Edited by: Emmanuel Carrera, University of Geneva, Switzerland
Reviewed by: Yue-hua Li, Shanghai Sixth People's Hospital, China; Maria Hernandez-Perez, Hospital Germans Trias i Pujol, Spain
This article was submitted to Stroke, a section of the journal Frontiers in Neurology
†These authors have contributed equally to this work
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There have been few studies about the association between intracranial carotid artery calcification (ICAC) and acute ischemic stroke (AIS) prognosis after intravenous thrombolysis (IVT). We aimed to analyze the association between ICAC and prognosis (including symptomatic intracranial hemorrhage (sICH), functional outcome and death) of AIS patients treated with IVT. In this retrospective study, we consecutively included 232 AIS patients treated with IVT between April 2012 and December 2018. ICAC was evaluated using the modified Woodcock calcification visual score on non-enhanced cranial computed tomography scans. Poor functional outcome was defined as a modified Rankin Scale score > 2 at 3 months. We found that the modified Woodcock calcification score was associated with ICH, poor outcome, and death in univariable analyses on the symptomatic side and/or bilaterally. However, after adjustment for other different covariates, the results showed no significant difference. We documented that the presence and severity of ICAC did not significantly modify the beneficial effects of rtPA treatment in AIS.
Early recanalization therapy is recognized as the only effective method to decrease disability and mortality due to acute ischemic stroke (AIS), and it mainly includes arterial intervention and intravenous thrombolysis (IVT) (
Artery calcification is one of the constituents of atherosclerotic plaques and has been used as a marker of the presence, severity and prognosis of atherosclerosis (
The development of neuroimaging technology has provided an objective diagnosis and treatment basis for many nervous system diseases (
The presence of calcification of the carotid siphon is defined as the portion of internal carotid artery stenosis between the petrous apex and anterior clinoid, and it is an indicator of internal carotid artery stenosis (
Therefore, the present study aimed to analyze the association between the modified Woodcock calcification score and prognosis (including symptomatic intracranial hemorrhage (sICH), functional outcome and death) of AIS patients treated with IVT.
This was a retrospective study of AIS patients who were treated with IVT between April 2012 and December 2018 at the Department of Neurology of the Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The indication and contraindication for IVT were conducted according to the Guidelines for the early management of patients with acute ischemic stroke from the American Heart Association/American Stroke Association (
During the study period, a total of 410 patients were submitted to IVT in our center. In the present study, the reasons for exclusion were: (1) posterior circulation infarction (
Study flow chart. AIS, acute ischemic stroke; rt-PA, recombinant tissue-type plasminogen activator; mRS, modified Rankin scale; CT, computed tomography.
This study was approved by the ethic committee of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was exempted by the committee because of the retrospective study based on routine clinical data (Ethical approval number: 2016-221-T170).
IVT was done with rtPA (Actilyse, Boehringer Ingelheim, Germany), according to internationally recognized guidelines (
Additionally, T1 and T2 weighted magnetic resonance (MR) imaging, diffusion-weighted MR imaging, and/or fluid-attenuated inversion recovery (FLAIR), and at least one kind of cerebral angiography (MR angiography, CT angiography or digital subtraction angiography), carotid ultrasound examination, and electrocardiogram were performed in the following days.
Age, gender, medical history of hypertension, diabetes, CHD and atrial fibrillation, smoking and drinking, associated laboratory tests and imaging information were retrieved from our medical institutional database. Risk factors were defined as follows: hypertension (systolic blood pressure / diastolic blood pressure ≥ 140/90 mmHg, a history of hypertension or by the use of antihypertensive treatment), diabetes mellitus (fasting blood glucose level ≥ 7.0 mmol/L, a history of diabetes, or by the use of diabetic medications), dyslipidemia (serum triglycerides > 1.7 mmol/L, low-density lipoprotein > 3.4 mmol/L, high-density lipoprotein cholesterol < 0.8 mmol/L, or by the use of lipid-lowering agents), smoking (smoked at the time of stroke or had quit smoking within 1 year of the stroke), and drinking (>2 standard alcoholic beverages consumed per day).
Stroke was classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification: (1) large artery atherosclerosis (LAA); (2) small vessel occlusion (SVO); (3) cardioembolism (CE); (4) stroke of other determined etiology; and (5) stroke of undetermined etiology (
Clinical functional outcome was assessed at 3 months after stroke by a specialized research nurse who was blinded to the carotid artery calcification scores. The modified Rankin Scale (mRS) score was evaluated. mRS ≤ 2 indicated a good outcome, while mRS > 2 indicated a poor outcome (
All included patients had available non-contrast cranial CT axial scan (Philips Brilliance 64 CT Scanner; Philips Healthcare, Andover, MA, USA) with slice thickness of 5 mm at admission (routine practice in China).
We detected ICAC scores according to the modified version of the Woodcock visual scoring (
Schematic representation of calcification patterns on bone window of computed tomography (CT).
Continuous data with a normal distribution were presented as mean ± standard deviation (SD). Continuous without a normal distribution were presented as median (interquartile range). Categorical data were presented as frequency and percentage. The differences of scores between the two observers were analyzed by the ICC method. For univariate analyses, unpaired Student's
Eventually, 232 patients with AIS were included in this study (
Baseline characteristics of patients.
Age, years | 68.0 (59.3, 79.8) | 63.0 (58.0, 72.0) | 79.0 (70.0, 84.0) | < 0.001 |
Male, |
137 (59.1) | 90 (70.3) | 31 (37.8) | < 0.001 |
Hypertension | 211 (90.9) | 114 (89.1) | 76 (92.7) | 0.383 |
Diabetes mellitus | 96 (41.4) | 40 (31.2) | 44 (53.7) | 0.001 |
Dyslipidaemia | 134 (57.8) | 80 (62.5) | 40 (48.8) | 0.069 |
Coronary heart disease | 60 (25.9) | 28 (21.9) | 26 (31.7) | 0.112 |
Atrial fibrillation | 67 (28.9) | 22 (17.2) | 38 (46.3) | < 0.001 |
Smoking | 73 (31.5) | 54 (42.2) | 13 (15.9) | < 0.001 |
Drinking | 48 (29.7) | 38 (29.7) | 8 (9.8) | 0.001 |
HbA1c, % | 5.9 (5.5, 6.6) | 5.8 (5.5, 6.4) | 6.1 (5.6, 6.6) | 0.068 |
Homocysteine, μmol/L | 12.9 (9.8, 16.8) | 12.5 (9.2, 16.6) | 14.2 (10.0, 18.6) | 0.277 |
Creatinine, μmol/L | 85 (69, 100) | 84 (70, 100) | 93 (72, 111) | 0.982 |
NIHSS before IVT, points | 5.5 (3, 13) | 4 (2, 8) | 12 (5, 17) | < 0.001 |
ICH, |
26 (11.2) | 9 (7.0) | 17 (20.7) | 0.003 |
Time to rt-PA treatment, min | 153 (107, 194) | 159 (121, 200) | 157 (107, 200) | 0.724 |
Large-artery atherosclerosis | 78 (33.6) | 45 (35.2) | 26 (31.7) | 0.606 |
Cardioembolism | 50 (21.6) | 15 (11.7) | 30 (36.6) | < 0.001 |
Small-vessel occlusion | 63 (27.2) | 49 (38.3) | 7 (8.5) | < 0.001 |
Others | 41 (17.7) | 19 (14.8) | 19 (23.2) | 0.126 |
The total modified Woodcock score (sum of the bilateral sides) were 3.0 (1.1, 5.0), and the symptomatic side score was 1.5 (1.0, 2.5). In addition, the scores were higher in patients with LAA than in patients with other TOAST types [3.8 (2.0, 6.0) vs. 3.0 (1.0, 5.0),
The NIHSS score was 5.5 (
Modified Woodcock scores stratified by clinical parameters.
M-to-S stroke | 3.5 (2.0, 5.5) | 3.0 (1.0, 5.0) | 0.201 | 2.0 (1.0, 3.0) | 1.5 (1.0, 2.5) | 0.505 |
ICH | 4.5 (3.0, 6.0) | 3.0 (1.0, 5.0) | 0.029 | 2.0 (1.4, 3.0) | 1.5 (1.0, 2.5) | 0.094 |
sICH | 4.0 (3.4, 5.9) | 3.0 (1.0, 5.5) | 0.234 | 2.3 (1.4, 2.6) | 1.5 (1.0, 3.0) | 0.196 |
Poor outcome | 4.5 (3.0, 6.0) | 3.0 (1.0, 5.0) | 0.005 | 2.0 (1.4, 3.0) | 1.5 (1.0, 2.5) | 0.008 |
Mortality | 5.0 (3.0, 6.0) | 3.5 (1.8, 5.0) | 0.060 | 2.5 (1.3, 3.0) | 1.5 (1.0, 2.5) | 0.022 |
ICH complication was detected in 26 patients. Patients with ICH had higher total modified Woodcock scores than patients without ICH (
Adjusted association of Modified Woodcock scores to clinical parameters.
Symptomatic side | / | / | 1.15 (0.90, 1.46) | 0.274 | 1.17 (0.97, 1.41) | 0.099 |
Total | 0.309 (0.94, 1.23) | 0.309 | 1.08 (0.94, 1.24) | 0.301 | / | / |
A total of 210 patients (90.5%) were followed up at 3 months; 82 (39.0%) of them had poor outcomes. The basic characteristics of the two groups are shown in
Three months after their strokes, 21 (10.0%) subjects had died. The modified Woodcock score on the symptomatic side was associated with mortality (
In the present study, no associations were observed of the modified Woodcock carotid artery calcification score with stroke severity, sICH, functional outcome, and mortality in AIS patients with IVT after adjustment for potential confounders, either on symptomatic side or bilaterally. We documented that the presence of ICAC does not modify significantly the beneficial effects of rtPA treatment in AIS.
Some recent studies have identified factors associated with prognosis, such as age, severity of stroke, and subtype of stroke (
ICAC scores were higher in patients with LAA strokes, which understandably differs significantly from other etiological types of stroke. Previous studies have demonstrated that calcifications increase with atherosclerosis burden and vascular stenosis and aggravate cerebral ischemia symptoms (
Although several studies have focused on the presence and load of ICAC in other recanalization therapies, including endovascular interventions, the results are still highly controversial. Lee et al. (
Studies about the association between ICAC and the prognosis of AIS patients treated with IVT have been relatively few. Lin et al. (
The modified Woodcock scale method can be suitably applied in acute clinical settings because it can be assessed quickly and consistently (
ICAC leads to significant stenosis of the lumen, accompanied by more atherosclerotic changes and arterial tortuosity (
The present study has some limitations. Indeed, the number of patients eligible for evaluation was small, likely because of the limited time window for IVT after AIS onset and the inclusion and exclusion criteria of this study. A large-scale, multicenter investigation combined could be conducted to validate and refine the results of the present study, and subgroup analysis based on TOAST classification in such studies is a better method may lead to find some new findings. Second, different calcification distributions and calcification types are presumed to have different pathological mechanisms and thus could have distinct clinical consequences (
In conclusion, ICAC was not associated with the prognosis of AIS patients treated with IVT. The presence and severity of ICAC did not significantly modify the beneficial effects of rtPA treatment.
The datasets generated for this study are available on request to the corresponding author.
This study was approved by the ethic committee of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was exempted by the committee because of the retrospective study based on routine clinical data (Ethical approval number: 2016-221-T170).
X-WH, RZ, and G-FL carried out the studies, participated in collecting data, and drafted the manuscript. BZ, Y-LW, Y-HS, Y-SL, M-TZ, and J-WY performed the statistical analysis and participated in its design. G-HC and J-RL designed and supervised the study, and revised the manuscript. All authors read and approved the final manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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