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Background: The MR CLEAN-LATE trial has shown that patient selection for endovascular treatment (EVT) in the late window (6–24 h after onset or last-seen-well) based on the presence of collateral flow on CT-angiography is safe and effective. We aimed to assess the cost-effectiveness of late-window collateral-based EVT-selection compared to best medical management (BMM) over a lifetime horizon (until 95 years of age).Materials and Methods: A model-based economic evaluation was performed from a societal perspective in The Netherlands. A decision tree was combined with a state-transition (Markov) model. Health states were defined by the modified Rankin Scale (mRS). Initial probabilities at 3-months post-stroke were based on MR CLEAN-LATE data. Transition probabilities were derived from previous literature. Information on short- and long-term resource use and utilities was obtained from a study using MR CLEAN-LATE and cross-sectional data. All costs are expressed in 2022 euros. Costs and quality-adjusted life years (QALYs) were discounted at a rate of 4% and 1.5%, respectively. The effect of parameter uncertainty was assessed using probabilistic sensitivity analysis (PSA).Results: On average, the EVT strategy cost €159,592 (95% CI: €140,830–€180,154) and generated 3.46 QALYs (95% CI: 3.04–3.90) per patient, whereas the costs and QALYs associated with BMM were €149,935 (95% CI: €130,841–€171,776) and 2.88 (95% CI: 2.48–3.29), respectively. The incremental cost-effectiveness ratio per QALY and the incremental net monetary benefit were €16,442 and €19,710, respectively. At a cost-effectiveness threshold of €50,000/QALY, EVT was cost-effective in 87% of replications.Discussion and Conclusion: Collateral-based selection for late-window EVT is likely cost-effective from a societal perspective in The Netherlands.

Introduction: High systolic blood pressure (SBP) is associated with poor functional outcome. We analysed whether the association of SBP with outcomes after endovascular treatment (EVT) is modified by prior intravenous thrombolysis (IVT).Patients and methods: This was a post-hoc analysis of MR CLEAN-NO IV, a randomised trial of IVT with alteplase followed by EVT versus EVT alone, within 4.5 h from stroke onset. SBP was recorded on hospital admission. The primary outcome was 90-day modified Rankin Scale (mRS) score and secondary outcomes included symptomatic intracranial haemorrhage (sICH) and successful reperfusion (eTICI 2b-3), analysed with (ordinal) logistic regression. Estimates were calculated per 10 mmHg change in SBP. We assessed whether IVT modified the associations of SBP with these outcomes using multiplicative interaction terms.Results: Of 539 randomised patients, 266 received IVT. The association of SBP with mRS score was J-shaped, with an inflection point at 150 mmHg. Using 150 mmHg as a reference point, SBPs higher than 150 mmHg were associated with poor functional outcome (acOR: 1.23, 95% CI: 1.09–1.38), but lower SBPs were not (acOR: 1.14, 95% CI: 0.99–1.30). Higher SBP was not associated with the risk of sICH (aOR: 1.09, 95% CI: 0.93–1.27) nor with the probability of successful reperfusion (aOR: 1.00, 95% CI: 0.91–1.10). Our main result was that we found no effect modification by IVT (p-values for interaction, mRS = 0.94; sICH = 0.26; successful reperfusion = 0.58).Discussion and conclusion: There was no effect modification of IVT with SBP for any of the clinical outcomes. Therefore, the level of SBP (if ⩽185/110 mmHg) should not guide IVT decisions in patients otherwise eligible for both IVT and EVT within the 4.5-h time window.Trial registration: ISRCTN80619088, https://www.isrctn.com/ISRCTN80619088.

IMPORTANCE: Dual thrombolytic treatment with small bolus alteplase and mutant prourokinase has the potential to be a safer and more efficacious treatment for ischemic stroke than alteplase alone because mutant prourokinase is designed to act only on degraded fibrin without affecting circulating fibrinogen. OBJECTIVE: To assess the safety and efficacy of this dual thrombolytic treatment compared with alteplase. DESIGN, SETTING, AND PARTICIPANTS: This controlled, open-label randomized clinical trial with a blinded end point was conducted from August 10, 2019, to March 26, 2022, with a total follow-up of 30 days. Adult patients with ischemic stroke from 4 stroke centers in the Netherlands were enrolled. INTERVENTIONS: Patients were randomized (1:1) to receive a bolus of 5 mg of intravenous alteplase and 40 mg of an intravenous infusion of mutant prourokinase (intervention) or usual care with 0.9 mg/kg of intravenous alteplase (control). MAIN OUTCOMES AND MEASURES: The primary outcome was any intracranial hemorrhage (ICH) on neuroimaging at 24 hours. Secondary outcomes included functional outcome at 30 days, symptomatic ICH, and fibrinogen levels within 24 hours. Analyses were by intention to treat. Treatment effects were adjusted for baseline prognostic factors. RESULTS: A total of 268 patients were randomized, and 238 (median [IQR] age, 69 [59-77] years; 147 [61.8%] male) provided deferred consent and were included in the intention-to-treat population (121 in the intervention group and 117 in the control group). The median baseline score on the National Institutes of Health Stroke Scale was 3 (IQR, 2-5). Any ICH occurred in 16 of 121 patients (13.2%) in the intervention group and 16 of 117 patients (13.7%) in the control group (adjusted odds ratio, 0.98; 95% CI, 0.46-2.12). Mutant prourokinase led to a nonsignificant shift toward better modified Rankin Scale scores (adjusted common odds ratio, 1.16; 95% CI, 0.74-1.84). Symptomatic ICH occurred in none of the patients in the intervention group and 3 of 117 patients (2.6%) in the control group. Plasma fibrinogen levels at 1 hour remained constant in the intervention group but decreased in the control group (β = 65 mg/dL; 95% CI, 26-105 mg/dL). CONCLUSIONS AND RELEVANCE: In this trial, dual thrombolytic treatment with small bolus alteplase and mutant prourokinase was found to be safe and did not result in fibrinogen depletion. Further evaluation of thrombolytic treatment with mutant prourokinase in larger trials to improve outcomes in patients with larger ischemic strokes is needed. Overall, in patients with minor ischemic stroke who met indications for treatment with intravenous thrombolytics but were not eligible for treatment with endovascular therapy, dual thrombolytic therapy with intravenous mutant prourokinase was not superior to treatment with intravenous alteplase alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04256473

Objective: To determine the association between early post-endovascular treatment (EVT) contrast extravasation (CE) on dual-energy CT (DECT) and stroke outcomes.Methods: EVT records in 2010–2019 were screened. Exclusion criteria included the occurrence of immediate post-procedural intracranial haemorrhage (ICH). Hyperdense areas on iodine overlay maps were scored according to the Alberta Stroke Programme Early CT Score (ASPECTS), thus forming a CE-ASPECTS. Maximum parenchymal iodine concentration and maximum iodine concentration relative to the torcula were recorded. Follow-up imaging was reviewed for ICH. The primary outcome measure was the modified Rankin Scale (mRS) at 90 days.Results: Out of 651 records, 402 patients were included. CE was found in 318 patients (79%). Thirty-five patients developed ICH on follow-up imaging. Fourteen ICHs were symptomatic. Stroke progression occurred in 59 patients. Multivariable regression showed a significant association between decreasing CE-ASPECTS and the mRS at 90 days (adjusted (a)cOR: 1.10, 95% CI: 1.03–1.18), NIHSS at 24–48 h (aβ: 0.57, 95% CI: 0.29–0.84), stroke progression (aOR: 1.14, 95% CI: 1.03–1.26) and ICH (aOR: 1.21, 95% CI: 1.06–1.39), but not symptomatic ICH (aOR 1.19, 95% CI: 0.95–1.38). Iodine concentration was significantly associated with the mRS (acOR: 1.18, 95% CI: 1.06–1.32), NIHSS (aβ: 0.68, 95% CI: 0.30–1.06), ICH (aOR: 1.37, 95% CI: 1.04–1.81) and symptomatic ICH (aOR: 1.19, 95% CI: 1.02–1.38), but not stroke progression (aOR: 0.99, 95% CI: 0.86–1.15). Results of the analyses with relative iodine concentration were similar and did not improve prediction.Conclusions: CE-ASPECTS and iodine concentration are both associated with short- and long-term stroke outcomes. CE-ASPECTS is likely a better predictor for stroke progression.

Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6–24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA).

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) is performed in intervention centers that provide the full range of neuro(endo)vascular care (level 1) and centers that only perform EVT for AIS (level 2). We compared outcomes between these center types and assessed whether differences in outcomes could be explained by center volume (CV).Patients and methods: We analyzed patients included in the MR CLEAN Registry (2014–2018), a registry of all EVT-treated patients in the Netherlands. Our primary outcome was the shift on the modified Rankin scale (mRS) after 90 days (ordinal regression). Secondary outcomes were the NIHSS 24–48 h post-EVT, door-to-groin time (DTGT), procedure time (linear regression), and recanalization (binary logistic regression). We compared outcomes between level 1 and 2 centers using multilevel regression models, with center as random intercept. We adjusted for relevant baseline factors, and in case of observed differences, we additionally adjusted for CV.Results: Of the 5144 patients 62% were treated in level 1 centers. We observed no significant differences between center types in mRS (adjusted(a)cOR: 0.79, 95% CI: 0.40 to 1.54), NIHSS (aβ: 0.31, 95% CI: −0.52 to 1.14), procedure duration (aβ: 0.88, 95% CI: −5.21 to 6.97), or DTGT (aβ: 4.24, 95% CI: −7.09 to 15.57). The probability for recanalization was higher in level 1 centers compared to level 2 centers (aOR 1.60, 95% CI: 1.10 to 2.33), and this difference probably depended on CV.Conclusions: We found no significant differences, that were independent of CV, in the outcomes of EVT for AIS between level 1 and level 2 intervention centers.

BackgroundPre-stroke dependent patients (modified Rankin Scale score (mRS) ≥3) were excluded from most trials on endovascular treatment (EVT) for acute ischemic stroke (AIS) in the anterior circulation. Therefore, little evidence exists for EVT in those patients. We aimed to investigate the safety and benefit of EVT in pre-stroke patients with mRS score 3.MethodsWe used data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic stroke in the Netherlands (MR CLEAN) Registry. All patients treated with EVT for anterior circulation AIS with pre-stroke mRS 3 were included. We assessed causes for dependence and compared patients with successful reperfusion (defined as expanded Thrombolysis in Cerebral Ischemia scale (eTICI) 2b–3) to patients without successful reperfusion. We used regression analyses with pre-specified adjustments. Our primary outcome was 90-day mRS 0–3 (functional improvement or return to baseline).ResultsA total of 192 patients were included, of whom 82 (43%) had eTICI <2b and 108 (56%) eTICI ≥2b. The median age was 80 years (IQR 73–87). Fifty-one of the 192 patients (27%) suffered from previous stroke and 36/192 (19%) had cardiopulmonary disease. Patients with eTICI ≥2b more often returned to their baseline functional state or improved (n=26 (26%) vs n=15 (19%); adjusted odds ratio (aOR) 2.91 (95% CI 1.08 to 7.82)) and had lower mortality rates (n=49 (49%) vs n=50 (64%); aOR 0.42 (95% CI 0.19 to 0.93)) compared with patients with eTICI <2b.ConclusionsAlthough patients with AIS with pre-stroke mRS 3 comprise a heterogenous group of disability causes, we observed improved outcomes when patients achieved successful reperfusion after EVT.

Necrotizing external otitis (NEO) is a rare infectious disease of the skull base. The purpose of this study was to determine whether clinical outcomes of NEO can be correlated to different infectious spread patterns.

Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke.

Supplemental Digital Content is available in the text.

ABSTRACTTreatment of glioblastoma xenografts with chloroquine results in macroautophagy/autophagy inhibition, resulting in a reduction of tumor hypoxia and sensitization to radiation. Preclinical data show that EGFRvIII-expressing glioblastoma may benefit most from chloroquine because of autophagy dependency. This study is the first to explore the safety, pharmacokinetics and maximum tolerated dose of chloroquine in combination with radiotherapy and concurrent daily temozolomide in patients with a newly diagnosed glioblastoma. This study is a single-center, open-label, dose-finding phase I trial. Patients received oral chloroquine daily starting one week before the course of chemoradiation (temozolomide 75 mg/m2/d) until the end of radiotherapy (59.4 Gy/33 fractions). Thirteen patients were included in the study (n = 6: 200 mg, n = 3: 300 mg, n = 4: 400 mg chloroquine). A total of 44 adverse events, possibly related to chloroquine, were registered including electrocardiogram QTc prolongation, irreversible blurred vision and nausea/vomiting resulting in cessation of temozolomide or delay of adjuvant cycles. The maximum tolerated dose was 200 mg chloroquine. Median overall survival was 16 months (range 2–32). Median survival was 11.5 months for EGFRvIII- patients and 20 months for EGFRvIII+ patients. A daily dose of 200 mg chloroquine was determined to be the maximum tolerated dose when combined with radiotherapy and concurrent temozolomide for newly diagnosed glioblastoma. Favorable toxicity and promising overall survival support further clinical studies.Abbreviations:AE: adverse events; CQ: chloroquine; DLT: dose-limiting toxicities; EGFR: epidermal growth factor receptor; GBM: glioblastoma; HCQ: hydroxychloroquine; IDH1/2: isocitrate dehydrogenase (NADP(+)) 1/2; MTD: maximum tolerated dose; CTC: National Cancer Institute Common Toxicity Criteria; MGMT: O-6-methylguanine-DNA methyltransferase; OS: overall survival; po qd: per os quaque die; SAE: serious adverse events; TMZ: temozolomide; WHO: World Health Organization

The blood-brain barrier (BBB) is the interface between the blood and brain tissue, which regulates the maintenance of homeostasis within the brain. Impaired BBB integrity is increasingly associated with various neurological diseases. To gain a better understanding of the underlying processes involved in BBB breakdown, magnetic resonance imaging (MRI) techniques are highly suitable for noninvasive BBB assessment. Commonly used MRI techniques to assess BBB integrity are dynamic contrast-enhanced and dynamic susceptibility contrast MRI, both relying on leakage of gadolinium-based contrast agents. A number of conceptually different methods exist that target other aspects of the BBB. These alternative techniques make use of endogenous markers, such as water and glucose, as contrast media. A comprehensive overview of currently available MRI techniques to assess the BBB condition is provided from a scientific point of view, including potential applications in disease. Improvements that are required to make these techniques clinically more easily applicable will also be discussed.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Recent research has shown promising results for the development of a clinically feasible vestibular implant in the near future. However, correct electrode placement remains a challenge. It was shown that fluoroscopy was able to visualize the semicircular canal ampullae and electrodes, and guide electrode insertion in real time. Ninety-four percent of the 18 electrodes were implanted correctly (<1.5 mm distance to target). The median distances were 0.60 mm, 0.85 mm, and 0.65 mm for the superior, lateral, and posterior semicircular canal, respectively. These findings suggest that fluoroscopy can significantly improve electrode placement during vestibular implantation.

Intracranial multiple myeloma (MM) is a rare manifestation of MM, a malignant plasma cell disorder that primarily affects bone marrow. Dural involvement in MM is even rarer and can manifest as a dural mass. We present a case of MM presenting as an intracranial dural tumor with primary hemi-dural involvement.

The Plaque at RISK (PARISK) study demonstrated that patients with a carotid plaque with intraplaque hemorrhage (IPH) have an increased risk of recurrent ipsilateral ischemic cerebrovascular events. It was previously reported that symptomatic carotid plaques with IPH showed higher IPH signal intensity ratios (SIR) and larger IPH volumes than asymptomatic plaques. We explored whether IPH SIR and IPH volume are associated with future ipsilateral ischemic cerebrovascular events beyond the presence of IPH.

To determine the incidence and predictors of cerebral arterial air emboli (CAAE) on immediate post-endovascular treatment (EVT) dual-energy CT (DECT) in acute ischaemic stroke (AIS) patients, and describe their association with clinical outcomes.

A 10-year-old-girl was admitted with headache and vomiting. Nonenhanced CT showed hyperdense intraparenchymal hematoma with a hypodense area, consistent with swirl sign, a classic sign of active bleeding (figure 1).

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

To describe the incidence, risk factors, and prognostic relevance of intracranial haemorrhage (ICH) immediately after endovascular treatment (EVT) for ischaemic stroke in the anterior circulation.

A 10-year-old-girl was admitted with headache and vomiting. Nonenhanced CT showed hyperdense intraparenchymal hematoma with a hypodense area, consistent with swirl sign, a classic sign of active bleeding (figure 1).

Cerebral folate transport deficiency is caused by homozygous or compound heterozygous mutations of the FOLR1gene.1Recently, we found a homozygous FOLR1mutation (NM_016725.2: c.562C>G p.[Leu188Val]) in a 2.5-year-old boy with febrile and nonfebrile status epilepticus, progressive ataxia, and progressive MRI abnormalities. Until the diagnosis was made, serial MRI had been performed (figure). CSF analysis (5-methyltetrahydrofolate <2 nmol/L, normal >40 nmol/L) and magnetic resonance spectroscopy showing a low choline peak validated the pathogenicity of our findings.2

A 36-year-old man presented with pain radiating from his right hip to the knee, after a heavy fall on his back 2 months earlier. At neurologic examination, bilateral Lasegue's sign (straight leg raise test) was present. MRI revealed a ventral epidural space-occupying lesion at L2-L3 (figure). The differential diagnosis consisted of a sequestered disc, a ventral synovial cyst, and an epidural hematoma.