Risk Factors, Recurrence and Short-Term Outcomes for Progressive Cerebral Infarction: A Retrospective Study
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.333493
Source of Support: None, Conflict of Interest: None
Keywords: Cerebral infarction recurrence, progressive cerebral infarction, pulmonary infection, recurrence, risk factor, short-term outcome
Progressive cerebral infarction (PCI) is a type of cerebral ischemia attack in which the initial clinical manifestations of a cerebral infarction (CI), an area of dead tissue resulting from the blockage of blood and oxygen, worsen over time. PCI neurological symptoms worsen in a stepwise manner within 7 days after onset, and PCI account for 20–40% of CIs. The clinical treatment of PCI is relatively difficult, and the high disability and mortality rates of PCI treatment negatively influence patients' quality of life and finances. Therefore, all measures for decreasing these disability and mortality rates are extremely important.
Although many studies investigated PCI, most were focused on screening for PCI risk factors and assessing short-term prognoses.,, Only a few studies have investigated the risk factors for PCI prognosis and the relationship between PCI and CI recurrence in 1 year. Early finding and treatment of risk factors of PCI and PCI prognosis will definitely reduce its recurrence, disability, and mortality rate.
Thus, this study aimed to explore the risk factors of PCI and risk factors for its prognosis and evaluate the relationship between CI recurrence, all-cause death, adverse short-term outcomes within 1 year, and PCI.
A total of 623 CI patients who were admitted to the neurology department of The Affiliated Shuyang Hospital of Xuzhou Medical University, Shuyang, Jiangsu, China, between August 2014 and August 2017 were considered for inclusion in this retrospective study. Informed consent was obtained from the patients, and the protocol was approved by the Academic Committee and Ethics Committee of Shuyang People's Hospital.
The inclusion criteria were as follows: (1) cranial computed tomography (CT) or magnetic resonance imaging (MRI) scans suggesting acute CIs, (2) diagnosis in accordance with the guidelines for diagnosis and treatment of acute ischemic stroke in China (2014), (3) within 7 days after CI onset, (4) aged ≥ 18 years, and (5) clear consciousness. The exclusion criteria were as follows: (1) patients were experiencing transient ischemic attacks, hemorrhagic stroke, stroke accompanied with trauma, tumor, and inflammation, brain tumors, and unspecified strokes, (2) patients were experiencing more serious diseases (such as cancer, renal, heart, and liver failure, severe anemia) and hematopoietic system diseases, (3) patients with C-reactive protein (CRP) levels affected by any disease (asthma, arthritis, liver disease, bronchitis, etc.) due to possible acute stroke interference; (4) patients who died during hospitalization; and (5) patients without complete clinical and follow up data.
Of the 623 patients, 36 were seriously ill or had other serious diseases, 81 were in the nonacute phase of stroke during hospital admission, 258 had incomplete clinical data, 12 died before discharge, and 15 refused to participate in the follow-up assessment. All these patients were excluded; finally, 221 patients with complete clinical data who underwent the follow-up assessment were identified. Of these 221 patients, 91 were diagnosed with PCI and were divided into the observation group. The other 130 patients who did not have PCI were divided into the control group.
Diagnostic criteria for PCI
Patients were diagnosed with PCI if (1) their National Institutes of Health Stroke Scale (NIHSS) score became ≥2 points within 1 week after onset and (2), after aggravation, their head CT scan excluded cerebral and subarachnoid hemorrhages.
After admission, patient's venous blood was collected on an empty stomach the next morning for routine laboratory blood analyses (i.e., coagulation function, homocysteine, and liver function). Then, patients underwent head MRI and cervical vascular color Doppler ultrasound examinations. NIHSS scores at admission were used to evaluate impairment in neurological function. Disease history, living habits (i.e., drinking and smoking habits), biochemical indicators (i.e., glucose, lipid and bilirubin), and arterial stenoses were recorded and evaluated for being possible PCI risk factors.
Follow-up and outcome assessments
Follow-up assessments were conducted via telephone. Patients who were unable to answer questions underwent agent interviews. At every 3 months postintervention, for 12 months, patients were asked to answer standardized follow-up questions. These questions collected data regarding CI recurrence, disabilities, all-cause death, and recurrent cerebrovascular events, which included hemorrhagic stroke and ischemic stroke. At 12 months postintervention, the modified Rankin scale (mRS) was used to measure the degree of patients' neurological disabilities. A score of 3–6 on the mRS was defined as stroke disability. A score of 0–2 on the mRS was defined as a good outcome. Death from any cause was defined as all-cause death.
Statistical analyses were performed by the SPSS software package version 17.0 (SPSS Inc., Chicago, IL, USA). Continuous variables expressed as mean ± standard deviation and were analyzed with independent sample t-tests. Categorical data, expressed as numbers or percentages, were analyzed with the Chi-square test. Binary logistic analysis was used to determine the relationship between PCI, PCI prognosis, and possible risk factors. A Cox proportional hazards model was established to analyze the hazard ratio of adverse outcomes. Factors that may affect the patient's adverse outcomes, such as age, sex, hypertension, pneumonia, homocysteine, and atherosclerotic stenosis, were included in this model. P < 0.05 was considered statistically significant.
Factors influencing PCI as determined via univariate analysis
Our univariate analyses showed that PCI was significantly associated with hypertension (P = 0.021), diabetes (P = 0.001), NIHSS score at admission (P = 0.000), carotid stenosis (P = 0.020), intracranial artery stenosis (P = 0.000), pneumonia complications (P = 0.004), total bilirubin (P = 0.016), homocysteine (P = 0.002), total cholesterol (P = 0.012), low-density lipoprotein (P = 0.036), glucose (P = 0.022), CRP (P = 0.025), and fibrinogen level (P = 0.000) [Table 1].
Factors influencing PCI as determined via binary logistic analysis
Binary logistic analysis showed that diabetes (P = 0.001), NIHSS score at admission (P = 0.000), homocysteine (P = 0.042), fibrinogen (P = 0.029), and intracranial artery stenosis (P = 0.004) were significantly associated with PCI [Table 2].
Risk factors for PCI prognosis
In the observation group, 43 patients suffered from adverse outcomes, who were divided into the adverse outcome group, and the rest were divided into the good outcome group. Binary logistic analysis revealed that NIHSS score at admission (P = 0.021), age (P = 0.001), and pneumonia (P = 0.005) were significantly associated with PCI prognosis [Table 3].
CI recurrence and PCI outcomes
During the 12-month study period, 38 (17.19%) patients experienced CI recurrence, 13 died (5.88%), and 71 (32.12%) suffered adverse functional outcomes. In the control group, 26 (20%) patients experienced CI recurrence, 28 (21.54%) suffered adverse outcomes, and 4 (3.08%) died (CI, n = 2; myocardial infarction, n = 1; cerebral trauma, n = 1). In the observation group, 12 (13.18%) patients experienced CI recurrence and 43 (47.25%) suffered adverse outcomes. In total, 9 (9.89%) died (heart disease, n = 2; recurrent CI, n = 4; cerebral hemorrhage, n = 1; pneumonia, n = 1; unknown cause, n = 1). When compared, the observation group had higher mortality (P = 0.034) and adverse outcome (P = 0.000) rate than the control group. However, the CI recurrence rates did not significantly differ between them (P = 0.186) [Table 1]. Survival analysis showed that adverse outcomes were significantly related to age (P = 0.001), PCI (P = 0.001), and homocysteine (P = 0.032) [Table 4].
Comparison of clinical characteristics in men and women
Male was younger than female (P = 0.027). Women had higher incidences of atrial fibrillation (P = 0.034) and intracranial artery stenosis (P = 0.035). Men had higher rates of smoking (P = 0.000) and drinking (P = 0.000) [Table 5].
The pathogenesis of PCI is generally considered through cerebral ischemia or insufficient cerebral perfusion, which results in increased thrombosis and decreased collateral circulation. This then leads to the increase of the CI area and aggravation of neurological deficit symptoms. The etiology of PCI is relatively complex and usually considered to be related to diabetes, hypertension, thrombotic expansion, and other factors, such as long-term hypertension, which can lead to the increase of stenosis of the cerebral artery and cerebrovascular resistance and then decrease blood flow, resulting in further PCI development.,
Clinical research has shown that 50% of PCI cases occurred within 24 h of CI onset and reached their peak damage at 48 h post-CI onset. Therefore, the key prevention period of PCI is the first 2 days after CI occurrence. Furthermore, it is very important to clearly know PCI risk factors to develop more targeted treatments. Our results showed that diabetes, NIHSS score at admission, homocysteine, fibrinogen, and intracranial arterial stenosis were independent risk factors for PCI.
Researchers reported that diabetes could be an independent risk factor of early neurological deterioration (END) caused by PCI.,, Similarly, we found that diabetes was associated with END. The possible mechanism is that hyperglycemia can accelerate oxygen free radical production, thereby damaging the endothelial barrier. At the same time, under the conditions of cerebral ischemia and hypoxia, hyperglycemia can cause intracellular and extracellular acidosis, thereby causing brain cell edema formation and ischemic necrosis.,,,,
Furthermore, in this study, the NIHSS score was independently related to PCI. Many researchers found that NIHSS score could independently predict the occurrence of END.,, Our finding was consistent with those findings.
Fibrinogen is also a predictor of END. Lee et al. found that fibrinogen was dose dependently related to END in diabetes patients following acute ischemic strokes. Audebert found that END was significantly related to high fibrinogen concentrations upon admission. High fibrinogen levels can lead to decreased blood flow through increasing blood viscosity, promoting red blood cell aggregation, and accelerating platelet activation to form thrombi., Our finding was consistent with them.
Our study also showed that high homocysteine levels at admission were not only an important predictor of PCI but also significantly related to adverse outcomes. Many studies also found that homocysteine levels were related to END and END prognosis.,, Studies reported that homocysteine levels were positively related to the degree of cerebral artery stenosis., Homocysteine can promote endothelial dysfunction and apoptosis via multiple approaches such as endoplasmic reticulum stress., Our study showed that homocysteine level and intracranial artery stenosis were independent risk factors of PCI and support the above viewpoints to an extent.
Furthermore, our study revealed that intracranial artery stenosis was a strong predictor of PCI. Cerebral vascular stenosis can easily cause CI progression. Arterial stenosis can cause trunk and collateral circulation vessel obstruction, or even complete stagnation, thereby leading to the deterioration of clinical symptoms. In addition, thrombosis is prone to occur in the location of cerebral vascular stenosis. If the collateral circulation is not established in time, thrombosis may aggravate cerebral ischemia. The thrombus may also extend or detach from the proximal vessel and block the distal vessel, leading to progression of infarction.,
Some studies concluded that old age, disease severity, and disease complications affect the prognosis of CI patients, which were consistent with the results of our study. Older people are more susceptible to these complications than younger people because older people typically lacked effective physical functions. In addition, older people often have lower desires to take the initiative recovery than younger people, thereby worsening their prognoses. NIHSS scores at admission directly reflect patients' conditions. The higher the NIHSS score, the worse the patient's condition. Muir et al. believed that the NIHSS score more than 13 could best predict the outcomes of 3 months in CI. Moreover, Zhao et al. found that NIHSS score had a good predictive value for acute CI prognosis.
Pulmonary infection is a common complication after CI. After the central nervous system is damaged, intracranial pressure will increase, which can lead to neurogenic pulmonary edema and pulmonary congestion. This will directly cause patients to suffer from respiratory failure and systemic hypoxia, which makes it easier for patients to catch pulmonary infections., Li et al. found that poststroke pneumonia was closely related to long-term adverse outcomes and mortality in patients with CI. Therefore, poststroke pneumonia should be paid enough attention and preventive measures should be taken as early as possible.
As is known to all, male have a higher incidence of stroke than female, so we explored the gender characteristics of PCI. Arboix et al. found that female patients usually had older age, higher blood pressure, more atrial fibrillation and cardiogenic CI, but decreased length of hospital stay and mortality during 24-year follow-up in acute stroke patients. Women were older and more prone to atrial fibrillation and intracranial artery stenosis in this study, and this finding supports the above viewpoint to an extent. However, there was no difference in mortality, which may due to heterogeneity of the types of stroke and our short follow-up time.
We found the CI recurrence rate of PCI group was not significantly increased than that of no PCI group. Geng et al. found that the PCI recurrence rate did not differ from the CI recurrence. Additionally, Wang et al. reported a 6-month PCI recurrence rate of approximately 8.7%, which was consistent with our 6-month PCI recurrence rate of 7.69%. Furthermore, the mortality (P = 0.034) and adverse outcome rate (P = 0.000) of the PCI group were significantly increased than those of the no PCI group in univariate analysis. Our Cox proportional hazards model also showed that PCI was a strong predictor of longer-term (1 year) adverse outcomes in ischemic stroke patients than other studies.,, This finding was consistent with that of Geng et al.
There were several limitations. First, patients with previous CI episodes were not rule out. This meant that patients who experienced CIs prior to our study would have poorer long-term clinical prognoses. The possible mechanism for this may be that PCI patients had relatively high NIHSS scores and they experienced severe symptoms, such as severe intracranial atherosclerosis and poor collateral circulation, which resulted in poor functional recovery. Second, the sample size was small, and the conclusions maybe biased.
In the future, an indispensable line of research would be precisely the assessment of ischemic stroke subtypes and its potential relationship with PCI and outcomes. For example, the area around the lateral ventricle infarction could easily deteriorate, patients with recurrent multiple lacunar infarctions were prone to cognitive dysfunction, and early recurrent embolization in cardioembolic stroke would lead to increased in-hospital mortality.,
Independent risk factors of PCI included diabetes, NIHSS score, homocysteine, fibrinogen, and intracranial artery stenosis. Our study showed that PCI did not have a significant effect on the CI recurrence rate and the observation group had significantly higher mortality and adverse outcome rate than the control group, which suggested that PCI was a powerful predictor of poor prognosis. The control of PCI risk factors should be strengthened in clinical settings so that PCI interventions could be performed more efficiently and effectively. Further research needs to focus on reducing adverse outcomes and treatment of PCI.
We acknowledge and thank the subjects involved in the study.
Financial support and sponsorship
This study was supported by a research grant from the health and family planning commission of Jiangsu province (Grant number Q201616).
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]