Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial.

BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial.

BACKGROUND: Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care. METHODS: In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual. FINDINGS: Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis. FUNDING: Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

Non-ECG-gated cardiac CT angiography in acute stroke is feasible and detects sources of embolism.

BACKGROUND: A significant portion of cryptogenic stroke is hypothesized to be secondary to cardiac embolism. However, transthoracic echocardiogram is usually delayed after stroke, and more detailed cardiac imaging is not routinely done. AIMS: This study aimed to determine whether non-ECG-gated cardiac CT angiography (cCTA) during hyperacute stroke would provide diagnostic quality images and act as an adjunct modality of cardiac imaging to detect sources of emboli. METHODS: In this single-center prospective cohort study, modified Code Stroke imaging was implemented with a 64-slice CT scanner, where the longitudinal axis of CT angiography was extended from the carina to the diaphragm. The primary outcomes of image quality, recruitment feasibility, impact on hyperacute time metrics, and additional radiation dose were assessed. Secondary outcomes consisted of detection of high-risk cardiac sources of embolism, mediastinal or lung pathology, and impact on etiologic classification. RESULTS: One hundred and twenty eligible patients were enrolled, of which 105 (87.5%) had good/moderate quality images for motion artifact and 119 (99.2%) for contrast opacification. Total CT time, door-to-needle time, and door-to-groin puncture time were unchanged with the addition of cCTA. Eighty-nine patients received a final diagnosis of ischemic stroke, of which 12/89 (13.5%) had high-risk cardioembolic findings on cCTA. Incidental findings, such as pulmonary embolism (PE) (7/89, 7.9%) and malignancy (6/89, 6.7%), were observed. cCTA led to changes in management for 19/120 (15.8%) of all patients, and reclassification of stroke etiology for 8/89 (9%) of patients. CONCLUSIONS: Non-ECG-gated cCTA can be feasibly incorporated into Code Stroke and provide diagnostic quality images without delays in hyperacute time metrics. It can detect high-risk cardiac sources, and other findings impacting patient care. This may help reclassify a subset of cryptogenic stroke cases and improve secondary prevention.

Atrial cardiopathy in patients with embolic strokes of unknown source and other stroke etiologies.

OBJECTIVE: To investigate the prevalence and clinical determinants of atrial cardiopathy in patients with embolic stroke of unknown source (ESUS) and compare with other established stroke etiologies. METHODS: In a cross-sectional study of 846 consecutive patients with ischemic stroke, we compared the prevalence of atrial cardiopathy (defined by p-wave terminal force in V1 >5,000 µV·ms or severe left atrial enlargement) between ESUS patients and patients with large artery atherosclerosis (LAA) and small vessel disease (SVD) strokes. Baseline characteristics were also compared between ESUS and cardioembolic (CE) patients. RESULTS: Of all, 158 (19%) patients met ESUS diagnostic criteria, while others were classified into LAA (n = 224, 26%), SVD (n = 154, 18%), and CE (n = 310, 37%). The prevalence of atrial cardiopathy was higher in ESUS patients compared to noncardioembolic stroke patients (26.6% vs 12.1% in LAA vs 16.9% in SVD; p = 0.001). ESUS patients were younger, were less hypertensive, and had higher cholesterol and low-density lipoprotein levels, but also had less left ventricular or atrial abnormalities when compared to CE patients. CONCLUSION: The prevalence of atrial cardiopathy was high in ESUS patients compared with patients with nonembolic strokes. Interestingly, ESUS patients were also clinically different from CE patients. While the presence of atrial cardiopathy may reflect a unique mechanism of thromboembolism in ESUS patients, it is still unclear if they may benefit from anticoagulation, or if the presence of atrial cardiopathy in this population could serve as a risk-stratifying marker for stroke recurrence. Further efforts are necessary to provide better characterization of the ESUS population in order to develop better stroke preventive strategies.

Raised Intracellular Calcium Contributes to Ischemia-Induced Depression of Evoked Synaptic Transmission.

Oxygen-glucose deprivation (OGD) leads to depression of evoked synaptic transmission, for which the mechanisms remain unclear. We hypothesized that increased presynaptic [Ca2+]i during transient OGD contributes to the depression of evoked field excitatory postsynaptic potentials (fEPSPs). Additionally, we hypothesized that increased buffering of intracellular calcium would shorten electrophysiological recovery after transient ischemia. Mouse hippocampal slices were exposed to 2 to 8 min of OGD. fEPSPs evoked by Schaffer collateral stimulation were recorded in the stratum radiatum, and whole cell current or voltage clamp recordings were performed in CA1 neurons. Transient ischemia led to increased presynaptic [Ca2+]i, (shown by calcium imaging), increased spontaneous miniature EPSP/Cs, and depressed evoked fEPSPs, partially mediated by adenosine. Buffering of intracellular Ca2+ during OGD by membrane-permeant chelators (BAPTA-AM or EGTA-AM) partially prevented fEPSP depression and promoted faster electrophysiological recovery when the OGD challenge was stopped. The blocker of BK channels, charybdotoxin (ChTX), also prevented fEPSP depression, but did not accelerate post-ischemic recovery. These results suggest that OGD leads to elevated presynaptic [Ca2+]i, which reduces evoked transmitter release; this effect can be reversed by increased intracellular Ca2+ buffering which also speeds recovery.

Medication-induced acute dystonic reaction: the challenge of diagnosing movement disorders in the intensive care unit.

A 62-year-old man presented with left middle cerebral artery stroke. 1 h postadministration of tissue plasminogen activator, he received a total of 4 mg of haloperidol for combativeness. He developed partial complex status epilepticus, requiring benzodiazepines, phenytoin, propofol and intubation. 5 h later, he developed recurrent stereotyped tonic movements involving arching of the back, extension of the arms and contraction of opposing muscle groups. Repeat CT scan of the head showed evolving insular infarct. Differential diagnoses for these movements included tonic/clonic seizures, extensor (decerebrate) posturing from haemorrhagic conversion, neuroleptic malignant syndrome, or dystonic reaction. Given the lack of response to antiseizure medications, the recent administration of haloperidol, and the prompt resolution of movements following diphenhydramine administration, an acute dystonic reaction was considered. This atypical case of a critically ill patient with stroke highlights the fact that these patients may have multiple abnormal movements requiring careful analysis to guide diagnosis-specific management.

Activation of large-conductance Ca(2+)-activated K(+) channels depresses basal synaptic transmission in the hippocampal CA1 area in APP (swe/ind) TgCRND8 mice.

Large-conductance Ca(2+)-activated K(+) (BK) channels regulate synaptic transmission by contributing to the repolarization phase of the action potential that invades the presynaptic terminal. BK channels are prone to activation under pathological conditions, such as brain ischemia and epilepsy. It is unclear if activation of these channels contributes to the depression of synaptic transmission observed in the early stage of Alzheimer's disease (AD). In this study, we recorded the field excitatory postsynaptic potentials (fEPSPs) in the hippocampus CA1 region of brain slices from 6 to 9 weeks (pre-plaque) TgCRND8 mice, a mouse model of Alzheimer's disease that harbors a double amyloid precursor mutation (KM670N/671L "Swedish" and V717F "Indiana"). Compared to age-matched controls, the fEPSPs in these animals are significantly depressed. This depression is largely mediated by the activation of presynaptic BK channels in the CA1 area. Both BK channel blockers (charybdotoxin and paxilline), and the fast binding calcium chelator, BAPTA-AM, enhance the fEPSP by deactivating the BK channels. Repetitive stimulation to the afferent pathway enhances fEPSP. This enhancement is more prominent when BK channel blockers are added in Tg slices, suggesting that repetitive stimulation further promotes BK channel activation in Tg slices. The potential candidates that mediate the activation of BK channels in these pre-plaque Alzheimer's disease model mice might involve impaired calcium homeostasis and AD related over-generation of reactive oxygen species.

Early ischemia enhances action potential-dependent, spontaneous glutamatergic responses in CA1 neurons.

Two types of quantal spontaneous neurotransmitter release are present in the nervous system, namely action potential (AP)-dependent release and AP-independent release. Previous studies have identified and characterized AP-independent release during hypoxia and ischemia. However, the relative contribution of AP-dependent spontaneous release to the overall glutamate released during transient ischemia has not been quantified. Furthermore, the neuronal activity that mediates such release has not been identified. Using acute brain slices, we show that AP-dependent release constitutes approximately one-third of the overall glutamate-mediated excitatory postsynaptic potentials/currents (EPSPs/EPSCs) measured onto hippocampal CA1 pyramidal neurons. However, during transient (2 mins) in vitro hypoxia-hypoglycemia, large-amplitude, AP-dependent spontaneous release is significantly enhanced and contributes to 74% of the overall glutamatergic responses. This increased AP-dependent release is due to hyper-excitability in the presynaptic CA3 neurons, which is mediated by the activity of NMDA receptors. Spontaneous glutamate release during ischemia can lead to excitotoxicity and perturbation of neural network functions.