The Role of the Octarepeat Region in Neuroprotective Function of the Cellular Prion Protein

Structural alterations of the cellular prion protein (PrP(C)) seem to be the core of the pathogenesis of prion diseases. However, the physiological function of PrP(C) remains an enigma. Cell culture experiments have indicated that PrP(C) and in particular its N-terminal octarepeat region together with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways have a fundamental involvement in neuroprotection and oxidative stress reactions. We used wild-type mice, PrP knockout (Prnp(−/−)) animals and transgenic mice that lack the octarepeat region (C4/−) and subjected them to controlled ischemia. We identified an increased cleavage and synthesis of PrP(C) in ischemic brain areas of wild-type mice compared with sham controls. The infarct size in Prnp(−/−) animals was increased threefold when compared with wild-type mice. The infarct size in C4/− animals was identical to Prnp(−/−) mice, that is, around three times larger than in wild-type mice. We showed that the PrP in C4/− mice does not functionally rescue the Prnp(−/−) phenotype; furthermore it is unable to undergo β cleavage, although an increased amount of C1 fragments was found in ischemic brain areas compared with sham controls. We demonstrated that the N-terminal octarepeat region has a lead function in PrP(C) physiology and neuroprotection against oxidative stress in vivo

Real-life experience with the specific reversal agent idarucizumab for the management of emergency situations in dabigatran-treated patients : a series of 11 cases

Non-vitamin K antagonist oral anticoagulants (NOACs) have a favorable benefit-risk profile compared with vitamin K antagonists. However, the lack of specific reversal agents has made the management of some patients receiving long-term treatment with NOACs problematic in emergency situations such as major bleeding events or urgent procedures. Idarucizumab, a fully humanized Fab antibody fragment that binds specifically and with high affinity to dabigatran, was recently approved for use in adult patients treated with dabigatran when rapid reversal of its anticoagulant effect is required. Clinical experience with idarucizumab is currently limited. We report 11 real-life clinical cases in which idarucizumab was used after multidisciplinary consultation in a variety of emergency situations including severe postoperative bleeding, emergency high-bleeding-risk surgery (hip/spine surgery and neurosurgery), invasive diagnostic testing (lumbar puncture), intracranial bleeding (pre-pontine subarachnoid hemorrhage and lobar intracerebral hemorrhage) and thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke. This case series illustrates the role of idarucizumab in improving patient safety in rare emergency situations requiring rapid reversal of the anticoagulant effect of dabigatran, while highlighting the importance of information and education about the availability and appropriate use of this recently approved specific reversal agent

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial

Background: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. Methods: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. Findings: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77–1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80–1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79–1·60; p=0·53). Interpretation: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care

PHAryngeal electrical STimulation for early decannulation in TRACheotomised stroke patients with neurogenic dysphagia (PHAST-TRAC): a prospective randomised single-blinded trial

Background Dysphagia after stroke is common, especially in severely affected, tracheotomised patients. In a pilot trial, pharyngeal electrical stimulation (PES) improved swallowing function in this group of patients. The PHAryngeal electrical STimulation for early decannulation in TRACheotomised stroke patients with neurogenic dysphagia trial (PHAST-TRAC) was designed to replicate and extend this single-centre experience. Methods Patients with recent stroke who required tracheotomy were randomised to receive three days of PES or sham. All patients had the stimulation catheter inserted; sham treatment was applied by connecting the base station to a simulator box instead of the catheter. Randomisation was done via a computerised interactive system with randomisation (stratified by site) in blocks of 4 patients per site. Patients and investigators applying PES were not masked. The primary-endpoint was assessed blinded to treatment assignment by a separate investigator at each site. The primary outcome was readiness for decannulation 24-72 hours post-treatment, assessed using fiberoptic endoscopic evaluation of swallowing and based on a standardised protocol including absence of massive saliva, presence of spontaneous swallows and laryngeal sensation. We planned a sequential statistical analysis of superiority for the primary endpoint. Interim analyses were to be performed after primary outcome data were available for 50 patients (futility), 70 patients, and every additional 10 patients thereafter up to 140. Analysis was by intention-to-treat. The trial was registered as ISRCTN18137204. Findings From 29th May 2015 to 5th July 2017, 69 patients (PES 35, sham 34) from 9 sites (7 acute care hospitals, 2 rehabilitation facilities) in Germany, Austria and Italy were included: PES group mean age 61.7 (SD 13.0) years, 8 (23%) patients with haemorrhagic stroke, median time onset to randomisation 28.0 [IQR 20, 49] days; sham group age 66.8 (10.3) years, 12 (35%) patients with haemorrhagic stroke, onset to randomisation 28.0 [18, 40] days). The Independent Data & Safety Monitoring Board recommended to stop the trial early for efficacy after 70 patients had been recruited and primary endpoint data of 69 patients were available. This decision was approved by the steering committee. PES was associated with more patients being ready for decannulation as compared to sham: 17 (49%) vs. 3 (9%), odds ratio (OR) 7.00 (2.41-19.88), p=0.00082). No patient required recannulation within 48 hours or during their documented follow-up period up to 30 days or hospital discharge. Adverse events (AEs) were reported in 24 patients (69%) of the PES group and 24 patients (71%) of the sham group. The number of patients with at least one serious adverse event (SAE) did not differ between the groups: 10 (29%) vs. 8 (23%), OR 1.3 (0.44-3.83), p=0.7851). 7 patients (20%) from the PES group and 3 patients (9%) from the sham group died during the study period. None of the patient deaths or SAEs reported were judged to be PES-treatment- or investigational device-related. Interpretation PES increased the proportion of patients with stroke and subsequent tracheotomy who were ready for decannulation in this study population, many of whom received PES within a month of their stroke. Future trials should confirm whether PES is beneficial in tracheostomised patients who receive stimulation similarly early after stroke and explore its effects in other cohorts

Pharyngeal electrical stimulation for neurogenic dysphagia following stroke, traumatic brain injury or other causes: Main results from the PHADER cohort study

BackgroundNeurogenic dysphagia is common and has no definitive treatment. We assessed whether pharyngeal electrical stimulation (PES) is associated with reduced dysphagia.MethodsThe PHAryngeal electrical stimulation for treatment of neurogenic Dysphagia European Registry (PHADER) was a prospective single-arm observational cohort study. Participants were recruited with neurogenic dysphagia (comprising five groups – stroke not needing ventilation; stroke needing ventilation; ventilation acquired; traumatic brain injury; other neurological causes). PES was administered once daily for three days. The primary outcome was the validated dysphagia severity rating scale (DSRS, score best-worst 0–12) at 3 months.FindingsOf 255 enrolled patients from 14 centres in Austria, Germany and UK, 10 failed screening. At baseline, mean (standard deviation) or median [interquartile range]: age 68 (14) years, male 71%, DSRS 11·4 (1·7), time from onset to treatment 32 [44] days; age, time and DSRS differed between diagnostic groups. Insertion of PES catheters was successfully inserted in 239/245 (98%) participants, and was typically easy taking 11·8 min. 9 participants withdrew before the end of treatment. DSRS improved significantly in all dysphagia groups, difference in means (95% confidence intervals, CI) from 0 to 3 months: stroke (n = 79) –6·7 (–7·8, –5·5), ventilated stroke (n = 98) –6·5 (–7·6, –5·5); ventilation acquired (n = 35) –6·6 (–8·4, –4·8); traumatic brain injury (n = 24) -4·5 (–6·6, –2·4). The results for DSRS were mirrored for instrumentally assessed penetration aspiration scale scores. DSRS improved in both supratentorial and infratentorial stroke, with no difference between them (p = 0·32). In previously ventilated participants with tracheotomy, DSRS improved more in participants who could be decannulated (n = 66) –7·5 (–8·6, –6·5) versus not decannulated (n = 33) –2·1 (–3·2, –1·0) (

Machine Learning Based Color Classification by Means of Visually Evoked Potentials

Visually evoked potentials (VEPs) are widely used for diagnoses of different neurological diseases. Interestingly, there is limited research about the impact of the stimulus color onto the evoked response. Therefore, in our study we investigated the possibility of automatically classifying the stimulus color. The visual stimuli were selected to be red/black and green/black checkerboard patterns with equal light density. Both of these stimuli were presented in a random manner to nine subjects, while the electroencephalogram was recorded at the occipital lobe. After pre-processing and aligning the evoked potentials, an artificial neural network with one hidden layer was used to investigate the general possibility to automatically classify the stimulus color in three different settings. First, color classification with individually trained models, color classification with a common model, and color classification for each individual volunteer with a model trained on the data of the remaining subjects. With an average accuracy (ACC) of 0.83, the best results were achieved for the individually trained model. Also, the second (mean ACC = 0.76) and third experiments (mean ACC = 0.71) indicated a reasonable predictive accuracy across all subjects. Consequently, machine learning tools are able to appropriately classify stimuli colors based on VEPs. Although further studies are needed to improve the classification performance of our approach, this opens new fields of applications for VEPs

Machine Learning Based Color Classification by Means of Visually Evoked Potentials

Visually evoked potentials (VEPs) are widely used for diagnoses of different neurological diseases. Interestingly, there is limited research about the impact of the stimulus color onto the evoked response. Therefore, in our study we investigated the possibility of automatically classifying the stimulus color. The visual stimuli were selected to be red/black and green/black checkerboard patterns with equal light density. Both of these stimuli were presented in a random manner to nine subjects, while the electroencephalogram was recorded at the occipital lobe. After pre-processing and aligning the evoked potentials, an artificial neural network with one hidden layer was used to investigate the general possibility to automatically classify the stimulus color in three different settings. First, color classification with individually trained models, color classification with a common model, and color classification for each individual volunteer with a model trained on the data of the remaining subjects. With an average accuracy (ACC) of 0.83, the best results were achieved for the individually trained model. Also, the second (mean ACC = 0.76) and third experiments (mean ACC = 0.71) indicated a reasonable predictive accuracy across all subjects. Consequently, machine learning tools are able to appropriately classify stimuli colors based on VEPs. Although further studies are needed to improve the classification performance of our approach, this opens new fields of applications for VEPs

Dabigatran in Cerebral Sinus Vein Thrombosis and Thrombophilia

Background and Purpose: Thrombophilic gene alterations are a major risk factor for cerebral sinus vein thrombosis (CSVT). Up to 30% of all patients with cerebral sinus vein thrombosis (CSVT) are found to have thrombophilic defects such as prothrombin mutation (PTM) or factor V Leiden (FVL). Their repercussions on the plasma levels of dabigatran etexilate are unclear. In this prospective case–control study, we aimed to investigate whether thrombophilia in CSVT has an influence on dabigatran peak-plasma levels. Methods: We monitored 10 patients over 12 months with acute CSVT, genetic thrombophilia with off-label use of dabigatran etexilate 150 mg twice a day and measured dabigatran peak-plasma levels and radiological outcome. We also monitored patients without genetic thrombophilia with dabigatran etexilate 150 mg twice a day and compared the efficiency and dabigatran peak-plasma levels. Results: Patients with homozygote PTM had significantly lower dabigatran peak concentration compared to patients with FVL or the control group (23 ± 4.2 vs. 152.3 ± 27.5 and 159.6 ± 63.08; p-value ≤ 0.05) There was no significant difference in dabigatran etexilate plasma levels between the heterozygote PTM group compared to patients with FVL or the control group (p = 0.29). There was no correlation between dabigatran peak concentration and delayed thrombus dissolution. Conclusions: Dabigatran peak concentration was stable in patients with heterozygote FVL and heterozygote PTM, but not in homozygote PTM, compared to controls. Genetic screening for thrombophilia in patients after CSVT may be useful to make patient tailored therapeutic decisions regarding oral anticoagulation and may decrease thrombotic events