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Acute ischemic stroke (AIS) is a leading cause of death and disability worldwide. In approximately one third of patients AIS is caused by a large vessel occlusion (LVO). Since 2015, endovascular treatment (EVT) has been proven clinical effective for AIS caused by LVO, with a number-needed-to-treat of less than three for improved clinical outcome. The focus of this thesis is to provide information on the long-term clinical follow-up, cost-effectiveness, and optimization of implementation of EVT for AIS patients. In our two-year clinical follow-up study in patients of the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands trial (MR CLEAN) we found that patients randomized to EVT had a higher probability to achieve good clinical outcome (functional independence) compared to control. Additionally, we executed an economic evaluation, which showed that EVT dominated standard treatment with €76,937 saved per additional quality adjusted life year. Moreover, introduction of EVT in the Netherlands resulted in estimated net annual savings on the health care budget of €2.9 million in 2015 to €58 million in 2021. Furthermore, in a post-hoc analysis of MR CLEAN we looked at the effect of anaesthetic management during EVT and observed that there was only a significant treatment effect of EVT in patients treated without general anesthesia. Lastly, we studied innovations that were made to the local EVT workflow protocol in the Greater Amsterdam Area. Results showed that these innovations led to shorter times from hospital presentation to start of EVT and improved clinical outcomes.

This thesis focused on advances in thrombus imaging and retrieval. We found that AI-based automated LVO detection is accurate and fast and therefore can be valuable in clinical practice. Furthermore, we showed that the use of thrombus imaging characteristics (thrombus length and distal location) aids in identifying patients who are most likely to benefit from IVT. However, thrombus imaging characteristics were of limited use for outcome prediction in patients who underwent EVT or for selection of first-line EVT device. While thrombus radiomics features describing volume and texture were associated with an increasing number of passes to achieve reperfusion, thrombus radiomics features had no added value for predicting procedural and functional outcome when compared to clinical variables and conventional thrombus measurements. Additionally, we investigated two topics that could possibly contribute to advancement in thrombus retrieval. First, we investigated the effect of number of passes in relation to final reperfusion score and functional outcome in patients with anterior circulation stroke. We found similar outcomes in patients with single pass eTICI 2B and multiple pass eTICI 2C/3, indicating that the advantage of eTICI 2C/3 over eTICI 2B diminishes with an increasing number of passes. Second, we investigated the effect of first-line EVT approach on functional outcome in patients with posterior circulation stroke and found better patient outcomes with first-line aspiration EVT. Our findings suggested that first-line aspiration EVT is a better first-line EVT approach in posterior circulation stroke patients.

Outcomes after acute ischemic stroke have greatly improved due to new treatment options that can achieve fast reperfusion. Intravenous alteplase was proven effective as a thrombolytic, and endovascular treatment (EVT) greatly improved outcomes for patients with large, proximal occlusions. Despite this progress however, today, still nearly 30% of large occlusion patients die or remain dependent on daily nursing care after stroke. The goal of this thesis was to investigate three ways to further improve patient outcomes after stroke by optimizing reperfusion strategies. Part I describes the progress of EVT. In a literature review, we summarize results of EVT approaches in the most proximal large vessel occlusions. Subsequently, we describe results of EVT in daily practice from 2014-2017. Outcomes continue to improve, most likely due to faster workflow and improved reperfusion rates. In Part II, we studied imaging factors that could (or should not) guide imaging-based stroke treatment selection for each patient. We found that patients with early ischemic changes on CT could still benefit from reperfusion by EVT. Furthermore, we found that patients with pervious thrombi, thrombi that are permeable to contrast, showed a better response to intravenous alteplase. Part III of this thesis focuses on intravenous alteplase administration before EVT. In the final two chapters, the design and results of an international, multicenter randomized controlled trial on intravenous alteplase administration prior to EVT are described: MR CLEAN-NO IV. Acute ischemic stroke care is complex, evolving, and improving. Individualized treatment selection based on patient-specific, clinical, and imaging-based factors may allow us to further improve reperfusion rates and thereby clinical outcomes.

Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of stroke that occurs at a relatively young age and has a poor outcome. Delayed cerebral ischemia (DCI) is a complication of aSAH, which is associated with high mortality and a poor functional outcome. The aims of this thesis are firstly to improve the prediction of DCI and secondly to improve the prediction of outcome in patients with aSAH. To achieve this goal we first systematically reviewed the literature on the association of currently commonly used methods of grading the amount of blood after aSAH on NCCT with DCI. Subsequently we developed and present a fully automated SAH segmentation method based on machine learning techniques. Finally, we utilized automated SAH segmentation techniques to develop and validate new prediction models for DCI and outcome using both regression and machine learning models. The most important conclusions of this thesis are that using quantified total blood volume and machine learning only moderately accurate prediction models for predicting DCI were developed. On the other hand, we have developed accurate prediction models for clinical outcome after aSAH. These models could provide clinicians with valuable information in counselling patients and their families and therefore further optimize the process of shared-decision making.

X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder caused by mutations in the ABCD1-gene on the X-chromosome. Progressive myelopathy is the main clinical manifestation, occurring in all male and >80% of female patients. Clinically, it presents as a slowly progressive gait disorder due to spastic paraparesis and sensory ataxia. Treatment is currently supportive only, but disease modifying treatments are under development. For these therapies to be tested in clinical trials, there is a need for sensitive outcome measures. In this thesis, we evaluate the potential of several clinical (standardized neurological examination, clinical disability scales, timed walking activities) and surrogate outcomes (spinal cord MRI/DTI, optical coherence tomography, blood neurofilament light and GFAP, postural body sway) to measure disease severity and progression in ALD. We demonstrate that some of these outcome measures are more sensitive and reproducible than the currently available ‘traditional’ outcomes. Especially when combining clinical and surrogate outcomes with different test characteristics, they can complement each other in demonstrating a treatment effect, bringing ALD a step closer towards clinical trial readiness.

The aim of this thesis is to improve detection of embolic sources of ischemic stroke along the heart-brain axis. The structure of the thesis follows this anatomical pathway. In the first part of this thesis (The Heart), we focused on sources of embolism from the heart which are detected through imaging. We performed three studies on the diagnostic yield of cardiac CT-angiography for detection of high-risk cardio-aortic sources of embolism in acute ischemic stroke patients. In the second part of this thesis (The Arteries), we explored (rare) sources of embolism from the arteries in an effort to increase awareness in the medical community. We conducted studies in ischemic stroke patients with an underlying acute aortic dissection, multiple cervical artery dissections, and a carotid web. In addition, we investigated the hypothesis that patients with ischemic stroke due to cervical carotid atherosclerosis have a more extensive collateral circulation and better outcomes than patients with cardioembolism.

Het acute herseninfarct is een van de grootste oorzaken van verloren gezonde levensjaren ter wereld. Voor patiënten met een groot herseninfarct is het verwijderen van het stolsel dat het infarct veroorzaakt via de slagaders nu vaak de standaardbehandeling. Deze behandeling is complex en uitkomsten na de behandeling zijn afhankelijk van vele factoren. In dit proefschrift zijn studies gebundeld waarin mogelijke aanknopingspunten voor verbetering van de endovasculaire behandeling werden onderzocht volgens een drieledige benadering. Allereerst zijn uitkomsten beter als het vat sneller weer doorgankelijk is. Daarom is optimalisatie van de logistiek voorafgaand aan de behandeling noodzakelijk zodat patiënten sneller behandeling kunnen ondergaan. Ook zouden radiologische of klinische parameters mogelijk het nut van de behandeling kunnen voorspellen. Als laatste zou de behandeling via de vaten zelf nog verbeterd kunnen worden. Wij vonden geen bewijs dat de leeftijd van de patiënt of de geschatte hoeveelheid stolsel in de slagaders op zichzelf gebruikt konden worden om het effect van de behandeling te voorspellen. We lieten wel zien dat een goede regionale samenwerking van belang is om patiënten zo snel mogelijk te behandelen en zo mogelijk uitkomsten te verbeteren. Ook bleek dat operateurs hun eigen behandelsucces beter inschatten dan onafhankelijke beoordelaars. Daarnaast zagen we dat terwijl de behandeling via de slagaders erg effectief is, complicaties nog wel vóórkomen tijdens de behandeling. Door op basis van deze resultaten eventuele veranderingen in de behandelstrategie door te voeren zouden uitkomsten voor patiënten met een acuut herseninfarct mogelijk verder kunnen worden verbeterd.

Reperfusion therapy for patients with acute ischemic stroke is focused at restoring blood flow and saving the penumbra. It is currently comprised of intravenous thrombolysis and endovascular thrombectomy. Both treatments have rapidly evolved over the years, extending the time window in which patients can be treated, and thereby increasing the number of eligible patients. The emphasis should be focused on timely treatment, as time it brain. This thesis describes the results of several workflow improvements both regional as national, and results of clinical decision making in the acute stroke care setting.

In patients with acute headache who present to the emergency room the yield of a CTA is highest in patients with an abnormality on head NCCT. The yield in patients with normal NCCT is low. A multivariable prediction model showed that clinical symptoms have no added value over the variable ‘normal NCCT’ alone. In patients with acute headache and a normal NCCT the yield of CTA is higher than in the general population, but findings consist mainly of unruptured intracranial aneurysms that do not always have treatment implications and may generate anxiety. The sporadically found cervical dissection, CVT or RCVS may justify performing CTA. At the moment there are no clinical factors, which can predict which patients will have an abnormality on CTA after a normal NCCT. In patients who are suspected of CVT but who have no additional risk factors besides headache, CT venography is unnecessary if the D-dimer level in serum is normal. The negative predictive value of D-dimer in this group is very high for excluding CVT. If CSF testing for the presence of bilirubin is required, the Leiden method, an iterative calculation model, is 100% sensitive. Specificity can be increased if the UK NEQAS method is applied on the CSF’s that test positive with the Leiden method. This workflow assures both highest specificity and highest laboratory workforce efficiency. In patients suspected of bacterial meningitis procalcitonin determination in CSF may become a valuable marker particularly in patients with confounding factors such as recent neurosurgical intervention. The differentiation from aseptic or septic meningitis in this group is difficult and an additional marker would be valuable to avoid unnecessary antibiotic treatment.

Time is of the essence when treating acute ischemic stroke, to limit the damage caused. One form of intra-arterial treatment (IAT) used in such cases is the mechanical removal of the blood clot using stent-retrievers. It is thought that patient selection for IAT requires improvement and that CT imaging might be useful to improve this selection. The aim of this thesis is to increase insight into the value of CT-based patient selection for IAT. There are at least three important requirements CT imaging biomarkers must fulfill to become a valuable tool for patient selection. First, there should be treatment modification by the imaging biomarker. Treatment effect modification means that the treatment effect differs for subgroups of patients. If IAT is effective for one subgroup of patients but not for another subgroup of patients, there is a rationale to select patients. Therefore, a first step towards the use of CT imaging for patient selection should be to determine if there is treatment effect modification. Second, measurement of the imaging biomarker must be robust because erroneous determination of a biomarker may result in incorrectly withholding a patient from treatment. Third, if image data is used for patient selection all image data must be available to the interventionalist before a patient is transferred for IAT so that the interventionalist can determine whether the patients is eligible for IAT. This thesis consists of 2 parts. In the first part a cloud-based platform for telemedicine in acute ischemic stroke care is presented. Furthermore, the accuracy of several CT-based biomarker measurements is determined. In the second part the association of several CT biomarkers with outcome in patients with acute ischemic stroke is evaluated. Moreover, it was investigated whether these CT biomarkers modify the treatment effect of IAT compared to best medical care, including IV alteplase.

Acute ischemic strokes arising from blockages of the major brain-supplying arteries put patients at risk for extensive brain injury. Left untreated, these major strokes produce significant disability and death. Fortunately, recent advances in stroke devices have improved clinical outcomes in such patients, provided that they are treated early enough after their stroke onset. Using minimally invasive techniques, these devices are delivered through the arteries using catheters in order to remove the thrombus, or blood clot, that is blocking blood flow to the brain. However, further progress is needed, as approximately half of the major stroke patients who are treated in this way remain dependent or dead at 3 months after their stroke. In particular, a better understanding of which patients are likely to benefit from intervention is crucial. This thesis investigates the role of brain imaging to improve patient selection. Part I examines the use of various imaging approaches to identify those stroke patients who have already suffered large areas of brain injury, and as a result are unlikely to do well after treatment. Excluding such patients will improve the risk-benefit profile of stroke intervention and make treatment more cost effective. Part II explores the emerging field of thrombus imaging and the impact of thrombus characteristics on outcomes after intervention. Through this work, advances in stroke devices and procedural techniques can be targeted to the most difficult to treat thrombi. The thesis concludes with a discussion of the key research questions on the horizon.

This thesis deals with current issues in the field of acute ischemic stroke. The main objective has been to proof the effectiveness and safety of intra-arterial treatment in patients with acute ischemic stroke. MR CLEAN was the first study to proof the safety and effectiveness of intra-arterial treatment in patients presenting with an acute ischemic stroke caused by a large vessel occlusion treatable within six hours after symptom onset. Together with the results from the other recently published trials and the subsequent meta-analysis, intra-arterial treatment has become standard of care for acute ischemic stroke and has been incorporated in national and international guidelines. Intra-arterial treatment will have an enormous impact on health care systems and on the health and quality of life of countless patients across the globe.

In Nederland krijgen jaarlijks 47.000 mensen een beroerte, wat meestal op een herseninfarct berust. In het proefschrift ‘Optimizing thrombolysis in acute ischaemic stroke’ staat het verbeteren van de acute behandeling van het herseninfarct centraal. Met de huidige behandeling, die bestaat uit intraveneuze trombolyse binnen 4,5 uur na het ontstaan van de klachten, herstelt slechts 50% van de patiënten goed, dat wil zeggen dat zij 3 maanden na het herseninfarct zelfstandig kunnen functioneren. Het eerste deel van het proefschrift richt zich op de vraag of de toevoeging van acetylsalicylzuur (aspirine) aan intraveneuze trombolyse de kans op herstel verbetert. Door middel van een gerandomiseerde klinische trial is aangetoond dat de toevoeging van aspirine het herstel niet bevordert. De huidige standaardbehandeling hoeft daarom niet aangepast te worden. Omdat de effectiviteit van intraveneuze trombolyse afneemt naarmate de tijd vanaf het ontstaan van de symptomen verstrijkt, onderzoekt het tweede deel van het proefschrift een aantal mogelijkheden om zo snel mogelijk de behandeling met intraveneuze trombolyse te starten. Het stroomlijnen van de opvang en behandeling van patiënten met een herseninfarct in het ziekenhuis heeft een aanzienlijke verkorting van de behandelingstijd opgeleverd. Ook toont dit proefschrift dat intraveneuze trombolyse veilig lijkt bij patiënten met een herseninfarct op basis van een scheur (dissectie) in één van de halsslagaderen en bij patiënten die achteraf toch geen herseninfarct gehad blijken te hebben. Het is in de acute fase daarom niet nodig om extra en tijdrovend onderzoek te verrichten om deze oorzaken uit te sluiten.