient time 45% higher than that of the contralateral hemisphere. Core is the area with cerebral blood volume of 2 mL/100 g. Core-penumbra ratio is the ischemic core divided by the total volume of hypoperfused tissue (core plus penumbra) multiplied by 100. Adjustments were made for age, sex, NIHSS on admission, onset-imaging time and diabetes mellitus. Results: Hundred seventy-three patients were included. Median glucose level on admission was 6.5 mmol/L (IQR 5.8–7.5 mmol/L) and thirty-five patients (20%) were hyperglycemic. Median core volume was 33.3 mL (IQR 13.6–62.4 mL), median penumbra volume was 80.2 mL (IQR 36.3–123.5 mL) and median core-penumbra ratio was 28.5% (IQR 18.6–45.8%). Patients with hyperglycemia on admission had larger core volumes and core penumbra ratio than normoglycemic patients with a regression coefficient of 15.1 (95% confidence interval (CI), 1.8 to 28.3) and 11.5 (95% confidence interval (CI), 3.4 to 19.7) respectively. Conclusion: Hyperglycemia on admission was associated with larger ischemic core volume and larger core-penumbra ratio in patients with acute ischemic stroke who underwent endovascular treatment

Unsupervised Deep Learning for Stroke Lesion Segmentation on Follow-up CT Based on Generative Adversarial Networks

BACKGROUND AND PURPOSE: Supervised deep learning is the state-of-the-art method for stroke lesion segmentation on NCCT. Supervised methods require manual lesion annotations for model development, while unsupervised deep learning methods such as generative adversarial networks do not. The aim of this study was to develop and evaluate a generative adversarial network to segment infarct and hemorrhagic stroke lesions on follow-up NCCT scans. MATERIALS AND METHODS: Training data consisted of 820 patients with baseline and follow-up NCCT from 3 Dutch acute ischemic stroke trials. A generative adversarial network was optimized to transform a follow-up scan with a lesion to a generated baseline scan without a lesion by generating a difference map that was subtracted from the follow-up scan. The generated difference map was used to automatically extract lesion segmentations. Segmentation of primary hemorrhagic lesions, hemorrhagic transformation of ischemic stroke, and 24-hour and 1-week follow-up infarct lesions were evaluated relative to expert annotations with the Dice similarity coefficient, Bland-Altman analysis, and intraclass correlation coefficient. RESULTS: The median Dice similarity coefficient was 0.31 (interquartile range, 0.08-0.59) and 0.59 (interquartile range, 0.29-0.74) for the 24-hour and 1-week infarct lesions, respectively. A much lower Dice similarity coefficient was measured for hemorrhagic transformation (median, 0.02; interquartile range, 0-0.14) and primary hemorrhage lesions (median, 0.08; interquartile range, 0.01-0.35). Predicted lesion volume and the intraclass correlation coefficient were good for the 24-hour (bias, 3 mL; limits of agreement, -64-59mL; intraclass correlation coefficient, 0.83; 95% CI, 0.78-0.88) and excellent for the 1-week (bias, -4 m; limits of agreement,-66-58 mL; intraclass correlation coefficient, 0.90; 95% CI, 0.83-0.93) follow-up infarct lesions. CONCLUSIONS: An unsupervised generative adversarial network can be used to obtain automated infarct lesion segmentations with a moderate Dice similarity coefficient and good volumetric correspondence

Data-efficient deep learning of radiological image data for outcome prediction after endovascular treatment of patients with acute ischemic stroke

Treatment selection is becoming increasingly more important in acute ischemic stroke patient care. Clinical variables and radiological image biomarkers (old age, pre-stroke mRS, NIHSS, occlusion location, ASPECTS, among others) have an important role in treatment selection and prognosis. Radiological biomarkers require expert annotation and are subject to inter-observer variability. Recently, Deep Learning has been introduced to reproduce these radiological image biomarkers. Instead of reproducing these biomarkers, in this work, we investigated Deep Learning techniques for building models to directly predict good reperfusion after endovascular treatment (EVT) and good functional outcome using CT angiography images. These models do not require image annotation and are fast to compute. We compare the Deep Learning models to Machine Learning models using traditional radiological image biomarkers. We explored Residual Neural Network (ResNet) architectures, adapted them with Structured Receptive Fields (RFNN) and auto-encoders (AE) for network weight initialization. We further included model visualization techniques to provide insight into the network's decision-making process. We applied the methods on the MR CLEAN Registry dataset with 1301 patients. The Deep Learning models outperformed the models using traditional radiological image biomarkers in three out of four cross-validation folds for functional outcome (average AUC of 0.71) and for all folds for reperfusion (average AUC of 0.65). Model visualization showed that the arteries were relevant features for functional outcome prediction. The best results were obtained for the ResNet models with RFNN. Auto-encoder initialization often improved the results. We concluded that, in our dataset, automated image analysis with Deep Learning methods outperforms radiological image biomarkers for stroke outcome prediction and has the potential to improve treatment selection

Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data

Background: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care. Methods: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered. Findings: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09–2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75–3·10, p&lt;0·0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1·53, 95% CI 1·14–2·04, p=0·0044). The risk of bias and variability between studies was assessed to be low. Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons