Special Issue Article
Predictors of neurological deterioration during hospitalization: results from the Chinese Intracranial Atherosclerosis (CICAS) Study Yuetao Ma1,2,3,4, Liping Liu1,2,3,4, Yuehua Pu1,2,3,4, Xinying Zou1,2,3,4, Yuesong Pan1,2,3,4, Yannie Soo5, Xingquan Zhao1,2,3,4, Yilong Wang1,2,3,4, Kasing Wong5, Yongjun Wang1,2,3,4 1
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University,China, 2 China National Clinical Research Center for Neurological Diseases, China, 3 Stroke Center, Beijing Institute for Brain Disorders, China, 4 Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, China, 5 Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, China Objectives: Neurological deterioration (ND) after ischaemic stroke has been indicated as an independent risk factor for poor outcome. Previous studies have focussed on ND within the first few days after symptom onset, but many patients are likely to experience deterioration outside of this time frame. We aimed to investigate the predictors of ND during hospitalisation. Methods: Data were obtained from the Chinese Intracranial Atherosclerosis (CICAS) Study, and patients who were diagnosed with ischaemic stroke and arrived at the hospital within 72 hours after symptom onset were included in the present study. Neurological deterioration was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score of i2 points at discharge compared with admission. MR angiography (MRA) and duplex colour Doppler ultrasound were used to document the presence of intracranial or extracranial artery stenosis. Intracranial artery stenosis was defined as a reduction in the artery diameter of i50% on MRA. Multivariate analyses were conducted to determine the potential predictors of ND during hospitalisation. Results: Of the 1996 patients included in this study, 84 (4.21%) developed ND during hospitalisation. Compared with non-ND patients, ND patients showed higher rates of pneumonia (25.0 vs 9.5%, Pv0.001), urinary infection (7.1 vs 1.2%, Pv0.01), stroke recurrence (14.3 vs 1.9%, Pv0.001), watershed infarct (15.5 vs 5.4%, P50.002), intracranial internal carotid artery (ICA) stenosis (11.9 vs 6.0%, P50.041), middle cerebral artery (MCA) stenosis (39.3 vs 22.0%, Pv0.001) and basilar artery (BA) stenosis (16.7 vs 7.1%, P50.011). Multivariate analysis indicated that watershed infarcts (OR, 2.85; 95% CI, 1.04–7.81), MCA (OR, 2.23; 95% CI, 1.17–4.25) and BA (OR, 2.86; 95% CI, 1.19–6.87) stenosis or occlusion were independent risk factors for ND, as was pneumonia (OR, 3.4; 95% CI, 1.46–7.9). Discussion: Patients with watershed infarcts and MCA or BA stenosis or occlusion should be monitored closely, and various therapeutic strategies should be administered simultaneously to prevent pneumonia during hospitalisation. Keywords: Intracranial artery stenosis, Neurological deterioration, Radiological, Stroke
Introduction Patient conditions during the first hours or days after stroke may not be stable; some patients deteriorate, and others improve, which could be due to the natural process of the stroke or be partially explained by the fate of ischaemic penumbra, which further depends on the severity and duration of the stroke.1 Neurological deterioration (ND) has been observed in approximately 8.5–31% of patients with acute ischaemic stroke due to Correspondence to: Yongjun Wang, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China. Email: [email protected]
ß W. S. Maney and Son Ltd 2015 DOI 10.1179/1743132815Y.0000000024
the different definitions used for ND and different target populations,2–6 and approximately half of all cases occur within 24 hours after admission. The Canadian Neurological Scale and the Scandinavian Stroke Scale have been used in earlier studies, but recently, the National Institutes of Health Stroke Scale (NIHSS) has become the most common neurological scoring system used in clinical trials. An increase in the NIHSS score of i2 points has been recommended by some researchers as the definition of ND because worse outcomes have been demonstrated in patients with these scores.7
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Previous studies have focussed on the deterioration of neurological symptoms occurring in the first few days after stroke, and several risk factors have been identified, such as systolic blood pressure at admission,6,8,9 diabetes mellitus,4,6,9,10 stroke severity,3,9,11,12 haemoglobin,5 C-reactive protein13 and intracranial internal carotid artery (ICA) occlusion.4,13 However, a certain number of patients still develop ND outside of this timeframe, and the risk factors for these cases have not been well established. Thus, our study evaluated the influence of clinical factors, including demographic and biochemical factors, and radiological factors on ND during hospitalisation following acute ischaemic stroke.
Methods Study design and participants The Chinese Intracranial Atherosclerosis (CICAS) Study was a prospective, multicenter, hospital-based study including 22 general hospitals across China from 2007 to 2009. Patients who presented with acute cerebral ischaemia, including ischaemic stroke and transient ischaemic attack (TIA), within 7 days after symptom onset were screened. The inclusion and exclusion criteria have been described elsewhere.14 A standardised case report form was used for data collection. Baseline data, including demographic information, medical history, physical examination, biochemical results, and NIHSS score, were collected at admission. All patients underwent a brain MR scan, 3-dimensional (3D) time-of-flight MR angiography (MRA), and duplex colour Doppler ultrasound for intra/extracranial artery evaluation. The NIHSS score assessment was repeated at discharge. After the exclusion of patients with incomplete cerebrovascular workups, 2864 consecutive patients remained. Among the participants, those who were diagnosed with ischaemic stroke and arrived at hospital within 72 hours after symptom onset, were included in the current study. This study was approved by the institutional review board of Beijing Tiantan Hospital, and written informed consent was obtained from all participants or their legal relatives.
(smoked continuously for 6 months, i1 cigarette per day), heavy drinking (i2 standard alcoholic drinks per day), ischaemic heart disease (a history of myocardial infarction, angina pectoris or congestive heart failure), and previous medication use. Inhospital complications, such as pneumonia (having fever and coarse breathing or crackling sounds, confirmed by chest X-ray), deep vein thrombosis (having clinical symptoms of deep vein thrombosis, with a deep vein thrombosis confirmed by venous Doppler, excluding cellulitis or an infection of the leg), urinary tract infection (having clinical symptoms of urinary tract infection with positive presentation of abnormal white and red blood cells in the urine) and upper gastrointestinal bleeding (having coffee-ground emesis, haematemesis, blood in the nasogastric tube or melaena) were also recorded. In addition, a physical examination was conducted, and blood pressure, BMI, and biochemical markers, including white blood cell counts, haemoglobin, C-reactive protein, creatinine, homocysteine, glycosylated haemoglobin and lipoprotein, were recorded. An increase in the NIHSS score of i2 points was defined as ND.
Imaging evaluation Measurements of intracranial stenosis were determined with 69 Wiha Digi Max Digital Callipers (Germany) to a resolution of 0.01–0.03 mm for 0–100 mm, and the degree of stenosis on MRA was calculated using the published method for the Warfarin–Aspirin Symptomatic Intracranial Disease Study.15 The following arterial segments were assessed: the bilateral ICA (distal to the ophthalmic artery), anterior cerebral artery (ACA) A1, middle cerebral artery (MCA) M1, posterior cerebral artery (PCA) P1 and the basilar artery (BA). Vessels with w50% stenosis or occlusion were categorised as showing intracranial stenosis. All MRI/MRA images were examined by two neurologists who were blinded to the participants’ clinical information, and disagreements of greater than 10% were further reviewed by a third experienced researcher. The extracranial part of the ICA was evaluated with an ultrasonographic examination according to the published diagnostic criteria.16
Data collection and definitions We recorded patient characteristics, such as age and gender, and risk factors, including hypertension (a history of hypertension or a requirement for regular antihypertensive treatment), diabetes mellitus (a history of diabetes mellitus, treatment with hypoglycaemic agents or glycosylated haemoglobin i7%), hyperlipidaemia (low-density lipoprotein cholesterol w2.6 mmol/L at the time of admission, a history of hyperlipidaemia or the receipt of lipidlowering treatments), concurrent smoking
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Statistical analysis Continuous variables were summarised as the means (SD) or medians (interquartile range, IQR) and evaluated with a t-test or Kruskal–Wallis test. Categorical variables were presented as n (%) and analysed with a chi-square test or Fisher’s exact test. Owing to the relatively small number of patients with ND compared with the entire patient group, twice the number of non-ND patients matched by age, gender, and admission NIHSS score were included
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for the study. Multivariate conditional logistic regression was used in the multivariable analysis to evaluate the association of possible determinants and ND during hospitalisation. Variables with a P value v0.10 were included in the multivariate regression analysis. All analyses were performed with SAS software, version 9.1 (SAS Institute Inc., Cary, NC, US), and a two-tailed probability value v0.05 was considered statistically significant.
Results From October 2007 to June 2009, a total of 1996 ischaemic stroke patients who met the inclusion criteria were included in this study, and of these patients, 84 (4.21%) developed ND during hospitalisation. Owing to the difference in patient number between the ND and non-ND groups, this study used a case–control design, and 168 non-ND patients were matched based on age, gender and NIHSS score at admission. The clinical features between the two patient groups are presented in Table 1. The mean age of all of the patients was 65.14+ 10.71 years, and 36.90% of the patients were women. Pneumonia was more commonly
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observed in patients with ND than those without ND (25.00 vs 9.52%, P50.0001). The same pattern was also observed for urinary infections (7.14 vs 1.19%, P50.0075). Stroke recurrence in the ND group was also higher than that in the non-ND group (14.29 vs 1.85%, P50.0004). No differences in risk factors, biochemical markers, other in-hospital complications or hospital treatments were observed between the two groups. ND significantly prolonged the hospital stay of patients (19.0 [13.5–26.5] vs 15.0 [11.0–18.0] days, Pv0.0001).
Discussion To our knowledge, this is the first study to examine ND during hospitalisation after acute ischaemic stroke in Chinese patients. Our findings indicated that ND occurred in 4.21% of all patients, and this frequency was lower than those of previous studies,4,13 which may be because previous studies used an increase in the NIHSS score of i1 point as the definition for ND. In addition, we excluded patients who could not complete the MR examination, including patients who had previously received stent implants in coronary
Table 1 Clinical characteristics of patients with and without ND during hospitalisation Total (n5252) Mean age (years) Female (%) Median NIHSS scores (IQR) Hypertension (%) Hyperlipidaemia (%) Diabetes mellitus (%) Coronary heart disease (%) Current smoking (%) Heavy drinking (%) Unconsciousness (%) Haemoglobin (g/L) Creatinine (mmol/L) Leucocytes (109/L) C-reactive protein (mg/L) Homocysteine (mmol/L) Fasting blood glucose (mmol/L) Glycosylated haemoglobin (%) Triglyceride (mmol/L) Total cholesterol (mmol/L) LDL-C (mmol/L) SBP at admission (mmHg) DBP at admission (mmHg) BMI (kg/m2) Thrombolysis (%) In-hospital antihypertensive (%) In-hospital complications (%) Pneumonia Urinary infection Upper gastrointestinal bleeding Deep vein thrombosis Stroke recurrence Hospital stay (IQR), days
ND (n584)
Non-ND (n5168)
P value
0.4054 0.7995 0.6547 0.1266 0.0961 0.8658 0.5637 0.8025 0.8288 0.6207 0.6925 0.4246 0.5510 0.1684 0.1628 0.2188 0.5785 0.4473 0.5513 0.9008 0.4142 0.0845
65.14+ 10.71 93 (36.90) 4.0 (2.0–7.0) 201 (79.76) 188 (74.60) 89 (35.32) 22 (8.73) 87 (34.52) 29 (11.51) 11 (4.37) 138.26+ 22.29 79.71+ 28.82 7.93+ 2.90 5.62+ 9.65 17.90+ 11.91 6.41+ 2.43 6.76+ 1.93 1.70+ 1.04 4.79+ 1.09 2.92+ 0.99 152.74+ 24.32 87.19+ 12.23 24.60+ 3.16 6 (2.90) 142 (56.35)
65.48+ 10.92 31 (36.90) 4.0 (2.0–7.0) 69 (82.14) 62 (73.81) 31 (36.90) 5 (5.95) 25 (29.76) 10 (11.90) 3 (3.57) 138.15+ 30.04 80.20+ 33.94 8.06+ 3.47 5.60+ 5.56 16.99+ 9.96 6.54+ 2.51 6.70+ 1.79 1.60+ 0.92 4.71+ 1.24 2.98+ 0.94 154.54+ 23.75 87.42+ 11.43 24.75+ 3.26 3 (4.23) 42 (50.00)
64.98+ 10.63 62 (36.90) 4.0 (2.0–7.0) 132 (78.57) 126 (75.00) 58 (34.52) 17 (10.12) 62 (36.90) 19 (11.31) 8 (4.76) 138.32+ 17.38 79.47+ 26.05 7.86+ 2.58 5.64+ 11.53 18.42+ 12.93 6.34+ 2.39 6.79+ 2.01 1.75+ 1.10 4.82+ 1.02 2.89+ 1.02 151.75+ 24.65 87.07+ 12.69 24.53+ 3.12 3 (2.21) 100 (59.52)
37 (14.68) 8 (3.17) 6 (2.38) 2 (0.79) 14 (5.86) 16.0 (11.5–21.0)
21 (25.00) 6 (7.14) 4 (4.76) 1 (1.19) 11 (14.29) 19.0 (13.5–26.5)
16 (9.52) 2 (1.19) 2 (1.19) 1 (0.60) 3 (1.85) 15.0 (11.0–18.0)
0.0001 0.0075 0.0578 0.5637 0.0004 v0.0001
NIHSS: National Institutes of Health Stroke Scale; IQR: inter-quartile range; LDL-C: low-density lipoprotein cholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index. The radiological characteristics of patients in the ND and non-ND groups are shown in Table 2. Patients with watershed infarcts were more likely to develop ND during hospitalisation (15.48 vs 5.36%, P50.0023). In addition, intracranial ICA, MCA and BA stenosis or occlusion were all significantly more commonly observed in patients with stroke progression (11.90 vs 5.95%, 39.29 vs 22.02% and 16.67 vs 7.14%, respectively; all Pv0.05). No differences in stroke classification, distributions of the infarcts, extracranial ICA stenosis or white matter lesions were detected between the two groups.
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Table 2 Radiological characteristics of patients with and without ND
OSCP classification (%) PACI TACI LACI POCI Distribution of infarct (%) Anterior Posterior Both Location of infarct (%) Cortical or subcortical infarct Basal ganglia infarct Watershed infarct Confluent white matter lesion (%) Incomplete circle of Willis (%) Extracranial ICA stenosis or occlusion (%) Intracranial ICA stenosis or occlusion (%) MCA stenosis or occlusion (%) BA stenosis or occlusion (%)
Total (n5252)
ND (n584)
Non-ND (n5168)
P value
155 (63.52) 12 (4.92) 23 (9.43) 54 (22.13)
50 (62.50) 4 (5.00) 4 (5.00) 22 (27.50)
105 (64.02) 8 (4.88) 19 (11.59) 32 (19.51)
0.2566
140 (55.56) 76 (30.16) 4 (1.59)
46 (54.76) 27 (32.14) 1 (1.19)
94 (55.95) 49 (29.17) 3 (1.79)
0.8312 0.5737 0.6547
154 (61.11) 97 (38.49) 22 (8.73) 88 (34.92) 240 (95.24) 30 (13.95) 7 (2.78) 70 (27.78) 26 (10.32)
48 (57.14) 35 (41.67) 13 (15.48) 32 (38.10) 79 (94.05) 11 (15.94) 10 (11.90) 33 (39.29) 14 (16.67)
106 (63.10) 62 (36.90) 9 (5.36) 56 (33.33) 161 (95.83) 19 (13.01) 10 (5.95) 37 (22.02) 12 (7.14)
0.2918 0.3770 0.0023 0.3711 0.4386 0.4652 0.0412 0.0006 0.0114
OSCP: Oxfordshire Community Stroke Project; PACI: partial anterior circulation infarction; TACI: total anterior circulation infarction; LACI: lacunar infarction; POCI: posterior circulation infarction; ICA: internal carotid artery; MCA: middle cerebral artery; BA: basilar artery. After controlling for confounding factors, including stroke recurrence, the multivariate logistic regression analysis showed that pneumonia (OR, 3.4; 95% CI, 1.46–7.9; P50.0045), watershed infarct (OR, 2.85; 95% CI, 1.04–7.81; P50.0426), MCA stenosis or occlusion (OR, 2.23; 95% CI, 1.17–4.25; P50.0151) and BA stenosis or occlusion (OR, 2.86; 95% CI, 1.19–6.87; P50.0185) were independently associated with ND during hospitalisation (Table 3).
Table 3 Odds ratio (95% CI) for ND during hospitalization using multivariate logistic regression Variable OR 95% CI P Pneumonia 3.4 Watershed infarct 2.85 MCA stenosis or 2.23 occlusion BA stenosis or occlusion 2.86
1.46 7.9 1.04 7.81 1.17 4.25
0.0045 0.0426 0.0151
1.19 6.87
0.0185
MCA, middle cerebral artery; BA, basilar artery.
arteries or intra/extra cranial arteries, and thus may have had more severe atherosclerotic disease and may have been more likely to deteriorate following stroke. We also excluded critically ill patients who were more likely to deteriorate compared with patients with milder illness. Our study demonstrated that pneumonia played a very important role in ND development during hospitalisation. Pneumonia is a common inpatient complication after stroke, with an incidence of approximately 10%. Numerous factors have been associated with pneumonia after stroke, such as diabetes, age, consciousness, days of hospitalisation, tracheal intubation, tracheal incision and nasal feeding treatment.17,18 Pneumonia has been associated with higher mortality and worse outcome in previous studies.18,19 Our colleagues have previously reported that pneumonia occurred in 11.9% of patients in the CNSR study, and patients with pneumonia had a significantly higher risk of death during hospitalisation and at 3, 6 and 12 months post-stroke
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compared with those without pneumonia.20 Our study revealed that pneumonia occurred in 14.68% of stroke patients, and pneumonia was an independent risk factor for ND during hospitalisation, which has not been reported previously. Owing to the adverse effect of pneumonia on both short-term and long-term outcomes after stroke, we strongly recommend active dysphagia screening as early as possible in addition to effective management of blood pressure, glucose and other critical conditions to prevent aspiration, as it has been reported that the risk of pneumonia was 3-fold higher in patients with dysphagia compared with those without and 11-fold higher when dysphagia was severe enough to result in aspiration.21 Our study also demonstrated important radiological findings for ND development. Watershed infarcts comprise approximately 10% of all brain infarcts22 and have been recognised to result from haemodynamic impairment, although microembolic aetiology cannot be excluded.23 A study by Li et al. included 27 patients with internal watershed (IWS) infarctions, and 22 (81.5%) patients had severe stenosis (w70%) or occlusion in either the ICA or MCA, demonstrating a close relationship between IWS and occlusive diseases of the carotid arteries.24 Another study compared the early postoperative outcomes of a carotid endarterectomy (CEA) after acute ischaemic stroke between patients with territorial infarcts and those with watershed infarcts, and found that after adjustments for age, sex and other confounding factors, watershed infarcts were the only independent predictor of neurologic morbidity after CEA,25 demonstrating the unstable haemodynamic
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state in these patients. In our study, the incidence of watershed infarcts was 8.73%, which was similar to a previous study,22 and the multivariate analysis revealed that watershed infarcts were an independent risk factor for ND during hospitalisation. Regarding the relationship between intra- or extracranial large arteries and ND development, previous studies have reported that ICA and MCA occlusion are independently associated with ND.4,13,26 In our study, a stenosis severity of more than 50% or an occlusion of the ICA, MCA or BA was all associated with ND in the univariate analysis, but after adjusting for confounding factors, only MCA and BA stenosis or occlusion were independently associated with ND development, which may partially be explained by the definition used for intracranial artery evaluation, which included both stenosis and occlusion, whereas previous studies did not consider stenosis. In addition, we further divided the ICA into two segments, the intracranial and extracranial segment, and did not detect any differences in extracranial ICA stenosis or occlusion between the two groups. However, the segments of the ICA used for evaluation have not been described in detail in previous studies.4,26 Our results showed that BA stenosis or occlusion was independently associated with ND, which has not been reported in the previous studies; however, in the study by Sumer et al., the involvement of posterior circulation was independently associated with ND,27 suggesting a possible relationship between the BA and ND development. In light of the unstable haemodynamics in the presence of intracranial artery stenosis or occlusion during the acute phase of stroke, it may be helpful to retain enough blood volume to ensure perfusion in the ischaemic area, instead of lowering the blood pressure too much. Several other factors have been reported to influence the development of ND, such as diabetes,4,8–10 systolic blood pressure,8,9,11,28 white blood cell counts,26,29 haemoglobin5 and NIHSS score,9,11,26 although there have been conflicting results.30 Our study did not detect any differences in these factors between the two groups. Our study also had some limitations. We evaluated the stenosis or occlusion of intracranial arteries but did not specifically evaluate the responsible artery, which might decrease the correlation between the stenosis or occlusion of these arteries and ND. In addition, we did not evaluate the haemodynamic factors and the compensation from adjacent arteries, which could result in disregarding useful information.
Conclusions In conclusion, our study demonstrated that watershed infarcts and stenosis or occlusion of the MCA or BA were important radiological predictors of ND during hospitalisation. Patients with such problems should be monitored closely, and various therapeutic strategies
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should be administered simultaneously to prevent pneumonia after stroke during hospitalisation. Future studies evaluating the responsible arteries and haemodynamic information are needed.
Acknowledgements The authors thank all of the participating hospitals and colleagues who contributed to this study.
Disclaimer Statements Contributors Wrote the article: YM; study design: LL, XQZ, YiW, KW and YoW; data collection: YM, YPu, XZ and YS; statistical analysis: YM and YPa. Funding This study was funded by the Ministry of Science and Technology and the Ministry of Health of the People’s Republic of China. The grants are from the National 11th & 12th Five–year S&T Major Project (2006BAI01A11, 2011BAI08B01, 2011BAI08B02), National Key Technology Research and Development Program (2013BAI09B03) and Beijing Talents Project (2010D003034000023). Conflicts of interest The authors declare no conflict of interest. This article has not been submitted elsewhere. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Ethics approval This study was approved by the institutional review board of the Beijing Tiantan Hospital.
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22 Mangla R, Kolar B, Almast J, Ekholm SE. Border zone infarcts: pathophysiologic and imaging characteristics. Radiographics. 2011;31:1201–14. 23 D’Amore C, Paciaroni M. Border-zone and watershed infarctions. Front Neurol Neurosci. 2012;30:181–4. 24 Li HF, Zhang X, Zhang Y, Pan XD, Zhao HQ, Li H. Clinical and neuroradiological features of internal watershed infarction and the occlusive diseases of carotid artery system. Neurol Res. 2010;32:1090–6. 25 Jean-Baptiste E, Perini P, Suissa L, Lachaud S, Declemy S, Mahagne MH. Prognostic value of preoperative border-zone (watershed) infarcts on the early postoperative outcomes of carotid endarterectomy after acute ischemic stroke. Eur J Vasc Endovasc Surg. 2013;45:210–7. 26 Miyamoto N, Tanaka Y, Ueno Y, Kawamura M, Shimada Y, Tanaka R. Demographic, clinical, and radiologic predictors of neurologic deterioration in patients with acute ischemic stroke. J Stroke Cerebrovasc Dis. 2013;22:205–10. 27 Sumer M, Ozdemir I, Erturk O. Progression in acute ischemic stroke: frequency, risk factors and prognosis. J Clin Neurosci. 2003;10:177–80. 28 Muscari A, Puddu GM, Serafini C, Fabbri E, Vizioli L, Zoli M. Predictors of short-term improvement of ischemic stroke. Neurol Res. 2013;35:594–601. 29 Nardi K, Milia P, Eusebi P, Paciaroni M, Caso V, Agnelli G. Admission leukocytosis in acute cerebral ischemia: influence on early outcome. J Stroke Cerebrovasc Dis. 2012;21:819–24. 30 Christensen H, Boysen G, Johannesen HH, Christensen E, Bendtzen K. Deteriorating ischaemic stroke. cytokines, soluble cytokine receptors, ferritin, systemic blood pressure, body temperature, blood glucose, diabetes, stroke severity, and CT infarction-volume as predictors of deteriorating ischaemic stroke. J Neurol Sci. 2002;201:1–7.
Predictors of neurological deterioration during hospitalization: results from the Chinese Intracranial Atherosclerosis (CICAS) Study Yuetao Ma1,2,3,4, Liping Liu1,2,3,4, Yuehua Pu1,2,3,4, Xinying Zou1,2,3,4, Yuesong Pan1,2,3,4, Yannie Soo5, Xingquan Zhao1,2,3,4, Yilong Wang1,2,3,4, Kasing Wong5, Yongjun Wang1,2,3,4 1
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University,China, 2 China National Clinical Research Center for Neurological Diseases, China, 3 Stroke Center, Beijing Institute for Brain Disorders, China, 4 Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, China, 5 Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, China Objectives: Neurological deterioration (ND) after ischaemic stroke has been indicated as an independent risk factor for poor outcome. Previous studies have focussed on ND within the first few days after symptom onset, but many patients are likely to experience deterioration outside of this time frame. We aimed to investigate the predictors of ND during hospitalisation. Methods: Data were obtained from the Chinese Intracranial Atherosclerosis (CICAS) Study, and patients who were diagnosed with ischaemic stroke and arrived at the hospital within 72 hours after symptom onset were included in the present study. Neurological deterioration was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score of i2 points at discharge compared with admission. MR angiography (MRA) and duplex colour Doppler ultrasound were used to document the presence of intracranial or extracranial artery stenosis. Intracranial artery stenosis was defined as a reduction in the artery diameter of i50% on MRA. Multivariate analyses were conducted to determine the potential predictors of ND during hospitalisation. Results: Of the 1996 patients included in this study, 84 (4.21%) developed ND during hospitalisation. Compared with non-ND patients, ND patients showed higher rates of pneumonia (25.0 vs 9.5%, Pv0.001), urinary infection (7.1 vs 1.2%, Pv0.01), stroke recurrence (14.3 vs 1.9%, Pv0.001), watershed infarct (15.5 vs 5.4%, P50.002), intracranial internal carotid artery (ICA) stenosis (11.9 vs 6.0%, P50.041), middle cerebral artery (MCA) stenosis (39.3 vs 22.0%, Pv0.001) and basilar artery (BA) stenosis (16.7 vs 7.1%, P50.011). Multivariate analysis indicated that watershed infarcts (OR, 2.85; 95% CI, 1.04–7.81), MCA (OR, 2.23; 95% CI, 1.17–4.25) and BA (OR, 2.86; 95% CI, 1.19–6.87) stenosis or occlusion were independent risk factors for ND, as was pneumonia (OR, 3.4; 95% CI, 1.46–7.9). Discussion: Patients with watershed infarcts and MCA or BA stenosis or occlusion should be monitored closely, and various therapeutic strategies should be administered simultaneously to prevent pneumonia during hospitalisation. Keywords: Intracranial artery stenosis, Neurological deterioration, Radiological, Stroke
Introduction Patient conditions during the first hours or days after stroke may not be stable; some patients deteriorate, and others improve, which could be due to the natural process of the stroke or be partially explained by the fate of ischaemic penumbra, which further depends on the severity and duration of the stroke.1 Neurological deterioration (ND) has been observed in approximately 8.5–31% of patients with acute ischaemic stroke due to Correspondence to: Yongjun Wang, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China. Email: [email protected]
ß W. S. Maney and Son Ltd 2015 DOI 10.1179/1743132815Y.0000000024
the different definitions used for ND and different target populations,2–6 and approximately half of all cases occur within 24 hours after admission. The Canadian Neurological Scale and the Scandinavian Stroke Scale have been used in earlier studies, but recently, the National Institutes of Health Stroke Scale (NIHSS) has become the most common neurological scoring system used in clinical trials. An increase in the NIHSS score of i2 points has been recommended by some researchers as the definition of ND because worse outcomes have been demonstrated in patients with these scores.7
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Previous studies have focussed on the deterioration of neurological symptoms occurring in the first few days after stroke, and several risk factors have been identified, such as systolic blood pressure at admission,6,8,9 diabetes mellitus,4,6,9,10 stroke severity,3,9,11,12 haemoglobin,5 C-reactive protein13 and intracranial internal carotid artery (ICA) occlusion.4,13 However, a certain number of patients still develop ND outside of this timeframe, and the risk factors for these cases have not been well established. Thus, our study evaluated the influence of clinical factors, including demographic and biochemical factors, and radiological factors on ND during hospitalisation following acute ischaemic stroke.
Methods Study design and participants The Chinese Intracranial Atherosclerosis (CICAS) Study was a prospective, multicenter, hospital-based study including 22 general hospitals across China from 2007 to 2009. Patients who presented with acute cerebral ischaemia, including ischaemic stroke and transient ischaemic attack (TIA), within 7 days after symptom onset were screened. The inclusion and exclusion criteria have been described elsewhere.14 A standardised case report form was used for data collection. Baseline data, including demographic information, medical history, physical examination, biochemical results, and NIHSS score, were collected at admission. All patients underwent a brain MR scan, 3-dimensional (3D) time-of-flight MR angiography (MRA), and duplex colour Doppler ultrasound for intra/extracranial artery evaluation. The NIHSS score assessment was repeated at discharge. After the exclusion of patients with incomplete cerebrovascular workups, 2864 consecutive patients remained. Among the participants, those who were diagnosed with ischaemic stroke and arrived at hospital within 72 hours after symptom onset, were included in the current study. This study was approved by the institutional review board of Beijing Tiantan Hospital, and written informed consent was obtained from all participants or their legal relatives.
(smoked continuously for 6 months, i1 cigarette per day), heavy drinking (i2 standard alcoholic drinks per day), ischaemic heart disease (a history of myocardial infarction, angina pectoris or congestive heart failure), and previous medication use. Inhospital complications, such as pneumonia (having fever and coarse breathing or crackling sounds, confirmed by chest X-ray), deep vein thrombosis (having clinical symptoms of deep vein thrombosis, with a deep vein thrombosis confirmed by venous Doppler, excluding cellulitis or an infection of the leg), urinary tract infection (having clinical symptoms of urinary tract infection with positive presentation of abnormal white and red blood cells in the urine) and upper gastrointestinal bleeding (having coffee-ground emesis, haematemesis, blood in the nasogastric tube or melaena) were also recorded. In addition, a physical examination was conducted, and blood pressure, BMI, and biochemical markers, including white blood cell counts, haemoglobin, C-reactive protein, creatinine, homocysteine, glycosylated haemoglobin and lipoprotein, were recorded. An increase in the NIHSS score of i2 points was defined as ND.
Imaging evaluation Measurements of intracranial stenosis were determined with 69 Wiha Digi Max Digital Callipers (Germany) to a resolution of 0.01–0.03 mm for 0–100 mm, and the degree of stenosis on MRA was calculated using the published method for the Warfarin–Aspirin Symptomatic Intracranial Disease Study.15 The following arterial segments were assessed: the bilateral ICA (distal to the ophthalmic artery), anterior cerebral artery (ACA) A1, middle cerebral artery (MCA) M1, posterior cerebral artery (PCA) P1 and the basilar artery (BA). Vessels with w50% stenosis or occlusion were categorised as showing intracranial stenosis. All MRI/MRA images were examined by two neurologists who were blinded to the participants’ clinical information, and disagreements of greater than 10% were further reviewed by a third experienced researcher. The extracranial part of the ICA was evaluated with an ultrasonographic examination according to the published diagnostic criteria.16
Data collection and definitions We recorded patient characteristics, such as age and gender, and risk factors, including hypertension (a history of hypertension or a requirement for regular antihypertensive treatment), diabetes mellitus (a history of diabetes mellitus, treatment with hypoglycaemic agents or glycosylated haemoglobin i7%), hyperlipidaemia (low-density lipoprotein cholesterol w2.6 mmol/L at the time of admission, a history of hyperlipidaemia or the receipt of lipidlowering treatments), concurrent smoking
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Statistical analysis Continuous variables were summarised as the means (SD) or medians (interquartile range, IQR) and evaluated with a t-test or Kruskal–Wallis test. Categorical variables were presented as n (%) and analysed with a chi-square test or Fisher’s exact test. Owing to the relatively small number of patients with ND compared with the entire patient group, twice the number of non-ND patients matched by age, gender, and admission NIHSS score were included
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for the study. Multivariate conditional logistic regression was used in the multivariable analysis to evaluate the association of possible determinants and ND during hospitalisation. Variables with a P value v0.10 were included in the multivariate regression analysis. All analyses were performed with SAS software, version 9.1 (SAS Institute Inc., Cary, NC, US), and a two-tailed probability value v0.05 was considered statistically significant.
Results From October 2007 to June 2009, a total of 1996 ischaemic stroke patients who met the inclusion criteria were included in this study, and of these patients, 84 (4.21%) developed ND during hospitalisation. Owing to the difference in patient number between the ND and non-ND groups, this study used a case–control design, and 168 non-ND patients were matched based on age, gender and NIHSS score at admission. The clinical features between the two patient groups are presented in Table 1. The mean age of all of the patients was 65.14+ 10.71 years, and 36.90% of the patients were women. Pneumonia was more commonly
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observed in patients with ND than those without ND (25.00 vs 9.52%, P50.0001). The same pattern was also observed for urinary infections (7.14 vs 1.19%, P50.0075). Stroke recurrence in the ND group was also higher than that in the non-ND group (14.29 vs 1.85%, P50.0004). No differences in risk factors, biochemical markers, other in-hospital complications or hospital treatments were observed between the two groups. ND significantly prolonged the hospital stay of patients (19.0 [13.5–26.5] vs 15.0 [11.0–18.0] days, Pv0.0001).
Discussion To our knowledge, this is the first study to examine ND during hospitalisation after acute ischaemic stroke in Chinese patients. Our findings indicated that ND occurred in 4.21% of all patients, and this frequency was lower than those of previous studies,4,13 which may be because previous studies used an increase in the NIHSS score of i1 point as the definition for ND. In addition, we excluded patients who could not complete the MR examination, including patients who had previously received stent implants in coronary
Table 1 Clinical characteristics of patients with and without ND during hospitalisation Total (n5252) Mean age (years) Female (%) Median NIHSS scores (IQR) Hypertension (%) Hyperlipidaemia (%) Diabetes mellitus (%) Coronary heart disease (%) Current smoking (%) Heavy drinking (%) Unconsciousness (%) Haemoglobin (g/L) Creatinine (mmol/L) Leucocytes (109/L) C-reactive protein (mg/L) Homocysteine (mmol/L) Fasting blood glucose (mmol/L) Glycosylated haemoglobin (%) Triglyceride (mmol/L) Total cholesterol (mmol/L) LDL-C (mmol/L) SBP at admission (mmHg) DBP at admission (mmHg) BMI (kg/m2) Thrombolysis (%) In-hospital antihypertensive (%) In-hospital complications (%) Pneumonia Urinary infection Upper gastrointestinal bleeding Deep vein thrombosis Stroke recurrence Hospital stay (IQR), days
ND (n584)
Non-ND (n5168)
P value
0.4054 0.7995 0.6547 0.1266 0.0961 0.8658 0.5637 0.8025 0.8288 0.6207 0.6925 0.4246 0.5510 0.1684 0.1628 0.2188 0.5785 0.4473 0.5513 0.9008 0.4142 0.0845
65.14+ 10.71 93 (36.90) 4.0 (2.0–7.0) 201 (79.76) 188 (74.60) 89 (35.32) 22 (8.73) 87 (34.52) 29 (11.51) 11 (4.37) 138.26+ 22.29 79.71+ 28.82 7.93+ 2.90 5.62+ 9.65 17.90+ 11.91 6.41+ 2.43 6.76+ 1.93 1.70+ 1.04 4.79+ 1.09 2.92+ 0.99 152.74+ 24.32 87.19+ 12.23 24.60+ 3.16 6 (2.90) 142 (56.35)
65.48+ 10.92 31 (36.90) 4.0 (2.0–7.0) 69 (82.14) 62 (73.81) 31 (36.90) 5 (5.95) 25 (29.76) 10 (11.90) 3 (3.57) 138.15+ 30.04 80.20+ 33.94 8.06+ 3.47 5.60+ 5.56 16.99+ 9.96 6.54+ 2.51 6.70+ 1.79 1.60+ 0.92 4.71+ 1.24 2.98+ 0.94 154.54+ 23.75 87.42+ 11.43 24.75+ 3.26 3 (4.23) 42 (50.00)
64.98+ 10.63 62 (36.90) 4.0 (2.0–7.0) 132 (78.57) 126 (75.00) 58 (34.52) 17 (10.12) 62 (36.90) 19 (11.31) 8 (4.76) 138.32+ 17.38 79.47+ 26.05 7.86+ 2.58 5.64+ 11.53 18.42+ 12.93 6.34+ 2.39 6.79+ 2.01 1.75+ 1.10 4.82+ 1.02 2.89+ 1.02 151.75+ 24.65 87.07+ 12.69 24.53+ 3.12 3 (2.21) 100 (59.52)
37 (14.68) 8 (3.17) 6 (2.38) 2 (0.79) 14 (5.86) 16.0 (11.5–21.0)
21 (25.00) 6 (7.14) 4 (4.76) 1 (1.19) 11 (14.29) 19.0 (13.5–26.5)
16 (9.52) 2 (1.19) 2 (1.19) 1 (0.60) 3 (1.85) 15.0 (11.0–18.0)
0.0001 0.0075 0.0578 0.5637 0.0004 v0.0001
NIHSS: National Institutes of Health Stroke Scale; IQR: inter-quartile range; LDL-C: low-density lipoprotein cholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index. The radiological characteristics of patients in the ND and non-ND groups are shown in Table 2. Patients with watershed infarcts were more likely to develop ND during hospitalisation (15.48 vs 5.36%, P50.0023). In addition, intracranial ICA, MCA and BA stenosis or occlusion were all significantly more commonly observed in patients with stroke progression (11.90 vs 5.95%, 39.29 vs 22.02% and 16.67 vs 7.14%, respectively; all Pv0.05). No differences in stroke classification, distributions of the infarcts, extracranial ICA stenosis or white matter lesions were detected between the two groups.
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Table 2 Radiological characteristics of patients with and without ND
OSCP classification (%) PACI TACI LACI POCI Distribution of infarct (%) Anterior Posterior Both Location of infarct (%) Cortical or subcortical infarct Basal ganglia infarct Watershed infarct Confluent white matter lesion (%) Incomplete circle of Willis (%) Extracranial ICA stenosis or occlusion (%) Intracranial ICA stenosis or occlusion (%) MCA stenosis or occlusion (%) BA stenosis or occlusion (%)
Total (n5252)
ND (n584)
Non-ND (n5168)
P value
155 (63.52) 12 (4.92) 23 (9.43) 54 (22.13)
50 (62.50) 4 (5.00) 4 (5.00) 22 (27.50)
105 (64.02) 8 (4.88) 19 (11.59) 32 (19.51)
0.2566
140 (55.56) 76 (30.16) 4 (1.59)
46 (54.76) 27 (32.14) 1 (1.19)
94 (55.95) 49 (29.17) 3 (1.79)
0.8312 0.5737 0.6547
154 (61.11) 97 (38.49) 22 (8.73) 88 (34.92) 240 (95.24) 30 (13.95) 7 (2.78) 70 (27.78) 26 (10.32)
48 (57.14) 35 (41.67) 13 (15.48) 32 (38.10) 79 (94.05) 11 (15.94) 10 (11.90) 33 (39.29) 14 (16.67)
106 (63.10) 62 (36.90) 9 (5.36) 56 (33.33) 161 (95.83) 19 (13.01) 10 (5.95) 37 (22.02) 12 (7.14)
0.2918 0.3770 0.0023 0.3711 0.4386 0.4652 0.0412 0.0006 0.0114
OSCP: Oxfordshire Community Stroke Project; PACI: partial anterior circulation infarction; TACI: total anterior circulation infarction; LACI: lacunar infarction; POCI: posterior circulation infarction; ICA: internal carotid artery; MCA: middle cerebral artery; BA: basilar artery. After controlling for confounding factors, including stroke recurrence, the multivariate logistic regression analysis showed that pneumonia (OR, 3.4; 95% CI, 1.46–7.9; P50.0045), watershed infarct (OR, 2.85; 95% CI, 1.04–7.81; P50.0426), MCA stenosis or occlusion (OR, 2.23; 95% CI, 1.17–4.25; P50.0151) and BA stenosis or occlusion (OR, 2.86; 95% CI, 1.19–6.87; P50.0185) were independently associated with ND during hospitalisation (Table 3).
Table 3 Odds ratio (95% CI) for ND during hospitalization using multivariate logistic regression Variable OR 95% CI P Pneumonia 3.4 Watershed infarct 2.85 MCA stenosis or 2.23 occlusion BA stenosis or occlusion 2.86
1.46 7.9 1.04 7.81 1.17 4.25
0.0045 0.0426 0.0151
1.19 6.87
0.0185
MCA, middle cerebral artery; BA, basilar artery.
arteries or intra/extra cranial arteries, and thus may have had more severe atherosclerotic disease and may have been more likely to deteriorate following stroke. We also excluded critically ill patients who were more likely to deteriorate compared with patients with milder illness. Our study demonstrated that pneumonia played a very important role in ND development during hospitalisation. Pneumonia is a common inpatient complication after stroke, with an incidence of approximately 10%. Numerous factors have been associated with pneumonia after stroke, such as diabetes, age, consciousness, days of hospitalisation, tracheal intubation, tracheal incision and nasal feeding treatment.17,18 Pneumonia has been associated with higher mortality and worse outcome in previous studies.18,19 Our colleagues have previously reported that pneumonia occurred in 11.9% of patients in the CNSR study, and patients with pneumonia had a significantly higher risk of death during hospitalisation and at 3, 6 and 12 months post-stroke
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compared with those without pneumonia.20 Our study revealed that pneumonia occurred in 14.68% of stroke patients, and pneumonia was an independent risk factor for ND during hospitalisation, which has not been reported previously. Owing to the adverse effect of pneumonia on both short-term and long-term outcomes after stroke, we strongly recommend active dysphagia screening as early as possible in addition to effective management of blood pressure, glucose and other critical conditions to prevent aspiration, as it has been reported that the risk of pneumonia was 3-fold higher in patients with dysphagia compared with those without and 11-fold higher when dysphagia was severe enough to result in aspiration.21 Our study also demonstrated important radiological findings for ND development. Watershed infarcts comprise approximately 10% of all brain infarcts22 and have been recognised to result from haemodynamic impairment, although microembolic aetiology cannot be excluded.23 A study by Li et al. included 27 patients with internal watershed (IWS) infarctions, and 22 (81.5%) patients had severe stenosis (w70%) or occlusion in either the ICA or MCA, demonstrating a close relationship between IWS and occlusive diseases of the carotid arteries.24 Another study compared the early postoperative outcomes of a carotid endarterectomy (CEA) after acute ischaemic stroke between patients with territorial infarcts and those with watershed infarcts, and found that after adjustments for age, sex and other confounding factors, watershed infarcts were the only independent predictor of neurologic morbidity after CEA,25 demonstrating the unstable haemodynamic
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state in these patients. In our study, the incidence of watershed infarcts was 8.73%, which was similar to a previous study,22 and the multivariate analysis revealed that watershed infarcts were an independent risk factor for ND during hospitalisation. Regarding the relationship between intra- or extracranial large arteries and ND development, previous studies have reported that ICA and MCA occlusion are independently associated with ND.4,13,26 In our study, a stenosis severity of more than 50% or an occlusion of the ICA, MCA or BA was all associated with ND in the univariate analysis, but after adjusting for confounding factors, only MCA and BA stenosis or occlusion were independently associated with ND development, which may partially be explained by the definition used for intracranial artery evaluation, which included both stenosis and occlusion, whereas previous studies did not consider stenosis. In addition, we further divided the ICA into two segments, the intracranial and extracranial segment, and did not detect any differences in extracranial ICA stenosis or occlusion between the two groups. However, the segments of the ICA used for evaluation have not been described in detail in previous studies.4,26 Our results showed that BA stenosis or occlusion was independently associated with ND, which has not been reported in the previous studies; however, in the study by Sumer et al., the involvement of posterior circulation was independently associated with ND,27 suggesting a possible relationship between the BA and ND development. In light of the unstable haemodynamics in the presence of intracranial artery stenosis or occlusion during the acute phase of stroke, it may be helpful to retain enough blood volume to ensure perfusion in the ischaemic area, instead of lowering the blood pressure too much. Several other factors have been reported to influence the development of ND, such as diabetes,4,8–10 systolic blood pressure,8,9,11,28 white blood cell counts,26,29 haemoglobin5 and NIHSS score,9,11,26 although there have been conflicting results.30 Our study did not detect any differences in these factors between the two groups. Our study also had some limitations. We evaluated the stenosis or occlusion of intracranial arteries but did not specifically evaluate the responsible artery, which might decrease the correlation between the stenosis or occlusion of these arteries and ND. In addition, we did not evaluate the haemodynamic factors and the compensation from adjacent arteries, which could result in disregarding useful information.
Conclusions In conclusion, our study demonstrated that watershed infarcts and stenosis or occlusion of the MCA or BA were important radiological predictors of ND during hospitalisation. Patients with such problems should be monitored closely, and various therapeutic strategies
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should be administered simultaneously to prevent pneumonia after stroke during hospitalisation. Future studies evaluating the responsible arteries and haemodynamic information are needed.
Acknowledgements The authors thank all of the participating hospitals and colleagues who contributed to this study.
Disclaimer Statements Contributors Wrote the article: YM; study design: LL, XQZ, YiW, KW and YoW; data collection: YM, YPu, XZ and YS; statistical analysis: YM and YPa. Funding This study was funded by the Ministry of Science and Technology and the Ministry of Health of the People’s Republic of China. The grants are from the National 11th & 12th Five–year S&T Major Project (2006BAI01A11, 2011BAI08B01, 2011BAI08B02), National Key Technology Research and Development Program (2013BAI09B03) and Beijing Talents Project (2010D003034000023). Conflicts of interest The authors declare no conflict of interest. This article has not been submitted elsewhere. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Ethics approval This study was approved by the institutional review board of the Beijing Tiantan Hospital.
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