American Heart Association

Monthly Archives: September 2015

Controversies in Stroke: Is CTP Ready for “Prime Time?”

Computed Tomography Perfusion in Acute Ischemic Stroke

Mark N. Rubin, MD

David S. Liebeskind, MD; Mark W. Parsons, PhD; Max Wintermark, MD. Computed Tomography Perfusion Is Beyond Prime Time. Stroke. 2015

Magdy Selim, MD, PhD; Carlos A. Molina, MD. Computed Tomography Perfusion in Acute Ischemic Stroke: Is It Ready for Prime Time? Stroke. 2015
Michael H. Lev, MD. and Ramón G. González, MD, PhD.Computed Tomography Perfusion Is Not Ready for Prime Time. Stroke. 2015

In the East Coast vs West Coast (yes, Australia is honorarily part of our West Coast) stroke-neuroimaging-related battle of the year, these major players in the science of acute stroke treatment and imaging “discuss” whether or not computed tomography perfusion (CTP), clinically available for decades but recently in the treatment trial spotlight, should be broadly implemented in hyperacute stroke.

Team West Coast kicked things off with reminding us how simple and broadly available CTP is in the United States, extolled the virtues of its ability to give us mission-critical data for acute stroke therapy while easily integrated into already common CT-based stroke imaging protocols, then, for the knockout, also reminded us about how resounding positive the CTP-based selection trials were for therapy.

Team East Coast took the skeptical approach – perhaps with a bit of irony considering their contribution to CTP stroke science – citing that CTP is too imprecise on an individual patient level and diffusion magnetic resonance imaging (MRI) provides much more accurate “tissue data.”

For what it’s worth, in my experience I find the truth West-of-Center in this debate. Although I agree CTP is widely available, it is not always fast (performance or processing), does give a fair amount of radiation, can be obscured by patient motion and/or poor cardiac output, and is best for “gestalt” as the Partners suggest as CBV does not always cleanly match up with DWI changes. Dr. Liebeskind’s own colleague let us know every minute matters, and it is not clearly established that all patients should undergo this test – however many minutes it may take – if not of clear benefit.

That said, it has its uses, particularly in ischemic stroke of unknown time of onset but suspect within 6 hours and severe strokes (most typically associated with large-artery syndromes) for which an endovascular intervention is being considered. I also agree with the West Coast group that acute MRI is not feasible regionally, let alone nationally, let alone globally. If the mission is to reduce ischemic stroke morbidity and mortality broadly, then our diagnostics must be broadly applicable and MRI is cost-prohibitive in this sense.

Make sure you read this edition of Controversies in Stroke for yourself, as it’s rather crispy.

By |September 16th, 2015|controversy|0 Comments

Ethical considerations before decompressive hemicraniectomy for large hemispheric infarction

Alexander E. Merkler, MD

Honeybul S, Ho KM, and Gillett G. Outcome Following Decompressive Hemicraniectomy for Malignant Cerebral Infarction: Ethical Considerations. Stroke. 2015
There have now been six randomized controlled trials comparing decompressive hemicraniectomy for large hemispheric infarction (LHI) with standard medical therapy. Hemicraniectomy confers a 50% absolute risk reduction in mortality, but at what cost? Most patients are left with moderate to severe disability – approximately 40% of patients who undergo decompressive craniectomy become disabled, with a modified Rankin scale (mRS) of 4 (unable to walk without assistance and unable to attend to own bodily needs without assistance). But is mRS an adequate outcome measure in these patients? What constitutes a good functional outcome? And most importantly, who decides what is a good functional outcome? 

In the article by Honeybul et al, the authors ask us to consider the ethical ramifications of decompressive hemicraniectomy and to acknowledge that a “one size fits all” approach for treating patients with LHI is neither adequate nor appropriate.

In the 2007 meta-analysis of the three European trials, surgery as compared to medical treatment alone was significantly associated with an improvement in favorable outcome (75 vs 24%), but a “favorable” outcome was defined as a mRS of four or less. Thus, as the authors point out, a favorable outcome included patients who were unable to attend to their own bodily needs without assistance.

Of course, we need to keep in mind that the mRS is not a perfect measurement of outcome. It is a scale largely based on ambulation and does not consider other extremely important measures of functionality such as language, cognition, and depression, all of which may equally impact quality of life as compared to motor function.

Despite the large percentage of patients left with disability, several studies showed that the majority of patients who underwent hemicraniectomy would have “retrospectively” provided consent for the procedure (if it would have been possible to answer it themselves at the time). As Honeybul et al explain, it is inherently difficult to give sufficient merit to these claims. First, patients answering these questions may not be at their cognitive baseline. Second, as a testament to human nature and the will to survive, patients may have adapted to the new level of neurological disability, one which they may previously have deemed unacceptable.

So what should neurologists consider when evaluating a patient with a LHI? It is our responsibility to individualize treatment of LHI by thoroughly evaluating what would constitute an acceptable outcome, much the same way we do for patients regarding code status. Each person is entitled to his or her belief of what a life worth living would mean—for some it may mean the ability to read and write, for others it may mean walking independently, and for others it may mean just simply being able to breathe. We as clinicians must make a diligent effort to determine what a patient would have wanted before we assign them a life they never would have desired.

Tweet: Ethical considerations important when considering decompressive surgery for large hemispheric infarction

By |September 15th, 2015|treatment|0 Comments

Mannitol does not improve outcome in intracranial hemorrhage.

Jay Shah, MD
Wang X, Arima H, Yang J, Zhang S, Wu G, Woodward M, et al. Mannitol and Outcome in Intracerebral Hemorrhage: Propensity Score and Multivariable Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 Results. Stroke. 2015

Mannitol is an intravascular osmotic agent that reduces cerebral edema, thereby decreasing intracranial pressure. It is frequently used in malignant ischemic strokes and also recommended in intracerebral hemorrhage (ICH). However, in the latter, the magnitude of potential benefit remains uncertain. In this study, the authors hypothesized that mannitol would improve clinical outcomes in severe ICH. They analyzed data from Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). 

INTERACT2 was an international, randomized control trial that included 2839 patients with spontaneous ICH with elevated blood pressure who were assigned to either intensive blood pressure control (systolic < 140mmHg within 1 hour) or guideline-recommended control (systolic < 180mmHg). Data on any use of mannitol within 7 days of ICH were recorded. Propensity score and multivariable analysis were performed to investigate a potential relationship between mannitol and primary outcome, defined as death or major disability at 90 days. In total, there were 1533 patients treated with mannitol versus 993 who did not receive mannitol therapy. 

Overall, there was no significant difference in primary outcome. There was an apparent benefit of mannitol in patients with large hematomas (>15ml), however, this finding did not remain consistent across other cut-off points suggesting the finding was spurious. This result was in agreement with prior smaller observational and randomized control trial data. However, an analytical approach to this study is a limitation as INTERACT2 was not designed to evaluate use of mannitol. Thus, there was great variability in dose and duration of therapy. Authors attempted to account for such variability using statistical methods, but it is likely confounding variables were nonetheless present. Furthermore, patients with large hematomas or requiring early surgery were excluded from INTERACT2. Such patients would have higher intracranial pressures and presumably mannitol would have the most benefit. Further studies can evaluate mannitol treatment in this population.

By |September 14th, 2015|treatment|0 Comments

Absolute Monocyte Count Associated with early ICH Mortality

Mark N. Rubin, MD

Walsh KB, Sekar P, Langefeld CD, Moomaw CJ, Elkind MSV, Boehme AK, et al. Monocyte Count and 30-Day Case Fatality in Intracerebral Hemorrhage. Stroke. 2015

As we’ve discussed over, and over, and over again, intracerebral hemorrhage (ICH) is bad disease. Although it represents only ~10-20% of all strokes, it is accountable for upwards of 50% of stroke mortality and is typically quite disabling. We have no targeted therapies available in clinical practice, for the acute or chronic phases, that definitely change the neurologic and/or mortality outcome.

These investigators had previously published their observation that early mortality after ICH was associated with absolute monocyte count (AMC) independent of ICH volume, with the putative mechanism being inflammatory neuronal apoptosis and/or a contribution to cerebral edema. The current publication highlights similar findings in a larger, more ethnically diverse population: those enrolled in Ethnic/Racial variations of IntraCerebral Hemorrhage (ERICH) cohort. In brief, they found that independent of the most important confounders including age, NIHSS, ICH volume and location, AMC was not associated with ICH volume but was associated with 30 day mortality. From these results, they concluded that the association of AMC with mortality may be generalizable and its lack of association with ICH volume suggests a mechanism beyond ICH-related mass effect and neuronal destruction.

As the authors correctly address in their discussion, this represents a potential target for early neuroprotection in ICH. With immunomodulatory therapies directed at monocyte action, we may be able to mitigate whatever role (assuming this finding is causal and not associational) monocytes play in the process. Clinical trials will likely depend on the elucidation of the mechanism prior to attempting (potentially dangerous) immunomodulatory therapy in already typically gravely ill patients.

Genetics of Lacunar Stroke

Russell Mitesh Cerejo, MD

Traylor M, Bevan S, Baron JC, Hassan A, Lewis CM, and Markus HS. Genetic Architecture of Lacunar Stroke. Stroke. 2015 
From Dechambre to CM Fisher, we have come along way in understanding the pathogenesis of lacunar strokes. While vascular risk factors play a major role, little is known about its genetics. Dr. Traylor and colleagues in their paper “The genetic architecture of lacunar stroke” set out to investigate the genetics and heritability of lacunar strokes and its subtypes.

They investigated 1029 subjects with MRI confirmed lacunar strokes and 964 controls. The dataset was genotyped on the Illumina HumanExomeCore array, which contains both exome content (~250,000 SNPs) and common tag SNPs (~250,000 SNPs) found on conventional GWAS arrays, and imputed to 1000 Genomes phase 1. The lacunar strokes were sub-typed as follows: isolated lacunar infarcts (ILI) and multiple infarcts and leukoaraiosis (MLI/LA). They used genetic restricted maximum likelihood (GREML) methods to estimate the proportion of phenotypic variance on the liability scale explained by the genetic relationships between individuals based on common SNPs. They also investigated whether the heritability of lacunar stroke was enriched for regulatory sites in the autosome.

They found that lacunar stroke and its subtypes were significantly heritable with estimates being higher for the MLI/LA subtype and slightly lower for the ILI subtype. This heritable component was significantly enriched for sites affecting expression of genes. The two subtypes of lacunar stroke in isolation, but not in combination, was associated with rare variation in the genome, suggesting that they may have distinct genetic susceptibility factors. Such studies are the stepping-stone to understanding the genetic composition of complex diseases and pave way for future studies.

Cohort Gives Insight into the State of Current Treatments and Outcomes for Pediatric Cavernous Sinus Thrombosis

Danny R. Rose, Jr., MD

Press CA, Lindsay A, Stence NV, Fenton LZ, Bernard TJ, and Mirsky DM. Cavernous Sinus Thrombosis in Children: Imaging Characteristics and Clinical Outcomes. Stroke. 2015
Cavernous sinus thrombosis (CST) is a rare, but potentially serious complication of a variety of conditions including meningitis, sinusitis, and acute otitis media. Given its proximity to the internal carotid artery (ICA), cerebrovascular sequelae are common in this setting and include carotid artery narrowing, vasospasm, embolic and hypoperfusion-related infarcts. The widespread use of antibiotics has likely reduced the incidence of CST, and because of its rarity, determining both the optimal treatment regimen and current morbidity and mortality is challenging. To shed some light on the natural history of CST in children, Press et al. conducted an analysis of a retrospective cohort with CST cared for at a single pediatric tertiary care center focusing on clinical presentation, risk factors, imaging, treatment, incidence of infarct, complications of treatment and outcome.

The study included ten patients identified between 2003-2014, ranging in age from 3-17 years. The most common presenting symptom was headache, which was found in seven of the patients. Fever and vomiting were the second most common presenting symptoms occurring in six. Streptococcus/staphylococcus species were found in the vast majority of cases, with S. anginosus being the most common pathogen. Despite a prothrombotic evaluation conducted for all of the patients, only one patient had a coagulation abnormality (heterozygous for a Factor V Leiden mutation).

Radiographically, expansion of the cavernous sinus and filling defects on contrasted studies were the most common findings. Additionally, subdural empyema and narrowing of the ICA with arterial wall enhancement was present in every case, the majority of which had narrowing of the ICA by greater than 50% by WASID criteria. This narrowing completely resolved in six of the patients, and only two had a residual stenosis greater than 50% on their last available imaging study. Thromboses of additional veins/venous sinuses was frequent, with thromboses of the superior ophthalmic vein, draining and tributary veins of the CS, internal jugular vein and sigmoid sinus also reported. These thromboses were usually associated with restricted diffusion. Multiple areas of parenchymal restricted diffusion suggesting embolic and/or hypoperfusive infarction was found in six of the patients, and one had a complete middle cerebral artery territory infarction. 

Medical management involved a combination of antibiotics, anticoagulation, anti-platelets, nimodipine and/or steroids. Antibiotics were used on all of the children, with appropriate broad-spectrum antibiotics and narrowing based on microbial sensitivities. Eight patients were treated with anticoagulation. Three of the patients developed new infarcts while anticoagulated and half of the anticoagulated patients developed bleeding complications. Bleeding was most often post-procedural and was not catastrophic, with one extracranial bleed and three <20mL intracerebral hemorrhages with minimal intraventricular extension. Nimodipine was used to treat presumed vasospasm in two patients who had developed infarctions while on anticoagulation, with one of the two developing further infarcts while on nimodipine. The majority of the patients were managed operatively with endoscopic sinus surgery, with a total of six having more extensive procedures that included ventriculostomy, orbital decompression, mastoidectomy, orbital exenteration and cerebral debridement.

Four patients became blind in the affected eye (one bilateral) due to either injury to the optic nerve or orbital exenteration. Seven patients were discharged with a mRS of ≤ 1, with a median mRS of 1 at the time of last follow up (range 0-3). One patient had care withdrawn due to stroke-related neurologic injury.

This cohort provides valuable insights into the current state of childhood CST diagnosis and management. Despite a high incidence of infarction and significant ICA narrowing, the majority of patients had a favorable outcome. This is likely due in part to current aggressive, multimodal CST treatment. It is also worth noting that the only death in this study was a patient who had a large infarction that was identified before initiation of anticoagulation or antiplatelet therapy. Although bleeding complications were relatively common, these did not appear to have adversely affected the outcome of the affected patients.

Infarction was a common finding in this study, and may be more common than previously assumed. The precise mechanism of cerebrovascular sequelae in CST remains unclear, but likely involves a combination of thrombotic, hemodynamic and inflammatory arteritic causes. Given this uncertainty and the lack of sufficient patients for comparative study, the optimal management for prevention of cerebrovascular complications in CST has yet to be determined. Despite this limitation, in comparison to the historically poor aftermath of CST, this study provides additional evidence that outcomes can be good with aggressive treatment. Additional multicenter studies will likely be needed to provide more clarity on the issue.

Predicting Fall Risk in Stroke Patients

Ilana Spokoyny, MD

Minet LR, Peterson E, von Koch L, and Ytterberg C. Occurrence and Predictors of Falls in People With Stroke: Six-Year Prospective Study. Stroke. 2015
Falls post-stroke are common but not enough data exists on which stroke patients tend to have falls, and when. This information is obviously needed in order to design fall prevention strategies. Minet et al. carried out the first prospective long-term study on falls post-stroke which was comprised of 121 patients from the “Life After Stroke” cohort in Sweden. The cohort originally had 349 patients but the remainder were either deceased or declined to participate.

The variable studied was self-reported falls, at intervals of 3 months, 6 months, 12 months, and 6 years. Variables included in the univariate model were age, sex, SOC (sense of coherence, an assessment of attitude toward life post-stroke and ability to cope with stressful situations), stroke severity, cognitive function, perceived impact of stroke in eight domains, self-rated recovery, gait/balance disability, social/lifestyle activities, and occurrence of falls in the first 3 months post-stroke.

At each time point, about 1/3 of patients reported falling in the preceding time period (the time period was the last 3 months for the 3- and 6-month assessments and the last 6 months for 12 month and 6 year assessments). Predictors of future falls were:

– a clinically significant decrease in the Stoke Impact Scale score (more than 15 point drop)
– report of falls at 3 months, and
ABSENCE of gait/balance disability at baseline

Interestingly, the odds for falling decreased over time for those with gait/balance disability at baseline, but increased for those without disability.

Of the relatively large proportion of patients who were alive but did not follow up, the mean age was higher than those who followed up, and there was a lower proportion of mild strokes. This may represent healthy survivor bias, and should not be overlooked. There may also have been a component of recall bias, in that falls were self-reported. Another possible confounding factor is that if some patients with significant gait disability were no longer ambulatory (wheelchair-bound), they would be expected to have a lower fall risk.

Participants with gait/balance disability at baseline are routinely given access to rehabilitation services (with the level of intensity determined by physical and occupational therapists), which help not only with improvement of current functioning but also teach safety strategies to prevent falls in the future. This study highlights the importance of assessment of fall risk longitudinally, and may lend support to multi-disciplinary clinics for stroke patients (in which they have access to therapists as well as medical providers).

By |September 8th, 2015|clinical|0 Comments

Expanding the patient population for endovascular therapy: Treating large DWI lesions may still confer benefit

Peggy Nguyen, MD 

Gilgen MD, Klimek D, Liesirova KT, Meisterernst J, Klinger-Gratz PP, Schroth G, et al. Younger Stroke Patients With Large Pretreatment Diffusion-Weighted Imaging Lesions May Benefit From Endovascular Treatment. Stroke. 2015 

What are some of the factors that we, as clinicians, take into account when deciding whether a patient is an endovascular candidate? Certainly last known well time is one, and often times, lesion size is another. Previous studies have reported poorer outcomes in patient with large lesion size, and therefore, patients with large DWI lesions pre-treatment have traditionally been excluded from clinical practice as well as research studies. This patient population is very poorly characterized in the endovascular therapy group. Here, the authors try to fill in this gap with an analysis of patients with either ICA or MCA lesions who underwent thrombectomy, specifically evaluating outcomes in patients with large DWI lesions.

Not unexpectedly, when compared to patients with a DWI lesion volume < 70 mL (n=292), patients with DWI lesions > 70 mL (n=66) had lower rates of favorable outcomes, lower survival, and more symptomatic ICH (sICH), especially in patients who received thrombolysis preceding thrombectomy. However, in patients who achieved good reperfusion (as determined as a TICI 2b-3 score), 11/31 patients, or nearly 1/3rd of patients, had a good outcome compared to 3/35 patients with a TICI 0-2a. In the overall group of patients with lesion size > 70 mL, independent predictors of favorable outcomes were smaller DWI size, younger age, and reperfusion success. Younger patients had better outcomes compared to older patients, with no patients older than 75 years of age having a favorable outcome. The authors also evaluated patients when stratified by lesion size < 100 mL vs > 100 mL, with similarly poor outcomes and less survival in patients with larger lesions, but again, better outcomes when patients achieved better reperfusion.

This study confirmed that indeed, patients with large DWI lesions do have poorer outcomes; however, this is qualified by the finding that even in this population, a favorable outcome was seen in every third patient when endovascular reperfusion was successful. No size cut off was identified, but the treatment effect was better in younger patients. Although there may have been a selection bias, in that large lesions in younger patients may have been more likely to be selected for endovascular therapy, this study suggests that contrary to current practice, large DWI lesions may not be a contraindication to thrombectomy.

By |September 4th, 2015|treatment|0 Comments

Using CHADS2 and CHA2DS2-VASc Scores to Predict Atrial Fibrillation after Stroke

Neal S. Parikh, MD

Fauchier L, Clementy N, Pelade C, Collignon C, Nicolle E, and LipGYH. Patients With Ischemic Stroke and Incident Atrial Fibrillation: A Nationwide Cohort Study. Stroke. 2015
In this issue of Stroke, Fauchier and colleagues seek to identify predictors of incident atrial fibrillation (AF) after ischemic stroke. The prediction and therefore timely diagnosis of atrial fibrillation is of significant public health importance given that, as the authors point out, one in five of stroke can be attributed to AF.

The authors utilize a robust dataset that includes all hospitalizations in France. They identified 48,992 patients without known AF discharged after ischemic stroke during 2009 and calculated their CHADS2 and CHA2DS2-VASc scores. Patients with primary cardiac conditions served as a control, though only for a part of the analysis.

Over 15±5 months of follow-up, 4,828 patients were diagnosed with AF during a hospitalization. 7.88 patients per 100-person years developed incident AF after stroke, whereas the rate was 5.91% after a cardiac diagnosis. As a continuous variable, the CHADS2 and CHA2DS2-VASc scores were associated with incident AF with HR 1.70 (95% CI, 1.66-1.75) and 1.45 (1.42-1.48), respectively. The c statistic was a moderate 0.7. Unsurprisingly, of the CHADS2 and CHA2DS2-VASc variables, only age, hypertension, heart failure and vascular disease independently predicted AF.

The major limitations of this study are as follows: 1. They did not determine if CHADS2 and CHA2DS2-VASc scores predict AF in their control group; 2. To call AF diagnosed after a stroke “incident” is misleading – AF may have been present prior to the stroke as well; 3. AF is often asymptomatic – many patients with “incident” AF may never be hospitalized with AF; 4. Cryptogenic stroke patients in 2009 did not routinely undergo prolonged cardiac rhythm monitoring, the results of which would have been an ideal outcome measure.

The authors hope that their findings will help identify patients after a stroke who may benefit from prolonged monitoring for AF. The CHADS2 and CHA2DS2-VASc scores are inadequate for this purpose. If the goal is identification of patients for prolonged cardiac monitoring upon discharge after stroke, the use of CHADS2 and CHA2DS2-VASc scores presents an unnecessary handicap. Stroke patients routinely have additional data including echocardiogram (left atrial dilatation), MRI (e.g. embolic pattern of strokes), telemetry (frequent premature atrial complexes), labs (B-type natriuretic peptide) that may be helpful.

However, when it comes to stroke, secondary prevention is too late; primary prevention is the Holy Grail. It is for this purpose – for general population AF screening purposes – that the CHADS2 and CHA2DS2-VASc scores may be helpful. Unfortunately, the authors did not assess the test characteristics of these scores in their control group.

Safety of full dose tPA and eptifibatide: Results from the CLEAR-FDR trial

Peggy Nguyen, MD

Adeoye O, Sucharew H, Khoury J, Vagal A, Schmit PA, Ewing I, et al. Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke-Full Dose Regimen Stroke Trial. Stroke. 2015

Intravenous tissue plasminogen activator (IV tPA) is an effective medical therapy for acute ischemic stroke, but recanalization rates of large arterial occlusions with tPA is only 50%. Combination treatment with tPA and eptifibatide, a glycoprotein 2b/3a inhibitor, has previously been studied and reported in the CLEAR trial, on the premise that delivering a platelet aggregation inhibitor together with tPA might augment clot lysis, although no benefit was seen. A follow up study, the CLEAR-ER study, was suggestive of a direction in favor of combination therapy when tPA was used at a higher dose of 0.6 mg/kg and eptifibatide was bloused as a higher dose of 135 ug/kg. In order to proceed to a phase 3 trial of full dose tPA with eptifibatide, the researchers here look at the rates of symptomatic ICH (sICH) as a complication of therapy in a protocol using full dose tPA of 0.9 mg/kg with high dose eptifibatide.

The primary purpose of this study is to demonstrate safety in terms of sICH rates only, not to determine functional outcome. Researchers established a pre-determined stopping point of 3 events out of 19 patients, or 4 events of 29 patients, which would be consistent with sICH rate less than 8%, equal to that seen in the NINDS trial. Enrollment stopped at 27 patients, with only one patient having developed sICH. The number of patients enrolled was not sufficient to determine functional outcomes; however, the study does demonstrate that full dose tPA with full dose eptifibatide is safe and feasible for use.

In the near-future, could we be using tPA together with eptifibatide on our patients prior to sending them on their way to endovascular treatment? If the phase 3 trial shows improved recanalization rates with a similarly preserved safety profile, this could potentially alter the landscape of acute ischemic stroke treatment and lend an additional medical therapy toward the armory of the vascular neurologist.

Tweet: Safety of full dose tPA and eptifibatide: results from the CLEAR-FDR trial

By |September 2nd, 2015|treatment|0 Comments