S-100B Levels in Stroke Patients

ORIGINAL ARTICLE S-100B Levels in Stroke Patients: Is It Useful for Showing Short-term Mortality? Salim Satar, MD,* Ayc¸a Ac¸ıkalın, MD,* Onur Akpınar, MD,w Filiz Koc, MD,z Mustafa Sahan, MD,y Muge Gulen, MD,* Ferhat Icme, MD,8 Metin Topal, MD,* and Mehmet O. Ay, MD* Background: Serum S100B is found in the glial cells and is elevated with stroke. It can be used in the diagnostic and prognostic utility. However, the use of S100B in the emergency room is controversial. In our study, we wish to determine if the National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) have utility in predicting the acute and first month poststroke mortality and morbidity in emergency room patients, as measured by serum S100B and clinical evaluations. Methods: A total of 62 consecutive patients who applied to the emergency service with acute ischemic stroke were enrolled in the study. Following a detailed neurological examination, GCS and NIHSS were used to determine the consciousness of the patients. Their serum samples were obtained as soon as they arrived into the emergency service and at the time of discharge. As outcome variables, the scores on the modified Rankin Disability Scale (mRDS) at 1 month were determined. Results: The S100B level immediately after the stroke was significantly related to the NIHSS and GCS scores. In addition, the clinical state and S100B levels of patients varied with the length of time between the stroke onset and emergency room treatment. Nine patients (14.5%) died while in the hospital. The stepwise Logistic regression analysis showed that NIHSS was an independent predictor of mortality (odds ratio = 1.48; 95% confidence interval, 1.01-2.18; Pr0.05). Thirty days poststroke, the mRDS levels significantly correlated with the initial and later S100B levels and GCS and NIHSS scores. The linear Logistic regression analysis indicated that NIHSS score and age were independent risk factors of mRDS (odds ratio= 1.48; 95% confidence interval, 1.01-2.18; Pr0.05) in our study population. Conclusions: The NIHSS scale is a much more reliable method to determine mortality and morbidity and also adds no extra cost. Therefore, it is not recommended to measure S100B in the From the *Department of Emergency Medicine, Adana Numune Education and Research Hospital; wDepartment of Cardiology, BSK Metropark Hospital; zDepartment of Neurology, Cukurova University, School of Medicine, Adana; yEmergency Medicine Service, Elazıg Education and Research Hospital, Elazıg; and 8Emergency Medicine Service, Ankara Ataturk Education and Research Hospital, Ankara, Turkey. The authors declare no conflict of interest. Reprints: Salim Satar, MD, Department of Emergency Medicine, Adana Numune Education and Research Hospital, Adana, Turkey 01170 (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins Neurosurg Q  Volume 24, Number 1, February 2014 emergency room, but if it is measured, then the time between measurement and onset of stroke symptoms should be determined. Key Words: acute ischemic stroke, S100B, GCS, NIHSS (Neurosurg Q 2014;24:87–90) C erebrovascular accidents are currently the second most common cause of mortality in the world. It is important to recognize the symptoms and diagnose this disease as early as possible. Serum S100B is found primarily in the glial cells of the central and peripheral nervous system and is elevated with stroke, cerebral hemorrhage, hypoxic brain damage, traumatic brain injury, or neurodegenerative disorders.1–7 The glial-derived protein S100B is used in the diagnosis of several diseases and as a predictive marker for improving clinical management, outcome, and survival of patients.8,9 However, it is controversial whether S100B has diagnostic and prognostic utility in the emergency room setting. It has been established that the current measures used to clinically evaluate patients in the emergency room are for the most part useful to determine the prognosis of patients. In particular, the Glasgow Coma Scale (GCS) is used to evaluate patients with head trauma or lesions in the primary central nervous system. It can also be used during initial evaluations of emergency room patients with conscious disorder.10 In addition, the National Institutes of Health Stroke Scale (NIHSS) is used to measure neurological deficits in acute stroke incidents.11 The current scales used to measure cerebrovascular accidents have advantages either in cost or manufacturing time, but the goal for the new diagnostic and prognostic criteria is that they would better categorize progression of the early and late stages of the disease. In this study, we wish to determine whether the NIHSS and GCS have utility in predicting the acute and first month poststroke mortality and morbidity in emergency room patients, as measured by serum S100B and clinical evaluations. MATERIALS AND METHODS The study group was composed of 62 consecutive patients who were admitted to the emergency room with www.neurosurgery-quarterly.com | 87 Satar et al Neurosurg Q  Volume 24, Number 1, February 2014 TABLE 1. Comparison of Characteristics Data Between Alive and Dead Subjects in Hospital Age (y) S100B-1 S100B-2 GCS NIHSS Infarct volume Alive (n = 53) Dead (n = 9) 68.3 ± 12.4 0.29 ± 0.38 0.21 ± 0.38 13.4 ± 2.1 8.9 ± 6.5 34767 ± 67496 68.8 ± 9.0 1.46 ± 1.46 — 9.3 ± 1.4 24.1 ± 4.2 80885 ± 185512 P 0.532 0.043 — < 0.001 < 0.001 0.481 The results are expressed as mean ± SD. GCS indicates Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale; S100B-1, on admission; S100B-2, before discharged. acute ischemic stroke and were hospitalized within the intensive care unit of the Neurology Department. All of the patients were examined thoroughly and the diagnoses were confirmed using applied cerebral computed tomography and a consultation from the Neurology Department. Serum samples were drawn to measure S100B on admission and before discharged. After a detailed neurological examination, GCS and NIHSS were used to determine the consciousness of the patients. Patients with a score between 0 and 6 on the NIHSS scale were classified as having a mild stroke, between 7 and 15 a moderate stroke and between 16 and 38 a serious stroke.12,13 After initial medical care in the emergency room, patients were transferred to the Neurology intensive care unit and received standard, universally accepted medical therapy. The mortality rate of the study group was measured and serum samples were obtained at the time of discharge to measure S100B. One month after stroke onset, the functional status of each patient was determined using the modified Rankin Disability Scale (mRDS) as part of a program monitoring the quality of inpatient stroke care. The mRDS score ranges from 0 to 6, with higher scores indicating greater impairment (6 indicates death). Before analysis, the mRDS score was categorized into “good outcome” (0 to 2; patient is independent) versus “poor outcome” (3 to 6; patient is dependent or dead).14,15 This study complies with the Principles of Ethical Publishing as described in the International Journal of Cardiology.16 FIGURE 1. Serum S100B levels compared with the National Institutes of Health Stroke Scale (NIHSS). FIGURE 3. Serum S100B levels compared with the modified Rankin Disability Scale (mRDS) at 1 month. 88 | www.neurosurgery-quarterly.com FIGURE 2. Serum S100B levels compared with the Glasgow Coma Scale (GCS). Estimation of the Total Infarction Volume The total volume of the infarction areas that were present in the computed tomography scans were estimated by multiplying these areas by the thickness (2 mm) and adding them together. r 2013 Lippincott Williams & Wilkins Neurosurg Q  Volume 24, Number 1, February 2014 S-100B Levels and Mortality TABLE 2. Functional Outcome Modified Rankin Disability Scale (mRDS Score) at 1 Month mRDS Age (y) S100B-1 S100B-2 GCS NIHSS Infarct volume 1 (n = 19) 2 (n = 11) 3 (n = 8) 4 (n = 10) 5 (n = 1) 6 (n = 4) P 64.0 ± 11.0 0.23 ± 0.27 0.10 ± 0.14 14.5 ± 1.2 5.3 ± 4.9 15365 ± 31868 70.0 ± 10.3 0.07 ± 0.03 0.06 ± 0.03 13.8 ± 1.9 7.3 ± 4.1 35216 ± 55407 64.6 ± 18.2 0.14 ± 0.11 0.04 ± 0.02 12.8 ± 2.6 10.4 ± 6.1 32856 ± 57794 76.0 ± 9.6 0.43 ± 0.36 0.35 ± 0.55 12.3 ± 2.2 12.1 ± 5.0 76958 ± 122139 60.0 ± 0.0 0.09 ± 0.0 0.03 ± 0.0 12.0 ± 0.0 24.0 ± 0.0 6280 ± 0.0 73.8 ± 10.1 0.50 ± 0.42 1.13 ± 2.04 11.5 ± 2.6 15.6 ± 9.5 31163 ± 38412 0.130 0.017 0.038 0.017 < 0.001 0.347 The results are expressed as mean ± SD. GCS indicates Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale; S100B-1, on admission; S100B-2, before discharged. Laboratory Parameters S100B levels were determined using the electrochemiluminescence method on the Elecsys-2010 analyzer. Statistical Analysis Statistics were performed using SPSS 11.0. The parametric data are presented as mean and SD values, whereas the nonparametric data are presented as frequencies. The parametric demographic parameters were evaluated using the Student t test and the nonparametric parameters were evaluated using the w2 test. When correlation analysis was used to determine the relationship between variables, multiple regression analysis was performed in order to estimate independent risk factors. of patients varied with the length of time between the stroke onset and emergency room treatment (Figs. 1–3). Thirty days after stroke, the mRDS levels significantly correlated with S100B levels on admission and before discharged and GCS and NIHSS scores. In addition, the time between stroke onset and admission to the emergency room was related to the S100B levels (Table 2, Fig. 3). The linear logistic regression analysis indicated that NIHSS score and age were independent risk factors of mRDS (odds ratio = 1.48; 95% confidence interval, 1.01-2.18; P < 0.05) in our study population. At the 30-day follow-up, 4 patients (14.5%) died (Tables 2, 3). The NIHSS level of this dead patients were higher than alive patients; however, because of low number of patients, there was not found statistical significance (15.8 ± 9.5 and 8.4 ± 5.9, P = 0.218). RESULTS The average age of the study group patients (28 males and 34 females) was 68.3 ± 11.9 (26 to 88) years. GCS scores ranged from 8 to 15 (average = 12.8 ± 2.5) and NIHSS scores from 1 to 30 (average = 11.1 ± 8.2). The average hospital stay was 11.7 ± 6.2 (1 to 38) days. Nine patients (14.5%) died while in the hospital. When comparing the patients who died to those who did not, it was found that the average age was similar but the S100B level and NIHSS score was significantly higher and the GCS score was significantly lower in the patient who died (Table 1). The stepwise logistic regression analysis showed that NIHSS was an independent predictor of mortality in hospital (odds ratio = 1.48; 95% confidence interval, 1.01-2.18; P < 0.05). It was found that the S100B level immediately after the stroke was significantly related to the NIHSS and GCS scores (r = 0.543, P < 0.001 and r = 0.459, P < 0.001). In addition, the clinical state and S100B levels DISCUSSION S100B is a low molecular weight calcium-binding protein and is found especially in glial cells of the central and peripheral nervous system.17,18 The serum S100B level is elevated after destruction of cerebral structures, as occurs during stroke, hypoxic brain damage, traumatic brain injury, or neurodegenerative disorders.1–7 The S100B levels reach a maximum 3 days after acute ischemic stroke and there is a gradual increase in levels starting 8 to 10 hours after symptom onset.1,19 In addition, serum S100B levels are strongly correlated with brain infarct volume.4,8 In the study by Abraha et al,9 it was determined that there is a correlation between serum S100B levels and clinical outcome as evaluated by the modified Barthel index, Rankin scale, and Lindley score. It was concluded that the S100B protein is a prognostic factor predicting clinical outcome after acute stroke and that further studies should TABLE 3. Four Patient’s Modified Rankin Disability Scale Levels Were 6 (Exitus) in 1 Month After Stroke Patients 1 2 3 4 Age (y) Sex NIHSS GCS Infarct Volume S100B-1 S100B-2 59 77 77 82 Male Female Female Male 4 14 27 18 15 12 10 9 3368 19233 87920 14130 0.264 0.368 1.120 0.229 0.010 0.231 4.190 0.078 GCS indicates Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale; S100B-1, on admission; S100B-2, before discharged. r 2013 Lippincott Williams & Wilkins www.neurosurgery-quarterly.com | 89 Satar et al Neurosurg Q be performed to determine how treatment affects S100B levels. In addition, Foerch et al5 demonstrated that S100B protein levels decrease after successful thrombolysis in acute stroke; S100B serum levels were significantly reduced in acute stroke patients who had early recanalization after intravenous administration of t-PA. Past studies have shown that serum S100B levels are elevated within the first 3 days after ischemic stroke onset. Meta-analysis suggested that S100B is not a valuable biomarker for diagnosing acute ischemic stroke because of its low specificity and delayed kinetics and the results of this study agree with this conclusion.19 Similar results were also found in our study. In this study, patients who died from stroke while in the emergency room had high S100B levels; however, the NIHSS score was a better predictor of mortality. The S100B levels were evaluated along with the NIHSS and GCS scores and it was found that patients who came to the hospital longer after their initial stroke symptoms had high S100B levels, whereas patients who came sooner after the onset of their symptoms had lower S100B levels (Figs. 2, 3). One potential explanation for these results in that S100B serum levels reach a maximum at 3 days after stroke. Thus, it may not be useful to measure S100B levels in the early poststroke period after admission to the emergency room, and if S100B levels are measured in this context, they should be evaluated in light of the time stroke symptoms started. Studies show that S100B can help predict long-term prognosis. One study showed that patients with acute stroke and S100B levels higher that 0.2 g/L measured 48 hours after stroke had a much worse functional status.6 Another study showed that patients who had faster changes in S100B levels in the first 24 hours after stroke had worse outcomes at the 3-month follow-up visit.20 Fassbender et al7 reported that there was a relationship between neurological outcomes as determined by the Scandinavian Stroke Scale and serum S100B levels. In our study, we found that initial S100B levels measured while the patients were in the emergency room were better predictors of 1-month outcomes than later S100B levels but that the most useful prognostic measure was the NIHSS score. It was determined by regression analysis that NIHSS and age were independent predictors of long-term mRDS values. It was concluded that 1 reason that S100B was not determined to be clinically valuable as a prognostic indicator was because it was measured in the early poststroke period. In addition, increased S100B levels were seen in 2 patients during follow-up and their mRDS levels were high in 1 month after stroke. It is hypothesized that increased S100B levels during follow-up are related to continuing cell death and that it may be useful to measure S100B levels to predict long-term prognosis. CONCLUSIONS For patients who come to the emergency room with a stroke prediagnosis, the S100B levels may be a useful prognostic measure initially and during follow-up. How- 90 | www.neurosurgery-quarterly.com  Volume 24, Number 1, February 2014 ever, it has been observed that the NIHSS scale is a much more reliable method to determine mortality and mobility and also adds no extra cost. Therefore, on the basis of the results of this study, it is not recommended to measure S100B in the emergency room, but if it is measured, then the time between measurement and onset of stroke symptoms should be determined. REFERENCES 1. Stroick M, Fatar M, Ragoschke-Schumm A, et al. Protein S-100B—a prognostic marker for cerebral damage. Curr Med Chem. 2006;13: 3053–3060. 2. Persson L, Hardemark HG, Gustafsson J, et al. S-100 protein and neuron-specific enolase in cerebrospinal-fluid and serum—markers of cell-damage in human central-nervous system. Stroke. 1987;18:911–918. 3. Elting JW, de Jager AEJ, Teelken AW, et al. Comparison of serum S-100 protein levels following stroke and traumatic brain injury. J Neurol Sci. 2000;181:104–110. 4. Herrmann M, Vos P, Wunderlich MT, et al. Release of glial tissuespecific proteins after acute stroke: a comparative analysis of serum concentrations of protein S-100B and glial fibrillary acidic protein. Stroke. 2000;31:2670–2677. 5. Foerch C, du Mesnil de Rochemont R, Singer O, et al. S100B as a surrogate marker for successful clot lysis in hyperacute middle cerebral artery occlusion. J Neurol Neurosurg Psychiatry. 2003;74: 322–325. 6. Wunderlich MT, Wallesch CW, Goertler M. Release of neurobiochemical markers of brain damage is related to the neurovascular status on admission and the site of arterial occlusion in acute ischemic stroke. J Neurol Sci. 2004;227:49–53. 7. Fassbender K, Schmidt R, Schreiner A, et al. Leakage of brainoriginated proteins in peripheral blood: temporal profile and diagnostic value in early ischemic stroke. J Neurol Sci. 1997;148: 101–105. 8. Missler U, Wiesmann M, Friedrich C, et al. S-100 protein and neuron-specific enolase concentrations in blood as indicators of infarction volume and prognosis in acute ischemic stroke. Stroke. 1997;28:1956–1960. 9. Abraha HD, Butterworth RJ, Bath PM, et al. Serum S-100 protein, relationship to clinical outcome in acute stroke. Ann Clin Biochem. 1997;34:366–370. 10. Edwards SL. Using the Glasgow Coma Scale: analysis and limitations. Br J Nurs. 2001;10:92–101. 11. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864–870. 12. Adams HP Jr, Davis PH, Leira EC, et al. Baseline NIH stroke Scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999; 53:126–131. 13. DeGraba TJ, Hallenbeck JM, Pettigrew KD, et al. Progression in acute stroke: value of initial NIH Stroke Scale score on patient stratification in future trials. Stroke. 1999;30:1208–1212. 14. van Swieten JC, Koudstaal PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604–607. 15. Sulter G, Steen C, De Keyser J. Use of the Barthel index and modified Rankin scale in acute stroke trials. Stroke. 1999;30:1538–1541. 16. Coats AJ. Ethical authorship and publishing. Int J Cardiol. 2009;131:149–150. 17. Cocchia D, Michetti F, Donato R. Immunochemical and immunocytochemical localization of S-100 antigen in normal human skin. Nature. 1981;294:85–87. 18. Donato R. S-100 proteins. Cell Calcium. 1986;7:123–145. 19. Dassan P, Keir G, Brown MM. Criteria for a clinically informative serum biomarker in acute ischaemic stroke: a review of S100B. Cerebrovasc Dis. 2009;27:295–302. 20. Jauch EC, Lindsell C, Broderick J, et al. Association of serial biochemical markers with acute ischemic stroke—the National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study. Stroke. 2006;37:2508–2513. r 2013 Lippincott Williams & Wilkins