Intravenous thrombolysis may not improve clinical outcome of acute ischemic stroke patients without a baseline vessel occlusion

Background and Purpose: The benefit of thrombolysis in ischemic stroke patients without a visible vessel occlusion still requires investigation. This study tested the hypothesis that non-lacunar stroke patients with no visible vessel occlusion on baseline imaging would have a favorable outcome regardless of treatment with alteplase. Methods: We utilized a prospectively collected registry of ischemic stroke patients [the International Stroke Perfusion Imaging Registry (INSPIRE)] who had baseline computed tomographic perfusion and computed tomographic angiography. The rates of patients achieving modified Rankin Scale (mRS) 0-1 were compared between alteplase treated and untreated patients using logistic regression to generate odds ratios. Results: Of 1569 patients in the INSPIRE registry, 1,277 were eligible for inclusion. Of these, 306 (24%) had no identifiable occlusion and were eligible for alteplase, with 141 (46%) of these patients receiving thrombolysis. The treated and untreated groups had significantly different median baseline National Institutes of Health Stroke Scale (NIHSS) [alteplase 8, interquartile range (IQR) 5-10, untreated 6, IQR 4-8, P < 0.001] and median volume of baseline perfusion lesion [alteplase 5.6 mL, IQR 1.3-17.7 mL, untreated 2.6 mL, IQR 0-6.7 mL, P < 0.001]. After propensity analysis, alteplase treated patients without a vessel occlusion were less likely to have an excellent outcome (mRS 0-1; 56%) than untreated (78.8%, OR, 0.42, 95% confidence interval, 0.24-0.75, P = 0.003). Conclusions: In this non-randomized comparison, alteplase treatment in patients without an identifiable vessel occlusion did not result in higher rates of favorable outcome compared to untreated. However, treated patients displayed less favorable baseline prognostic factors than the untreated group. Further studies may be required to confirm this data.Huiqiao Tian, Mark W. Parsons, Christopher R. Levi, Xin Cheng, Richard I. Aviv, Neil J. Spratt, Timothy J. Kleinig, Billy O'Brien, Kenneth S. Butcher, Longting Lin, Jingfen Zhang, Qiang Dong, Chushuang Chen and Andrew Bivar

Back pain and leg weakness

Practical neurology-3Back pain is very common; it has a point prevalence of 25% and is the third most common reason for consultation in Australian general practice. A thorough history and examination can identify the minority of patients who require urgent neuroimaging or other targeted investigations. Careful correlation of clinical and radiological findings is required when abnormal neurological findings are detected. Radiological investigations may detect abnormalities at multiple levels but cannot confirm which level is primarily responsible for a patient's symptoms. A trial of conservative treatment is appropriate, even in cases of radiculopathy. Most patients with an acute episode of back pain recover within 6-12 weeks, but at least a third go on to have a recurrent episode within 1 year. Various invasive treatments, such as transforaminal steroid injection and discectomy, may speed up recovery from radiculopathy, but the long-term benefits of invasive treatment are uncertain.Timothy J Kleinig, Brian P Brophy, Chris G Mahe

Cerebral amyloid angiopathy causing cortical microinfarction

Abstract not availableW. Vallat, A. Maundrell, J. Leyden, T.J. Kleini

Stroke thrombolysis and the third international stroke trial: examining 'the totality of the evidence'

EditorialTimothy John Kleinig, Leonid Churilov, Cathrin Sibylle Parsch, Helen M Dewey and P Alan Barbe

Large Burden of Stroke Incidence in People with Cardiac Disease: A Linked Data Cohort Study.

Purpose: People with cardiac disease have 2–4 times greater risk of stroke than the general population. We measured stroke incidence in people with coronary heart disease (CHD), atrial fibrillation (AF) or valvular heart disease (VHD). Methods: We used a person-linked hospitalization/mortality dataset to identify all people hospitalized with CHD, AF or VHD (1985– 2017), and stratified them as pre-existing (hospitalized 1985–2012 and alive at October 31, 2012) or new (first-ever cardiac hospitalization in the five-year study period, 2012–2017). We identified first-ever strokes occurring from 2012 to 2017 in patients aged 20–94 years and calculated age-specific and age-standardized rates (ASR) for each cardiac cohort. Results: Of the 175,560 people in the cohort, most had CHD (69.9%); 16.3% had multiple cardiac conditions. From 2012–17, 5871 first-ever strokes occurred. ASRs were greater in females than males in single and multiple condition cardiac groups, largely driven by rates in females aged ≥75 years, with stroke incidence in this age group being at least 20% greater in females than males in each cardiac subgroup. In females aged 20–54 years, stroke incidence was 4.9-fold greater in those with multiple versus single cardiac conditions. This differential declined with increasing age. Non-fatal stroke incidence was greater than fatal stroke in all age groups except in the 85–94 age group. Incidence rate ratios were up to 2-fold larger in new versus pre-existing cardiac disease. Conclusion: Stroke incidence in people with cardiac disease is substantial, with older females, and younger patients with multiple cardiac conditions, at elevated risk. These patients should be specifically targeted for evidence-based management to minimize the burden of stroke.Keira Robinson, Judith M Katzenellenbogen, Timothy J Kleinig, Joosup Kim, Charley A Budgeon, Amanda G Thrift, Lee Nedkof

Cost-effectiveness of tenecteplase before thrombectomy for ischemic stroke

BACKGROUND AND PURPOSE: Tenecteplase improved functional outcomes and reduced the requirement for endovascular thrombectomy in ischemic stroke patients with large vessel occlusion in the EXTEND-IA TNK randomized trial. We assessed the cost-effectiveness of tenecteplase versus alteplase in this trial. METHODS: Post hoc within-trial economic analysis included costs of index emergency department and inpatient stroke hospitalization, rehabilitation/subacute care, and rehospitalization due to stroke within 90 days. Sources for cost included key study site complemented by published literature and government websites. Quality-adjusted life-years were estimated using utility scores derived from the modified Rankin Scale score at 90 days. Long-term modeled cost-effectiveness analysis used a Markov model with 7 health states corresponding to 7 modified Rankin Scale scores. Probabilistic sensitivity analyses were performed. RESULTS: Within the 202 patients in the randomized controlled trial, total cost was nonsignificantly lower in the tenecteplase-treated patients (40 997 Australian dollars [AUD]) compared with alteplase-treated patients (46 188 AUD) for the first 90 days(P=0.125). Tenecteplase was the dominant treatment strategy in the short term, with similar cost (5412 AUD [95% CI, -13 348 to 2523]; P=0.181) and higher benefits (0.099 quality-adjusted life-years [95% CI, 0.001-0.1967]; P=0.048), with a 97.4% probability of being cost-effective. In the long-term, tenecteplase was associated with less additional lifetime cost (96 357 versus 106 304 AUD) and greater benefits (quality-adjusted life-years, 7.77 versus 6.48), and had a 100% probability of being cost-effective. Both deterministic sensitivity analysis and probabilistic sensitivity analyses yielded similar results. CONCLUSIONS: Both within-trial and long-term economic analyses showed that tenecteplase was highly likely to be cost-effective for patients with acute stroke before thrombectomy. Recommending the use of tenecteplase over alteplase could lead to a cost saving to the healthcare system both in the short and long term. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388061.Lan Gao, Marj Moodie, Peter J. Mitchell, Leonid Churilov, Timothy J. Kleinig, Nawaf Yassi ... et al

Postpartum Period Is a Risk Factor for Cerebral Venous Thrombosis A Case-Control Study

Thrombosis and Hemostasi

Does tranexamic acid affect intraventricular hemorrhage growth in acute ICH? An analysis of the STOP-AUST trial

Background: Trials of tranexamic acid (TXA) in acute intracerebral hemorrhage (ICH) have focused on the imaging outcomes of intraparenchymal hematoma growth. However, intraventricular hemorrhage (IVH) growth is also strongly associated with outcome after ICH. Revised definitions of hematoma expansion incorporating IVH growth have been proposed. Aims: We sought to evaluate the effect of TXA on IVH growth. Methods: We analyzed data from the STOP-AUST trial, a prospective randomized trial comparing TXA to placebo in ICH patients presenting ≤ 4.5 h from symptom onset with a CT-angiography spot sign. New IVH development at follow-up, any interval IVH growth, and IVH growth ≥ 1 mL were compared between the treatment groups using logistic regression. The treatment effect of TXA against placebo using conventional (> 6 mL or 33%), and revised definitions of hematoma expansion (> 6 mL or 33% or IVH expansion ≥ 1 mL, > 6 mL or 33%, or any IVH expansion, and > 6 mL or 33% or new IVH development) were also assessed. Treatment effects were adjusted for baseline ICH volume. Results: The analysis population consisted of 99 patients (50 placebo, 49 TXA). New IVH development at follow-up was observed in 6/49 (12%) who received TXA and 13/50 (26%) who received placebo (aOR: 0.38 [95% CI: 0.13–1.13]). Any interval IVH growth was observed in 12/49 (25%) who received TXA versus 26/50 (32%) receiving placebo (aOR: 0.69 [95% CI: 0.28–1.66]). IVH growth ≥ 1 mL did not differ between the two groups. Using revised definitions of hematoma expansion, no significant difference in treatment effect was observed between TXA and placebo. Conclusions: IVH may be attenuated by TXA following ICH; however, studies with larger cohorts are required to investigate this further.Vignan Yogendrakumar, Teddy Y Wu, Leonid Churilov, Turgut Tatlisumak, Daniel Strbian , Jiann-Shing Jeng, Timothy J Kleinig, Gagan Sharma, Bruce CV Campbell, Henry Zhao, Chung Y Hsu, Atte Meretoja, Geoffrey A Donnan, Stephen M Davis, and Nawaf Yassi

Prevalence and Significance of Impaired Microvascular Tissue Reperfusion Despite Macrovascular Angiographic Reperfusion (No-Reflow)

Background and Objectives The relevance of impaired microvascular tissue-level reperfusion despite complete upstream macrovascular angiographic reperfusion (no-reflow) in human stroke remains controversial. We investigated the prevalence and clinical-radiologic features of this phenomenon and its associations with outcomes in 3 international randomized controlled thrombectomy trials with prespecified follow-up perfusion imaging. Methods In a pooled analysis of the Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial (EXTEND-IA; ClinicalTrials.gov NCT01492725), Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK; NCT02388061), and Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke (EXTEND-IA TNK Part 2; NCT03340493) trials, patients undergoing thrombectomy with final angiographic expanded Treatment in Cerebral Infarction score of 2c to 3 score for anterior circulation large vessel occlusion and 24-hour follow-up CT or MRI perfusion imaging were included. No-reflow was defined as regions of visually demonstrable persistent hypoperfusion on relative cerebral blood volume or flow maps within the infarct and verified quantitatively by >15% asymmetry compared to a mirror homolog in the absence of carotid stenosis or reocclusion. Results Regions of no-reflow were identified in 33 of 130 patients (25.3%), encompassed a median of 60.2% (interquartile range 47.8%–70.7%) of the infarct volume, and involved both subcortical (n = 26 of 33, 78.8%) and cortical (n = 10 of 33, 30.3%) regions. Patients with no-reflow had a median 25.2% (interquartile range 16.4%–32.2%, p < 0.00001) relative cerebral blood volume interside reduction and 19.1% (interquartile range 3.9%–28.3%, p = 0.00011) relative cerebral blood flow reduction but similar mean transit time (median −3.3%, interquartile range −11.9% to 24.4%, p = 0.24) within the infarcted region. Baseline characteristics were similar between patients with and those without no-reflow. The presence of no-reflow was associated with hemorrhagic transformation (adjusted odds ratio [aOR] 1.79, 95% confidence interval [CI] 2.32–15.57, p = 0.0002), greater infarct growth (β = 11.00, 95% CI 5.22–16.78, p = 0.00027), reduced NIH Stroke Scale score improvement at 24 hours (β = −4.06, 95% CI 6.78–1.34, p = 0.004) and being dependent or dead at 90 days as assessed by the modified Rankin Scale (aOR 3.72, 95% CI 1.35–10.20, p = 0.011) in multivariable analysis. Discussion Cerebral no-reflow in humans is common, can be detected by its characteristic perfusion imaging profile using readily available sequences in the clinical setting, and is associated with posttreatment complications and being dependent or dead. Further studies evaluating the role of no-reflow in secondary injury after angiographic reperfusion are warranted. Classification of Evidence This study provides Class II evidence that cerebral no-reflow on CT/MRI perfusion imaging at 24 hours is associated with posttreatment complications and poor 3-month functional outcome.Felix C. Ng, Leonid Churilov, Nawaf Yassi, Timothy John Kleinig, Vincent Thijs, Teddy Wu, Darshan Shah, Helen Dewey, Gagan Sharma, Patricia Desmond, Bernard Yan, Mark Parsons, Geoffrey Donnan, Stephen Davis, Peter Mitchell, Bruce Campbel

Association between pre-treatment perfusion profile and cerebral edema after reperfusion therapies in ischemic stroke

The relationship between reperfusion and edema is unclear, with experimental and clinical data yielding conflicting results. We investigated whether the extent of salvageable and irreversibly-injured tissue at baseline influenced the effect of therapeutic reperfusion on cerebral edema. In a pooled analysis of 415 patients with anterior circulation large vessel occlusion from the Tenecteplase-versus-Alteplase-before-Endovascular-Therapy-for-Ischemic-Stroke (EXTEND-IA TNK) part 1 and 2 trials, associations between core and mismatch volume on pre-treatment CT-Perfusion with cerebral edema at 24-hours, and their interactions with reperfusion were tested. Core volume was associated with increased edema (p < 0.001) with no significant interaction with reperfusion (p = 0.82). In comparison, a significant interaction between reperfusion and mismatch volume (p = 0.03) was observed: Mismatch volume was associated with increased edema in the absence of reperfusion (p = 0.009) but not with reperfusion (p = 0.27). When mismatch volume was dichotomized at the median (102 ml), reperfusion was associated with reduced edema in patients with large mismatch volume (p < 0.001) but not with smaller mismatch volume (p = 0.35). The effect of reperfusion on edema may be variable and dependent on the physiological state of the cerebral tissue. In patients with small to moderate ischemic core volume, the benefit of reperfusion in reducing edema is related to penumbral salvage.Felix C Ng, Leonid Churilov, Nawaf Yassi, Timothy J Kleinig, Vincent Thijs, Teddy Y Wu ... et al