American Heart Association

Monthly Archives: February 2013

Impact of Early Blood Pressure Variability on Stroke Outcomes after Thrombolysis

Aaron Tansy, MD


Consensus agreement supports permissive hypertension as a mainstay in the non-thrombolytic treatment of hyperacute/early acute ischemic stroke to compensate for loss of autoregulation and promote cerebral perfusion. Beyond that, what the best practice may be for blood pressure (BP) management in the acute ischemic setting, especially for patients treated with intravenous thrombolysis, has kept the stroke community scratching its collective head for some time.

To that end, Kaoru Endo and colleagues report on early and late clinical outcomes seen across differing BP courses in early acute ischemic stroke treated with thrombolytic therapy. Culled from the SAMURAI rt-PA registry, data for 527 patients were analyzed retrospectively. BP values for each patient were recorded once immediately prior to and 7 times after rt-PA administration over a 24 hour period, and were converted into individual BP statistical profiles (max, min, mean, difference between max and min, standard deviation, and coefficient of variation). Clinical outcomes assessed were symptomatic intracerebral hemorrhage (sICH) within 36 hours (early) and modified Rankin Scale (mRS) score or death at 3 months (late). Associations between BP profiles and outcomes were performed using binomial logistic regression models.

The group’s analysis yielded two major findings: severity of BP elevation and variability both appeared to influence clinical outcomes. On the one hand, patients with sICH tended to have a higher overall BP course during the first 24 hours of ischemic stroke while, on the other, those with a low (0-1) mRS score had a significantly lower one. In addition, both patients with sICH and who died had BP courses of significantly larger variability early after ischemic stroke while those with a low mRS score had ones of significantly lesser variability.

Although the finding that an early elevated BP course is predictive of poor outcomes is not surprising, the study has noteworthy results. For one, the study’s overall findings make it the first to highlight the prognostic potential of monitoring the early BP course in thrombolytic-treated acute ischemic stroke. Additionally, and perhaps more importantly, it is the first to suggest that degree of BP variability no less significantly impacts clinical outcome than degree of BP elevation.

So, while the trial doesn’t provide any definitive answers regarding BP management for thrombolytic-treated acute ischemic stroke, it does open a few new doorways worth exploring that may bring us a few steps closer to some.

By |February 28th, 2013|Uncategorized|1 Comment

High-density Lipoprotein–based Therapy Reduces Hemorrhagic Complications

Vasileios-Arsenios Lioutas, MD

IV tPA is the main weapon in our armamentarium for acute stroke treatment. Its beneficial effect comes at the cost of symptomatic intracranial hemorrhage with significant impact on mortality and functional outcome for the affected patients, especially with delayed administration. An agent that would attenuate the hemorrhage risk without interfering with the fibrinolytic activity would be ideal as adjunctive therapy.

In this interesting proof of concept study, Amarenco et al investigated the effect of HDL administered intravenously along with tPA in ischemic stroke in rats. Two different models of middle cerebral artery occlusion characterized by high incidence of post tPA parenchymal hematoma formation and mortality. HDLs were chosen due to their suggested pleiotropic endothelial protective effects (e.g. anti-oxidant, anti-inflammatory).

Infarct volume and 24-hour mortality were significantly decreased and the incidence of parenchymal hemorrhage was decreased by 90% in the HDL treated group compared to tPA alone. Moreover, both in vivo and in vitro data unequivocally showed a beneficial effect of HDL in blood-brain barrier integrity, without attenuation of tPA’s fibrinolytic activity in vitro or ex vivo.

These are undeniably impressive results that offer support to the original hypothesis that HDLs have a neuro- and vasculo- protective effect. Several points need to be underlined: HDLs comprise a structurally and functionally heterogeneous group of lipoproteins. Their in vivo function is quite complex, as they very likely act as transporters of other molecules that render their biological action acutely efficacious. Their composition and functionality are altered in the context of disease processes. Therefore, HDLs derived from plasma of healthy individuals are very likely biologically different compared to those from patients with metabolic syndrome and recombinant HDLs created in the lab. 

The results of this study are promising, but limited to short term outcome and need to be replicated by further experiments. First and foremost, it remains to be seen whether HDLs will have the fate of so many other neuroprotective agents, which failed the ultimate test of human stroke clinical trials despite auspicious results in preclinical studies.

By |February 27th, 2013|Uncategorized|1 Comment

Acute Cerebrovascular Disease in the Young

 Osman Mir, MD
Current knowledge of genomics of stroke has dramatically increased in recent time. Stroke poses a huge burden of disability on society. This is especially true for stroke survivors who are young in age. Stroke in the young although less prevalent, is nevertheless even more devastating due to high probability of long term survival with disability. Stroke in the young can have different than traditional risk factors. This is where genomics of stroke has made an impact. Following this in this journal of stroke Rolfs et al did a study of role of Fabry disease – an α-Galactosidase A gene defect resulting in the accumulation of glycosphingolipids – in stroke in the young. This is done in a cohort of multicenter European Stroke In Young Fabry Patients study (sifap) as a prospective observational study. Rolfs et al found that a small subset of stroke in the young patients upto 0.5% roughly 27 out of 5023 patients had definite Fabry’s disease which was defined as either significantly reduced biochemical activity of AGLA or presence of a causative mutation or in those cases with massive increase of at least two independent biochemical markers. Another additional 18 patients 0.4 % were diagnosed as Probable Fabry’s disease. Most common type of stroke in Fabry’s disease patients was Ischemic Stroke. Another interesting finding was that in younger group 18-34 there were more females however when the age group 35-55 there were more males. The largest group was “undetermined etiology” comprising 33.4% of all patients, being more common among females than males (38.0% versus 30.5%) and becoming less frequent in older patients. Contrary to expectations though the other etiologies were more or less similar to conventional populations studied. Other etiologies were in similar ranges (13.5% to 18.7%) of which large-artery atherosclerosis and small-vessel disease were more common among males and both more prevalent in older patients, whereas cardioembolism was equally common between genders.
This study had several strengths especially since it is prospective cohort which had standardized extensive investigation including MRI and hypercoaguable work up. Also this was a multi center study with a broad population base in multiple different countries. Also Rolfs et al used advanced molecular testing for rare etiologies. This study highlights the future of work up for stroke not only in young but probably in all patients in whom stroke is of unknown etiology. Another highpoint of this study was difficulty of establishing the diagnosis of Fabry’s disease despite extensive work up it was only definite in 0.5% and probable in 0.4%. Maybe there was another subgroup which was difficult to identify despite comprehensive work up. 

By |February 26th, 2013|Uncategorized|0 Comments

Real-time Validation of Transcranial Doppler Criteria in Assessing Recanalization

Diogo C. Haussen, MD

Tsivgoulis et al. validated the utilization of transcranial Doppler (TCD) for the assessment of recanalization of large vessel acute ischemic strokes. This was achieved by comparing TCD to digital substraction angiography (DSA) during endovascular revascularization procedures. The authors evaluated time-linked DSA-TCD images from 96 angiographic runs during intra-arterial reperfusion procedures in 62 consecutive acute stroke patients.
Ultrasonographic recanalization (according to the Thrombolysis in Brain Ischemia – TIBI transcranial Doppler flow scale) was directly compared to angiographic recanalization (according to the thrombolysis in myocardial ischemia – TIMI score). The study’s main finding is that TCD could accurately predict reperfusion. The inter-rater reliability for evaluation of TIBI grades in the study was excellent. TCD had a sensitivity of 88%, specificity of 89%, and overall accuracy of 89% compared to DSA for the diagnosis of complete recanalization. When considering partial recanalization, the numbers were even more impressive. Moreover, the study found that complete recanalization by TCD was independently correlated with higher likelihood of good functional outcome at three months. The authors, however, do not provide a multivariate analysis for partial recanalization.
In the report, TCD was used by identifying the worst detectable residual flow-signals at a constant angle with transtemporal insonation. It is interesting that the authors were able to manage the difficult task of performing continuous TCD monitoring in agitated and uncooperative patients with large vessel occlusion.
In summary, the study comes timely considering that scarce data is available regarding the accuracy of TCD for detecting recanalization compared to DSA – or even MRA or CTA. It is a very well designed and executed study that encompassed a large sample size and included patients with occlusion in diverse intracranial locations (hence, enhancing its validity). It defines the precision of TCD in determining the arterial status during large vessel occlusion strokes, and promotes the utilization of this valuable – and possibly underutilized – tool.
By |February 25th, 2013|Uncategorized|0 Comments

Neuroimaging Findings in Cryptogenic Stroke Patients with and without PFO

Claude Nguyen, MD

Although many patients with cryptogenic strokes have a patent foramen ovale (PFO), the high prevalence of PFO in the general population suggests that some of these may be incidental. Therefore, neuroimaging in patients with PFO may assist with understanding the etiology in this stroke subtype. Thaler et al. sought to look at radiographic characteristics of such patients with cryptogenic stroke and PFO, also comparing those with “high risk” PFO characteristics (large shunt, shunt at rest, or associated hypermobile septum).

Using a database from the Risk of Paradoxical Embolism (RoPE) Study, which was constructed from 12 component databases, Thaler et al. reviewed neuroimaging, with preference for MRI over CT when available, based on established definitions for the index stroke size, location, and whether multiple or prior strokes were seen. Generalized linear mixed models were used to attempt to control for heterogeneity between component databases, and to look at patients with “high risk” PFO characteristics.

In all, 2680 subjects were included. Thaler et al. found a significant association between PFO and large, superficially-located strokes; conversely, those without PFO were more likely to have smaller, deeper, more chronic infarcts. Those with a PFO were not found to be associated with previous strokes or multiple infarcts; this was thought to be age-related, as those with PFO tended to be younger. There was no association between “high risk” PFO features and imaging characteristics.

This is the largest study to look at the imaging characteristics of those with cryptogenic stroke, limited mainly by the imaging assessments of the component databases. This work strengthens some of the traditional associations between PFO-related strokes and neuroimaging; however, as the authors caution, it is not always easy to distinguish between embolic and local disease. Also, conventional stroke risk factors may in fact contribute to stroke risk in those cryptogenic strokes appearing as small and deep infarcts. Therefore, neuroimaging characteristics should augment, not replace, clinical judgment in the quest to better characterize cryptogenic strokes.

By |February 22nd, 2013|Uncategorized|0 Comments

Chronic apraxia of Speech and “Broca’s Area”

Shruti Sonni, MD

Apraxia of speech (AOS) is a speech impairment characterized by deficits of motor planning and programming of speech articulation. There is currently no consensus regarding the site of lesion that causes AOS. Earlier studies have localized it to an area supplied by the superior division of the left middle cerebral artery (MCA), and more recently to the anterior insula (suggesting a clot in the MCA stem).  Gottesman et al. postulated that the insula may not actually be associated with AOS in the acute phase, but more so in recovery. In this study they tested the hypothesis that chronic AOS (lasting more than 12 months) is associated with large lesions involving the insula and Brodmann area 44/45 (Broca’s area).
Thirty-four right-handed English-speaking patients with chronic left sided supratentorial infarcts were enrolled in this study and administered the Apraxia Battery for Adults (ABA II). Their MRI FLAIR sequences were analyzed for location of infarct as well as size by volumetric analysis. Association between impairment on AOS measures and infarct location and volumes were calculated. Interestingly, none of the patients were found to have pure AOS, but rather AOS with some components of Broca’s aphasia (impaired fluency, naming etc.). There was a strong association between lesion volume and AOS on some subtests on the ABA II. Using stringent measures, AOS was found to be associated with left Brodmann area 44 and posterior insula.


Contrary to prior studies, the anterior insula was not associated with AOS in this population. This was explained by damage to the anterior insula in large strokes, suggesting that this was a possible confounder. AOS is difficult to reliably assess, and there is a lot of disagreement among speech language pathologists and neurologists regarding the existence and definition of this entity. In this study, subtle technical distinctions were made in AOS measures and localization, making it difficult to interpret the results clinically. The methodology section noted that patients selected were all English speaking. This raises the question if non English speaking patients have different findings than this population.
This is a good overview of the historical and current perspective on AOS, with well defined criteria for diagnosis. The authors conclude that chronic AOS is associated with larger infarcts, as many different areas are involved in speech praxis, and are capable of compensating for damage to single regions. The most important regions that were found to be associated with chronic AOS, independent of lesion volume, were Broca’s area, anterior temporal cortex and posterior insula, likely key areas in motor speech recovery. The suggested etiology for these lesions was likely embolic, probably from carotid dissection. The clinical significance of this paper is that patients with large left MCA strokes will probably benefit from early introduction of speech therapy and language rehabilitation. Further studies are needed for a convincing localization of speech praxis.
By |February 21st, 2013|Uncategorized|0 Comments

Predictors for Recurrent Primary Intracerebral Hemorrhage

Waimei Tai, MD
Huhtakangas J, Löppönen P, Tetri S, Juvela S, Saloheimo P, Bode MK, et al. Predictors for Recurrent Primary Intracerebral Hemorrhage: A Retrospective Population-Based Study. Stroke.  STROKEAHA.112.671230. Published online before print January 17, 2013.

Recently Huhtakangas et. al. in Finland published an interesting study on independent predictors for recurrent hemorrhage. They found that prior history of ischemic stroke was a strong predictive factor in having hemorrhage (HR 2.22 95% CI 1.22-4.05). Diabetes also suggested a trend towards hemorrhage but confidence interval reached below 1. Wellcontrolled hypertension was correlated with less likelihood of hemorrhage. 

Given the large national registry data that Finland has, this study had robust medication history and was able to explore previous work which suggested an interaction with SSRIs (selective serotonin reuptake inhibitors) and the signal of increased hemorrhage risk. Fortunately, this study did not find any additional suspicion that this widely prescribed class of medications was associated with additional hemorrhage risk.

This paper is useful in that it suggests patients who need SSRI’s ought not to fear about a possible increased risk of intracranial hemorrhage. This paper does suggest that for those with prior history of stroke, prevention of future hemorrhage is a good reason to be even more aggressive with diabetes management.

By |February 20th, 2013|Uncategorized|0 Comments

Pulse Wave Velocity and Cognitive Decline in Elders

Claude Nguyen, MD 
Al Hazzouri AZ, Newman AB, Simonsick E, Sink KM, Tyrrell KS, Watson N, et al. Pulse Wave Velocity and Cognitive Decline in Elders: The Health, Aging, and Body Composition StudyStroke. 2013;44:388-393.

Arterial stiffness is a risk factor for subclinical cardiovascular risk that increases with age.  By contributing to systolic hypertension, arterial stiffness has been shown to promote cerebrovascular disease, in turn influencing cognitive decline.  Previously, pulse wave velocity (PWV), a measure of arterial stiffness using transcranial doppler, has not been consistently shown to correlate with changes in cognition.

Al-Hazzouri et al. looked at the relationship between pulse wave velocity and change in cognitive function over 9 years, using a cohort from the Health, Aging and Body Composition Study (Health ABC).  This is a biracial population that has been prospectively followed starting prior to any functional deficits.  2,488 of these had arterial stiffness measurements at baseline based on PWV.  Cognitive function was assessed using Modified Mini Mental State Examination (3MS).  The 3MS was repeated at years 3, 5, 8, and 10.  They also looked at covariates including race/ethnicity, age, sex, years of education, alcohol consumption, smoking status, cholesterol, diabetic status, coronary disease status, blood pressure, and depression.

The study found that those with higher PWV were associated with lower cognitive score.  Even after correcting for cardiovascular risk factors, ApoE4 allele, and socioeconomic factors, there was still a significant association between PWV and poor cognition: those with middle-range PWV had 40% greater odds of cognitive impairment, while those with higher PWV had 59% greater odds of cognitive impairment.  They also found an association between higher PWV and poor performance on visuo-spatial and language tasks, not on memory or executive function. 
What is remarkable about the study is that prospectively, Al-Hazzouri et al. were able to show a relationship between high PWV and faster cognitive decline over a period of 9 years, even after controlling for traditional causes of arterial stiffness, such as cardiovascular risk.  There was a high dropout rate due to mortality, which may diminish the results; however, this is still the strongest evidence yet of an association between arterial stiffness and cognitive decline.  This provides evidence that interventions targeting hemodynamic stress and cerebral microvasculature may help to delay cognitive decline.

By |February 19th, 2013|Uncategorized|0 Comments

Heme Iron Intake and Risk of Stroke

Tareq Kasshout, MD

Kaluza J, Wolk A , Larsson SC. Heme Iron Intake and Risk of Stroke: A Prospective Study of Men. Stroke. 2013; 44: 334-339.

In a study recently published online in Stroke, Kaluza and colleagues are proposing an association between high heme iron intake and increased risk of stroke in normal weight patients. Inconsistent results were reported in the past about the relation between total iron intake and risk of stroke. This study was the first to separately differentiate between heme iron and non-heme iron in its relationship to stroke.

This population-based prospective Cohort of Swedish Men (COSM) showed, after 11.7 years of follow up, that intake of heme iron, but not non-heme iron, is associated with an increased risk of total stroke and cerebral infarction. This increased risk of stroke was only observed among men in the highest quintile of heme iron intake. Moreover, this observed association was confined only to the normal weight men.
The potential adverse effect of excessive heme iron intake, as based on results from animal studies, may be due to its pro-oxidative properties. However, the effect of reducing heme iron intake on risk of stroke in primary prevention is yet to be validated in further prospective studies.
By |February 15th, 2013|Uncategorized|0 Comments

Reliability (Inter-rater Agreement) of the Barthel Index

Aaron Tansy, MD

Duffy L, Gajree S, Langhorne P, Stott DJ, Quinn TJ. Reliability (Inter-rater Agreement) of the Barthel Index for Assessment of Stroke Survivors: Systematic Review and Meta-analysis. Stroke. 2013; 44:462-468.

The Barthel Index (BI), a ten item measure of activities of daily living, is a frequently employed outcome metric in the clinical practice and investigation of stroke.  Its pervasive use commands it a powerful degree of influence within the stroke community: perhaps, nowhere more so than in the research space where it oft determines the success or failure of many potential therapies.

Surprisingly then, whether or not the BI is robustly reliable across a diverse observership in this patient cohort had not been examined formally – until now. In an upcoming issue of Stroke, Laura Duffy and colleagues take the first stab at establishing whether the BI stands strong or wilts in the face of scrutiny as a bona fide assessment of functional recovery in stroke.   

The authors set about to accomplish this task in a three-step process. First, they briefly lay their groundwork, based in a priori classical test theory, for what are the most critical facets that define a clinical measure as robust and reliable: in the case of a metric like the BI that is utilized in clinical trials with multiple observers, low inter-rater variability is cited as most important. Next, they conducted a thoroughly exhaustive electronic database search for titles that met a strict inclusion criterion from which they culled a short list of original stroke clinical research (10 studies; n=543 subjects) in which the BI was administered via equivalent interview methods and for which inter-rater reliability data was reported. Lastly, after performing quality and risk of bias assessments on the trials of interest, they conducted a meta-analysis on BI inter-observer variability.  

Results indicated that inter-rater reliability was excellent (kw: 0.95, 95% CI: 0.94-0.96 fixed-effects modeling; kw: 0.93, 95% CI: 0.90-0.96 random-effects modeling). Furthermore, although a non-significant trend, sub-group analysis also suggested that BI training conferred a possible improvement in reliability between raters. In total, these findings suggested that the BI is a robust and reliable measure of stroke functional recovery.  

Despite demonstrating favorable results, as a meta-analysis, this study suffered some limitations largely with respect to its chosen data set. For one, it demonstrated significant clinical heterogeneity across studies with respect to BI observers, populations studied, and number examined. Moreover, only 20% (2) of the chosen studies were evaluated as high quality based upon the authors’ own chosen index of quality and risk of bias. So, does this study herald the BI’s imminent overtaking of the spotlight from the mRS in stroke? It seems unlikely. Both indices measure different functional parameters and have different inherent limitations providing support for their combined use.  And finally now, both have a little evidence to back it up.

By |February 14th, 2013|Uncategorized|0 Comments