American Heart Association

Monthly Archives: April 2015

Hints of the Heart: Predictors of Finding Occult Atrial Fibrillation after Stroke

Vikas Pandey, MD

Favilla C, Ingala E, Jara J, Fessler E, Cucchiara B, Messe S, et al. Predictors of Finding Occult Atrial Fibrillation after Cryptogenic Stroke. Stroke. 2015

Imagine you are a detective at the scene of a crime and discover bullet holes in the wall of the crime scene. While every indication in such a scenario would point toward a gun being fired, the situation is not definitive until the culprit weapon used is found. The weapon may not be found at the scene of the crime or with a 24 or 48 hour search, but all common sense would tell us that a gun was used. Similarly, stroke neurologists are dealt with a similar predicament when they see a stroke on imaging that appears embolic in etiology, but treatment is usually not sought until the atrial fibrillation is found, even if other risk factors such as advanced age are present. While short term cardiac monitoring such as cardiac telemetry during the hospital admission and 24-48 hour Holter monitoring may not implicate cardiac arrhythmia as the etiology, the evidence is becoming stronger that long-term cardiac monitoring will eventually be able to find the anomaly in question. 



The group out of the University of Pennsylvania devised a trial retrospectively analyzing consecutive patients who underwent 28-day outpatient cardiac telemetry after a cryptogenic stroke or TIA to see if there were certain predictors that could be separated to be able to predict if atrial fibrillation would be found. Their study had a total of 227 patients with stroke or TIA of which 14% (95% CI 9-18%) eventually had paroxysmal atrial fibrillation discovered. 58% of these episodes were greater than or equal to 30 seconds in duration (The ACC/AHA threshold for defining paroxysmal atrial fibrillation). They found that age > 60 years, and prior cortical or cerebellar infarction seen on neuroimaging were independently significant predictors of atrial fibrillation and 33% of the patients with both of these risk factors eventually were found to have atrial fibrillation. Interestingly, they found that none of the “CHADS-VASc” factors or echocardiographic findings, including left atrial size, commonly thought of as a predictor of atrial fibrillation, were not significant predictors in the study. 


The study confirms the more recent data that extending the length of time of outpatient cardiac telemetry has been yielding more diagnoses of atrial fibrillation and changing the treatment plan of many patients that have previously been labeled “cryptogenic”. The group’s study fortifies the evidence that long-term outpatient cardiac telemetry is not only cost-effective, but also effective in finding a treatable risk factor for stroke, thus should be a considered as a potent weapon for stroke prevention.

@DrVikasNeuro

Premature Ventricular Complexes on Routine ECG and Ischemic Stroke Risk

Abdel Salam R. Kaleel M.D, MSc

Agarwal SK, Chao J, Peace F, Judd SE, Kissela B, Kleindorfer D, et al. Premature Ventricular Complexes on Screening Electrocardiogram and Risk of Ischemic Stroke. Stroke. 2015

Previously, the Atherosclerosis Risk in Communities (ARIC) study found an association of higher ischemic stroke in patients with PVCs on a 2 minute ECG rhythm strip. This study sought to determine if Premature Ventricular Contractions (PVC) seen on routine ECG were also associated with an increased risk of ischemic stroke. This analysis included 24,460 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Exclusions were made for patients with prevalent stroke or transient ischemic stroke, poor quality ECG, and missing covariates. 




Participants in the REGARDS study were followed every 6 months by telephone for possible stroke events and PVCS were ascertained from baseline ECG between 2003-2007. Further, incident strokes were logged through 2011. Cox proportional hazard models were then used to examine the association between PVCs and ischemic stroke.

During an average follow up of approximately six years, incident rate of ischemic stroke was higher in those with versus without PVCs (6.7 vs 4.2 per 1000 patients, p< 0.01) – PVCs were associated with a 38% increased risk of ischemic stroke.

The authors concluded that the underlying mechanism of increased risk is not very clear, but indicated that PVCs may represent an underlying cardiac arrhythmia or cardiac disease. Finally, the authors concluded that the presence of PVCs on routine ECG is associated with an increased risk of stroke, independent of other traditional risk factors.

Cerebral hemodynamics in chronic carotid occlusion: a novel approach to study “Penumbra” in chronic intracranial hypoperfusion

Chirantan Banerjee, MD

Saura H, Ogasawara K, Beppu T, Yoshida K, Kobayashi M, Yoshida K, et al. Hypoxic Viable Tissue in Human Chronic Cerebral Ischemia Because of Unilateral Major Cerebral Artery Steno-Occlusive Disease. Stroke. 2015


Cerebral autoregulation is a unique and powerful feature of the intracranial vasculature. Powers in a seminal article in 1991 described the stages of intracranial hemodynamic failure with progressively decreasing cerebral perfusion pressures (CPP). In Stage 1, cerebral blood flow (CBF) is maintained despite falling CPPs by vasodilation of resistance arterioles. In Stage 2, with further reductions in CPP, the autoregulatory capacity is exhausted and CBF falls as a function of pressure. However, a compensatory increase in the oxygen extraction fraction (OEF) maintains cerebral oxygen metabolism and tissue function. In Stage 3, further CPP reduction leads to true ischemia and possible permanent injury. Several PET studies over the years have replicated these findings. 



15O tracer in PET has been used as a correlate of OEF in prior studies, which may correlate with future stroke risk. However, OEF might not be the best marker as in stage 3, as OEF may actually decrease in this stage due to tissue damage from ischemia. 18F-FRP170 is a nitroimidazole PET tracer which is a marker of hypoxic but viable brain tissue. In the current study by Saura et al, the authors use PET with this 18F-FRP170 tracer in 52 patients with unilateral symptomatic MCA or ICA high-grade stenosis/occlusion and 20 healthy controls. The authors were able to show the presence of hypoxic but viable tissue in chronic hypoperfusion, and found that the 18F-FRP170 ratio correlated well with OEF. Also, the combination of an elevated 18F-FRP170 ratio and OEF together had much higher positive predictive value and specificity than individual markers. This is an important finding, as it may prove to be a reliable modality to stratify stroke risk in these patients in the future, as well as provide further insights into cerebral hemodynamics.

Effects of Particulate Matter and Living Near Major Roads on Brain Structure

Rizwan Kalani, MD

Wilker EH, Preis SR, Beiser AS, Wolf PA, Au R, Kloog I, et al. Long-Term Exposure to Fine Particulate Matter, Residential Proximity to Major Roads and Measures of Brain Structure. Stroke. 2015

Particulate air pollution has been associated with stroke and cognitive impairment. In this study, Wilker et al. evaluated the association between fine particulate matter (PM2.5) exposure and residential proximity to major roads with brain structure on MRI – total cerebral brain volume (TCBV), hippocampal volume (HV), white matter hyperintensity volume (WMHV), and silent brain infarcts (SBI).

This was done as part of the Framingham Offspring Study. Nine hundred forty-three community dwellers from New England ≥60 years of age, without a history of stroke or dementia, evaluated between 1998-2001 (which included a brain MRI) were included. PM2.5 were predicted by using satellite-derived measurements and participant home distance to major roadways (United States A1, A2, or A3 highways) were calculated. Volumetric brain MRI measurements of TCBV (ratio of brain parenchymal volume to total cranial volume), HV, WMH (based on ratio of WMHV volume / total cranial volume), extensive (E-WMHV: >1 standard deviation above mean), and SBI (based on size and location) were determined. Vascular risk factors and education history, as well as blood pressure measurements and fasting plasma homocysteine levels were obtained from patients during clinical evaluation.
 
Higher PM2.5 was associated with smaller TCBV and higher odds of SBI; no association was demonstrated with HV, WMHV, or E-WMHV. A 2µg/m3 increase in PM2.5 was associated with an average -0.32% change in TCBV (95% CI -0.59 to -0.05); higher PM2.5 conferred a 1.46 times (95% CI 1.10-1.94) higher odds of SBI. An IQR difference in subject residence distance to a major road (173 meters) was associated with 0.10 higher WMHV (95% CI 0.01-0.19). Proximity to a major road was not associated with E-WMHV, TCBV, HV, or SBI. Sex, diabetes, obesity, tobacco exposure, or income (below 25th percentile) did not have an effect on the associations seen.
 
This report provides additional evidence that long-term environmental air pollution exposure is associated with structural brain changes – atrophy and small vessel cerebrovascular disease – that are linked with cognitive and functional impairment in older adults. Major limitations of this manuscript include the possibility of additional confounding variables that may impact results and evaluation of a relatively homogenous population from New England (which may limit generalizability of findings). Future work will have to include elucidating mechanisms by which ambient air pollutants cause the structural brain alterations observed as well the assessment of their impact in regions with high long-term pollution exposure.

Intervention for Cerebral Venous Thrombosis: How aggressive should we be?

Michelle Christina Johansen, MD

Siddiqui FM, Dandapat S, Banerjee C, Zuurbier SM, Johnson M, Stam J, and Coutinho JM. Mechanical Thrombectomy in Cerebral Venous Thrombosis: Systematic Review of 185 Cases. Stroke. 2015

Compared to arterial disease, research targeting the venous system may appear overlooked or disregarded. There is not a lot published on this subject matter although the patient cohort impacted by cerebral venous thrombosis has been well described. How many neurologists experience frustration while looking into the face of a previously healthy twenty some year old female who is not on oral contraception, without an underlying hypercoagulable state and struggled to answer her “Why me” question? While ongoing international studies such as BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis study) may help provide some answers to that question one day in the future, neurologists continue to focus on providing timely therapy with anticoagulation.




What about the patient for whom this is not an option? What about those who do not respond to anticoagulation or present with severe venous infarcts? How aggressive should we be in managing these patients? What about venous thrombectomy?

Dr. Siddiqui et al. performed a systematic review of 185 cases in order to gain a better understanding of the efficacy and safety of mechanical thrombectomy (MT) in patients with cerebral venous thrombosis (CVT). They reviewed studies (1995-2014) and included all cases of CVT in whom MT was performed. They classified intervals from symptom onset to intervention as acute (<21 days) or chronic (>21 days). They also analyzed clinical outcomes based on modified Rankin scale with good defined as 0-2. Recanalization was defined as: no recanalization/technical failure, partial recanalization if there was contrast visible but the lumen was too narrow and complete/near complete recanalization.

Of the studies evaluated, 66% were single case reports and there were no randomized trials. The patients demographically were female (64%) and in their mid-thirties. The population was ill with 86% having rapid clinical deterioration on heparin, 82% having thrombosis of at least two sinuses and 76% presenting acutely. Regarding the procedure, AngioJet was the most frequently used device and 71% also received concurrent intra-sinus thrombolytics.

The authors found 84% to have a good outcome (mRS 0-2) but 22 patients died, majority with worsening hemorrhage and herniation. Recanalization rates were near to complete in 74%. The predominant procedural complication was new or increased ICH which occurred in 18 patients. Subgroup analysis found that use of the AngioJet was associated with a lower chance of good outcomes and higher risk of complications although the authors make note of the insufficient power to adjust for confounders.

So should we consider mechanical thrombectomy for our patients with CVT? This review suggests it is a consideration in patients who present with a severe clinical picture (comatose, rapid deterioration etc.) as the outcome was “good” in 84% but the authors appropriately caution the physician from acting on this information alone. Would those patients with less severe symptoms have done just as well or better on anticoagulation alone? Would adjusting the designated interval from symptom onset to intervention to <1 week (acute), 1 week to 21 days (subacute) and >21 days (chronic) have led to different results? Publication bias may also sway the literature towards those cases with good outcomes further necessitating caution when interpreting these results.

Nevertheless, we should be grateful for literature concerning cerebral venous thrombosis and the results of this review emphasizes that more randomized trials targeting the venous system is needed.

It’s just not that simple: descriptive statistics miss the nuances in trends of “Onset to Treatment” times

Mark N. Rubin, MD

McMeekin P, Wildman J, Ford GA, Vale L, and Price CI. Relative Distributions: A Novel Method for Examining Trends Between Stroke Onset and Thrombolysis Time. Stroke. 2015


In acute stroke therapy studies, we are used to seeing “onset to treatment” (OTT) as an important variable. OTT gives the reader a sense of “The Machine:” how quickly can someone activate emergency care personnel, get transported to the appropriate hospital and have guideline-based treatment administered? When we scrutinize OTT between trials, or at our own stroke center meetings after practice improvement initiatives, we frequently compare median OTT. This is mostly probably because…it’s easy to understand, and perhaps we have a sense that – given the incredible heterogeneity from one case to the next from stroke syndrome to treatment approach – the median “corrects” these disparities.



Some colleagues in the UK suggest otherwise. They point out that descriptive statistics such as the median fail to clearly demonstrate the relative distribution a particular intervention may have had within a cohort. As an example, if median OTT goes down between two chronologically-consecutive cohorts, is it because everyone received earlier treatment? Did some get ultra-early treatment and the rest of the cohort stay relatively the same? These investigators suggest a statistical method novel to stroke research, relative distributions, may be more informative than descriptive statistics.

They applied the principles of relative distributions to the SITS-UK stroke registry, selecting a reference cohort from 1/2003-1/2007 with a median OTT of 160min and a comparator cohort from 10/2009-9/2010 with a median OTT of 145min. The natural hypothesis from comparison of the medians is that doctors and systems became more experienced and/or recognition among the community has increased over those time periods. Applying the relative distribution techniques demonstrated that only some of the latter cohort actually received faster treatment and that a fair amount of the cohort actually received later treatment as compared to the reference cohort. They acknowledge this is multifactorial and reasons are speculative, but the point is we can be more granular with our scrutiny of the system with an assessment based on relative distributions rather than medians, because it’s just not that simple!

By |April 17th, 2015|treatment|1 Comment

Vitamins and Stroke Mortality: Will an over the counter supplement reduce risk?

Mark McAllister, MD

Dong JY, Iso H, Kitamura A, Tamakoshi A. Multivitamin Use and Risk of Stroke Mortality: The Japan Collaborative Cohort Study. Stroke. 2015

Many patients seeking to improve their overall health and reduce risk of disease turn to the vitamin store. A plethora of products are available and represent a multibillion dollar industry. Previous investigations are divided in whether vitamins reduce the risk of cardiovascular disease, cancer, or other diseases—including the possibility that vitamin supplementation may actually increase risks. The effects of multivitamins on stroke outcomes are not clear.


The Japan Collaborative Cohort study involves collection of many types of data regarding lifestyle habits and health outcomes. Over 72,000 patients were included in this analysis, looking at the risk of death due to stroke by their self-reported multivitamin use. In the adjusted analysis there was a trend towards lower stroke-related mortality in the multivitamin users, but this did not reach statistical significance. In a subgroup analysis there was a significant reduction in stroke mortality in multivitamin users eating fruits and vegetables fewer than three times a day. This effect was not seen in individuals eating fruits and vegetables three or more times a day.

Should we advise patients to add multivitamins to their daily regimen to reduce their risk of stroke? I think it’s difficult to arrive at that conclusion from this observational study. What is likely best is that we continue to advocate for overall healthy patterns of behavior, including a varied diet rich in fruits and vegetables. Reliance on an easy fix in pill form is unlikely to substitute for lifelong healthy habits.

Changes in Stroke Incidence and Case Fatality in Norway

Rizwan Kalani, MD

Vangen-Lønne AM, Wilsgaard T,  Johnsen SH, Carlsson M, and Mathiesen EB. Time Trends in Incidence and Case Fatality of Ischemic Stroke: The Tromsø Study 1977–2010. Stroke. 2015


Though overall stroke incidence and mortality have declined in high-income countries over the past few decades, an increasing incidence in younger populations has been observed. In this study, the authors evaluated the trends in incidence and case fatality of first-ever ischemic stroke in Norway from 1977 to 2010.

Estimated trends came from a population-based, prospective cohort study from Tromso, Norway. First stroke was identified from clinical registries from the University Hospital of North Norway and National Causes of Death Registry. Ischemic stroke was defined per the WHO clinical definition – with no other apparent cause of symptoms demonstrated by brain CT, MRI, or autopsy. Case fatality was determined from the patients who died in the first 30 days after stroke.



Of the 36,575 individuals (over the age of 30 years, without prior stroke) included, there were 1214 incident cases of ischemic stroke. As expected, the incidence rates increased with age and were higher in men. From 1995 to 2010, there was an age- and sex-adjusted 24% decline in incidence; 32% reduction in women and 19% in men. However, for the 30-49 year age group, there was an increasing incidence in women and a (non-significant) rising trend in men. The case fatality for ischemic stroke was 7% for the 30-84 year age group and 20% in those ≥85 years. The age-adjusted case fatality was higher for women compared to men. In older age groups, incidence declined or remained stable (age ≥ 75 years) in both men and women. Over the time period evaluated, though there was a declining case fatality for men 30-84 years, it remained unchanged for women (it actually declined and then increased).

Increasing incidence of ischemic stroke of younger individuals (particularly women) in this population-based study from Norway is consistent with reports from France, Sweden, Netherlands, and the US. This is occurring despite the declining incidence in older individuals in high-income countries. Overall, case fatality declined (in men) or remained stable (in women) in this study. These epidemiologic trends require further investigation to elucidate the causes for increasing stroke in younger age groups and understand the heterogeneity seen between and within different populations. Stroke incidence and associated mortality will need to be followed over time, ideally along with implementation of multifaceted strategies to stroke prevention that targets the high risk groups.

A History of the TOAST Classification

Vikas Pandey, MD

Adams, HP Jr, Bendixenb BH, Kappelle LJ, Biller J, Love BB, Gordon DL, and Marsh EE, 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 2015

The TOAST Classification system was developed to be able to better classify ischemic strokes that patients had suffered on the basis of etiology as this had an impact on the patient’s prognosis and risk of stroke recurrence. Additionally, the TOAST classification system has been used by different research trials to be able to report the stroke subtype population that their study encountered and by using the same system across different studies, the populations could be better compared with one another.


The article by Drs. Adams and Biller emphasizes the history of the TOAST (or the obviously more convenient name Trial of Org 10172 in Acute Stroke Treatment) classification system, specifically how and why it was developed, and the idea behind which stroke etiologies should be included in the five broad categories (Large artery, small artery, cardioembolic, other, undetermined). An example is how it was intended for large artery strokes to specifically mean strokes related to large artery atherosclerotic disease, and that these patients should usually have evidence of symptomatic atherosclerotic disease elsewhere i.e. coronary or peripheral arteries. They clearly defined that the “other” category included patients that had an established cause of stroke but could not be categorized in the large artery, small artery, or cardioembolic categories, such as non-atherosclerotic vasculopathies, dissections, hypercoagulable states, etc. The reason for inclusion in the “undetermined” group was three-fold as this category included patients for which no etiology was found due to complete but negative workup, incomplete workup, or multifactorial etiologies possible for stroke.

The TOAST scale is easy to use and has good inter-rater agreement and intra-rater reproducibility. The authors recognize the limitations and criticisms of the TOAST scale including how it cannot be applied to pediatric stroke, the plea for dissection-related strokes to be a separate category, and the varying prognosis of different cardioembolic disorders. They also mention how a full workup is always needed for patients to not be put in the undetermined category, so the application of the scale may not be omnipresent. The scale has undergone numerous modifications but the idea has endured the test of time and it is the basis for which new scales are being developed. The TOAST Scale original paper has been cited >4800 times making it one of the most commonly cited contributions to the Stroke journal. The TOAST scale has helped define the thought process that stroke neurologists around the world use when working up a stroke patient and its contribution to our field is invaluable.

@DrVikasNeuro

Poststroke Angiogenesis: Architect and/or Demolition Crew?

Mark N. Rubin, MD

Greenberg DA. Poststroke Angiogenesis, Pro: Making the Desert Bloom. Stroke. 2015


Adamczak J, and Hoehn M. Poststroke angiogenesis, Con: The Dark Side of Angiogenesis. Stroke. 2015


This installment of the “Controversy” series involves what to make of post-stroke angiogenesis: the hypoxia-triggered generation of new capillaries after a stroke of any subtype. The fact that angiogenesis exists in the post-stroke setting–experimental and clinical–is not the point of debate but to what degree this process influences patient outcome. Experimental, pathological case study and treatment trial data exist in this field, but a fundamental clinical question remains unanswered: does manipulating this pathophysiologic process make patients better?



Dr. Greenberg from the Buck Institute for Research on Aging proposes that post-stroke angiogenesis is a viable therapeutic target, mostly because it is fairly well understood at a biochemical level, broadly applicable across the patient population and there are myriad promising biochemical targets in the process that have not yet been investigated. Furthermore, there is the optimistic view that angiogenesis allows for more rapid clearing of ischemic debris, setting a clean slate for post-stroke neuronal reorganization (e.g., functional recovery). Prof. Doctors Adamczak and Hoehn from the Max Planck Institute argue that angiogenesis is more demolition crew than architect. While not arguing that restoration of cerebral blood flow is beneficial to neuronal tissue, they point out the double-edged sword of pro-angiogenic factors (namely Vascular Endothelial Growth Factor, better known as VEGF), which also promote increased cerebral edema which is injurious to brain. They cite evidence that supporting anti-angiogenic factors actually decreases infarct volume.

Dr. Liu from UCSF ties the debate together with a resounding “you’re probably both right but we don’t know enough in general. Plus, how does this all relate to collateralization, which is so hot right now?” She also suggests a careful marriage of nanotechnology and pharmacotherapy may help deliver the right mix of biochemicals–whichever those may be–to the right place at the right time, thus mitigating the known inefficacy and/or risks of systemic delivery of pro-angiogenic factors.

Read on for details of the Basic Science Controversy In Stroke!