Workflow Intervals of Endovascular Acute Stroke Therapy During On- Versus Off-Hours: The MR CLEAN Registry

The MR CLEAN Registry is an on-going, prospective, observational study in all centers that perform EVT in patients with acute ischemic stroke with proximal intracranial vessel occlusion in the Netherlands. All 16 centers that participated in the MR CLEAN trial registered consecutive patients who received EVT. For detailed information about the MR CLEAN Registry, we refer to the main article.²⁰ Ethics approval was granted by the central medical ethics committee of the Erasmus Medical Center Rotterdam, the Netherlands (MEC-2014–235), the need for individual patient consent was waived. Source data will not be made available because of legislatory issues on patient privacy, but detailed analytic methods and study materials, including log files of statistical analyses, will be made available to other researchers on request to the first author.

Enrollment in the MR CLEAN Registry started directly after the final randomization in the MR CLEAN trial on March 16, 2014. For the present study, we retrospectively analyzed data from patients undergoing EVT up to June 15, 2016. We included patients that adhered to the following criteria: arterial puncture within 6.5 hours of symptom onset, age ≥18 years, treatment in a center that participated in the MR CLEAN trial, and presence of a proximal intracranial large vessel occlusion in the anterior circulation (internal carotid artery, internal carotid artery terminus, middle [M1/M2] cerebral artery, or anterior [A1/A2] cerebral artery) shown by computed tomography (CT) angiography. Both patients referred directly to the intervention center (IC), and patients transferred from primary stroke centers (PSCs) to an IC for EVT were analyzed.

For detailed explanations of all study procedures, we refer to the main article of the MR CLEAN Registry.²⁰ In the current study, we tried to reduce missing ED door times of PSCs by additionally requesting these times. Workflow times were gathered from medical records by the local investigators. Imaging and procedural times were gathered by both local investigators and verified and corrected by the core imaging laboratory.

The primary outcome was the first door to groin time (FDGT). Secondary outcomes were workflow intervals, including time from onset to groin (OTGT), onset to first door, first door to first CT imaging, door to intravenous therapy (IVT) needle (DTNT), PSC door to IC door for transferred patients and groin to reperfusion.

Secondary clinical outcomes were functional outcome at 90 days, measured with the modified Rankin Scale (mRS) score, good functional outcome at 90 days (defined as mRS score of 0–2), reperfusion rate (defined as an extended Thrombolysis in Cerebral Infarction score of 2B or greater on final DSA in patients where a thrombectomy or aspiration device was used), and safety outcomes (mortality, symptomatic intracranial hemorrhage, stroke progression, and pneumonia).

We defined off-hour presentation as presentation at the first ED and IC ED during weekends (Friday 17:00 to Monday 8:00), Monday to Friday between 17:00 and 08:00 hours, and national holidays. PSCs were all centers that did not perform EVT but instead referred patients to ICs. Patients referred from PSCs to ICs by ambulance services were defined as transfers. Patients referred directly to the IC by ambulance services or by general practitioners were defined as direct referrals. First door time was defined as the moment of entry into the ED of the first hospital (either the PSC or the IC depending on transfer status). Groin time was defined as the time of arterial groin puncture by the neurointerventionist. Onset was defined as the time of first symptoms or, if this was unknown, the time of last seen well. CT imaging acquisition times were used to define the time of CT. The time of administering the alteplase bolus was registered as the needle time. Time of reperfusion was defined as the moment an extended Thrombolysis in Cerebral Infarction score of 2B or greater was achieved. When no reperfusion could be achieved, the time of last contrast bolus during EVT was used as the time of reperfusion. For transferred patients, we defined 2 additional intervals: PSC door to IC door time, meaning time of entry at the ED of the PSC to time of entry at the ED of the IC, and second door to groin time, meaning time of entry at the ED of the IC to groin puncture.

Intracranial hemorrhage was defined to be symptomatic if patients died or deteriorated neurologically (at least 4 points on the National Institutes of Health Stroke Scale), and the hemorrhage was related to the clinical deterioration (according to the Heidelberg criteria). Stroke progression was defined as progression of ischemic stroke resulting in a deterioration of at least 4 points on the National Institutes of Health Stroke Scale and no hemorrhage on CT imaging.

Baseline characteristics were described using standard statistics. We used linear and ordinal regression models to determine the association between time of presentation (on- versus off-hours) and primary and secondary outcome measures. Patients were stratified by transfer status. For regression analysis, we imputed missing observations of both baseline and outcome variables using multiple chained imputation. Workflow intervals were adjusted for age, treatment with IVT, National Institutes of Health Stroke Scale score at baseline, transfer status, and local anesthesia only. Clinical and safety outcomes were adjusted for age, treatment with IVT, National Institutes of Health Stroke Scale score at baseline, collaterals, occlusion segment on CT angiography, prestroke mRS, and time from onset to first door. Additional analyses were performed to assess the correlation and interaction of off- versus on-hour presentation in FDGT during the progress of the Registry. Statistical analyses were performed using Stata/SE 14.0 (StataCorp, TX).

From March 18, 2014 until June 15, 2016, 1627 patients were included in the MR CLEAN Registry. Of these, we excluded 139 patients (Figure 1). This resulted in 1488 patients eligible for analyses. In total, 936/1488 patients (62.9%) presented at the ED during off-hours. Baseline variables were similar across both groups except for transfer status and occlusion segment. More patients were transferred from PSCs during off-hours (57.9% versus 48.3%; P<0.001), and there were more internal carotid artery terminus occlusions during off-hours (17.9% versus 24.7%; Table 1).

FDGT was significantly longer in patients presenting during off-hours (140 versus 121 minutes; Table 2) Adjusted for prognostic factors, off-hour presentation was associated with a 14.6 minute (95% CI, 9.3–20.0) delay when compared with on-hour presentation (Table 2). Stratifying for transfer status showed an off-hour delay in FDGT of 16.7 minutes (95% CI, 9.8–23.7) for direct referrals, and a FDGT delay of 12.4 minutes (95% CI, 4.4–20.6) for transferred patients. The interaction between transfer status and off-hour presentation was not significant (P=0.469; Table 3).

OTGT was significantly longer during off-hours in both unadjusted and adjusted data with the latter showing a 12.2 minute (95% CI, 5.0–19.4) delay (Table 2). Stratifying for transfer status showed that the delay remained significant for direct referrals (20.9 minutes; 95% CI, 9.3–32.5), but not for transferred patients (4.8 minutes; 95% CI, −4.0 to 13.7; Table 3).

DTNT was also significantly longer during off-hours in both unadjusted and adjusted data with the latter showing a 3.5 minute (95% CI, 0.7–6.3) delay (Table 2). DTNT was not significantly delayed during off-hour presentation when stratifying for transfer status (Table 3). Duration of the endovascular procedure was similar in both groups; groin puncture to reperfusion time in off-hours versus on-hours presentation was −1.4 minutes (95% CI, −5.1 to 2.4; Table 2).

For transferred patients, the door to door time was nonsignificantly delayed by 7.2 (95% CI, 0–14.5; P=0.051) minutes during off-hours when compared with on-hours. The second door to groin time (ie, the intraIC delay) was significantly longer during off-hours (5.0 minutes; 95% CI, 0.5–9.6; Table 3).

We found no difference in functional outcome between on- versus off-hour presentation; the adjusted common odds ratio of a shift of 1 point on the mRS toward better outcome in off-hour patients was 0.91 (95% CI, 0.74–1.11; Figure 2). We also found no difference between on-hour and off-hour presentation in good functional outcome (adjusted odds ratio, 0.81 [95% CI, 0.63–1.05]). Reperfusion rates and safety outcomes were similar in both groups (Table 2).

Additional analysis to assess the change in delay of FDGT during the course of the Registry showed a very weak correlation (Pearson ρ=−0.1304) and no significant interaction between off-hour delay and year of inclusion (P=0.145; Figure 3).

Direct comparison between our main finding and the off-hour delays found in other studies is difficult because of heterogeneity in reported intervals. Few studies report FDGT as primary outcome.^9,11 Other time intervals are more readily available, including OTGT. The delay in FDGT and OTGT during off-hours we found is in line with the OTGT delays found by several studies.^9,10,12–15

Similar to the off-hour delay in FDGT, DTNTs were slightly longer during off-hours. Extensive literature exists about the effect of off-hour presentation on DTNT with the majority of studies showing no, or a similar slight delay during off-hours.^19,21–25

We did not observe a difference in functional outcome between off- and on-hour presentation on both the shift analysis of the mRS and the dichotomized scale. According to analysis of the MR CLEAN Registry, the chance of good functional outcome decreases with 5.3% for each hour of OTGT delay.⁸ However, we only found a OTGT delay of 12 minutes which means, based on the MR CLEAN Registry and assuming a linear relationship, a reduced chance of good functional outcome of 1.06% would have been expected. The MR CLEAN Registry is probably not powered to find such a small effect.

We found a significantly higher rate of interhospital transfer during off-hours versus on-hours (58% versus 48%). When compared with the MR CLEAN trial, the overall transfer rates were higher for both off- and on-hours (48% versus 36%), but the difference between the 2 groups was similar.⁹ In the HERMES collaboration (Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials) and the STRATIS registry (Systematic Evaluation of Patients Treated With Stroke Devices for Acute Ischemic Stroke), no data about off- versus on-hour differences in transfer rates were reported, but overall reported transfer rates were lower.^7,26 We defined off-hour presentation as off-hour entry into the PSC ED and off-hour entry into the IC ED. This is different from the definition used in other studies that only looked at entry into the IC ED. Our chosen categorization might explain the difference in transfer rate between on-hour and off-hour presentation. We chose this definition because PSCs and ICs are equally responsible for the logistic workflow. However, it might have led to a small bias where patients with longer delays in the PSC during on-hours eventually arrived during off-hours in the IC and were therefore classified as off-hours. When changing the off-hour definition to include only ED entry of the PSC, the difference in number of patients that presented during off- versus on-hours was no longer observed (56% versus 52%, P=0.210). The off-hour delay in FDGT however was still present (12.0 minutes [95% CI, 6.7–17.2]; online-only Data Supplement).

Of all analyzed time intervals, FDGT, OTGT, DTNT, and for transfer patients, IC door to groin time were significantly longer during off-hours when compared with on-hours. The prehospital workflow and the workflow until first imaging (first door to CT imaging) were not affected by off-hour presentation in the main analysis. As DTNTs were only slightly delayed by 3.5 minutes (95% CI, 0.7–6.3), most of the delay in FDGT during off-hours can therefore be reasonably assumed to occur in the time interval between administering IVT and groin puncture. This time interval has previously been identified in literature as a major potential source of workflow delays.^27,28 Many crucial logistic steps take place in this time interval, including CTA assessment, preparation of the angio-suite, transport of the patient to the angio-suite, and preparation of the patient for EVT. In the current study, we were not able to shed more light on this interval because of a lack of recorded time data.

For transferred patients, door to door times (ie, the preIC interval) showed a trend toward longer duration during off-hours with 7.2 minutes (95% CI, 0–14.5; P=0.051) delay. The intraIC interval (second door to groin time) was significantly longer during off-hours by 5.0 minutes (95% CI, 0.5–9.6). For direct patients, the intraIC interval (ie, FDGT in this case) was also significantly delayed by 16.7 minutes (95% CI, 9.8–23.7; Table 3). By definition, these centers are highly specialized and have 24/7 availability of personnel. The reasons for this intraIC delay are unknown but could be because of busy call schedules with limited personnel, shorter prehospital notification in case of direct referrals, and on-call versus in-house availability of interventionists. Therefore, although the preIC (including transfer) interval should remain of interest for logistics optimization, the intraIC interval seems to be delayed and should be a focus for further optimization.

When stratifying for transfer status, we found a significant interaction (P=0.031) between OTGT delay during off-hours in direct referrals (20.9 minutes) and transferred patients (4.8 minutes; Table 3). This difference is because of differences in onset to first door times, which were delayed during off-hours in direct patients by 4.2 minutes, but were shorter during off-hours for transferred patients by 7.6 minutes. The reason for this difference in onset to first door times is unclear. In the Netherlands, emergency medical services (EMS) regions have uniform prehospital triage protocols. All patients are transferred to the nearest PSC for evaluation, imaging, and IVT and no selection algorithm for PSC bypass, involving stroke severity, large vessel occlusion detection or time of presentation is used. Furthermore, as the MR CLEAN-Registry is an inhospital registration, we have no data on prehospital workflow intervals such as EMS response times or driving distances. Therefore, the difference in off-hour delay in onset to first door times and ultimately in OTGT between direct and transferred patients might be caused by differences in patient EMS call times, EMS response times, or simply because of chance.

We found no differences between patients presenting during off- and on-hours in use of local anesthesia only, groin puncture to reperfusion time or reperfusion rates (Table 2). One may conclude that the EVT procedure itself is not affected by off-hour presentation, which could be a result of sufficient standardization of this peri-procedural workflow in each of the participating centers.

Our study has several strengths. First of all, the large number of included patients and the fact that the MR CLEAN Registry is a multicenter, nationwide registry of all patients treated with EVT in daily practice in a country with a highly organized stroke care network. In addition, we looked at the entire intra- and interhospital workflow, including PSCs. Combined, we think our results can act as both a goal for what is possible in a well-organized stroke network, and as a guide for potential areas of improvement. We chose not to use OTGT as our primary end point because this interval includes onset to first door times, which is mostly influenced by patient delay and potentially EMS delay.²⁹ Both of these factors are important causes of total OTGT delay, but they cannot be easily influenced by individual centers.

There are several limitations of the current study. PSC ED door times were responsible for most of the missing workflow times and although we retrospectively tried to reduce the amount of missing door times, we were not able to do so for all cases. In total, door times were missing in 195/1488 cases (13.1%) and equally distributed between the off- and on-hour groups.

Because of the design of the registry, we were unable to retrieve information on door out (eg, start of transfer) and time of EMS call. This prevents us from forming conclusions about the crucial interval between imaging and arrival at the IC for transferred patients and between imaging and angio-suite arrival for patients directly referred to the IC.

Finally, our results are specific to the EVT situation in the Netherlands. Other stroke networks with different levels and methods of regional acute care organization might have different logistical bottlenecks. However, our results can direct focus to potential areas for improvement in other stroke networks.

Executive committee: Diederik W.J. Dippel (Department of Neurology, Erasmus MC University Medical Center); Aad van der Lugt (Department of Radiology, Erasmus MC University Medical Center); Charles B.L.M. Majoie (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam); Yvo B.W.E.M. Roos (Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam); Robert J. van Oostenbrugge (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Wim H. van Zwam (Department of Radiology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Jelis Boiten(Department of Neurology, Haaglanden MC, the Hague); Jan Albert Vos (Department of Radiology, Sint Antonius Hospital, Nieuwegein)

Study coordinators: Ivo G.H. Jansen (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Maxim J.H.L. Mulder (Departments of Neurology and Radiology, Erasmus MC University Medical Center); Robert-Jan B. Goldhoorn (Departments of Neurology and Radiology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Kars C.J. Compagne(Department of Radiology, Erasmus MC University Medical Center); Manon Kappelhof(Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam).

Local principal investigators: Wouter J. Schonewille (Department of Neurology, Sint Antonius Hospital, Nieuwegein); Jan Albert Vos (Department of Radiology, Sint Antonius Hospital, Nieuwegein); Charles B.L.M. Majoie (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Jonathan M. Coutinho(Department of Neurology, Amsterdam UMC, University of Amsterdam); Marieke J.H. Wermer (Department of Neurology, Leiden University Medical Center); Marianne A.A. van Walderveen (Department of Radiology, Leiden University Medical Center); Julie Staals (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Wim H. van Zwam (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Jeannette Hofmeijer (Department of Neurology, Rijnstate Hospital, Arnhem); Jasper M. Martens (Department of Radiology, Rijnstate Hospital, Arnhem); Geert J. Lycklama à Nijeholt (Department of Radiology, Haaglanden MC, the Hague); Jelis Boiten (Department of Neurology, Haaglanden MC, the Hague); Bob Roozenbeek (Department of Neurology, Erasmus MC University Medical Center); Bart J. Emmer (Department of Radiology, Erasmus MC University Medical Center); Sebastiaan F. de Bruijn (Department of Neurology, HAGA Hospital, the Hague); Lukas C. van Dijk (Department of Radiology, HAGA Hospital, the Hague); H. Bart van der Worp (Department of Neurology, University Medical Center Utrecht); Rob H. Lo (Department of Radiology, University Medical Center Utrecht); Ewoud J. van Dijk (Department of Neurology, Radboud University Medical Center, Nijmegen); Hieronymus D. Boogaarts (Department of Neurosurgery, Radboud University Medical Center, Nijmegen); Paul L.M. de Kort (Department of Neurology, Sint Elisabeth Hospital, Tilburg); Jo J.P. Peluso (Department of Radiology, Sint Elisabeth Hospital, Tilburg); Jan S.P. van den Berg (Department of Neurology, Isala Klinieken, Zwolle); Boudewijn A.A.M. van Hasselt (Department of Radiology, Isala Klinieken, Zwolle); Leo A.M. Aerden (Department of Neurology, Reinier de Graaf Gasthuis, Delft); René J. Dallinga (Department of Radiology, Reinier de Graaf Gasthuis, Delft); Maarten Uyttenboogaart(Department of Neurology, University Medical Center Groningen); Omid Eshghi(Department of Radiology, University Medical Center Groningen); Tobien H.C.M.L. Schreuder (Department of Neurology, Atrium Medical Center, Heerlen); Roel J.J. Heijboer (Department of Radiology, Atrium Medical Center, Heerlen); Koos Keizer (Department of Neurology, Catharina Hospital, Eindhoven); Lonneke S.F. Yo (Department of Radiology, Catharina Hospital, Eindhoven); Heleen M. den Hertog (Department of Neurology, Isala Klinieken, Zwolle); Emiel J.C. Sturm (Department of Radiology, Medical Spectrum Twente, Enschede).

Imaging assessment committee: Charles B.L.M. Majoie (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Wim H. van Zwam (Department of Radiology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Aad van der Lugt (Department of Radiology, Erasmus MC University Medical Center); Geert J. Lycklama à Nijeholt (Department of Radiology, Haaglanden MC, the Hague); Marianne A.A. van Walderveen (Department of Radiology, Leiden University Medical Center); Marieke E.S. Sprengers (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Sjoerd F.M. Jenniskens (Department of Radiology, Radboud University Medical Center, Nijmegen); René van den Berg (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Albert J. Yoo (Department of Radiology, Texas Stroke Institute); Ludo F.M. Beenen (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Alida A. Postma (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Stefan D. Roosendaal (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Bas F.W. van der Kallen (Department of Radiology, Haaglanden MC, the Hague); Ido R. van den Wijngaard(Department of Radiology, Haaglanden MC, the Hague); Adriaan C.G.M. van Es (Department of Radiology, Erasmus MC University Medical Center); Bart J. Emmer (Department of Radiology, Erasmus MC University Medical Center); Jasper M. Martens(Department of Radiology, Rijnstate Hospital, Arnhem); Lonneke S.F. Yo (Department of Radiology, Catharina Hospital, Eindhoven); Jan Albert Vos (Department of Radiology, Sint Antonius Hospital, Nieuwegein); Joost Bot (Department of Radiology, Amsterdam UMC, Vrije Universiteit van Amsterdam); Pieter-Jan van Doormaal (Department of Radiology, Erasmus MC University Medical Center).

Writing committee: Diederik W.J. Dippel ((Department of Neurology, Erasmus MC University Medical Center); Aad van der Lugt (Department of Radiology, Erasmus MC University Medical Center); Charles B.L.M. Majoie (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Yvo B.W.E.M. Roos (Department of Neurology, Amsterdam UMC, University of Amsterdam); Robert J. van Oostenbrugge (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Wim H. van Zwam (Department of Radiology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Geert J. Lycklama à Nijeholt (Department of Radiology, Haaglanden MC, the Hague); Jelis Boiten (Department of Neurology, Haaglanden MC, the Hague); Jan Albert Vos (Department of Radiology, Sint Antonius Hospital, Nieuwegei); Wouter J. Schonewille (Department of Neurology, Sint Antonius Hospital, Nieuwegein); Jeannette Hofmeijer ((Department of Neurology, Rijnstate Hospital, Arnhem); Jasper M. Martens ((Department of Radiology, Rijnstate Hospital, Arnhem); H. Bart van der Worp(Department of Neurology, University Medical Center Utrecht); Rob H. Lo (Department of Radiology, University Medical Center Utrecht)

Adverse event committee: Robert J. van Oostenbrugge (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Jeannette Hofmeijer (Department of Neurology, Rijnstate Hospital, Arnhem); H. Zwenneke Flach (Department of Radiology, Isala Klinieken, Zwolle)

Trial methodologist: Hester F. Lingsma (Department of Public Health, Erasmus MC University Medical Center).

Research nurses/local trial coordinators: Naziha el Ghannouti (Department of Neurology, Erasmus MC University Medical Center); Martin Sterrenberg (Department of Neurology, Erasmus MC University Medical Center); Corina Puppels (Department of Neurology, Sint Antonius Hospital, Nieuwegein); Wilma Pellikaan (Department of Neurology, Sint Antonius Hospital, Nieuwegein); Rita Sprengers (Department of Neurology, Amsterdam UMC, University of Amsterdam); Marjan Elfrink (Department of Neurology, Rijnstate Hospital, Arnhem); Joke de Meris (Department of Neurology, Haaglanden MC, the Hague); Tamara Vermeulen (Department of Neurology, Haaglanden MC, the Hague); Annet Geerlings (Department of Neurology, Radboud University Medical Center, Nijmegen); Gina van Vemde (Department of Neurology, Isala Klinieken, Zwolle); Tiny Simons (Department of Neurology, Atrium Medical Center, Heerlen); Cathelijn van Rijswijk (Department of Neurology, Sint Elisabeth Hospital, Tilburg); Gert Messchendorp (Department of Neurology, University Medical Center Groningen); Hester Bongenaar (Department of Neurology, Catharina Hospital, Eindhoven); Karin Bodde (Department of Neurology, Reinier de Graaf Gasthuis, Delft); Sandra Kleijn (Department of Neurology, Medical Spectrum Twente, Enschede); Jasmijn Lodico (Department of Neurology, Medical Spectrum Twente, Enschede); Hanneke Droste (Department of Neurology, Medical Spectrum Twente, Enschede); M. Wollaert (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); D. Jeurrissen (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Ernas Bos (Department of Neurology, Leiden University Medical Center); Yvonne Drabbe (Department of Neurology, HAGA Hospital, the Hague); Nicoline Aaldering (Department of Neurology, Rijnstate Hospital, Arnhem); Berber Zweedijk (Department of Neurology, University Medical Center Utrecht); Mostafa Khalilzada (Department of Neurology, HAGA Hospital, the Hague).

PhD/Medical students: Esmee Venema (Department of Public Health, Erasmus MC University Medical Center); Vicky Chalos (Departments of Neurology and Public Health, Erasmus MC University Medical Center); Ralph R. Geuskens (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Tim van Straaten (Department of Neurology, Radboud University Medical Center, Nijmegen); Saliha Ergezen (Department of Neurology, Erasmus MC University Medical Center); Roger R.M. Harmsma ((Department of Neurology, Erasmus MC University Medical Center); Daan Muijres (Department of Neurology, Erasmus MC University Medical Center); Anouk de Jong (Department of Neurology, Erasmus MC University Medical Center); Wouter Hinsenveld (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Olvert A. Berkhemer (Department of Neurology, Erasmus MC University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam) (Department of Neurology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht); Anna M.M. Boersc (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); J. Huguet (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); P.F.C. Groot (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Marieke A. Mens (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Katinka R. van Kranendonk (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Kilian M. Treurniet (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Manon L. Tolhuijsen (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam); Heitor Alves (Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam).