American Heart Association

Monthly Archives: April 2013

BCAA in rat model of stroke

Tareq Kass-Hout, MD

 In a study recently published online in Stroke, Kimberly and colleagues found an association between reduced levels of Branched Chain Amino Acids (BCAA) and cerebral ischemia in both animal model and human subjects. Such a novel biomarker will be the first to show changes in circulating plasma metabolites in the setting of cerebral ischemia, which in turn, may provide an insight on the pathogenesis of acute cardioembolic stroke.

The investigators compared plasma and CSF levels of multiple metabolites rats undergoing cerebral ischemia and controls. They also analyzed plasma samples from controls and acute stroke patients. They found significantly lower levels of branched chain amino acids (BCAA; valine, leucine, isoleucine) in rat plasma, rat CSF and human plasma compared to respective controls (16%, 23% and 17%, respectively; p<0.01 for each). Also, in human subjects presenting with acute stroke, lower BCAA levels were correlated with poor neurological outcome (mRS 0-2 versus 3-6, p=0.002). Whether BCAA are in a causal pathway or are an epiphenomenon of ischemic stroke remains to be determined.
There is limited information about changes in metabolism during acute ischemic stroke. Although this study point towards a key role for BCAA in stroke, this correlation in a multivariate regression must be interpreted with caution in such a small patient cohort.

Luminal Narrowing of Leptomeningeal Arteries in CADASIL

Jose Gutierrez, MD, MPH

Dong H, Ding H, Young K, Blaivas M, Christensen PJ, Wang MM. Advanced Intimal Hyperplasia Without Luminal Narrowing of Leptomeningeal Arteries in CADASIL. Stroke. 2013

CADASIL is the most common form of heritable stroke and vascular dementia. The clinical presentation is very well known, although less is known about the pathophysiology of the disease. In this issue, Dong et al. investigated leptomeningeal arteries of 6 patients with genetically diagnosed CADASIL, 6 controls within the age range that those with CADASIL and 6 aged controls. The authors obtained morphometric and immunological arterial characteristics in cases and controls. The authors found that in arteries from patients with CADASIL, the intima was 5 fold thicker, the media was thinner and the sclerotic index was greater than in those without CADASIL. Surprisingly, the lumen was not significantly smaller despite the intima hyperplasia. The hyperplastic intima expressed muscle-like proteins.

If the intima was 5 times thicker and the lumen remained the same, why do patients ultimately develop strokes? How could an intact lumen be associated with cortical dysfunction that eventually leads to dementia as the authors suggested? Several explanations come to mind. We don’t know based on the published data if all leptomeningeal arteries had the same size across groups. This is important, because the proportion of the intima and the media vary according to arterial size. Also, these specimens might represent a very early form of intima hyperplasia. According to the classic model of atherosclerosis by Glagov et al. we know that coronary arteries enlarge to compensate for up to 40% of intima thickening before the lumen becomes compromised. Although this is less well-established in brain arteries, it could be an explanation. If these findings are confirmed in larger datasets, one might think of potential ways treat this disease. Antiproliferative measures could be imagined to arrest the intima thickening and preserve the lumen. If we could identify the process even earlier, more aggressive controls of concomitant vascular risk factor might be warranted to avoid further intima thickening. The work by Dong et al. broadens the horizons to imagine new treatments of this and other arteriopathies that cause stroke and vascular dementia.


Validation of the ABCD3-I Score

Waimei Tai, MD


Bo. et. al. compares two prediction calculators for use in predicting near term stroke risk in patients who present with TIA. One is a purely clinical score (ABCD2) which incorporates age, history of diabetes, blood pressure, and clinical symptoms and duration of symptoms into the calculation. The second uses similar clinical metrics in addition 3 other signs (recurrent TIA within 7 days, ipsilateral vessel narrowing, DWI lesion). 

Patients were often moved from low to medium, or medium to high risk using the additional criteria in the ABCD3-I score. Those in the highest strata in the ABCD- I score had a 41% risk of stroke in 90 days while those in the lowest strata had no stroke at 90 days.

This study highlights and validates the higher positive predictive value of the modified ABCD2 score (ABCD3-I) and validates it in an ethnically different cohort than the previously retrospectively identified TIA cohorts.

Based on the new(-ish) TIA guidelines published by the AHA in 2009, using a tissue based definition, it makes sense that those with a DWI lesion have a higher risk of recurrent event. Similarly, having a prior episode of TIA also increases your risk of near term ischemic event (TIA begets TIA). Carotid stenosis has long been proven to contribute to a larger proportion of near term stroke risk. I think using imaging criteria to help identify patients at highest of near term events will aid in appropriate triaging of patients in a resource constrained environment.

I suggest that vessel imaging be used in the ED to triage patients into low, medium and high risk strata, and allow this to guide an outpatient evaluation and management of TIA (similar to other groups in Paris or Australia). To my knowledge, only a few centers in the US do this.  What is the practice in your area? What would you do if you had additional information in the ED? Do you routinely recommend vessel imaging to help triage patients?

Occult atrial fibrillation in cryptogenic stroke

Shruti Sonni, MD

A well known cause of cryptogenic stroke is intermittent atrial fibrillation (AF). Different cardiac monitors have been used for varying amounts of time to detect AF, with low sensitivities. Ritter et al. implanted 60 patients with acute cryptogenic stroke with insertable cardiac monitors (ICM) for a minimum of 12 months, and set them up with 7-day Holter monitors as well. Intermittent AF was identified in 10 patients with ICM between 1- 556 days after implantation, only one of which was also found on Holter monitoring. The authors concluded that ICM implantation was feasible, safe and had a higher diagnostic yield than 7-day Holter monitoring.

The ideal duration of ICM is yet to be determined. Often patients with ICMs and their physicians choose to leave the monitor in for a prolonged period of time, likely due to the convenience aspect, making one wonder about the cost-effectiveness of this diagnostic service. However, compliance is superior to the 7-day Holter group, making efficacy of prolonged (30 day) Holter monitoring perhaps even more questionable. Although minimally invasive, it may be a good idea to use ICMs after a negative study with 7-day Holter monitoring, to possibly spare 1 in 10 patients the implantation procedure. The authors also identify an important clinical question- are few minutes of AF identified on ICM as much a risk for stroke, and do these patients deserve treatment with anticoagulation? Hopefully the TRACK-AF study, a prospective study by this group, will provide more answers.

Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Repeat Doses of GSK249320

Tareq Kass-Hout, MD

In a study recently published online in Stroke, Cramer and colleagues are proposing the monoclonal antibody (GSK249320) as a neurobiology modulator of human brain repair system after stroke. Promising results were reported in the past about the potential benefit of restorative therapies in reducing disability and improving outcomes in stroke patients. This study was the first to objectively evaluate the safety and tolerability of these antibodies and its translation in a better motor function. 


This is a small prospective Cohort of 42 patients with mild-moderate stroke showed randomized to IV (GSK249320) (1,5 or 15 mg/kg per infusion) vs. Placebo. After 112 days of follow up, that monoclonal antibodies (GSK249320) in escalating doses had no safety concerns compared to placebo. Global outcome measures were similar across all groups. Moreover, one of the functional outcomes (gait velocity) showed a trend towards improvement with monoclonal antibodies. 

This novel approach to brain repair after stroke with monoclonal antibodies infusion support the safety and tolerability of this pharmaceutical compound. Future studies might explore this efficacy as a restorative therapy for stroke.


Association of hypertension with stroke recurrence depends on ischemic stroke subtype

Osman Mir, MD

Wang Y, Xu J, Zhao X, Wang D, Wang C, Liu L, et al. Association of Hypertension With Stroke Recurrence Depends onIschemic Stroke Subtype. Stroke. 2013.


It is well known that hypertension is one of the leading stroke risk factors. The association between hypertension and stroke recurrence, however, is not well defined. Wang et al. explore the relationship between hypertension and stroke recurrence, and hypothesize that this association varies by stroke subtype. They test this hypothesis on more than 11,000 patients from a  Chinese stroke registry. 

This is a very large retrospective study. As expected,  the authors find that hypertension is highly prevalent in patients with ischemic stroke (over 70% of patients in their registry had hypertension). They also find an association  between HTN and stroke recurrence. After controlling for various factors,  they only find solid evidence of the relationship with small vessel disease and not with other subtypes. This is important because in order to address stroke recurrence we need to tackle the risk factors responsible for that. But when interpreting this finding we need to remember that this was a retrospective study. 

Prospective trials such as WASID and SAMPRIS have clearly found an association between  hypertension control and lower stroke recurrence. The current study provides some food for thought: ischemic stroke is a heterogeneous disease with heterogeneous risk factors and in order to address recurrence we need to concentrate on specific risk factors for that stroke sub-type. It also makes a case for investigating ischemic stroke cause thoroughly as that might help differentiate the stroke sub-type leading to change in the management. 

Magnetic Resonance Imaging-DRAGON Score

Nandakumar Nagaraja, MD, MS

 
MRI-DRAGON score is an adaptation of CT DRAGON score to predict 3 month outcome in acute anterior circulation stroke patients who had MRI as initial diagnostic workup and were treated with IV t-PA within 4.5 hours.

One point each is given for M1 occlusion, DWI ASPECTS ≤ 5, prestroke mRS >1, Age 65-79, Glucose level >8mmol/l prior to t-PA, Onset to treat time >90 min and NIHSS 5-9 prior to IV t-PA. Two points each is given for age ≥ 80 and NIHSS 10-15. Patients with NIHSS>15 get 3 points. With MRI-DRAGON score total of 10 points is possible.

Among 228 patients evaluated with the MRI-DRAGON score in the study all patients with total score ≤ 2 (n=22) had a good outcome (mRS 0-2) while those with score ≥ 8 (n=11) had poor outcome (mRS 5-6). Poor outcome was significantly associated with all parameters considered in the MRI-DRAGON score except onset to treat time and prestroke mRS>1 which only had a nonsignificant trend towards poor outcome.

It is well known from previous studies that the odds of good outcome is higher for those patients treated within 90 min of symptom onset compared to those treated in 90-180 min and 180-270min of symptom onset. However it is interesting to note in this study that onset to treat time>90min had only a nonsignificant trend for association with poor outcome.

This tool incorporates only information that is available prior to IV t-PA administration. Therefore it may be helpful in selecting patients for therapeutic interventions in clinical trials, for example, excluding patients with higher MRI-DRAGON score (≥ 8) due to increased probability of poor outcome at 3 months in these patients.

Early prediction of delayed cerebral ischemia after SAH

Diogo C. Haussen, MD
 

de Rooij NK, Greving JP, Rinkel GJE, Frijns CJM. Early prediction of delayed cerebral ischemia after SAH: development and validation of a practical risk chart. Stroke. 2013.

Delayed cerebral ischemia (DCI) is a common complication in the setting of subarachnoid hemorrhage and it may be a major determinant of morbidity and mortality. De Rooij et al. report the development and validation of a risk chart that incorporates only variables collected at admission and aims to predict the risk of infarcts related to delayed cerebral ischemia. 

The authors carefully studied data derived from 371 prospectively collected patients in order to create a prognostic model, and validated the findings in an additional cohort of 255 patients. Not unexpectedly, the variables that more robustly predicted DCI-related infarcts were poor clinical grade, larger amount of blood on CT, and age. Based on these factors, the chart predicted a chance as low as 12% of developing DCI-related infarct in patients with low Fisher Scale/ low World Federation of Neurological Surgeons Scale (WFNS) grade and age ≥55, and as high as 61% in patients with thick subarachnoid hemorrhage, high WFNS grade and younger age. The authors suggest that lower risk patients could be considered for an earlier discharge from the unit, and state that the chart should be used to “predict absolute risks of DCI in individual patients”. 

In practice, it works as a well-ordered paradigm, however it is intriguing to consider its application to certain “individual” cases, such as a 60 years-old patient with modified Fisher II and WFNS V (in whom the risk of infarct from DCI would be read as low). Moreover, multiple medical variables such as fever, anemia, hyperglycemia, cardiac and pulmonary issues, hemodynamic and/or electrolyte changes, etc, are considered to influence the morbidity of these patients and need to be intensively followed. Therefore, the benefit of early identification of an increased risk of DCI/infarct based on admission variables would not be relatively so important, and providers could have time to incorporate variables collected within the few days into the risk stratification. In summary, Rooij et al. provide us with solid and meticulously analyzed data that may aid in the decision making of such a commonly encountered scenario.

Twitter feed: A score to predict delayed ischemia after SAH?