Background. In recent years, the clinical significance of collateral circulation in vascular embolism has been gradually found.
Objectives. To investigate the relationship between collateral circulation and short-term prognosis of wake-up stroke patients.
Material and methods. The present observational study enrolled 269 cases of wake-up ischemic stroke patients. All patients presented with mismatched low perfusion volume/main infraction volume and received thrombolytic therapy after admission. The hemorrhagic transformation rate was recorded. The American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading was used for evaluation of collateral circulation. The stroke condition was determined using the National Institutes of Health Stroke Scale (NIHSS). The Barthel Index (BI) score was used for measurement of quality of life. The Modified Rankin Scale (mRS) was used for measurement of prognosis.
Results. The hypertension, diabetes and current smoker rates were significantly higher. The baseline NHISS scores and NIHSS scores after 24 h were remarkably lower. The NIHSS scores were markedly lower in ASITN/SIR grade 2–3 patients compared with ASITN/SIR grade 0–1 patients at 1 week, 2 weeks, 4 weeks, and 3 months after treatment. Patients with ASITN/SIR grade 2–3 had lower mRS score and higher BI scores. The ASITN/SIR grade was an independent risk factor for bad prognosis of wake-up ischemic stroke patients in 3 months.
Conclusions. Collateral circulation condition may be associated with short-term prognosis of wake-up stroke patients. Patients with worse collateral circulation may present higher risk for bad short-term prognosis.
Key words: outcomes, coronary collateral circulation, NHISS, wake-up stroke
Despite the development of treatment methods and molecular mechanisms, the incidence of stroke is still high, with almost 7 million of ischemic stroke patients and 3 million of hemorrhagic stroke patients worldwide in 2013 among 20–64 years-old adults.1, 2, 3 It is also reported that about 1.5~2.0 million of new stroke cases are diagnosed every year in China.4, 5 Among the stroke patients, about 20–25% ischemic stroke patients are healthy before sleep and wake up with neurological deficits.6, 7, 8 Since the accurate time of stroke onset is difficult to determine for wake-up stroke patients, the application of thrombolysis treatment for these patients is still controversial.9, 10
In recent years, the clinical significance of collateral circulation in vascular embolism has been gradually noticed.11 It is thought that collateral circulation is associated with intravenous thrombolysis,12 coronary chronic total occlusion13 and also ischemic stroke.14 However, up to now, few studies focused on role of collateral circulation in wake-up stroke.
In the present study, we demonstrated for the first time that collateral circulation was associated with short-term prognosis of wake-up stroke patients. The worse collateral circulation predicted higher risk for bad short-term prognosis. This research might provide more clinical evidence for collateral circulation in wake-up stroke patients.
Material and methods
The present observational study enrolled 269 cases of wake-up ischemic stroke patients who reported to our hospital from January 2017 to June 2019. All patients were healthy before sleep and were found to show typical stroke symptoms after waking up, including a side face, arm or leg numbness or sudden onset of deviation, hemiplegia, confusion, difficulty in speaking or understanding, difficulty in single or binocular vision, difficulty in walking, dizziness, and loss of balance or coordination. The diagnosis of ischemic stroke was confirmed with computed tomography (CT) or magnetic resonance imaging (MRI) methods according to the guidelines of Chinese Medical Association.15 All patients were consecutively enrolled. The following patients were excluded: patients with hemorrhagic stroke, patients who received anticoagulation therapy within 1 month before the study, patients who received intracranial or spinal surgeries within 3 months before the study, patients who had stroke or brain trauma within 3 months before the study, and patients with severe dysfunction of liver, kidney or heart. Written informed consent was obtained from all study participants. The present study was approved by the Ethic Committee of Shanghai Pudong New Area Hospital of Traditional Chinese Medicine, China.
All patients included in this research received thrombolytic therapy after admission. The computed tomography perfusion (CTP) was conducted using a Dual Source Imaging System (Siemens, Munich, Germany). The multimode MRI was performed using a General Electric Corporation 3.0T Magnetic Resonance Instrument (Signa Excite HD; General Electric Medical Systems, Chicago, USA). The image reconstruction was then conducted using MIStar® software (Apollo Medical Imaging Technology Ltd., Melbourne, Australia). The peak time picture of cerebral blood flow (Tmax) was obtained and the area with Tmax > 6 s was defined as low perfusion volume.16 The diffusion-weighted imaging (DWI) high-signal volume or a volume of lesion side which reduced more than 30% of the normal side on the cerebral blood flow (CBF) picture was regarded as the main infraction volume. The thrombolytic therapy was only conducted for patients with low perfusion volume/main infraction volume ≥120% and ≥10 mL.17, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19
The thrombolytic therapy was conducted using the recombinant tissue plasminogen activator (rt-PA) with a dose of 0.9 mg/kg. The first 10% of the drug was intravenously injected at once, and the rest of the dose was injected using a venous micropump within 60 min. The hemorrhagic transformation was evaluated using CT or MRI after 24 h of treatment.
Evaluation of collateral circulation
For evaluation of collateral circulation, the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading was used after digital subtraction angiography (DSA).20 The ASITN/SIR grade 0–1 was defined as bad collateral circulation compensatory, ASITN/SIR grade 2 was defined as moderate compensatory and ASITN/SIR grade 3–4 was considered as good compensatory.
The study population was then divided into 2 groups: ASITN/SIR grade 0–1 patients and ASITN/SIR grade 2–3 patients.
Demographic data such as age and gender, and clinical information including complications and medication condition were also recorded. The stroke condition was determined using the National Institutes of Health Stroke Scale (NIHSS). The Barthel Index (BI) score was used for measurement of quality of life after 3 months of treatment. The Modified Rankin Scale (mRS) was used for measurement of prognosis after 3 months of treatment. The mRS score ≤2 was defined as good prognosis while mRS score >2 was a bad prognosis. The NIHSS scores were measured before treatment, 24 h after treatment, and 1 week, 2 weeks, 4 weeks and 3 months after treatment. The follow-up lasted for 3 months.
Continuous data was expressed using mean ± standard deviation (SD). The χ2 test was used to compare the counting materials and rates. Comparison between the 2 groups was performed using the Student t-test. The Kaplan–Meier (K–M) curve was used to determine the relationship between NHISS scores and three-month mortality. Logical regression was used to analyze risk factors for three-month prognosis using a binary logistic regression model with step-back method. A value of p < 0.05 was considered statistically significant. All calculations were made using SPSS v. 22.0 (IBM Corp., Armonk, USA).
Basic characteristics for all patients
The basic characteristics of all patients were shown in Table 1. Among the 269 patients, 142 cases had the ASITN/SIR grade 0–1 and 127 cases had the ASITN/SIR grade 2–3. The hypertension, diabetes and current smoker rates were found significantly higher in ASITN/SIR grade 0–1 patients (p < 0.05). Besides, the baseline NHISS scores were remarkably lower in ASITN/SIR grade 2–3 patients (p < 0.05). Moreover, NIHSS scores after 24 h were also lower in ASITN/SIR grade 2–3 patients (p < 0.05). No significant differences were found in other indices.
Dynamic changes of NIHSS scores
and its relationship with ASITN/SIR grading
To further investigate the relationship between ASITN/SIR grading and clinical outcomes of wake-up stroke, NIHSS scores were evaluated before treatment, 24 h after treatment, and 1 week, 2 weeks, 4 weeks and 3 months after treatment. As shown in Figure 1, at all timepoints, the NIHSS scores were remarkably lower in ASITN/SIR grade 2–3 patients compared with ASITN/SIR grade 0–1 patients (p < 0.05), indicating that the ASITN/SIR grade at admission might be associated with the treatment outcomes.
Prediction value of ASITN/SIR grading for three-month prognosis of wake-up ischemic stroke patients
Finally, we analyzed the relationship between ASITN/SIR grading and three-month prognosis of wake-up ischemic stroke patients. Both mRS and BI scores were measured 3 months after treatment. Results showed that patients with ASITN/SIR grade 2–3 had lower mRS score and higher BI scores than patients with ASITN/SIR grade 0–1 (Table 2). However, the three-month mortality rate did not show significant difference. Then, we defined mRS score >2 as bad prognosis and analyzed risk factors for three-month prognosis. Results showed that the ASITN/SIR grade was the independent risk factor for bad prognosis of wake-up ischemic stroke patients in 3 months (Table 3). The K–M curve showed patients with ASITN/SIR grade 2–3 might have longer survival in 3 months; however, the difference was not statistically significant (Figure 2, p = 0.116).
Despite numerous studies on ischemic stroke, the wake-up stroke is still a clinical problem, especially due to the difficulty to determine the accurate time of onset. In recent years, the importance of collateral circulation has been noticed in embolism diseases. In a clinical trial, it was found that the coronary collateral circulation could be increased by intensive exercise for coronary artery disease patients.21 In patients with celiac artery compression syndrome, the authors also found that different types of collateral circulation were also observed in patients with celiac artery compression syndrome.22 However, up to now, no research reported the relationship between collateral circulation and wake-up stroke. In the present research, we demonstrated that collateral circulation condition was associated with short-term clinical outcomes of wake-up stroke patients after thrombolytic therapy. Better collateral circulation condition predicted better clinical outcomes, and collateral circulation was also an independent risk factor for bad short-term prognosis of wake-up stroke patients.
The treatment of wake-up stroke is still a clinical challenge and the application of thrombolytic therapy shows different outcomes in different studies. Kurz et al. considered that stroke onset occurred close to wake-up and not during earlier sleep phases in the wake-up stroke patients, and thus the proper use of MRI could select patients who would benefit from thrombolysis.23 Another clinical research also demonstrated that the wake-up stroke and normal stroke within therapeutic window had similar clinical severity, imaging characteristics and clinical outcome.24 Odland et al. also stated that current diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR) mismatch concept might exclude lager amount of wake-up stroke patients who might benefit from thrombolysis.25 In our research, we also used thrombolytic therapy only in patients with mismatched low perfusion volume and main infraction volume. Results showed the application of thrombolytic therapy could achieve good clinical outcomes. Meanwhile, the treatment outcomes were associated with collateral circulation.
Studies on collateral circulation in stroke have also been reported. It was considered that the premature rarefaction of the collateral circulation might be associated with ischemic tissue injury, and cardiovascular risk factors might enhance the risk.26 In a review, Iwasawa et al. demonstrated the development of collateral circulation in ischemic stroke and pointed that good collateral circulation was associated with better neurological outcomes and smaller infarct volume in stroke patients.27 Seyman et al. demonstrated in a clinical research that collateral circulation determined cortical infarct volume in anterior circulation ischemic stroke.28 A meta-analysis also showed that good collateral circulation predicted favorable outcomes in intravenous thrombolysis in stroke patients.12 In this study, we demonstrated for the first time that better collateral circulation condition was associated with better clinical outcomes of wake-up stroke patients.
The present study has also some limitations. Firstly, the study only included a small sample size. Secondly, we mainly showed the relationship between ASITN/SIR grading, NIHSS score and prognosis. The relationship between ASITN/SIR grading and other laboratory indices requires further studies to confirm.
We conducted a prospective observational study and found that collateral circulation condition was associated with short-term prognosis of wake-up stroke patients. Patients with worse collateral circulation might present a higher risk for bad short-term prognosis. This study might give more clinical evidence for the use of collateral circulation measurement in prediction of prognosis of stroke patients.