American Heart Association

diagnosis and imaging

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.

Cortical Venous Filling in Dynamic CTA Predicts Clinical Outcome in Proximal MCA Occlusion

Danny R. Rose, Jr., MD

As the scope and availability of endovascular treatment for large vessel occlusions in patients with ischemic stroke continues to increase, it is important for providers to have the ability to screen and predict which patients will benefit from these therapies. The most effective approach has been a topic of much debate and research, including utilizing ancillary testing to account for individual variations in collateral circulation and other factors that could potentially extend treatment indications and predict outcomes. Nearly all endovascular treatment trials use some combination of noncontrast head CT (NCCT), CT angiography (CTA) and/or CT perfusion (CTP) imaging to assist in clinical decision making due to the speed and availability of such scans. However, recent studies found that the currently utilized modalities may be insufficient to predict treatment effect or outcome. Wijngaard et al. sought to use cortical venous filling (CVF), a potential marker for collateral extent and perfusion, to assess whether the  extent or velocity of CVF as obtained through dynamic CTA predicts clinical outcome at 3 months in ischemic stroke patients with proximal middle cerebral artery occlusion.

All patients received a NCCT evaluated for early ischemic changes (ASPECTS); CTP/CTA was used for clot burden score, collateral status, cerebral-blood-flow (CBF), cerebral-blood-volume (CBV), mean-transit-time (MTT) and time-to-peak (TTP). Using the dynamic CTAHo, CVF was assessed visually—cortical venous contrast opacification and the number of cortical and anastomotic veins were evaluated in comparison with the contralateral hemisphere. The number of seconds to reach first CVF (appearance of any cortical vein draining into the superior sagittal sinus), optimal CVF (maximum contrast opacification of all cortical veins), and end of venous filling (complete absence of contrast) was measured. The velocity of CVF was calculated as the median differences between venous filling of the affected versus non-affected hemisphere. In addition, the extent of CVF was defined as either “good” or “poor,” based on comparing the extent of cortical vein filling at optimal CVF with the unaffected hemisphere using 50% as a cutoff.

A total of 88 patients were selected from two Dutch medical centers from previously published studies (DUST and MR-CLEAN). The mean age of participants was 67 years; median NIHSS was 15 and 50% of the participants were women. The median time from onset to imaging was 77 minutes. Most patients (59%) were treated with IV thrombolysis alone, with 25% of patients receiving intra-arterial therapy. At 3 months, 54 patients (61%) had a poor clinical outcome (mRS 3-6), and 22 of 88 patients (25%) had died. Venous predictors of poor outcome at 3 months were: poor extent of optimal CVF (RR 1.8; 95% CI 1.4-2.4) and slow velocity of optimal CVF (RR 1.6; 95% CI 1.1-2.2). Logistic regression models were utilized, using a layered approach in which successive models included more variables. Model 1 included age, NIHSS, treatment and ASPECT score, model 2 included CBF, model 3 included collateral status, and model 4 included extent and velocity of CVF. The addition of venous filling parameters resulted in a significant (p<0.02) improvement in prediction of clinical outcome. Although only 22 patients underwent mechanical thrombectomy, good CVF parameters (good extent and fast CVF) predicted good clinical outcomes in patients with mTICI 2b and 3 reperfusion (RR 3.3; 95% CI 1.1-10.6, p<0.05), compared with patient groups with poor CVF and/or poor perfusion status combined.

This study represents a novel use of venous filling parameters in predicting clinical outcome after ischemic stroke, resulting in a more accurate prediction when used in combination with previously studied measures. Based on these preliminary findings, one of the more promising applications may be its utility in predicting treatment effect of mechanical thrombectomy, but the small number of patients examined requires evaluation in a larger, prospective trial. If supported in additional research, CVF has the potential to become an important part in future trial design with respect to selecting patients for endovascular intervention. The authors’ choice to utilize dynamic CTA, however, limits its widespread application, as the more ubiquitous single-phase CTA cannot obtain time-resolved measurements. Parameters designed for use in single-phase CTA could be evaluated in a future study for its potential utility in facilities without dynamic CTA.  

Cerebral Microbleeds and Intracerebral Hemorrhage

Russell Mitesh Cerejo, MD

Pasquini M, Benedictus MR, Boulouis G, Rossi C, Dequatre-Ponchelle N, Cordonnier C. Incident Cerebral Microbleeds in a Cohort of Intracerebral Hemorrhage. Stroke. 2016

The authors studied prognostic factors of incident cerebral microbleeds (CMBs) in the PITCH study primary intracerebral hemorrhage (ICH) cohort with at least 2 MRIs and survival for 6 months post event, stratifying the findings according to the index ICH location. 

Amongst 168 included patients (median age 64 years) with ICH, 53% had at least 1 CMB. 

Anatomical distribution and number of CMBs were similar in patients with lobar and non-lobar ICH. Incident CMBs appeared in 80 patients (48%) in a median delay of 3.4 years (including 29 patients without CMBs at ICH onset), with a total number of 285 new CMBs, leading to an incidence rate of 14.2 per 100 person-years. Patients with CMBs at ICH onset had an almost 2.5 fold increased risk of developing incident CMBs during the follow-up period compared with patients without CMBs at ICH onset (aOR 2.27; 95% CI 1.18-4.35). In non-lobar ICH, incident CMBs were associated with incident lacunes (aOR 2.86; 95%CI 1.04-7.85) and with the use of antiplatelet agents during follow-up (aOR 2.89; 95%CI 1.14-7.32), while in lobar ICH incident CMBs were associated with incident radiological macro-hemorrhages (aOR 9.76; 95%CI 1.07-88.77). However, the proportion of antiplatelet agents use was similar in lobar and non-lobar ICH (31% and 32% respectively; p=0.89). 

This study provides long term MRI data and a better understanding into the possible etiologies of primary ICH as related to CMBs, which may be interesting surrogate markers.

Is a CT Within 6 Hours of Headache Onset Enough to Rule Out SAH?

Alexander E. Merkler, MD

Dubosh NM, Bellolio MF, Rabinstein AA, Edlow, JA. Sensitivity of Early Brain Computed Tomography to Exclude Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis. Stroke. 2016

Subarachnoid hemorrhage (SAH) is the most devastating type of stroke – 50% of survivors are dead within six months and among those patients who survive, only 50% return to their previous level of functioning. For decades, classic neurology dogma has stated that in order to rule out a SAH, any patient who presents with a thunderclap headache (HA) must receive a lumbar puncture (LP) if the head CT is negative. However, recent data suggests that in neurologically intact patients, a CT is 100% sensitive to rule out SAH when performed within six hours using a modern generation CT scanner (16-slice or greater). Hence, is there is no longer a need to perform an LP after a negative head CT that is performed within six hours of HA onset?

In this manuscript, Dr. Dubosh et al perform a meta-analysis to determine the sensitivity of modern generation CT scanners to rule out SAH in patients presenting to an emergency department within six hours of thunderclap HA. The authors identified five articles that met their inclusion criteria; four were retrospective and one was prospective. In total, 8,907 patients with thunderclap HA underwent a CT within six hours.

Overall, thirteen out of the 8,907 patients had a missed SAH. The overall sensitivity of CT was 0.987 (95% CI 0.971-0.994), specificity was 0.999 (95% CI 0.993-1.0) and the likelihood ratio of a negative CT was 0.010 (95% CI 0.003-0.034). This equated to a miss rate of 1.5 per 1000 patients who present with thunderclap HA and receive a modern CT scan within six hours.

It is important to note that each of the five studies had certain limitations. For example, perimesencephalic hemorrhage1 and SAH caused by a cervical arteriovenous malformation2 were considered missed causes of SAH. In addition, in the one prospective study by Perry et al3 (in which there were no documented missed cases of SAH), an LP was not performed in every patient who presented with thunderclap HA and had a negative CT. Although there was close follow-up using telephone interviews and monitoring coroner’s records, there may have been missed cases of SAH.

Modern CT performed within 6 hours of patients presenting with thunderclap HA is an extremely sensitive tool to rule-out SAH. As with most tests, it is impossible to say that it is 100% sensitive, but it certainly approaches it. Although perhaps very few cases of SAH may be missed, clinicians must weigh this against the potential consequences of performing an LP including time, anxiety, post-LP complications, unnecessary vascular imaging (CTA, MRA, angiography) and probably most importantly subsequent ramifications such as inappropriate procedures for incidentally found vascular lesions. Of course, missing a SAH may be life threatening and can lead to significant consequences including death.


1. Blok KM, Rinkel GJ, Majoie CB, Hendrikse J, Braaksma M, Tijssen CC et al. CT within 6 hours of headache onset to rule out subarachnoid hemorrhage in nonacademic hospitals. Neurology. 2015;12:1927-193.

2. Backes D, Rinkel GJ, Kemperman H, Linn FH, Vergouwen MD. Time-dependent test characteristics of head computed tomography in patients suspected of nontraumatic subarachnoid hemorrhage. Stroke. 2012;43:2115-2119.

3. Perry JJ, Stiell IG, Sivilotti ML, Bullard MJ, Emond M, Symington C et al. Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study. BMJ. 2011;343:d4277.

Thrombus Length Estimation on Delayed Gadolinium-Enhanced T1

Russell Mitesh Cerejo, MD

Yan S, Chen Q, Xu M, Sun J, Liebeskind DS, Lou M. Thrombus Length Estimation on Delayed Gadolinium–Enhanced T1. Stroke. 2016

The authors, in keeping with their previous studies on thrombus morphology on MRI, have found a new method to assess for thrombus length. They further correlated this thrombus length with recanalization and outcomes with IV thrombolysis. They evaluated patients over ~5 years with acute stroke due to M1 occlusion, received IV thrombolysis and had MRI pre and post thrombolysis. 

They obtained delayed gadolinium-enhanced T1 (dGE-T1) after perfusion imaging and co-registered the imaging with the time of flight MRA. Thrombus length on dGE-T1 was 8.18 ± 4.56 mm (range 1.63-30.26 mm). Recanalization occurred in 38 (51.4%) patients and no recanalization in 36 (48.6%). Thrombus length on dGE-T1 was significantly longer in patients without recanalization in univariate analysis. Thrombus length and M1 occlusion were independent predictors for no recanalization of MCA. Thrombus length of 6.77 mm, yielded a sensitivity of 77.8% and a specificity of 57.9%, and odds ratio 4.81 (95% CI: 1.742 to 13.292; p=0.002). No one achieved recanalization after IVT when length of thrombus exceeded 14 mm on dGE-T1 (see figure).

This study highlights the utility of MRI in assessing thrombus length without increasing the scan time or the contrast load. This may also be useful in acute stroke therapy to determine thrombus length and success of mechanical thrombectomy. 

Arterial Spin Labeling MRI Estimation of Antegrade and Collateral Flow in Unilateral Middle Cerebral Artery Stenosis

Russell Mitesh Cerejo, MD

Lyu J, Ma N, Liebeskind DS, Wang DJJ, Ma L, Xu Y, et al. Arterial Spin Labeling Magnetic Resonance Imaging Estimation of Antegrade and Collateral Flow in Unilateral Middle Cerebral Artery Stenosis. Stroke. 2016

The authors in their above titled paper describe a novel way to non-invasively assess for

antegrade and collateral blood flow in intracranial stenosis patients. They evaluated 41 consecutive patients with symptomatic intracranial stenosis of the M1 segment of the middle cerebral artery due to atherosclerosis. These patients underwent three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) with 3.0T MRI. The calculated perfusion on the CBF map of post labeling delay (PLD) 1.5s as early-arriving flow, and perfusion on the CBF map of PLD 2.5s as combination of early-arriving flow, late-arriving antegrade flow and late-arriving retrograde flow. The mean early arriving flow proportion was 78.3%±14.9%. The mean late-arriving retrograde flow proportion was 16.1%±10.2%. Half patients underwent cerebral angiography with calculation of Modified TICI scale and ASITN/SIR collateral grade.

The authors found significant correlations between early-arriving flow and late-arriving flow on two-PLD pCASL with conventional angiographic antegrade and collateral scales, suggesting that the early-arriving flow and late-arriving retrograde flow to the territory supplied by the stenotic MCA may primarily represent antegrade and collateral flow, respectively.

This is an interesting study, which has tried to use a novel non-invasive technique to assess for collaterals that are important not only in chronic stenoses but also acute occlusions.

Intracranial Arterial Remodeling and the Risk of Stroke

Alexander E. Merkler, MD

Qiao Y, Anwar Z, Intrapiromkul J, Liu L, Zeiler SR, Leigh R, et al. Patterns and Implications of Intracranial Arterial Remodeling in Stroke Patients. Stroke. 2016

Intracranial atherosclerotic disease (ICAD) is a common cause of stroke; patients with ICAD face high rates of recurrent stroke despite aggressive medical and lifestyle modification. Currently, the diagnosis of ICAD is based on the degree of vessel stenosis, but perhaps, as Drs. Qiao et al discuss, this is not the best measure of either plaque burden, or more importantly, stroke risk.

Based on coronary plaque research, Drs. Qiao et al studied the impact of vessel remodeling in ICAD. Although plaque may lead to hemodynamic stenosis, remodeling of the vessel may either preserve (positive remodeling) or further impair (negative remodeling) the degree of stenosis. In addition, although positive remodeling may preserve the vessel lumen, it may make plaque more vulnerable to rupture or lead to clinical symptoms.

In this study, the authors used High-resolution black blood MRI (BBMRI) to assess vessel remodeling in ICAD and its association with ischemic events. Forty-five patients with ICAD with >50% stenosis in a large intracranial artery who also had a stroke or TIA in the distribution referable to that stenosis were included. The authors identified 137 plaques, of which 56 exhibited positive remodeling, 53 negative remodeling, and 28 intermediate remodeling. There was higher burden of plaque within the posterior circulation as compared to the anterior circulation and positive remodeling was more frequent in the posterior circulation (58% vs 31%). Furthermore, positive remodeling was associated with a trend towards culprit plaque classification. Finally, the authors found that the lumen begins to narrow (ie when remodeling fails to preserve the lumen) when plaque burden reached 55.3%.

This study challenges the current theory that ICAD is purely based on degree of vessel stenosis. As in the coronary vessels, remodeling occurs when plaque is present and may either augment or decrease the vessel lumen size. Furthermore, intracranial remodeling may lead to an underestimation of plaque burden (based on the current definition of vessel stenosis >50%), and therefore an underdiagnosis of ICAD, particularly in the posterior circulation. Further research to assess remodeling and its impact on stroke risk is warranted.

Assessing Mismatch Using DWI and FLAIR Predicts Favorable Outcome Following Recanalization With IV-tPA

Jay Shah, MD

Legrand L, Tisserand M, Turc G, Edjlali M, Calvet D, Trystram D, et al. Fluid-Attenuated Inversion Recovery Vascular Hyperintensities–Diffusion-Weighted Imaging Mismatch Identifies Acute Stroke Patients Most Likely to Benefit From Recanalization. Stroke. 2016

Perfusion-Diffusion mismatch on MRI has been proposed to select ischemic stroke patients for revascularization therapy. However, this strategy is time consuming and requires gadolinium. The authors previously have reported using mismatch between Fluid-attenuated inversion recovery (FLAIR) vascular hyperintensities (FVH) and diffusion for penumbral evaluation. FVH represent slow retrograde flow in leptomeningeal collaterals and are thought to represent impaired but viable tissue. The authors hypothesize that recanalization after IV-tPA would have better outcomes within FVH-DWI mismatch patients than non-mismatch patients. 

This study was a retrospective analysis of a prospective registry of patients treated exclusively with standard IV-tPA dosing for acute stroke between 2004-14. Other inclusion criteria included proximal M1 occlusion, pre-treatment and 24-hour follow-up MRI, and 3 month modified rankin scale (mRS) score. FVH-DWI mismatch was considered present when FVH extended beyond boundaries of the cortical DWI lesion. In total, 164 patients were included in the analysis. 121 patients had FVH-DWI mismatch. Complete recanalization occurred in 50 patients. Association between recanalization and favorable outcome was significant in patients with FVH-DWI mismatch (OR= 16.2). 

This study shows that DWI and FLAIR images can identify patients who are more likely to benefit from recanalization and the authors propose that this modality can be used as a surrogate to perfusion imaging. However, it is clearly understood that clinical outcomes in acute ischemic stroke is strongly associated with recanalization of the occluded artery. Non-mismatch patients also demonstrated benefit, albeit to a lesser degree and therefore revascularization should not be withheld for a perceived lack of benefit. Furthermore, all patients within this study had M1 occlusion but did not undergo endovascular intervention which is now established as the standard of care. For such patients, if recanalization can be achieved according to guideline recommendations, there should not be a need for further penumbral evaluation. However, in patients with a prolonged presentation or an unknown time of onset, assessment of mismatch could provide utility in selecting appropriate patients. Further studies should focus on this patient population.

The MRI Spot Sign: A Marker of Clinical outcomes in Patients with Primary ICH

Peggy Nguyen, MD

Schindlbeck KA, Santaella A, Galinovic I, Krause T, Rocco A, Nolte CH, et al. Spot Sign in Acute Intracerebral Hemorrhage in Dynamic T1-Weighted Magnetic Resonance Imaging. Stroke. 2016

The spot sign on CTA has been previously correlated with hematoma expansion, mortality, and poor clinical outcomes in patients with primary ICH. In practice, the CTA spot sign is likely to be of greatest relevance, given hyperacute stroke imaging is still largely predicated on CT imaging. However, MR imaging has increasingly been used early in the course of acute stroke imaging, but there is no equivalent sign that has been validated. Here, the authors report on an equivalent MR spot sign on contrast enhance T1 weighted imaging in 50 consecutive primary ICH patients presenting within 24 hours of an acute stroke syndrome. 

Contrast enhancement within the hematoma on MR (spot sign) was demonstrated in 23 of 50 patients (46%) with primary ICH. Larger spot signs were seen with larger hematomas and correlated with the outcome based on mRS; specifically when spot signs were dichotomized as large (> 1 mL) vs small (< 1mL), large spot signs were characterized by larger hematoma volumes (36 mL vs 5 mL) and worse outcomes (median mRS 5). When patients were dichotomized according to presence or absence of a spot sign, patients with the spot sign had worse outcomes (median mRS 4) despite similar NIHSS on admission. On follow up imaging, however, no significant difference was seen in regards to hematoma expansion between those who had a spot sign and those who did not.

Although the MR spot sign was not demonstrated to be predictive of hematoma expansion, it was predictive of clinical outcome. Given that MR allows evaluation of hematoma age and often provides additional information on possible etiology of hemorrhage, the validation of an equivalent spot sign on MR adds another tool to the arsenal of MR interpretation for ICH.