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Differential Characteristics of Ischemic and Hemorrhagic Stroke in Patients with Cerebral Small Vessel Disease
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.310106
Keywords: Cerebral small vessel disease, lacunar stroke, subcortical hemorrhage
Lacunar infarcts and hemorrhages in the subcortical structures have been recognized as the consequences of cerebral small vessel disease (SVD) of the brain parenchyma. The concept of SVD has been recently reassessed in view of its important role in stroke, dementia with the aging of the population, and the increased use of MRI identifying more asymptomatic people with small vessel alterations.[1] Lacunes account for 15–25% of all ischemic strokes, with reported incidence rates of 15.8 cases per 100,000 population.[2] In addition, each year 14.8 per 100,000 people in Europe suffer from a primary intracerebral hemorrhage, 42.8% of which is estimated to affect deep subcortical structures.[3] A number of studies have compared predictive factors of ischemic versus hemorrhagic stroke, as well as differences in clinical profiles, risk factors, and outcomes according to the topography of ischemia or the site of bleeding.[4],[5],[6],[7],[8] However, as far as we are aware, little is known about predictive factors of ischemic or hemorrhagic manifestations of underlying cerebral SVD. Therefore, this study based on a large number of patients collected from a prospective hospital-based registry was designed to compare clinical features and early outcome of lacunar infarction and subcortical hemorrhage, which are both distinct manifestations of cerebral SVD as a common anatomic substrate.
Design and setting A retrospective clinical study based on prospectively collected data available from an ongoing hospital-based stroke registry was conducted. The objective of the study was to identify characteristics associated with lacunar stroke compared with subcortical intracerebral hemorrhage. Identification of specific predictors for ischemic or hemorrhagic manifestations of cerebral SVD may be useful for risk stratification and better patient's care. Since 1986, the Sagrat Cor Hospital (an acute-care 350-bed teaching hospital in the city of Barcelona, Spain, serving a population of approximately 300,000) has an ongoing hospital-based stroke registry, the details of which have been previously described.[9] The department of neurology has 25 beds and an acute stroke unit. Data from first-ever stroke patients are entered following a standardized protocol with 186 items detailing demographics, risk factors, clinical features, laboratory and neuroimaging findings, topography, diagnostic studies, complications, and outcome. The study protocol for data exploitation of data from the stroke registry database was approved by the Clinical Research Ethics Committee of the Sagrat Cor University Hospital, Barcelona, Spain. Written informed consent has been obtained from each patient at the time of the index admission episode. Patients and study procedures This study is based on data included in the registry up to December 2009, a time at which 4,567 patients had been entered into the database. For the purpose of the study, consecutive patients diagnosed with lacunar infarction and subcortical intracerebral hemorrhage were selected. Subtypes of stroke were classified according to the Cerebrovascular Study Group of the Catalan Society of Neurology,[10] which is similar to the National Institute of Neurological Disorders and Stroke (NINDS) classification.[11] To classify a patient as having lacunar stroke required the following: (a) sudden or gradual onset of a focal neurological deficit lasting >24 hours of the type described in the classical lacunar syndromes (pure motor hemiparesis, pure sensory stroke, sensorimotor stroke, ataxic hemiparesis, dysarthria-clumsy hand, and atypical lacunar syndromes); and (b) computed tomography (CT) scan or brain magnetic resonance imaging (MRI) were either normal or demonstrated only small, localized brain lesions with diameter <20 mm located in perforating vessels' irrigation territory, having previously excluded cortical cerebral ischemia, a supra-aortic arterial stenosis >50% or cardioembolisms (by means of electrocardiography and transthoracic echocardiogram). In the presence of a normal CT scan, a second CT was obtained within the first week of admission. Recurrent lacunar stroke was considered when the diagnosis of lacunar infarction was established in a patient with a history of a previous stroke of the lacunar type. On the other hand, subcortical hemorrhages were defined as hyperdense lesions identified on neuroimaging studies, located in subcortical areas including internal capsule, basal ganglia, and thalamus. For the purpose of the study lobar, cerebellar, brain stem and isolated intraventricular hemorrhages were excluded. In patients without hypertension, vascular malformations and neoplasms were excluded by intracranial angio-MRI studies. Cerebrovascular risk factors were defined as in other studies by our group.[12] All patients were admitted to hospital within 48 hours of the onset of symptoms. On admission, demographic characteristics, salient features of clinical history and neurological examination, results of laboratory tests, chest radiography, and 12 lead electrocardiography were recorded. In all patients, brain CT scan and/or MRI were performed within the first week of hospital admission. Medical complications (respiratory, urinary, cardiac, vascular, and infectious) and mortality during the acute phase of the disease were assessed. The degree of clinical disability at discharge from the hospital was evaluated according to the modified Rankin scale (mRS).[13] Statistical analysis Categorical variables are expressed as frequencies and percentages, and continuous variables as mean and standard deviation (SD). The distribution of variables in patients with lacunar stroke and in those with subcortical hemorrhage was compared with the Chi-square (χ2) test or the Fisher's exact test for categorical variables and the Student's t-test for quantitative variables. Statistical significance was set at P < 0.05. Covariates with a P-value <0.20 in the univariate testing were then entered into multivariable logistic regression models with a stepwise selection method, in which the presence of lacunar infarct (versus subcortical hemorrhage) was the dependent variable. Three regression models based on data collected from the medical history, including clinical manifestations, signs on physical examination, and clinical course during a stay in the hospital, were constructed; model 1 was based on demographics and risk factors, and clinical features (model 2) and outcome (model 3) were added to it. The odds ratio (OR) and 95% confidence interval (CI) were calculated for the final statistically significant variables independently associated with lacunar stroke and subcortical hemorrhage. Statistical analysis was performed using the SPSS software package.
A total of 440 patients diagnosed with lacunar infarction and 210 with subcortical hemorrhage were included in the study. The distribution of lacunar syndromes included pure motor hemiparesis in 201 patients, pure sensory stroke in 99, sensorimotor stroke in 51, atypical lacunar syndromes in 48, dysarthria-clumsy hand in 33, and ataxic hemiparesis in 8. In the subcortical hemorrhage group, sites of bleeding included the basal ganglia in 119 cases, the thalamus in 94, the internal capsule in 84, and mixed cases involving two or more of the aforementioned bleeding sites in 80 cases. More than 50% of patients either with lacunar infarction or subcortical hemorrhage were men, with a mean (SD) age of 73.5 (57.6) years. Results of univariate analysis are shown in [Table 1]. In relation to risk factors, heart rhythm disorders, chronic liver disease, and anticoagulation therapy were significantly more frequent in the subcortical hemorrhage group, whereas diabetes mellitus, current smoking, and dyslipidemia were more frequent in the lacunar stroke group. Regarding clinical features, all manifestations except for acute onset (hours) or nonsudden onset of stroke were significantly more common among patients with subcortical hemorrhage. Complications during hospitalization were also significantly more frequent in the subcortical hemorrhage group. The early outcome was better in the lacunar stroke group. Symptom-free on discharge was more frequent in lacunar strokes compared to patients with subcortical hemorrhage. However, the percentage of patients with severe neurological impairment at hospital discharge, the length of hospital stay, and in-hospital mortality were significantly higher among patients with subcortical hemorrhage.
Results of multivariate analysis are shown in [Table 2]. In the first logistic regression model based on demographics and risk factors, dyslipidemia, current smoking, and diabetes were independent variables associated with lacunar infarction, whereas chronic liver disease and anticoagulation therapy were associated with subcortical hemorrhage. In the second model with demographics, risk factors, and clinical features, dyslipidemia and diabetes continued to be associated with lacunar infarction, whereas anticoagulation therapy, sudden stroke onset, headache, altered consciousness, motor impairment, and visual disturbances were associated with subcortical hemorrhage. In the third model of demographics, risk factors, clinical features, and outcome, dyslipidemia (OR 2.06) and diabetes (OR 1.97) were significantly associated with lacunar infarction, whereas anticoagulation therapy (OR 0.05), sudden onset of stroke symptoms (OR 0.51), headache (OR 0.23), altered consciousness (OR 0.10), motor impairment (OR 0.44), respiratory events (OR 0.19), and in-hospital death (OR 0.08) were associated with subcortical hemorrhage. According to these models, cases of lacunar infarction versus subcortical hemorrhage were correctly classified in 60% of the cases for model 1, 77.1% of the cases for model 2, and 82.6% of the cases for model 3.
This study adds to evidence of differences in the clinical profile of patients with cerebral SVD manifested as ischemic (lacunar infarct) or hemorrhagic (subcortical hemorrhage) events. It is interesting to assess the characteristics that may predispose a patient to develop a lacunar infarction instead of a deep subcortical hemorrhage, and vice versa. In relation to risk factors for cerebrovascular disease, we identified that diabetes, current smoking, and dyslipidemia were associated with lacunar infarction. Chronic liver disease and anticoagulation therapy were associated with subcortical hemorrhage. The observation of diabetes, hypercholesterolemia, and smoking as risk factors for lacunar stroke is consistent with previous studies. In a nested case-control study within the Framingham Heart Study comparing 118 lacunar stroke and 108 intracerebral hemorrhage events, diabetes mellitus, and smoking were strongly associated with lacunar infarction.[14] It is possible that micro and macrovascular effects of diabetes constitute an important mediator predisposing to a thrombogenic process. Interestingly, in our study, hypertension was not found to be a significant risk factor for neither lacunar stroke nor subcortical hemorrhage. Hypertension, however, is one of the most common risk factors for intracerebral hemorrhage and lacuna stroke, although it is less frequent in cardioembolic infarcts and in cerebral infarction of unknown origin.[15] The role of dyslipidemia in the formation of atheromatous plaques is well established, and in other studies, diabetes, hyperlipidemia, and smoking have been identified as risk factors for lacunar stroke.[16],[17],[18] In a population-based incidence study in which lacunar infarct was compared to deep intracerebral hemorrhage, patients with lacunar stroke were older and more likely to have diabetes and elevated cholesterol levels than patients with intracerebral hemorrhage.[19] Anticoagulation therapy is strongly related to intracerebral hemorrhage due to the increased risk of bleeding associated with the use of these drugs.[20],[21] Intracerebral hemorrhage in patients with anticoagulant therapy is an increasingly prevalent problem in large part due to the aging population and the increased use of anticoagulants in patients are at risk for thrombosis.[21] However, the specific anticoagulant drugs and other concomitant medications such as antiplatelet agents or statins were not investigated in our study. We also found that chronic liver disease was associated with subcortical hemorrhage. Liver dysfunction is commonly associated with clinical and laboratory evidence of coagulopathy,[22] but the relationship between liver disease and intracerebral hemorrhage remains unclear. In a population-based case-control study carried out in Denmark, the risk of intracerebral hemorrhage among hospitalized patients with liver cirrhosis and other liver diseases was examined;[23] there was a markedly increased risk for intracerebral bleeding in patients with liver cirrhosis and noncirrhotic alcoholic liver disease after controlling possible confounders of intracerebral hemorrhage. Presentation of TIA prior lacunar infarction is usually less frequent as compared with the history of TIA prior large vessel atherosclerotic disease.[24] The absence of statistically significant differences between the study groups in relation to this risk factor is explained by SVD as the common vascular substrate in both entities. In relation to clinical features, sudden stroke onset (minutes), headache, altered consciousness, motor symptoms, and visual disturbances are independently associated with subcortical hemorrhage. Sudden onset of symptoms is a characteristic manifestation of intracerebral hemorrhage affecting different locations including the thalamus, the internal capsule, and the basal ganglia.[25] The motor deficit, altered consciousness, and headache are also common symptoms in patients with intracerebral hemorrhage. Visual disturbances including upward gaze palsy with miotic unreactive pupils, and/or skew ocular deviation have been reported in patients with intracerebral hemorrhage affecting the thalamus.[25] Respiratory complications were also significantly more frequent in patients with subcortical hemorrhage, which are due to the expansion of the hematoma compressing pontine and midbrain structures affecting the respiratory center. It has been reported that almost one-third of patients with intracerebral hemorrhage develop pulmonary complications such as pneumonia, pulmonary edema, or pulmonary embolism.[26],[27] Patients with subcortical hemorrhage had a poorer prognosis as compared to those with lacunar infarction as shown by a longer hospital stay, higher in-hospital mortality, and greater disability at discharge. These findings indicate a substantially worse outcome for patients whose cerebral SVD is hemorrhagic rather than ischemic. A few studies have examined differences in the risk profile of patients with lacunar infarction versus subcortical symptomatic intracerebral hemorrhage. Marsh et al.[28] assessed predictors of intracerebral hemorrhage as compared to lacunar disease in patients with long-standing hypertension. The presence of cerebral microbleeds predicted hemorrhagic stroke and severe periventricular white matter disease predicted ischemia. In addition, increased carotid artery intima-media thickness has been identified as a factor favoring lacunar infarction over intracerebral hemorrhage in patients with hypertension.[29] Morotti et al.[30] assessed risk factors in a series of 1434 lacunar stroke patients and 497 patients with deep intracerebral hemorrhage enrolled consecutively in a multicenter for Italian study. They found that current smoking was associated with lacunar infarction whereas hypertension, excessive alcohol consumption, and treatment with warfarin and statins were associated with intracerebral hemorrhage. In other series, older age, hypertension, diabetes, smoking, obesity, and increased cholesterol levels were strongly associated with lacunar stroke.[14],[19] These findings are consistent with the present study, in which diabetes, dyslipidemia, and current smoking were predictors of lacunar infarction. Limitations of the study include the retrospective analysis of data based on a single-center stroke registry so that a hospital referral selection bias cannot be excluded. Laboratory and neuroimaging variables were not included in the multivariate analysis which would have provided a more robust regression model. Other possible confounding variables (e.g., concomitant medications) were not evaluated. Strengths of the study are a large number of patients analyzed, the systematic evaluation of risk factors, clinical features, and evolution of symptoms, and particularly, the fact that variables related to in-hospital complications and early outcome were included in the logistic regression analysis. In summary, this study shows that ischemic and hemorrhagic manifestations of cerebral SVD present distinct risk factors, clinical symptoms, and outcome profiles. This retrospective analysis confirms that dyslipidemia and diabetes are more strongly associated with lacunar infarction whereas anticoagulant therapy, sudden onset of symptoms, of which headache, altered consciousness, motor impairment, as well as respiratory complications and in-hospital fatal outcome were all significant predictors of subcortical intracerebral hemorrhage. This information is useful in terms of disease-risk stratification in the current progress toward more personalized medicine. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. Acknowledgements The authors thank Marta Pulido, MD, Ph.D., for editing the manuscript and editorial assistance. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2]
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