American Heart Association

Monthly Archives: July 2015

Blending In: The use of the CT “Blend sign” to Predict Early Hematoma Growth

Vikas Pandey, MD

Li Q, Zhang G, Huang YJ, Dong MX, Lv FJ, Wei X, et al. Blend Sign on Computed Tomography: Novel and Reliable Predictor for Early Hematoma Growth in Patients with Intracerebral Hemorrhage. Stroke. 2015 
Intracerebral hemorrhage is a medical issue with numerous complications. In the majority of cases, the hematoma that is found on imaging is treated as an unpredictable mass of hemorrhage that clinicians usually take a “wait-and-see” approach in management with vague blood pressure goals and automatic follow up imaging. The group of authors from China decided to try to take some of the guesswork out of intracerebral hemorrhage management by coming up with a radiologic sign that may have some utility in prediction of hematoma expansion, dubbed the “blend sign”.

The blend sign refers to an area on a CT brain scan within a cerebral hematoma that shows blending of a hypoattenuating and a hyperattenuating region with a well-defined margin in between the two areas (please refer to image A on the attached image figure). The thought process between why the blend sign may be a predictive factor for hematoma growth is that blood clots within the hematoma and becomes hyperattenuating whereas hypoattenuating blood may be a sign of more liquid blood signifying active bleeding. The data the group compiled included a total of 172 patients of which the blend sign was seen in 16.9% (29 of 172). Out of the 61 patients that ended up having hematoma growth, 24 (39.3%) had a blend sign on the admission CT. The interobserver agreement showed a K-value of 0.957. The sensitivity, specificity, positive and negative predictive values of the blend sign were 39.3%, 95.5%, 82.7%, and 74.1%, respectively.

The blend sign shows promise as a reliable, easy to use and highly specific marker for hematoma growth. As neurologists and radiologists clamor to find the best markers for predicting hematoma growth (blend sign, spot sign, swirl sign, etc), the end-goal is always to prevent deterioration in the patient’s condition and any additional factor that can aid this should be embraced during the hospital care process for these patients.


Thrombolysis and long term outcome: A glimpse 5 years into the future

Chirantan Banerjee, MD

Machado C, João Pinho J, Nuno Alves J, Filipa Santos A, do Céu Ferreira M, João Abreu J, et al. Five-Year Outcome in Stroke Patients Submitted to Thrombolysis. Stroke. 2015

Thrombolysis revolutionized stroke care in the 1990s. We continue to advance stroke care, most recently with the advent of newer generation and more effective intra-arterial thrombolytic techniques. In all of the randomized trials and registries, the outcome is mostly assessed at 90 days. There are a few studies that have followed patients up to a year. Long term outcome data is very limited. Schmitz et al in 2014 reported that among Danish patients, treatment with intravenous tPA was associated with a lower risk of long-term mortality (adjusted hazard ratio, 0.66) at 1.4 years. In a Swiss cohort, at 3 years after IVT, approximately 1 of 3 stroke patients had an excellent outcome, and 1 of 3 had died.

In the current study, Machado et al report on functional outcome at 5 years in a prospective registry of patients who underwent IV thrombolysis at their stroke unit in Braga, Portugal between 2007-2010. Five year outcome was determined using telephonic interviews with patients or family surrogates. They report that one third of patients had mRS 0-1, but nearly half had died in the interim. They also found that NIHSS 24 hours after thrombolysis, rather than admission NIHSS was a predictor of excellent five year outcome. This is heartening to see, as it emphasizes the importance of vessel recanalization even 5 years down the line, regardless of initial clinical severity. With regards to mortality, because of limited data on post thrombolysis mortality at 5 years, it is difficult to contrast this data against others. But it is a little upsetting to note that as compared to natural history data from the pre-thrombolytic era, there isn’t a notable improvement, despite improvement in overall medical care since. This highlights the need to focus on developing more concrete protocols that would prevent medical complications after stroke, like pneumonia, deep venous thrombosis etc. Stroke should be viewed not just an acute neurologic insult, but a chronic medical ailment, needing continued aggressive outpatient care, even years after the initial injury.

Keeping the Blood Pressure Up!

Duy Le, MD

Löwhagen Hendén PL, Rentzos A, Karlsson JE, Rosengren L, Sundeman H, Reinsfelt B, and Ricksten SE. Hypotension During Endovascular Treatment of Ischemic Stroke Is a Risk Factor for Poor Neurological Outcome. Stroke. 2015

With the advent of endovascular therapy becoming a standard of care for acute ischemic stroke (AIS), much work is being done on optimizing the procedure itself. How long is too long? Which patients are the most appropriate candidates? Which is better: general anesthesia (GA) or conscious sedation (CS)? Most recently, we were relayed information that CS portended to better outcomes in AIS patients undergoing endovascular therapy. However, the study was limited due to the inherent nature of being a retrospective study. Nonetheless, the results leave us wondering what, if not for potential confounding factors; could this be due to?
Lowhagen et al attempt to tackle this question by retrospectively evaluating 108, consecutive, AIS patients who underwent endovascular therapy with GA, between 2007-2012. They find that patients who had a MAP drop of greater than 40% during the procedure (when compared to induction MAP) had an OR of 2.8 worse outcome. From a physiology standpoint, this argument appears to make sense. Lowering blood pressure decreases perfusion to the penumbra and collateralization, leading to more ischemic infarct, hence a poorer outcome. While it is tempting to draw lines and conclude that GA may lead to worse outcomes because of a drop in blood pressure, this study is too limited to conclude such a process.
I applaud Lowhagen et al for not attempting to make conclusions that go beyond the scope of this study. Limitations include 1) a small sample size in light of an extensive logistic regression analysis 2) slightly outdated data (including patients from 2007-2012) and more importantly, outdated devices 3) evaluating patients who underwent GA only 4) ultimately being retrospective in nature. Nonetheless, this study raises a number of questions which must be answered; mainly on what optimal blood pressure should be during endovascular therapy; and whether GA vs CS affect this. Lowhagen et al point towards work that needs to be done in the future; that which we are all clamoring for: A prospective randomized trial evaluating GA vs. CS in AIS patients undergoing endovascular therapy.
By |July 24th, 2015|treatment|0 Comments

Seizures After Stroke in Young Adults Are Associated with Mortality

Mark N. Rubin, MD
Arntz RM, Rutten-Jacobs LCA, Maaijwee NAM, Schoonderwaldt HC, Dorresteijn LDA, van Dijk EJ, and de Leeuw FE. Poststroke Epilepsy Is Associated With a High Mortality After a Stroke at Young Age: Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation Study. Stroke. 2015 

As if decades of disability or premature death is not enough for young adults who suffer an ischemic stroke, the development of post-stroke epilepsy – which is not entirely rare – is associated with a dramatic climb in short- and long-term post-stroke mortality. 

The authors of this study bring us the results of a large Dutch cohort (631 patients) recruited over a 30 year period (1980-2010) with substantial follow up (mean 12.5 years) scrutinizing the association between post-stroke epilepsy and mortality in young adults (age 18-50 years). Overall 76 of the patients (~12%) developed epilepsy in their post-stroke course. The cumulative 30-day case fatality difference was astounding: 27.4% vs 2.1% in those with and without post-stroke epilepsy, respectively. After adjusting for confounders, the development of epilepsy remained independently associated with mortality (HR 4.8, 95% CI 1.7-14), with the index stroke being the major cause of death in these patients.

There are other data that provide nuance to the consideration of post-stroke epilepsy as a reason to raise the hairs on the back of a provider’s neck, but the punchline is thus: a stroke severe enough to cause a seizure is also severe enough to take a life. It’s a Biomarker of Badness, although not quite so bad being singled out by Oscar!

By |July 23rd, 2015|prognosis|0 Comments

The renocerebrovascular nexus and small vessel strokes

Chirantan Banerjee, MD

Xiao L, Lan W, Sun W, Dai Q, Xiong Y, Li L, et al. Chronic Kidney Disease in Patients With Lacunar Stroke: Association With Enlarged Perivascular Spaces and Total Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease. Stroke. 2015
Renal and cerebrovascular beds share several physiologic characteristics like autoregulation and low resistance. Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease, cardiovascular mortality, as well as ischemic stroke. But the relationship is complicated, with several modifiers including traditional risk factors and race. A meta-analysis in 2010 (Lee et al) confirmed the association, as well as found a dose response relationship and a stronger relationship in Asian patients. Only African Americans were found to have an association between CKD and cardiovascular risk in a multi-ethnic cohort (NOMAS, Nickolas et al). Most of these studies are plagued by the issue of residual confounding by traditional cerebrovascular risk factors, as it is difficult to adjust for duration and severity of hypertension, diabetes etc. 

In the current study, Xiao et al studied the association between CKD and markers of cerebral small vessel disease in patients with lacunar stroke. 413 consecutive patients with mean age of 64 years were prospectively enrolled at Jingling Hospital in Nanjing, China. 3T MRI was performed, with enlarged perivascular spaces (EPVS) at the level of basal ganglia and centrum semiovale chosen as the dependent biomarker, as it hasn’t been independently studied previously in this context. The authors also then computed a ordinal cerebral small vessel disease burden scale ranging 0-4, incorporating the four MRI markers lacune, white matter hyperintensities (WMH), cerebral microbleeds (CMBs), and EPVS. eGFR and proteinuria were dichotomized and chosen as the independent variables. Logistic regression was performed adjusting for potential confounders like age, sex, hypertension, diabetes, smoking, hyperlipidemia etc. as well as brain atrophy index. Both impaired GFR and proteinuria were found to be independently associated with increasing severity of EPVS, as well as cSVD burden on MRI.

This study adds to the growing evidence of CKD being associated with cerebral small vessel disease, with the fact that every single biomarker for cSVD was significantly associated speaking for itself. The fact that 3T MR was used in the study makes generalizability difficult as most centers still use 1.5T MR. Also, eGFR was calculated using CKD-EPI equation. Regardless, it again highlights the renocerebrovascular nexus. Whether they are causally related, or different phenotypic manifestations of the same underlying risk factors remains to be answered.

Rare Variants in Intracranial Hemorrhage

Michelle Christina Johansen, MD 

Radmanesh F, Falcone GJ, Anderson CD, McWilliams D, Devan WJ, Brown WM, et al. Rare Coding Variation and Risk of Intracerebral Hemorrhage. Stroke. 2015

The world of intracranial hemorrhage (ICH) is too often left at the doorstep of neurosurgery while vascular neurology focuses on ischemic stroke. As residents and fellows, we learn the basic pathophysiology and localization in order to derive likely etiology, but do we really understand what predisposes one person with the same risk factors to ICH versus another?

Radmanesh et al. through a collaborative effort sought to identify rare coding variants that might be associated with the presence of ICH. 757 cases and 795 controls were genotyped and a meta-analyses of single-variant and gene-based association was computed. The group found a signal with three common variants on chromosome 19q13 which encompassed TOMM40, APOE and APOC1. However after adjusting for the APOE epsilon alleles (ε2 and ε4 alleles), it was no longer associated with ICH. The group concludes that the small sample size severely limits the data analysis and that studies in the future must pull together resources from international consortia.

Where does this leave the vascular neurologist? There have been critics of the genome-wide association study (GWAS) movement stating that GWAS has yet to deliver meaningful biologically relevant knowledge, results are spurious and the substantial grant money invested has been wasteful. There has been literature that offers evidence to the contrary. There have been recent discoveries in ALS, MS and RA from such targeted genetic research. As pointed out in this study, the price of performing a genome-wide association study has continued to decrease making it more plausible.

What about ICH? It is interesting that the investigators found an association with APOE, something more familiar perhaps to those in the cognitive realm. The presence of one or more copies of the ε4 allele is a potent risk factor for the occurrence of Alzheimer dementia. Is there perhaps some underlying pathophysiology that leads to an association between this and the presence of cerebral amyloid angiopathy? In one study in Neurology 2014, the presence of APOE variants was found to increase the risk of lobar ICH independent of the presence of Warfarin, although notably this study was also limited by power. TOMM40 lies close to APOE. How does it play a role? A total of 14 SNPs within TOMM40 were associated with AD but not CAA-related ICH according to Valant et al. in 2012.

There is clearly more work to be done in the field of ICH genetics. As academic centers focus on building secure genetic databases and increase collaboration, we will learn more about rare variants and then perhaps begin to understand the pathogenic pathway leading to ICH.

Natural history of MR in minor ischemic stroke

Chirantan Banerjee, MD

Kate MP, Riaz P, Gioia L, Sivakumar L, Jeerakathil T, Buck B, et al. Dynamic Evolution of Diffusion-Weighted Imaging Lesions in Patients With Minor Ischemic Stroke. Stroke. 2015
MRI revolutionized ischemic stroke care with its advent. Diffusion weighted imaging (DWI) was initially believed to represent infarct core. But that hypothesis was disproved as cases of “DWI reversal” came to light. The definition of TIA changed from the arbitrary time-based definition to a tissue based one, and our best clinical surrogate for tissue status is MR, which is used to make the distinction between TIA and minor stroke (when clinical symptoms have resolved). However, studies have showed that detecting DWI signal may be contingent on the timing of MR after stroke. Do it early, or lose they say. Also, up to one third of acute infarcts on DWI were not found to have a corresponding FLAIR lesion at 90 days.

In the current study, Kate et al study the temporal evolution of DWI lesions in minor acute ischemic stroke patients in the first 30 days. 114 patients with acute ischemic stroke who had NIHSS <= 3 were enrolled within 48 hours of stroke onset, and underwent 1.5T MRI within 48 hours, at 7 days and 30 days. 2 raters used a semi-automated method to assess DWI and FLAIR lesion volume. A difference of 0.3ml was considered significant when ascertaining infarct volume increase of decrease between the initial DWI lesion volume, and 30 day FLAIR lesion volume. 43% patients had infarct volume reduction at day 7, and 63% at day 30. Infarct growth occurred in 25% patients at day 7 and 14% at day 30. Larger baseline DWI lesion volume correlated with both volume reduction as well as growth. However, only 6 out of 114 (5.3%) patients had complete lesion reversal at 30 days, 5 of whom had reversed at 1 week. A higher mean baseline rADC, and isolated cortical location correlated with reversal. Interestingly, lesion evolution did not correlate with 90 day functional outcome at all.

Although the 5.3% proportion of patients with complete reversal at 30 days is much lower than the prior study which had complete reversal in 1/3rd patients at 90 days, about 2/3rds had lesion volume reduction. It would have been very helpful to have another follow-up MR at 90 days. The 5mm slice thickness I felt was the major limitation of the study, which results in loss of sensitivity. Regardless, the findings do shed light on how minor ischemic lesions evolve on MRI in the early post-stroke period. The more we study MR evolution after stroke, the closer we get to deciphering what the initial DWI lesion means!

White Matter Lesions Increase the Risk of Intracerebral Hemorrhage after Thrombolysis

Cerebral white matter lesions (WML), a manifestation of small vessel disease, has been associated with intracerebral hemorrhage (ICH). In this report, Curtze et al evaluated the risk of spontaneous ICH conferred by WML in ischemic stroke patients treated with intravenous thrombolysis (IVT). 

2485 consecutive patients treated with IVT over a 14 year period at the Helsinki University Central Hospital were evaluated. In addition to the baseline CT completed prior to IVT administration, a 24-hour post-IVT head CT scan was routinely done in this cohort (as well as when ICH was suspected). Symptomatic ICH (sICH) was defined per the ECASS-2 criteria; remote parenchymal hemorrhage was also assessed. WML grading (by four visual rating scales – Gorter scale, van Swieten scale, Blennow rating scale, and Wahlund rating scale) was completed from baseline CT scans by stroke neurologists blinded to patient data and outcomes.

124 patients developed sICH (5%). All of the rating scales (tested as continuous variables and dichotomized with different cut-off points) were associated with an increased risk of sICH (in univariate and multivariate models). A Wahlund scale score >1 (at least moderate focal WML) conferred a 2.7 (95% CI 1.87-3.90) higher odds of developing sICH in univariate analysis. This association remained (OR 2.64, 95% CI 1.71-4.02) even after adjusting for confounding variables. A Blennow score of 5 had the highest association with sICH (OR 3.59, 95% CI 1.72-7.5) in multivariate analysis. A Blennow score >4 (high burden of WML) also was associated with remote parenchymal hemorrhage (multivariable adjusted OR 4.11, 95% CI 2.38-7.1).

This study suggests that IVT-eligible patients with moderate-to-severe WML on baseline CT could have over two-fold higher risk of sICH. It the largest study on this topic; prior reports have evaluated smaller cohorts and demonstrated conflicting results. The notable limitations to this study are that it did not include a non-IVT treated stroke patient cohort and that it was a retrospective analysis. Though multiple factors contribute to sICH risk after IVT, this association should be kept in mind when discussing IVT with patients.

Early recurrence and cerebral bleeding in patients with acute ischemic stroke and AF

Rajbeer Singh Sangha, MD

Paciaroni M, Agnelli G, Falocci N, Caso V, Becattini C, Marcheselli S, et al. Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation: Effect of Anticoagulation and Its Timing: The RAF Study. Stroke. 2015 

The authors of this study tackled an important question and one that has always been a grey area for stroke neurologists. They looked to answer the question of when anticoagulation should be initiated following a cardioembolic stroke. This international prospective multicenter study looked at three main questions which included the risk of recurrent ischemic events and bleeding following a cardioembolic stroke, the risk factors which are associated with these events and finally what is the rate of recurrence and bleeding when anticoagulation has been initiated.

The study looked at 1029 patients out of which 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or TIA or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding and 14 (1.4%) major extracranial bleeding. Primary study outcome looked at recurrent ischemic cerebrovascular events (stroke or TIA) and symptomatic systemic Embolisms and also symptomatic cerebral bleedings and major extra-cerebral bleeding at 90 days. At 90 days, 50% of the patients were either deceased or disabled (mRS≥3), and 10.9% were deceased. Factors predictive of the primary study outcomes included CHA2DS2-VASc score, high NIHSS, large ischemic lesion and type of anticoagulant. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared to initiating treatment before the aforementioned time period. About 7% of the patients treated with oral anticoagulants alone had an outcome event compared to 16.8% and 12.3% of the patients treated with low molecular weight heparins (LMWHs) alone or followed by oral anticoagulants, respectively (p=0.003).

Patients who received a direct oral anticoagulant were found to have low risks for both
symptomatic intracranial bleeding (2.1%) and ischemic event (4.3%), suggesting the need for further testing the new class of novel anticoagulant drugs in the acute phase of ischemic stroke in patients with AF. The advent of the novel anticoagulants has allowed for a reduction not only in ischemic events secondary to AF but also reduced bleed rates and thus I ask how far can we push the boundaries of starting these medications before we run into greater risks than benefits. This topic continues to be one of contention as the point in time to start anticoagulation is likely to be stratified secondary to multiple factors; perhaps a composite score should be created and tested in future studies.

Proteinuria, A New Disease Marker?

Ali Saad, MD

Sandsmark DK, Messé SR, Zhang X, Roy J, Nessel L, Hamm LL, et al. Proteinuria, but Not eGFR, Predicts Stroke Risk in Chronic Kidney Disease: Chronic Renal Insufficiency Cohort Study. Stroke. 2015

In the CRIC study (chronic renal insufficiency cohort) they took about 4000 people with CKD (chronic kidney disease) and followed them prospectively to see if they had strokes. 143 stroke events (25 of them were intracerebral hemorrhage) occurred over 6.4 years and proteinuria was found to be a risk factor for stroke independent of eGFR (estimated glomerular filtration rate) (HR 3.1, p<0.0001). Albuminuria more specifically was an even greater risk factor (HR 3.6, p<0.0001). Albuminuria remained statistically significant at all abnormal value ranges after multivariable analysis while proteinuria remained significant only at the mid and high abnormal value ranges. Another important result is that using an ACEI/ARB to decrease proteinuria did not decrease stroke risk. 

These patients were not dialysis dependant or on immunotherapy for renal disease or vasculitis. The ones who had strokes were also more likely to be older, black, have a history DM, MI, stroke, tobacco use, or alcohol use. Although there was a dose dependant response of lower eGFR correlating with a greater risk of stroke, it didn’t reach statistical significance once demographics were controlled for in multivariable analysis.
Limitations of this study:
– the results don’t necessarily mean that low eGFR is not a stroke risk factor since there were no healthy controls and everyone had renal dysfunction
– stroke subtypes were not specified, but one would think that most of these people would have small vessel disease strokes
– history and meds were self reported
– not enough ICH to make any conclusions about the association between ICH and proteinuria. also there is no distinction between primary ICH and hemorrhagic conversion of an ischemic stroke
– TIAs were not included
– patients were only followed for about 6 years
– population was mostly black males in their 50s-70s
– strokes were defined as definite/probable by patient reporting which then triggered medical records review, but there is no mention of whether this was based on neuroimaging

How does this study change my practice?
I already cite CKD as a stroke risk factor to patients, there’s just more data to back it up now. I wouldn’t collect a 24 hour urine sample in order to help risk stratify someone as it isn’t practical. It’s hard enough getting people to agree to heart monitors. Perhaps albuminuria can be incorporated into a stroke risk calculator like the CHA2DS2-VASc score or something similar?