http://informahealthcare.com/bij ISSN: 0269-9052 (print), 1362-301X (electronic) Brain Inj, 2015; 29(1): 33–40 ! 2015 Informa UK Ltd. DOI: 10.3109/02699052.2014.948068
ORIGINAL ARTICLE
Prediction of neuropsychological outcome after mild traumatic brain injury using clinical parameters, serum S100B protein and findings on computed tomography Kamran Heidari1, Shadi Asadollahi2, Morteza Jamshidian3, Shohreh Nasiri Abrishamchi3, & Mahdi Nouroozi3 Department of Emergency Medicine, Loghman Hakim Hospital, 2School of Medicine, and 3Department of Emergency Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abstract
Keywords
Primary objective: To identify if demographics, clinical and computed tomographic (CT) characteristics at first presentation and S100B concentrations at 3 and 6 hours after mild traumatic brain injury (MTBI) predict the development of post-concussion syndrome (PCS) after 1 month. Research design and methods: All consecutive MTBI patients (Glasgow Coma Scale [GCS] score 13–15) admitted to the Emergency Department aged older than 15 were included in this prospective, observational study. Outcome was assessed using a Rivermead Post-Concussion Symptoms Questionnaire to identify the patients with and without PCS 1 month after the injury. Main outcomes and results: A total of 176 patients with isolated MTBI were included in the study. After multivariate analysis of the demographics, clinical variables, and CT abnormalities, headache (OR ¼ 2.09, 95% CI ¼ 1.04–4.21, p ¼ 0.038), seizure (OR ¼ 5.64, 95% CI ¼ 1.55–20.54, p ¼ 0.009), the presence of subarachnoid haemorrhage on CT (OR ¼ 3.67, 95% CI ¼ 1.46–9.24, p ¼ 0.006) and 6-hour S100B concentration (OR ¼ 2.22, 95% CI ¼ 1.15–4.28, p ¼ 0.017) were independently significant predictors of the outcome. Conclusions: Outcome prediction using baseline characteristics (post-traumatic headache and seizure), CT and laboratory findings (6-hour S100B) were valuable factors for identification of the individual MTBI patient at risk for developing PCS 1 month after the injury.
Computed tomography, outcome, post-concussion syndrome, prognosis, S100 protein, traumatic brain injury
Introduction Traumatic brain injury is the cause of one third to one half of all trauma deaths and the leading cause of disability in people under 40 [1,2]. The injury is one of the major causes of persisting neurobehavioural disorders, especially in minor head injuries [3]. Mild traumatic brain injury (MTBI) accounts for 90% of traumatic brain injuries, with increasing prevalence in the world, significant socioeconomic implications and considerable morbidity [4–6]. Despite the absence of any abnormalities on traditional neuroradiologic examinations, a substantial number of patients complain about post-traumatic neuropsychological dysfunction or postconcussional symptoms [7]. Neuropsychiatric sequelae such as persistent headaches, nausea, memory impairment, motor impairment and personality changes may be identified clinically, but intracranial abnormalities in neuroimaging studies rarely reveal consistent brain changes to explain these problems [8]. Symptoms Correspondence: Shadi Asadollahi, MD, School of Medicine, Shahid Beheshti University of Medical Sciences, Daneshju Blv, Chamran Hwy, Tehran, Iran. Tel: +98-912 770 91 49. Fax: +98-21-552 037 97. E-mail: [email protected]; [email protected]
History Received 14 March 2014 Revised 4 July 2014 Accepted 20 July 2014 Published online 10 September 2014
associated with MTBI are difficult to quantify and qualityof-life may be significantly impaired. Emergency physicians treating the patients often make therapeutic decisions based on their assessment of prognosis. Timely management decisions are critical in optimizing outcomes of MTBI and identifying patients under risk of developing post-concussion syndrome (PCS). Therefore, knowledge of the demographic, clinical, biochemical and radiological parameters related to the outcome is essential [9–11]. During the past decade, neurobiochemical markers of brain damage have gained increasing interest both in experimental and clinical neurotraumatology [12, 13]. Recently, protein S100B has attained growing attraction in clinical research due to commercial availability and detectability in serum samples [8]. Increased concentration of S100B in serum and cerebrospinal fluid has been reported to be markers of cell damage in the human central nervous system (CNS) after MTBI [13–16]. This biochemical marker is a part of a family of diverse Ca2+ binding proteins, the cellular synthesis of which has predominantly been localized in astroglial and Schwann cells [17]. Although early increased S100B concentration in serum seemed to predict neuropsychological dysfunction [8, 17, 18], few studies have been published on prognostic effects of
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primary clinical presentations and biochemical markers on PCS after MTBI. The aim of the present study was to identify clinical symptoms, a biochemical marker and imaging findings—a combination of variables—at first presentation that are predictive of the risk of PCS 1 month following MTBI. This study also analysed the association between S100B concentrations and clinical symptoms and intracranial pathologies as demonstrated in primary computed tomography (CT) imaging.
Methods
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Study design and setting The authors performed a prospective, observational study of patients with isolated MTBI presenting to the Emergency Department (ED) of a level I trauma centre with a referral area of 7.8 million inhabitants. This study was reviewed and approved by a Research Review Board. Written informed consent was obtained from all the patients or their relatives before the investigation. The study was carried out according to the principles of the Declaration of Helsinki.
Brain Inj, 2015; 29(1): 33–40
presence of headache and coagulopathy in the ED, the presence of seizure and vomiting at the trauma scene, the concentration of biochemical marker (S100B) in serum taken at 3 and 6 hours after the trauma and brain CT findings characteristics: skull fracture, epidural haematoma (EDH), subdural haematoma (SDH) subarachnoid haemorrhage (SAH), intracranial haemorrhage (ICH), brain oedema and cerebral contusion. Biochemical analysis Venous blood samples were taken from the cubital vein at the first 3 and 6 hours after the trauma event. Blood was allowed to clot and was centrifuged (1000 rpm for 10 minutes) within 30 minutes after sampling. Serum was frozen at 78 C and stored for analysis. The concentrations of S100B were measured using a fully-automated electrochemoluminometric immunoassay (Elecsys S100Õ ; Roche Diagnostics, Penzberg, Germany) with a detection limit of 0.005 ng mL1. Outcome measures
Between July–October 2013, all consecutive patients admitted to the ED with diagnosis of MTBI were enrolled in the study. Inclusion criteria included patients who: (1) were older than 15 years; (2) were presented to the ED within 2 hours after the trauma; and (3) had sustained a blunt traumatic brain injury due to accidental or non-accidental trauma. According to the guidelines proposed by the European Federation of Neurological Societies (EFNS) [19], the patients were considered to be affected by MTBI if they were presented with: (1) a GCS score of 13–14; (2) a GCS score of 15 with loss of consciousness (LOC) 530 minutes, post-traumatic amnesia (PTA)51 hour; or (3) a GCS score of 15 without LOC or PTA. Patients were excluded if they suffered from polytrauma with Injury Severity Score (ISS) 16 and intoxication with alcohol or drugs. Additionally, patients with previous history of TBI and CNS surgery, history of psychiatric disease or neurological disease (e.g. multiple sclerosis, cerebral tumour, epilepsy, stroke, serious mental disease) and alcohol abuse were excluded. This study also excluded patients who died in the ED.
Outcome variables were collected at 1-month follow-up interviews including neuropsychologic status relevant to PCS definition. In the event that the subject could not attend this clinic visit, due to distance or convenience, all efforts were made by the neuropsychologists to obtain a home visit for evaluation or, at last resort, a telephone interview with the subject or the subject’s relatives. The standardized questionnaire completed by two neuropsychologists and the interviewers were not aware of the study purpose and design. The Rivermead Post Concussion Symptoms Questionnaire (RPQ), a previously validated telephone survey tool, was used to elicit PCS symptoms [20]. PCS was defined according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria [21]. The syndrome was considered to be present if three or more of the symptoms listed in the RPQ were present. This questionnaire contains questions on the following symptoms which are most commonly experienced after MTBI, not present pre-injury: headache, dizziness, nausea and/or vomiting, noise sensitivity, sleep disturbance, easy fatigability, being irritable, feeling depressed, feeling frustrated, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision and restlessness.
Potential predictive variables
Statistical analysis
On admission to the trauma ED, patients were initially evaluated, resuscitated (with crystalloids) and underwent care management according to EFNS guidelines and CT scanning within 6 hours after the trauma [19]. The subjects were assessed by emergency physicians and neurosurgeons and data were collected prospectively by trained emergency physicians. The following parameters were recorded for all patients on admission: demographics (age at injury, gender), time and mechanism of injury, type of injury (road traffic accident, assault, fall or other), prior consumption of alcohol and drugs, duration of LOC and PTA and physical examination data (initial GCS score, area of skull struck, presence of laceration or haematoma). Additional information were the
Statistical analyses were performed using SPSS 22.0 software (SPSS Inc., Chicago, IL) for Windows. A univariate analysis was used to test the ability of the primary factors to predict the risk of PCS. Patients were classified into a PCS group and a non-PCS group. Categorical variables were compared by means of Fischer’s exact test or chi-square test, as appropriate. Continuous variables were compared between PCS and nonPCS group using two-sample t-test. For data without a symmetric distribution, values in two groups were compared with Mann–Whitney U-test. If the variables follow a normal distribution, mean and standard deviation (SD) was used, while asymmetric distributions were presented as median and interquartile range (25–75%). Normality of the variables
Study setting and population
DOI: 10.3109/02699052.2014.948068
was verified using Kolmogorov-Smirnov test. Multivariate Logistic regression adjusted for possible confounding variables was used to estimate the associations between PCS after 1 month and possible predictive variables. All tests of significance were two-sided and a p value50.05 was considered significant.
Results
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Characteristics of the patients Between July–October 2013, a total of 488 consecutive patients (331 males, 157 females) with MTBI were admitted to the trauma ED. Of all, 176 patients were included in the study and 312 did not meet the inclusion criteria on primary assessment (Figure 1). Table I shows results from the univariate analysis of demographic and clinical symptoms at presentation. The mean age was 35.82 ± 15.8 years. The causes of head injury were as follows: motor vehicle crashes (49.1%), motorcycle accidents (20.0%), assault (12.1%), fall from height (10.3%) and miscellaneous (8.5%). The time duration since trauma to ED admission was 35.84 ± 25.2 minutes. No correlation was observed between age at injury, gender, duration from injury to ED admission and the proportion of patients with PCS at 1-month follow-up. Acute clinical findings and outcome assessment Follow-up was attempted in all patients. Of the 176 MTBI cases enrolled, telephone follow-up data were available for 165; thus, these patients’ data were used for final analysis. None of the subjects had died or undergone operative
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procedure at the regional neurosurgical centre within the follow-up period. Eighty-one (49%) patients reported the persistence of three or more symptoms at 1-month follow-up and qualified for the diagnosis of PCS. The post-traumatic headache, PTA, LOC, vomiting, seizure and coagulopathy were reported by 69.0%, 61.8%, 54.5%, 56.7%, 10.9% and 2.4%, respectively. In univariate analysis, the proportion of patients with headache was significantly higher in the PCS group (63/81) compared with the non-PCS group (51/84, p ¼ 0.018). There was a significant correlation between the post-traumatic seizure and PCS after 1 month. The presence of other clinical symptoms (PTA, LOC, vomiting and coagulopathy) was not indicative of outcome at 1 month (Table I). After multivariate analysis of the demographic, clinical and CT variables, headache (OR ¼ 2.09, 95% CI ¼ 1.04–4.21, p ¼ 0.038) and seizure (OR ¼ 5.64, 95% CI ¼ 1.55–20.54, p ¼ 0.009) proved to be outcome predictors. Computed tomography The head CT scanning was performed on all included patients. Positive findings were as follows: skull fracture (n ¼ 87), SAH (n ¼ 51), brain oedema (n ¼ 27), ICH (n ¼ 24), subdural (n ¼ 21) and epidural (n ¼ 21) haematoma and cerebral contusion (n ¼ 6). Multivariate analysis of potential CT predictors revealed that only the presence of SAH on CT scanning was a predictor of the outcome (OR ¼ 3.67, 95% CI ¼ 1.46–9.24, p ¼ 0.006). The head CT findings also correlated positively with the S100B values at 3 and 6 hours following MTBI (Mann–Whitney U-test, p50.001 for both S100B values).
Figure 1. Flow diagram of included patients. TBI, traumatic brain injury; CNS, central nervous system.
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Table I. Patients’ demographic and clinical characteristics at hospital admission.
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No. (%) of patients Characteristics
PCS (n ¼ 81)
Non-PCS (n ¼ 84)
p Value
Age, years Gender, M/F Time duration from injury to admission, minutes Mechanism of injury Motor vehicle accident Motorcycle accident Assault Fall from heighta Other Post-traumatic acute symptoms Headache PTA LOC Vomiting Seizure Coagulopathy
36.48 ± 17.3 54/27 36.37 ± 23.6
35.18 ± 14.3 60/24 35.33 ± 26.8
0.600 0.508 0.227
37 (45.6) 19 (23.4) 9 (11.1) 7 (8.6) 9 (11.1)
44 14 11 10 5
(52.3) (16.6) (13.0) (11.9) (5.9)
0.389 0.276 0.696 0.491 0.235
63 55 47 51 15 3
51 47 43 42 3 1
(60.7) (55.9) (51.2) (50.0) (3.5) (1.2)
0.018* 0.325 0.712 0.093 0.002* 0.294
(77.7) (67.9) (58.0) (62.9) (18.5) (3.7)
a
More than 1 metre or five stairs. Plus/minus values are mean ± SD. PCS, post-concussion syndrome; PTA, post-traumatic amnesia; LOC, loss of consciousness. *p50.05.
Median values and interquartile range of the S100B concentrations in plasma by the presence of intracranial lesions are given in Figure 2. The highest post-traumatic S100B median value at 3 hours was found in those showing ICH on CT scan at 0.90 (0.22–1.06) ng mL1 and the lowest value was found in those with cerebral contusion at 0.06 (0.03–0.08 ng mL1, p ¼ 0.003). Thus, the highest S100B levels occurred in the patients with the most severe brain injury. Similar results were found for S100B concentration at 6 hours after injury. The median concentration of S100B was 2.05 (0.53–3.4) ng mL1 in patients with ICH and 0.25 (0.09–0.32) ng mL1 in those with contusion (p50.001). Among all CT findings, the presence of SAH and ICH independently increased serum S100B concentrations at 3 and 6 hours in patients with MTBI. Compared with patients without SAH on CT, patients with this finding had a higher median concentration of S100B protein at 3 hours (0.20 [0.12–0.34] vs. 0.76 [0.27–0.91] ng mL1, p ¼ 0.001) and 6 hours after the head trauma (0.41 [0.28–0.99] vs. 1.05 [0.57–1.75] ng mL1, p50.001). The corresponding median values and interquartile range in those with ICH on CT were 0.23 (0.12–0.76) vs. 0.90 (0.22–1.06) ng mL1 for 3hour S100B (p ¼ 0.001) and 0.48 (0.28–1.05) vs. 2.05 (0.53– 3.41) ng mL1 for 6-hour S100B concentration (p50.001). Serum levels of S-I00 protein and outcome assessment Seventy-eight per cent (n ¼ 129) of the S100B concentrations were elevated (412 ng mL1) concerning the first samples taken at 3 hours post-trauma. Univariate regression analysis revealed a significant difference between the PCS group and non-PCS group with regard to 3-hour S100B concentration (0.54 [0.17–0.90] vs. 0.19 [0.10–0.35] ng mL 1, p ¼ 0.005). Similarly, patients with PCS had a higher 6-hour S100B concentration of 0.95 (0.41–1.85) ng mL1 compared with patients without PCS at 0.37 (0.18 ± 1.02 ng mL1, p50.001). On multivariate analysis of S100B concentration,
a positive correlation was observed between the 6-hour protein concentration and PCS risk. The resultant adjusted OR was 2.22 (95% CI ¼ 1.15–4.28, p ¼ 0.017). Additional evaluation was conducted to investigate the association of initial serum levels of S100B protein with acute clinical symptoms on admission. Similar results were found regarding the presence of seizure and vomiting after the trauma. These results are presented in Figures 3 and 4.
Discussion Outcome assessment after MTBI is a necessary first step toward secondary prevention of the disability associated with head injuries. A reliable estimate of neuropsychological function and identification of high risk MTBI cases before PCS development can help patients and healthcare professionals develop a plan that will aid the patients’ recovery to the greatest extent possible. The prediction can motivate more intensive and targeted intervention [22, 23]. This is the first attempt to predict PCS after acute MTBI according to clinical admission characteristics, CT admission variables and S100B concentration at 3 and 6 hours following a head injury. According to the DSM-IV criteria used in the present study, 49% of patients developed PCS 1 month after MTBI. Of the clinical variables, PTA (present in 62% of patients), LOC (54.5%), vomiting (56.3%) and coagulopathy (2.4%) did not show predictive value after univariate analysis. The percentage of the patients with LOC and/or PTA appears to be similar to that found in the literature, where LOC was present in 47.2–64.4% [24–26] and PTA was present in 69.2–73.7% of MTBI patients [27]. The only clinical variables that were most independently predictive of PCS outcome included headache at admission and seizure after the injury. In the study of De Kruijk et al. [28] the presence of symptoms in ED (headache, dizziness, nausea, vomiting and neck pain) and biochemical markers (neurone specific enolase and S100B) in serum were assessed. The purpose of this study was to
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Figure 2. Box-and-whisker plot showing distributions of serum level of S100B protein (ng mL1) at 3 and 6 hours post-trauma in patients with and without intracranial lesions. The boxes represent the 25th to 75th percentiles and horizontal lines within the box represent median values. The whiskers represent the lowest and highest value in the 25th percentile minus 1.5IQR and 75th percentile plus 1.5IQR regions, respectively. *p50.05. O, Outlier; ?, Extreme score.
Figure 3. Box-and-whisker plots showing distributions of serum 3-hour S100B levels (ng mL1) for PCS predictors. The boxes represent the 25th to 75th percentiles and horizontal lines within the box represent median values. The whiskers represent the lowest and highest value in the 25th percentile minus 1.5IQR and 75th percentile plus 1.5IQR regions, respectively. *p50.05. Significant results were found for patients with headache, LOC and seizure following the trauma. O, Outlier; ?, Extreme score; PTA, post-traumatic amnesia; LOC, loss of consciousness.
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Figure 4. Box-and-whisker plots showing distributions of serum 6-hour S100B levels (ng mL1) for PCS predictors. The boxes represent the 25th to 75th percentiles and horizontal lines within the box represent median values. The whiskers represent the lowest and highest value in the 25th percentile minus 1.5IQR and 75th percentile plus 1.5IQR regions, respectively. *p50.05. Significant results were found for patients with headache, LOC, vomiting and seizure following the trauma. O, Outlier; ?, Extreme score; PTA, post-traumatic amnesia; LOC, loss of consciousness.
determine possible predictive variables for the severity of post-traumatic complaints (headache, dizziness, drowsiness, loss of memory and concentration problems) 6 months after the trauma. After adjustment for baseline variables, they observed that at least 2-fold increased severity of all of posttraumatic complaints was reported by those patients reporting headache in ED. In this study, several individual CT characteristics were evaluated regarding their predictive value for 1-month PCS after MTBI. After multivariate regression analysis, only one independent predictor of outcome was found on CT scanning (the presence of SAH). This study also indicated that brain lesions including EDH, SAH and ICH independently increased serum S100B in the cases. These results are inconsistent with the Raabe et al. [29] study. They investigated the association between initial levels of serum S100B protein and the severity of radiologically visible brain damage and outcome after traumatic head injury. Traumatic SAH was found in 26 (59%) of the initial 44 CT scans. Moreover, serum S100B was significantly increased in patients with SAH compared with those without SAH (1.0 mg L1 vs. 0.12 mg L1, p50.001, Mann-Whitney U-test). With regard to the diagnostic value of S100B measurement in serum, Biberthaler et al. [30] published a prospective multi-centre study on 1309 patients with minor head injury. They reported that with a cut-off point of 0.10 ng mL1 for S100B, patients with intracranial lesions were identified with sensitivity and a specificity level of 99% and 30%, respectively. This study used a cut-off value of 0.12 ng mL1, as recommended previously on the basis of ROC (Receiver Operating Characteristics) curve analysis
[31, 32]. These results are also consistent with findings by Egea-Guerrero et al. [33] who evaluated the efficacy of S100B protein in detecting intracranial lesions on CT. The results indicated a positive correlation between the presence of pathological CT findings and high levels of S100B (p ¼ 0.007). The median value of S100B serum level in patients with intracranial lesions was 0.220 ng mL1 compared with 0.350 ng mL1 in cases without the lesions. In this series, a cut-off limit of 0.130 ng m L1 was proved to be the best point with 100% sensitivity. The data also showed that a higher cut-off, at 0.130 ng mL1, increases specificity up to 32.81%. Several biochemical substances have been studies to find a specific neuronal marker indicating cell damage. Recently, measurement of S100B, released into serum of patients with head injury, has been discussed as a valuable screening tool of mild cerebral injuries [34]. A positive correlation noted between S100B and an unfavourable outcome in brain injury patients, suggested that S100B may also have some prognostic significance [35–37]. In MTBI patients, a poor neuropsychological outcome and the presence of PCS have been reported to be associated with elevated S100B concentration [27, 38, 39]. It has been shown in this prospective study that early serum levels of the protein (3 and 6 hours) after MTBI seemed to be predictive concerning the outcome. These results are in agreement with the findings of Scandinavian studies which showed that early post-traumatic S100B concentrations were correlated with long-term neuropsychological disorders [7, 15]. Moreover, several previous studies showed significantly worse neuropsychological outcome with higher S100B levels 1 month or sooner from the
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time of injury [27, 40, 41]. Recently, Ingebrigtsen et al. [15] found a positive correlation between serum S100B and PCS in 50 patients with minor head injury and normal CT scans. The same authors reported increased serum levels in four of 24 patients with minor head injury and magnetic resonance imaging demonstrating contusion in two cases [18]. Another study found significantly higher initial S100B values in patients with poor outcome at discharge [42]. To date, several factors were determined to contribute to the development of PCS after a head trauma. Main groups include: pre-injury factors (demographics, psychosocial, cognitive and socioeconomic factors); injury factors (mechanism of injury, location and extent of brain injury); and post-injury factors (drugs, hormonal state and neural plasticity and repair) [43]. Serum biomarkers after MTBI presumably reflect some aspect of brain trauma and, thus, provide information on only one of these contributing factors. A combination of clinical elements and biochemical markers are necessary to develop a comprehensive decision plan that more accurately predicts PCS and identifies high risk patients most likely to benefit from early follow-up with a specialist. Several recent studies have attempted to create clinical prediction rules incorporating both clinical predictors and biochemical markers [28, 44]. It is in this manner that biomarkers may find utility in mild TBI. Finally, for TBI researchers, the identification of these patients permits controlled trials of interventions designed to reduce the incidence and duration of PCS after the MTBI but before PCS symptoms begin. These interventions which range from central nervous system stimulant therapy to behavioural therapy have the potential to improve the lives of many and reduce the economic burden of PCS on the community. In the present study, there are several limitations which need to be considered. The primary limitation is the relatively small sample size, which may have resulted in an under-estimate of statistical significance of some variables. Although less likely, it is also possible that some of the variables would contribute to outcome differently, with a larger sample size resulting in less significance for some associations. Other potential limitations include the short follow-up period and the fact that this study is from a single institution, which may introduce institutional bias in relation to patient selection and measurement of post-traumatic predictors. In this observational study, results may be confounded by unmeasured factors. This study attempted to include main potential predictors, although comprehensive evaluation of injury variables, serial measurements of S100B and other biomarkers and using sophisticated brain imaging techniques (functional MRI, PET, and SPECT scans) may allow drawing more comprehensive conclusion. The goal of this study was to find a set of clinical, imaging and laboratory findings that could be used to predict PCS in patients with mild head injury. The results suggested that such patients can be identified by the presence of one or more of the following findings: post-traumatic headache, seizure and SAH on CT scan. Moreover, the present data revealed that the initial measurement of post-traumatic release of S100B protein as a neurobiochemical marker of
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brain damage might be a helpful tool in identifying patients who run a risk of PCS. It is thought that these findings are encouraging for further studies on a larger population to evaluate the results and the prognostic significance of demographics, clinical factors and other biomarkers in more detail and, in other data sets, to follow-up this hypothesisgenerating finding.
Acknowledgements The authors thank the people who took part in this study. The study was financially supported by a grant from Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran (Iran).
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Bruns Jr J, Hauser WA. The epidemiology of traumatic brain injury: A review. Epilepsia 2003;44(Suppl 10)2–10. 2. Fleminger S, Ponsford J. (2005) Long term outcome after traumatic brain injury. British Medical Journal 2005;331:1419–1420. 3. Consensus conference. Rehabilitation of persons with traumatic brain injury. NIH Consensus Development Panel on Rehabilitation of Persons with Traumatic Brain Injury. Journal of the American Medical Association 1999;282:974–983. 4. Kraus JF, McArthur DL, Silverman TA, Jayaraman M. Epidemiology of brain injury. In: Narayan RK, Wilberger JE, and Povlishock JT, editors. Neurotrauma. New York: McGraw-Hill; 1996. p 13–30. 5. Thornhill S, Teasdale GM, Murray GD, McEwen J, Roy CW, Penny KI. Disability in young people and adults one year after head injury: Prospective cohort study. British Medical Journal 2000;320: 1631–1635. 6. Meerhoff SR, de Kruijk JR, Rutten J, Leffers P, Twijnstra A. Incidence of traumatic head or brain injuries in catchment area of Academic Hospital Maastricht in 1997. Nederlands Tijdschrift voor Geneeskunde 1997;144:1915–1918. 7. Waterloo K, Ingebrigtsen T, Romner B. Neuropsychological function in patients with increased serum levels of protein S-100 after minor head injury. Acta Neurochirurgica (Wien) 1997;139: 26–31. 8. Herrmann M, Curio N, Jost S, Grubich C, Ebert AD, Fork ML, Synowitz H. Release of biochemical markers of damage to neuronal and glial brain tissue is associated with short and long term neuropsychological outcome after traumatic brain injury. Journal of Neurology, Neurosurgery & Psychiatry 2001;70:95–100. 9. Sharma R, Laskowitz DT. Biomarkers in traumatic brain injury. Current Neurology & Neuroscience Reports 2012;12:560–569. 10. Perel P, Wasserberg J, Ravi RR, Shakur H, Edwards P, Roberts I. Prognosis following head injury: A survey of doctors from developing and developed countries. Journal of Evaluation in Clinical Practice 2007;13:464–465. 11. Murray LS, Teasdale GM, Jennett B, Kelly D, Murray GD, Miller JD, Jennett B, Miller JD, Pickard JD, Shaw MD, et al. Does prediction of outcome alter patient management? The Lancet 1993; 341:1487–1491. 12. Ha˚rdemark HG, Ericsson N, Kotwica Z, Rundstro¨m G, MendelHartvig I, Olsson Y, Pa˚hlman S, Persson L. S-100 protein and neuron-specific enolase in CSF after experimental traumatic or focal ischemic brain damage. Journal of Neurosurgery 1989;71: 727–731. 13. Raabe A, Grolms C, Sorge O, Zimmermann M, Seifert V. Serum S-100B protein in severe head injury. Neurosurgery 1999;45: 477–483. 14. Skogseid IM, Nordby HK, Urdal P, Paus E, Lilleaas F. Increased serum creatine kinase BB and neuron specific enolase following
40
15.
16.
17. 18.
Brain Inj Downloaded from informahealthcare.com by Thomas Jefferson University on 12/26/14 For personal use only.
19.
20.
21. 22.
23. 24. 25.
26.
27. 28.
29.
K. Heidari et al. head injury indicates brain damage. Acta Neurochirurgica (Wien) 1992;1:106–111. Ingebrigtsen T, Romner B, Trumpy JH. Management of minor head injury: The value of early computed tomography and serum protein S-100 measurements. Journal of Clinical Neuroscience 1997;4: 29–33. de Kruijk JR, Leffers P, Menheere PP, Meerhoff S, Twijnstra A. S-100B and neuron-specific enolase in serum of mild traumatic brain injury patients. A comparison with health controls. Acta Neurologica Scandinavica 2001;103:175–179. Heizmann CW, Fritz G, Scha¨fer BW. S100 proteins: Structure, functions and pathology. Frontiers in Bioscience 2007;7: 1356–1368. Ingebrigtsen T, Waterloo K, Jacobsen EA, Langbakk B, Romner B. Traumatic brain damage in minor head injury: Relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioral outcome. Neurosurgery 1999;45:468–475. Vos PE, Battistin L, Birbamer G, Gerstenbrand F, Potapov A, Prevec T, Stepan ChA, Traubner P, Twijnstra A, Vecsei L, von Wild K; European Federation of Neurological Societies. EFNS guideline on mild traumatic brain injury: Report of an EFNS task force. European Journal of Neurology 2002;9:207–219. King NS, Crawford S, Wenden FJ, Moss NE, Wade DT. The Rivermead Post Concussion Symptoms Questionnaire: A measure of symptoms commonly experienced after head injury and its reliability. Journal of Neurology 1995;242:587–592. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. [Appendix B]. Washington, DC: APA; 1994. p 704–706. NIH Consensus Development Panel on Rehabilitation of Persons with Traumatic Brain Injury. Rehabilitation of persons with traumatic brain injury. Journal of the American Medical Association 1999;282:974–983. Kushner D. Mild traumatic brain injury: Toward understanding manifestations and treatment. Archives of Internal Medicine 1998; 158:1617–1624. Borczuk P. Predictors of intracranial injury in patients with mild head trauma. Annals of Emergency Medicine 1995;25:731–736. Smits M, Dippel DW, de Haan GG, Dekker HM, Vos PE, Kool DR, Nederkoorn PJ, Hofman PA, Twijnstra A, Tanghe HL, Hunink MG. External validation of the Canadian CT Head Rule and the New Orleans Criteria for CT scanning in patients with minor head injury. Journal of the American Medical Association 2005;294: 1519–1525. Stiell IG, Clement CM, Rowe BH, Schull MJ, Brison R, Cass D, Eisenhauer MA, McKnight RD, Bandiera G, Holroyd B, et al. Comparison of the Canadian CT Head Rule and the New Orleans Criteria in patients with minor head injury. Journal of the American Medical Association 2005;294:1511–1518. Savola O, Hillbom M. Early predictors of post-concussion symptoms in patients with mild head injury. European Journal of Neurology 2005;10:175–181. De Kruijk JR, Leffers P, Menheere PP, Meerhoff S, Rutten J, Twijnstra A. Prediction of post-traumatic complaints after mild traumatic brain injury: Early symptoms and biochemical markers. Journal of Neurology, Neurosurgery & Psychiatry 2002;73: 727–732. Raabe A, Grolms C, Keller M, Do¨hnert J, Sorge O, Seifert V. Correlation of computed tomography findings and serum brain damage markers following severe head injury. Acta Neurochirurgica (Wien) 1998;140:787–791.
Brain Inj, 2015; 29(1): 33–40
30. Biberthaler P, Linsenmeier U, Pfeifer KJ, Kroetz M, Mussack T, Kanz KG, Hoecherl EF, Jonas F, Marzi I, Leucht P, et al. Serum S-100B concentration provides additional information for the indication of computed tomography in patients after minor head injury: A prospective multicenter study. Shock 2006;25:446–453. 31. Biberthaler P, Mussack T, Wiedemann E, Kanz KG, Mutschler W, Linsenmaier U, Pfeifer KJ, Gippner-Steppert C, Jochum M. Rapid identification of high-risk patients after minor head trauma (MHT) by assessment of S-100B: Ascertainment of a cut-off level. European Journal of Medical Research 2002;7:164–170. 32. Zongo D, Ribe´reau-Gayon R, Masson F, Laborey M, Contrand B, Salmi LR, Montaudon D, Beaudeux JL, Meurin A, Dousset V, et al. S100-B protein as a screening tool for the early assessment of minor head injury. Annals of Emergency Medicine 2012;59: 209–218. 33. Egea-Guerrero JJ, Revuelto-Rey J, Murillo-Cabezas F, Munoz-Sanchez MA, Vilches-Arenas A, Sanchez-Linares P, Dominguez-Roldan JM, Leon-Carrion J. Accuracy of the S100 b protein as a marker of brain damage in traumatic brain injury. Brain Injury 2012;26:76–82. 34. Biberthaler P, Mussack T, Wiedemann E, Kanz KG, Koelsch M, Gippner-Steppert C, Jochum M. Evaluation of S-100b as a specific marker for neuronal damage due to minor head trauma. World Journal of Surgery 2001;25:93–97. 35. Raabe A, Grolms C, Sorge O, Zimmermann M, Seifert V. Serum S-100B protein in severe head injury. Neurosurgery 1999;45: 477–483. 36. Woertgen C, Rothoerl RD, Metz C, Brawanski A. Comparison of clinical, radiologic, and serum marker as prognostic factors after severe head injury. Journal of Trauma 1999;47:1126–1130. 37. Raabe A, Grolms C, Seifert V. Serum markers of brain damage and outcome prediction in patients after severe head injury. British Journal of Neurosurgery 1999;13:56–59. 38. Herrmann M, Curio N, Jost S, Grubich C, Ebert AD, Fork ML, Synowitz H. Release of biochemical markers of damage to neuronal and glial brain tissue is associated with short and long term neuropsychological outcome after traumatic brain injury. Journal of Neurology, Neurosurgery & Psychiatry 2001;70:95–100. 39. Ingebrigtsen T, Romner B, Trumpy JH. Management of minor head injury: The value of early computed tomography and serum protein S-100 measurements. Journal of Clinical Neuroscience 1997;4: 29–33. 40. Townend WJ, Guy MJ, Pani MA, Martin B, Yates DW. Head injury outcome prediction in the emergency department: A role for protein S-100B? Journal of Neurology, Neurosurgery & Psychiatry 2002; 73:542–546. 41. Stranjalis G, Korfias S, Papapetrou C, Kouyialis A, Boviatsis E, Psachoulia C, Sakas DE. Elevated serum S-100B protein as a predictor of failure to short-term return to work or activities after mild head injury. Journal of Neurotrauma 2004;21:1070–1075. 42. Woertgen C, Rothoerl RD, Holzschuh M, Metz C, Brawanski A. Comparison of serial S-100 and NSE serum measurements after severe head injury. Acta Neurochirurgica (Wien) 1997;139: 1161–1164. 43. Ryan LM, Warden DL. Post concussion syndrome. International Review of Psychiatry 2003;15:310–316. 44. Savola O, Pyhtinen J, Leino TK, Siitonen S, Niemela¨ O, Hillbom M. Effects of head and extracranial injuries on serum protein S100B levels in trauma patients. Journal of Trauma 2004;56: 1229–1234.
ORIGINAL ARTICLE
Prediction of neuropsychological outcome after mild traumatic brain injury using clinical parameters, serum S100B protein and findings on computed tomography Kamran Heidari1, Shadi Asadollahi2, Morteza Jamshidian3, Shohreh Nasiri Abrishamchi3, & Mahdi Nouroozi3 Department of Emergency Medicine, Loghman Hakim Hospital, 2School of Medicine, and 3Department of Emergency Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Abstract
Keywords
Primary objective: To identify if demographics, clinical and computed tomographic (CT) characteristics at first presentation and S100B concentrations at 3 and 6 hours after mild traumatic brain injury (MTBI) predict the development of post-concussion syndrome (PCS) after 1 month. Research design and methods: All consecutive MTBI patients (Glasgow Coma Scale [GCS] score 13–15) admitted to the Emergency Department aged older than 15 were included in this prospective, observational study. Outcome was assessed using a Rivermead Post-Concussion Symptoms Questionnaire to identify the patients with and without PCS 1 month after the injury. Main outcomes and results: A total of 176 patients with isolated MTBI were included in the study. After multivariate analysis of the demographics, clinical variables, and CT abnormalities, headache (OR ¼ 2.09, 95% CI ¼ 1.04–4.21, p ¼ 0.038), seizure (OR ¼ 5.64, 95% CI ¼ 1.55–20.54, p ¼ 0.009), the presence of subarachnoid haemorrhage on CT (OR ¼ 3.67, 95% CI ¼ 1.46–9.24, p ¼ 0.006) and 6-hour S100B concentration (OR ¼ 2.22, 95% CI ¼ 1.15–4.28, p ¼ 0.017) were independently significant predictors of the outcome. Conclusions: Outcome prediction using baseline characteristics (post-traumatic headache and seizure), CT and laboratory findings (6-hour S100B) were valuable factors for identification of the individual MTBI patient at risk for developing PCS 1 month after the injury.
Computed tomography, outcome, post-concussion syndrome, prognosis, S100 protein, traumatic brain injury
Introduction Traumatic brain injury is the cause of one third to one half of all trauma deaths and the leading cause of disability in people under 40 [1,2]. The injury is one of the major causes of persisting neurobehavioural disorders, especially in minor head injuries [3]. Mild traumatic brain injury (MTBI) accounts for 90% of traumatic brain injuries, with increasing prevalence in the world, significant socioeconomic implications and considerable morbidity [4–6]. Despite the absence of any abnormalities on traditional neuroradiologic examinations, a substantial number of patients complain about post-traumatic neuropsychological dysfunction or postconcussional symptoms [7]. Neuropsychiatric sequelae such as persistent headaches, nausea, memory impairment, motor impairment and personality changes may be identified clinically, but intracranial abnormalities in neuroimaging studies rarely reveal consistent brain changes to explain these problems [8]. Symptoms Correspondence: Shadi Asadollahi, MD, School of Medicine, Shahid Beheshti University of Medical Sciences, Daneshju Blv, Chamran Hwy, Tehran, Iran. Tel: +98-912 770 91 49. Fax: +98-21-552 037 97. E-mail: [email protected]; [email protected]
History Received 14 March 2014 Revised 4 July 2014 Accepted 20 July 2014 Published online 10 September 2014
associated with MTBI are difficult to quantify and qualityof-life may be significantly impaired. Emergency physicians treating the patients often make therapeutic decisions based on their assessment of prognosis. Timely management decisions are critical in optimizing outcomes of MTBI and identifying patients under risk of developing post-concussion syndrome (PCS). Therefore, knowledge of the demographic, clinical, biochemical and radiological parameters related to the outcome is essential [9–11]. During the past decade, neurobiochemical markers of brain damage have gained increasing interest both in experimental and clinical neurotraumatology [12, 13]. Recently, protein S100B has attained growing attraction in clinical research due to commercial availability and detectability in serum samples [8]. Increased concentration of S100B in serum and cerebrospinal fluid has been reported to be markers of cell damage in the human central nervous system (CNS) after MTBI [13–16]. This biochemical marker is a part of a family of diverse Ca2+ binding proteins, the cellular synthesis of which has predominantly been localized in astroglial and Schwann cells [17]. Although early increased S100B concentration in serum seemed to predict neuropsychological dysfunction [8, 17, 18], few studies have been published on prognostic effects of
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primary clinical presentations and biochemical markers on PCS after MTBI. The aim of the present study was to identify clinical symptoms, a biochemical marker and imaging findings—a combination of variables—at first presentation that are predictive of the risk of PCS 1 month following MTBI. This study also analysed the association between S100B concentrations and clinical symptoms and intracranial pathologies as demonstrated in primary computed tomography (CT) imaging.
Methods
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Study design and setting The authors performed a prospective, observational study of patients with isolated MTBI presenting to the Emergency Department (ED) of a level I trauma centre with a referral area of 7.8 million inhabitants. This study was reviewed and approved by a Research Review Board. Written informed consent was obtained from all the patients or their relatives before the investigation. The study was carried out according to the principles of the Declaration of Helsinki.
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presence of headache and coagulopathy in the ED, the presence of seizure and vomiting at the trauma scene, the concentration of biochemical marker (S100B) in serum taken at 3 and 6 hours after the trauma and brain CT findings characteristics: skull fracture, epidural haematoma (EDH), subdural haematoma (SDH) subarachnoid haemorrhage (SAH), intracranial haemorrhage (ICH), brain oedema and cerebral contusion. Biochemical analysis Venous blood samples were taken from the cubital vein at the first 3 and 6 hours after the trauma event. Blood was allowed to clot and was centrifuged (1000 rpm for 10 minutes) within 30 minutes after sampling. Serum was frozen at 78 C and stored for analysis. The concentrations of S100B were measured using a fully-automated electrochemoluminometric immunoassay (Elecsys S100Õ ; Roche Diagnostics, Penzberg, Germany) with a detection limit of 0.005 ng mL1. Outcome measures
Between July–October 2013, all consecutive patients admitted to the ED with diagnosis of MTBI were enrolled in the study. Inclusion criteria included patients who: (1) were older than 15 years; (2) were presented to the ED within 2 hours after the trauma; and (3) had sustained a blunt traumatic brain injury due to accidental or non-accidental trauma. According to the guidelines proposed by the European Federation of Neurological Societies (EFNS) [19], the patients were considered to be affected by MTBI if they were presented with: (1) a GCS score of 13–14; (2) a GCS score of 15 with loss of consciousness (LOC) 530 minutes, post-traumatic amnesia (PTA)51 hour; or (3) a GCS score of 15 without LOC or PTA. Patients were excluded if they suffered from polytrauma with Injury Severity Score (ISS) 16 and intoxication with alcohol or drugs. Additionally, patients with previous history of TBI and CNS surgery, history of psychiatric disease or neurological disease (e.g. multiple sclerosis, cerebral tumour, epilepsy, stroke, serious mental disease) and alcohol abuse were excluded. This study also excluded patients who died in the ED.
Outcome variables were collected at 1-month follow-up interviews including neuropsychologic status relevant to PCS definition. In the event that the subject could not attend this clinic visit, due to distance or convenience, all efforts were made by the neuropsychologists to obtain a home visit for evaluation or, at last resort, a telephone interview with the subject or the subject’s relatives. The standardized questionnaire completed by two neuropsychologists and the interviewers were not aware of the study purpose and design. The Rivermead Post Concussion Symptoms Questionnaire (RPQ), a previously validated telephone survey tool, was used to elicit PCS symptoms [20]. PCS was defined according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria [21]. The syndrome was considered to be present if three or more of the symptoms listed in the RPQ were present. This questionnaire contains questions on the following symptoms which are most commonly experienced after MTBI, not present pre-injury: headache, dizziness, nausea and/or vomiting, noise sensitivity, sleep disturbance, easy fatigability, being irritable, feeling depressed, feeling frustrated, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision and restlessness.
Potential predictive variables
Statistical analysis
On admission to the trauma ED, patients were initially evaluated, resuscitated (with crystalloids) and underwent care management according to EFNS guidelines and CT scanning within 6 hours after the trauma [19]. The subjects were assessed by emergency physicians and neurosurgeons and data were collected prospectively by trained emergency physicians. The following parameters were recorded for all patients on admission: demographics (age at injury, gender), time and mechanism of injury, type of injury (road traffic accident, assault, fall or other), prior consumption of alcohol and drugs, duration of LOC and PTA and physical examination data (initial GCS score, area of skull struck, presence of laceration or haematoma). Additional information were the
Statistical analyses were performed using SPSS 22.0 software (SPSS Inc., Chicago, IL) for Windows. A univariate analysis was used to test the ability of the primary factors to predict the risk of PCS. Patients were classified into a PCS group and a non-PCS group. Categorical variables were compared by means of Fischer’s exact test or chi-square test, as appropriate. Continuous variables were compared between PCS and nonPCS group using two-sample t-test. For data without a symmetric distribution, values in two groups were compared with Mann–Whitney U-test. If the variables follow a normal distribution, mean and standard deviation (SD) was used, while asymmetric distributions were presented as median and interquartile range (25–75%). Normality of the variables
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was verified using Kolmogorov-Smirnov test. Multivariate Logistic regression adjusted for possible confounding variables was used to estimate the associations between PCS after 1 month and possible predictive variables. All tests of significance were two-sided and a p value50.05 was considered significant.
Results
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Characteristics of the patients Between July–October 2013, a total of 488 consecutive patients (331 males, 157 females) with MTBI were admitted to the trauma ED. Of all, 176 patients were included in the study and 312 did not meet the inclusion criteria on primary assessment (Figure 1). Table I shows results from the univariate analysis of demographic and clinical symptoms at presentation. The mean age was 35.82 ± 15.8 years. The causes of head injury were as follows: motor vehicle crashes (49.1%), motorcycle accidents (20.0%), assault (12.1%), fall from height (10.3%) and miscellaneous (8.5%). The time duration since trauma to ED admission was 35.84 ± 25.2 minutes. No correlation was observed between age at injury, gender, duration from injury to ED admission and the proportion of patients with PCS at 1-month follow-up. Acute clinical findings and outcome assessment Follow-up was attempted in all patients. Of the 176 MTBI cases enrolled, telephone follow-up data were available for 165; thus, these patients’ data were used for final analysis. None of the subjects had died or undergone operative
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procedure at the regional neurosurgical centre within the follow-up period. Eighty-one (49%) patients reported the persistence of three or more symptoms at 1-month follow-up and qualified for the diagnosis of PCS. The post-traumatic headache, PTA, LOC, vomiting, seizure and coagulopathy were reported by 69.0%, 61.8%, 54.5%, 56.7%, 10.9% and 2.4%, respectively. In univariate analysis, the proportion of patients with headache was significantly higher in the PCS group (63/81) compared with the non-PCS group (51/84, p ¼ 0.018). There was a significant correlation between the post-traumatic seizure and PCS after 1 month. The presence of other clinical symptoms (PTA, LOC, vomiting and coagulopathy) was not indicative of outcome at 1 month (Table I). After multivariate analysis of the demographic, clinical and CT variables, headache (OR ¼ 2.09, 95% CI ¼ 1.04–4.21, p ¼ 0.038) and seizure (OR ¼ 5.64, 95% CI ¼ 1.55–20.54, p ¼ 0.009) proved to be outcome predictors. Computed tomography The head CT scanning was performed on all included patients. Positive findings were as follows: skull fracture (n ¼ 87), SAH (n ¼ 51), brain oedema (n ¼ 27), ICH (n ¼ 24), subdural (n ¼ 21) and epidural (n ¼ 21) haematoma and cerebral contusion (n ¼ 6). Multivariate analysis of potential CT predictors revealed that only the presence of SAH on CT scanning was a predictor of the outcome (OR ¼ 3.67, 95% CI ¼ 1.46–9.24, p ¼ 0.006). The head CT findings also correlated positively with the S100B values at 3 and 6 hours following MTBI (Mann–Whitney U-test, p50.001 for both S100B values).
Figure 1. Flow diagram of included patients. TBI, traumatic brain injury; CNS, central nervous system.
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Table I. Patients’ demographic and clinical characteristics at hospital admission.
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No. (%) of patients Characteristics
PCS (n ¼ 81)
Non-PCS (n ¼ 84)
p Value
Age, years Gender, M/F Time duration from injury to admission, minutes Mechanism of injury Motor vehicle accident Motorcycle accident Assault Fall from heighta Other Post-traumatic acute symptoms Headache PTA LOC Vomiting Seizure Coagulopathy
36.48 ± 17.3 54/27 36.37 ± 23.6
35.18 ± 14.3 60/24 35.33 ± 26.8
0.600 0.508 0.227
37 (45.6) 19 (23.4) 9 (11.1) 7 (8.6) 9 (11.1)
44 14 11 10 5
(52.3) (16.6) (13.0) (11.9) (5.9)
0.389 0.276 0.696 0.491 0.235
63 55 47 51 15 3
51 47 43 42 3 1
(60.7) (55.9) (51.2) (50.0) (3.5) (1.2)
0.018* 0.325 0.712 0.093 0.002* 0.294
(77.7) (67.9) (58.0) (62.9) (18.5) (3.7)
a
More than 1 metre or five stairs. Plus/minus values are mean ± SD. PCS, post-concussion syndrome; PTA, post-traumatic amnesia; LOC, loss of consciousness. *p50.05.
Median values and interquartile range of the S100B concentrations in plasma by the presence of intracranial lesions are given in Figure 2. The highest post-traumatic S100B median value at 3 hours was found in those showing ICH on CT scan at 0.90 (0.22–1.06) ng mL1 and the lowest value was found in those with cerebral contusion at 0.06 (0.03–0.08 ng mL1, p ¼ 0.003). Thus, the highest S100B levels occurred in the patients with the most severe brain injury. Similar results were found for S100B concentration at 6 hours after injury. The median concentration of S100B was 2.05 (0.53–3.4) ng mL1 in patients with ICH and 0.25 (0.09–0.32) ng mL1 in those with contusion (p50.001). Among all CT findings, the presence of SAH and ICH independently increased serum S100B concentrations at 3 and 6 hours in patients with MTBI. Compared with patients without SAH on CT, patients with this finding had a higher median concentration of S100B protein at 3 hours (0.20 [0.12–0.34] vs. 0.76 [0.27–0.91] ng mL1, p ¼ 0.001) and 6 hours after the head trauma (0.41 [0.28–0.99] vs. 1.05 [0.57–1.75] ng mL1, p50.001). The corresponding median values and interquartile range in those with ICH on CT were 0.23 (0.12–0.76) vs. 0.90 (0.22–1.06) ng mL1 for 3hour S100B (p ¼ 0.001) and 0.48 (0.28–1.05) vs. 2.05 (0.53– 3.41) ng mL1 for 6-hour S100B concentration (p50.001). Serum levels of S-I00 protein and outcome assessment Seventy-eight per cent (n ¼ 129) of the S100B concentrations were elevated (412 ng mL1) concerning the first samples taken at 3 hours post-trauma. Univariate regression analysis revealed a significant difference between the PCS group and non-PCS group with regard to 3-hour S100B concentration (0.54 [0.17–0.90] vs. 0.19 [0.10–0.35] ng mL 1, p ¼ 0.005). Similarly, patients with PCS had a higher 6-hour S100B concentration of 0.95 (0.41–1.85) ng mL1 compared with patients without PCS at 0.37 (0.18 ± 1.02 ng mL1, p50.001). On multivariate analysis of S100B concentration,
a positive correlation was observed between the 6-hour protein concentration and PCS risk. The resultant adjusted OR was 2.22 (95% CI ¼ 1.15–4.28, p ¼ 0.017). Additional evaluation was conducted to investigate the association of initial serum levels of S100B protein with acute clinical symptoms on admission. Similar results were found regarding the presence of seizure and vomiting after the trauma. These results are presented in Figures 3 and 4.
Discussion Outcome assessment after MTBI is a necessary first step toward secondary prevention of the disability associated with head injuries. A reliable estimate of neuropsychological function and identification of high risk MTBI cases before PCS development can help patients and healthcare professionals develop a plan that will aid the patients’ recovery to the greatest extent possible. The prediction can motivate more intensive and targeted intervention [22, 23]. This is the first attempt to predict PCS after acute MTBI according to clinical admission characteristics, CT admission variables and S100B concentration at 3 and 6 hours following a head injury. According to the DSM-IV criteria used in the present study, 49% of patients developed PCS 1 month after MTBI. Of the clinical variables, PTA (present in 62% of patients), LOC (54.5%), vomiting (56.3%) and coagulopathy (2.4%) did not show predictive value after univariate analysis. The percentage of the patients with LOC and/or PTA appears to be similar to that found in the literature, where LOC was present in 47.2–64.4% [24–26] and PTA was present in 69.2–73.7% of MTBI patients [27]. The only clinical variables that were most independently predictive of PCS outcome included headache at admission and seizure after the injury. In the study of De Kruijk et al. [28] the presence of symptoms in ED (headache, dizziness, nausea, vomiting and neck pain) and biochemical markers (neurone specific enolase and S100B) in serum were assessed. The purpose of this study was to
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Figure 2. Box-and-whisker plot showing distributions of serum level of S100B protein (ng mL1) at 3 and 6 hours post-trauma in patients with and without intracranial lesions. The boxes represent the 25th to 75th percentiles and horizontal lines within the box represent median values. The whiskers represent the lowest and highest value in the 25th percentile minus 1.5IQR and 75th percentile plus 1.5IQR regions, respectively. *p50.05. O, Outlier; ?, Extreme score.
Figure 3. Box-and-whisker plots showing distributions of serum 3-hour S100B levels (ng mL1) for PCS predictors. The boxes represent the 25th to 75th percentiles and horizontal lines within the box represent median values. The whiskers represent the lowest and highest value in the 25th percentile minus 1.5IQR and 75th percentile plus 1.5IQR regions, respectively. *p50.05. Significant results were found for patients with headache, LOC and seizure following the trauma. O, Outlier; ?, Extreme score; PTA, post-traumatic amnesia; LOC, loss of consciousness.
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Figure 4. Box-and-whisker plots showing distributions of serum 6-hour S100B levels (ng mL1) for PCS predictors. The boxes represent the 25th to 75th percentiles and horizontal lines within the box represent median values. The whiskers represent the lowest and highest value in the 25th percentile minus 1.5IQR and 75th percentile plus 1.5IQR regions, respectively. *p50.05. Significant results were found for patients with headache, LOC, vomiting and seizure following the trauma. O, Outlier; ?, Extreme score; PTA, post-traumatic amnesia; LOC, loss of consciousness.
determine possible predictive variables for the severity of post-traumatic complaints (headache, dizziness, drowsiness, loss of memory and concentration problems) 6 months after the trauma. After adjustment for baseline variables, they observed that at least 2-fold increased severity of all of posttraumatic complaints was reported by those patients reporting headache in ED. In this study, several individual CT characteristics were evaluated regarding their predictive value for 1-month PCS after MTBI. After multivariate regression analysis, only one independent predictor of outcome was found on CT scanning (the presence of SAH). This study also indicated that brain lesions including EDH, SAH and ICH independently increased serum S100B in the cases. These results are inconsistent with the Raabe et al. [29] study. They investigated the association between initial levels of serum S100B protein and the severity of radiologically visible brain damage and outcome after traumatic head injury. Traumatic SAH was found in 26 (59%) of the initial 44 CT scans. Moreover, serum S100B was significantly increased in patients with SAH compared with those without SAH (1.0 mg L1 vs. 0.12 mg L1, p50.001, Mann-Whitney U-test). With regard to the diagnostic value of S100B measurement in serum, Biberthaler et al. [30] published a prospective multi-centre study on 1309 patients with minor head injury. They reported that with a cut-off point of 0.10 ng mL1 for S100B, patients with intracranial lesions were identified with sensitivity and a specificity level of 99% and 30%, respectively. This study used a cut-off value of 0.12 ng mL1, as recommended previously on the basis of ROC (Receiver Operating Characteristics) curve analysis
[31, 32]. These results are also consistent with findings by Egea-Guerrero et al. [33] who evaluated the efficacy of S100B protein in detecting intracranial lesions on CT. The results indicated a positive correlation between the presence of pathological CT findings and high levels of S100B (p ¼ 0.007). The median value of S100B serum level in patients with intracranial lesions was 0.220 ng mL1 compared with 0.350 ng mL1 in cases without the lesions. In this series, a cut-off limit of 0.130 ng m L1 was proved to be the best point with 100% sensitivity. The data also showed that a higher cut-off, at 0.130 ng mL1, increases specificity up to 32.81%. Several biochemical substances have been studies to find a specific neuronal marker indicating cell damage. Recently, measurement of S100B, released into serum of patients with head injury, has been discussed as a valuable screening tool of mild cerebral injuries [34]. A positive correlation noted between S100B and an unfavourable outcome in brain injury patients, suggested that S100B may also have some prognostic significance [35–37]. In MTBI patients, a poor neuropsychological outcome and the presence of PCS have been reported to be associated with elevated S100B concentration [27, 38, 39]. It has been shown in this prospective study that early serum levels of the protein (3 and 6 hours) after MTBI seemed to be predictive concerning the outcome. These results are in agreement with the findings of Scandinavian studies which showed that early post-traumatic S100B concentrations were correlated with long-term neuropsychological disorders [7, 15]. Moreover, several previous studies showed significantly worse neuropsychological outcome with higher S100B levels 1 month or sooner from the
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DOI: 10.3109/02699052.2014.948068
time of injury [27, 40, 41]. Recently, Ingebrigtsen et al. [15] found a positive correlation between serum S100B and PCS in 50 patients with minor head injury and normal CT scans. The same authors reported increased serum levels in four of 24 patients with minor head injury and magnetic resonance imaging demonstrating contusion in two cases [18]. Another study found significantly higher initial S100B values in patients with poor outcome at discharge [42]. To date, several factors were determined to contribute to the development of PCS after a head trauma. Main groups include: pre-injury factors (demographics, psychosocial, cognitive and socioeconomic factors); injury factors (mechanism of injury, location and extent of brain injury); and post-injury factors (drugs, hormonal state and neural plasticity and repair) [43]. Serum biomarkers after MTBI presumably reflect some aspect of brain trauma and, thus, provide information on only one of these contributing factors. A combination of clinical elements and biochemical markers are necessary to develop a comprehensive decision plan that more accurately predicts PCS and identifies high risk patients most likely to benefit from early follow-up with a specialist. Several recent studies have attempted to create clinical prediction rules incorporating both clinical predictors and biochemical markers [28, 44]. It is in this manner that biomarkers may find utility in mild TBI. Finally, for TBI researchers, the identification of these patients permits controlled trials of interventions designed to reduce the incidence and duration of PCS after the MTBI but before PCS symptoms begin. These interventions which range from central nervous system stimulant therapy to behavioural therapy have the potential to improve the lives of many and reduce the economic burden of PCS on the community. In the present study, there are several limitations which need to be considered. The primary limitation is the relatively small sample size, which may have resulted in an under-estimate of statistical significance of some variables. Although less likely, it is also possible that some of the variables would contribute to outcome differently, with a larger sample size resulting in less significance for some associations. Other potential limitations include the short follow-up period and the fact that this study is from a single institution, which may introduce institutional bias in relation to patient selection and measurement of post-traumatic predictors. In this observational study, results may be confounded by unmeasured factors. This study attempted to include main potential predictors, although comprehensive evaluation of injury variables, serial measurements of S100B and other biomarkers and using sophisticated brain imaging techniques (functional MRI, PET, and SPECT scans) may allow drawing more comprehensive conclusion. The goal of this study was to find a set of clinical, imaging and laboratory findings that could be used to predict PCS in patients with mild head injury. The results suggested that such patients can be identified by the presence of one or more of the following findings: post-traumatic headache, seizure and SAH on CT scan. Moreover, the present data revealed that the initial measurement of post-traumatic release of S100B protein as a neurobiochemical marker of
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brain damage might be a helpful tool in identifying patients who run a risk of PCS. It is thought that these findings are encouraging for further studies on a larger population to evaluate the results and the prognostic significance of demographics, clinical factors and other biomarkers in more detail and, in other data sets, to follow-up this hypothesisgenerating finding.
Acknowledgements The authors thank the people who took part in this study. The study was financially supported by a grant from Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran (Iran).
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Bruns Jr J, Hauser WA. The epidemiology of traumatic brain injury: A review. Epilepsia 2003;44(Suppl 10)2–10. 2. Fleminger S, Ponsford J. (2005) Long term outcome after traumatic brain injury. British Medical Journal 2005;331:1419–1420. 3. Consensus conference. Rehabilitation of persons with traumatic brain injury. NIH Consensus Development Panel on Rehabilitation of Persons with Traumatic Brain Injury. Journal of the American Medical Association 1999;282:974–983. 4. Kraus JF, McArthur DL, Silverman TA, Jayaraman M. Epidemiology of brain injury. In: Narayan RK, Wilberger JE, and Povlishock JT, editors. Neurotrauma. New York: McGraw-Hill; 1996. p 13–30. 5. Thornhill S, Teasdale GM, Murray GD, McEwen J, Roy CW, Penny KI. Disability in young people and adults one year after head injury: Prospective cohort study. British Medical Journal 2000;320: 1631–1635. 6. Meerhoff SR, de Kruijk JR, Rutten J, Leffers P, Twijnstra A. Incidence of traumatic head or brain injuries in catchment area of Academic Hospital Maastricht in 1997. Nederlands Tijdschrift voor Geneeskunde 1997;144:1915–1918. 7. Waterloo K, Ingebrigtsen T, Romner B. Neuropsychological function in patients with increased serum levels of protein S-100 after minor head injury. Acta Neurochirurgica (Wien) 1997;139: 26–31. 8. Herrmann M, Curio N, Jost S, Grubich C, Ebert AD, Fork ML, Synowitz H. Release of biochemical markers of damage to neuronal and glial brain tissue is associated with short and long term neuropsychological outcome after traumatic brain injury. Journal of Neurology, Neurosurgery & Psychiatry 2001;70:95–100. 9. Sharma R, Laskowitz DT. Biomarkers in traumatic brain injury. Current Neurology & Neuroscience Reports 2012;12:560–569. 10. Perel P, Wasserberg J, Ravi RR, Shakur H, Edwards P, Roberts I. Prognosis following head injury: A survey of doctors from developing and developed countries. Journal of Evaluation in Clinical Practice 2007;13:464–465. 11. Murray LS, Teasdale GM, Jennett B, Kelly D, Murray GD, Miller JD, Jennett B, Miller JD, Pickard JD, Shaw MD, et al. Does prediction of outcome alter patient management? The Lancet 1993; 341:1487–1491. 12. Ha˚rdemark HG, Ericsson N, Kotwica Z, Rundstro¨m G, MendelHartvig I, Olsson Y, Pa˚hlman S, Persson L. S-100 protein and neuron-specific enolase in CSF after experimental traumatic or focal ischemic brain damage. Journal of Neurosurgery 1989;71: 727–731. 13. Raabe A, Grolms C, Sorge O, Zimmermann M, Seifert V. Serum S-100B protein in severe head injury. Neurosurgery 1999;45: 477–483. 14. Skogseid IM, Nordby HK, Urdal P, Paus E, Lilleaas F. Increased serum creatine kinase BB and neuron specific enolase following
40
15.
16.
17. 18.
Brain Inj Downloaded from informahealthcare.com by Thomas Jefferson University on 12/26/14 For personal use only.
19.
20.
21. 22.
23. 24. 25.
26.
27. 28.
29.
K. Heidari et al. head injury indicates brain damage. Acta Neurochirurgica (Wien) 1992;1:106–111. Ingebrigtsen T, Romner B, Trumpy JH. Management of minor head injury: The value of early computed tomography and serum protein S-100 measurements. Journal of Clinical Neuroscience 1997;4: 29–33. de Kruijk JR, Leffers P, Menheere PP, Meerhoff S, Twijnstra A. S-100B and neuron-specific enolase in serum of mild traumatic brain injury patients. A comparison with health controls. Acta Neurologica Scandinavica 2001;103:175–179. Heizmann CW, Fritz G, Scha¨fer BW. S100 proteins: Structure, functions and pathology. Frontiers in Bioscience 2007;7: 1356–1368. Ingebrigtsen T, Waterloo K, Jacobsen EA, Langbakk B, Romner B. Traumatic brain damage in minor head injury: Relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioral outcome. Neurosurgery 1999;45:468–475. Vos PE, Battistin L, Birbamer G, Gerstenbrand F, Potapov A, Prevec T, Stepan ChA, Traubner P, Twijnstra A, Vecsei L, von Wild K; European Federation of Neurological Societies. EFNS guideline on mild traumatic brain injury: Report of an EFNS task force. European Journal of Neurology 2002;9:207–219. King NS, Crawford S, Wenden FJ, Moss NE, Wade DT. The Rivermead Post Concussion Symptoms Questionnaire: A measure of symptoms commonly experienced after head injury and its reliability. Journal of Neurology 1995;242:587–592. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. [Appendix B]. Washington, DC: APA; 1994. p 704–706. NIH Consensus Development Panel on Rehabilitation of Persons with Traumatic Brain Injury. Rehabilitation of persons with traumatic brain injury. Journal of the American Medical Association 1999;282:974–983. Kushner D. Mild traumatic brain injury: Toward understanding manifestations and treatment. Archives of Internal Medicine 1998; 158:1617–1624. Borczuk P. Predictors of intracranial injury in patients with mild head trauma. Annals of Emergency Medicine 1995;25:731–736. Smits M, Dippel DW, de Haan GG, Dekker HM, Vos PE, Kool DR, Nederkoorn PJ, Hofman PA, Twijnstra A, Tanghe HL, Hunink MG. External validation of the Canadian CT Head Rule and the New Orleans Criteria for CT scanning in patients with minor head injury. Journal of the American Medical Association 2005;294: 1519–1525. Stiell IG, Clement CM, Rowe BH, Schull MJ, Brison R, Cass D, Eisenhauer MA, McKnight RD, Bandiera G, Holroyd B, et al. Comparison of the Canadian CT Head Rule and the New Orleans Criteria in patients with minor head injury. Journal of the American Medical Association 2005;294:1511–1518. Savola O, Hillbom M. Early predictors of post-concussion symptoms in patients with mild head injury. European Journal of Neurology 2005;10:175–181. De Kruijk JR, Leffers P, Menheere PP, Meerhoff S, Rutten J, Twijnstra A. Prediction of post-traumatic complaints after mild traumatic brain injury: Early symptoms and biochemical markers. Journal of Neurology, Neurosurgery & Psychiatry 2002;73: 727–732. Raabe A, Grolms C, Keller M, Do¨hnert J, Sorge O, Seifert V. Correlation of computed tomography findings and serum brain damage markers following severe head injury. Acta Neurochirurgica (Wien) 1998;140:787–791.
Brain Inj, 2015; 29(1): 33–40
30. Biberthaler P, Linsenmeier U, Pfeifer KJ, Kroetz M, Mussack T, Kanz KG, Hoecherl EF, Jonas F, Marzi I, Leucht P, et al. Serum S-100B concentration provides additional information for the indication of computed tomography in patients after minor head injury: A prospective multicenter study. Shock 2006;25:446–453. 31. Biberthaler P, Mussack T, Wiedemann E, Kanz KG, Mutschler W, Linsenmaier U, Pfeifer KJ, Gippner-Steppert C, Jochum M. Rapid identification of high-risk patients after minor head trauma (MHT) by assessment of S-100B: Ascertainment of a cut-off level. European Journal of Medical Research 2002;7:164–170. 32. Zongo D, Ribe´reau-Gayon R, Masson F, Laborey M, Contrand B, Salmi LR, Montaudon D, Beaudeux JL, Meurin A, Dousset V, et al. S100-B protein as a screening tool for the early assessment of minor head injury. Annals of Emergency Medicine 2012;59: 209–218. 33. Egea-Guerrero JJ, Revuelto-Rey J, Murillo-Cabezas F, Munoz-Sanchez MA, Vilches-Arenas A, Sanchez-Linares P, Dominguez-Roldan JM, Leon-Carrion J. Accuracy of the S100 b protein as a marker of brain damage in traumatic brain injury. Brain Injury 2012;26:76–82. 34. Biberthaler P, Mussack T, Wiedemann E, Kanz KG, Koelsch M, Gippner-Steppert C, Jochum M. Evaluation of S-100b as a specific marker for neuronal damage due to minor head trauma. World Journal of Surgery 2001;25:93–97. 35. Raabe A, Grolms C, Sorge O, Zimmermann M, Seifert V. Serum S-100B protein in severe head injury. Neurosurgery 1999;45: 477–483. 36. Woertgen C, Rothoerl RD, Metz C, Brawanski A. Comparison of clinical, radiologic, and serum marker as prognostic factors after severe head injury. Journal of Trauma 1999;47:1126–1130. 37. Raabe A, Grolms C, Seifert V. Serum markers of brain damage and outcome prediction in patients after severe head injury. British Journal of Neurosurgery 1999;13:56–59. 38. Herrmann M, Curio N, Jost S, Grubich C, Ebert AD, Fork ML, Synowitz H. Release of biochemical markers of damage to neuronal and glial brain tissue is associated with short and long term neuropsychological outcome after traumatic brain injury. Journal of Neurology, Neurosurgery & Psychiatry 2001;70:95–100. 39. Ingebrigtsen T, Romner B, Trumpy JH. Management of minor head injury: The value of early computed tomography and serum protein S-100 measurements. Journal of Clinical Neuroscience 1997;4: 29–33. 40. Townend WJ, Guy MJ, Pani MA, Martin B, Yates DW. Head injury outcome prediction in the emergency department: A role for protein S-100B? Journal of Neurology, Neurosurgery & Psychiatry 2002; 73:542–546. 41. Stranjalis G, Korfias S, Papapetrou C, Kouyialis A, Boviatsis E, Psachoulia C, Sakas DE. Elevated serum S-100B protein as a predictor of failure to short-term return to work or activities after mild head injury. Journal of Neurotrauma 2004;21:1070–1075. 42. Woertgen C, Rothoerl RD, Holzschuh M, Metz C, Brawanski A. Comparison of serial S-100 and NSE serum measurements after severe head injury. Acta Neurochirurgica (Wien) 1997;139: 1161–1164. 43. Ryan LM, Warden DL. Post concussion syndrome. International Review of Psychiatry 2003;15:310–316. 44. Savola O, Pyhtinen J, Leino TK, Siitonen S, Niemela¨ O, Hillbom M. Effects of head and extracranial injuries on serum protein S100B levels in trauma patients. Journal of Trauma 2004;56: 1229–1234.
