Role of cardiac computed tomography in hyperacute stroke assessment.

BACKGROUND: Incorporating cardiac CT with hyperacute stroke imaging may increase the yield for cardioembolic sources. It is not clarified whether stroke severity influences on rates of intracardiac thrombus. We aimed to investigate a National Institutes of Health Stroke Scale (NIHSS) threshold below which acute cardiac CT was unnecessary. METHODS: Consecutive patients with suspected stroke who underwent multimodal brain imaging and concurrent non-gated cardiac CT with delayed timing were prospectively recruited from 1st December 2020 to 30th November 2021. We performed receiver operating characteristics analysis of the NIHSS and intracardiac thrombus on hyperacute cardiac CT. RESULTS: A total of 314 patients were assessed (median age 69 years, 61% male). Final diagnoses were ischemic stroke (n=205; 132 etiology-confirmed stroke, independent of cardiac CT and 73 cryptogenic), transient ischemic attack (TIA) (n=21) and stroke-mimic syndromes (n=88). The total yield of cardiac CT was 8 intracardiac thrombus and 1 dissection. Cardiac CT identified an intracardiac thrombus in 6 (4.5%) with etiology-confirmed stroke, 2 (2.7%) with cryptogenic stroke, and none in patients with TIA or stroke-mimic. All of those with intracardiac thrombus had NIHSS ≥4 and this was the threshold below which hyperacute cardiac CT was not justified (sensitivity 100%, specificity 38%, positive predictive value 4.0%, negative predictive value 100%). CONCLUSIONS: A cutoff NIHSS ≥4 may be useful to stratify patients for cardiac CT in the hyperacute stroke setting to optimize its diagnostic yield and reduce additional radiation exposure.

Whole Blood Viscosity and Cerebral Blood Flow in Acute Ischemic Stroke.

Existing effective treatments for ischemic stroke restore blood supply to the ischemic region using thrombolysis or mechanical removal of clot. However, it is increasingly recognized that successful removal of occlusive thrombus from the large artery-recanalization, may not always be accompanied by successful restoration of blood flow to the downstream tissues-reperfusion. Ultimately, brain tissue survival depends on cerebral perfusion, and a functioning microcirculation. Because capillary diameter is often equal to or smaller than an erythrocyte, microcirculation is largely dependent on erythrocyte rheological (hemorheological) factors such as whole blood viscosity (WBV). Several studies in the past have demonstrated elevated WBV in stroke compared with healthy controls. Also, elevated WBV has shown to be an independent risk factor for stroke. Elevated WBV leads to endothelial dysfunction, decreases nitric oxide-dependent flow-mediated vasodilation, and promotes hemostatic alterations/thrombosis, all leading to microcirculation sludging. Compromised microcirculation further leads to decreased cerebral perfusion. Hence, modulating WBV through pharmacological agents might be beneficial to improve cerebral perfusion in stroke. This review discusses the effect of elevated WBV on endothelial function, hemostatic alterations, and thrombosis leading to reduced cerebral perfusion in stroke.

Whole blood viscosity is associated with baseline cerebral perfusion in acute ischemic stroke.

Whole blood viscosity (WBV) is the intrinsic resistance to flow developed due to the frictional force between adjacent layers of flowing blood. Elevated WBV is an independent risk factor for stroke. Poor microcirculation due to elevated WBV can prevent adequate perfusion of the brain and might act as an important secondary factor for hypoperfusion in acute ischaemic stroke. In the present study, we examined the association of WBV with basal cerebral perfusion assessed by CT perfusion in acute ischaemic stroke. Confirmed acute ischemic stroke patients (n = 82) presenting in hours were recruited from the single centre. Patients underwent baseline multimodal CT (non-contrast CT, CT angiography and CT perfusion). Where clinically warranted, patients also underwent follow-up DWI. WBV was measured in duplicate within 2 h after sampling from 5-mL EDTA blood sample. WBV was significantly correlated with CT perfusion parameters such as perfusion lesion volume, ischemic core volume and mismatch ratio; DWI volume and baseline NIHSS. In a multivariate linear regression model, WBV significantly predicted acute perfusion lesion volume, core volume and mismatch ratio after adjusting for the effect of occlusion site and collateral status. Association of WBV with hypoperfusion (increased perfusion lesion volume, ischaemic core volume and mismatch ratio) suggest the role of erythrocyte rheology in cerebral haemodynamic of acute ischemic stroke. The present findings open new possibilities for therapeutic strategies targeting erythrocyte rheology to improve cerebral microcirculation in stroke.

Transition in Incidence Rate of Hospitalised Stroke and Case Fatality Rate in the Hunter Region, Australia, 2001-2019: A Prospective Hospital-Based Study.

INTRODUCTION: Continuous surveillance of stroke admissions has been conducted in the Hunter region, Australia, over the past two decades. We aimed to describe the trends in incidence rates of hospitalised stroke and case-fatality rates in this region, 2001-2019. METHODS: From a hospital-based stroke registry, data for admitted adult stroke patients residing in the Hunter region were collected using ICD-10 codes for ischemic and haemorrhagic stroke. Negative binomial regression and logistic regression analysis were used to analyse trends for age-standardised and age-specific incidence rates of hospitalised stroke and 28-day case-fatality rates. RESULTS: A total of 14,662 hospitalisations for stroke in 13,242 individuals were registered. The age-standardised incidence rate declined from 123 per 100,000 population in the 2001-2005 epoch to 96 in the 2016-2019 epoch (mean annual change -2.0%, incidence rate ratio (IRR) = 0.980 [95%CI: 0.976-0.984]). Age-specific analyses identified significant reduction in the group aged 75-84 (1039 per 100,000 population in 2001-2005 to 633 in 2016-2019, annual change -3.5%, IRR= 0.965 [95%CI: 0.960-0.970]). The 28-day case-fatality rates fluctuated over time (18.5% in 2001-2005, 20.8% in 2010-2015, and 17.8% in 2016-2019).  Projected population aging suggests annual volume of patients with new stroke will increase by 77% by 2041 if incidence rates remain unchanged at the 2016-2019 level. CONCLUSION: Although age-standardised hospitalised stroke incidence rates have declined in the Hunter region, the health system will face an increase in stroke hospitalisations related to the aging population.

Role of Computed Tomography Perfusion in Identification of Acute Lacunar Stroke Syndromes.

BACKGROUND AND PURPOSE: Lacunar syndromes correlate with a lacunar stroke on imaging in 50% to 60% of cases. Computed tomography perfusion (CTP) is becoming the preferred imaging modality for acute stroke triage. We aimed to estimate the sensitivity, specificity, and predictive values for noncontrast computed tomography and CTP in lacunar syndromes, and for cortical, subcortical, and posterior fossa regions. METHODS: A retrospective analysis of confirmed ischemic stroke patients who underwent acute CTP and follow-up magnetic resonance imaging between 2010 and 2018 was performed. Brain noncontrast computed tomography and CTP were assessed independently by 2 stroke neurologists. Receiver operating characteristic curve analysis was performed to estimate sensitivity, specificity, and area under the curve (AUC) for the detection of strokes in patients with lacunar syndromes using different CTP maps. RESULTS: We found 106 clinical lacunar syndromes, but on diffusion-weighted imaging, these consisted of 59 lacunar, 33 cortical, and 14 posterior fossa strokes. The discrimination of ischemia identification was very poor using noncontrast computed tomography in all 3 regions, but good for cortical (AUC, 0.82) and poor for subcortical and posterior regions (AUCs, 0.55 and 0.66) using automated core-penumbra maps. The addition of delay time and mean transient time maps substantially increased subcortical (AUC, 0.80) and slightly posterior stroke detection (AUC, 0.69). CONCLUSIONS: Analysis of mean transient time and delay time maps in combination with core-penumbra maps improves detection of subcortical and posterior strokes.

Computed Tomography Perfusion Identifies Patients With Stroke With Impaired Cardiac Function.

Background and Purpose- Low left ventricular ejection fraction (LVEF) leads to worse outcomes after stroke. We hypothesized that the arterial input function (AIF) variability on perfusion computed tomography, especially the time between scan onset and end of AIF (SO-EndAIF), would reflect reduction of cardiac output. Methods- Retrospective analysis of consecutive stroke patients, who underwent computed tomography between January 2013 and September 2018, was performed in 2 parts. (1) To determine the correlation between SO-EndAIF and LVEF, all patients with a transthoracic echocardiogram performed ±6 months from the time of stroke were included. LVEF was dichotomized as either normal (≥50%) or decreased (<50%). (2) AIF was compared with hypoperfusion volume, defined as delay time >3 seconds and with clinical outcome measured using 3-month modified Rankin Scale. Results- A total of 732 ischemic stroke patients underwent computed tomography, 231 with transthoracic echocardiogram were included in part (1), 393 with outcome data were included in part (2). In part (1), 193/231 (83.5%) had normal LVEF (median 61%) and 38/231 (16.5%) decreased LVEF (median 39%). The low-LVEF group had significantly prolonged SO-EndAIF compared with normal-LVEF group (mean of 39.7 versus 26 second; P<0.001), and larger hypoperfusion lesions (94.9 versus 37.6 mL; P<0.001). SO-EndAIF time was strongly associated with EF, with an area under the curve of 0.86. Twenty nine seconds was the best threshold to distinguish between normal and impaired EF (area under the curve, 0.77). In part (2), the SO-EndAIF ≥29 second group had larger hypoperfusion volumes (21.8 versus 89.7 mL; P<0.001) and infarct core (12.2 versus 2.3 mL; P<0.0001) and patients with SO-EndAIF ≥29 seconds had fewer excellent or good clinical outcomes (modified Rankin Scale score 0-1; 40% versus 22%; OR, 2.79; P<0.001, modified Rankin Scale score 0-2; 65% versus 35%; OR, 1.41; P=0.033). Conclusions- AIF width correlates with ejection fraction in acute ischemic stroke. A 29-second threshold from scan onset to end of AIF accurately predicts reduced LVEF and identifies patients more likely to have worse outcomes after stroke.

Predicting Modafinil-Treatment Response in Poststroke Fatigue Using Brain Morphometry and Functional Connectivity.

Background and Purpose- Poststroke fatigue affects a large proportion of stroke survivors and is associated with a poor quality of life. In a recent trial, modafinil was shown to be an effective agent in reducing poststroke fatigue; however, not all patients reported a significant decrease in fatigue with therapy. We sought to investigate clinical and radiological predictors of fatigue reduction with modafinil therapy in a stroke survivor cohort. Methods- Twenty-six participants with severe fatigue (multidimensional fatigue inventory-20 ≥60) underwent magnetic resonance imaging at baseline and during the last week of a 6-week treatment period of 200 mg modafinil taken daily. Resting-state functional magnetic resonance imaging and high-resolution structural imaging data were obtained, and functional connectivity and regional brain volumes within the fronto-striato-thalamic network were obtained. Linear regression analysis was used to identify predictors of modafinil-induced fatigue reduction. Results- Multiple regression analysis showed that baseline multidimensional fatigue inventory-20 score (ß=0.576, P=0.006) and functional connectivity between the dorsolateral prefrontal cortex and the caudate nucleus (ß=-0.424, P=0.008) were significant predictors of modafinil-associated decreases in poststroke fatigue (adjusted r2=0.52, area under the receiver operator characteristic curve=0.939). Conclusions- Fronto-striato-thalamic functional connectivity predicted modafinil response for poststroke fatigue. Fatigue in other neurological disease has been attributed to altered function of the fronto-striato-thalamic network and may indicate that poststroke fatigue has a similar mechanism to other neurological injury related fatigue. Self-reported fatigue in patients with normal fronto-striato-thalamic functional connectivity may have a different mechanism and require alternate therapeutic approaches. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: ACTRN12615000350527.

Transient Ischemic Attack Results in Delayed Brain Atrophy and Cognitive Decline.

BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) initiates an ischemic cascade without resulting in frank infarction and, as such, represents a novel model to study the effects of this ischemic cascade and secondary neurodegeneration in humans. METHODS: Patients with suspected TIA underwent acute brain perfusion imaging, and those with acute ischemia were enrolled into a prospective observational study. We collected baseline and 90-day magnetic resonance imaging, including MP-RAGE (high-resolution T1 sequence) and cognitive assessment with the Montreal Cognitive Assessment. Brain morphometry and within patient statistical analysis were performed to identify changes between baseline and 90-day imaging and clinical assessments. RESULTS: Fifty patients with TIA with acute perfusion lesions were studied. All patients experienced a decrease in global cortical gray matter (P=0.005). Patients with anterior circulation TIA (n=31) also had a significant reduction in the volume of the pons (P<0.001), ipsilesional parietal lobe (P<0.001), occipital lobe (P=0.002), frontal lobe (P<0.001), temporal lobe (P=0.003), and thalamus (P=0.016). Patients with an anterior perfusion lesion on acute imaging also had a significant decrease in Montreal Cognitive Assessment between baseline and day 90 (P=0.027), which may be related to the volume of thalamic atrophy (R2=0.28; P=0.009). CONCLUSIONS: In a prospective observational study, patients with TIA confirmed by acute perfusion imaging experienced a significant reduction in global gray matter and focal structural atrophy related to the area of acute ischemia. The atrophy also resulted in a proportional decreased cognitive performance on the Montreal Cognitive Assessment. Further studies are required to identify the mechanisms of this atrophy.

MIDAS (Modafinil in Debilitating Fatigue After Stroke): A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial.

BACKGROUND AND PURPOSE: This study aimed to assess the efficacy of modafinil, a wakefulness-promoting agent in alleviating post-stroke fatigue ≥3 months after stroke. We hypothesized that 200 mg of modafinil daily for 6 weeks would result in reduced symptoms of fatigue compared with placebo. METHODS: This single-center phase 2 trial used a randomized, double-blind, placebo-controlled, crossover design. The key inclusion criterion was a multidimensional fatigue inventory score of ≥60. Patients were randomized to either modafinil or placebo for 6 weeks of therapy, then after a 1 week washout period swapped treatment arms for a second 6 weeks of therapy. The primary outcome was the multidimensional fatigue inventory; secondary outcomes included the Montreal cognitive assessment, the Depression, Anxiety, and Stress Scale (DASS), and the Stroke-Specific Quality of Life (SSQoL) scale. The multidimensional fatigue inventory is a self-administered questionnaire with a range of 0 to 100. Treatment efficacy was assessed using linear regression by estimating within-person, baseline-adjusted differences in mean outcomes after therapy. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000350527). RESULTS: A total of 232 stroke survivors were screened and 36 were randomized. Participants receiving modafinil reported a significant decrease in fatigue (multidimensional fatigue inventory, -7.38; 95% CI, -21.76 to -2.99; P<0.001) and improved quality of life (SSQoL, 11.81; 95% CI, 2.31 to 21.31; P=0.0148) compared with placebo. Montreal cognitive assessment and DASS were not significantly improved with modafinil therapy during the study period (P>0.05). CONCLUSIONS: Stroke survivors with nonresolving fatigue reported reduced fatigue and improved quality of life after taking 200 mg daily treatment with modafinil. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368268. Unique identifier: ACTRN12615000350527.

Finite element modeling of optic chiasmal compression.

BACKGROUND: The precise mechanism of bitemporal hemianopia is still not clear. Our study investigated the mechanism of bitemporal hemianopia by studying the biomechanics of chiasmal compression caused by a pituitary tumor growing below the optic chiasm. METHODS: Chiasmal compression and nerve fiber interaction in the chiasm were simulated numerically using finite element modeling software. Detailed mechanical strain distributions in the chiasm were obtained to help understand the mechanical behavior of the optic chiasm. Nerve fiber models were built to determine the relative difference in strain experienced by crossed and uncrossed nerve fibers. RESULTS: The central aspect of the chiasm always experienced higher strains than the peripheral aspect when the chiasm was loaded centrally from beneath. Strains in the nasal (crossed) nerve fibers were dramatically higher than in temporal (uncrossed) nerve fibers. CONCLUSIONS: The simulation results of the macroscopic chiasmal model are in agreement with the limited experimental results available, suggesting that the finite element method is an appropriate tool for analyzing chiasmal compression. Although the microscopic nerve fiber model was unvalidated because of lack of experimental data, it provided useful insights into a possible mechanism of bitemporal hemianopia. Specifically, it showed that the strain difference between crossed and uncrossed nerve fibers may account for the selective nerve damage, which gives rise to bitemporal hemianopia.

Ischemic Lesion Growth in Patients with a Persistent Target Mismatch After Large Vessel Occlusion.

BACKGROUND: Failure to reperfuse a cerebral occlusion resulting in a persistent penumbral pattern has not been fully described. METHODS: We retrospectively reviewed patients with anterior large vessel occlusion who did not receive reperfusion, and underwent repeated perfusion imaging, with baseline imaging < 6 h after onset and follow-up scans from 16-168 h. A persistent target mismatch (PTM) was defined as core volume of < 100 mL, mismatch ratio > 1.2, and mismatch volume > 10 mL on follow-up imaging. Patients were divided into PTM or non-PTM groups. Ischemic core and penumbral volumes were compared between baseline and follow-up imaging between the two groups, and collateral flow status assessed using CT perfusion collateral index. RESULTS: A total of 25 patients (14 PTM and 11 non-PTM) were enrolled in the study. Median core volumes increased slightly in the PTM group, from 22 to 36 ml. There was a much greater increase in the non-PTM group, from 57 to 190 ml. Penumbral volumes were stable in the PTM group from a median of 79 ml at baseline to 88 ml at follow-up, whereas penumbra was reduced in the non-PTM group, from 120 to 0 ml. Collateral flow status was also better in the PTM group and the median collateral index was 33% compared with 44% in the non-PTM group (p = 0.043). CONCLUSION: Multiple patients were identified with limited core growth and large penumbra (persistent target mismatch) > 16 h after stroke onset, likely due to more favorable collateral flow.

The Need for Structured Strategies to Improve Stroke Care in a Rural Telestroke Network in Northern New South Wales, Australia: An Observational Study.

Introduction: A telestroke network in Northern New South Wales, Australia has been developed since 2017. We theorized that the telestroke network development would drive a progressive improvement in stroke care metrics over time. Aim: This study aimed to describe changes in acute stroke workflow metrics over time to determine whether they improved with network experience. Methods: We prospectively collected data of patients assessed by telestroke who received multimodal computed tomography (mCT) and were diagnosed with ischemic stroke or transient ischemic attack from January 2017 to July 2019. The period was divided into two phases (phase 1: January 2017 - October 2018 and phase 2: November 2018 - July 2019). We compared median door-to-call, door-to-image, and door-to-decision time between the two phases. Results: We included 433 patients (243 in phase 1 and 190 in phase 2). Each spoke site treated 1.5-5.2 patients per month. There were Door-to-call time (median 39 in phase 1, 35 min in phase 2, p = 0.18), and door-to-decision time (median 81.5 vs. 83 min, p = 0.31) were not improved significantly. Similarly, in the reperfusion therapy subgroup, door-to-call time (median 29 vs. 24.5 min, p = 0.12) and door-to-decision time (median 70.5 vs. 67.5 min, p = 0.75) remained substantially unchanged. Regression analysis showed no association between time in the network and door-to-decision time (coefficient 1.5, p = 0.32). Conclusion: In our telestroke network, acute stroke timing metrics did not improve over time. There is the need for targeted education and training focusing on both stroke reperfusion competencies and the technical aspects of telestroke in areas with limited workforce and high turnover.

Multimodal Computed Tomography Increases the Detection of Posterior Fossa Strokes Compared to Brain Non-contrast Computed Tomography.

Aims: Multimodal computed tomography (mCT) (non-contrast CT, CT angiography, and CT perfusion) is not routinely used to assess posterior fossa strokes. We described the area under the curve (AUC) of brain NCCT, WB-CTP automated core-penumbra maps and comprehensive CTP analysis (automated core-penumbra maps and all perfusion maps) for posterior fossa strokes. Methods: We included consecutive patients with signs and symptoms of posterior fossa stroke who underwent acute mCT and follow up magnetic resonance diffusion weighted imaging (DWI). Multimodal CT images were reviewed blindly and independently by two stroke neurologists and area under the receiver operating characteristic curve (AUC) was used to compare imaging modalities. Results: From January 2014 to December 2019, 83 patients presented with symptoms suggestive of posterior fossa strokes and had complete imaging suitable for inclusion (49 posterior fossa strokes and 34 DWI negative patients). For posterior fossa strokes, comprehensive CTP analysis had an AUC of 0.68 vs. 0.62 for automated core-penumbra maps and 0.55 for NCCT. For cerebellar lesions >5 mL, the AUC was 0.87, 0.81, and 0.66, respectively. Conclusion: Comprehensive CTP analysis increases the detection of posterior fossa lesions compared to NCCT and should be implemented as part of the routine imaging assessment in posterior fossa strokes.

Air vs. Road Decision for Endovascular Clot Retrieval in a Rural Telestroke Network.

Background and Purpose: Telestroke aims to increase access to endovascular clot retrieval (ECR) for rural areas. There is limited information on transfer workflow for ECR in rural settings. We sought to describe the transfer metrics for ECR in a rural telestroke network with respect to decision making. Methods: A retrospective cohort study was employed on consecutive patients transferred to the comprehensive stroke center (CSC) for ECR in a rural hub-and-spoke telestroke network between April 2013 and October 2019, by road or air. Key time-based metrics were analyzed. Results: Sixty-two patients were included. Mean age was 66 years [standard deviation (SD), 14] and median National Institutes of Health Stroke Scale 13 [interquartile range (IQR), 8-18]. Median rural-hospital-door-to-CSC-door (D2D) was 308 min (IQR, 254-351), of which 68% was spent at rural hospitals [door-in-door-out (DIDO); 214 min; IQR, 171-247]. DIDO was longer for air transfers than road (P = 0.004), primarily because of a median 87 min greater decision-to-departure time (Decision-DO, P < 0.001). In multiple linear regression analysis, intubation but not thrombolysis was associated with significantly longer DIDO. The distance at which the extra speed of an aircraft made up for the delays involved in booking an aircraft was 299 km from the CSC. Conclusions: DIDO is longer for air retrievals compared with road. Decision-DO represents the most important component of DIDO, being longer for air transfers. Systems for rapid transportation of rural ECR candidates need optimization for best patient outcomes, with decision support seen as a potential tool to achieve this.

No Evidence of the "Weekend Effect" in the Northern New South Wales Telestroke Network.

Background: Admission outside normal business hours has been associated with prolonged door-to-treatment times and poorer patient outcomes, the so called "weekend effect. " This is the first examination of the weekend effect in a telestroke service that uses multi-modal computed tomography. Aims: To examine differences in workflow and triage between in-hours and out-of-hours calls to a telestroke service. Methods: All patients assessed using the Northern New South Wales (N-NSW) telestroke service from April 2013 to January 2019 were eligible for inclusion (674 in total; 539 with complete data). The primary outcomes measured were differences between in-hours and out-of-hours in door-to-call-to-decision-to-needle times, differences in the proportion of patients confirmed to have strokes or of patients selected for reperfusion therapies or patients with a modified Rankin Score (mRS ≤ 2) at 90 days. Results: There were no significant differences between in-hours and out-of-hours in any of the measured times, nor in the proportions of patients confirmed to have strokes (67.6 and 69.6%, respectively, p = 0.93); selected for reperfusion therapies (22.7 and 22.6%, respectively, p = 0.56); or independent at 3 months (34.8 and 33.6%, respectively, p = 0.770). There were significant differences in times between individual hospitals, and patient presentation more than 4.5 h after symptom onset was associated with slower times (21 minute delay in door-to-call, p = 0.002 and 22 min delay in door-to-image, p = 0.001). Conclusions: The weekend effect is not evident in the Northern NSW telestroke network experience, though this study did identify some opportunities for improvement in the delivery of acute stroke therapies.

Developing a multivariable prediction model for functional outcome after reperfusion therapy for acute ischaemic stroke: study protocol for the Targeting Optimal Thrombolysis Outcomes (TOTO) multicentre cohort study.

INTRODUCTION: Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) is the only approved pharmacological reperfusion therapy for acute ischaemic stroke. Despite population benefit, IVT is not equally effective in all patients, nor is it without significant risk. Uncertain treatment outcome prediction complicates patient treatment selection. This study will develop and validate predictive algorithms for IVT response, using clinical, radiological and blood-based biomarker measures. A secondary objective is to develop predictive algorithms for endovascular thrombectomy (EVT), which has been proven as an effective reperfusion therapy since study inception. METHODS AND ANALYSIS: The Targeting Optimal Thrombolysis Outcomes Study is a multicenter prospective cohort study of ischaemic stroke patients treated at participating Australian Stroke Centres with IVT and/or EVT. Patients undergo neuroimaging using multimodal CT or MRI at baseline with repeat neuroimaging 24 hours post-treatment. Baseline and follow-up blood samples are provided for research use. The primary outcome is good functional outcome at 90 days poststroke, defined as a modified Rankin Scale (mRS) Score of 0-2. Secondary outcomes are reperfusion, recanalisation, infarct core growth, change in stroke severity, poor functional outcome, excellent functional outcome and ordinal mRS at 90 days. Primary predictive models will be developed and validated in patients treated only with rt-PA. Models will be built using regression methods and include clinical variables, radiological measures from multimodal neuroimaging and blood-based biomarkers measured by mass spectrometry. Predictive accuracy will be quantified using c-statistics and R2. In secondary analyses, models will be developed in patients treated using EVT, with or without prior IVT, reflecting practice changes since original study design. ETHICS AND DISSEMINATION: Patients, or relatives when patients could not consent, provide written informed consent to participate. This study received approval from the Hunter New England Local Health District Human Research Ethics Committee (reference 14/10/15/4.02). Findings will be disseminated via peer-reviewed publications and conference presentations.

Plasmin Generation Potential and Recanalization in Acute Ischaemic Stroke; an Observational Cohort Study of Stroke Biobank Samples.

Rationale: More than half of patients who receive thrombolysis for acute ischaemic stroke fail to recanalize. Elucidating biological factors which predict recanalization could identify therapeutic targets for increasing thrombolysis success. Hypothesis: We hypothesize that individual patient plasmin potential, as measured by in vitro response to recombinant tissue-type plasminogen activator (rt-PA), is a biomarker of rt-PA response, and that patients with greater plasmin response are more likely to recanalize early. Methods: This study will use historical samples from the Barcelona Stroke Thrombolysis Biobank, comprised of 350 pre-thrombolysis plasma samples from ischaemic stroke patients who received serial transcranial-Doppler (TCD) measurements before and after thrombolysis. The plasmin potential of each patient will be measured using the level of plasmin-antiplasmin complex (PAP) generated after in-vitro addition of rt-PA. Levels of antiplasmin, plasminogen, t-PA activity, and PAI-1 activity will also be determined. Association between plasmin potential variables and time to recanalization [assessed on serial TCD using the thrombolysis in brain ischemia (TIBI) score] will be assessed using Cox proportional hazards models, adjusted for potential confounders. Outcomes: The primary outcome will be time to recanalization detected by TCD (defined as TIBI ≥4). Secondary outcomes will be recanalization within 6-h and recanalization and/or haemorrhagic transformation at 24-h. This analysis will utilize an expanded cohort including ~120 patients from the Targeting Optimal Thrombolysis Outcomes (TOTO) study. Discussion: If association between proteolytic response to rt-PA and recanalization is confirmed, future clinical treatment may customize thrombolytic therapy to maximize outcomes and minimize adverse effects for individual patients.

Modafinil treatment modulates functional connectivity in stroke survivors with severe fatigue.

Post-stroke fatigue has a significant impact on stroke survivors' mental and physical well-being. Our recent clinical trial showed significant reduction of post-stroke fatigue with modafinil treatment, however functional connectivity changes in response to modafinil have not yet been explored in stroke survivors with post-stroke fatigue. Twenty-eight participants (multidimensional fatigue inventory-20 ≥ 60) had MRI scans at baseline, and during modafinil and placebo treatment. Resting-state functional MRI data were obtained, and independent component analysis was used to extract functional networks. Resting-state functional connectivity (rsFC) was examined between baseline, modafinil and placebo treatment using permutation testing with threshold-free cluster enhancement. Overall twenty-eight participants (mean age: 62 ± 14.3, mean baseline MFI-20: 72.3 ± 9.24) were included. During modafinil treatment, increased rsFC was observed in the right hippocampus (p = 0.004, 11 voxels) compared to placebo. This coincided with lower rsFC in the left frontoparietal (inferior parietal lobule, p = 0.023, 13 voxels), somatosensory (primary somatosensory cortex; p = 0.009, 32 voxels) and mesolimbic network (temporal pole, p = 0.016, 35 voxels). In conclusion, modafinil treatment induces significant changes in rsFC in post-stroke fatigue. This modulation of rsFC may relate to a reduction of post-stroke fatigue; however, the relationship between sensory processing, neurotransmitter expression and fatigue requires further exploration.

Short- and Long-Term Efficacy of Modafinil at Improving Quality of Life in Stroke Survivors: A Post Hoc Sub Study of the Modafinil in Debilitating Fatigue After Stroke Trial.

BACKGROUND: The phase-II modafinil in debilitating fatigue after stroke trial demonstrated that modafinil improves fatigue and quality of life in severely fatigued stroke survivors. For this study, we sought to examine the interaction between fatigue and quality of life after stroke and determine whether reducing fatigue resulted in improved quality of life. In addition, we followed up a subset of patients 12-months after the trial to assess the long-term outcomes of modafinil therapy. METHODS: We used linear regression to analyze interaction between baseline fatigue, as measured by the multidimensional fatigue inventory (MFI), and quality of life, as measured by the stroke-specific quality of life scale (SSQoL); and between changes in MFI and SSQoL during treatment. Patients also took part in semi-structured interviews and study assessments 12-months after trial completion to assess long-term patterns of modafinil use, safety and efficacy. RESULTS: MFI and SSQoL were significantly correlated at baseline (ß = -1.975 95% CI -3.082, -0.869, p < 0.001), as were changes in MFI and SSQoL during treatment (ß = -1.054 95% CI -1.556, -0.553, p < 0.001). 18 patients agreed to 12-month follow-up, of whom 5 had continued to use modafinil. Patients taking modafinil daily demonstrated sustained improvement of 33-38 points in MFI compared to baseline. Two adverse events were reported and there was no evidence of drug tolerance. CONCLUSION: Modafinil appears to be safe and, for at least some patients, effective long-term in fatigued stroke survivors. Alleviating fatigue has a significant relationship with improved quality of life. CLINICAL TRIAL REGISTRATION: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368268, unique-identifier: ACTRN12615000350527.

Growth Hormone Deficiency Is Frequent After Recent Stroke.

Introduction: The incidence of pituitary dysfunction after severe ischemic stroke is unknown, however given the increasing attention to pituitary dysfunction after neurological injuries such as traumatic brain injury, this may represent a novel area of research in stroke. Methods: We perform an arginine and human growth hormone releasing hormone challenge on ischemic stroke patients within a week of symptom onset. Results: Over the study period, 13 patients were successfully tested within a week of stroke (baseline NIHSS 10, range 7-16). Overall, 9(69%) patients had a poor response, with 7(54%) of these patients meeting the criteria for had human growth hormone deficiency. Other measures of pituitary function were within normal ranges. Conclusion: After major ischemic stroke, low GH levels are common and may play a role in stroke recovery.