Grand Rounds
Can High-Sensitivity C-Reactive Protein and Ferritin Predict Functional Outcome in Acute Ischemic Stroke? A Prospective Study Aslihan Kusvuran Ozkan, MD,1 Oya Umit Yemisci, MD,2 Sacide Nur Saracgil Cosar, MD,2 Pinar Oztop, MD,3 and Nur Turhan, Prof. Dr4 1
Kadirli Government Hospital, Physical Medicine and Rehabilitation Clinic, Osmaniye, Turkey; 2Baskent University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Ankara, Turkey; 3Baskent University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Istanbul, Turkey; 4Bayindir Hospital, Department of Physical Medicine and Rehabilitation, Istanbul, Turkey Background: Inflammation may not only be the consequence of brain infarction but it may also contribute to ischemic damage. However, the role of inflammatory markers in predicting functional outcome in stroke remains controversial. Objective: This study was conducted to evaluate the predictive value of admission high-sensitivity C-reactive protein (hs-CRP) and ferritin levels for functional disability in patients with acute ischemic stroke at 3-month follow-up and investigate the relationship between inflammatory markers and subtypes, severity, and risk factors of ischemic stroke. Methods: Sixty-two patients were examined prospectively within 48 hours after onset of ischemic stroke. Plasma hs-CRP and ferritin measurements were obtained from patients within 48 hours after onset and at 3-month follow-up. Patients were divided into 2 groups based on the level of hs-CRP: elevated (serum hs-CRP ≥0.5 mg/dL) and normal (serum hs-CRP .05). Conclusion: This study revealed that neither hs-CRP nor ferritin levels could predict functional disability 3 months after stroke onset. FIM, FAS, and NIHSS scores were more useful in predicting functional outcome 3 months after stroke onset than the laboratory markers evaluated in this study. Key words: ferritin, functional disability, high-sensitivity C-reactive protein, ischemic stroke
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troke is one of the most frequent causes of death and disability worldwide and has significant clinical and socioeconomic impact. A growing number of individuals survive stroke and become dependent for activities of daily living. Rehabilitation becomes the essential medical need soon after onset and has primary importance in affecting functional outcome and quality of life. Although different mechanisms are involved in the pathogenesis of stroke, there is increasing evidence that inflammation may not only be the consequence of brain infarction but may also contribute to ischemic damage, at least in the acute stages.1-3 Elevated C-reactive protein (CRP) levels have been observed in the circulation of patients after acute stroke.4-7 However the role of CRP in the pathogenesis of ischemic stroke is still not completely understood. It is unclear whether CRP is just a marker of systemic inflammatory process or is directly involved in pathogenesis of cerebral tissue damage.8 528
Several studies have been conducted to investigate the asssociation between highsensitivity CRP (hs-CRP) levels and ischemic stroke and have mainly focused on the correlation between CRP levels and stroke severity,2,6,9 extent of ischemic lesion, 1,2,6,10 and the prognostic significance of these associations.2,5-7,11,12 However, the results are disputable. Winbeck et al7 found that the CRP levels measured within 12 hours after symptom onset of an acute ischemic stroke were not independently related to long-term prognosis. On the other hand, Anuk et al5 reported that admission levels of inflammatory markers have long-term prognostic implications in patients with acute ischemic neurologic events. Top Stroke Rehabil 2013;20(6):528–536 2013;20(1):528–536 © 2013 Thomas Land Publishers, Inc. www.thomasland.com www.strokejournal.com doi: 10.1310/tsr2006-528 10.1310/tscir2001-528
High-Sensitivity C-Reactive Protein and Ferritin
Ferritin is also an important biomarker of inflammation and oxidative stress. A few clinical studies have shown an association between high ferritin levels in blood and poor clinical outcome in patients with acute ischemic stroke.13,14 However, to our knowledge, the association between ferritin and functional disability at long-term follow-up has not been investigated. The aims of this study were (1) to investigate the usefulness of hs-CRP and ferritin measurements in correlating with the severity of disability in patients with acute ischemic stroke at 3-month follow-up and compare them with more conventional functional evaluation tools such as the Functional Independence Measure (FIM) and Functional Ambulation Scale (FAS), (2) to evaluate the relationship between hs-CRP and ferritin levels with different stroke subtypes, and (3) to determine the relationship between inflammatory markers and stroke severity and stroke risk factors. Methods Subjects
Ninety-six patients, admitted consecutively to the neurointensive care unit and neurology unit of a university-affiliated hospital with a diagnosis of acute ischemic stroke between April 2009 and August 2009, were studied prospectively. Patients who had common characteristics of stroke, defined by the World Health Organization as a vascular lesion of the brain that results in rapidly developing clinical signs or focal or global loss of brain function that lasts at least 24 hours documented by brain computerized tomography (CT) or MRI, were included in the study.15 The study was approved by the hospital’s ethics committee and carried out according to the institutional guidelines and the principles of the Declaration of Helsinki. Patients were not included in the study if they had a medical history of infection in the previous 2 weeks; history of transient ischemic attack; signs of acquired in-hospital infection; surgery or trauma in the previous month; malignancy; systemic inflammatory diseases; major cardiac, renal, hepatic, or endocrinologic disorder; hemochromatosis; immunosuppressive diseases;
529
received immunosuppressive therapy, or if their functional level was too low for immediate rehabilitation care. The patients included in the study underwent a rehabilitation program 6 days per week, which aimed to normalize movement patterns and minimize spasticity. Physical therapy included static and dynamic control of position, balance skills, weight shift, and activities of daily living. Assessments
A complete medical history (including selfreported or family-reported risk factors for cerebrovascular disease) was obtained for each patient. All patients had physical and neurologic examinations, complete blood count, white blood cell count and differential, determination of erythrocyte sedimentation rate, renal and hepatic function tests, urinalysis, 12-lead electrocardiogram, chest x-ray, immunological study, and brain MRI with cerebral angiography, if indicated, to verify that they met the inclusion criteria. We also assessed vascular risk factors for stroke by evaluating the patients’ medical records and laboratory findings to examine the relationship between these factors and inflammatory markers. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, a diastolic blood pressure ≥90 mm Hg, or current use of antihypertensive medications. Cigarette smoking was defined as present if the patient reported smoking cigarettes during the past 5 years. Hypercholesterolemia was defined as a low-density lipoprotein cholesterol concentration ≥130 mg/dL or current use of lipidlowering agents. Diabetes mellitus (DM) was defined as a history of fasting glucose ≥126 mg/ dL or current use of hypoglycemic agents.16,17 Heart disease, such as atrial fibrillation, valvular heart disease, or myocardial infarction, was also assessed by 12-lead electrocardiogram and echocardiography. Venous blood samples for hs-CRP and ferritin measurements were obtained from the patients on admission, within the first 48 hours after symptom onset, and at the end of the third month. Based on the level of serum hs-CRP measured within 48 hours after stroke onset, subjects were
530
TOPICS IN STROKE REHABILITATION/NOV-DEC 2013
divided into 2 groups: elevated (serum hs-CRP ≥0.5 mg/dL) and normal (serum hs-CRP
Can High-Sensitivity C-Reactive Protein and Ferritin Predict Functional Outcome in Acute Ischemic Stroke? A Prospective Study Aslihan Kusvuran Ozkan, MD,1 Oya Umit Yemisci, MD,2 Sacide Nur Saracgil Cosar, MD,2 Pinar Oztop, MD,3 and Nur Turhan, Prof. Dr4 1
Kadirli Government Hospital, Physical Medicine and Rehabilitation Clinic, Osmaniye, Turkey; 2Baskent University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Ankara, Turkey; 3Baskent University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Istanbul, Turkey; 4Bayindir Hospital, Department of Physical Medicine and Rehabilitation, Istanbul, Turkey Background: Inflammation may not only be the consequence of brain infarction but it may also contribute to ischemic damage. However, the role of inflammatory markers in predicting functional outcome in stroke remains controversial. Objective: This study was conducted to evaluate the predictive value of admission high-sensitivity C-reactive protein (hs-CRP) and ferritin levels for functional disability in patients with acute ischemic stroke at 3-month follow-up and investigate the relationship between inflammatory markers and subtypes, severity, and risk factors of ischemic stroke. Methods: Sixty-two patients were examined prospectively within 48 hours after onset of ischemic stroke. Plasma hs-CRP and ferritin measurements were obtained from patients within 48 hours after onset and at 3-month follow-up. Patients were divided into 2 groups based on the level of hs-CRP: elevated (serum hs-CRP ≥0.5 mg/dL) and normal (serum hs-CRP .05). Conclusion: This study revealed that neither hs-CRP nor ferritin levels could predict functional disability 3 months after stroke onset. FIM, FAS, and NIHSS scores were more useful in predicting functional outcome 3 months after stroke onset than the laboratory markers evaluated in this study. Key words: ferritin, functional disability, high-sensitivity C-reactive protein, ischemic stroke
S
troke is one of the most frequent causes of death and disability worldwide and has significant clinical and socioeconomic impact. A growing number of individuals survive stroke and become dependent for activities of daily living. Rehabilitation becomes the essential medical need soon after onset and has primary importance in affecting functional outcome and quality of life. Although different mechanisms are involved in the pathogenesis of stroke, there is increasing evidence that inflammation may not only be the consequence of brain infarction but may also contribute to ischemic damage, at least in the acute stages.1-3 Elevated C-reactive protein (CRP) levels have been observed in the circulation of patients after acute stroke.4-7 However the role of CRP in the pathogenesis of ischemic stroke is still not completely understood. It is unclear whether CRP is just a marker of systemic inflammatory process or is directly involved in pathogenesis of cerebral tissue damage.8 528
Several studies have been conducted to investigate the asssociation between highsensitivity CRP (hs-CRP) levels and ischemic stroke and have mainly focused on the correlation between CRP levels and stroke severity,2,6,9 extent of ischemic lesion, 1,2,6,10 and the prognostic significance of these associations.2,5-7,11,12 However, the results are disputable. Winbeck et al7 found that the CRP levels measured within 12 hours after symptom onset of an acute ischemic stroke were not independently related to long-term prognosis. On the other hand, Anuk et al5 reported that admission levels of inflammatory markers have long-term prognostic implications in patients with acute ischemic neurologic events. Top Stroke Rehabil 2013;20(6):528–536 2013;20(1):528–536 © 2013 Thomas Land Publishers, Inc. www.thomasland.com www.strokejournal.com doi: 10.1310/tsr2006-528 10.1310/tscir2001-528
High-Sensitivity C-Reactive Protein and Ferritin
Ferritin is also an important biomarker of inflammation and oxidative stress. A few clinical studies have shown an association between high ferritin levels in blood and poor clinical outcome in patients with acute ischemic stroke.13,14 However, to our knowledge, the association between ferritin and functional disability at long-term follow-up has not been investigated. The aims of this study were (1) to investigate the usefulness of hs-CRP and ferritin measurements in correlating with the severity of disability in patients with acute ischemic stroke at 3-month follow-up and compare them with more conventional functional evaluation tools such as the Functional Independence Measure (FIM) and Functional Ambulation Scale (FAS), (2) to evaluate the relationship between hs-CRP and ferritin levels with different stroke subtypes, and (3) to determine the relationship between inflammatory markers and stroke severity and stroke risk factors. Methods Subjects
Ninety-six patients, admitted consecutively to the neurointensive care unit and neurology unit of a university-affiliated hospital with a diagnosis of acute ischemic stroke between April 2009 and August 2009, were studied prospectively. Patients who had common characteristics of stroke, defined by the World Health Organization as a vascular lesion of the brain that results in rapidly developing clinical signs or focal or global loss of brain function that lasts at least 24 hours documented by brain computerized tomography (CT) or MRI, were included in the study.15 The study was approved by the hospital’s ethics committee and carried out according to the institutional guidelines and the principles of the Declaration of Helsinki. Patients were not included in the study if they had a medical history of infection in the previous 2 weeks; history of transient ischemic attack; signs of acquired in-hospital infection; surgery or trauma in the previous month; malignancy; systemic inflammatory diseases; major cardiac, renal, hepatic, or endocrinologic disorder; hemochromatosis; immunosuppressive diseases;
529
received immunosuppressive therapy, or if their functional level was too low for immediate rehabilitation care. The patients included in the study underwent a rehabilitation program 6 days per week, which aimed to normalize movement patterns and minimize spasticity. Physical therapy included static and dynamic control of position, balance skills, weight shift, and activities of daily living. Assessments
A complete medical history (including selfreported or family-reported risk factors for cerebrovascular disease) was obtained for each patient. All patients had physical and neurologic examinations, complete blood count, white blood cell count and differential, determination of erythrocyte sedimentation rate, renal and hepatic function tests, urinalysis, 12-lead electrocardiogram, chest x-ray, immunological study, and brain MRI with cerebral angiography, if indicated, to verify that they met the inclusion criteria. We also assessed vascular risk factors for stroke by evaluating the patients’ medical records and laboratory findings to examine the relationship between these factors and inflammatory markers. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, a diastolic blood pressure ≥90 mm Hg, or current use of antihypertensive medications. Cigarette smoking was defined as present if the patient reported smoking cigarettes during the past 5 years. Hypercholesterolemia was defined as a low-density lipoprotein cholesterol concentration ≥130 mg/dL or current use of lipidlowering agents. Diabetes mellitus (DM) was defined as a history of fasting glucose ≥126 mg/ dL or current use of hypoglycemic agents.16,17 Heart disease, such as atrial fibrillation, valvular heart disease, or myocardial infarction, was also assessed by 12-lead electrocardiogram and echocardiography. Venous blood samples for hs-CRP and ferritin measurements were obtained from the patients on admission, within the first 48 hours after symptom onset, and at the end of the third month. Based on the level of serum hs-CRP measured within 48 hours after stroke onset, subjects were
530
TOPICS IN STROKE REHABILITATION/NOV-DEC 2013
divided into 2 groups: elevated (serum hs-CRP ≥0.5 mg/dL) and normal (serum hs-CRP
