American Heart Association


Does tPA Really Save Lives?

Kevin S. Attenhofer, MD

Muruet W, Rudd A, Wolfe C, and Douiri A. Long-Term Survival After Intravenous Thrombolysis for Ischemic Stoke: A Propensity Score-Matched Cohort with up to 10-Year Follow-Up. Stroke. 2018

Although tissue plasminogen activator (tPA) has been approved in the United States for treatment of acute ischemic stroke since the mid-90s, there persists a sharp divide between neurologists and the emergency medicine community regarding the safety and efficacy of tPA. Imbalances between the treatment and control groups in the NINDS tPA study, criticisms of the subjective nature of functional outcome scores, and allegations of conflicts of interest have all contributed to the lingering controversy surrounding tPA. I have personally encountered significant resistance and hostility to IV tPA from other providers over 20 years after its approval. In this article, Muruet et al. add to a growing volume of literature that should help the community neurologist assuage the concerns of fellow providers.

By |April 18th, 2018|clinical, prognosis|Comments Off on Does tPA Really Save Lives?

Predicting Blood in the Real World

Kevin S. Attenhofer, MD

Hilkens NA, Li L, Rothwell PM, Algra A, Greving JP. External Validation of Risk Scores for Major Bleeding in a Population-Based Cohort of Transient Ischemic Attack and Ischemic Stroke Patients. Stroke. 2018

You can’t discuss stroke prevention without talking about antiplatelet drugs. Drugs like Aspirin and Clopidigrel are frequently used by stroke neurologists as the secondary prevention treatment of choice for patients with TIA and non-cardioembolic ischemic strokes. However, we must remember that bleeding is a clinically important and potentially life-threatening side effect of these agents. Reliably predicting who is most likely to bleed would dramatically inform the clinician’s decision-making process and likely result in improved patient outcomes.

To that end, the S2TOP-BLEED score was derived from patient data from six randomized trials (CAPRIE, ESPS-2, MATCH, CHARISMA, ESPRIT, and PRoFESS). It is a 28-point score that incorporates readily available patient characteristics: Sex, Smoking history, Type of antiplatelet, Outcome (mRS), Prior stroke, Blood pressure, Low BMI, Elderly, Ethnicity, Diabetes. It was validated in the PERFORM trial (Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack Study). In this paper, Hilkens et al. externally validate the S2TOP-BLEED score in observational data from a real-world setting.

By |March 30th, 2018|clinical, prognosis|Comments Off on Predicting Blood in the Real World

Stressing Over Sugar: Prognostic Implications of Stress Hyperglycemia After Stroke

Kevin S. Attenhofer, MD

Pan Y, Cai X, Jing J, Meng X, Li H, Wang Y, et al. Stress Hyperglycemia and Prognosis of Minor Ischemic Stroke and Transient Ischemic Attack: The CHANCE Study (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events). Stroke. 2017

Diabetes is becoming increasingly prevalent worldwide, with over 30 million people diagnosed in the United States as of 2015. It is no secret that diabetes is an independent risk factor for stroke. In fact, mortality is higher and post-stroke outcomes are poorer in patients with stroke and uncontrolled glucose levels.

In some patients, a phenomenon of stress hyperglycemia is observed at the time of stroke. This is a relative increase in glucose during an acute critical illness. It is an ill-defined metric with no consistent definition in the literature. Previous studies have shown that stress hyperglycemia is a better predictive biomarker of critical illness than absolute hyperglycemia. The authors of this paper sought to determine an association between stress hyperglycemia and incidence of new stroke or TIA following index ischemic stroke.

By |January 10th, 2018|clinical, prognosis|Comments Off on Stressing Over Sugar: Prognostic Implications of Stress Hyperglycemia After Stroke

Serum Gamma-Glutamyl Transferase at Time of Stroke is Associated With Post-Stroke Mortality and Recurrent, Fatal Stroke

Neal S. Parikh, MD 

Tu W, Liu Q, Cao J, Zhao S, Zeng X, Deng A. γ-Glutamyl Transferase as a Risk Factor for All-Cause or Cardiovascular Disease Mortality Among 5912 Ischemic Stroke. Stroke. 2017

In light of an increasing interest in and understanding of the association between liver disease and cerebrovascular disease, Wen-Jun Tu and colleagues sought to explore the association between serum γ-glutamyl transferase (GGT) and post-stroke mortality.

In their well-designed and well-powered prospective, multicenter cohort observational study, the authors enrolled 5,912 patients within 24 hours of acute ischemic stroke. The study was conducted in China. They excluded patients with known hepatobiliary disease and alcohol abuse. Serum GGT level at baseline was the exposure of interest, and patients were followed for a median of 1 year with regular telephone interviews and review of death certificates. The primary outcome was all-cause mortality, and cardiovascular death (including fatal stroke) was separately adjudicated. Men and women were analyzed differently because normative values for GGT are sex-specific.

By |October 25th, 2017|clinical, prognosis|Comments Off on Serum Gamma-Glutamyl Transferase at Time of Stroke is Associated With Post-Stroke Mortality and Recurrent, Fatal Stroke

Predicting Stroke Outcome with Multimodality CT

Kevin S. Attenhofer, MD

Dankbaar JW, Horsch AD, van den Hoven AF, Kappelle LJ, van der Schaaf IC, van Seeters T, et al. Prediction of Clinical Outcome After Acute Ischemic Stroke: The Value of Repeated Noncontrast Computed Tomography, Computed Tomographic Angiography, and Computed Tomographic Perfusion. Stroke. 2017

A significant aspect of stroke care is the long-term ramifications with respect to a patient’s ability to manage their activities of daily living. Part of the physician’s role is to help the patient navigate this challenge to maintain as much independence as possible. Understanding likely outcomes helps set the stage for realistic expectations and goals. Today, the most commonly used metric to score outcomes is the modified Rankin scale (mRS) performed well after the index event (often 90 days).

In stroke research, follow-up imaging markers such as computed tomographic angiography (CTA) recanalization and computed tomographic perfusion (CTP) reperfusion are sometimes used as proxy measurements for clinical outcomes. In this study, Dankbaar et al. used multimodality commuted tomography to predict mRS at 90 days.

By |September 11th, 2017|clinical, prognosis|Comments Off on Predicting Stroke Outcome with Multimodality CT

Stroke Risk Stratification in Non-Valvular Atrial Fibrillation — Validating CHA2DS2-VASc in an Asian Cohort

Gurmeen Kaur, MBBS

Kim T, Yang P, Uhm J, Kim J, Pak H, Lee M, et al. CHA2DS2-VASc Score (Congestive Heart Failure, Hypertension, Age ≥75 [Doubled], Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack [Doubled], Vascular Disease, Age 65–74, Female) for Stroke in Asian Patients With Atrial Fibrillation: A Korean Nationwide Sample Cohort Study. Stroke. 2017

Non-valvular atrial fibrillation (AF) is a cause of at least 15-20% of strokes in the U.S., with a 5-times increased risk when compared to patients with no atrial fibrillation. The safety, efficacy and availability of oral anticoagulants, in addition to Vitamin K antagonists like warfarin, have made strokes secondary to atrial fibrillation virtually preventable. This has created a need for accurate Stroke Risk Assessment and Stratification.

Various stroke risk schemas over the years have included AFI/ SPAF (1994), CHADS2 (2001), Framingham (2003), NICE (2006) and the relatively recent CHA2DS2-VASc Score, also referred to as Birmingham 2009, that accounts for congestive heart failure, hypertension, 75 years of age and older (2 points), diabetes mellitus, previous stroke or transient ischemic attack (2 points), vascular disease, 65 to 74 years of age, female sex.

Kim et al study a total of 5855 oral anticoagulant (OAC) naïve patients with AF to determine whether the CHA2DS2-VASc score could be reliably used for the Asian population, because the validation studies were performed in an all-Caucasian cohort and various Asian studies have previously reported ethnic differences in the conventional stroke risk factors.

By |August 14th, 2017|clinical, prognosis|Comments Off on Stroke Risk Stratification in Non-Valvular Atrial Fibrillation — Validating CHA2DS2-VASc in an Asian Cohort

As in adults, TIA heralds stroke in Children

Alexander E. Merkler, MD

Lehman LL, Watson CG, Kapur K, Danehy AR, and Rivkin MJ. Predictors of Stroke After Transient Ischemic Attack in Children. Stroke. 2015

Pediatric stroke is a leading cause of death and disability in children. In adults, stroke occurs in 10-15% of adults within 3 months of transient ischemic attack (TIA), but little is known about risk of stroke after TIA in children. In this manuscript, Dr. Lehman et al evaluate predictors of stroke after TIA in children.

63 children were identified as having a TIA at Boston Children’s Hospital. TIA was defined using the time-based definition: a focal neurological deficit that resolved within 24 hours. All patients were required to have an MRI within 3 months of TIA. Similar to adults, almost 80% of patients had motor symptoms. Headache accompanied TIA in 54% of children, but only 10% of patients carried a diagnosis of migraine.

After a median follow-up of 4.5 years, 10/63 children (16%) developed MRI evidence of stroke, 4 (6%) of whom had imaging evidence of stroke at the time of TIA, and 8 (13%) of whom developed new imaging evidence of ischemic injury not seen on the MRI done at the time of TIA.

Independent predictors for stroke after TIA included female sex (OR 11.3, 95% CI, 1.3-98.7), cerebral arteriopathy (OR 24.5, 95% CI, 4.0-149.8), and presence of autoimmune disorders (OR 26.5, 95% CI, 3.6-191.6).

Limitations included 1) small number of patients and therefore wide confidence intervals; 2) retrospective design; 3) use of a time-based definition of TIA thereby likely included cerebrovascular mimics such as migraine.

Overall, similar to adults, children with TIA seem to have a significant risk of developing a stroke. Risk factors for stroke after TIA include female sex, cerebral arteriopathy, and presence of an autoimmune disorder. Further research will be necessary to confirm these findings and help prevent the development of stroke in the pediatric population.

By |December 23rd, 2015|prognosis|Comments Off on As in adults, TIA heralds stroke in Children

Copeptin: a promising marker in risk stratification after ischemic stroke and TIA

Luciana Catanese, MD

Griesenegger S, Segal HC, Burgess AI, Poole DL, Mehta Z, Rothwell PM. Copeptin and Long-Term Risk of Recurrent Vascular Events after TIA and Ischemic Stroke: Population-Based Study. Stroke. 2015.

Copeptin is a stress hormone released in an equal proportion to vasopressin (AVP), and serves a surrogate marker for the hypothalamo-pituitary-adrenal axis. Prior literature has suggested that Copeptin is a promising prognostic biomarker in vascular diseases such as MI, CHF and ischemic stroke/TIA. However, the prognostic value of Copeptin in regard to long-term risk of vascular events after TIA and stroke remains uncertain.

In this issue of Stroke, Griesenegger et al. present a longitudinal population-based study with a mean follow–up of 5.7 years, to determine whether Copeptin levels could predict the long-term risk of vascular events in patients with TIA or ischemic stroke. The authors also contrasted Copeptin level amongst different etiological subtypes of stroke/TIA.

Of 92,728 individuals in the Oxford Vascular Study, 1076 eligible patients (mean age 75) with TIA, minor and major ischemic stroke recruited from 2002-2007, were included. Copeptin level was obtained at baseline (median time to sampling 5 days) and repeated in 384 patients after one year.

After about 6000 patient-years of follow-up, the cox regression analysis including age, sex, hypertension, diabetes, previous MI, stroke, peripheral vascular disease, smoking, CHF, atrial fibrillation, and treatment with antiplatelets, statins or antihypertensive agents, showed that Copeptin significantly predicted subsequent vascular events (HR 1.47), recurrent ischemic stroke (HR 1.22), vascular death (HR 1.85) and all cause death (HR 1.75). The predictive value of Copeptin was greatest following a cardioembolic cerebrovascular event. Moreover, Copeptin outperformed other circulating biomarkers of thrombosis, inflammation and neuronal/myocardial injury within this population.

Inclusion of Copeptin into a model containing the aforementioned vascular risk factors improved the model’s predictive ability for recurrent vascular events, vascular death, death and recurrent stroke by 32%, 55%, 66% and 16%, respectively.

Overall, Copeptin seems to be a promising biomarker in risk stratification after ischemic stroke and TIA, particularly in patients with cardiogenic strokes/TIA. One of the main limitations of the study is the lack of adjustment for other possible confounding factors, such as indices of cardiac function. Therefore, further validation of these findings with the inclusion of cardiac markers is warranted.

By |November 10th, 2015|prognosis|Comments Off on Copeptin: a promising marker in risk stratification after ischemic stroke and TIA

Poor collateral status independently predicts developing malignant anterior circulation infarction

Jay Shah, MD

Flores A, Rubiera M, Ribó M, Pagola J, Rodriguez-Luna D, Muchada M, et al. Poor Collateral Circulation Assessed by Multiphase Computed Tomographic Angiography Predicts Malignant Middle Cerebral Artery Evolution After Reperfusion Therapies. Stroke. 2015 

A potential fatal complication of ischemic stroke is malignant middle cereberal artery infarction (mMCAi) often requiring decompressive craniectomy. Therefore, early detection is paramount and several predictors have been evaluated. One such factor is leptomeningeal or pial collateral circulation (CC) status which has been associated with outcomes and infarct volume. Traditional single-phase CT angiogram (CTA) may lack temporal resolution to accurately detect collateral status but multi-phase CTA may improve CC evaluation. The relationship between CC and development of mMCAi is unknown and the authors predict that poor CC status may be an early predictor of malignant edema. 

The study was a prospective study that enrolled consecutive ischemic stroke patients who presented less than 4.5 hours from onset with proximal anterior circulation occlusion. Collaterals were measured with a multi-phase CTA and scored on a 5 point scale with scores 0-3 given “poor” designation while 4 and 5 were stratified as “good”. The primary outcome was presence of mMCAi. In total, 81 patients were enrolled. 15 developed mMCAi with 5 requiring surgery. mMCAi patients presented more often with ICA occlusion and expectedly, had significantly higher infarct volume. 38 patients were identified as poor CC and there was significant association with mMCAi evolution. In the multivariate analysis, poor CC status was the only independent predictor of mMCAi.

This study shows that poor collateral status is an independent predictor of developing malignant infarction, especially in patients who did not achieve recanalization. Multi-phase CTA can identify patients who may be at higher risk of developing malignant edema, potentially requiring decompressive surgery. Early surgery can potentially improve prognosis and outcome. A potential limitation to this study was the low number of patients, especially in the mMCAi group (n=15). Furthermore, obtaining multi-phase CTA and timely radiological interpretation may not be readily available which could limit its utilization. Any delay could preclude its use altogether as infarct volume can be calculated from follow-up imaging which also correlates with developing mMCAi.

By |October 30th, 2015|prognosis|Comments Off on Poor collateral status independently predicts developing malignant anterior circulation infarction

Associations between metabolic risk factors and incidental MRI markers of small vessel disease: Results from the Atherosclerosis Risk in Communities Study

Danny R. Rose, Jr., MD

Increasing evidence indicates that small vessel-type intracranial disease is not a homogeneous entity. Pathologic studies demonstrate that the radiographic manifestations of small vessel disease such as white matter hyperintensities (WMHs) and lacunar infarctions have distinct histopathological appearances. Even for lacunar infarctions, the work of CM Fisher and others dating back several decades suggest a different pathogenesis for larger lacunes (i.e., microatheroma formation) versus smaller lacunes (i.e., lipohyalinosis). Given this, it is reasonable to hypothesize that the risk factors for these different processes also differ. Dearborn et al. sought to investigate these potential associations using the Atherosclerosis Risk in Communities (ARIC) study cohort, specifically evaluating radiographic progression of small vessel disease reflected by MRI over 10-years.

The ARIC study was designed to investigate the causes of atherosclerosis and its outcomes and includes a prospective cohort that began recruitment in 1987. The analytic population for the current analysis consisted of 934 participants without a prior history of stroke who had two brain MRI scans approximately 10-years apart that were analyzed for the presence and size of incident lacunar infarctions as well as the presence and extent of white matter hyperintensities using both a visual scale and volumetric measurements. Risk factor assessment included components of metabolic syndrome (i.e., abdominal girth, HDL, blood pressure, triglycerides, fasting glucose) as well as an ad-hoc Insulin Resistance score, which was intended to examine the clustering of metabolic risk factors. The IR score included seven variables selected to exclude highly correlated factors and included log-transformed values for insulin and homeostatic model analysis for insulin resistance (HOMA-IR), BMI, waist-to-hip ratio and waist circumference.

Elevated triglycerides and decreased HDL were associated with an increase incident of all lacunar infarction, but not WMHs. Systolic blood pressure was associated with WMH and incident lacunes in unadjusted models, but did not reach statistical significance for lacunes in adjusted models. No significant difference was observed comparing the progression of WMH in patients with and without metabolic syndrome, but patients with metabolic syndrome did have more incident lacunes, with the increase being predominantly due to an increase in the number of larger lacunes.

Higher insulin levels, HOMA-IR and BMI were not associated with either measure. Increasing HOMA-IR and BMI were associated with incident large lacunes, but only in unadjusted models. Abdominal obesity as measured by waist circumference and waist-to-hip ratio was associated with incident lacunes, with a larger effect size for larger lacunes. The IR score was associated with increased odds of incident lacunes, with increased effect size for larger lacunes.

The results of this cohort study reinforce previously held assumptions, provide suggestions of novel associations, and question some previously reported associations. Given the different histopathologic appearance of WMH, small lacunes and large lacunes, the different associations found in the study are not surprising. The association of WMHs with hypertension and not with other metabolic factors mirrors the pathophysiology of leukoaraiosis. The role of atherosclerosis in the presumed pathogenesis of larger lacunes seems to be supported by its association with dyslipidemia. The IR score may represent a useful measure of the metabolic sequelae of insulin resistance aside from the effects of hyperglycemia. 

The study does have limitations. It is based on an observational cohort, which limits statistical adjustment for potential cofounders. The categorization of lacune sizes established in prior ARIC studies is somewhat arbitrary, but reflects the pathologic spectrum of lacunar disease for separating what are probably distinct pathophysiologic mechanisms for Fisher’s two “types” of lacunar infarcts. Prospective studies focusing on interventions for these presumed causative factors would further support these associations and potentially provide novel therapeutic targets.

By |October 28th, 2015|prognosis|Comments Off on Associations between metabolic risk factors and incidental MRI markers of small vessel disease: Results from the Atherosclerosis Risk in Communities Study