American Heart Association

Monthly Archives: November 2013

How much is too much? White matter hyperintensity burden on MRI

Pete Hannon, MD

King KS, Peshock RM, Rossetti HC, McColl RW, Ayers CR, Hulsey KM, et al. (HCR)Effect of Normal Aging Versus Hypertension, Abnormal Body Mass Index,and Diabetes Mellitus on White Matter Hyperintensity Volume. Stroke. 2013

“White matter changes consistent with non-specific chronic microvascular disease.” These words, or something similar, grace a very large percentage of our MRI reads, and have caused much consternation to patients, not to mention any number of Neurology referrals. When it comes to white matter changes, how much is too much? What is normal?



To help answer these questions, authors Dr. Kevin King and colleagues have compared age-related differences in MRI white matter hyperintesity (WMH) volume in healthy individuals vs. those with comorbid hypertension, abnormal BMI and/or diabetes. From 2007 to 2009, MRIs of 2011 participants were evaluated for WMH volume. Of that number, 285 lacked the pre-specified comorbidities (relative healthy controls), 973 had hypertension, 245 had diabetes, and 1578 had abnormal BMI. Participants were subgrouped by ethnicity, sex and age. Per authors, there was a linear association between age and a greater log WMH volume. Before age 50 there was no significant difference between the two groups, however after age 50 a more rapid increase in WMH volume was noted in the group with comorbidities (p=0.0008).

Within the scope of the subgroups selected, it is evident that “normal” aging carries with it some increase in WMH burden. Unfortunately within the control group, there is no mention of smoking history, cholesterol levels, or other cardiovascular risk factors, and the two groups had significant difference at baseline regarding sec and race, making it difficult to generalize what WMH volume can be attributed to normal aging, free of other comorbities. The marked cutoff after age 50 does highlight the role that HTN, DM and obesity to play in WMH burden, however, especially as we age.

It’s commendable that this study aims to find what WMH can be attributed to normal aging, and that which may be attributed to other causes. In the future it will be nice to have specific criteria for what burden of WMH burden can be considered “within normal limits.”

By |November 15th, 2013|Uncategorized|0 Comments

Intracerebral Hemorrhage due to Oral Anticoagulant use in the Netherlands

Vivek Rai, MD

Schols AMR, Schreuder FHBM, van Raak EPM, Schreuder THCML, Rooyer FA, van Oostenbrugge RJ, et al. Incidence of Oral Anticoagulant–Associated Intracerebral Hemorrhage inthe Netherlands. Stroke. 2013.

Bleeding, especially Intra-cerebral hemorrhage (ICH), is a serious complication of oral anticoagulant (OAC) use. In the Netherlands, acenocoumarol and phenprocoumon are mainly used under dose regulation guided by specialized anticoagulation clinic. Schols and colleagues retrospectively analyzed all adult cases of confirmed non-traumatic ICH while on OAC between 2007 and 2009. 



Authors report that acenocoumarol was used by 134 (79.8%) patients, 20 (11.9%) patients were using phenprocoumon and 14 (8.3%) patients used a combination of OAC with another antithrombotic drug. Of all ICH cases, 168 (25.8%) were OAC-associated and 153 of these (91.1%) were first-ever OAC- ICH. The absolute risk of OAC-ICH was 0.46% per patient-year of OAC treatment.

This reported absolute risk, although slightly higher than previously reported rate, is well within the range of bleeding risk reported in clinical trials using Warfarin. It is to be kept in mind that this is an estimated risk only and that usually controlled environment of trials tends to underestimate the risk. 

I think that slightly higher annual risk in this study is reflective of increasing number of patients using anticoagulants in a more controlled (specialized clinics) environment through which adverse event reporting tends to be more accurate. While the exact numbers may not be applicable to population is the United States, this study provides good estimation of OAC-ICH risk that can be used in discussion with the patients while making decision about use of OAC.

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

Adiponectin and Risk of Stroke

Hassanain Toma, MD

Arregui M, Buijsse B, Fritsche A, di Giuseppe R, Schulze MB, Sabine Westphal, et al. Adiponectin and Risk of Stroke: Prospective Study and Meta-analysis. Stroke. 2013

Adiponectin is a hormone that is derived from adipose tissue. It is believed to have anti-inflammatory, anti-atherogenic and insulin-sensitizing properties. Due to these favorable cardiovascular effects, Arregui et al. sought to study the relationship between plasma adiponectin and stroke, through a prospective case-cohort design, and meta-analysis of 9 prospective studies.



The authors found that in their study population, adiponectin was associated with higher HDL-cholesterol and lower C-reactive protein, triglyceride levels, and diabetes, interestingly however, they found adiponectin to be directly associated with stroke, with a hazard ratio of 1.31 (95% CI 1.04-1.64).

The association between adiponectin and stroke was lost when combining their data with 9 other studies through a meta-analysis, with a pooled relative risk was 1.08 (1.01-1.15).

I totally expected adiponectin to be inversely related to stroke risk because of its ability to provide overall favorable cardiovascular effects; improved lipid profile, anti-inflammatory and anti-diabetic effects. However, the results of the cohort study showed the complete opposite. The authors did a good job in providing possible explanation for this discrepancy. On the other hand, the pooled meta-analysis did not show an association between adiponectin and stroke. I am not a statistician, but on reviewing the pooled studies, I feel more confident in the results of their cohort population than in the meta-analysis. The previous studies were adjusted for different variables, and one study was unadjusted for any variables. This may have resulted in the loss of association between adiponectin and stroke. Perhaps an individual patient-level data meta-analysis would be a more meaningful study in this case.

Furthermore, adiponectin exists as globular-adiponectin and as full-length fractions of low-, medium-, and high-molecular weight. The authors noted that they only assessed the total adiponectin, and provided partial rationalization for it. This would be analogous to assessing your patients’ cardiovascular risk based on total cholesterol and omitting the value of LDL-cholesterol. As far as I am concerned, the race for understanding the relationship between adiponectin and stroke continues.

By |November 13th, 2013|Uncategorized|0 Comments

Cerebral vasomotor reactivity and the risk of mortality: the Rotterdam Study

Sebina Bulic, MD

Portegies MLP, de Bruijn RFAG, Hofman A, Koudstaal PJ, and Ikram MA. Cerebral Vasomotor Reactivity and Risk of Mortality: The Rotterdam Study. Stroke. 2013

Vasomotor reactivity has been identified as a prognostic marker for cerebrovascular damage. It is measured using TCD, which allows continuous monitoring and assessment of the intracranial circulation with each heartbeat providing physiologic information. Basis of vasomotor reactivity is the ability of vessel to dilatate in response to increased blood CO2 content. Typical use of vasomotor reactivity has been associated with the assessment for the risk of perioperative stroke during cardiopulmonary bypass and during other major surgeries, during other procedures with hypotension risk and for the stroke risk stratification from asymptomatic carotid stenosis. 



Vasomotor reactivity has been measured within the population-based Rotterdam Study, but no association between vasomotor reactivity and stroke was found. This impressive, population based study aimed to assess whether impaired cerebral vasomotor reactivity has associates with poorer survival and all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, and stroke in a general elderly population. From 1997-1999, 2732 patients underwent vasomotor reactivity assessment. Follow up was completed January 2011. The associations with both all-cause mortality and cardiovascular mortality remained significant after censoring for incident stroke suggest that a low vasomotor reactivity is a marker of accumulating vascular damage. The main causes of cardiovascular death after censoring for strokes were heart failure, cardiac arrest, sudden death with unknown cause, and myocardial infarction which supports the hypothesis that loss of cerebral vasomotor reactivity is a reflection of a more systemic dysfunction of the vascular system rather than only cerebrovascular damage.

Our world faces increase in the vascular disease. The authors spotlight identification of parameters predictive of such burden using non-invasive measurement of hemodynamic change when cerebral-vascular circulation is challenged. I commend the authors on these efforts, impressive recruitment and follow up. However, as an RVT who knows limitations of TCD well, I don’t foresee its use in prognosis or clinical management of the conditions where association was established.

By |November 12th, 2013|Uncategorized|0 Comments

Therapeutic Hypothermia After Recanalization in Acute Ischemic Stroke (HARIS)

Alireza Noorian, MD

Hong JM, Lee JS, Song HJ, Jung HS, Choi HA, and Lee K. Therapeutic Hypothermia After Recanalization in Patients With AcuteIschemic Stroke. Stroke. 2013

Therapeutic Hypothermia (TH) is one of the neuroprotective strategies that can potentially be beneficial in acute ischemic stroke especially along with fast recanalization, by impacting multiple molecular pathways including excitotoxicity, oxidative injury, inflammatory response and ischemia-reperfusion injury.



In their recent study, Hong et al, did a prospective analysis on acute ischemic strokes due to large vessel occlusion strokes in the anterior circulation with NIHSS≥10 with successful recanalization (≥TICI 2b). They investigated the clinical and radiological outcomes in two groups of these patients, with and without TH (mild [34.5 C], over 48 hr period with rewarming in the following 48 hrs) in two centers along with mechanical ventilation and standard medical care in both centers.
The hypothermia group had less cerebral edema, hemorrhagic transformation and better functional outcome in a statistically significant manner compared to the normothermic group. There was no difference in the rate of mortality, hemicraniectomy rate and medical complications. Following adjustments for confounders, TH and distal occlusions were the independent predictors for good outcome. 

Despite being a small pilot study, inherent differences in the two treatment centers, the study points towards a potential benefit for concurrent hypothermia along with recanalization strategies to improve outcome, which should be considered in future randomized trials.


By |November 11th, 2013|Uncategorized|2 Comments

Endothelial stem cells impact stroke recovery

Nirali Vora, MD

Ishikawa H, Tajiri N, Shinozuka K, Vasconcellos J, Kaneko Y, Lee HJ, et al. Vasculogenesis in Experimental Stroke After Human Cerebral EndothelialCell Transplantation. Stroke. 2013

Stem cell trials in stroke have primarily targeted clinical endpoints, but how does stem cell transplantation actually work on the molecular or histological level? The authors of this study have tested the hypothesis that direct vascular repair by endothelial cells contributes to neurogenesis/neuro-protection. 


In the study, they transplanted cerebral endothelial cells called HEN6, of varying doses vs. placebo, into the striatum of rats with experimentally-induced MCA ischemic stroke. At 7 days, they found a dose-dependent relationship with higher HEN6 associated with smaller infarct volumes, and better functional outcome in terms of rat behavior. Histologically, they found less reactive gliosis (decreased GFAP staining) and more vasculogenesis (more collagen-IV staining). An in-vitro portion of the study also showed the positive effect of VEGF with HEN6 in reducing apoptosis compared to placebo.

This study supports the role of endothelial stem cells (HEN6) in vasculogenesis and better outcomes at 7 days post-stroke when transplantation occurs acutely. We have a stem cell study at our institution that is for stroke patients that are at least 6 months out from their stroke. Would the impact on functional recovery be similar at this time? 

By |November 8th, 2013|Uncategorized|0 Comments

The SCAR rule may predict lower procedural risk of carotid artery stenting

Adam de Havenon, MD

Touzé T, Trinquart L, Felgueiras R, Rerkasem K, Bonati LH, Meliksetyan G, et al. A Clinical Rule (Sex, Contralateral Occlusion, Age, and Restenosis) to Select Patients for Stenting Versus Carotid Endarterectomy: Systematic Review of Observational Studies With Validation in Randomized Trials. Stroke. 2013


The CREST trial and several other large-scale studies have shown that carotid artery stenting (CAS) is associated with a higher periprocedural risk of stroke than carotid endarterectomy (CEA) in patients with symptomatic carotid stenosis. Selected patients would benefit from CAS given increased surgical risk, anatomical abnormality of the neck, or low procedural risk of CAS. Apart from younger age, though, no other variable has been associated with reduced periprocedural risk in CAS. 


In the paper by Emmanuel Touzé et al., a meta-analysis of existing literature was used to find four variables that were significantly associated with equal periprocedural risk for CAS and CEA. They were: sex (female), contralateral occlusion, age (<75), and restenosis (SCAR rule). If any of the criteria were present patients were deemed SCAR negative. The rule was then validated with data from the EVA-3S, SPACE, and ICSS randomized trials with a primary outcome of procedural risk of stroke or death. The rule was then relaxed to identify SCAR negative as having two criteria present and was again validated.

For SCAR negative patients the primary outcome was the same between CAS and CEA, but for SCAR positive patients the risk of CAS was more than twice that of CEA. The statistical methods used to derive and test the rule are incredibly complex and draw on heterogeneous data from a large number of sources. Although the authors suggest that the SCAR rule can “already be considered useful for clinical practice,” I would temper that enthusiasm until other researchers have also validated it. 

Possible clue to the cause of SAH-induced vasospasm revealed

Matthew Edwardson, MD

Raya A, Zipfel GJ, Diringer MN, Dacey JR, RG, Derdeyn CP, Rich KM, et al. Pattern Not Volume of Bleeding Predicts Angiographic Vasospasm in Nonaneurysmal Subarachnoid Hemorrhage. Stroke. 2013


Vasospasm and delayed cerebral ischemia (DCI) are dreaded complications of subarachnoid hemorrhage (SAH). Why vasospasm occurs after SAH remains a mystery. The most accepted theory entails pro-spasmodic substances released in close proximity to cerebral vessels during subarachnoid clot lysis. It follows that a larger burden of subarachnoid blood should lead to increased rates of vasospasm and DCI; while this association has borne out in studies of aneurysmal SAH, it remains unproven in non-aneurysmal SAH.




Raya and colleagues retrospectively studied patients with atraumatic, angiographically proven non-aneurysmal SAH seen at Washington University in St. Louis and separated them into diffuse SAH (n=29) and perimesencephalic SAH (PM-SAH) (n=60). The authors found higher rates of vasospasm in the diffuse SAH group (OR 2.9, p = 0.08) and wondered whether increased clot burden might explain this. They used the Hijdra and IVH scores to estimate clot burden and found that the diffuse SAH group still had higher rates of vasospasm than the PM-SAH group even after correcting for Hijdra/IVH score (OR 2.2, p = 0.18). 

This study is intriguing because it implies that there are more factors at play than just volume of subarachnoid blood in determining risk for vasospasm and DCI. PM-SAH patients are well known to have lower risk for developing vasospasm / DCI. If this lower risk is not entirely attributable to lower subarachnoid clot burden, then what could it be? Location of blood in a less spasmogenic area is one possibility; perimesencephalic blood contacts fewer intracerebral vessels than blood engulfing the circle of Willis. Another possibility is the long-theorized venous rather than arterial source of subarachnoid blood in PM-SAH patients. If venous blood contains less pro-spasmodic substances than arterial blood it might explain the benign disease course in PM-SAH. This could lead to interesting avenues of research – trying to isolate substances found only in arterial blood and testing them for their spasmodic properties. Such research may one day help us unravel the mystery behind SAH-induced cerebral vasospasm.

By |November 6th, 2013|Uncategorized|0 Comments

How Much does Intracranial Hemorrhage Cost?

Waimei Tai, MD


Specogna et al did an interesting analysis of a large cohort of intracranial hemorrhage (ICH) patients in one large tertiary care facility in Calgary, Alberta Canada. The demonstrated using administrative database in their single payer system that the median cost of an was about $USD 10,500 in 2008 adjusted dollars. There was a wide range (no surprise). What was interesting was that higher patient age and in-hospital mortality lowered the cost of the hospitalization. This is different that ischemic stroke data that suggests in-hospital mortality would likely increase the cost of hospital care. Perhaps this is due to the generally more medically sick ICH patients and a shorter length of stay associated with in-hospital mortality that contributes significantly to hospitalization costs.




A higher Charlson Comorbidity Index and having surgery for ICH also increased the acute care costs (no surprise).


Over all this study is useful in better understanding contributors to the cost of acute care in a single payer economy such as Alberta to develop predictive tools to help forecast expeditures. The medical drivers of cost are predictable. I think this case study should serve as an example to other payer/hospital systems to also critically look at drivers of cost of acute care as the quality/cost debate continues to grow as regulators in the U.S are looking to reimburse using value metrics. Better understanding who the drivers are allows us to selectively provide care that is most appropriate and cost effective. Hopefully the data on ICH surgery will provide more selection criteria to identify the best surgical candidates to offer this expensive intervention to.

Government policy drives stroke center certification

Nirali Vora, MD

Schuberg S, Song S, Saver JL, Mack WJ, Cen SY, and Sanossian N. Impact of Emergency Medical Services Stroke Routing Protocols onPrimary Stroke Center Certification in California. Stroke. 2013

Pre-hospital delays in stroke care are an ongoing target in the battle of time vs. brain. One way to save time is to have paramedics divert patients directly to stroke centers capable of acute treatment rather going to the nearest hospital until transfer to a stroke center is arranged.



The body that governs the process of routing patients is not uniform. In California, it is governed at a county level, with progressive adoption in the last 10 years of paramedics routing stroke patients only to hospitals designated as “Primary Stroke Center” (PSC). Schuberg and colleagues found the rate of hospitals seeking PSC certification increased dramatically around the time the routing policy was adopted in that county. Makes sense. If I was a hospital administrator, I would not want to lose all the stroke business because I wasn’t certified. There are added variables like increased Medicare reimbursement for tPa in 2005 that may also have contributed to PSC growth.

The authors go on to suggest that adopting a national policy to route patients to stroke centers would continue to increase rates of PSCs, and therefore lead to better stroke care. While I certainly expect the economic motivation to drive more PSCs, the last part about improved care is a bit of an assumption. I live in one of the top 4 counties with greatest number of PSCs in California and recognize that there are variable services and care offered at each hospital, despite the label of “PSC.” With the advent of Comprehensive Stroke Center (CSC) designation by the Joint Commission, an even higher complexity certification is available. Should EMS be routing patients only to CSCs? Do labels really guarantee quality? Maybe we should study disability (mRS) at 7, 30, or 90 days in stroke patients treated at centers before and after certification, or compared to non-certified centers. What do you think? 

By |November 4th, 2013|Uncategorized|0 Comments