American Heart Association

Monthly Archives: April 2016

The Leakage Sign: A New Predictor for Hematoma Expansion in ICH

Alexander E. Merkler, MD

Orito K, Hirohata M, Nakamura Y, Takeshige N, Aoki T, Hattori G, et al. Leakage Sign for Primary Intracerebral Hemorrhage: A Novel Predictor of Hematoma Growth. Stroke. 2016

Intracerebral hemorrhage (ICH) is a devastating disease with a one-month mortality of 40%. Although initial ICH volume is the strongest predictor of mortality, hematoma expansion is a potentially modifiable risk factor that correlates well with both functional outcome and death and occurs in up to 40% of patients with ICH. Research has therefore been focused on methods to 1) identify patients at risk of hematoma expansion and 2) reduce hematoma expansion.

The “spot sign” has been previously correlated with both hematoma expansion and poor functional outcome; however, the spot sign is not a perfect predictor of hematoma expansion. Although the specificity of the spot sign is high, the sensitivity is only around 50%. In this study, Drs. Orito and Morioka et al evaluate a new predictor for hematoma expansion in ICH: the “leakage sign.”

The authors evaluate 80 patients with a primary ICH who underwent a CTA and a second CT (delayed phase image) 5 minutes later. The leakage sign was determined by comparing the arterial and delayed phase CT images. Each neuroradiologist measured a region of interest (ROI) of 1-cm diameter on the delayed phase images. This region was considered the highest change in Hounsfield Units between the delayed and arterial phase images and represented the leakage of contrast medium into the hematoma. The same ROI circle was then drawn on the arterial phase CT image and the Hounsfield Units were measured. A change >10% in Hounsfield Units was considered a positive leakage sign, or hematoma expansion. A follow-up CT was performed 24 hours later where hematoma expansion was defined as >10% change in hematoma volume from the initial CT.

The authors found that the spot sign was positive in 18 (22%) of patients and that the leakage sign was positive in 35 (43%) of patients. 33 of the 35 patients with a positive leakage sign also had positive spot signs. Overall, leakage sign had a higher sensitivity and specificity than the spot sign: 93.3% and 88.9%, respectively, versus 77.8% and 73.8%. In addition, the leakage sign proved to be a better predictor of outcomes than the spot sign. Patients with a positive leakage sign had significantly poorer outcomes (20.0% versus 51.5%), but outcomes were unaffected in patients with a positive spot sign.

In conclusion, the leakage sign appears to be both an easy and reliable method to predict hematoma expansion in patients with ICH.

Missed Strokes in the ED: An Opportunity for Systems Change

Ilana Spokoyny, MD
Arch AE, Weisman DC, Coca S, Nystrom KV, Wira III CR, Schindler JL. Missed Ischemic Stroke Diagnosis in the Emergency Department by Emergency Medicine and Neurology Services. Stroke. 2016

Ischemic stroke presentations can vary significantly and some presentations are more likely to be overlooked or thought to be stroke mimics. Additionally, some patient populations (such as young patients, women, and minorities) are more likely to be attributed nonstroke etiologies. The danger is, of course, missed treatment opportunities. However, patients with missed strokes are also less likely to receive appropriate monitoring for neurological progression or stroke-related complications.

The authors of this study performed a retrospective chart review to determine the rates of diagnosis and misdiagnosis of stroke patients at one academic hospital and one community hospital. Patients were identified by discharge billing code. TIAs were excluded, as were imaging-negative strokes. A stroke was “missed” if practitioners in the Emergency Department (ED) did not initially consider stroke in the differential or the diagnosis was delayed, causing the patient to miss the therapeutic window for thrombolytic therapy. A stroke was also considered “missed” if ED physicians consulted neurology for a possible stroke diagnosis and the neurology consultant felt that the patient did not have a stroke and admitted the patient to a medicine service. 

A third of missed cases presented within a 3-hour time window, and an additional 11% presented within 3 to 6 hours. Of all missed cases of ischemic stroke at the academic hospital, 20/55 (35%) were seen by neurology in the ED but early diagnosis was still missed. Nine (45%) of these cases missed by neurology presented within the time window for rt-PA, and an additional 3 (15%) presented within 6 hours. Only 8% of missed stroke patients were triaged in the ED as stroke codes. Comparing these patients to those with accurate diagnoses, of whom 46% presented as stroke codes (p<0.001), the 46% seems low. However, stroke codes are not routinely called at this institution for patients who are out of the time window for intervention or clinical trial, and patients where acute cerebrovascular event is not part of the initial differential diagnosis. Forty percent of missed strokes patients did not have neurological examinations with elements of the NIHSS, compared with 8% of the accurately diagnosed stroke patients (p<0.001). Patients with nausea/vomiting, dizziness, and prior strokes were more likely to be misdiagnosed. Patients with focal weakness, vision changes, gaze preference, and dysarthria were more likely to be correctly diagnosed. More posterior strokes were initially misdiagnosed than anterior strokes. There did not appear to be a difference in the rates of misdiagnosis between an academic and community hospitals. For readmission rates, 33% of misdiagnosed patients were readmitted at 60 days post-discharge, compared with 17% of accurately diagnosed patients (p=0.012). 

The study population consisted of predominantly white, older adults who presented to an ED at a primary stroke center. A larger scale analysis would be important to perform, to determine if the rates of misdiagnosis vary among race/ethnicity. This study did not include truly misdiagnosed patients (those presenting with symptoms, who had a stroke that was never diagnosed, and who did not have brain imaging). It would be interesting to evaluate patients diagnosed with stroke who have had ED visits within the week prior to admission (for similar symptoms/presentation), to identify characteristics of truly misdiagnosed strokes. 

There are several factors identified in this study which can lead to systemic changes in the stroke triage process. First, there is a large discrepancy in the frequency of stroke codes called when comparing those with correct diagnoses to those who were missed. A balance must be found between high sensitivity and high specificity. Limiting the stroke code activation to those within the treatment window may be problematic. We know from other studies that the last known well time is often incorrectly identified in the ED, and that patients are only later refined into or out of the treatment window and their treatment options may change. Additionally, as the endovascular window extends, more patients may benefit from having acute neurologic evaluation in the ED, in the form of a stroke code. So, calling stroke codes on anyone with neurologic symptoms within a longer period of time, such as 12 hours, would greatly improve sensitivity. However, this comes at a resource costspecifically, neurology consultant time, CT scanner immediate availability, and pharmacy time spent at bedside. An analysis could be performed to determine how many additional stroke codes would have been activated with these broader criteria, and the resource cost of this, and compare this to how many additional patients would have been correctly identified and treated promptly. Overall, this was an eye-opening study on how we need to do better in the correct identification of our stroke patients.

Adherence to DASH Diet Associated With Lower Stroke Risk

Neal S. Parikh, MD

The Dietary Approaches to Stop Hypertension (DASH) diet is known reduce blood pressure in hypertensive and normotensive individuals. The authors assessed whether DASH diet adherence is associated with incident stroke.
The authors performed their analyses in two large, prospective Swedish cohorts of middle-aged to older men and women free of incident stroke.  The participants answered a 350-item questionnaire on diet and vascular risk factors in the late 1990s and were followed by linkage with the National Patient Register and the Cause of Death Register.
The exposure variable was a modified DASH diet score, assessed based on a validated food-frequency questionnaire. Covariates included standard demographics and vascular risk factors (hypertension, hyperlipidemia, diabetes, atrial fibrillation, smoking history, aspirin use, family history of myocardial infarction at early age, and body mass index).  Total caloric intake was included as a covariate, but dietary sodium was not. The outcome measure was incident stroke (ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage).  Participants were classified into quartiles based on their DASH diet score. Multivariate analyses were performed to test the association between DASH adherence and incident stroke.
Participants with high adherence to the DASH diet were fairly similar to participants with low adherence. The mean age was 60 years. Approximately 50% were overweight. Approximately 20% had hypertension, 10% had hyperlipidemia, and 6% had diabetes.  Over 882,727 person-years of follow-up, there were 3,896 ischemic strokes, 560 intracerebral hemorrhages, and 176 subarachnoid hemorrhages. High adherence to the DASH diet was associated with a lower risk of ischemic stroke and a trend towards lower risk of intracerebral hemorrhage. Participants in the highest quartile had a 14% lower risk of ischemic stroke than those in the lowest quartile.
This study adds to two prior studies that suggested that adherence to a DASH diet is associated with lower risk of stroke. The two prior studies and this study are likely underpowered for intracerebral hemorrhage and subarachnoid hemorrhage. The authors note that a similar association between the Mediterranean diet and stroke risk has been identified. Features shared by the DASH and Mediterranean diets may be responsible for lower stroke risk.  
The main limitations of this study are the observational design and the outdated cohort, which likely did not benefit from contemporary vascular risk factor management. However, in the context of prior studies, this study provides compelling evidence in support of a healthy diet for the prevention of stroke.
By |April 11th, 2016|prevention|1 Comment

IV-tPA Treatment Prior to Mechanical Thrombectomy Did Not Improve Outcome in a Retrospective Matched Analysis

Jay Shah, MD

Broeg-Morvay A, Mordasini P, Bernasconi C, Bühlmann M, Pult F, Arnold M, et al. Direct Mechanical Intervention Versus Combined Intravenous and Mechanical Intervention in Large Artery Anterior Circulation Stroke: A Matched-Pairs Analysis. Stroke. 2016

Recently, 5 trials have consistently shown that mechanical thromectomy (MT) improves outcomes in acute ischemia due to proximal occlusion within the anterior circulation. In these trials, rates of intravenous tissue-type plasminogen activator (IV-tPA) were similar among treatment and medical arms thus raising the question whether pre-treatment with IV-tPA is necessary. In this study, the investigators compared clinical outcomes and safety of direct MT alone versus bridging IV-tPA.

This retrospective study is based on a stroke registry that registered stroke patients across a 5 year span. In total, 156 patients were treated with bridging tPA and 239 with direct MT. 40 patients within the latter group had no contraindications to IV-tPA but were opted for direct MT therapy. These patients were matched with patients receiving bridging therapy. Clinical outcomes at three months did not differ between groups; however, there was a trend toward better improvement in the direct MT group. While the rate of symptomatic hemorrhage did not differ, there was higher rates of asymptomatic hemorrhage in the bridging group. Lastly, recanalization and reperfusion rates were similar in both groups.

This study raises an interesting clinical question. Certainly, IV-tPA has been the standard of care for acute ischemic stroke patients. However, in the current new era of endovascular intervention, its role has been questioned in patients who qualify for MT. The majority of patients within the 5 randomized trials did receive IV-tPA per standard practice. Thus, guidelines have recommended to treat with IV-tPA if patients are eligible. tPA can usually be administered quicker and may aid in recanalization. However, recanalization rates of large vessel occlusions are poor and these patients will require MT. IV-tPA treatment in this group, as this study points out, does not improve clinical outcome and may increase rate of hemorrhage. This study was a retrospective study and the number of patients are relatively small. The reason for excluding IV-tPA to the 40 eligible patients is not clear and thus subject to selection bias. tPA may recanalize small vessels particularly within the penumbra and this may be important until recanalization of the proximal occluded artery can be achieved. From a practical standpoint, most hospitals are not endovascular-capable and thus need to transported to a comprehensive stroke center leading to an extensive time difference between tPA administration and MT. Therefore, IV-tPA use should follow current established guidelines. However, future prospective trials should address bridging IV-tPA in combination with MT.

By |April 8th, 2016|treatment|0 Comments

Streamlined Hyperacute MRI Identifies tPA Eligible Stroke Patients Among Stroke Mimics

Peggy Nguyen, MD

Goyal MS, Hoff BG, Williams J, Khoury N, Wiesehan R, Heitsch L, et al. Streamlined Hyperacute Magnetic Resonance Imaging Protocol Identifies Tissue-Type Plasminogen Activator–Eligible Stroke Patients When Clinical Impression Is Stroke Mimic. Stroke. 2016

Despite advances in imaging, the radiologic component of the tPA decision-making is predicated on a non-contrast CT head, guided by the clinical history and exam. Sometimes, however, the clinical exam or history can be confusing and the CT scan does not provide much additional diagnostic data; stroke mimics make up anywhere between 1-16% of the patients presenting with stroke-like symptoms at large institutions. The use of a hyperacute MRI (hMRI) can help differentiate strokes from stroke mimics, and potentially minimize tPA given to mimics and, perhaps more importantly, ensure that tPA is not withheld from patients who are suspected to be mimics, but are actually strokes.

Here, the authors report an institution-specific streamlined hMRI protocol in the setting of acute stroke. The hMRI protocol described here provides DWI/ADC, FLAIR, and T2*GRE sequences in just under 6 minutes. In order to avoid overutilization, physicians were instructed to order the hMRI only when the initial diagnostic impression was likely stroke mimic, but ischemic stroke could not be entirely ruled out and, if MRI was not available at their institution, the physician would not give the patient tPA. 57 patients, identified as stroke mimics, underwent the hMRI protocol, with 11 having the final diagnosis of stroke, 4 with the final diagnosis of TIA, and the remaining diagnoses being conversion disorder, seizure, complicated migraine, and other. Seven of the 11 stroke patients received IV tPA. There were no differences in door-to-needle, onset-to-needle, or door-to-arrival times for all IV tPA treated patients pre- and post-hMRI; however, the door-to-needle time for tPA treated patients screened with CT alone were significantly shorter than the 7 tPA patients screened with hMRI (37 minutes vs 112 minutes).

Although the overall metrics (door to needle, onset to needle, etc) did not change much with the institution of hMRI protocol, likely due to the minority of patients who went on to receive tPA under the protocol, using the hMRI protocol did lead to substantially longer door-to-needle times for patients who received tPA. However, longer door-to-needle times are preferable than withholding tPA, and it is probable that these patients, having been initially identified as stroke mimics, would not have received tPA otherwise. The use of a hMRI does have its limitations, given it is not widely available and many institutions may not have the resources to staff it emergently, but in institutions where the resources are available, it could potentially increase tPA usage to patients with strokes and decrease tPA usage to patients without strokes.

Small Vessel Disease is Associated With a Worse Outcome After Intracranial Hemorrhage

Neal S. Parikh, MD

Question & Rationale
Small vessel disease (SVD), as reflected by white matter lesions (WML), brain atrophy and lacunar strokes, is associated with hypertension and possibly abnormal autoregulation. The INTERACT 2 investigators therefore hypothesized that SVD is associated with a poor outcome after intracranial hemorrhage (ICH) and investigated whether this association is mediated by intensive blood pressure lowering in ICH treatment.
The INTERACT2 cohort was used for this study. In this international, multicenter, open, blinded endpoint, randomized trial, patients with spontaneous ICH were randomized within 6 hours to SBP<140 versus SBP<180. The cohort did not include patients with pre-existing advanced dementia or disability.

Exposures, Outcomes, and Covariates

There were three measures of SVD on baseline CT: WML, atrophy, and lacunar strokes. On baseline CT, WML were graded by the van Swieten scale.  Atrophy was measured by linear measurements (frontal ratio, third ventricle Sylvian fissure distance) and visual inspection. Lacunar stroke was defined as a round/ovoid cavity of 3-15 millimeters in diameter. The outcome was defined as 90 days death or major disability. Interaction term analysis was used to determine effect of intensive BP lowering on outcome. 

Covariates were age, gender, location, history of ischemic stroke, hypertension, diabetes, use of anti-thrombotic and lipid lowering agents, onset to randomization time, systolic BP, NIHSS, volume/location of hematoma, and intraventricular extension.

In crude and adjusted regression analyses, measures of WML and atrophy were associated with death or major disability. Lacunar stroke was not associated with the outcome in crude or multivariate models. High intensity BP lowering did not result in excess poor outcomes in patients with evidence of SVD.

There was only fair-moderate intra-class correlation for WML, brain atrophy, and especially lacunes. Additionally, the study was not pre-specified and therefore subject to type I error. Last, pre-ICH cognitive and physical disability were not rigorously assessed; however, this is compatible with clinical practice – it is often not possible to thoroughly assess a patient’s pre-ICH function at the time of ICH.

Pre-existing SVD burden may be associated with poor outcome after ICH, and this relationship is not mediated by intensity of blood pressure control. Therefore, these data allay fears regarding intensive BP management after ICH in patients with sequela of chronic hypertension such as SVD. 

Meta-Analysis Concludes Utility of CTA Spot Sign is Dependent Upon Timing and is Not Sufficient to Predict Hematoma Expansion in Acute ICH

Danny R. Rose, Jr., MD

Dowlatshahi D, Brouwers HB, Demchuk AM, Hill MD, Aviv RI, Ufholz L-A, et al. Predicting Intracerebral Hemorrhage Growth With the Spot Sign: The Effect of Onset-to-Scan Time. Stroke. 2016

Intracerebral hemorrhage (ICH) causes a significant amount of stroke-related morbidity and mortality. Of the various prognostic factors in ICH, hematoma expansion is one of the few potentially modifiable ones and as such has been a topic of increasing research. Unfortunately, large-scale randomized controlled trials aimed at preventing hematoma expansion have not shown robust results, possibly owing to the limited ability of clinicians to predict which patients are at greatest risk. One of the more promising diagnostic features in identifying such patients is the “spot sign” of contrast extravasation in the hematoma bed of ICH patients undergoing CT angiography (CTA). However, the predictive value of the spot sign has differed widely across studies, which may reflect variability in delay between ictus and CTA acquisition. Dowlatshahi et al. sought to examine the predictive value of the spot sign in relationship to onset-to-CTA times in patients with acute ICH by conducting a systematic review and patient-level meta-analysis.

The authors found eight studies in which patient-level data was able to be obtained regarding spot sign status, baseline and follow-up hematoma volumes and time from onset to presentation and CTA. Onset-to-CTA time was categorized a priori into five strata: <120 minutes, 120-239 minutes, 240-359 minutes, 360-479 minutes, and >480 minutes.  Hematoma size was measured by computer-assisted planimetry in three studies and the ABC/2 in five studies. A total of 1343 patients were evaluated across the eight studies, with 1176 having baseline hematoma volumes, spot sign status and time-to-CTA, 1039 of whom had follow-up hematoma volume measurements. 
There was significant heterogeneity of spot sign frequency among the studies (I2 = 20.67, p=0.004), due to heterogeneity in the 0-2h (I2 = 15.5, p=0.016) and the 2-4h stratas (I2 = 16.5, p=0.011). There was no heterogeneity for the later time strata. The frequency of the spot sign was 26% for the group as a whole with a significant relationship with onset-to-CTA time strata (p<0.001), decreasing from 39% within two hours of onset to 13% after eight hours. There was no heterogeneity in hematoma expansion between studies (F=0.45, p=0.87) or time strata (F=0.75, p=0.56). Across all time intervals, the median volume of hematoma expansion was greater for spot positive as compared to spot negative patients, and there was no change in median hematoma expansion by time-strata in spot positive patients (F=1.28, p=0.14). Spot positivity and significant hematoma expansion (defined as 6mL or ≥33%) as onset-to-CTA time strata increased. Sensitivity and PPV of the spot sign for hematoma expansion was greatest in the earlier time strata, whereas the specificity and negative predictive value (NPV) of spot sign increased with time. 

This study suggests that the utility of spot sign assessment may be dichotomized depending on onset-to-CTA time. The earlier time strata had the highest sensitivity and PPV which both decreased with time, and the later time strata suggested a high specificity and NPV. Identifying patients at risk for hematoma expansion as well as patients who likely have stable hematomas are both of value to clinicians, and understanding this information in the context of CTA timing suggests clinically relevant information can be gleaned regardless of the time of onset-to-CTA. Even in the acute setting, however, the best sensitivity to detect hematoma expansion was only 60%. This suggests that the spot sign alone is insufficient to identify at-risk patients and should be incorporated into future studies designed to identify other potential predictive factors. As the authors were unable to include any studies published after 2013 due to the time needed to acquire regulatory approvals for patient-level data, analysis of more recent studies would be helpful to validate these results.

Intra-Arterial Therapy, Post-Treatment Infarct Volumes, and Functional Outcomes in the ESCAPE Trial

Peggy Nguyen, MD

Al-Ajlan FS, Goyal M, Demchuk AM, Minhas P, Sabiq F, Assis Z, et al. Intra-Arterial Therapy and Post-Treatment Infarct Volumes: Insights From the ESCAPE Randomized Controlled Trial. Stroke. 2016

Outcome measurements in stroke trials commonly use measurements such as the mRS, NIHSS, or Barthel index as surrogates of functional improvement; the primary outcome measurement in the ESCAPE trial was the commonly used 3-month mRS. However, the relationship between outcomes at the functional level versus outcomes at a radiologic or anatomical level are not always delineated. Here, the authors perform a post-hoc analysis of the ESCAPE trial data, to evaluate the effect of IAT on saving brain tissue, and secondarily analyzed (1) clinical and imaging variables at baseline associated with post treatment infarct volume as well (2) the relationship between post treatment infarct volume and the 3-month mRS.

In the ESCAPE trial, the median post treatment infarct volume in the IAT group was significantly
lower than the control group (15.5 mL vs 33.5 mL, p < 0.01). Similarly, regardless of the intervention, successful recanalization in both groups was associated with smaller infarct volumes (14.5 mL vs 35 mL, p < 0.01). Baseline variables that were independently associated with smaller post treatment infarct volume were baseline NIHSS, site of occlusion, baseline ASPECTS and recanalization status, while age, sex, treatment type, IV tPA and time from onset to randomization were not. Post treatment infarct volume was found to strongly predict the 3-month mRS, particularly when including the change from baseline NIHSS.

Some interesting points came out of this study. The results reinforce the finding that recanalization, regardless of intervention, is a significant predictor of smaller infarct volumes. Interestingly, age had no interaction with the infarct volumes; one of the current debates in the stroke world these days is the benefit of IAT in older populations and this finding seems to suggest that age might not be a criteria for intervention if other variables are equal. Thirdly, the association of post treatment infarct volume with 3-month mRS was strongest when modeled with the change in baseline NIHSS, which makes sense, given large strokes in silent areas do not necessarily lead to better (or worse) outcomes, and small strokes in eloquent areas may have small post-treatment infarct volumes, but poor functional outcomes. This last finding, in a roundabout way, reinforces the utility of functional measures, such as mRS or Barthel index as outcome measures for clinical trials, rather than anatomical or radiological markers. 
By |April 4th, 2016|treatment|0 Comments

Silent Brain Infarctions Are Associated With an Increased Risk of Future Stroke

Neal S. Parikh, MD

Citing the potential utility of silent brain infarcts (SBI) as both a possible stroke risk factor and a surrogate outcome in stroke trials, Dr. Gupta and colleagues performed a systematic review and meta-analysis to evaluate the precise association between SBI and subsequent stroke.

The authors selected studies of adults who had baseline MRI-ascertained SBI and at least 12 months of follow-up for clinical stroke. Studies were vetted and abstracted in a rigorous, pre-specified manner. Meta-analyses were performed with random effects modelling, which controls for occult heterogeneity between individual study samples. The risks of selection bias and publication bias were assessed and found to be low.

Thirteen studies were ultimately included. All studies defined SBI as T2 hyperintense lesions at least three millimeters in size, with various methods employed to distinguish SBI from leukoaraiosis and dilated perivascular spaces. Clinical ischemic stroke was typically defined as a neurological deficit lasting greater than 24 hours in the absence of hemorrhage. Not all studies distinguished between ischemic and hemorrhagic stroke.

A total of 14,764 subjects were included, and the mean follow-up for clinical stroke was 76 months. Most subjects were middle-aged or elderly. 3,007 (20%) had SBI on MRI. The crude relative risk of clinical stroke in patients with SBI was 2.94 (95% confidence interval (CI), 2.24-3.86). Eight of the 13 studies provided covariate-adjusted hazard ratios (HR); the aggregate adjusted HR was 2.08 (95% CI, 1.69-2.56).

Subgroup analyses found that the association between SBI and subsequent stroke was present in both stroke-free community-dwelling patients and in patients with prevalent stroke. In both groups, patients with SBI experienced a two-fold increased risk of subsequent stroke.

The major limitations of their study are: variable definitions of SBI as diagnosed on MRIs of variable magnetic field strength, variable inclusion of relevant covariates, inconsistent reporting of ischemic versus hemorrhagic stroke, non-tissue based definition of ischemic stroke, and outdated cohorts (e.g. not subject to contemporary maximum medical therapy of vascular risk factors). These limitations do not, on the whole, negate the study’s findings.

There appears to be a clear, positive association between SBI and subsequent stroke. In current clinical practice, incidental SBIs do not prompt thorough stroke mechanism evaluation or personalized secondary prevention. Our evolving understanding of this entity will surely impact our practice patterns.