Pierre Seners

Clinical Scales Do Not Reliably Identify Acute Ischemic Stroke Patients With Large-Artery Occlusion

Background and Purpose— It remains debated whether clinical scores can help identify acute ischemic stroke patients with large-artery occlusion and hence improve triage in the era of thrombectomy. We aimed to determine the accuracy of published clinical scores to predict large-artery occlusion. Methods— We assessed the performance of 13 clinical scores to predict large-artery occlusion in consecutive patients with acute ischemic stroke undergoing clinical examination and magnetic resonance or computed tomographic angiography ⩽6 hours of symptom onset. When no cutoff was published, we used the cutoff maximizing the sum of sensitivity and specificity in our cohort. We also determined, for each score, the cutoff associated with a false-negative rate ⩽10%. Results— Of 1004 patients (median National Institute of Health Stroke Scale score, 7; range, 0–40), 328 (32.7%) had an occlusion of the internal carotid artery, M1 segment of the middle cerebral artery, or basilar artery. The highest accuracy (79%; 95% confidence interval, 77–82) was observed for National Institute of Health Stroke Scale score ≥11 and Rapid Arterial Occlusion Evaluation Scale score ≥5. However, these cutoffs were associated with false-negative rates >25%. Cutoffs associated with an false-negative rate ⩽10% were 5, 1, and 0 for National Institute of Health Stroke Scale, Rapid Arterial Occlusion Evaluation Scale, and Cincinnati Prehospital Stroke Severity Scale, respectively. Conclusions— Using published cutoffs for triage would result in a loss of opportunity for ≥20% of patients with large-artery occlusion who would be inappropriately sent to a center lacking neurointerventional facilities. Conversely, using cutoffs reducing the false-negative rate to 10% would result in sending almost every patient to a comprehensive stroke center. Our findings, therefore, suggest that intracranial arterial imaging should be performed in all patients with acute ischemic stroke presenting within 6 hours of symptom onset.

Incidence, causes and predictors of neurological deterioration occurring within 24 h following acute ischaemic stroke: a systematic review with pathophysiological implications

Early neurological deterioration (END) following ischaemic stroke is a serious event with manageable causes in only a fraction of patients. The incidence, causes and predictors of END occurring within 24 h of acute ischaemic stroke (END24) have not been systematically reviewed. We systematically reviewed Medline and Embase from January 1990 to April 2013 for all studies on END24 following acute ischaemic stroke (<8 h from onset). We recorded the incidence and presumed causes of and factors associated with END24. Thirty-six studies were included. Depending on the definition used, the incidence of END24 markedly varied among studies. Using the most widely used change in National Institutes of Health Stroke Scale ≥4 definition, the pooled incidence was 13.8% following thrombolysis, ascribed to intracranial haemorrhage and malignant oedema each in ∼20% of these. As other mechanisms were rarely reported, in the majority no clear cause was identified. Few data on END24 occurring in non-thrombolysed patients were available. Across thrombolysed and non-thrombolysed samples, the strongest and most consistent admission predictors were hyperglycaemia, no prior aspirin use, prior transient ischaemic attacks, proximal arterial occlusion and presence of early CT changes, and the most consistent 24 h follow-up associated factors were no recanalisation/reocclusion, large infarcts and intracranial haemorrhage. Finally, END24 was strongly predictive of poor outcome. The above findings are discussed with emphasis on END without a clear mechanism. Data on incidence and predictors of the latter subtype is scarce, and future studies using systematic imaging protocols should address its underlying pathophysiology. This may in turn lead to rational preventative and therapeutic measures for this ominous event.

Incidence and Predictors of Early Recanalization After Intravenous Thrombolysis: A Systematic Review and Meta-Analysis

Background and Purpose— After the demonstration of efficacy of bridging therapy, reliably predicting early recanalization (ER; ⩽3 hours after start of intravenous thrombolysis) would be essential to limit futile, resource-consuming, interhospital transfers. We present the first systematic review on the incidence and predictors of ER after intravenous thrombolysis alone. Methods— We systematically searched for studies including patients solely treated by intravenous thrombolysis that reported incidence of ER and its association with baseline variables. Using meta-analyses, we estimated pooled incidence of ER, including according to occlusion site, and summarized the available evidence regarding predictors of no-ER. Results— We identified 26 studies that together included 2063 patients. The overall incidence of partial or complete ER was 33% (95% confidence interval, 27–40). It varied according to occlusion site: 52% (39–64) for distal middle cerebral artery, 35% (28–42) for proximal middle cerebral artery, 13% (6–22) for intracranial carotid artery, and 13% (0–35) for basilar occlusion. Corresponding rates for complete ER were 38% (22–54), 21% (15–29), 4% (1–8), and 4% (0–22), respectively. Proximal occlusion and higher National Institute of Health Stroke Scale were the most consistent no-ER predictors. Other factors, such as long or totally occlusive thrombus and poor collateral circulation, emerged as potential predictors but will need confirmation. Conclusion— The overall incidence of ER after intravenous thrombolysis is substantial, highlighting the importance of reliably predicting ER to limit futile, interhospital transfers. Incidence of no-ER is particularly high for proximal occlusion and severe strokes. Given the scarcity of published data, further studies are needed to improve no-ER prediction accuracy.

Unexplained Early Neurological Deterioration After Intravenous Thrombolysis: Incidence, Predictors, and Associated Factors

Background and Purpose— Early neurological deterioration (END) after anterior circulation stroke is a serious clinical event strongly associated with poor outcome. Regarding specifically END occurring within 24 hours of intravenous recombinant tissue-type plasminogen activator, apart from definite causes such as symptomatic intracranial hemorrhage and malignant edema whose incidence, predictors, and clinical management are well established, little is known about END without clear mechanism (ENDunexplained). Methods— We analyzed 309 consecutive patients thrombolysed intravenously ⩽4.5 hours from onset of anterior circulation stroke. ENDunexplained was defined as a ≥4-point deterioration on 24-hour National Institutes of Health Stroke Scale, without definite mechanism on concomitant imaging. ENDunexplained and no-END patients were compared for pretreatment clinical and imaging (including magnetic resonance diffusion and diffusion/perfusion mismatch volumes) data and 24-hour post-treatment clinical (including blood pressure and glycemic changes) and imaging (24-hour recanalization) data, using univariate logistic regression. Exploratory multivariate analysis was also performed after variable reduction, with bootstrap analysis for internal validation. Results— Among 33 END patients, 23 (7% of whole sample) had ENDunexplained. ENDunexplained was associated with poor 3-month outcome (P<0.01). In univariate analysis, admission predictors of ENDunexplained included no prior use of antiplatelets (P=0.02), lower National Institutes of Health Stroke Scale score (P<0.01), higher glycemia (P=0.03), larger mismatch volume (P=0.03), and proximal occlusion (P=0.01), with consistent results from the multivariate analysis. Among factors recorded during the first 24 hours, only no recanalization was associated with ENDunexplained in multivariate analysis (P=0.02). Conclusions— ENDunexplained affected 7% of patients and accounted for most cases of END. Several predictors and associated factors were identified, with important implications regarding underlying mechanisms and potential prevention of this ominous event.

Does Diffusion Lesion Volume Above 70 mL Preclude Favorable Outcome Despite Post-Thrombolysis Recanalization?

Background and Purpose— Whether to withhold recanalization treatment when the diffusion-weighted imaging (DWI) lesion exceeds a given volume is unsettled. Our aim was to assess the impact of recanalization on outcome in patients with baseline DWI lesion ≥70 mL (DWI≥70 mL) treated ⩽4.5 hours from onset. We hypothesized that recanalization is beneficial in a sizeable fraction of these patients and that this is associated with a larger DWI lesion reversal. Methods— We analyzed 267 consecutive patients treated with intravenous recombinant tissue-type plasminogen activator for middle cerebral artery territory stroke in whom an occlusion was present on magnetic resonance angiography and 24-hour recanalization and 90-day clinical outcome could be assessed. After stratification relative to the 70-mL DWI lesion cut point, we calculated the odds ratio for recanalization of the primary arterial occlusive lesion (AOL score ≥2) to predict favorable outcome (modified Rankin scale score ⩽2). DWI lesion reversal was compared between recanalizers with DWI≥70 mL with favorable and unfavorable outcomes. Results— Median (interquartile range) DWI lesion volume was 22 mL (10–60), and median onset time to imaging was 116 minutes (86–151). Twelve (22%) of the 54 patients with DWI≥70 mL experienced favorable outcome, of which 9 had recanalized. In patients with DWI≥70 mL, recanalization was significantly associated with favorable outcome after adjustment for age and National Institutes of Health Stroke Scale (odds ratio =4.72 [1.09–20.32]; P=0.0375). Among recanalizers with DWI≥70 mL, absolute and relative DWI reversal volumes were larger in those with favorable as compared with unfavorable outcome (18.8 mL [12.2–47.6] versus 8.5 mL [4.3–31.1]; P=0.17; and 19.6% [10.9–62.8] versus 8.7% [3.9–16.5], respectively; P=0.049). Conclusions— Patients with DWI lesion volume ≥70 mL can benefit from recanalization after intravenous recombinant tissue-type plasminogen activator. This may partly reflect a larger amount of DWI lesion reversal.

Is White Matter More Prone to Diffusion Lesion Reversal After Thrombolysis

Background and Purpose— In acute ischemic stroke, white matter (WM) is considered more resistant to infarction than gray matter (GM). To test this hypothesis, we compared the fate of WM and GM voxels belonging to the acute diffusion-weighted imaging (DWI) lesion, expecting WM voxels to be more prone to reversal after thrombolysis. Methods— Reversible acute DWI (RAD) lesion was defined voxel-wise as an acute lesion on initial DWI (DWI1) with no visible lesion on 24-hour DWI (DWI2). Only patients with RAD lesions >10 mL and >10% of DWI1 from our previously reported cohort were eligible. The core was defined as voxels hyperintense on DWI1 and DWI2. Semiautomated segmentation of DWI1, core, and RAD lesions, normalization into standard space, and WM/GM segmentation allowed calculations of WM/GM proportions in each region of interest using a voxel-counting algorithm. Results— Thirty patients were eligible (RAD lesion median volume [interquartile range], 23.3 mL [19.1–35.0 mL]; onset-to-treatment time, 134 minutes [105–185 minutes]). WM voxels fraction was greater in RAD lesions than in the core (59.4% [52.8%–68.9%] versus 49.6% [43.0%–57.5%]; P=0.011). The proportion of reversibility was greater for WM than for GM voxels (60.8% [25.5%–88.7%] versus 53.5% [21.1%–77.3%]; P=0.02). The percentage of RAD lesions increased with the proportion of WM present in the acute DWI lesion (P<0.0001; R=0.67). Conclusions— Acute DWI lesions predominantly involving WM may be more prone to reversal and, hence, to respond to therapy than their GM counterparts.

Comparison between voxel-based and subtraction methods for measuring diffusion-weighted imaging lesion growth after thrombolysis

Background Infarct growth (IG) is used as surrogate end-point in therapeutic trials. For practical reasons, infarct growth is commonly assessed using simple subtraction of acute from follow-up diffusion-weighted imaging (DWI) lesion volumes. However, the volume subtraction method will underestimate true infarct growth in case of diffusion-weighted imaging lesion reversal. Aim To measure the size of the difference between true infarct growth on voxel-based coregistration and infarct growth approximated with simple volume subtraction. Methods We retrospectively analyzed 322 consecutive stroke patients (median (IQR) age: 70 years (57–80), National Institute of Health Stroke Score at admission 14 (8–19)), who underwent a magnetic resonance imaging before (DWI1) and ≈24 h (DWI2) after IV-thrombolysis. IGvoxel-based was defined as the volume of signal changes on DWI2 that did not overlap with that on coregistered DWI1. This was compared with simply subtracting DWI1 from DWI2 lesion volume (IGsubtracted). We also compared these two metrics for the prediction of three-month unfavorable outcome (mRS ≥ 2) using c-statistics of multivariable models, adjusted for age, and National Institute of Health Stroke Score. Results Infarct growth volume metrics were strongly correlated (ρ = 0.94), but IGsubtracted substantially underestimated IGvoxel-based (median (IQR): 9.52 (0.23–38.9) vs. 16.98 (4.4–45.4) mL). Of the 75 patients with shrinking or stable diffusion-weighted imaging lesion using volume subtraction, IGvoxel-based was ≥5 mL in 20 (27% of the subset, 6.2% of the whole population). Moreover, IGvoxel-based better predicted unfavorable outcome than IGsubtracted (c-statistics = 0.86 (95% CI, 0.82–0.90) vs. 0.82 (0.78–0.87), P = 0.003). Conclusion At early post-thrombolysis time points, the simple subtraction of lesion volumes masked substantial diffusion-weighted imaging lesion growth in 6.2% of patients. Although more time-consuming, the voxel-based method may impact results of trials that use infarct growth attenuation as an end-point.

Letter by Turc et al Regarding Article, “Defining Clinically Relevant Cerebral Hemorrhage After Thrombolytic Therapy for Stroke: Analysis of the National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator Trials”

We read with interest the important article by Rao et al.1 Using publicly available data from the National Institute of Neurological Disorders and Stroke Tissue-Type Plasminogen Activator (NINDS-tPA) trials, the authors compared 4 definitions of intracranial hemorrhage (ICH) after thrombolysis to identify the most clinically relevant. They conclude that the European Cooperative Acute Stroke Study 2 (ECASS-2) and Modified Safe Implementation of Thrombolysis in Stroke-Monitoring Study (mSITS-MOST) definitions best identify tissue-type plasminogen activator hemorrhages that alter final outcome, but that their results favor the ECASS-2 definition, in line with previous reports. One important feature of the ECASS-2 definition is that it encompasses minor ICH, sometimes unlikely to cause neurological deterioration such as hemorrhagic infarction type 1 or 2. In relation to this, we are puzzled by the fate of the 6 patients (No. 22–27) who had a symptomatic ICH according to ECASS-2 and were all dead at 3 months, yet did not have parenchymal hemorrhage, raising the question whether these patients’ …

Mechanical Thrombectomy After Intravenous Thrombolysis vs Mechanical Thrombectomy Alone in Acute Stroke

Mechanical Thrombectomy After Intravenous Thrombolysis vs Mechanical Thrombectomy Alone in Acute Stroke To the Editor In their recent article, Coutinho et al1 address whether patients who have had an acute stroke with proximal occlusion should undergo intravenous thrombolysis (IVT) before a mechanical thrombectomy (MT). In this analysis of pooled data from the SWIFT and STAR trials, MT after IVT did not appear to provide clinical benefits over MT alone. The authors concluded that randomized clinical trials should confirm their observation.1 The main reason for withholding IVT would be that the occurrence of early recanalization (ER) after IVT is too low to justify the additional hemorrhagic risk, cost, and time lost. However, the SWIFT and STAR trials were not designed to compare these 2 paradigms, as in both trials persistent proximal occlusion on the first angiographic run was an inclusion criterion.2,3 To address this shortcoming, Coutinho et al1 argue that ER following IVT is rare in proximal occlusions. Based on the ESCAPE, SWIFT PRIME, REVASCAT, and MR CLEAN trial data, they quote post-IVT recanalization rates of 3% to 7% on the first angiographic run. However, this is an underestimation, because in these trials, patient selection was based on vascular imaging that was mostly conducted after the start of IVT. Thus, an unknown fraction of patients with post-IVT ER before selection imaging were excluded a priori. In our meta-analysis reviewing all 26 studies implementing vascular imaging before starting IVT —which therefore excluded the previously mentioned trials but included EXTEND-IA—4 complete ER within 3 hours of undergoing IVT was indeed very low (4%) in intracranial carotid occlusion, but substantial in M1 and M2 occlusions (21% and 38%, respectively).4 These figures were recently confirmed in a large prospective study, even when recanalization was evaluated 60 minutes after IVT.5 Early recanalization rates depend on the amount of time that has elapsed since IVT.5 Thus, ER rates are expected to be lower in the case of direct admissions to comprehensive stroke “drip and ship” paradigm, in which IVT-to-angiography times are often less than 60 minutes vs up to 3 hours, respectively. Consequently, the results of Coutinho et al1 may approximate the former, but they cannot be translated to the latter paradigm, which is the most frequent day-to-day situation currently and will likely remain so in most countries. We concur with Coutinho et al1 that randomized clinical trials comparing MT after IVT with MT alone are needed. However, given the substantial ER rates among unselected populations, such trials should only include patients with a very low probability of developing IVT-related ER.

Design and Methodology of a Pilot Randomized Controlled Trial of Transcranial Direct Current Stimulation in Acute Middle Cerebral Artery Stroke (STICA)

Background: Stroke is a major cause of death and disability worldwide. The related burden is expected to further increase due to aging populations, calling for more efficient treatment. Ischemic stroke results from a focal reduction in cerebral blood flow due to the sudden occlusion of a brain artery. Ischemic brain injury results from a sequence of pathophysiological events that evolve over time and space. This cascade includes excitotoxicity and peri-infarct depolarizations (PIDs). Focal impairment of cerebral blood flow restricts the delivery of energetics substrates and impairs ionic gradients. Membrane potential is eventually lost, and neurons depolarize. Although recanalization therapies target the ischemic penumbra, they can only rescue the penumbra still present at the time of reperfusion. A promising novel approach is to “freeze” the penumbra until reperfusion occurs. Transcranial direct current stimulation (tDCS) is a non-invasive method of neuromodulation. Based on preclinical evidence, we propose to test the penumbra freezing concept in a clinical phase IIa trial assessing whether cathodal tDCS—shown in rodents to reduce infarction volume—prevents early infarct growth in human acute Middle Cerebral Artery (MCA) stroke, in adjunction to conventional revascularization methods. Methods: This is a monocentric randomized, double-blind, and placebo-controlled trial performed in patients with acute MCA stroke eligible to revascularization procedures. Primary outcome is infarct volume growth on diffusion weighted imaging (DWI) at day 1 relative to baseline. Secondary outcomes include safety and clinical efficacy. Significance: Results from this clinical trial are expected to provide rationale for a phase III study. Clinical trial registration—EUDRACT: 2016-A00160-51