Comparison of edoxaban and enoxaparin in a rat model of AlCl3-induced thrombosis of the superior sagittal sinus.

Cerebral sinus venous thrombosis (CSVT) is an uncommon disease that is usually treated with anticoagulation (heparin, low-molecular heparin, or vitamin K-antagonists). We compared treatment with edoxaban, an oral factor Xa-antagonist, that has not been approved in patients with CSVT, with enoxaparin, a well-established therapy, in a rat model of CSVT. Fifty male Wistar rats were randomized into 5 groups (10 animals each) and subjected to aluminum chloride (AlCl3)-induced thrombosis of the superior sagittal sinus (SSS) or sham procedure. Animals with thrombosis of the SSS were treated with edoxaban, enoxaparin, or placebo. Diagnostic workup included neurological examination, MRI imaging, MR-flow measurements of the SSS, and immunohistochemical staining. Neurological examination revealed no differences between treatment groups. Seven days after initial thrombosis, flow in the SSS was lower in the active treatment group as compared to sham-operated animals (p < 0.05). Flow in the SSS in the active treatment groups (edoxaban 1 h prior to thrombosis: 0.16 cm/s ± 0.06 cm/s; edoxaban 6 h after thrombosis: 0.13 cm/s ± 0.05 cm/s; enoxaparin: 0.13 cm/s ± 0.04 cm/s; placebo: 0.07 cm/s ± 0.02 cm/s) was higher as compared to placebo (p < 0.05), but there were no differences between the active treatment groups (p > 0.05). Immunohistochemical staining showed no differences in the actively treated animals. Edoxaban proved to be similar to enoxaparin in a model of experimental AlCl3-induced CSVT.

A Sphingosine-1-Phosphate Receptor Modulator Attenuated Secondary Brain Injury and Improved Neurological Functions of Mice after ICH.

BACKGROUND: Stroke activates the immune system and induces brain infiltration by immune cells, aggravating brain injury. Poststroke immunomodulation via (S1P-)receptor modulation is beneficial; however, the S1P-modulator in clinical use (FTY-720) is unspecific, and undesirable side effects have been reported. Previously, we tested effects of a novel selective S1P-receptor modulator, Siponimod, on ICH-induced brain injury in acute stage of the disease. In the current study, we investigated whether protective effects of Siponimod, evaluated in a short-term study, will protect the brain of ICH animals at long term as well. METHODS: 134 C57BL/6N mice were divided into sham and ICH-operated groups. Collagenase model of ICH was employed. ICH animals were divided into Siponimod treated and nontreated. Dose- and time-dependent effects of Siponimod were investigated. Contraplay between development of brain injury and the number of lymphocytes infiltrating the brain was investigated by forelimb placing, T-Maze test, brain water content calculation, MRI scanning, and immunostaining. RESULTS: Depending on the therapeutic strategy, Siponimod attenuated the development of brain edema, decreased ICH-induced ventriculomegaly and improved neurological functions of animals after ICH. It was associated with less lymphocytes in the brain of ICH animals. CONCLUSION: Siponimod is able to decrease the brain injury and improves neurological functions of animals after ICH.

Serelaxin activates eNOS, suppresses inflammation, attenuates developmental delay and improves cognitive functions of neonatal rats after germinal matrix hemorrhage.

Germinal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury. Following GMH-mediated eNOS inhibition, inflammation arises, contributing to GMH-induced brain injury. We investigated the beneficial effects of Serelaxin, a clinical tested recombinant Relaxin-2 protein, on brain injury after GMH in rats. We investigated whether effects of Serelaxin are mediated by its ability to activate the GMH-suppressed eNOS pathway resulting in attenuation of inflammatory marker overproduction. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U). Seven day old Sprague-Dawley rat pups (P7) were used (n = 63). GMH animals were divided in vehicle or serelaxin treated (3 µg once, 30 µg once, 30 µg multiple, i.p., starting 30 after GMH and then daily). Sham operated animals were used. We monitored the developmental profile working memory and spatial function (T-maze and open field test respectively). At day 28, all rats underwent MRI-scans for assessment of changes in cortical thickness and white matter loss. Effects of Serelaxin on eNOS pathway activation and post-GMH inflammation were evaluated. We demonstrated that Serelaxin dose-dependently attenuated GMH-induced developmental delay, protected brain and improved cognitive functions of rats after GMH. That was associated with the decreased post-GMH inflammation, mediated at least partly by amelioration of GMH-induced eNOS inhibition.

[Management of oral anticoagulation related intracerebral hemorrhage]. / Management von intrazerebralen Blutungen unter oraler Antikoagulation.

The incidence of intracerebral hemorrhage (ICH) in patients using oral anticoagulation (OAC) will continue to increase with the demographic change of an aging population. As compared to primary spontaneous ICH, OAC-ICH is characterized by larger hematoma volumes, more frequent hematoma enlargement and intraventricular hemorrhage resulting in an even worse prognosis. Specific treatment should focus on immediate reversal of anticoagulation in addition to the basic acute management of ICH. In ICH patients using vitamin K antagonists (VKA), complete anticoagulant reversal with an international normalized ratio (INR) <1.3 should be achieved as quickly as possible using prothrombin complex concentrate (PCC) with additional substitution of vitamin K. Patients with ICH under dabigatran treatment should receive idarucizumab. In ICH patients using factor-Xa inhibitors, andexanet should be administered as soon as approved in Europe or within clinical studies and if unavailable alternatively high-dose PCC administration. Regarding OAC resumption, results from randomized trials are pending. In comprehensive observational studies and meta-analyses ICH patients resuming OAC showed a reduced incidence of thromboembolic events and mortality without significantly increased rates of hemorrhagic complications. Non-vitamin K dependent oral anticoagulants (NOAC) might further increase the safety of OAC resumption, which should be initiated after 4-8 weeks for patients with atrial fibrillation. In contrast, VKA resumption in patients with mechanical heart valves should not take place earlier than 1 week after ICH. Generally, safety of OAC resumption appears to be affected by ICH localization along with the presence of cerebral microbleeding, cortical superficial siderosis and cortical/convexity subarachnoid hemorrhage, making it crucial to weigh up the individual patient risk with respect to thromboembolic versus hemorrhagic events.

[Current treatment concepts in intracerebral hemorrhage]. / Aktuelle Therapieziele bei intrazerebralen Blutungen.

BACKGROUND AND OBJECTIVE: In recent years, various important studies investigating the management of intracerebral hemorrhage (ICH) have been published. However, these have not entered guideline recommendations yet. Therefore, essential results are summarized here and the findings are integrated into current treatment concepts. MATERIALS AND METHODS: Based on a dedicated literature review and the authors' experience, up-to-date and high-quality investigations were identified. RESULTS AND DISCUSSION: Randomized data and meta-analyses provide evidence that aggressive blood-pressure reduction (targeting a systolic blood pressure <140 mm Hg) appears safe and reduces hematoma enlargement. ICH associated with intake of vitamin K antagonists should be reversed immediately using prothrombin complex concentrates (PCC) and vitamin K, targeting at least international normalized ratio levels below 1.3. For dabigatran-related ICH, an antidote (idarucizumab) is available for reversal, but in ICH under the use of factor Xa inhibitors evidence is poor. However, reversal should be carried out using high-dosed PCC (50 IU/kg PCC). Routine hematoma evacuation surgery cannot be advocated, yet new minimally invasive strategies provide promising results. In patients with acute occlusive hydrocephalus, an external ventricular drain should be placed and utilizing intraventricular lysis appears safe, reduces mortality, and is associated with improved functional outcome. Adding lumbar drainage to this treatment strategy may reduce permanent shunt dependency. The sum of treatment measures and specialized care at high-volume centers improves outcome in patients with ICH.

[Specialized neurological neurosurgical intensive care medicine]. / Spezialisierte neurologische neurochirurgische Intensivmedizin.

In Germany dedicated neurological-neurosurgical critical care (NCC) is the fastest growing specialty and one of the five big disciplines integrated within the German critical care society (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin; DIVI). High-quality investigations based on resilient evidence have underlined the need for technical advances, timely optimization of therapeutic procedures, and multidisciplinary team-work to treat those critically ill patients. This evolution has repeatedly raised questions, whether NCC-units should be run independently or better be incorporated within multidisciplinary critical care units, whether treatment variations exist that impact clinical outcome, and whether nowadays NCC-units can operate cost-efficiently? Stroke is the most frequent disease entity treated on NCC-units, one of the most common causes of death in Germany leading to a great socio-economic burden due to long-term disabled patients. The main aim of NCC employs surveillance of structural and functional integrity of the central nervous system as well as the avoidance of secondary brain damage. However, clinical evaluation of these severely injured commonly sedated and mechanically ventilated patients is challenging and highlights the importance of neuromonitoring to detect secondary damaging mechanisms. This multimodal strategy not only requires medical expertise but also enforces the need for specialized teams consisting of qualified nurses, technical assistants and medical therapists. The present article reviews most recent data and tries to answer the aforementioned questions.

[Intensive care therapy of space-occupying large hemispheric infarction. Summary of the NCS/DGNI guidelines]. / Intensivtherapie des raumfordernden ischämischen Hemisphäreninfarkts. Zusammenfassung der NCS/DGNI-Leitlinie.

Large hemispheric infarction (LHI), synonymously called malignant middle cerebral artery (MCA) infarction, is a severe neurological disease with a high mortality and morbidity. Treating physicians as well as relatives are often faced with few and low quality data when attempting to apply optimal treatment to these patients and make decisions. While current stroke treatment guidelines focus on risk factors, prevention and acute management, they include only limited recommendations concerning intensive care management of LHI. The Neurocritical Care Society (NCS) and the German Society for Neurocritical and Emergency Medicine (DGNI) organized an interdisciplinary consensus conference on intensive care management of LHI to meet this demand. European and American experts in neurology, neurocritical care, neurosurgery, neuroradiology and neuroanesthesiology were selected based on their expertise and research focus. Subgroups for several main topics elaborated a number of central clinical questions concerning this topic and evaluated the quality of the currently available data according to the grading of recommendation assessment, development and evaluation (GRADE) guideline system. Subsequently, evidence-based recommendations were compiled after weighing the advantages against the disadvantages of certain management options. This is a commented abridged version of the results of the consensus conference.

Early prediction of delayed cerebral ischemia in subarachnoid hemorrhage based on quantitative EEG: A prospective study in adults.

OBJECTIVES: Delayed cerebral infarction (DCI) has a significant impact on mortality and morbidity of patients with subarachnoid hemorrhage (SAH). The aim of this study was to define quantitative EEG (qEEG) parameters for the early and reliable prediction of DCI and compare the validity and time course of qEEG to standard procedures. METHODS: 12 consecutive unselected SAH patients (8 female, mean age 52 years, Hunt-and-Hess grade I-IV) were prospectively examined. Continuous six channel EEG monitoring was started within 48 h after admission (mean duration 5.2 days; range: 2-12 days). All raw and unselected EEG signal underwent automated artifact rejection, Short Time Fast Fourier Transformation and a detrending procedure in order to analyze regional spectral power changes in different frequency bands. According to clinical standards, transcranial Doppler sonography (TCD) was performed at least on alternate days and repeat cerebral computer tomography (CCT) as needed. RESULTS: 6 patients (50%) developed vasospasm/DCI. Decrease of ⩾40% in power persisting over ⩾5h in the alpha band and ⩾6h in the theta band marked the optimal cut-off to detect DCI (sensitivity 89%, specificity 77% for alpha). EEG changes preceded detection of vasospasm/DCI in standard procedures by 2.3d ays. Changes in the beta and delta band as well as in the alpha/delta ratio demonstrated lower correlation with imminent DCI. CONCLUSIONS: Focal reduction in alpha power may represent a valid, observer independent, non-invasive and continuous marker for vasospasm/DCI in SAH patients. SIGNIFICANCE: qEEG indicates imminent ischemia earlier than established diagnostic tools, such as TCD.

Advances in the management of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is one of the most detrimental sub-types of stroke and accounts for 10-15% of all strokes Qureshi et al. (Lancet 373(9675):1632-1644, 2009). ICH has an incidence of 10-30 cases per 100,000 people/year which is increasing and expected to double by the year 2050 Qureshi et al. (N Engl J Med 344 (19):1450-1460, 2001). Mortality rates still remain poor (30-50%) and functional dependency after ICH is high (~75%) van Asch et al. (Lancet Neurol 9 (2):167-176, 2010). Up to now, all randomized controlled trials investigating treatment approaches in ICH have failed to document improvements on clinical endpoints Mayer et al. (N Engl J Med 358 (20):2127-2137, 2008); Brouwers and Goldstein (Neurotherapeutics 9 (1):87-98, 2012). Only a specialized treatment of severely injured patients at dedicated neuro intensive care units [NICU] has been shown to be beneficial Qureshi et al. (Lancet 373(9675):1632-1644, 2009); Suarez et al. (Crit Care Med 32 (11):2311-2317, 2004). Currently, ongoing trials are investigating aggressive blood pressure lowering, hemostatic therapies, different operative strategies, intraventricular thrombolysis as well as neuroprotective approaches, and brain edema therapies. This review will summarize advanced treatment strategies and novel approaches which are currently under investigation.

Waiting for platelet counts causes unsubstantiated delay of thrombolysis therapy.

BACKGROUND: Platelet counts (PCs) <100,000/µl are considered as a contraindication for intravenous thrombolysis (IVT). While US guidelines recommend IVT initiation before the availability of clotting tests, the guidelines of the European Stroke Organization give no such practical advice. We aimed to assess the incidence of thrombocytopenia in IVT patients, outcome after thrombolysis in affected patients and the time gained by initiating treatment prior to availability of PC results. METHODS: All patients with thrombocytopenia were identified in our prospectively acquired thrombolysis database. Baseline demographic data, intracerebral hemorrhage rates as well as functional outcome were assessed. The median time between initiation of thrombolysis and availability of PCs was calculated. RESULTS: Of 625 IVT patients, 3 (0.5%) had thrombocytopenia at stroke onset. None of them developed intracerebral hemorrhage (ICH) or died during the follow-up. Waiting for PCs would have delayed treatment in 72.4% of the patients, with a median hypothetical delay of 22 min (interquartile range: 11-41 min). CONCLUSIONS: To date, there are no sufficient data to evaluate the ICH risk in thrombocytopenic patients. However, thrombocytopenia is rare in IVT patients. Thus, generally waiting for PC results prior to initiation of IVT is not warranted. Avoiding this significant delay yields shorter door-to-needle times and potentially more effective treatment.

[New treatment strategies for intraventricular hemorrhage]. / Neue Therapiestrategien bei zerebraler intraventrikulärer Blutung.

The presence of additional intraventricular hemorrhage (IVH) in patients with intracerebral hemorrhage (ICH) is associated with a much higher mortality and worse functional outcome. Although evidence-based specific treatment options for this entity are still lacking, knowledge about the pathophysiology of IVH has grown in recent decades, leading to the development of promising treatment strategies. Intraventricular fibrinolysis (IVF) accelerates IVH resolution and removal from the ventricular system. The additional usage of lumbar drains probably reduces the incidence of permanent posthemorrhagic hydrocephalus. The influence of these treatment modalities on functional outcome is currently being investigated in ongoing studies. The present article gives an overview of pathophysiological and clinical aspects of IVH, emphasizing novel treatment options.

Off-label thrombolysis for acute ischemic stroke: rate, clinical outcome and safety are influenced by the definition of 'minor stroke'.

BACKGROUND: Several contraindications for intravenous thrombolysis are not based on controlled trials. Specialized stroke centers often apply less restrictive criteria. The aim of our study was to analyze how many patients at our institution receive off-label thrombolysis. In addition, clinical outcome and safety data were compared to those from patients treated on-label, and the influence of different definitions of 'minor stroke' were examined. METHODS: Consecutive thrombolysis patients treated between January 2006 and January 2010 were included. Patients treated off-label were compared to patients given on-label therapy according to the European license. Since no specified definition for 'minor neurological deficit' exists in the license, two distinct definitions were considered off-label, i.e. National Institutes of Health Stroke Scale score (NIHSSS) <1 (definition 1) and NIHSSS ≤4 (definition 2). RESULTS: Of a total of 422 patients, 232 (55%) were treated off-label. The most prevalent off-label criteria (OLCs) were the following: age >80 years (n = 113), minor stroke (definition 1, n = 3; definition 2, n = 84), elevated blood pressure necessitating aggressive treatment (n = 75), time window >3 h (n = 71) and major surgery or trauma within the preceding 3 months (n = 20). In group comparisons, off-label patients had an overall worse outcome using definition 1 for minor stroke, while there was no difference when definition 2 was applied. In multivariate analysis, off-label therapy (definition 1) in general and age >80 years were independent predictors of poor outcome. None of the contraindications were associated with an increased bleeding risk. CONCLUSIONS: Off-label therapy is frequently applied at our center and is not associated with higher complication rates. Overall outcome of off-label treatment largely depends on the definition used for minor stroke. Besides age >80 years, a known poor prognostic factor, no other specific OLC was associated with poor outcome. Our data suggest that the criteria in the European license may be too restrictive.

Sonographic monitoring of ventricle enlargement in posthemorrhagic hydrocephalus.

BACKGROUND AND OBJECTIVE: Intraventricular hemorrhage often leads to obstructive hydrocephalus, necessitating placement of extraventricular drainage to prevent increasing intracranial pressure and subsequent herniation. For clamping and removal of the drainage, repeated CT scans are required to rule out recurrent hydrocephalus. We performed a prospective observational study on the use of transcranial duplex sonography to monitor changes in width of the lateral ventricles during clamping as an alternative to CT. METHODS: Patients with hydrocephalus after intracranial or subarachnoid hemorrhage were monitored by transcranial duplex sonography (TDS). Serial examinations were carried out before and directly after placement of extraventricular or lumbar drainage as well as every 12 hours until 48 hours after removal of all drainages. Clinicians were blinded for all ultrasound results. Receiver operating characteristic analysis and calculation of the positive and negative predictive values was used to identify the optimal cutoff point in increased ventricle width that best predicted reopening of the drainage by the clinician. RESULTS: Ninety-two attempts to clamp either lumbar or extraventricular drainage were monitored in 37 patients during a 1-year period. A cutoff value for increase of ventricular width of 5.5 mm yielded high sensitivity (100%) and specificity (83%) in combination with a 100% negative predictive value for reopening of the drainage. CONCLUSIONS: TDS can be used to monitor ventricular width in experienced neurologic intensive care units. Because of its noninvasive character and suitability for bedside use, it offers a valuable alternative to repeated CT scans.

Intravenous thrombolysis in posterior cerebral artery infarctions.

BACKGROUND: Approximately 5-10% of all acute ischemic strokes (AIS) occur in the territory of the posterior cerebral artery (PCA). Little is known about intravenous thrombolysis (IVT) in this infarct subgroup in terms of outcome and intracerebral hemorrhage rates. The aim of our study was to evaluate differences between supratentorial PCA infarcts and anterior circulation infarcts regarding baseline characteristics, stroke severity, outcome, safety and clinical findings, which would implicate a change in the existing thrombolysis practice in patients with PCA stroke. METHODS: All patients with AIS in the supratentorial PCA territory receiving IVT between 01/2006 and 01/2010 were selected from the Erlangen Thrombolysis Database (group 1, n = 21). They were compared to all IVT patients with strokes in other supratentorial vascular territories over the same period of time (group 2, n = 398). Baseline demographic data, as well as clinical and laboratory findings were analyzed. The outcome was assessed using the modified Rankin Scale at 3 months. RESULTS: Only serum glucose levels at baseline (110.5 ± 36.1 vs. 127.2 ± 48.2 mg/dl; p = 0.036) and the baseline National Institutes of Health Stroke Scale score (median 6.5 vs. 9; p = 0.016) were significantly lower in group 1 compared to group 2. Favorable clinical outcome (57.1 vs. 48.6%; p = 0.445) and intracerebral hemorrhage rates (4.8 vs. 4%; p = 1.000) were comparable in both groups. CONCLUSIONS: No substantial differences were found between supratentorial PCA and anterior circulation infarcts. Our data on safety and efficacy support the present common thrombolysis practice in supratentorial PCA infarct patients, though an indication for IVT should rather be based on the existence of functionally disabling deficit than merely on the National Institutes of Health Stroke Scale.

Characteristics and outcome of patients with early complete neurological recovery after thrombolysis for acute ischemic stroke.

BACKGROUND: Recombinant tissue plasminogen activator (rt-PA) is the only approved specific therapy for acute ischemic stroke. This study analyzes demographic and clinical characteristics of patients with early complete neurological recovery after thrombolysis. METHODS: Data of 320 consecutive patients treated with rt-PA within 3 h of stroke onset at our facility between April 2006 and March 2009 were extracted from our prospective institutional stroke and thrombolysis database. Baseline demographic parameters, risk factors, clinical characteristics as well as neuroradiologic findings of patients with complete recovery 24 h after treatment and at hospital discharge were analyzed. Outcome was evaluated using the modified Rankin Scale at 90 days. RESULTS: Thirty patients (9.4%) were asymptomatic 24 h after thrombolysis and 70 (22%) at hospital discharge. Patients with complete recovery were younger, more often male, had milder stroke symptoms, less often cardioembolic strokes, fewer bleeding complications and more often normal follow-up imaging. In addition, in-hospital time was shorter and these patients retained a better functional outcome at 90 days. Only 1 patient who had completely recovered at hospital discharge died during the follow-up time. In multivariate regression analysis, only the National Institute of Health Stroke Score (NIHSS) on admission was predictive for complete recovery at both examined time points. CONCLUSION: Rapid complete recovery can be achieved in up to a fifth of acute stroke patients treated with thrombolysis. These patients are younger and have milder strokes, less often with cardioembolic origin. Better outcome and lower mortality are sustained at 3 months.

Feasibility and safety of magnetic resonance imaging-based thrombolysis in patients with stroke on awakening: initial single-centre experience.

BACKGROUND: Up to 25% of all acute ischaemic strokes occur during sleep. Because of the unclear time window, patients with stroke on awakening are usually not considered for acute therapy and excluded from most acute treatment trials. AIM: To evaluate the feasibility of magnetic resonance imaging-based intravenous thrombolysis in patients with stroke on awakening in a routine clinical setting. METHODS: Forty-five patients with stroke on awakening clinically qualifying for intravenous thrombolysis and presenting within 6 h after symptom recognition were admitted to our institution between October 2006 and May 2008. Following an institutional protocol, patients received magnetic resonance imaging as a first-line imaging modality and were offered mismatch-based thrombolysis whenever possible. Baseline demographic data, clinical, laboratory and imaging findings were analysed. Outcome was assessed using the modified Rankin Scale score at 3 months. RESULTS: Magnetic resonance imaging screening was feasible in 43/45 patients (96%). After screening, 10 patients (22%) were treated with intravenous thrombolysis. There were no differences between treated and untreated patients regarding cardiovascular risk factors, stroke aetiology, previous prophylactic treatment and symptom recognition to door time or door to imaging time. Outcome was comparable in both groups despite a trend towards more severe strokes in the intravenous thrombolysis group. Only one asymptomatic and no symptomatic haemorrhage were observed. CONCLUSION: Our data demonstrate that magnetic resonance imaging-based thrombolysis is feasible and possibly safe in patients with stroke on awakening (SOA). Randomised clinical trials for patients with stroke on awakening are needed to further test the safety and efficacy of intravenous thrombolysis in this patient group. The results of our study may help to initiate and design such studies.

[Wake up stroke: Overview on diagnostic and therapeutic options for ischemic stroke on awakening]. / "Wake-up Stroke": Ubersicht zu diagnostischen und therapeutischen Optionen des aus dem Schlaf heraus aufgetretenen ischämischen Schlaganfalls.

Up to 25 % of all acute ischemic strokes (AIS) occur during sleep with the patients or relatives becoming aware of their neurological deficits as they wake up. Because of the unclear time of stroke onset patients with stroke on awakening are usually not considered for acute therapies and excluded from most treatment trials. We give an overview of the published data regarding ischemic wake up strokes (WUS). In particular we focused on baseline characteristics, imaging methods and therapy strategies. Comparing WUS patients and patients with known stroke onset there were no major differences found regarding patient characteristics, etiology, clinical and radiological characteristics. Even though there is no existing gold standard multiparametric neuroimaging (CT; MRI) appears to be helpful for decision making whether to treat a WUS patient with thrombolysis or not. Especially multiparametric MRI which proved to be safe in patients within an extended time window might serve as an adequate diagnostic tool. The results of first pilot studies analyzing treatment of WUS demonstrate that a substantial number of these patients can be treated with IV thrombolysis (IVT) successfully. Large randomized, controlled, prospective clinical trials for patients with WUS are needed to test safety and efficacy of IVT and to evaluate the assumed benefit of multiparametric neuroimaging techniques in this patient group. The results of first pilot studies may be instrumental to help plan and design such trials.