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Monthly Archives: November 2014

Time to Angiographic Reperfusion in Acute Ischemic Stroke: A Decision Analysis

Daniel Korya, MD

Vagal AS, Khatri P, Broderick JP, Tomsick TA, Yeatts SD, and Eckman MH. Time to Angiographic Reperfusion in Acute Ischemic Stroke: Decision Analysis. Stroke. 2014

In an elegant and objective manner, Dr. Saver, from UCLA, published an article in Stroke (2006) quantifying the amount of neurons, synapses and myelinated fibers lost during each hour that a stroke progresses. He further reasoned and specified that in each minute, 1.9 million neurons, 14 billion synapses and 7.5 miles of myelinated fibers are destroyed. This sobering publication reaffirmed the importance of time to reperfusion and provided a numerical backing to the phrase “time is brain”.

Vagal and her colleagues understood the importance of time to reperfusion and designed a study that compared the outcomes of two different reperfusion methods: IV tPA alone versus IV tPA with endovascular treatment. Their study was meant to expand on one of the reasons for failure of the recently published randomized controlled trials comparing IV thrombolysis therapy to endovascular treatment of acute ischemic stroke (IMS III). Critics of IMS III pointed out that endovascular therapy with late reperfusion was bound to be futile, simply because the brain tissue was already infarcted and beyond the time of salvage.  
The data for this trial was derived from the IMS III database and medical literature. A subgroup of the IMS III trial patients with large vessel occlusion was used and the TICI score before and after treatment was evaluated to determine the degree of reperfusion. Of the 434 patients randomized to the endovascular arm in IMS III, 240 had complete large vessel occlusions and 175 achieved angiographic reperfusion. The average time to reperfusion in the endovascular arm was 325 minutes. In the IV tPA treatment arm, 83 had large vessel complete occlusion, but there was no follow-up data to determine reperfusion rates.
A decision analytic model was used with effectiveness measured in quality-adjusted life years (QALYs).  The modified Rankin Score (mRS) was essentially reduced to favorable versus unfavorable outcome where a 0 represented death and a 1 meant perfect health.  The researchers found that when a hypothetical patient presented with a large vessel occlusion and a moderate to severe stroke, endovascular treatment yielded a better outcome if reperfusion could be established within 347 minutes. However, if reperfusion took longer than 347 minutes, than IV tPA alone was better. A 30-minute delay to reperfusion was found to be associated with a 10% relative reduction in good outcome.
When the data were extrapolated and a second order Monte Carlo analysis performed, the conclusion was that for a 10,000 patient population with large vessel moderate to severe ischemic stroke, 78% will achieve a good outcome with endovascular treatment while only 22% can have a good outcome with IV tPA alone. 
It should be noted that this study was a post-hoc analysis of data derived from a subpopulation of the primary trial and therefor the findings may not be generalizable.  However, these findings warrant further research into the benefits of endovascular treatment for ischemic stroke. The newer devices that were not used in the IMS III trial can achieve faster and more complete reperfusion and could translate into even better outcomes. This study sheds new light on endovascular treatment and may allow for future trials with better designs and higher quality data.  

By |November 14th, 2014|treatment|2 Comments

IMS III: a sign of the times

Ali Saad, MD

Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Evolution of Practice During the Interventional Management of Stroke III Trial and Implications for Ongoing Trial. Stroke. 2014

One of the criticisms of IMS III was that practice parameters were changing throughout the 7-year course of the trial. The authors address this criticism by comparing various parameters between protocols 1-4 vs protocol 5 (the final protocol).

Patients in the final protocol tended to be older, have baseline CTAs, were less likely to have a premorbid mRS of 0, but were offset by quicker times to reperfusion and being less likely to get IA-tPA as part of the treatment. ultimately this didn’t improve outcome or safety measures. This was likely related to less statistical power and more lenient inclusion criteria for protocol 5 patients. but the authors cite that their efforts did decrease time to intervention and reperfusion as well as recanalization rates.
The final protocol may reflect the current practice parameters at many large academic institutions offering endovascular therapy and parallel the evolution of the field over time. In the post-IMS III era, stent retrievers are more commonly used, older patients are being offered treatment, and time to treatment is going down.
Endovascular intervention for acute ischemic stroke is a rapidly evolving field. in retrospect, IMS-III mirrors that evolution. although the trial did not demonstrate endovascular intervention + IV-tPA to be superior to IV-tPA alone, I firmly believe that it is simply a matter of time. There were several “negative” trials testing the efficacy of IV-tPA before the success of the landmark 1995 NINDS trial. decreasing the time to reperfusion is probably of the utmost importance, but patient selection by clinical and radiographic criteria is also critical. since the NINDS study, subsequent studies have been published showing greater efficacy and less risk when IV-tPA is given earlier to more carefully selected patients. i expect the field of endovascular therapy will follow a similar trajectory. Once a future trial hits the “sweet spot” and reaches statistical significance, it will start to become the standard of care for select patients at which point financial incentives will kick in and dramatically increase workflow efficiency and raise the field’s standards of practice.

By |November 13th, 2014|treatment|Comments Off on IMS III: a sign of the times

Surgical management of bAVM

Abdel Salam Kaleel, MD, MSc

Korja M, Bervini D, Assaad N, and Morgan MK. Role of Surgery in the Management of Brain Arteriovenous Malformations:Prospective Cohort Study. Stroke. 2014

Ruptured brain arteriovenous malformations (bAVM) are one of the most common causes of spontaneous intracerebral hemorrhage (ICH) under 40 years of age with a cumulative long-term risk of major morbidity or death for ruptured AVMs nearing 85%. However, the question remains: what is the best management approach for low and middle-grade bAVMs? Presently, interventional therapy for bAVM includes surgical resection, endovascular embolization, radiotherapy or a combination of these modalities, but the largest trial of unruptured bAVMs, ARUBA, mainly reflected embolization and radiotherapy outcomes, leaving surgical outcomes largely unexplored.

Between January 1989 and May 2014, 779 consecutively enrolled patients were assessed for inclusion in this prospective study, with outcome assessments performed using the modified Rankin scale (mRS) both pre-operatively and at follow up visits. Outcome variables were defined as overall adverse outcome from surgery mRS>1, major adverse outcome mRS>2, perioperative hemorrhage, or “deficit or near miss” (adverse outcome leading to mRS>1 or perioperative hemorhage). The 5-tier Spetzler-Martin grading (SMG) and 3-tier Spetzler- Ponce Class (SPC), measures of surgical risk, were utilized, assigning points for size, the presence of deep venous drainage, and location in “eloquent” brain.

For those patients who underwent surgery, adverse outcomes were seen to increase with increasing SPC grades. The mRS >1 surgical combined adverse outcome rates were 1.4% for SPC A, 19% for SPC B, and 39% for SPC C and adverse outcome rates leading to mRS >2 were 0.6%, 6%, and 19% for SPC A, B, and C, respectively. Complete bAVM resection was achieved in 99.1% of patients with SPC A and B bAVMS. Multiple logistic regression analyses identified possible risk factors for adverse outcomes, including patient age, preoperative hemorrhage, preoperative embolization, largest diameter of bAMV nidus, presence of deep venous drainage, eloquent location, lenticulostriate feeders, and surgical experience. 

The authors concluded that their comprehensive cohort study provided enough evidence that most low and middle grade bAVMs, whether ruptured or unruptured, can be relatively safely treated by surgery. These results however cannot be generalized for high grade, or SPC C bAVMs.

By |November 12th, 2014|treatment|Comments Off on Surgical management of bAVM

The Swelling is Telling: Presence of Brain Edema Regardless of Stroke Severity Predicts Outcome

Vikas Pandey, MD

Battey T, Karki M, Singhal A, Wu O, Sadaghiani S, Campbell B, et al. Brain Edema Predicts Outcome After Nonlacunar Ischemic Stroke. Stroke. 2014

Brain edema is the harbinger of bad things to come in patients with large volume ischemic strokes. It is the reason neurologists will order close neurochecks, follow-up imaging and intensive unit level care for patients who may initially seem rather stable. The poor outcomes related to herniation, such as delayed additional neurological deficits, altered mental sensorium or even death lead clinicians to consider tactics such as early decompressive craniectomy, or osmotic therapy in this patient cohort. Typically, these methods are reserved in those with large hemispheric strokes, however, what effect on outcome prediction does the presence of signs of swelling have even with those with “smaller volume strokes”? Battey, et al. set out to answer that question.

The group used serial research MRI scans during the first 2-5 days following stroke to investigate aspects of infarct growth as well as presence of edema via retrospective analysis of the NBO and EPITHET cohorts for which a baseline DWI and a follow up DWI were available, utilizing previously used cohorts with a broad range of stroke severities (average NIHSS 14 and 13 respectively for NBO and EPITHET subgroups). They used voxel analyzing software to calculate differences in DWI volumes on sequential scans representing infarct growth as well as subjective analysis of brain edema i.e. direct evidence of mass effect or new distortion of adjacent tissue, midline shift, or new effacement of sulci or lateral ventricles. The interrater agreement of this method had a kappa value of 0.41. The group used locations as defined by the ASPECTS criteria to define if a new anatomical territory was involved different from the baseline lesion. They found that in the cohorts, presence of swelling translated to poor 90-day outcome (mRS >2), but infarct growth itself did not predict poor 90-day outcome. This was independent of factors such as increased DWI volume, NIHSS, and age. Using volumetric analysis to differentiate between what was swelling and what increased infarct burden, swelling was still an independent predictor of poor outcome. 

Neuroimaging and how neurologists in particular use different aspects (no pun intended) of the images to translate to clinical care and outcome is an ever-changing process. The group put together a study that showed that infarct growth and edema even in milder stroke severities are notions that should not be taken lightly and may reflect outcome and their study is an excellent example of how we can use currently available weapons of imaging analysis and apply them to expand how we approach stroke patient care, even in ways that are not initially intended. The use of unique volumetric and voxel analysis also provides the possibility of using more advanced sequences during MRI scans to extract more information during these scans that can aid the patient and dictate pathways of stroke care.


A look at another ASPECT of the ASPECTS score

Prachi Mehndiratta, MD

Schröder J, Cheng B, Ebinger M, Köhrmann M, Wu O, Kang DW, et al. Validity of Acute Stroke Lesion Volume Estimation by Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomographic Score Depends on Lesion Location in 496 Patients With Middle Cerebral Artery Stroke. Stroke. 2014

A large area of diffusion restriction seen on a MRI scan is predictive of increased risk of symptomatic intracranial hemorrhage. The ASPECTS score has been extensively studied and is used in clinical practice to estimate early ischemic changes and define a malignant infarct in the anterior circulation on a non-contrast CT scan. The authors of this study aimed to utilize the DWI ASPECTS score similarly to establish ischemic volume and predict a malignant infarct with volume >100ml. 

Clinical, demographic and imaging data was obtained from the PRE FLAIR study database that was a multicenter observational study of patients with acute ischemic stroke that underwent a MRI scan within 12 hours of symptom onset. Only patients with MCA infarction were included and a stroke neurologist scored DWI ASPECTS. DWI lesion volumes were calculated utilizing a developed software tool in three MCA territories- deep MCA, superficial MCA and both superficial and deep MCA territories. Correlations between DWI-ASPECTS, DWI lesion volume and NIHSS were calculated using Pearson’s correlation coefficient. Receivers operating characteristic (ROC) curves were generated to determine the optimal DWI-ASPECTS cut off point to characterize a DWI lesion volume≥100 ml.

A total of 496 patients were included in the final analysis, mean age was 66+/1- 15 years and 47% of patients were female. The DWI volume of superficial MCA stroke lesions was higher as compared to those with deep MCA strokes (21.2ml vs. 7.2ml) while there was no difference between the two groups on median ASPECTS score. There was a significant negative correlation between DWI-ASPECTS and DWI lesion volume for all patients (r=-0.78, p<0.0001) as well as the DWI-ASPECTS and initial NIHSS (r=-0.49, p<0.0001). The negative correlation was stronger for patients with superficial MCA lesions as well as combination of both superficial and deep MCA lesions. ASPECTS score <6 was a predictor of a malignant MCA infarct with volume >100ml with a low positive predictive value but a high negative predictive value.

While ASPECTS was a good predictor of infarct volume in the patients with superficial MCA lesions, DWI ASPECTS inaccurately estimated the deep MCA stroke volume. A wide range of lesion volumes was identified per ASPECTS score value. The question arises – will we be using the DWI ASPECTS score in clinical practice for thrombolysis? Current guidelines recommend utilizing the non-contrast CT and the CT ASPECTS score has been validated in this regard. Additionally is it time efficient to obtain an MRI and calculate a DWI ASPECTS? We need to take a look at several aspects before we come to a conclusion about the DWI ASPECTS score.

Technological advances in the calculation of hematoma volumes

Rajbeer Singh Sangha, MD

Xu X, Chen X, Zhang J, Zheng Y, Sun G, Yu X, et al. Comparison of the Tada Formula With Software Slicer: Precise and Low-Cost Method for Volume Assessment of Intracerebral Hematoma. Stroke. 2014

The volume of ICH has been validated to be an important independent predictor for prognosis. In order to calculate the volume of ICH, the ABC/2 formula has been widely used for bedside estimation of hematoma volume however given the nature of its calculation it is subject to error. The authors of this study utilized 3D Slicer, which is a free open source software platform for biomedical research to validate the size-dependent and shape-dependent estimation error of the ABC/2 formula by comparison with 3D Slicer. 3D Slicer not only supports versatile visualizations but also provides advanced function, such as automated segmentation and registration for various applications.

The CT scans of 294 patients were analyzed and the mean hematoma volume was 58.41±37.83 cm3 with the ABC/2 formula and 50.38±31.93cm3 with 3D Slicer method (t=10.010, P<0.01). When divided by hematoma shape, the ABC/2 formula produced a significant estimation error of 3.33 cm3, 7.19 cm3, and 29.39 cm3 in regular, irregular, and multi-lobular hematomas (p<0.05 in each group). The percent deviation was significantly larger in irregular and multi-lobular hematomas compared with regular hematomas (H=63.052, p<0.001).
The authors suggest that inaccurate hematoma volumes may influence treatment decisions as well as clinical trials in terms of the surrogate endpoints. It is difficult to say how much clinical treatment decisions are affected by the degree of inaccuracy in the ABC/2 method and perhaps that can be a future study.  If the 3D slicer is an easily accessible mode of calculating hematoma volume it should be utilized readily. However accessibility and ease of use is always the key components to adopting a new methodology. I would be curious to see how this application is utilized and applied going forward and whether new technologies do address the need for a higher level of accuracy when it comes to calculating hematoma volumes.  
By |November 7th, 2014|diagnosis and imaging|Comments Off on Technological advances in the calculation of hematoma volumes

Anticoagulation and Cerebral Microhemorrhages

Rizwan Kalani, MD

Akoudad S, Darweesh SKL, Leening MJG, Koudstaal PJ, Hofman A, van der Lugt A, et al. Use of Coumarin Anticoagulants and Cerebral Microbleeds in the General Population. Stroke. 2014

The worst complication of anticoagulation use is intracerebral macro-hemorrhage. In this study, Akoudad et al evaluated the effect of coumarins on microbleeds (MB) from a large, prospective, population-based cohort study (Rotterdam Study).

Evaluating data on 4945 subjects with a baseline brain MRI (with T2*-GRE sequences) and 3069 with follow-up MRI’s, the prevalence and incidence of MB was compared between those on coumarin vs those who were never exposed to it. After adjusting for age, sex, and vascular risk factors, the association between coumarin use and MB’s was evaluated. The authors also looked at the relationship between maximum INR as well as its variability with MB presence.

8.6% of participants (427/4945) had used coumarin anticoagulants (at some time) prior to the first MRI and 19.4% (957) had ≧1 MB present. 5.9% (181/3069) of those with follow-up MRI’s had used them at some point prior to the second scan. The cumulative incidence was 6.9% over an average follow-up period of approximately 4 years. Anticoagulated subjects had a higher prevalence of deep or infratentorial MB (with or without lobar MB) compared to those who had never been exposed (OR 1.70, 95% CI 1.24-2.34). A trend toward increased risk of developing new MB was found in those using coumarin vs those who never had, but this was not statistically significant (OR 1.44, 95% CI 0.89-2.32). Results were similar even after excluding those who used other antithrombotics and those with infarcts on MRI. Deep/Infratentorial MB were more frequent in those with higher maximal INR compared to never-users. Amongst those using coumarin, higher INR variability was associated with deep/infratentorial MB.

This study is unique as it comes from a large cohort study involving a population from the suburbs of Rotterdam, making it more generalizable. Notable limitations from this observational study include – 1) some MB could have been present prior to anticoagulant use and; 2) participants more likely to be on coumarin were the same as those with increased risk of MB (i.e. those with vascular risk factors). Furthermore, as noted by the authors, results may not apply for novel oral anticoagulants (NOACs).

Future studies will have to evaluate the safety of anticoagulation over time in distinct cohorts that are separated by age, blood pressure control, APOe genotype, and suspected MB pathology (hypertensive, amyloid angiopathy). The effect of NOACs on MB will also need to be investigated.

Nevertheless, this study reaffirms the fact that we should be vigilant about blood pressure control and INR monitoring in patients on coumarin anticoagulants.

By |November 6th, 2014|epidemiology and genetics|Comments Off on Anticoagulation and Cerebral Microhemorrhages

Inequality in Stroke Mortality: Poor People Die From Strokes More Often

Mark McAllister, MD

Andersen KK, Dalton SO, Steding-Jessen M, Olsen TS. Socioeconomic Position and Survival After Stroke in Denmark 2003 to 2012: Nationwide Hospital-Based Study. Stroke. 2014

The poor face numerous staggering inequalities, and their health is no exception. Health outcomes by almost every metric are worse for those with lower socioeconomic status, and we know that the incidence of stroke is substantially higher in the poor.The authors of this study investigate the rates of mortality by socioeconomic position.

Individuals over 40 with no history of prior stroke were extracted from the Danish stroke registry leading to a population of over 56,000 patients studied. The authors divided patients by income quintile as well education level. Unsurprisingly patients with the lowest income and education levels suffered more severe strokes and had more preventable risk factors than richer patients. A dramatic relationship between income level and risk of death after stroke was demonstrated as well, and this was intact after adjustment for risk factors. This relationship was not evident with education level.

While the finding that the poorest patients are those most likely to die after stroke does not astonish, it should raise our concern. On a systems level we fail our most vulnerable citizens. This particular study was performed in Denmark, a rich (21st in GDP per capita) industrialized nation with public healthcare. Even so, it appears that the impoverished are set up for poor health outcomes, and often pay with their lives.

By |November 5th, 2014|epidemiology and genetics|Comments Off on Inequality in Stroke Mortality: Poor People Die From Strokes More Often

Gradual Blood Pressure Lowering in Hemorrhagic Stroke: Another look at the SCAST data

Michelle Christina Johansen, MD

Jusufovic M, Sandset EC, Bath PMW, and Berge E, on behalf of the Scandinavian Candesartan Acute Stroke Trial Study Group. Blood Pressure–Lowering Treatment With Candesartan in Patients With Acute Hemorrhagic Stroke. Stroke. 2014

Never has the mantra an ounce of prevention is worth a pound of cure rung truer than in the field of Vascular Neurology. Hypertension remains the most important risk factor for both ischemic and hemorrhagic stroke. It has been well proven that blood pressure lowering to a goal of normotensive strongly correlates with decreased stroke risk in primary prevention, but the question then becomes how and when to treat blood pressure in acute stroke? 

Expert data generally recommends permissive hypertension (220/120mm Hg) if not treated with thrombolytics for the first 24 hours. Acute hemorrhagic stroke presents a particularly difficult situation. Blood pressures tend to run high in these patients and this has been found to be an independent predictor of poor prognosis. The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) enrolled 404 patients after acute intracerebral hemorrhage to either an intensive blood pressure lowering arm (≤140mmHg in one hour maintained for seven days) or guideline based therapy (goal systolic of 180mmHg). The first phase of this study published in 2008 found intensive lowering of blood pressure was feasible and associated with a decreased relative risk of hematoma growth.  The primary outcome in the final analysis (INTERACT2) was death or major disability using the modified Rankin score (mRS). There was a significantly lower mRS in patients undergoing intensive therapy with no increase in mortality or nonfatal serious events.

Jusufovic et al sought to re-evaluate this important question by using data from the Scandinavian Candesartan Acute Stroke Trial (SCAST). The group isolated the 274 patients with hemorrhagic stroke from the original cohort in an effort to re-evaluate the trial’s original primary end points: composite of vascular death, stroke or myocardial infarction as well as mRS at 6 months. In the original SCAST trial, patients were randomized to Candesartan or Placebo around 18hrs after stroke onset. Therapy was continued for 7 days with dose escalation from 4mg to 16mg over a period of days. The new analysis performed by Jusufovic et al demonstrated that isolation of those with hemorrhagic stroke from the original population did not change the final interpretation. There was no benefit of Candesartan in any of the cohorts and was statistically associated with a poorerfunctional outcome.

Does this then present a paradox? How is the vascular neurologist to proceed?  The authors importantly point out fundamental differences between the two trials that are important to consider in analysis of the data. The SCAST trial did not implement therapy until 18hrs after stroke onset while the intensive arm of INTERACT lowered blood pressure within one hour. It is also notable that 90% of patients in the intensive arm of INTERACT used some type of intravenous therapy during the study with great variance in the agent chosen.  Notably 32% was an alpha-adrenergic antagonist. SCAST utilized an angiotensin receptor blocker. As has been raised in criticism of INTERACT, the different mechanisms of the various antihypertensives clearly play an important role. So where does this leave the clinician? Hypertension is a risk factor yet hypotension has been associated with recurrent stroke and the SCAST study suggests that Candesartan is associated with a worse outcome!      
A better understanding of which clinical characteristics are associated with benefits from antihypertensive therapy paired with the understanding that timing of therapy remains essential in all aspects of stroke care must continue to guide our research in the future.  
By |November 4th, 2014|treatment|Comments Off on Gradual Blood Pressure Lowering in Hemorrhagic Stroke: Another look at the SCAST data

Long term annual cost of ischemic stroke and intracranial hemorrahge

Duy Le, MD

Previous attempts have been made to evaluate the economic burden of ischemic stroke. The NEMESIS study, an Australian based study, evaluated costs 3 to 5 years out from the original stroke event. Gloede et al push the envelope by attempting to quantify the cost of ischemic stroke (IS) and intracranial hemorrhage (ICH) 10 years out. They used The Model of Resource Utilization Costs and Outcomes for Stroke (MORUCS) which was also employed by the NEMESIS study. NEMESIS patients were evaluated in this study and followed out to 10 years. The cost of illness models for both IS and ICH were updated from a 2004 to 2010 reference year, adjusting for inflation. The Australian population was used in this model and currency translated to USD in terms of cost.  

For first ever IS, 243/283 of the NEMESIS participants were interviewed (86% responder rate). For first ever ICH, 43/50 of the NEMESIS participants were interviewed. For IS, the overall average annual direct cost at 10 years was similar to survivors between 3-5 years (5,207 USD). The distribution of the costs however varied, as medication increased from 13% to 20%, while cost for rehabilitation services and facilities decreased over that same time span. ICH on the other hand had an increase of 24% in annual direct costs (from  5,807 USD to 7,607). Aged-care facility-costs for ICH were noted to be 64% higher at 10 years compared to 3-5 years. Costs were highest within the first year for both IS and ICH. Although the most practical way to evaluate the question of long term cost is to employ surveys as this study did; this is also the study’s biggest limitation. Surveys inherently can be biased, depending on the responder. Additionally, an Australian population was analyzed in an attempt to extrapolate costs for US patients. 

From this study, we find out that the cost of a first time ischemic stroke goes beyond the initial costs up front. The annual cost 10 years post IS however are not different from 3-5 years post IS. While some may argue this does not offer much information to us, it still reaffirms the fact that the financial burden of stroke is felt long after in the initial event. On the other end, ICH costs increase annually at 10 years compared to 3-5 years due to increased care facility costs; further making the point that the financial burden of these disease processes continue long after the index event.  Patient, families and physicians should be aware of this when dealing with patients in both the inpatient and outpatient setting with these disease processes.