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Intravenous thrombolysis is not recommended in anticoagulated patients receiving direct oral anticoagulants (DOACs) and a recent intake within the last 48 hours in US and European guidelines. However, three observational studies now suggest safety of thrombolysis in patients with recent intake of DOACs, and thus support previous experimental data. In this perspective, the current evidence and practical consequences are discussed., Competing Interests: Competing interests: JCP has received consultation fees and travel expenses from Akcea, Bayer, Boehringer Ingelheim, Daiichi Sankyo and BMS/Pfizer, outside the submitted work. TRM reports grants from Bangerter-Rhyner Foundation. YX has received a research grant from the National Institute on Aging, American Heart Association and Genentech, and honorarium from Boehringer Ingelheim. DJS is on the advisory board of Bayer Switzerland and Portola/Alexion. He reports research funding from the Swiss National Science Foundation, Swiss Heart Foundation, Bangerter-Rhyner Foundation, Bayer Foundation and Portola/Alexion. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: For patients experiencing ischemic stroke despite receiving therapy with direct oral anticoagulants (DOAC) and without endovascular treatment options, therapeutic prospects are currently dismal. Current guidelines recommend intravenous thrombolysis (IVT) only for patients who have received DOAC in very restricted settings, as an increased risk of bleeding is suspected. However, recent retrospective observational studies suggest that IVT is safe despite DOAC pretreatment., Objectives: To provide further evidence that IVT despite previous DOAC treatment is not associated with an increased risk of bleeding., Design: Observational retrospective study., Methods: Demographic, clinical, and radiological data of patients who received IVT (+/- endovascular thrombectomy) despite DOAC pretreatment between June 2021 and January 2024 were analyzed using descriptive statistics, including DOAC plasma concentration at admission. Secondary intracranial hemorrhages and functional outcomes at 3 months were assessed. Since 2023, patients have been treated according to a modified local standard operating procedure at our hospital, allowing for IVT despite DOAC pretreatment regardless of DOAC plasma levels or the use of reversal agents., Results: Of 1821 patients treated with acute recanalization procedures during the study period, N  = 35 had received IVT with (18) or without (17) additional endovascular therapy. Among these patients with a wide age range (42-97 years) and DOAC plasma concentrations up to 369 ng/ml, only one developed symptomatic intracranial hemorrhage. A favorable outcome (modified Rankin scale score 0-2) after 3 months was observed in 57% (20) of the patients., Conclusion: IVT despite direct oral anticoagulation seems to be safe, even at advanced age and high DOAC plasma levels., (© The Author(s), 2024.)

Background: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes., Methods: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE)., Results: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome., Conclusions: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

Background: There is little evidence of endovascular therapy (EVT) being performed in acute ischemic stroke beyond 24 h, and that evidence is limited to anterior circulation stroke., Objective: To extend evidence of efficacy and safety of EVT after more than 24 h in both anterior and posterior circulation stroke., Methods: Local, prospectively collected registries were screened for patients with acute ischemic stroke and large-vessel occlusion who had received either EVT > 24 h after last-seen-well but <24 h after symptom recognition (EVT >24LSW ) or EVT > 24 h since first (definitive) symptom recognition (EVT >24DEF ). Patients treated <24 h served as a group for comparison. Favorable outcome was defined as modified Rankin scale (mRS) 0-2 or return to prestroke mRS at 3 months., Results: Between January 2014 and August 2021, N  = 2347 were treated with EVT at our comprehensive stroke center, of whom n  = 43 met the inclusion criteria (EVT >24LSW , n  = 16, EVT >24DEF , n  = 27). EVT >24LSW patients were treated at a median of 28.7 h [interquartile range (IQR) = 27.3-32.8] after last-seen-well and 7.3 h (IQR = 2.8-14.3) after symptom recognition; EVT >24DEF patients were treated 52.5 h (IQR = 26.5-94.2) after first symptoms. Favorable outcome was achieved by 23.3% (10/43) in the EVT > 24 compared with 39.4% (886/2250) in the EVT < 24 group ( p  = 0.04). Bleeding rates were similar across groups. Mortality was also similar [EVT > 24, 27.9% (12/43) versus EVT < 24, 25.7% (584/2264), p  = 0.727; posterior circulation, EVT > 24, 41.7% (5/12) versus EVT < 24, 36.5% (92/252) p  = 0.764]., Conclusion: In selected patients, EVT seems effective and safe beyond 24 h for both anterior and posterior circulation stroke., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JCP has received consultation fees and travel expenses from Akcea, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer. PAR received speaker fees from Bayer, Boehringer Ingelheim, Daiichi Sanyko, and Pfizer. SN reports consulting fees from Brainomix and lecture fees from Boehringer Ingelheim and BMS Pfizer. MM has received consulting honoraria, speaker honoraria, and travel support outside this work from Covidien/Medtronic, MicroVention, and Stryker. The other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Objective: Data regarding the efficacy and safety of bridging thrombolysis (BT) initiated before transfer for evaluation of endovascular therapy is heterogeneous. We, therefore, analyse efficacy and safety of BT in patients treated within a drip-and-ship stroke service., Methods: Consecutive adult patients suffering from acute ischaemic stroke and large-vessel occlusions (LVO) transferred to our comprehensive stroke centre for evaluation of endovascular therapy in 2017-2020 were identified from a local prospective stroke database and categorised according to BT and no-BT. BT was defined as intravenous thrombolysis initiated before transfer. LVO was assessed before and after transfer. Functional outcome before stroke and at 3 months using the modified Rankin scale (mRS) was determined. Excellent outcome was defined as mRS 0-1 or return to prestroke mRS. For safety analysis, intracranial haemorrhages and mortality at 3 months were analysed. Main analysis was limited to patients with anterior circulation stroke., Results: Of N=714 patients, n=394 (55.2%) received BT. More patients in the BT group with documented LVO before transfer recanalised without endovascular therapy (n=46, 11.7%) than patients who did not receive BT before transfer (n=4, 1.3%, p<0.001). In multivariate analysis, BT was the strongest independent predictor of early recanalisation (adjusted OR 10.9, 95% CI 3.8 to 31.1, p<0.001). BT tended to be an independent predictor of an excellent outcome at 3 months (adjusted OR 1.38, 95% CI 0.97 to 1.96, p=0.077). There were no differences in safety between the BT and no-BT groups., Conclusions: BT initiated before transfer was a strong independent predictor of early recanalisation., Competing Interests: Competing interests: JCP has received consultation fees and travel expenses from Akcea, Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer. MM reports grants/grants pending from Balt, Medtronic, MicroVention, Stryker (money paid to the institution). PAR received travel support and lecture fees from Boeheringer Ingelheim, Daiichi Sankyo, Pfizer, and Bayer. SN has received consulting fees from Brainomix and Boehringer Ingelheim and lecture fees and travel expenses from Medtronic and Pfizer. CG is speaker of the commission telemedicine service of the German Stroke Society., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DS: advisory board Bayer Switzerland and Portola/Alexion. Research funding by Swiss National Science Foundation, Swiss Heart Foundation, Bangerter-Rhyner Foundation and Bayer Foundatin. JP: has received consultation fees and travel expenses from Abbott, Akcea, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer. SP: received research grants from BMS/Pfizer, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, and speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen.

Background: Managing acute ischemic stroke (AIS) in patients receiving treatment with vitamin K antagonists (VKA) or non-VKA oral anticoagulants (NOACs) is difficult and the challenge this poses for stroke telemedicine remains unexplored., Methods: We analyzed data from a random sample ( n = 1500) of all teleneurological consultations conducted between July 2015 and December 2017. Management of patients suffering AIS with and without prior oral anticoagulation treatment was characterized, including potential vs. actual treatment with intravenous thrombolysis (IVT) and reasons for withholding it., Results: n = 359 patients had suffered an AIS, of whom 63 (17.5%) were under treatment with oral anticoagulants (VKA, n = 24; NOAC, n = 39). Administration of IVT was more common in patients who had not received prior oral anticoagulation treatment (20.3% vs. 3.2%, p < 0.001). NOAC intake was the primary reason for withholding IVT in 37% of orally anticoagulated patients who were found potentially eligible for IVT. Furthermore, patients under oral anticoagulation tended to be transported to the comprehensive stroke center more often (23.8% vs. 13.9%, p = 0.056)., Conclusions: AIS in patients on oral anticoagulation treatment is a frequent reason for telestroke consultation, and NOAC intake constitutes an important barrier to administering IVT.

Background: The accuracy of diagnosing acute cerebrovascular disease via a teleneurology service and the characteristics of misdiagnosed patients are insufficiently known., Methods: A random sample ( n = 1500) of all teleneurological consultations conducted between July 2015 and December 2017 was screened. Teleneurological diagnosis and hospital discharge diagnosis were compared. Diagnoses were then grouped into two main categories: cerebrovascular disease (CVD) and noncerebrovascular disease. Test characteristics were calculated., Results: Out of 1078 consultations, 52% ( n = 561) had a final diagnosis of CVD. Patients with CVD could be accurately identified via teleneurological consultation (sensitivity 95.2%, 95% CI 93.2-96.8), but we observed a tendency towards false-positive diagnosis (specificity 77.4%, 95% CI 73.6-80.8). Characteristics of patients with a false-negative CVD diagnosis were similar to those of patients with a true-positive diagnosis, but patients with a false-negative CVD diagnosis had ischemic heart disease less frequently. In retrospect, one patient would have been considered a candidate for intravenous thrombolysis (0.2%)., Conclusions: Teleneurological consultations are accurate for identifying patients with CVD, and there is a very low rate of missed candidates for thrombolysis. Apart from a lower prevalence of ischemic heart disease, characteristics of "stroke chameleons" were similar to those of correctly identified CVD patients.

Speidel, Victor, Jan Christoph Purrucker, and Katarína Klobučníková. Manifestation of intracranial lesions at high altitude: case report and review of the literature. High Alt Med Biol . 22:87-89, 2021.-A 32-year-old man trekked to the South Everest Base Camp (5,364 m) in Nepal. On the last day of the ascent, he noticed some dysesthesia in his right leg and descended by helicopter. He suffered a generalized seizure shortly after his descent, followed by right-sided hemiparesis and speech arrest. Without the possibility of cerebral imaging, the patient was given dexamethasone intravenously who showed a marked improvement and regained the ability to speak. Magnetic resonance imaging later revealed a lesion in the left frontotemporal region with compression of brain parenchyma and minimal paralesional edema. A meningioma was later surgically resected. Although seizures are a common first manifestation of meningioma, we argue that the exposure to high altitude may have contributed to his symptoms, either by increasing the peritumoral edema by pathophysiology similar to high-altitude cerebral edema (HACE) or lowering the seizure threshold otherwise. This case shows a before unknown pre-existing condition becoming symptomatic at high altitude and illustrates the necessity for careful and immediate evaluation of every patient with new onset of unexplained focal neurological deficits or seizures at high altitude in addition to unspecific neurological symptoms commonly associated with HACE such as headaches, dizziness, lightheadedness, or ataxia.

Background: Transient ischemic attack (TIA) needs further diagnostic evaluation to prevent future ischemic stroke. However, prophylaxis can be harmful in elderly if the diagnosis is wrong. We aimed at characterizing differences in TIA mimics in younger and older patients to enhance diagnostic accuracy in elderly patients. Methods: In a dedicated neurological emergency room (nER) of a tertiary care University hospital, patients with transient neurological symptoms suspicious of TIA (<24 h) were retrospectively analyzed regarding their final diagnoses and their symptoms. These parameters were compared between patients aged 18-70 and >70 years using descriptive, univariable, and multivariable statistics. Results: From November 2018 until August 2019, 386 consecutive patients were included. 271 (70%) had cardiovascular risk factors and all patients received cerebral imaging, mostly CT [376 (97%)]. There was no difference in the rate of diagnosed TIA between the age groups [85 (46%) vs. 58 (39%); p = 0.213].TIA mimics in the elderly were more often internal medicine diseases [35 (19%) vs. 7 (5%); p < 0.001] and epileptic seizures [48 (26%) vs. 24 (16%); p = 0.032] but less often migraine [2 (1%) vs. 20 (13%); p < 0.001]. The most frequent symptoms in all patients were aphasia and dysarthria [107 (28%) and 92 (24%)]. Sensory impairments were less frequent in elderly patients [23 (11%) vs. 54 (30%); p < 0.001]. Impaired consciousness and orientation were independent predictors for TIA mimics ( p < 0.001) whereas facial palsy ( p < 0.001) motor weakness ( p < 0.001), dysarthria ( p = 0.022) and sensory impairment ( p < 0.001) were independent predictors of TIA. Conclusion: TIA mimics in elderly patients are more likely to be internal medicine diseases and epilepsy compared to younger patients. Excluding internal medicine diseases seems to be important in elderly patients. Facial palsy, motor weakness, dysarthria and sensory impairment are associated with TIA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ippen, Walter, Hametner, Gumbinger, Nagel, Purrucker and Mundiyanapurath.)

Background: Reducing the number of ischemic strokes in patients with atrial fibrillation despite oral anticoagulation remains an important, yet largely unsolved challenge. Therefore, we assessed the etiology of ischemic strokes despite anticoagulation with vitamin K antagonists (VKA) or non-VKA oral anticoagulants (NOACs)., Methods: Patients with known atrial fibrillation (AF), treatment with VKA or NOAC, and acute ischemic stroke admitted between 2015 and 2018 (1st half) were identified from the hospital database. Brain imaging data were independently reviewed. An integrated etiologic classification according to the ASCOD system was made. Medication errors (admission INR <2.0 in the VKA- or NOAC-specific concentration <10 ng/mL) or dosage/dosing errors were also analyzed., Results: Of 3610 patients screened, n = 341 were included (VKA, n = 127; NOAC, n = 214). An overall increasing rate of OAC-associated stroke per year was observed. In 95.3% of patients with adequate diagnostic work-up ( n = 321/337), at least one additional potential, uncertain, or unlikely non-cardiac cause of stroke was identified. More patients in the VKA than in the NOAC group had a medication error (81/127, 63.8% vs. 102/205, 49.8%; p = 0.013)., Conclusions: Stroke risk factors despite atrial fibrillation were highly prevalent. Although less common with NOACs than VKAs, medication errors are still frequent.

Objective: To quantify peripheral nerve lesions in symptomatic and asymptomatic hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PNP) by analyzing the magnetization transfer ratio (MTR) of the sciatic nerve, and to test its potential as a novel biomarker for macromolecular changes., Methods: Twenty-five patients with symptomatic ATTRv-PNP, 30 asymptomatic carriers of the mutant transthyretin gene (mutTTR), and 20 age-/sex-matched healthy controls prospectively underwent magnetization transfer contrast imaging at 3 Tesla. Two axial three-dimensional gradient echo sequences with and without an off-resonance saturation rapid frequency pulse were conducted at the right distal thigh. Sciatic nerve regions of interest were manually drawn on 10 consecutive axial slices in the images without off-resonance saturation, and then transferred to the corresponding slices that were generated by the sequence with the off-resonance saturation pulse. Subsequently, the MTR and cross-sectional area (CSA) of the sciatic nerve were evaluated. Detailed neurologic and electrophysiologic examinations were conducted in all ATTRv-PNP patients and mutTTR-carriers., Results: Sciatic nerve MTR and CSA reliably differentiated between ATTRv-PNP, mutTTR-carriers, and controls. MTR was lower in ATTRv-PNP (26.4 ± 0.7; P < 0.0001) and in mutTTR-carriers (32.6 ± 0.8; P = 0.0005) versus controls (39.4 ± 2.1), and was also lower in ATTRv-PNP versus mutTTR-carriers (P = 0.0009). MTR correlated negatively with the NIS-LL and positively with CMAPs and SNAPs. CSA was higher in ATTRv-PNP (34.3 ± 1.7 mm 3 ) versus mutTTR-carriers (26.0 ± 1.1 mm 3 ; P = 0.0005) and versus controls (20.4 ± 1.2 mm 3 ; P < 0.0001). CSA was also higher in mutTTR-carriers versus controls., Interpretation: MTR is a novel imaging marker that can quantify macromolecular changes in ATTRv-PNP and differentiate between symptomatic ATTRv-PNP and asymptomatic mutTTR-carriers and correlates with electrophysiology., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The aim of the present European Stroke Organisation guideline document is to provide clinically useful evidence-based recommendation on reversal of anticoagulant activity VKA (warfarin, phenprocoumon and acenocoumarol), direct factor II (thrombin) inhibitors (dabigatran etexilat) and factor-Xa-inhibitors (apixaban, edoxaban and rivaroxaban) in patients with acute intracerebral haemorrhage. The guideline was prepared following the Standard Operational Procedure for a European Stroke Organisation guideline document and according to GRADE methodology. As a basic principle, we defined use of oral anticoagulation pragmatically: oral anticoagulation use is assumed by positive medical history unless relevant anticoagulant activity is regarded unlikely by medical history or has been ruled out by laboratory testing. Overall, we strongly recommend using prothrombin complex over no treatment and fresh-frozen plasma in patients on VKA plus vitamin K. We further strongly recommend using idarucizumab in patients on dabigatran and make a recommendation for andexanet alfa in patients on rivaroxaban and apixaban over no treatment. We make a weak recommendation on using high-dose prothrombin complex concentrate (50 IU/kg) for all patients taking edoxaban and for patients on rivaroxaban or apixaban in case andexanet alfa is not available. We recommend against using tranexamic acid and rFVIIa, outside of trials. The presented treatment recommendations aim to normalise coagulation, there is no or only indirect data on effects on functional outcome or mortality, and only little data from randomised controlled trials., (© European Stroke Organisation 2019.)

Background: Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making., Case Presentation: We describe the case of a 75 year-old woman with atrial fibrillation maintained on apixaban who was admitted due to suspected acute stroke. Clinical work-up did not confirm ischemic or hemorrhagic stroke but routine quantification of apixaban revealed an excessively high apixaban plasma concentration (~ 3 h after the last drug intake: 1100 ng/ml (expected range: 91-321 ng/ml); ~ 12 h after drug intake: 900 ng/ml (expected range: 41-230 ng/ml)) and a substantially prolonged elimination half-life (~ 31 h). The corresponding apixaban concentration-to-dose ratio was 9900 (ng/ml)/(mg/kg/d) and 8100 (ng/ml)/(mg/kg/d), respectively (expected range: 249-463 (ng/ml)/(mg/kg/d)). Renal function was only moderately impaired (creatinine 1.36 mg/dl (0.5-1.1 mg/dl), creatinine clearance 40 ml/min). Genotype analyses revealed that the patient was a CYP3A5*3/*3 non-expressor, a heterozygous carrier of the ABCG2 c.421C/A alleles, and a homozygous carrier of ABCB1 c.2677 T/T and ABCB1 c.3435 T/T. In the absence of known drug interactions explaining apixaban clearance impairment, excessive apixaban concentrations were most probably caused by moderate renal impairment combined with multiple functional polymorphisms of apixaban clearance pathways., Conclusions: This case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure.

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

Background: Anticoagulation with vitamin K antagonists and non-vitamin K antagonists oral anticoagulants (NOAC) is effective in stroke prevention in patients with atrial fibrillation. However, anticoagulation also poses a major challenge for emergency treatment of patients suffering ischaemic stroke or intracerebral haemorrhage., Aim: The registry RASUNOA-prime is designed to describe current patterns of emergency management, clinical course and outcome of patients with atrial fibrillation experiencing an acute ischaemic stroke or intracerebral haemorrhage under different anticoagulation schemes prior to stroke (NOAC, vitamin K antagonists or no anticoagulation)., Methods and Design: RASUNOA-prime (ClinicalTrials.gov, NCT02533960) is a prospective, investigator-initiated, multicentre, observational cohort study aiming to recruit 3000 patients with acute ischaemic stroke and atrial fibrillation, and 1000 patients with acute intracerebral haemorrhage and atrial fibrillation with different anticoagulation schemes pre-stroke. It is a non-interventional triple-armed study aiming at a balanced inclusion of ischaemic stroke and intracerebral haemorrhage patients according to the different anticoagulation schemes. Patients will be followed up for clinical course, management and outcome up to three months after the event. Findings in ischaemic stroke and intracerebral haemorrhage patients on NOAC will be compared with patients taking vitamin K antagonists or no anticoagulant pre-stroke., Study Outcomes: Primary endpoint for ischaemic stroke patients: occurrence of symptomatic intracerebral haemorrhage, for intracerebral haemorrhage patients: occurrence of secondary haematoma expansion. Secondary endpoints include assessment of coagulation, use of thrombolysis and/or mechanical thrombectomy, occurrence of complications, implementation of secondary prevention., Summary: Describing the current patterns of early management as well as outcome of stroke patients with atrial fibrillation will help guide physicians to develop recommendations for emergency treatment of stroke patients under different anticoagulation schemes.

Objective: To develop an NIH Stroke Scale (NIHSS)-compatible, all-in-one scale for rapid and comprehensive prehospital stroke assessment including stroke recognition, severity grading and progression monitoring as well as prediction of large vessel occlusion (LVO)., Methods: Emergency medical services (EMS) personnel and stroke physicians (n=326) rated each item of the NIHSS regarding suitability for prehospital use; best rated items were included. Stroke recognition was evaluated retrospectively in 689 consecutive patients with acute stroke or stroke mimics, prediction of LVO in 741 consecutive patients with ischaemic stroke with acute vessel imaging independent of admission NIHSS score., Results: Nine of the NIHSS items were rated as 'suitable for prehospital use.' After excluding two items in order to increase specificity, the final scale (termed shortened NIHSS for EMS, sNIHSS-EMS) consists of 'level of consciousness', 'facial palsy', 'motor arm/leg', 'sensory', 'language' and 'dysarthria'. Sensitivity for stroke recognition of the sNIHSS-EMS is 91% (95% CI 86 to 94), specificity 52% (95% CI 47 to 56). Receiver operating curve analysis revealed an optimal cut-off point for LVO prediction of ≥6 (sensitivity 70% (95% CI 65 to 76), specificity 81% (95% CI 76 to 84), positive predictive value 70 (95% CI 65 to 75), area under the curve 0.81 (95% CI 0.78 to 0.84)). Test characteristics were non-inferior to non-comprehensive scales., Conclusions: The sNIHSS-EMS may overcome the sequential use of multiple emergency stroke scales by permitting parallel stroke recognition, severity grading and LVO prediction. Full NIHSS-item compatibility allows for evaluation of stroke progression starting at the prehospital phase., Competing Interests: Competing interests: Personal fees, travel support, speaker honoraria or research grants were received from Bayer Healthcare (FH, HR, PAR, SN, SP), BeneChill (SP), BMS Pfizer (PAR, SP), Boehringer 8 Ingelheim (JCP, PAR, SN, SP), Brainomix Ltd. (SN), Covidien (SP), C.R. Bard (SP), EMCOOLS (SP), Helena Laboratories (FH, SP), HVM Medical (SP), Medtronic (SN), Pfizer (JCP, SN), Raumedic (SP) and ZOLL (SP). The other authors report no conflicts of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background and Purpose: To evaluate the frequency and outcome of haemorrhagic transformation (HT) after ischaemic stroke in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs)., Methods: Patients with stroke on treatment with a NOAC were prospectively enrolled in this multicentre observational study between February 2012 and 2015. Brain imaging at admission and follow-up imaging until day 7 were reviewed for HT. Functional outcome was assessed by the modified Rankin scale (mRS) before the index event, at discharge, and at 3-months., Results: 231 patients without recanalisation therapy (no-RT), and 32 patients with RT were eligible for analysis. Any HT was present at admission in 9/231 no-RT patients (3.9%, 95% CI 2.0 to 7.3) and in none of the patients with RT. In patients with follow-up imaging (no-RT, n=129, and RT, n=32), HT was present in 14.0% (no-RT; 95% CI, 8.9 to 21.1), and 40.6% (RT, 95% CI, 25.5 to 57.8), respectively. After adjustment for stroke severity, this difference between the no-RT and RT groups became non-significant. Symptomatic ICH was observed in 1 patient per group. HT was not associated with unfavourable outcome (mRS 3-6) at 3-months in multivariable analysis. Resumption of OAC after stroke was delayed in patients with HT compared to those without (15 d [IQR, 5-26] vs. 1 d [0-4], P <0.001)., Conclusions: The frequency and severity of HT after stroke on NOAC appears similar to previous reports for vitamin K antagonists and no anticoagulation. Whether asymptomatic HT should delay resumption of preventive anticoagulation requires further investigation., Competing Interests: The authors have no financial conflicts of interest.

Background and Purpose: In patients who present with acute ischemic stroke while on treatment with non-vitamin K antagonist oral anticoagulants (NOACs), coagulation testing is necessary to confirm the eligibility for thrombolytic therapy. We evaluated the current use of coagulation testing in routine clinical practice in patients who were on NOAC treatment at the time of acute ischemic stroke., Methods: Prospective multicenter observational RASUNOA registry (Registry of Acute Stroke Under New Oral Anticoagulants; February 2012-2015). Results of locally performed nonspecific (international normalized ratio, activated partial thromboplastin time, and thrombin time) and specific (antifactor Xa tests, hemoclot assay) coagulation tests were documented. The implications of test results for thrombolysis decision-making were explored., Results: In the 290 patients enrolled, nonspecific coagulation tests were performed in ≥95% and specific coagulation tests in 26.9% of patients. Normal values of activated partial thromboplastin time and international normalized ratio did not reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11%-44% [95% confidence interval 1%-69%]). Twelve percent of patients apparently failed to take the prescribed NOAC prior to the acute event. Only 5.7% (9/159) of patients in the 4.5-hour time window received thrombolysis, and NOAC treatment was documented as main reason for not administering thrombolysis in 52.7% (79/150) of patients., Conclusions: NOAC treatment currently poses a significant barrier to thrombolysis in ischemic stroke. Because nonspecific coagulation test results within normal range have a high false-negative rate for detection of relevant drug concentrations, rapid drug-specific tests for thrombolysis decision-making should be established., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797., (© 2016 American Heart Association, Inc.)

Background and Purpose: Prospective data on the safety of endovascular thrombectomy in acute stroke patients on non-vitamin K antagonist oral anticoagulants are lacking., Methods: Prospective multicenter observational study. Patients with ischemic stroke undergoing thrombectomy with or without preceding thrombolysis were enrolled into the Registry of Acute Ischemic Stroke Under New Oral Anticoagulants. Baseline characteristics and functional outcome at 3 months were assessed. Hemorrhagic transformation and symptomatic intracranial hemorrhage were analyzed. Reperfusion was graded using the modified Thrombolysis in Cerebral Infarction score., Results: Of 28 patients treated with thrombectomy, 5 had received also systemic thrombolysis (18%). Intracranial hemorrhage was observed in 46%, but symptomatic intracranial hemorrhage occurred only in 1 patient. Successful reperfusion (Thrombolysis in Cerebral Infarction score, 2b-3) was achieved in 59%. At 3 months, 19% had a modified Rankin Scale score of 0 to 2, and mortality was 26%., Conclusions: Thrombectomy in non-vitamin K antagonist oral anticoagulant patients seems safe although a comparatively high rate of asymptomatic hemorrhagic transformation was noted. Confirmation in larger prospective controlled cohorts is necessary., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797., (© 2016 American Heart Association, Inc.)

Background: The anaesthetic conserving device, AnaConDa(®), allows use of inhaled anaesthetics for sedation in the intensive care unit. We prospectively measured cerebral and cardiopulmonary parameters in patients with acute stroke or subarachnoid haemorrhage during a switch from i.v. to inhalative sedation., Methods: 25 patients were switched from i.v. to an indefinite period of inhaled sedation with sevoflurane. Mean arterial (MAP), intracranial (ICP), and cerebral perfusion pressure (CPP), middle cerebral artery mean flow velocity (MFV) and fractional tissue oxygen extraction (FTOE), systemic cardiopulmonary parameters, and administered drugs were assessed before and after the change (-6 to +12 h)., Results: In 8 patients, critically reduced MAP or ICP crisis led to premature termination of sevoflurane sedation. In the other 17 patients, after the first hour, mean ICP increased [2.4 (4.5) mm Hg; P=0.046], MAP decreased [7.8 (14.1) mm Hg; P=0.036] and thus CPP decreased also [-10.2 (15.1) mm Hg; P=0.014]. MFV and FTOE did not change. Over a 12 hour post switch observational period, [Formula: see text] increased slightly [0.3 (0.8) kPa; P=0.104], ICP did not change [0.2 (3.9) mm Hg; P=0.865], but MAP [-6 (6.9) mm Hg; P=0.002] and thus CPP decreased [-6 (8.5) mm Hg; P=0.010]., Conclusion: Sevoflurane led to sufficient sedation, but decreased MAP and CPP in a selected cerebrovascular neurocritical care population. In about a third of these patients, severe adverse reactions, including intolerable ICP increases, were observed., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Epigenetic treatment concepts have long been ascribed as being tumour-selective. Over the last decade, it has become evident that epigenetic mechanisms are essential for a wide range of intracellular functions in healthy cells as well. Evaluation of possible side-effects and their underlying mechanisms in healthy human cells is necessary in order to improve not only patient safety, but also to support future drug development. Since epigenetic regulation directly interacts with genomic and chromosomal packaging density, increasing genomic instability may be a result subsequent to drug-induced epigenetic modifications. This review highlights past and current research efforts on the influence of epigenetic modification on genomic stability in healthy human cells.