Computed tomography perfusion and computed tomography angiography for prediction of clinical outcomes in ischemic stroke patients after thrombolysis

Jia-wei Pan, Xiang-rong Yu, Shu-yi Zhou Jian-hong Wang, Jun Zhang, Dao-ying Geng, Tian-yu Zhang Xin Cheng, Yi-feng Ling, Qiang Dong

1 Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China

2 Department of Radiology, Zhuhai Hospital of Jinan University, Zhuhai People’s Hospital, Zhuhai, Guangdong Province, China

3 Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

Computed tomography perfusion and computed tomography angiography for prediction of clinical outcomes in ischemic stroke patients after thrombolysis

Jia-wei Pan1,#, Xiang-rong Yu2,#, Shu-yi Zhou1, Jian-hong Wang3, Jun Zhang1,＊, Dao-ying Geng1,＊, Tian-yu Zhang1, Xin Cheng3, Yi-feng Ling3, Qiang Dong3

1 Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China

2 Department of Radiology, Zhuhai Hospital of Jinan University, Zhuhai People’s Hospital, Zhuhai, Guangdong Province, China

3 Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

How to cite this article:Pan JW, Yu XR, Zhou SY, Wang JH, Zhang J, Geng DY, Zhang TY, Cheng X, Ling YF, Dong Q (2017) Computed tomography perfusion and computed tomography angiography for prediction of clinical outcomes in ischemic stroke patients aer thrombolysis. Neural Regen Res 12(1):103-108.

Open access statement:is is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Graphical Abstract

Prediction of short-term clinical outcomes in ischemic stroke patients after thrombolysis

#

orcid: 0000-0003-1849-9199 (Jun Zhang) 0000-0002-6121-7866 (Dao-ying Geng)

Cerebral blood perfusion and cerebrovascular lesions are important factors that can a ff ect the therapeutic e ffi cacy of thrombolysis. At pres‐ent, the majority of studies focus on assessing the accuracy of lesion location using imaging methods before treatment, with less attention to predictions of outcomes aer thrombolysis.us, in the present study, we assessed the e fficacy of combined computed tomography (CT) perfusion and CT angiography in predicting clinical outcomes aer thrombolysis in ischemic stroke patients.e study included 52 patients who received both CT perfusion and CT angiography. Patients were grouped based on the following criteria to compare clinical outcomes: (1) thrombolytic and non‐thrombolytic patients, (2) thrombolytic patients with CT angiography showing the presence or ab‐sence of a vascular stenosis, (3) thrombolytic patients with CT perfusion showing the presence or absence of hemodynamic mismatch, and (4) di ff erent CT angiography and CT perfusion results. Short‐term outcome was assessed by the 24‐hour National Institution of Health Stroke Scale score change. Long‐term outcome was assessed by the 3‐month modi fi ed Rankin Scale score. Of 52 ischemic stroke patients, 29 were treated with thrombolysis and exhibited improved short‐term outcomes compared with those without thrombolysis treatment (23 patients). Patients with both vascular stenosis and blood fl ow mismatch (13 patients) exhibited the best short‐term outcome, while there was no correlation of long‐term outcome with CT angiography or CT perfusion fi ndings.ese data suggest that combined CT perfusion and CT angiography are useful for predicting short‐term outcome, but not long‐term outcome, aer thrombolysis.

nerve regeneration; ischemic stroke; 256-slice whole-brain CT perfusion; infarct core; penumbra; CT perfusion mismatch; CT angiography; vessel stenosis; intravenous thrombolysis; 24-hour National Institution of Health Stroke Scale; 3-month modi fi ed Rankin Scale; neural regeneration

Introduction

Computed tomography (CT) perfusion (CTP) and CT an‐giography (CTA) imaging techniques are widely used for diagnosis of ischemic stroke as they are safe, convenient, and accurate (Vagal et al., 2014; Yew et al., 2015). Cerebral blood fl ow perfusion and vascular conditions are critical for choice of optimal clinical treatment. However, although pa‐tients and their families are mostly concerned with clinical outcomes after thrombolysis, doctors are usually unable to make outcome predictions. Numerous studies have focused on improving the accuracy of imaging examination before treatment (Seeters et al., 2013; Smit et al., 2015), while the prognosis aer thrombolysis in patients with long‐term fol‐low‐up evaluation is poorly understood. In the present study, we examined role of combined CTP and CTA imaging in predicting clinical outcomes aer thrombolysis in ischemic stroke patients.

Subjects and Methods

Subjects

This study was approved by the local ethical committee (Institutional Review Board of Huashan Hospital, Fudan University, IRB number KY2013‐332), and written informed consent forms were obtained directly from patients or the next of kin. Patients were continuously collected in the Neu‐rological Emergency Department of Huashan Hospital of China from December 2011 to September 2012.

Inclusion criteria

According to China Cerebrovascular Disease Prevention and Control Guidelines (2ndEdition) (Rao, 2010), patients who met all the following factors were enrolled in this study: (1) sudden onset, focal, or comprehensive loss of neurological function and (2) symptoms lasted for 24 hours.

Exclusion criteria

Exclusion criteria included: (1) patients who did not meet one of the above two factors or refused to have the two ex‐ams; (2) patients with non‐vascular cerebral disease, and (3) patients with cerebral hemorrhage or other diseases by CT scan.

Criteria of the enrolled patients with thrombolytic therapy

(1) CT showed no sign of cerebral hemorrhage; (2) physical exam did not show active bleeding or acute trauma (fracture); (3) no use of oral anticoagulants or international standard ratio ≤ 1.5 if the patient had used oral anticoagulants; (4) activated partial thromboplastin time within normal limits; (5) platelet count ≥ 100 × 109/L, blood sugar concentration≥ 2.7 mM; (6) infarct size on CT less than 1/3 of the cerebral hemisphere; and (7) informed consent of the patient or fam‐ily members.

Criteria of enrolled patients without thrombolysis

(1) Met all the diagnostic criteria of acute ischemic stroke and (2) inconformity with one of the thrombolytic therapy criteria.

Every patient included in this study received a 256‐detector CTP and CTA scan (Brilliance iCT; Philips Medical Systems, Cleveland, OH, USA). A dual‐head power injector (Stellant Injection System; Medrad Inc., Indianola, PA, USA) was used to inject 40 mL of a nonionic contrast medium (Ultra‐vist, iodine 370 mg/mL; Bayer Healthcare, Berlin, Germany) at a rate of 5 mL/s, followed by a 20‐mL saline fl ush at a rate of 5 mL/s into an antecubital vein. CT scanning was initiated at 5 seconds aer the start of the injection with the following acquisition parameters: Jog mode, 80‐kV tube voltage, 150 mAs, 5‐mm slice thickness, 128 × 0.625‐mm collimation, 0.4‐second rotation time, 1.9‐second cycle time, 22‐cm fi eld of view, 512 × 512 image matrix size, 25 slices, and 120‐mm scan length. Helical scanning was not performed. A total of 325 slices were obtained with a scan time of approximately 50 seconds. Brain standard reconstruction was performed with the CT system. The gantry angle was parallel to and above the orbital roof to avoid radiation exposure to the lens.

Recombinant tissue plasminogen activator (0.9 mg/kg) was mixed with 100 mL normal saline. Ten percent of the solution was intravenously injected, and the rest was intra‐venously dripped over 1 hour (recombinant tissue plasmino‐gen activator maximum dose: 90 mg).

Image post-processing

Post‐processing software (MIStar, Apollo Medical Imaging Technology Pty. Ltd., Melbourne, Australia) (Yang, 2005, 2010; Bivard et al., 2011) was used for deconvolution of the tissue enhancement curve and the artery input function by model‐free singular value decomposition with a delay and dispersion correction (see appendix for more detail). CTP penumbra and infarct core parameters were set according to our previous research (Pan et al., 2013).e penumbra scale (a relative mean transfer time ≥ 150%) and the infarct core scale (relative cerebral blood volume ≤ 40%) were calculated by the soware.

Group assignment

(1) All patients were divided into two groups based on their acceptance of thrombolytic treatment. (2) All thrombolytic patients were divided into two groups according to whether CTA results showed a vascular stenosis. (3) All thrombolytic patients were divided into two groups according to whether CTP results showed a blood fl ow mismatch. (4) All throm‐bolytic patients were divided into three groups according to both CTA and CTP findings (vascular stenosis and blood flow mismatch, vascular stenosis without blood flow mis‐match, or blood flow mismatch without occlusive vascular stenosis).

A CTP penumbra volume and infarct core volume ratio (Vpenumbra/Vinfarct) ≥ 0.2 indicates a mismatch, while a ratio ＜ 0.2 represents no mismatch (infarct core, red; penumbra, green;Figure 1).is de fi nition is analogous to the magnetic reso‐nance perfusion weighted imaging (MR‐PWI) and di ff usion weighted imaging (MR‐DWI) mismatch, where the CTP infarct core is equivalent to MR‐DWI while the CTP penum‐bra is equivalent to MR‐PWI.us, the standard of an MR‐PWI and MR‐DWI mismatch is also applied to a CTP blood fl ow mismatch (Schlaug et al., 1999).

able 1 General information for thrombolytic and non-thrombolytic patients

able 1 General information for thrombolytic and non-thrombolytic patients

For short‐term outcome, better indicates a 24‐hour National Institution of Health Stroke Scale (NIHSS) score change ≥ 4, while worse indicates a 24‐hour NIHSS score change ＜ 4. For long‐term outcome, better indicates a 3‐month modified Rankin Scale (mRS) score ≤ 2, while worse indicates a 3‐month mRS score ＞ 2. *P＜ 0.05,vs. non‐thrombolytic (chi‐square test, 95% con fi dence interval: 1.137—19.484).

rombolytic Non‐thrombolyticn29 23 Age (mean [range], year) 62(41—81) 66(46—90) Gender (male/female,n) 20/9 18/5 Onset time (hour) 0—3 14 9 3—6 11 9＞ 6 4 5 Location Basal ganglia (n) 11 9 Cerebral cortex (n) 15 12 Brain stem (n) 3 2 Risk factors (n) Hypertension (n) 16 10 Heart disease (n) 2 3 Diabetes (n) 9 10 Anticoagulant or antiplatelet treatment (n) 1 2 Baseline NIHSS (mean ± SD, score) 7.9±3.8 5.6±2.9 24‐hour NIHSS (mean ± SD, score) 5.7±3.4 (24 hours aer thrombolysis) 4.9±2.6 #Short outcome (better/worse,n) (1)12/17*(2)3/20 &Long outcome (better/worse,n) (3)17/12 (4)15/8

CTA vascular stenosis was de fi ned as the degree of arterial stenosis ＞ 50%, using the following formula: diameter of the narrowest part of the artery/diameter of the normal part of the artery × 100%. We selected the following arter‐ies for evaluation: bilateral intracavernous internal carotid artery, supraclinoid portion of the internal carotid artery, A1 and A2 portion of the anterior cerebral artery, M1 and M2 portion of the middle cerebral artery, P1 and P2 por‐tion of the posterior cerebral artery, and the intracranial sector of the vertebral artery and basal artery. Evidence of stenosis was independently diagnosed by two radiologists, with positive fi ndings from both required for fi nal con fi r‐mation (Figure 2).

Outcome measures

Each patient received two follow‐up assessments: a 24‐hourNational Institution of Health Stroke Scale (NIHSS) (omas et al., 1989) and a 3‐month modified Rankin Scale (mRS) (Swieten et al., 1988).ese two criteria are the most com‐mon methods used by neurological physicians to evaluate patient prognosis. For the NIHSS, the total score indicating‐was calculated by adding each item score, with higher score indicating worse patient condition. When comparing at 24‐hour NIHSS score with baseline NIHSS score, a reduction ≥4 indicates improved short‐term outcome, while a reduction＜ 4 indicates a worse short‐term outcome. For the mRS, patients were asked what ranking they conformed to, with a higher score indicating a worse condition. A 3‐month mRS score ≤ 2 indicates improved long‐term outcome, while a 3‐month mRS score ＞ 2 indicates worse long‐term outcome.

able 2 General information of thrombolytic patients divided by Cangiography (CA) and Cperfusion (CP) results

able 2 General information of thrombolytic patients divided by Cangiography (CA) and Cperfusion (CP) results

ere were no di ff erences in age, sex, or onset time between the fi rst three groups. CTA vascular stenosis (CTA+) was de fi ned as the degree of arterial stenosis ＞ 50% (＜ 50% is CTA−).e CTA vascular stenosis formula is: diameter of the narrowest part of the artery / diameter of the normal part of the artery × 100%. A CTP penumbra volume and infarct core volume ratio (Vpenumbra/Vinfarct) ≥ 0.2 indicates the existence of a mismatch (CTP+), while a value ＜ 0.2 represents no mismatch (CTP−).

CTA (+)/ CTP (–) CTA (+)/ CTP (+) CTA (–)/ CTP (+) CTA (–)/ CTP (–)n13 5 7 4 Age (mean, range, year) 62(45–80)64(55–76)66(46–90)60(56–72) Gender (male/ female,n)9/4 4/2 5/2 2/1 Onset time (hour) 0—3 6 4 4 0 3—6 6 1 2 2＞ 6 1 0 1 2 Hypertension (n) 6 3 5 2 Heart disease (n) 1 0 1 0 Diabetes (n) 3 3 3 0 Anticoagulant or antiplatelet treatment (n) 0010

Statistical analysis

Data were analyzed using SPSS 20.0 software (IBM, Ar‐monk, NY, USA). All data were tested for normality. A chi‐square Armonk test was used to compare clinical outcomes (count data were calculated as a ratio) between the groups (inter‐group di ff erences). An independent samplet‐test was used to compare the general information (data were calculat‐ed as means) between the groups (inter‐group di ff erences). A value ofP＜ 0.05 was considered statistically signi fi cant.

Results

Among the 52 ischemic stroke patients, 29 received throm‐bolytic therapy and 23 did not (baseline information of these two groups are shown inable 1). Thrombolytic patients exhibited better short‐term outcomes than those without therapy (able 1).e thrombolytic e ff ect was not di ff erent between the various locations (Figure 3).

Baseline information of the thrombolytic patients isshown inable 2. The group of patients with both CTA vascular stenosis and a CTP blood fl ow mismatch exhibited a better short‐term clinical outcome than patients in other groups.ere were no other di ff erences between the groups (able 3).

able 3 Chi-square test results of di ff erent CP and CA examination results and clinical outcomes of thrombolytic patients

able 3 Chi-square test results of di ff erent CP and CA examination results and clinical outcomes of thrombolytic patients

*P＜ 0.05. CTA: Computed tomography angiography; CTP: computed tomography perfusion; NIHSS: National Institution of Health Stroke Scale;CI: con fi dence interval; mRS: modi fi ed Rankin Scale.

24‐hour NIHSS score change 3‐month mRS score≥ 4 ＜ 4 ≤ 2 ＞ 2 (1) CTA (+) 11 7 10 8 0.466 0.413, 8.611 (2) CTA (—) 5 6 9 2 (1)vs. (2) 0.234 0.046, 1.667 (3) CTP (+) 11 9 12 8 0.427 0.473, 2.629 (4) CTP (—) 3 6 7 2 0.431 0.070, 2.614 (5) CTA (+)/CTP (+) 10 3 8 5 (5)vs. (6) 0.047*1.048, 169.557 0.608 0.291, 19.784 (6) CTA (+)/CTP (—) 1 4 2 3 (5)vs. (7) 0.017*1.676, 238.630 1.000 0.185, 7.770 (7) CTA (—)/CTP (+) 1 6 4 3 (6)vs. (7) 1.000 0.071, 31.575 1.000 0.049, 5.154 Group Compared groupsPvalue 95%CI

Figure 1 CP post-processed image.

Figure 2 Computed tomography angiography post-processed picture.

Discussion

Relationship between thrombolysis and clinical outcomesWe found that patients who received thrombolysis had a bet‐ter short‐term clinical outcome than those without throm‐bolysis, with no effects of onset time or ischemic location. These data suggest that thrombolytic therapy can rapidly help to recover brain perfusion and maintain neurological function. However, there were no differences in long‐term outcomes between the two groups.

Figure 3rombolytic e ff ects for lesions at di ff erent locations.

Relationship between CA fi ndings and clinical outcomes after thrombolysis

As the target of thrombolytic therapy is the embolus or thein situthrombosis, patients with occlusive vessels should theoretically benefit more from thrombolysis than those with vascular stenosis. However, we found no di ff erence in short‐term or long‐term clinical outcomes between these pa‐tients.ese unexpected fi ndings may relate to the a ff ected brain region and the degree of embolism (Porelli et al., 2013; Sillanpaa et al., 2013). For cases with proximal obstructions of large blood vessels such as the internal carotid artery or the M1 segment of the middle cerebral artery, recanalization by intravenous thrombolysis is di ffi cult, especially when the embolus is greater than 5 mm in length (Kimura et al., 2011;Riedel et al., 2011). Clogging of larger blood vessels suggests a larger embolus volume, which would limit delivery of re‐combinant tissue plasminogen activator at the infarct site.us, our fi ndings may relate to thrombolytic failure in some occlusive vessels.

In addition, recanalization does not imply reperfusion, although these two concepts are oen used interchangeably (Tomsick et al., 2008; Soares et al., 2009). Recanalization is more focused on the vascular lumen, while reperfusion is largely related to blood supply to the brain (Tomsick, 2007).ere is some evidence that a large embolus can decompose into smaller emboli after thrombolysis and block smaller downstream vessels. Thus, the brain remains ischemic de‐spite appearance of recanalization of the original occlusive large vessels (Janjua et al., 2008). Finally, it is possible that despite the extinction of ischemic brain edema, no blood flow will reach the affected area (Zoppo, 2008). Thus, the presence of blood flow reperfusion rather than recanaliza‐tion is more widely used as a predictor of clinical outcomes.

Relationship between CP fi ndings and clinical outcomes after thrombolysis

In the present study, there were no differences in the short‐term and long‐term outcomes with respect to the presence of a blood flow mismatch. These data are consistent with other studies suggesting that the use of CTP findings to assess the efficacy of thrombolytic therapy remains unclear (Hassan et al., 2012). As the volume of the penumbra that can be saved by thrombolysis is related to the admission time and the selection of CTP parameters (Garcia et al., 2012), the safety and e ffi cacy of CTP require further con fi rmation (Michel et al., 2012).

Alternatively, it is possible that the blood flow mismatch was not caused by an acute vascular occlusion, but rather by an old infarction.us, the mismatch area may have existed for a long time, with no improvement in clinical symptoms following thrombolysis.e brain function in the mismatch area may also be compensated by other parts of the brain.us, despite positive imaging fi ndings, there are no di ff er‐ences in clinical function scores. Finally, the blood fl ow mis‐match may be caused by a transient ischemic attack without vascular occlusion. As such, thrombolysis will not be associ‐ated with clinical outcomes.

Relationship between CA and CP fi ndings and clinical outcomes after thrombolysis

By comparing both CTA and CTP results in thrombolytic patients with clinical outcomes, we found that patients with both vascular stenosis and a blood fl ow mismatch had better short‐term outcomes after thrombolysis, but no differenc‐es in long‐term outcomes. An association between CTP and CTA examination and prognosis of ischemic stroke patients was recently reported (Eckert et al., 2011; Suzuki et al., 2011). For patients with onset times longer than 3 hours, both CTP and CTA fi ndings should be considered to determine whether thrombolysis can significantly improve prognosis (Obach et al., 2011). Our findings of no differ‐ences between CTA and CTP data and long‐term outcomes after thrombolysis may be caused by a number of factors. (1) If patients have new infarct attacks over the period of 24 hours to 3 months, which they are unaware of (representing a second‐time ischemic stroke), the mRS score at 3 months will be significantly reduced. (2) The improved short‐term outcome may result from timely compensation of brain tis‐sue and potential collateral circulation opening, rather than vascular recanalization. Neurons subjected to this collateral circulation decompensation would quickly die, eventually leading to a poor long‐term outcome. (3) Other factors may in fl uence the cerebrovascular status and cerebral blood fl ow dynamics within the 3‐month time window, including blood pressure, blood sugar, triglycerides, and cholesterol. (4)e mRS score used to measure neural functional recovery in stroke patients considers all aspects of life, including dress‐ing, walking, eating, traveling, studying, and working. The mRS score is divided into six classes according to the sever‐ity of impairment. A patient’s condition is considered to be improving if there is at least a 2‐point di ff erence in the ac‐tivities in which the patient was competent before the onset of ischemia. However, for patients who can only complete a portion of the activities, the scoring criteria may vary relative to the narrator’s recall bias and the rater’s subjective judg‐ment. (5) Some low 24‐hour NIHSS score patients exhibited spontaneous recanalization aer 24 hours, which would im‐prove the long‐term outcome and in fl uence the di ff erences among groups.

Conclusions

Ischemic stroke patients with both vascular stenosis and blood fl ow mismatch have the best short‐term clinical out‐comes following thrombolysis. However, the long‐term out‐come is a ff ected by multiple other factors, and is not related to CTA or CTP results.ese fi ndings may also be attribut‐able to the small sample size of this study.

Declaration of patient consent:

Author contributions:DYG, QD and JZ designed this study. JWP, SYZ, JHW, YFL, XC and TYZ performed experiments. JWP, JHW and XRY analyzed data. JWP wrote the paper. All authors approved the fi nal version of the paper.

Con fl icts of interest:None declared.

Plagiarism check:This paper was screened twice using CrossCheck toverify originality before publication.

Peer review:

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Copyedited by Dean J, Hindle A, Wang J, Qiu Y, Li CH, Song LP, Zhao M

10.4103/1673-5374.198994

Accepted: 2016-11-03

＊Correspondence to: Jun Zhang, M.D. or Dao-ying Geng, M.D., zhj81828@163.com or daoyinggeng@163.com.