Introduction Intra-arterial therapy for acute ischemic stroke (AIS) now has an established role. We investigated if Hounsfield Units (HU) quantification on non-contrast CT is associated with ease and efficacy of mechanical thrombectomy and outcomes.
Methods We retrospectively studied a prospectively maintained database of cases of AIS given intra-arterial therapy between May 2008 and August 2012. Functional outcome was assessed by 90-day follow-up modified Rankin Scale (mRS). Patients were dichotomized based on time to recanalization. HU were calculated on head CT and thrombus location and length were determined on CT angiography. Simple linear regression was used to analyze the association between clot length, average HU and other clinical variables.
Results 141 patients were included. There was no difference in clot length or average HU among patients with good recanalization achieved within 1 h and those in which the procedures extended beyond 1 h. There was no relationship between clot length or density and recanalization. The thrombus length and density were not significantly different between patients with procedural complications and those without. Neither the presence of post-procedure intracranial hemorrhage nor the 90-day mRS was associated with thrombus length or density.
Conclusions We have not found any significant associations between either thrombus length or density and likelihood of recanalization, time to achieve recanalization, intraprocedural complications, postprocedural hemorrhage or functional outcome at 90 days. These results do not support a predictive value for thrombus quantification in the evaluation of AIS.
Statistics from Altmetric.com
Intra-arterial therapy for acute ischemic stroke (AIS) has an established role, albeit controversial in current times,1 alongside intravenous administration of thrombolytics2–4 and includes intra-arterial thrombolysis and devices for mechanical thrombectomy. Recent studies have identified clinical benefit for patients in whom mechanical recanalization can be achieved.5–11 Patient selection for intra-arterial therapy with physiologic imaging studies may be an essential component to intra-arterial therapy.12 Furthermore, any predictors of technical success that can be rapidly obtained with low inter-rater variability in the acute stroke imaging triage period may be beneficial to neurointerventionalists and stroke neurologists. The hyperdense middle cerebral artery sign, first described in 1988,13 is a frequent finding on CT imaging and has been associated with poor clinical outcomes.14–16 In addition, Hounsfield unit (HU) quantification of thrombus predicts recanalization following the administration of intravenous tissue plasminogen activator (tPA) with lower HU associated with a higher rate of recanalization.17 We investigated if HU quantification on non-contrast CT across all intracranial vessels is associated with ease and efficacy of mechanical thrombectomy and outcomes.
We retrospectively studied a prospectively maintained database of AIS cases that underwent intra-arterial therapy between May 2008 and August 2012 at a high-volume tertiary care center (Medical University of South Carolina). At our institution, mechanical thrombectomy is the preferred treatment modality for patients with AIS who do not qualify for intravenous tPA, do not improve with intravenous tPA or have severe strokes with large vessel occlusion. Candidacy for intervention is determined by CT perfusion imaging, irrespective of time of onset.12 During the study period the primary device for mechanical thrombectomy used was the Penumbra aspiration system (Penumbra, Alameda, California, USA),18 with first-generation stent retrievers used as the newer devices became available.
Medical records, procedural records, CT images and angiograms were reviewed. The intracranial vessel affected, recanalization status of affected vessel as determined by the Thrombolysis In Cerebral Ischemia (TICI) scale, intraprocedural complications, procedural time to recanalization and the presence of hemorrhage on the postprocedure head CT scan were extracted. Functional outcome was assessed by 90-day follow-up modified Rankin scale (mRS). Patients were then dichotomized into two groups: those in whom recanalization was achieved in ≤60 min and those in whom the procedures and recanalizations extended beyond 60 min (Spiotta et al, unpublished). For portions of the statistical analysis, time to recanalize was studied as a continuous variable.
Time to vessel recanalization was determined from percutaneous groin access (time zero) to the time that the affected vessel was recanalized. Time was monitored in minutes and seconds based on review of the time stamp of the angiographic images. If the patient suffered an intraprocedural complication requiring abortion of the procedure (eg, vessel rupture), the recanalization time was defined as the time of groin puncture to the time when the complication was documented on the angiographic run, not the final procedural time.
A blinded neuroradiologist (HH) obtained the thrombi HU and clot length quantification. Retrospectively, a database of patients requiring thrombectomy secondary to AIS was reviewed for the presence of a hyperdense middle cerebral artery (MCA) sign. Of those patients who demonstrated the sign, the HU of thrombi present on the non-contrast brain CT scan were calculated by drawing circular regions of interest (ROI). The smallest ROI obtainable via the Afga Impax archiving system (Afga HealthCare, Morstel, Belgium) was used to obtain the individual measurements (0.02 cm2). Three separate measurements were taken from different sections of the clot and averaged: (ROI1+ROI2+ROI3)/3. The same protocol for obtaining non-contrast head CT images was in place over the period of review. Images were acquired exclusively on a Siemens 64-slice CT scanner (Siemens Medical, Munich, Germany) with bolus tracking technology. Non-contrast head CT was helically acquired with 4.8 mm slice thickness and no overlap. The location and length of the thrombus was obtained from the CT angiogram (CTA) obtained as part of every AIS investigation. Thrombus length was estimated on the CTA by measuring the filling defect in the affected vessel on a picture archiving and communication system workstation (figure 1A,B). The most useful series for measurement of clot length proved to be the coronal plane of the maximum intensity projection (MIP) reconstruction; however, this tool was used alongside the axial raw data. MIP reconstructions (10 mm slab thickness, 2 mm reconstruction increment) were standardly provided in the axial, coronal and sagittal planes and sent alongside the raw CTA data acquired at 1.25 mm from the aortic arch through the vertex.
Statistical analyses were performed using SAS V.9.3 (SAS Institute, Cary, North Carolina, USA). A population of 141 subjects was analyzed using descriptive statistics to characterize thrombus measurements by clinical variables describing treatment, complications and outcomes. Measurements of the clots include the average of three separate calculations of HU per subject and the length of the clot. Differences in measurements among the clinical variables were tested using the Student t test. All tests were two-sided and assessed at a significance level of 0.05. Simple linear regression was used to analyze the association between clot length, average HU and other clinical variables.
One hundred and forty-one patients were included (table 1). Of these, 122 (86.5%) had an occlusion demonstrable on the admission CTA with sufficient back filling of the occluded vessel to measure the length of the clot and 95 (67.4%) had a hyperdense thrombus evident on the initial non-contrast brain CT scan. The mean thrombus length was 13.3±9.5 mm (range 3–72 mm) and the mean thrombus density was 59.9±25.7 HU (range 36.5–224.1 HU). There was no strong association between HU and thrombus length (R=0.0000000283, figure 2A) and there was no relationship between time from symptom onset and thrombus length or density (figure 2B,C).
Recanalization efficacy and time
There was no difference in clot length (14. 1±10.9 mm vs 12.4±8.4 mm; p=0.36) among patients in whom recanalization to TICI 2B or greater was achieved within 1 h compared with those in whom the procedures extended beyond 1 h (table 2). The average HU units were higher for subjects where the procedure time was >1 h compared with those in whom the procedure time was <1 h, but the difference was not statistically significant (55.3±7.5 HU vs 63.7±33.4 HU; p=0.08; table 3). There was no relationship between clot length or density and recanalization time as a continuous variable (figure 2D,E), and there was no relationship between thrombus length or density and recanalization status as defined by the TICI score (figure 2F,G).
The thrombus length and density were not significantly different between patients with procedural complications and those without. The presence of post-procedure intracranial hemorrhage was not associated with thrombus length or density.
Ninety-day outcome by mRS was not associated with either thrombus length or density when studied as a continuous variable (figure 2H,I) or when dichotomized to ‘Good’ (mRS 0–2) and ‘Poor’ (mRS 3–6).
We tested the hypothesis that longer and more dense thrombi on CT imaging in the AIS setting would be associated with increased procedural time required to achieve thrombectomy, higher complication rates and worse outcomes. The potential strength of such an association would be in its ease of application. HU quantification is an objective value that can be obtained quickly during the initial non-contrast CT scan obtained for every stroke patient. The prognostic information determined in this study could provide predictive value that is of benefit to the neurointerventionalist and could tip the balance in certain circumstances in the risk and benefit analysis. Earlier studies have suggested that patients presenting with hyperdense thrombus on CT (mainly M1) responded better to intra-arterial than to intravenous tPA.19 ,20 A plausible explanation of these findings is that a higher density thrombus may reflect heavier clot burden in the affected vessel, making it more resistant to non-targeted systemic thrombolytic therapy and necessitating mechanical disruption. In support of this rationale, lower HU quantification of thrombus has been associated with a higher incidence of recanalization following stand-alone intravenous tPA administration,17 while another recent study reported contradictory findings with thrombi with lower HU appearing to be more resistant to pharmacological lysis.21 Interestingly, the authors also found that successful mechanical thrombectomy was more likely among patients with higher HU quantification. Thus, considerable disagreement exists in the available literature with regard to the predictive value of HU quantification. With regard to clot length, a recent study found that clot length was more predictive of the response to intravenous tPA, with thrombi >8 mm never recanalizing with medical therapy alone.21
However, our study, which had a larger cohort of patients than has previously been published, did not find any significant associations between either thrombus length or density and likelihood of recanalization, time to achieve recanalization, intraprocedural complications, postprocedural hemorrhage or functional outcome at 90 days. As such, the results do not support a predictive value for thrombus quantification in the acute stroke triage period. Additionally, there was no relationship between time from symptom onset and thrombus length or density. These data discount the notion that thrombi causing acute intracranial occlusions tend to become more dense and larger in size over time.
There are several potential factors that may have led to a false negative association in our study. First, although HU quantification is an objective metric that can be rapidly obtained at the time of the initial non-contrast brain CT scan, there could be inter-rater variability. We attempted to minimize this possibility by enlisting one neuroradiologist to review all imaging who was blinded to patient treatment. Furthermore, each HU quantification was averaged over three measurements to reduce sampling error. Additionally, the non-contrast head CT slice thickness was 5 mm in our study. Since the MCA has a diameter of approximately 2.5 mm in humans, accurately assessing clot density is challenging. A recent study compared clot length of hyperdense MCA signs with thin-cut CT (1.25 and 2.5 mm) and CTA, and found the two to be highly correlated.22 While we are aware of the limitations of slice thickness in non-contrast head CT scans, most institutions acquire their images with a 5 mm slice thickness. By using the same slice thickness as other centers, we feel that our results are more applicable. With more widespread implementation of improved imaging modalities, clot length and density may be better delineated and ultimately found to be predictive of technical success of thrombectomy. However, in currently available imaging protocols, these data represent real-world data available to stroke neurologists and neurointervenionalists at the time of the acute stroke triage.
There has been debate in the literature regarding the sensitivity of the dense MCA sign, although HU >43 has been shown to have a higher specificity for the presence of thrombus.22 Mimics causing symmetric false positive hyperdense signs include elevated hematocrit and the presence of intravenous contrast medium, while asymmetric false positives may occur in the setting of vascular calcification. In our analysis we included only patients with clear-cut asymmetric hyperdense thrombus in the vessel of interest, excluding approximately one-third of patients to avert this source of error in our final analysis.
Our study setting included treatment of patients at a high-volume center with a homogenous approach to thrombectomy. The vast majority of patients during this time period underwent thrombectomy with the Penumbra aspiration system as the frontline device by three attending neurointerventionalists with a similar treatment philosophy. The Penumbra aspiration system involves maceration of the thrombus with a separator under direct aspiration to prevent showering of fragments. It is, however, possible that the findings of this report may not be as applicable as newer generation devices are introduced into practice such as the stent retriever family (Solitaire, ev3 Endovascular, Plymouth, Minnesota, USA; Trevo Pro, Stryker Neurovascular, Kalamazoo, Michigan, USA; and Penumbra three-dimensional separator, Penumbra, Alameda, California, USA), as these devices work by primarily engaging the clot for en bloc removal. Thus, the effectiveness of novel devices may be related to intrinsic properties of the thrombus itself such as density and length. Further study in a prospective fashion will be required to adequately determine if there is any predictive association between clot length and density and ease of thrombectomy and outcomes.
We did not find any significant associations between either thrombus length or density in the AIS setting and the likelihood of recanalization, time to achieve recanalization, intraprocedural complications, postprocedural hemorrhage or functional outcome at 90 days. These results do not support a predictive value for thrombus quantification in the evaluation of AIS.
Contributors All the authors made a material contribution to the article, the revision of the article and the approval of the final article for submission to this journal.
Competing interests None.
Ethical approval The study was approved by the institutional review board of the Medical University of South Carolina.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.