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Background: Global age related white matter changes (ARWMC) are associated with progressive gait disturbances and falls, hypothesised to result from interruptions of cortico-subcortical circuits controlling balance, posture and locomotion.Methods: The location of ARWMC in a large cohort of elderly non-disabled individuals with reported falls was analysed, using the cross sectional data of the Leukoaraiosis and Disability (LADIS) study. Detailed anatomical distributions of ARWMC assessed by MRI studies were analysed with respect to falls and balance performance.Results: The severity of global ARWMC was significantly associated with a history of falls in the year prior to study inclusion (22.2% in the mild, 31.6% in the moderate and 37.3% in the severe ARWMC group according to the Fazekas scale; p = 0.002). Analysing the anatomical distribution of ARWMC, using the semiquantitative Scheltens scale, in multivariate analysis, periventricular (p = 0.006) and frontal deep (p = 0.033) ARWMC were independently associated with falls. Furthermore, logistic regression identified frontal deep (p = 0.003) ARWMC, but not basal ganglia and infratentorial hyperintensities, as significantly associated with balance disturbances.Conclusion: The association of frontal and periventricular ARWMC with falls supports the hypothesis that interruption of frontal subcortical motor circuits lead to balance disturbances and hence to an increased risk for falls in ARWMC. [ABSTRACT FROM AUTHOR]

Background: Intravenous thrombolysis is contraindicated in patients with ischaemic stroke with blood pressure higher than 185/110 mm Hg. Prevailing guidelines recommend to actively lower blood pressure with intravenous antihypertensive agents to allow for thrombolysis; however, there is no robust evidence for this strategy. Because rapid declines in blood pressure can also adversely affect clinical outcomes, several Dutch stroke centres use a conservative strategy that does not involve the reduction of blood pressure. We aimed to compare the clinical outcomes of both strategies., Methods: Thrombolysis and Uncontrolled Hypertension (TRUTH) was a prospective, observational, cluster-based, parallel-group study conducted across 37 stroke centres in the Netherlands. Participating centres had to strictly adhere to an active blood-pressure-lowering strategy or to a non-lowering strategy. Eligible participants were adults (≥18 years) with ischaemic stroke who had blood pressure higher than 185/110 mm Hg but were otherwise eligible for intravenous thrombolysis. The primary outcome was functional status at 90 days, measured using the modified Rankin Scale and assessed through telephone interviews by trained research nurses. Secondary outcomes were symptomatic intracranial haemorrhage, the proportion of patients treated with intravenous thrombolysis, and door-to-needle time. All ordinal logistic regression analyses were adjusted for age, sex, stroke severity, endovascular thrombectomy, and baseline imbalances as fixed-effect variables and centre as a random-effect variable to account for the clustered design. Analyses were done according to the intention-to-treat principle, whereby all patients were analysed according to the treatment strategy of the participating centre at which they were treated., Findings: Recruitment began on Jan 1, 2015, and was prematurely halted because of a declining inclusion rate and insufficient funding on Jan 5, 2022. Between these dates, we recruited 853 patients from 27 centres that followed an active blood-pressure-lowering strategy and 199 patients from ten centres that followed a non-lowering strategy. Baseline characteristics of participants from the two groups were similar. The 90-day mRS score was missing for 15 patients. The adjusted odds ratio (aOR) for a shift towards a worse 90-day functional outcome was 1·27 (95% CI 0·96-1·68) for active blood-pressure reduction compared with no active blood-pressure reduction. 798 (94%) of 853 patients in the active blood-pressure-lowering group were treated with intravenous thrombolysis, with a median door-to-needle time of 35 min (IQR 25-52), compared with 104 (52%) of 199 patients treated in the non-lowering group with a median time of 47 min (29-78). 42 (5%) of 852 patients in the active blood-pressure-lowering group had a symptomatic intracranial haemorrhage compared with six (3%) of 199 of those in the non-lowering group (aOR 1·28 [95% CI 0·62-2·62])., Interpretation: Insufficient evidence was available to establish a difference between an active blood-pressure-lowering strategy-in which antihypertensive agents were administered to reduce blood pressure below 185/110 mm Hg-and a non-lowering strategy for the functional outcomes of patients with ischaemic stroke, despite higher intravenous thrombolysis rates and shorter door-to-needle times among those in the active blood-pressure-lowering group. Randomised controlled trials are needed to inform the use of an active blood-pressure-lowering strategy., Funding: Fonds NutsOhra., Competing Interests: Declaration of interests DWJD reports unrestricted research grants from Stryker Medtronic, Cerenovus, Penumbra, and Thrombolytic Science, all paid to his institution; and is chair of the data safety monitoring boards of the Act Global and LATE MT trials and a work package of the CONTRAST consortium. HBvdW reports research grants from the Dutch Heart Foundation (via the CONTRAST consortium), the European Commission, Stryker (via the CONTRAST consortium), Bayer, and Boehringer Ingelheim; consulting fees from TargED Biopharmaceuticals, Bayer, and Boehringer Ingelheim; and honoraria for presentations from the Netherlands Vascular Forum, all paid to his institution; is chair of the data safety monitoring board of the Ghrelin in Coma (GRECO) trial and a member of the advisory board of the TENSION trial; and is on the executive committee of—and is a past president of—the European Stroke Organisation. MJHW reports participation on the data safety monitoring board of the TRIDENT trial. YBWEMR is a minor shareholder of Nicolab. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

This article describes the 1-year follow-up of a study into the effectiveness of Schema Therapy (ST) for borderline personality disorder (BPD) and comorbid alcohol use disorder (AUD). In the original study, 20 of these patients participated in a multiple baseline case series design study. The results of the original study were promising (a significant decrease of BPD and AUD symptoms). The present study is aimed at examining the longer term benefits of ST for BPD and comorbid AUD. One year after the cessation of the investigational therapy, 17 of the original participants agreed to participate in this follow-up study. T- or Wilcoxon signed rank tests were performed to compare 1-year follow-up to start of therapy (baseline). The results suggest that the main therapeutic improvements were generally preserved at 1-year follow-up. These findings add to the idea that integrated ST for BPD and comorbid AUD might be effective, also in the long term. A randomized clinical trial is indicated to substantiate this idea., (© 2024 The Author(s). Clinical Psychology & Psychotherapy published by John Wiley & Sons Ltd.)

Haemorrhagic stroke is a severe condition with poor prognosis. Biological sex influences the risk factors, presentations, treatment, and patient outcomes of intracerebral haemorrhage, aneurysmal subarachnoid haemorrhage, and vascular malformations. Women are usually older at onset of intracerebral haemorrhage compared with men but have an increased risk of aneurysmal subarachnoid haemorrhage as they age. Female-specific factors such as pregnancy, eclampsia or pre-eclampsia, postmenopausal status, and hormone therapy influence a woman's long-term risk of haemorrhagic stroke. The presence of intracranial aneurysms, arteriovenous malformations, or cavernous malformations poses unique clinical dilemmas during pregnancy and delivery. In the absence of evidence-based guidelines for managing the low yet uncertain risk of haemorrhagic stroke during pregnancy and delivery in women with vascular malformations, multidisciplinary teams should carefully assess the risks and benefits of delivery methods for these patients. Health-care providers should recognise and address the challenges that women might have to confront when recovering from haemorrhagic stroke., Competing Interests: Declaration of interests ECS is national coordinator of the ANNEXAi trial (honoraria paid to the institution), is a steering committee member for the AXIOMATIC trial (BristolMyersSquibb) and OCEANIC trial (Bayer; also honoraria paid to the institution), and is on the European Stroke Organisation intracerebral haemorrhage committee. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

European marbled newts come in two species that have abutting ranges. The northern species, Triturus marmoratus, is found in France and the northern part of the Iberian Peninsula, whereas the southern species, T. pygmaeus, is found in the southwestern corner of the Iberian Peninsula. We study the intraspecific genetic differentiation of the group because morphological data show geographical variation and because the Iberian Peninsula is a recognized center of speciation and intraspecific genetic diversity for all kinds of organisms, amphibians included. We use target enrichment by sequence capture to generate c. 7 k nuclear DNA markers. We observe limited genetic exchange between the species, which confirms their distinctiveness. Both species show substantial genetic structuring that is only in part mirrored by morphological variation. Genetically differentiated groups are found in the south (T. marmoratus) and west (T. pygmaeus) of the species ranges. Our observations highlight the position of the Iberian Peninsula as a hotspot for genetic differentiation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Differences in clinical presentation of acute ischemic stroke between men and women may affect prehospital identification of anterior circulation large vessel occlusion (aLVO). We assessed sex differences in diagnostic performance of 8 prehospital scales to detect aLVO., Methods: We analyzed pooled individual patient data from 2 prospective cohort studies (LPSS [Leiden Prehospital Stroke Study] and PRESTO [Prehospital Triage of Patients With Suspected Stroke Study]) conducted in the Netherlands between 2018 and 2019, including consecutive patients ≥18 years suspected of acute stroke who presented within 6 hours after symptom onset. Ambulance paramedics assessed clinical items from 8 prehospital aLVO detection scales: Los Angeles Motor Scale, Rapid Arterial Occlusion Evaluation, Cincinnati Stroke Triage Assessment Tool, Cincinnati Prehospital Stroke Scale, Prehospital Acute Stroke Severity, gaze-face-arm-speech-time, Conveniently Grasped Field Assessment Stroke Triage, and Face-Arm-Speech-Time Plus Severe Arm or Leg Motor Deficit. We assessed the diagnostic performance of these scales for identifying aLVO at prespecified cut points for men and women., Results: Of 2358 patients with suspected stroke (median age, 73 years; 47% women), 231 (10%) had aLVO (100/1114 [9%] women and 131/1244 [11%] men). The area under the curve of the scales ranged from 0.70 (95% CI, 0.65-0.75) to 0.77 (95% CI, 0.73-0.82) in women versus 0.69 (95% CI, 0.64-0.73) to 0.75 (95% CI, 0.71-0.79) in men. Positive predictive values ranged from 0.23 (95% CI, 0.20-0.27) to 0.29 (95% CI, 0.26-0.31) in women versus 0.29 (95% CI, 0.24-0.33) to 0.37 (95% CI, 0.32-0.43) in men. Negative predictive values were similar (0.95 [95% CI, 0.94-0.96] to 0.98 [95% CI, 0.97-0.98] in women versus 0.94 [95% CI, 0.93-0.95] to 0.96 [95% CI, 0.94-0.97] in men). Sensitivity of the scales was slightly higher in women than in men (0.53 [95% CI, 0.43-0.63] to 0.76 [95% CI, 0.68-0.84] versus 0.49 [95% CI, 0.40-0.57] to 0.63 [95% CI, 0.55-0.73]), whereas specificity was lower (0.79 [95% CI, 0.76-0.81] to 0.87 [95% CI, 0.84-0.89] versus 0.82 [95% CI, 0.79-0.84] to 0.90 [95% CI, 0.88-0.91]). Rapid arterial occlusion evaluation showed the highest positive predictive values in both sexes (0.29 in women and 0.37 in men), reflecting the different event rates., Conclusions: aLVO scales show similar diagnostic performance in both sexes. The rapid arterial occlusion evaluation scale may help optimize prehospital transport decision-making in men as well as in women with suspected stroke., Competing Interests: Disclosures Dr Wermer reports receiving Clinical Established Investigator grant 2016T086 from the Dutch Heart Foundation and VIDI grant 9171337 from the Netherlands Organization for Health Research and Development (ZonMw) during the conduct of the original LPSS (Leiden Prehospital Stroke Study). Dr Kruyt reports receiving grant HA20 15.01.02 from the Dutch Brain Foundation, grant 3.240 from the Dutch Innovation Funds, and grant LSHM16041 from Health-Holland during the conduct of the study. Dr Roozenbeek reports funding from the Dutch Heart Foundation and the Netherlands Organization for Health Research and Development (ZonMw) during the conduct of this study, paid to the institution. Dr Dippel reports funding from the Dutch Heart Foundation, Brain Foundation Netherlands, the Netherlands Organisation for Health Research and Development, Health-Holland Top Sector Life Sciences & Health, and unrestricted grants from Penumbra Inc, Stryker, Medtronic, Thrombolytic Science, LLC, and Cerenovus for research, all paid to institution outside the submitted work. Dr van den Wijngaard reports compensation from Philips for consultant services, compensation from Medtronic for consultant services, and stock holdings in Neurophyxia BV. The other authors report no conflicts.

Background: Women with anterior circulation large vessel occlusion (LVO) have been reported to have worse outcomes after endovascular treatment (EVT) than men. Whether these disparities also exist in LVO of the posterior circulation is yet uncertain. We assessed sex differences in clinical, technical, and safety outcomes of EVT in posterior circulation LVO., Methods: We used data of patients with posterior circulation LVO included in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry (2014-2018). Primary outcome was the modified Rankin Scale (mRS) score at 90 days assessed with multivariable ordinal regression analysis. Secondary outcomes included favorable functional outcome (mRS ≤3), functional independence (mRS ≤2), death within 90 days, National Institutes of Health Stroke Scale (NIHSS) score 24-48 hours postintervention, complications, successful reperfusion (extended Thrombolysis in Cerebral Ischemia 2B-3), and procedure duration analyzed with multivariable logistic and linear regression analyses., Results: We included 264 patients (42% women). Compared with men, women were older (median age 68 vs 63 years), more often had prestroke disability (mRS ≥1: 37% vs 30%), and received intravenous thrombolytics less often (45% vs 56%). Clinical outcomes were similar between sexes (adjusted (common) OR (aOR) 0.82, 95% CI 0.51 to 1.34; favorable functional outcome 50% vs 43%, aOR 1.31, 95% CI 0.77 to 2.25; death 32% vs 29%, aOR 0.98, 95% CI 0.52 to 1.84). In addition, NIHSS score after 24-48 hours (median 7 vs 9), successful reperfusion (77% vs 73%), and complications did not differ between men and women., Conclusions: Outcomes in women treated with EVT for posterior circulation LVO were similar compared with men despite less favorable baseline characteristics in women. Therefore men and women may benefit equally from EVT., Competing Interests: Competing interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MJHW reports funding from NWO/ZonMw (VIDI 91717337 and Aspasia). JH reports funding from the Dutch Heart Foundation (CEI 2018T070). CBLMM reports funding from the TWIN Foundation, CVON/Dutch Heart Foundation, European Commission, Healthcare Evaluation Netherlands, and Stryker, all outside the submitted work (paid to institution). In addition, he is shareholder of Nicolab. IRvdW reports consulting fees from Philips, Medtronic, and Neurophyxia. DWJD reports funding from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and unrestricted grants from Penumbra Inc, Stryker European Operations BV, Medtronic, Thrombolytic Science, LLC and Cerenovus, all paid to the institution. The other authors had no conflicting interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Endovascular thrombectomy (EVT) is standard treatment for anterior large vessel occlusion stroke (LVO-a stroke). Prehospital diagnosis of LVO-a stroke would reduce time to EVT by allowing direct transportation to an EVT-capable hospital. We aim to evaluate the diagnostic accuracy of dry electrode EEG for the detection of LVO-a stroke in the prehospital setting., Methods: ELECTRA-STROKE was an investigator-initiated, prospective, multicenter, diagnostic study, performed in the prehospital setting. Adult patients were eligible if they had suspected stroke (as assessed by the attending ambulance nurse) and symptom onset <24 hours. A single dry electrode EEG recording (8 electrodes) was performed by ambulance personnel. Primary endpoint was the diagnostic accuracy of the theta/alpha frequency ratio for LVO-a stroke (intracranial ICA, A1, M1, or proximal M2 occlusion) detection among patients with EEG data of sufficient quality, expressed as the area under the receiver operating characteristic curve (AUC). Secondary endpoints were diagnostic accuracies of other EEG features quantifying frequency band power and the pairwise derived Brain Symmetry Index. Neuroimaging was assessed by a neuroradiologist blinded to EEG results., Results: Between August 2020 and September 2022, 311 patients were included. The median EEG duration time was 151 (interquartile range [IQR] 151-152) seconds. For 212/311 (68%) patients, EEG data were of sufficient quality for analysis. The median age was 74 (IQR 66-81) years, 90/212 (42%) were women, and the median baseline NIH Stroke Scale was 1 (IQR 0-4). Six (3%) patients had an LVO-a stroke, 109/212 (51%) had a non-LVO-a ischemic stroke, 32/212 (15%) had a transient ischemic attack, 8/212 (4%) had a hemorrhagic stroke, and 57/212 (27%) had a stroke mimic. AUC of the theta/alpha ratio was 0.80 (95% CI 0.58-1.00). Of the secondary endpoints, the pairwise derived Brain Symmetry Index in the delta frequency band had the highest diagnostic accuracy (AUC 0.91 [95% CI 0.73-1.00], sensitivity 80% [95% CI 38%-96%], specificity 93% [95% CI 88%-96%], positive likelihood ratio 11.0 [95% CI 5.5-21.7])., Discussion: The data from this study suggest that dry electrode EEG has the potential to detect LVO-a stroke among patients with suspected stroke in the prehospital setting. Toward future implementation of EEG in prehospital stroke care, EEG data quality needs to be improved., Trial Registration Information: ClinicalTrials.gov identifier: NCT03699397., Classification of Evidence: This study provides Class II evidence that prehospital dry electrode scalp EEG accurately detects LVO-a stroke among patients with suspected acute stroke.

The objective of this study was to determine whether there is an association between sex and outcome in trauma patients presented with severe traumatic brain injury (TBI). A retrospective multicenter study was performed in trauma patients aged ≥ 16 years who presented with severe TBI (Head Abbreviated Injury Scale (AIS) ≥ 4) over a 4-year-period. Subgroup analyses were performed for ages 16-44 and ≥45 years. Also, patients with isolated severe TBI (other AIS ≤ 2) were assessed, likewise, with subgroup analysis for age. Sex differences in mortality, Glasgow Outcome Score (GOS), ICU admission/length of stay (LOS), hospital LOS, and mechanical ventilation (MV) were examined. A total of 1566 severe TBI patients were included (831 patients with isolated TBI). Crude analysis shows an association between female sex and lower ICU admission rates, shorter ICU/hospital LOS, and less frequent and shorter MV in severe TBI patients ≥ 45 years. After adjusting, female sex appears to be associated with shorter ICU/hospital LOS. Sex differences in mortality and GOS were not found. In conclusion, this study found sex differences in patient outcomes following severe TBI, potentially favoring (older) females, which appear to indicate shorter ICU/hospital LOS (adjusted analysis). Large prospective studies are warranted to help unravel sex differences in outcomes after severe TBI.

Background: Women have been reported to have worse outcomes after endovascular treatment (EVT), despite a similar treatment effect in non-clinical trial populations. We aimed to assess sex differences at hospital presentation with respect to workflow metrics, prestroke disability, and presenting clinical symptoms., Methods: We included consecutive patients from the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in The Netherlands (MR CLEAN) Registry (2014-2018) who received EVT for anterior circulation large vessel occlusion (LVO). We assessed sex differences in workflow metrics, prestroke disability (modified Rankin Scale (mRS) score ≥1), and stroke severity and symptoms according to the National Institutes of Health Stroke Scale (NIHSS) score on hospital admission with logistic and linear regression analyses and calculated the adjusted OR (aOR)., Results: We included 4872 patients (47.6% women). Compared with men, women were older (median age 76 vs 70 years) and less often achieved good functional outcome at 90 days (mRS ≤2: 35.2% vs 46.4%, aOR 0.70, 95% CI 0.60 to 0.82). Mean onset-to-door time was longer in women (2 hours 16 min vs 2 hours 7 min, adjusted delay 9 min, 95% CI 4 to 13). This delay contributed to longer onset-to-groin times (3 hours 26 min in women vs 3 hours 13 min in men, adjusted delay 13 min, 95% CI 9 to 17). Women more often had prestroke disability (mRS ≥1: 41.1% vs 29.1%, aOR 1.57, 95% CI 1.36 to 1.82). NIHSS on admission was essentially similar in men and women (mean 15±6 vs 15±6, NIHSS <10 vs ≥10, aOR 0.91, 95% CI 0.78 to 1.06). There were no clear sex differences in the occurrence of specific stroke symptoms., Conclusion: Women with LVO had longer onset-to-door times and more often prestroke disability than men. Raising awareness of these differences at hospital presentation and investigating underlying causes may help to improve outcome after EVT in women., Competing Interests: Competing interests: MJHW reports funding from the Dutch Research Council (VIDI grant 91717337). CBLMM reports funding from the TWIN Foundation, CVON/Dutch Heart Foundation, European Commission, Health Evaluation Netherlands, and Stryker, all outside the submitted work (paid to institution); he is shareholder of Nicolab. DWJD reports funding from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences and Health, and unrestricted grants from Penumbra Inc, Stryker European Operations BV, Medtronic, Thrombolytic Science, and Cerenovus, all paid to institution. JH reports funding from the Dutch Heart Foundation, Brain Foundation Netherlands, and ZonMw, all paid to institution. IRvdW reports funding from Jacobus Stichting. PJN reports funding from the Dutch Heart Foundation and The Netherlands Organisation for Health Research and Development, both paid to institution., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

When two putatively cryptic species meet in nature, hybrid zone analysis can be used to estimate the extent of gene flow between them. Two recently recognized cryptic species of banded newt (genus Ommatotriton ) are suspected to meet in parapatry in Anatolia, but a formal hybrid zone analysis has never been conducted. We sample populations throughout the range, with a focus on the supposed contact zone, and genotype them for 31 nuclear DNA SNP markers and mtDNA. We determine the degree of genetic admixture, introgression, and niche overlap. We reveal an extremely narrow hybrid zone, suggesting strong selection against hybrids, in line with species status. The hybrid zone does not appear to be positioned at an ecological barrier, and there is significant niche overlap. Therefore, the hybrid zone is best classified as a tension zone, maintained by intrinsic selection against hybrids. While the two banded newt species can evidently backcross, we see negligible introgression and the pattern is symmetric, which we interpret as supporting the fact that the hybrid zone has been practically stationary since its origin (while extensive hybrid zone movement has been suggested in other newt genera in the region). Our study illustrates the use of hybrid zone analysis to test cryptic species status., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Background: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset., Methods: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308., Findings: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1-4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65-1·47]). In the target population (n=291), the 90-day mRS score was 2 (2-4) in the glyceryl trinitrate group and 3 (1-4) in the control group (0·92 [0·59-1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53-2·14]) or serious adverse events (unadjusted OR 1·23 [0·76-1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78-44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18-4·17])., Interpretation: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting., Funding: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation., Competing Interests: Declaration of interests HR reports financial support from the European Union's Horizon 2020 research and innovation program, paid to his institution. BJE reports financial support from Health Holland Top Sector Life Sciences & Health (via the Top Consortia for Knowledge and Innovation's public–private partnership), paid to his institution; and unpaid board membership of UEMS Neuroradiology and the Dutch Society of Radiology, Division of Neuroradiology. CBLMM, DWJD, PJN and HBvdW report funding from the Dutch Heart Foundation and Stryker, all paid to their institutions or the CONTRAST consortium. CBLMM reports financial support from the TWIN Foundation and Health Evaluation Netherlands, all paid to his institution. CBLMM and HBvdW report financial support from the European Commission, all paid to their institutions. CBLMM and YBWEMR are minor shareholders of Nicolab. DWJD reports grants from Medtronic, Cerenovus, Penumbra, Brain Foundation Netherlands, ZON MW–The Netherlands Organisation for Health Research and Development, and Health Holland Top Sector Life Sciences & Health, all paid to his institution. HBvdW reports honoraria for consultancy from Bayer and LivaNova, all paid to his institution. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: There is wide variability in radiographic grading systems in thoracolumbar spinous processes in horses. The aim of this study was to determine the agreement of grading different parameters, and combinations of those, in radiographs of the spinous processes of the equine thoracolumbar spine in the scope of a pre-purchase examination. We hypothesized that agreement is variable and interpretation of these radiographs is difficult., Methods: Radiographs of the thoracolumbar spine of healthy horses (N = 100) were assessed by three observers. Spinous processes were separately graded for interspinous space width, modelling, radiopacities, radiolucencies and isolated opacities dorsally. Inter- and intra-observer agreement was assessed for individual and combinations of parameters., Results: Agreement (inter- and intra-observer) was good for the following parameters: interspinous space width, isolated opacities dorsally, beak-shaped formations craniodorsally and modelling cranioventrally. The agreement increased slightly for a sum of specific parameters such as radiopacities, modelling, dorsal abnormalities and related abnormalities involving increased opacity, modelling and osseous cyst-like lesions. Agreement for the total radiographic abnormalities per back was moderate., Conclusions: Grading of thoracolumbar radiographs in horses without back pain showed good inter- and intra-observer agreement for specific parameters and these should be used in future grading of spinous processes. Limitations should be considered in pre-purchase examinations., (© 2021 British Veterinary Association.)

Background and Purpose: Women have worse outcomes than men after stroke. Differences in presentation may lead to misdiagnosis and, in part, explain these disparities. We investigated whether there are sex differences in clinical presentation of acute stroke or transient ischemic attack., Methods: We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Inclusion criteria were (1) cohort, cross-sectional, case-control, or randomized controlled trial design; (2) admission for (suspicion of) ischemic or hemorrhagic stroke or transient ischemic attack; and (3) comparisons possible between sexes in ≥1 nonfocal or focal acute stroke symptom(s). A random-effects model was used for our analyses. We performed sensitivity and subanalyses to help explain heterogeneity and used the Newcastle-Ottawa Scale to assess bias., Results: We included 60 studies (n=582 844; 50% women). In women, headache (pooled odds ratio [OR], 1.24 [95% CI, 1.11-1.39]; I 2 =75.2%; 30 studies) occurred more frequently than in men with any type of stroke, as well as changes in consciousness/mental status (OR, 1.38 [95% CI, 1.19-1.61]; I 2 =95.0%; 17 studies) and coma/stupor (OR, 1.39 [95% CI, 1.25-1.55]; I 2 =27.0%; 13 studies). Aspecific or other neurological symptoms (nonrotatory dizziness and non-neurological symptoms) occurred less frequently in women (OR, 0.96 [95% CI, 0.94-0.97]; I 2 =0.1%; 5 studies). Overall, the presence of focal symptoms was not associated with sex (pooled OR, 1.03) although dysarthria (OR, 1.14 [95% CI, 1.04-1.24]; I 2 =48.6%; 11 studies) and vertigo (OR, 1.23 [95% CI, 1.13-1.34]; I 2 =44.0%; 8 studies) occurred more frequently, whereas symptoms of paresis/hemiparesis (OR, 0.73 [95% CI, 0.54-0.97]; I 2 =72.6%; 7 studies) and focal visual disturbances (OR, 0.83 [95% CI, 0.70-0.99]; I 2 =62.8%; 16 studies) occurred less frequently in women compared with men with any type of stroke. Most studies contained possible sources of bias., Conclusions: There may be substantive differences in nonfocal and focal stroke symptoms between men and women presenting with acute stroke or transient ischemic attack, but sufficiently high-quality studies are lacking. More studies are needed to address this because sex differences in presentation may lead to misdiagnosis and undertreatment.

Background: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain unknown. This study aims to explore these sex differences to improve our understanding of pathophysiological mechanisms behind the migraine-stroke association. Methods: We included 2,492 patients with ischemic stroke from the prospective multicenter Dutch Parelsnoer Institute Initiative study, 425 (17%) of whom had a history of migraine. Cardiovascular risk profile, stroke cause (TOAST classification), and outcome [modified Rankin scale (mRS) at 3 months] were compared with both sexes between patients with and without migraine. Results: A history of migraine was not associated with sex differences in the prevalence of conventional cardiovascular risk factors. Women with migraine had an increased risk of stroke at young age (onset < 50 years) compared with women without migraine (RR: 1.7; 95% CI: 1.3-2.3). Men with migraine tended to have more often stroke in the TOAST category other determined etiology (RR: 1.7; 95% CI: 1.0-2.7) in comparison with men without migraine, whereas this increase was not found in women with migraine. Stroke outcome was similar for women with or without migraine (mRS ≥ 3 RR 1.1; 95% CI 0.7-1.5), whereas men seemed to have a higher risk of poor outcome compared with their counterparts without migraine (mRS ≥ 3 RR: 1.5; 95% CI: 1.0-2.1). Conclusion: Our results indicate possible sex differences in the pathophysiology underlying the migraine-stroke association, which are unrelated to conventional cardiovascular risk factors. Further research in larger cohorts is needed to validate these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Linstra, van Os, Ruigrok, Nederkoorn, van Dijk, Kappelle, Koudstaal, Visser, Ferrari, MaassenVanDenBrink, Terwindt and Wermer.)

Background: Obtaining informed consent for intravenous thrombolysis in acute ischemic stroke can be challenging, and little is known about if and how the informed consent procedure is performed by neurologists in clinical practice. This study examines the procedure of informed consent for intravenous thrombolysis in acute ischemic stroke in high-volume stroke centers in the Netherlands., Methods: In four high volume stroke centers, neurology residents and attending neurologists received an online questionnaire concerning informed consent for thrombolysis with tissue-type plasminogen activator (tPA). The respondents were asked to report their usual informed consent practice for tPA treatment and their considerations on whether informed consent should be obtained., Results: From the 203 invited clinicians, 50% (n = 101) completed the questionnaire. One-third of the neurology residents (n = 21) and 21% of the neurologists (n = 8) reported that they always obtain informed consent for tPA treatment. If a patient is not capable of providing informed consent, 30% of the residents (n = 19) reported that they start tPA treatment without informed consent. In these circumstances, 53% of the neurologists (n = 20) reported that the resident under their supervision would start tPA treatment without informed consent. Most neurologists (n = 21; 55%) and neurology residents (n = 45; 72%) obtained informed consent within one minute. None of the respondents used more than five minutes for informed consent. Important themes regarding obtaining informed consent for treatment were patients' capacity, and medical, ethical and legal considerations., Conclusion: The current practice of informed consent for thrombolysis in acute ischemic stroke varies among neurologists and neurology residents. If informed consent is obtained, most clinicians stated to obtain informed consent within one minute. In the future, a shortened information provision process may be applied, making a shift from informed consent to informed refusal, while still considering the patient's capacity, stroke severity, and possible treatment delays., (© 2021. The Author(s).)

Background and Purpose: There are concerns that the coronavirus disease 2019 (COVID-19) outbreak negatively affects the quality of care for acute cardiovascular conditions. We assessed the impact of the COVID-19 outbreak on trends in hospital admissions and workflow parameters of acute stroke care in Amsterdam, The Netherlands., Methods: We used data from the three hospitals that provide acute stroke care for the Amsterdam region. We compared two 7-week periods: one during the peak of the COVID-19 outbreak (March 16th-May 3th 2020) and one prior to the outbreak (October 21st-December 8th 2019). We included consecutive patients who presented to the emergency departments with a suspected stroke and assessed the change in number of patients as an incidence-rate ratio (IRR) using a Poisson regression analysis. Other outcomes were the IRR for stroke subtypes, change in use of reperfusion therapy, treatment times, and in-hospital complications., Results: During the COVID-19 period, 309 patients presented with a suspected stroke compared to 407 patients in the pre-COVID-19 period (IRR 0.76 95%CI 0.65-0.88). The proportion of men was higher during the COVID-19 period (59% vs. 47%, p < 0.001). There was no change in the proportion of stroke patients treated with intravenous thrombolysis (28% vs. 30%, p = 0.58) or endovascular thrombectomy (11% vs 12%, p = 0.82) or associated treatment times. Seven patients (all ischemic strokes) were diagnosed with COVID-19., Conclusion: We observed a 24% decrease in suspected stroke presentations during the COVID-19 outbreak, but no evidence for a decrease in quality of acute stroke care.

Background: Treatment outside office hours has been associated with increased workflow times for intravenous thrombolysis (IVT) in acute ischemic stroke (AIS). Limited data suggest that this "off-hours effect" also exists for endovascular treatment (EVT). We investigated this phenomenon in a well-organized acute stroke care region in the Netherlands., Methods: Retrospective, observational cohort study of consecutive patients with AIS who received reperfusion therapy in the Greater Amsterdam Area, consisting of 14 primary stroke centers and 1 comprehensive stroke center (IVT: 2009-2015, EVT: 2014-2017). Office hours were defined as presentation during weekdays between 8 AM and 5 PM, excluding National Festive days. Primary outcome was door-to-treatment time (door-to-needle [DNT] for IVT, door-to-groin [DGT] for EVT). For DGT, we used the door time of the first hospital. Other outcomes were in-hospital mortality, modified Rankin Scale (mRS) score at 90 days and symptomatic intracranial hemorrhage (sICH). We performed multivariable linear and logistic regression analyses and used multiple imputation to account for missing values., Results: In total, 59% (2450/4161) and 61% (239/395) of patients treated with IVT and EVT, respectively, presented outside office hours. Median DNT was minimally longer outside office hours (32 vs. 30 min, p = 0.024, adjusted difference 2.5 min, 95% CI 0.7-4.2). Presentation outside office hours was not associated with a longer DGT (median 130 min for both groups, adjusted difference 7.0 min, 95% CI - 4.2 to 18.1). Clinical outcome and sICH rate also did not differ., Conclusion: Presentation outside office hours did not lead to clinically relevant treatment delays for reperfusion therapy in patients with AIS.

In the field of rare bone diseases in particular, a broad care team of specialists embedded in multidisciplinary clinical and research environment is essential to generate new therapeutic solutions and approaches to care. Collaboration among clinical and research departments within a University Medical Center is often difficult to establish, and may be hindered by competition and non-equivalent cooperation inherent in a hierarchical structure. Here we describe the "collaborative organizational model" of the Amsterdam Bone Center (ABC), which emerged from and benefited the rare bone disease team. This team is often confronted with pathologically complex and under-investigated diseases. We describe the benefits of this model that still guarantees the autonomy of each team member, but combines and focuses our collective expertise on a clear shared goal, enabling us to capture synergistic and innovative opportunities for the patient, while avoiding self-interest and possible harmful competition., (Copyright © 2020 Eekhoff, Micha, Forouzanfar, de Vries, Netelenbos, Klein-Nulend, van Loon, Lubbers, Schwarte, Schober, Raijmakers, Teunissen, de Graaf, Lammertsma, Yaqub, Botman, Treurniet, Smilde, Bökenkamp, Boonstra, Kamp, Nieuwenhuijzen, Visser, Baayen, Dahele, Eeckhout, Goderie, Smits, Gilijamse, Karagozoglu, van de Valk, Dickhoff, Moll, Verbraak, Curro-Tafili, Ghyczy, Rustemeyer, Saeed, Maugeri, Pals, Ridwan-Pramana, Pekel, Schoenmaker, Lems, Winters, Botman, Giannakópoulos, Koolwijk, Janssen, Kloen, Bravenboer, Smit and Helder.)

This is an ethnographic study of decision-making concerning tube feeding in the acute phase after a severe stroke. It is based on 6 months of ethnographic research in three stroke units in the Netherlands, where the decision-making on life-sustaining treatment was studied in 16 cases of severe stroke patients. Data were collected through participant observation and interviews. For this article, the analysis was narrowed down to the decision whether or not the patient should receive tube feeding. The data on tube feeding were assembled and coded according to different modes of dealing with this decision in clinical practice, which we refer to as "repertoires." We discerned three different repertoires: choice, necessity, and comfort. Each repertoire structures clinical practice differently: It implies distinctive ethical imperatives, central concerns, sources of information, and temporalities. We hope our findings can improve decision-making by uncovering its underlying logics in clinical practice.

Background: A cardiac origin in ischemic stroke is more frequent than previously assumed, but it is not clear which patients benefit from cardiac work-up if obvious cardiac pathology is absent. We hypothesized that thromboembolic stroke with a cardiac source occurs more frequently in the posterior circulation compared with thromboembolic stroke of another etiology., Methods: We performed a multicenter observational study in 3,311 consecutive patients with ischemic stroke who were enrolled in an ongoing prospective stroke registry of 8 University hospitals between September 2009 and November 2014 in The Netherlands. In this initiative, the so-called Parelsnoer Institute-Cerebrovascular Accident Study Group, clinical data, imaging, and biomaterials of patients with stroke are prospectively and uniformly collected. We compared the proportions of posterior stroke location in patients with a cardiac stroke source with those with another stroke etiology and calculated risk ratios (RR) with corresponding 95% CI with Poisson regression analyses. To assess which patient or disease characteristics were most strongly associated with a cardiac etiology in patients with ischemic stroke, we performed a stepwise backward regression analysis., Results: For the primary aim, 1,428 patients were eligible for analyses. The proportion of patients with a posterior stroke location among patients with a cardiac origin of their stroke (28%) did not differ statistically significant to those with another origin (25%), age and sex adjusted RR 1.16; 95% CI 0.96-1.41. For the secondary aim, 1,955 patients were eligible for analyses. No recent history of smoking, no hyperlipidemia, coronary artery disease, a higher age, and a higher National Institutes of Health Stroke Scale (NIHSS) score were associated with a cardiac etiology of ischemic stroke., Conclusions: We could not confirm our hypothesis that thromboembolic stroke localized in the posterior circulation is associated with a cardioembolic source of ischemic stroke, and therefore posterior stroke localization on itself does not necessitate additional cardiac examination. The lack of determinants of atherosclerosis, for example, no recent history of smoking and no hyperlipidemia, coronary artery disease, a higher age, and a higher NIHSS score are stronger risk factors for a cardiac source of ischemic stroke., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: Patients with migraine might be more susceptible of spreading depolarizations, which are known to affect vascular and neuronal function and penumbra recovery after stroke. We investigated whether these patients have more severe stroke progression and less favorable outcomes after recanalization therapy., Methods: We included patients from a prospective multicenter ischemic stroke cohort. Lifetime migraine history was based on the International Classification of Headache Disorders II criteria. Patients without confirmed migraine diagnosis were excluded. Patients underwent CT angiography and CT perfusion <9 h of onset and follow-up CT after three days. On admission, presence of a perfusion deficit, infarct core and penumbra volume, and blood brain barrier permeability (BBBP) were assessed. At follow-up we assessed malignant edema, hemorrhagic transformation, and final infarct volume. Outcome at three months was evaluated with the modified Rankin Scale (mRS). We calculated adjusted relative risks (aRR) or difference of means (aB) with regression analyses., Results: We included 600 patients of whom 43 had migraine. There were no differences between patients with or without migraine in presence of a perfusion deficit on admission (aRR: 0.98, 95%CI: 0.77-1.25), infarct core volume (aB: -10.8, 95%CI: -27.04-5.51), penumbra volume (aB: -11.6, 95%CI: -26.52-3.38), mean blood brain barrier permeability (aB: 0.08, 95%CI: -3.11-2.96), malignant edema (0% vs. 5%), hemorrhagic transformation (aRR: 0.26, 95%CI: 0.04-1.73), final infarct volume (aB: -14.8, 95%CI: 29.9-0.2) or outcome after recanalization therapy (mRS > 2, aRR: 0.50, 95%CI: 0.21-1.22)., Conclusion: Elderly patients with a history of migraine do not seem to have more severe stroke progression and have similar treatment outcomes compared with patients without migraine.

Importance: Migraine is a highly prevalent disorder associated with cardiovascular diseases. Cardiovascular diseases are also associated with preeclampsia (PE). The adverse pregnancy outcomes PE, preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA) and placental abruption share aspects in their pathophysiology, which are also found in patients with migraine, such as inflammatory stress and hypercoagulability., Objective: To determine the association of adverse pregnancy outcomes including PE, PTB, LBW, SGA, and placental abruption with a history of migraine through a systematic review and meta-analysis., Evidence Acquisition: MEDLINE (PubMed), the Cochrane Library, and EMBASE, were searched from inception to November 11, 2018. Cohort studies and case-control studies evaluating migraine history and pregnancy complications were eligible., Results: Of 1388 screened references, 14 studies were included in the systematic review. There were higher risks of PE (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.51-2.85; I 2 = 76%) and LBW (OR, 1.18; 95% CI, 1.03-1.34; I 2 = 9%) in women with migraine compared with women without migraine. We observed no significant association between history of migraine and PTB (OR, 1.23; 95% CI, 0.97-1.55; I 2 = 61%) or SGA (OR, 1.06; 95% CI, 0.98-1.15; I 2 = 0%)., Conclusions: A history of migraine is significantly associated with an increased risk of adverse pregnancy outcomes including PE and LBW. We hypothesize that shared pathophysiology due to underlying preclinical cardiovascular risk in women with migraine might play a role during pregnancy., Relevance: Pregnant women with a history of migraine should be considered at higher risk of adverse pregnancy outcomes and should be informed, monitored, and treated preventively accordingly.

Background: Cryptococcal meningitis is most commonly found in HIV-infected patients. In HIV-negative patients, its low incidence can lead to prolonged time to diagnosis. Detailed case reports of chronic cryptococcal meningitis are scarce, but could provide clues for earlier diagnosis in this patient category., Case Presentation: A 60-year old man presented June 2015 with intermittent headaches for several months without any fever. Initial work-up showed a leukocytosis, raised CSF opening pressure and raised leukocytes and protein in the CSF. An MRI revealed leptomeningeal contrast enhancement and cerebellar oedema. While malignancy and various infectious causes were excluded, the patient had a spontaneous clinical and radiological recovery. One year later, the patient returned with complaints of headaches. Also, cerebellar oedema and leptomeningeal contrast enhancement had recurred. Eventually in March 2017, the novel cryptococcal antigen lateral flow assay (CrAg LFA) was positive on CSF, and one colony of Cryptococcus neoformans was cultured from CSF. The patient was treated with the standard antifungal regimen which resulted in resolution of his headaches. In retrospect, the cryptococcal antigen test was already positive on a serum sample from June 2015. Interestingly, post-treatment immunological analysis revealed both a low mannose-binding lectin (MBL) concentration and low naïve CD4 counts., Conclusions: We present a patient with cryptococcal meningitis in an HIV-negative patient with low MBL and low naïve CD4 count suffering a chronic relapsing meningo-encephalitis with relatively mild symptoms for around 2 years. In patients with an unexplained meningo-encephalitis such as this case, early performance of CrAg LFA on serum and/or CSF is an inexpensive and rapid method to reduce time-to diagnosis.

Objectives: Migraine is a risk factor for stroke, which might be explained by a higher prevalence in anatomical variants in the circle of Willis (CoW). Here, we compared the presence of CoW variants in patients with stroke with and without migraine., Materials and Methods: Participants were recruited from the prospective Dutch acute Stroke Study. All participants underwent CT angiography on admission. Lifetime migraine history was assessed with a screening questionnaire and confirmed by an interview based on International Classification of Headache Disorders criteria. The CoW was assessed for incompleteness/hypoplasia (any segment <1 mm), for anterior cerebral artery asymmetry (difference > 1/3), and for posterior communicating artery (Pcom) dominance (Pcom-P1 difference > 1/3). Odds ratios with adjustments for age and sex (aOR) were calculated with logistic regression., Results: We included 646 participants with stroke, of whom 52 had a history of migraine. Of these, 45 (87%) had an incomplete or hypoplastic CoW versus 506 (85%) of the 594 participants without migraine (aOR: 1.47; 95% CI: 0.63-3.44). There were no differences between participants with and without migraine in variations of the anterior or posterior CoW, anterior cerebral artery asymmetry (aOR: 0.86; 95% CI: 0.43-1.74), or Pcom dominance (aOR: 0.64; 95% CI: 0.32-1.30). There were no differences in CoW variations between migraine patients with or without aura., Conclusion: We found no significant difference in the completeness of the CoW in acute stroke patients with migraine compared to those without., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Purpose: Traumatic brain injury (TBI) is a major cause of trauma-related visits to emergency departments (ED). Determination of monitoring requirements of patients with apparently mild TBI is challenging. Patients may turn out to be more severely injured than initially assumed, and failure to identify these patients constitutes a serious threat to patient safety. We, therefore, aimed to identify clinical risk factors for more severe injuries in patients with apparently mild TBI., Methods: In a retrospective cohort analysis performed at two level I trauma centers, 808 patients aged ≥ 16 presenting to the ED with head trauma and a Glasgow Coma Scale (GCS) score 13-15 who received a head CT scan were studied. Discrepancies between the initial TBI severity as determined by GCS and severity as determined post hoc by the Head Abbreviated Injury Score were assessed. Multiple logistic regression was used to identify risk factors of such discrepancies., Results: 104 (12.9%) patients were more severely injured than initially classified. A GCS < 15 at presentation (GCS 13: OR 6.2, [95% CI 3.8-9.9]; GCS 14: OR 2.7, [2.0-3.7]), an SpO 2  < 90% (OR 5.4, [1.2-23.4]), loss of consciousness (OR 2.3, [1.5-3.5]), absence of equal and reactive pupils (OR 2.1, [1.6-2.7]), transport by ambulance (OR 2.0, [1.7-2.4]), and use of anticoagulant drugs (OR 1.2, [1.1-1.3]) were independent risk factors of more severe injury., Conclusions: Six risk factors of more severe injury in patients presenting with apparently mild TBI were identified. Patients with any of these factors should be thoroughly monitored for signs of neurologic deterioration.

Background: Infection with Borrelia burgdorferi sensu lato complex (B. b. sl) spirochetes can cause Lyme borreliosis, manifesting as localized infection (e.g. erythema migrans) or disseminated disease (e.g. Lyme neuroborreliosis). Generally, patients with disseminated Lyme borreliosis will produce an antibody response several weeks post-infection. So far, no case of neuroborreliosis has been described with persistently negative serology one month after infection., Case Presentation: We present a patient with a history of Mantle cell lymphoma and treatment with R-CHOP (rituximab, doxorubicine, vincristine, cyclofosfamide, prednisone), with a meningo-encephalitis, who was treated for a suspected lymphoma relapse. However, no malignant cells or other signs of malignancy were found, and microbial tests did not reveal any clues, including Borrelia serology. He did not recall being bitten by ticks, and a Borrelia PCR on CSF was negative. After spontaneous improvement of symptoms, he was discharged without definite diagnosis. Several weeks later, he was readmitted with a relapse of symptoms of meningo-encephalitis. This time however, a Borrelia PCR on CSF was positive, confirmed by two independent laboratories, and the patient received ceftriaxone upon which he partially recovered. Interestingly, during the diagnostic process of this exceptionally difficult case, a variety of different serological assays for Borrelia antibodies remained negative. Only P41 (flagellin) IgG was detected by blot and the Liaison IgG became equivocal 2 months after initial testing., Conclusions: To the best of our knowledge this is the first case of neuroborreliosis that is seronegative on repeated sera and multiple test modalities. This unique case demonstrates the difficulty to diagnose neuroborreliosis in severely immunocompromised patients. In this case, a delay in diagnosis was caused by broad differential diagnosis, an absent known history of tick bites, negative serology and the low sensitivity of PCR on CSF. Therefore, awareness of the diagnostic limitations to detect Borrelia infection in this specific patient category is warranted.

Introduction: The use of the new psychoactive substance 4-fluoroamphetamine (4-FA) and the number of 4-FA-related intoxications substantially increased in The Netherlands in recent years. We describe two patients with severe 4-FA-related complications and the characteristics of a large sample of 4-FA-intoxicated patients., Methods: Information on patients with 4-FA-related intoxications between January 2009 and June 2017 was available from the Monitor Drug-related Incidents. Detailed clinical information was obtained of two patients with haemorrhagic stroke after toxicologically confirmed 4-FA use., Results: We report on two patients who presented with headache and mild hypertension after 4-FA use. Patient A developed one-sided weakness and decreased consciousness after a few hours. A computed tomography scan showed a left-sided intracerebral haemorrhage. Because of life-threatening cerebral herniation, haematoma evacuation was performed. Postoperatively, she suffered from a right-sided hemiparalysis and severe aphasia, requiring clinical rehabilitation. Patient B had a subarachnoid haemorrhage without neurological deficits. In total, 939 4-FA-intoxicated patients were registered. These patients used 4-FA alone (44%) or in combination with alcohol (13%) and/or other drugs (43%)., Discussion: Patients using 4-FA are at risk for life-threatening health problems, including intracranial haemorrhage. Additional brain imaging should be considered in 4-FA-intoxicated patients, not only in the presence of neurological deficits, but also in the case of severe headache.

Background: Previous research has shown the importance of urgent initiation of antiplatelet therapy after transient ischemic attack (TIA) to reduce the risk of stroke. Many hospitals in the Netherlands have therefore implemented rapid pathways for assessment of patients with TIA. Dutch stroke guidelines lack clear directives for organization of TIA assessment and thus allow for variation. The aim of this study was to investigate variation in organization of TIA assessment in Dutch hospitals., Methods: One neurologist per hospital (of 88 Dutch hospitals) with special interest in stroke was invited to participate in a web-based survey addressing the organization, content, and timing of TIA assessment., Results: Seventy (80%) neurologists completed the survey, all of whom reported performing TIA assessment in their hospital. There was considerable variation in the method of application and the location of assessment. In 10% of the hospitals, patients with TIA are always admitted to the ward. The content of diagnostics is fairly similar, but hospitals vary in the extent of cardiological workup. Almost all hospitals aim for a swift start of assessment as directed by guidelines, but access time differs. Eighty-six percent of respondents reported that antiplatelet therapy is usually initiated before assessment, based on history., Conclusions: This study showed variation in organization of TIA assessment in Dutch hospitals, especially regarding location within the hospital, time to assessment after announcement, and cardiological workup. Further research is needed to investigate implications of this variation for quality of care., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Migraine is a well-established risk factor for ischemic stroke, but migraine is also related to other vascular diseases. This study aims to investigate the association between migraine and cerebrovascular atherosclerosis in patients with acute ischemic stroke., Methods: We retrieved data on patients with ischemic stroke from the DUST (Dutch Acute Stroke Study). Migraine history was assessed with a migraine screener and confirmed by telephone interview based on the ICHD criteria (International Classification of Headache Disorders). We assessed intra- and extracranial atherosclerotic changes and quantified intracranial internal carotid artery calcifications as measure of atherosclerotic burden on noncontrast computed tomography and computed tomographic angiography. We calculated risk ratios with adjustments for possible confounders with multivariable Poisson regression analyses., Results: We included 656 patients, aged 18 to 99 years, of whom 53 had a history of migraine (29 with aura). Patients with migraine did not have more frequent atherosclerotic changes in intracranial (51% versus 74%; adjusted risk ratio, 0.82; 95% confidence interval, 0.64-1.05) or extracranial vessels (62% versus 79%; adjusted risk ratio, 0.93; 95% confidence interval, 0.77-1.12) than patients without migraine and had comparable internal carotid artery calcification volumes (largest versus medium and smallest volume tertile, 23% versus 35%; adjusted risk ratio, 0.93; 95% confidence interval, 0.57-1.52)., Conclusions: Migraine is not associated with excess atherosclerosis in large vessels in patients with acute ischemic stroke. Our findings suggest that the biological mechanisms by which migraine results in ischemic stroke are not related to macrovascular cerebral atherosclerosis., (© 2017 American Heart Association, Inc.)

Background: Ischemic and hemorrhagic stroke are increasingly recognized as heterogeneous diseases with distinct subtypes and etiologies. Information on variation in distribution of vascular risk factors according to age in stroke subtypes is limited. We investigated the prevalence of vascular risk factors in stroke subtypes in relation to age., Methods and Results: We studied a prospective multicenter university hospital-based cohort of 4033 patients. For patients with ischemic stroke caused by large artery atherosclerosis, small vessel disease, or cardioembolism and for patients with spontaneous intracerebral hemorrhage or aneurysmal subarachnoid hemorrhage, we calculated prevalences of vascular risk factors in 4 age groups: <55, 55 to 65, 65 to 75, and ≥75 years, and mean differences with 95% CIs in relation to the reference age group. Patients aged <55 years were significantly more often of non-white origin (in particular in spontaneous intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage patients) and most often smoked (most prominent for aneurysmal subarachnoid hemorrhage patients). Patients aged <55 years with ischemic stroke caused by large artery atherosclerosis or small vessel disease more often had hypertension, hyperlipidemia, and diabetes mellitus than patients with ischemic stroke of cardiac origin. Overall, the frequency of hypertension, hyperlipidemia, and diabetes mellitus increased with age among all stroke subtypes, whereas smoking decreased with age. Regardless of age, accumulation of potentially modifiable risk factors was most pronounced in patients with ischemic stroke caused by large artery atherosclerosis or small vessel disease., Conclusions: The prevalence of common cardiovascular risk factors shows different age-specific patterns among various stroke subtypes. Recognition of these patterns may guide tailored stroke prevention efforts aimed at specific risk groups., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Introduction: We investigated whether baseline CT angiography (CTA) and CT perfusion (CTP) in acute ischemic stroke could improve prediction of infarct presence and infarct volume on follow-up imaging., Methods: We analyzed 906 patients with suspected anterior circulation stroke from the prospective multicenter Dutch acute stroke study (DUST). All patients underwent baseline non-contrast CT, CTA, and CTP and follow-up non-contrast CT/MRI after 3 days. Multivariable regression models were developed including patient characteristics and non-contrast CT, and subsequently, CTA and CTP measures were added. The increase in area under the curve (AUC) and R (2) was assessed to determine the additional value of CTA and CTP., Results: At follow-up, 612 patients (67.5%) had a detectable infarct on CT/MRI; median infarct volume was 14.8 mL (interquartile range (IQR) 2.8-69.6). Regarding infarct presence, the AUC of 0.82 (95% confidence interval (CI) 0.79-0.85) for patient characteristics and non-contrast CT was improved with addition of CTA measures (AUC 0.85 (95% CI 0.82-0.87); p < 0.001) and was even higher after addition of CTP measures (AUC 0.89 (95% CI 0.87-0.91); p < 0.001) and combined CTA/CTP measures (AUC 0.89 (95% CI 0.87-0.91); p < 0.001). For infarct volume, adding combined CTA/CTP measures (R (2) = 0.58) was superior to patient characteristics and non-contrast CT alone (R (2) = 0.44) and to addition of CTA alone (R (2) = 0.55) or CTP alone (R (2) = 0.54; all p < 0.001)., Conclusion: In the acute stage, CTA and CTP have additional value over patient characteristics and non-contrast CT for predicting infarct presence and infarct volume on follow-up imaging. These findings could be applied for patient selection in future trials on ischemic stroke treatment.

Centralization of intravenous thrombolysis (IVT) for acute ischemic stroke in high-volume centers is believed to improve the door-to-needle times (DNT), but limited data support this assumption. We examined the association between DNT and IVT volume in a large Dutch province. We identified consecutive patients treated with IVT between January 2009 and 2013. Based on annualized IVT volume, hospitals were categorized as low-volume (≤ 24), medium-volume (25-49) or high-volume (≥ 50). In logistic regression analysis, low-volume hospitals were used as reference category. Of 17,332 stroke patients from 11 participating hospitals, 1962 received IVT (11.3 %). We excluded 140 patients because of unknown DNT (n = 86) or in-hospital stroke (n = 54). There were two low-volume (total 101 patients), five medium-volume (747 patients) and four high-volume hospitals (974 patients). Median DNT was shorter in high-volume hospitals (30 min) than in medium-volume (42 min, p < 0.001) and low-volume hospitals (38 min, p < 0.001). Patients admitted to high-volume hospitals had a higher chance of DNT < 30 min (adjusted OR 3.13, 95 % CI 1.70-5.75), lower risk of symptomatic intracerebral hemorrhage (adjusted OR 0.39, 95 % CI 0.16-0.92), and a lower mortality risk (adjusted OR 0.45, 95 % CI 0.21-1.01), compared to low-volume centers. There was no difference in DNT between low- and medium-volume hospitals. Onset-to-needle times (ONT) did not differ between the groups. Hospitals in this Dutch province generally achieved short DNTs. Despite this overall good performance, higher IVT volumes were associated with shorter DNTs and lower complication risks. The ONT was not associated with IVT volume.

Importance: Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known., Objective: To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT., Design, Setting, and Participants: The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015., Main Outcomes and Measures: Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion., Results: Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours., Conclusion and Relevance: For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion., Trial Registration: trialregister.nl Identifier: NTR1804.

Background: In patients with a space-occupying middle cerebral artery (MCA) infarct surgical decompression reduces the risk of death, but increases the chance of survival with severe disability. We assessed quality of life (QoL), symptoms of depression, and caregiver burden at long-term follow-up., Methods: Patients treated in two academic centres between 2007 and 2012 were included. Follow-up was at least six months. Patients and caregivers were interviewed separately. QoL was assessed with a visual analogue scale and the 36-item Short-Form health survey (SF-36); depression with the Hospital Anxiety and Depression Scale; and caregiver burden with the Caregiver Strain Index., Results: Twenty five patients were enrolled, of whom seven had an infarct in the dominant hemisphere. After a median follow-up of 26 months (IQR 11-46) the median SF-36 mental component score was 54.4 (IQR 45-60), indicating a mental QoL comparable to that in the general population. The median SF-36 physical component score was 32.7 (IQR 22-38), indicating a worse physical QoL. Dominance of the hemisphere did not influence QoL. 79 % of patients and 65 % of caregivers would, in retrospect, again choose for surgery. 26 % of patients had signs of depression and 64 % of caregivers were substantially burdened in their daily life., Conclusions: Mental QoL after surgical decompression for space-occupying MCA infarct is comparable to that in the general population, whereas physical QoL is worse. Dominance of the hemisphere did not influence QoL. The majority of caregivers experience substantial burden. Most patients and caregivers stand by their decision for hemicraniectomy.

Background: Decision-making in the acute phase after a severe stroke is complex and may involve life-and-death decisions. Apart from the medical condition and prognosis, quality of life and the deliberation of palliative care should be part of the decision-making process. Relatives play an important role by informing physicians about the patient's values and preferences. However, little is known about how the patients' relatives experience the decision-making process., Aim: To elicit the perspective of relatives of severe stroke patients with regard to the decision-making process in the acute phase in order to understand how they participate in treatment decisions., Design: An exploratory qualitative interview approach guided by the principles of grounded theory., Settings/participants: Relatives of severe stroke patients (n = 15) were interviewed about their experiences in the decision-making process in the acute phase., Results: Four categories reflecting relatives' experiences were identified: (1) making decisions under time pressure, (2) the feeling of 'who am I' to decide, (3) reluctance in saying 'let her die' and (4) coping with unexpected changes. Following the treatment proposal of the physician was found to be the prevailing tendency of relatives in the decision-making process., Conclusion: A better understanding of the latent world of experiences of relatives that influence the decision-making process may help physicians and other health-care providers to better involve relatives in decision-making and enhance the care, including palliative care, for patients with severe stroke in line with their values and preferences. Communication between physician and relatives seems vital in this process., (© The Author(s) 2015.)