Jason J. Chang

Safety of Intravenous Thrombolysis in Stroke Mimics: Prospective 5-Year Study and Comprehensive Meta-Analysis

Background and Purpose— Shortening door-to-needle time may lead to inadvertent intravenous thrombolysis (IVT) administration in stroke mimics (SMs). We sought to determine the safety of IVT in SMs using prospective, single-center data and by conducting a comprehensive meta-analysis of reported case-series. Methods— We prospectively analyzed consecutive IVT-treated patients during a 5-year period at a tertiary care stroke center. A systematic review and meta-analysis of case-series reporting safety of IVT in SMs and confirmed acute ischemic stroke were conducted. Symptomatic intracerebral hemorrhage was defined as imaging evidence of ICH with an National Institutes of Health Stroke scale increase of ≥4 points. Favorable functional outcome at hospital discharge was defined as a modified Rankin Scale score of 0 to 1. Results— Of 516 consecutive IVT patients at our tertiary care center (50% men; mean age, 60±14 years; median National Institutes of Health Stroke scale, 11; range, 3–22), SMs comprised 75 cases. Symptomatic intracerebral hemorrhage occurred in 1 patient, whereas we documented no cases of orolingual edema or major extracranial hemorrhagic complications. In meta-analysis of 9 studies (8942 IVT-treated patients), the pooled rates of symptomatic intracerebral hemorrhage and orolingual edema among 392 patients with SM treated with IVT were 0.5% (95% confidence interval, 0%–2%) and 0.3% (95% confidence interval, 0%–2%), respectively. Patients with SM were found to have a significantly lower risk for symptomatic intracerebral hemorrhage compared with patients with acute ischemic stroke (risk ratio=0.33; 95% confidence interval, 0.14–0.77; P=0.010), with no evidence of heterogeneity or publication bias. Favorable functional outcome was almost 3-fold higher in patients with SM in comparison with patients with acute ischemic stroke (risk ratio=2.78; 95% confidence interval, 2.07–3.73; P<0.00001). Conclusions— Our prospective, single-center experience coupled with the findings of the comprehensive meta-analysis underscores the safety of IVT in SM.

Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury

Intracerebral hemorrhage (ICH) is associated with a higher degree of morbidity and mortality than other stroke subtypes. Despite this burden, currently approved treatments have demonstrated limited efficacy. To date, therapeutic strategies have principally targeted hematoma expansion and resultant mass effect. However, secondary mechanisms of brain injury are believed to be critical effectors of cell death and neurological outcome following ICH. This article reviews the pathophysiology of secondary brain injury relevant to ICH, examines pertinent experimental models, and highlights emerging therapeutic strategies. Treatment paradigms discussed include thrombin inhibitors, deferoxamine, minocycline, statins, granulocyte-colony stimulating factors, and therapeutic hypothermia. Despite promising experimental and preliminary human data, further studies are warranted prior to effective clinical translation.

Blood pressure levels post mechanical thrombectomy and outcomes in large vessel occlusion strokes

Objective: There are limited data evaluating the effect of post mechanical thrombectomy (MT) blood pressure (BP) levels on early outcomes of patients with large vessel occlusions (LVO). We sought to investigate the association of BP course following MT with early outcomes in LVO. Methods: Consecutive patients with LVO treated with MT during a 3-year period were evaluated. Hourly systolic BP (SBP) and diastolic BP (DBP) values were recorded for 24 hours following MT and maximum SBP and DBP levels were identified. LVO patients with complete reperfusion following MT were stratified in 3 groups based on post-MT achieved BP goals: <140/90 mm Hg (intensive), <160/90 mm Hg (moderate), and <220/110 mm Hg or <180/105 mm Hg when pretreated with IV thrombolysis (permissive hypertension). Three-month functional independence was defined as modified Rankin Scale score of 0–2. Results: A total of 217 acute ischemic stroke patients with LVO were prospectively evaluated. A 10 mm Hg increment in maximum SBP documented during the first 24 hours post MT was independently (p = 0.001) associated with a lower likelihood of 3-month functional independence (odds ratio [OR] 0.70; 95% confidence interval [CI] 0.56–0.87) and a higher odds of 3-month mortality (OR 1.49; 95% CI 1.18–1.88) after adjusting for potential confounders. In addition, achieving a BP goal of <160/90 mm Hg during the first 24 hours following MT was independently associated with a lower likelihood of 3-month mortality (OR 0.08; 95% CI 0.01–0.54; p = 0.010) in comparison to permissive hypertension. Conclusions: High maximum SBP levels following MT are independently associated with increased likelihood of 3-month mortality and functional dependence in LVO patients. Moderate BP control is also related to lower odds of 3-month mortality in comparison to permissive hypertension.

Magnesium: potential roles in neurovascular disease.

Objective: Magnesium therapy has been studied extensively in pre-clinical and clinical trials in multiple organ systems. Cerebrovascular diseases may benefit from its neuroprotective properties. This review summarizes current studies of magnesium in a wide range of neurovascular diseases. Methods: We searched relevant terms in the National Library of Medicine PubMed database and selected research including basic science, translational reports, meta-analyses, and clinical studies. Results: Studies examining magnesium administration in ischemic stroke have failed to show any benefit in clinical outcome. Data on magnesium for intracerebral hemorrhage (ICH) are limited. Preliminary investigations in subarachnoid hemorrhage (SAH) were promising, but definitive studies did not reveal differences in clinical outcome between magnesium and placebo-treated groups. Studies examining magnesium administration in global ischemia following cardiac arrest suggest a trend toward improved clinical outcome. The strongest evidence for clinically relevant neuroprotection following magnesium administration derives from studies of pre-term infants and patients undergoing cardiac bypass and carotid endarterectomy procedures. Magnesium was found to have an excellent safety profile across all investigations. Conclusion: Magnesium is easy to administer and possesses a favorable safety profile. Its utility as a neuroprotectant in cardiac surgery, carotid endarterectomy, and pre-term infant hypoxia remain promising. Value as a therapeutic agent in ischemic stroke, ICH, and SAH is unclear and appears to be limited by late administration. Ongoing clinical trials assessing magnesium administration in the first hours following symptom onset may help clarify the role of magnesium therapy in these disease processes.

Factors Affecting Clinical Outcome in Large-Vessel Occlusive Ischemic Strokes

Clinical outcome after large-vessel occlusive strokes depends on admitting clinical condition, successful recanalization, and robust collateral circulation. However, predicting successful recanalization and quantifying collateral status in the acute setting remain elusive. Successful recanalization has many predictive factors. Strong evidence supports increasing clot length being associated with poor recanalization. Current imaging techniques completed in the acute setting suggest that clot length can be estimated with a clot burden score. In vitro evidence suggests that clots with more red blood cells and less thrombin lyse more easily after systemic fibrinolysis. Clinical correlations with clot composition have been mixed, although one study suggested that clot composition could be predicted with computed tomography and correlate with successful recanalization. Finally, overwhelming proof shows that robust collateral circulation correlates with improved clinical outcome. Imaging modalities in the acute setting remain promising, with studies suggesting that collaterals can be quantified with computed tomography angiography and perfusion studies. Patients with large-vessel occlusive strokes have variable clinical responses to fibrinolysis and thrombectomy. Independent predictive variables that can possibly alter clinical outcome appear to be successful recanalization and robust collateral circulation. Future studies that allow for better prediction of successful recanalization and quantification of collateral status may help clinical decision-making when evaluating large-vessel occlusions.

Direct oral anticoagulant– vs vitamin K antagonist–related nontraumatic intracerebral hemorrhage

Objective: To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF). Methods: We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta-analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH. Results: We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 ± 9.8 years, 57.8% men, median admission NIH Stroke Scale [NIHSSadm] score 13 points, interquartile range 6–21). DOAC-related (n = 47) and VKA-related (n = 114) ICH did not differ in demographics, vascular risk factors, HAS-BLED and CHA2DS2-VASc scores, and antiplatelet pretreatment except for a higher prevalence of chronic kidney disease in VKA-related ICH. Patients with DOAC-related ICH had lower median NIHSSadm scores (8 [3–14] vs 15 [7–25] points, p = 0.003), median baseline hematoma volume (12.8 [4–40] vs 24.3 [11–58.8] cm3, p = 0.007), and median ICH score (1 [0–2] vs 2 [1–3] points, p = 0.049). Severe ICH (>2 points) was less prevalent in DOAC-related ICH (17.0% vs 36.8%, p = 0.013). In multivariable analyses, DOAC-related ICH was independently associated with lower baseline hematoma volume (p = 0.006), lower NIHSSadm scores (p = 0.022), and lower likelihood of severe ICH (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.13–0.87, p = 0.025). In meta-analysis of eligible studies, DOAC-related ICH was associated with lower baseline hematoma volumes on admission CT (standardized mean difference = −0.57, 95% CI −1.02 to −0.12, p = 0.010) and lower in-hospital mortality rates (OR = 0.44, 95% CI 0.21–0.91, p = 0.030). Conclusions: DOAC-related ICH is associated with smaller baseline hematoma volume and lesser neurologic deficit at hospital admission compared to VKA-related ICH.

Admission systolic blood pressure and outcomes in large vessel occlusion strokes treated with endovascular treatment

Background and purpose High admission blood pressure (BP) levels have been associated with lower recanalization rates after endovascular treatment (EVT) for patients with acute ischemic stroke (AIS) with emergent large vessel occlusion (ELVO). We sought to evaluate the association of admission BP with early outcomes in patients with ELVO treated with EVT. Methods Consecutive patients with AIS presenting with ELVO in a tertiary stroke center during a 4-year period were prospectively evaluated. Admission systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using automated cuff recordings. A blinded neuroradiologist calculated the final infarct volume (FIV) using standardized ABC/2 methodology. A favorable functional outcome (FFO) at 3 months was defined as modified Rankin Scale score of 0–2. Results Our study population consisted of 116 patients with AIS (mean age 63±13 years, median NIH Stroke Scale score 17 points (IQR 14–21), median FIV 30 cm3 (IQR 8–94)). Higher admission SBP correlated with higher FIV (r +0.225; p=0.020). Patients with FFO had lower admission SBP (151±24 mm Hg vs 165±28 mm Hg; p=0.010), while admission SBP levels were higher in patients who died during hospitalization (169±34 mm Hg vs 156±24 mm Hg; p=0.043). A 10 mm Hg increment in admission SBP was independently (p=0.010) associated with an increase of 12 cm3 in FIV (95% CI 3 to 21) in multiple linear regression models adjusting for potential confounders. A 10 mm Hg increment in admission SBP was independently (p=0.012) associated with a lower likelihood of FFO at 3 months (OR 0.64; 95% CI 0.45 to 0.91) in multiple logistic regression models adjusting for potential confounders. Conclusions Higher admission SBP is an independent predictor of increased FIV and lower likelihood of 3-month FFO in patients with ELVO treated with EVT.

FABS: An Intuitive Tool for Screening of Stroke Mimics in the Emergency Department

Background and Purpose— A large number of patients with symptoms of acute cerebral ischemia are stroke mimics (SMs). In this study, we sought to develop a scoring system (FABS) for screening and stratifying SM from acute cerebral ischemia and to identify patients who may require magnetic resonance imaging to confirm or refute a diagnosis of stroke in the emergency setting. Methods— We designed a scoring system: FABS (6 variables with 1 point for each variable present): absence of Facial droop, negative history of Atrial fibrillation, Age <50 years, systolic Blood pressure <150 mm Hg at presentation, history of Seizures, and isolated Sensory symptoms without weakness at presentation. We evaluated consecutive patients with symptoms of acute cerebral ischemia and a negative head computed tomography for any acute finding within 4.5 hours after symptom onset in 2 tertiary care stroke centers for validation of FABS. Results— A total of 784 patients (41% SMs) were evaluated. Receiver operating characteristic curve (C statistic, 0.95; 95% confidence interval [CI], 0.93–0.98) indicated that FABS≥3 could identify patients with SM with 90% sensitivity (95% CI, 86%–93%) and 91% specificity (95% CI, 88%–93%). The negative predictive value and positive predictive value were 93% (95% CI, 90%–95%) and 87% (95% CI, 83%–91%), respectively. Conclusions— FABS seems to be reliable in stratifying SM from acute cerebral ischemia cases among patients in whom the head computed tomography was negative for any acute findings. It can help clinicians consider advanced imaging for further diagnosis.

Diagnostic Accuracy of Transcranial Doppler for Brain Death Confirmation: Systematic Review and Meta-Analysis

BACKGROUND AND PURPOSE: Transcranial Doppler is a useful ancillary test for brain death confirmation because it is safe, noninvasive, and done at the bedside. Transcranial Doppler confirms brain death by evaluating cerebral circulatory arrest. Case series studies have generally reported good correlations between transcranial Doppler confirmation of cerebral circulatory arrest and clinical confirmation of brain death. The purpose of this study is to evaluate the utility of transcranial Doppler as an ancillary test in brain death confirmation. MATERIALS AND METHODS: We conducted a systematic review of the literature and a diagnostic test accuracy meta-analysis to compare the sensitivity and specificity of transcranial Doppler confirmation of cerebral circulatory arrest, by using clinical confirmation of brain death as the criterion standard. RESULTS: We identified 22 eligible studies (1671 patients total), dating from 1987 to 2014. Pooled sensitivity and specificity estimates from 12 study protocols that reported data for the calculation of both values were 0.90 (95% CI, 0.87–0.92) and 0.98 (95% CI, 0.96–0.99), respectively. Between-study differences in the diagnostic performance of transcranial Doppler were found for both sensitivity (I2 = 76%; P < .001) and specificity (I2 = 74.3%; P < .001). The threshold effect was not significant (Spearman r = −0.173; P = .612). The area under the curve with the corresponding standard error (SE) was 0.964 ± 0.018, while index Q test ± SE was estimated at 0.910 ± 0.028. CONCLUSIONS: The results of this meta-analysis suggest that transcranial Doppler is a highly accurate ancillary test for brain death confirmation. However, transcranial Doppler evaluates cerebral circulatory arrest rather than brain stem function, and this limitation needs to be taken into account when interpreting the results of this meta-analysis.

The Role of Matrix Metalloproteinase Polymorphisms in Ischemic Stroke

Stroke remains the fifth leading cause of mortality in the United States with an annual rate of over 128,000 deaths per year. Differences in incidence, pathogenesis, and clinical outcome have long been noted when comparing ischemic stroke among different ethnicities. The observation that racial disparities exist in clinical outcomes after stroke has resulted in genetic studies focusing on specific polymorphisms. Some studies have focused on matrix metalloproteinases (MMPs). MMPs are a ubiquitous group of proteins with extensive roles that include extracellular matrix remodeling and blood-brain barrier disruption. MMPs play an important role in ischemic stroke pathophysiology and clinical outcome. This review will evaluate the evidence for associations between polymorphisms in MMP-1, 2, 3, 9, and 12 with ischemic stroke incidence, pathophysiology, and clinical outcome. The role of polymorphisms in MMP genes may influence the presentation of ischemic stroke and be influenced by racial and ethnic background. However, contradictory evidence for the role of MMP polymorphisms does exist in the literature, and further studies will be necessary to consolidate our understanding of these multi-faceted proteins.