Prevalence and structure of symptoms at 3 months after mild traumatic brain injury in a national cohort

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1 Brain Injury, March 2009; 23(3): Prevalence and structure of symptoms at 3 months after mild traumatic brain injury in a national cohort MARIANNE LANNSJÖ 1,2, JEAN-LUC AF GEIJERSTAM 3, ULLA JOHANSSON 2, JOHAN BRING 4,&JÖRGEN BORG 1 Downloaded By: [Lanssjukhuset Gavle Sandviken] At: 07:44 16 July Department of Neuroscience, Rehabilitation Medicine, Uppsala University, Sweden, 2 Centre for Research and Development, Uppsala University/County Council of Gavleborg, Sweden, 3 Department of Medicine, Clinical Epidemiology Unit, Karolinska University Hospital, Stockholm, Sweden, and 4 Department of Mathematics, Natural and Computer Sciences, University of Gavle, Sweden (Received 18 September 2008; accepted 14 January 2009) Abstract Objectives: To describe symptom prevalence and structure after mild traumatic brain injury (MTBI) in a population-based cohort. Methods: Symptoms data were collected at 3 months post-mtbi by use of the Rivermead Post-concussion Symptoms Questionnaire (RPQ) at follow-up of 2602 patients attending 39 Swedish hospitals. Spearmans rank correlation analysis was used to explore correlations between symptoms and structural equation modelling (SEM) was performed by use of several fit indices to explore if data were compatible with one or more factors. Results: Questionnaires were received from 2523 (97%) patients with a mean age of 31 years (median 22, range 6 96). A majority of the respondents (56%) reported no remaining injury related symptoms, 24% reported three or more symptoms and 10% reported seven or more symptoms. All symptoms exhibited strong positive inter-relations and SEM provided strong support for a single or two factor solution. Fit indices were only slightly weaker for three and four factor solutions. Conclusions: A significant minority of patients reported multiple symptoms to persist at 3 months after MTBI. The observed structure of symptoms according to RPQ demonstrates a common factor for all symptoms, but also sub-groups of symptoms as previously suggested. Keywords: Mild Traumatic Brain Injury, Post-concussion Symptoms, Rivermead Post-concussion Symptoms Questionnaire Introduction The prognosis after mild traumatic brain injury (MTBI) is most often good, with symptoms resolving within weeks or months, as demonstrated in several studies and pointed out in recent reviews [1, 2]. However, in a minority of patients, symptoms persist and might be associated with other disabilities including reduced capacity to work [3, 4]. Available data on the proportion of patients with a poor outcome are not consistent, which probably reflect various outcome measures, definitions of such an outcome as well as study samples and settings [1]. Regarding the high incidence of MTBI, ranging / inhabitants in most reports of patients seen at hospital or higher in some reports [5, 6], even a small proportion of subjects with a poor outcome means a large number of subjects. Previous studies have pointed out a number of injury-related, demographic and health-related factors to be associated with poor outcome after MTBI. Some of these factors still remain to be clarified [1, 2, 7]. Symptom persistence is considered a key feature of a poor outcome after MTBI and is thus included Correspondence: Marianne Lannsjö, Rehabilitation Medicine, University Hospital, Uppsala 75185, Sweden. marianne.lannsjo@lg.se ISSN print/issn X online ß 2009 Informa Healthcare Ltd. DOI: /

2 214 M. Lannsjö et al. in suggested criteria sets for such an outcome. According to the ICD10 criteria, at least three symptoms are required for a diagnosis of postconcussion syndrome [8, 9]. The suggested DSM IV criteria also require three symptoms for a diagnosis of a post-concussion disorder and in addition signs of impaired cognitive function and social disability [10]. The number of persisting symptoms reported after MTBI varies between studies and the validity of three or more symptoms has not been demonstrated even if some studies indicate a correlation between number and intensity of symptoms and measures of disability [11 13]. Symptoms commonly reported after MTBI are not specific, but common in the general population [14] and reported by patients with various pain conditions [15 18]. The lack of symptom specificity is considered one argument against the concept of a unitary condition, i.e. a postconcussional syndrome [1, 2, 19 22]. In order to assess symptoms after MTBI, a number of measures have been described. One commonly used is the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), which has demonstrated reliability and validity [11, 23]. This questionnaire takes into account the high background prevalence of symptoms by asking the patients not only if symptoms are present, but also to rate the intensity of each of 16 symptoms as compared to before the MTBI. Recently, two studies have examined aspects of the structure of symptoms reported by patients after a MTBI by use of RPQ. In a confirmatory factor analysis by use of structural equation modelling (SEM), Potter et al. [24] tested a single factor model that would reflect PCS as a unitary syndrome and also a model of cognitive, somatic and emotional factors, as proposed by Smith-Seemiller et al. [16]. The study was based on RPQ data obtained from 168 respondents out of a sample of 1099 patients (15%), mainly with mild TBI, 6 months earlier. While the one-factor solution was rejected by the factor analysis, there was some support for separable constellations of cognitive, emotional and somatic symptoms. In another study, by Eyres et al. [25], the internal construct validity of RPQ by fit to the Rasch Measurement model was tested for RPQ data received from 369 out of a sample of 1689 patients (22%) with head injuries of varying severity. That study demonstrated two underlying constructs corresponding to three of the RPQ items (headache, dizziness and nausea) and the other 13 items, respectively. These two constructs only partially corresponded to the factors identified in the study by Potter et al. and argued against summation of RPQ scores from items belonging to each of the two constructs. Thus, there is a need for further evaluation with regard to the interpretation of data provided by the RPQ. The aim of this study was to expand the knowledge on the prevalence and structure of symptoms according to the RPQ by use of data from a national, prospective cohort study of patients followed up at 3 months after MTBI. Material and methods During the period May 2001 to January 2004, 39 out of 75 emergency departments in Sweden participated in a study comparing the medical effects and costs of two acute management policies for MTBI [26, 27]. Participating departments represent hospitals of all sizes and all parts of the country and correspond to the geographical distribution of the Swedish population. Patients with MTBI and aged 6 years or older were recruited to the study. The eligibility criteria were: a history of head trauma within the last 24 hours, confirmed or suspected loss of consciousness (LOC) and/or amnesia, normal neurological examination and a Glasgow Coma Scale (GCS) score of 15 and no associated injuries that required admission. A total of 2602 persons were recruited to the study. Three months after visiting the emergency department, participants were sent questionnaires (with a reminding letter after 2 weeks to those who had not answered) including the Rivermead Post- Concussion Symptoms Questionnaire (RPQ). The RPQ consists of 16 items asking the patient to rate symptoms according to the degree they are more of a problem since the head injury. Symptoms are rated on a scale from 0 4, where 0 ¼ not experienced at all, 1 ¼ it is no longer a problem, 2 ¼ a mild problem, 3 ¼ a moderate problem and 4 ¼ a severe problem. Questionnaires were received from 2523 participants (97%). The frequency of missing data in the 2523 questionnaires was less than 1.5% for each of the 16 items in RPQ. Statistics Descriptive statistics, frequencies, proportions, median and mean values were used to describe symptoms data. For some of the description, symptoms were dichotomized in no symptoms (ratings 0 and 1) vs any symptoms (ratings 2, 3 and 4). Correlations between the 16 items were analysed by non-parametric Spearmans rank correlation. Exploratory factor analyses were performed to study the structure of the data. Since there is no single criterion to be used for deciding the number of factors in a factor-analysis model, several measures were used including eigenvalues, parallel analysis, optimal coordinates, acceleration factor, RMSEAindex and others. Factor loading larger than 0.4 was

3 Prevalence and structure of symptoms after MTBI 215 Table I. Number of patients by symptoms and symptom scores. Symptom scores 0 (Not experienced symptom) 1 (No longer a problem) 2 (Mild problem) 3 (Moderate problem) 4 (Severe problem) Downloaded By: [Lanssjukhuset Gavle Sandviken] At: 07:44 16 July 2009 Headaches Dizziness Nausea Noise sensitivity Sleep disturbance Fatigue Irritability Depression Frustration Poor memory Poor concentration Longer to think Blurred vision Light sensitivity Double vision Restlessness considered relevant. The promax rotation method was used. Ethics No financial incentives were offered. Eligible patients received oral and written information about the study and gave their written consent to participate. Consent in children was obtained from a parent or accompanying caregiver. All regional research ethics committees in Sweden approved the study. The Swedish national health and pharmaceutical insurance plan covered all patients included in the study. Results Out of 2523 respondents, 1488 were male (59%) and 1035 female (41%). Mean age was 31 years, median 22 (range 6 96) years. Prevalence and intensity of symptoms The number of respondents reporting each of the symptom scores 0 4 for all 16 symptoms are summarized in Table I and the proportion of respondents reporting 0 7 or more symptoms to persist after MTBI (i.e. scored 2 4) are summarized in Table II. Thirty-eight per cent (966) of the respondents reported no symptoms ever (0 on all RPQ items) and 18% (445) reported that prior symptoms had resolved. Thus, in total, 56% (1411) of the respondents reported no remaining symptoms (0 or 1 on all items) and 44% (1112) reported one or more symptoms to persist at 3 months. Ten per cent (245) of the respondents reported only one Table II. Proportion of patients reporting 0 7 or more symptoms (scoring 2 4). Missing data 3%. Number of symptoms Frequency (valid%) symptom, 24% (615) reported three or more symptoms and 10% (259) reported seven or more symptoms. The proportion of respondents who reported each of the 16 symptoms respectively to persist after MTBI (i.e. scored any of 2 4) and the mean intensity of these symptoms are summarized in Table III Most frequently reported symptoms were fatigue, reported by 23%, headaches (22%) and dizziness (16%). The least frequent symptom was double vision (2%). Mean symptom intensities ranged between There was a positive relation between number of remaining symptoms and the intensity of these symptoms, as illustrated in Figure 1 Correlation between symptoms and factor structure The correlation matrix is shown in Table IV. All symptoms exhibited statistically significant, positive correlation with each other, with correlation coefficients ranging from

4 216 M. Lannsjö et al. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Table III. Proportion of patients reporting each of 16 symptoms (scoring 2 4) and mean intensity of these symptoms. Symptom Frequency (%) Mean intensity Fatigue Headaches Dizziness Poor memory Irritability Poor concentration Sleep disturbance Frustration Longer to think Restlessness Depression Noise sensitivity Light sensitivity Nausea Blurred vision Double vision s 2s 3s 4 6s 7 10s 11 16s Figure 1. Intensity of symptoms in relation to number of remaining symptoms. s ¼ symptoms; 2 ¼ mild problems; 3 ¼ moderate problems; 4 ¼ severe problems At factors analysis, the four largest eigenvalues were 7.92, 1.15, 0.97 and Hence, according to this criterion a two-factor solution would fit best. However, according to the acceleration factor criterion a one-factor model would fit best. The one factor solution does also get some support from the correlation matrix where all factors are positively correlated with each other. Data are also compatible with 3- and 4-factors solutions and there is no sharp decline in the different fit-indices for these models compared to the 1- and 2-factor solutions. Sub-groups of the symptoms according to the 2-, 3- and 4-factor solutions are presented in Table V. In the 3-factor solution, the factors can be labelled as somatic, cognitive and emotional in agreement with previous studies [16, 24]. In a 4-factor solution, the fourth factor included visual and Table V. Distribution of symptoms according to 2-, 3- and 4-factor models. 2 factor 3 factor 4 factor Headaches Dizziness Nausea Noise sensitivity Sleep disturbance Fatigue Irritability Depression Frustration Poor memory Poor concentration Longer to think Blurred vision Light sensitivity Double vision Restlessness Table IV. Correlation matrix Headaches Dizziness Nausea Noise sensit Sleep disturb Fatigue Irritability Depression Frustration Poor memory Poor concent Longer to th Blurred visio Light sensit Double vis Restlessness

5 auditory symptoms. Noise sensitivity had a weak but evident association to factor 4 (loading 0.34). Discussion This study demonstrates that a significant minority of patients reports multiple RPQ symptoms at 3 months after MTBI and that these symptoms correlate with each other but also occur in discernible sub-groups. Overall, the findings are in agreement with previous studies but expand the knowledge on the prevalence and structure of symptoms after MTBI. The large sample size and high follow-up rate of patients in this cohort support that the findings are representative for similar contexts. It should be pointed out that the study included only patients within the mild MTBI spectrum, i.e. with a presenting GCS score of 15. These patients constitute the vast majority of all patients with MTBI [28]. At 3 months after MTBI, almost half of the patients (44%) reported persisting symptoms. This observation is in agreement with findings in some previous studies that have used the RPQ [12, 24, 29]. Other studies have reported somewhat higher proportions, 60 70% of patients with persisting symptoms [13, 30, 31]. It might be speculated that this reflects that these studies included also patients with a presenting GCS score of 14 and 13. However, there is no strong evidence for a dose-response relation in terms of initial GCS or post-traumatic amnesia vs persisting problems after MTBI [1]. Another reason might be that these data are more representative than previous studies with regards to the source population, sample size and high followup rate. The data also allow further analysis with regards to the relation between age, gender and other factors, which may also be related to the frequency of persisting symptoms. One tenth of the respondents reported a large number of symptoms seven symptoms or more to persist at 3 months after MTBI. Alves et al. [32] reported that multiple, persisting symptoms were rare after MTBI, but the number of symptoms was not specified and only a minority of the study cohort was followed-up. Potter et al. [24] suggested a classification of symptom severity related to less than 75, 75, 90 and 95% limits as arbitrary cut-offs for minimal, mild, moderate and severe levels symptom levels corresponding to RPQ sum scores 0 12, 13 24, RPQ sum score 33 or more, respectively. When these criteria were applied to these data, the cumulative frequency curve had an almost similar shape but was shifted to the left, which might reflect that Potter et al. included patients within a wider Prevalence and structure of symptoms after MTBI 217 severity spectrum or that these data are derived from a larger, representative sample. The factor analyses demonstrated that symptoms were compatible both with one strong common factor but also with 2 4 separate factors. Roughly, these findings are in agreement with the findings reported by Potter et al. [24], but also provide more information. First, while Potter et al. observed a poor fit of their data to a one-factor solution, this factor analysis provided strong support for a factor in common, as further supported by the result of the correlation analysis. Secondly, while these data were compatible with a somatic, cognitive and emotional factor, as suggested by Smith-Seemiller et al. [16] and confirmed by Potter et al. [24], the large data set also revealed a fourth factor related to auditory and visual symptoms, including double vision. Thus, this study provides further support for the concept of separable somatic, cognitive and emotional symptoms after MTBI and also indicates a separable visual/auditory factor. Looking at the overall prevalence of symptoms belonging to each of these four factors, somatic symptoms were most prevalent, followed by cognitive and then emotional symptoms and auditory/visual were least prevalent. However, there was some overlap, e.g. the somatic factor included nausea that was less frequent than both noise and light sensitivity. Thus, symptoms within each factor had varying prevalence and any doseresponse relation seems to apply both to factors and to individual symptoms within each factor. The factor analysis does not provide any information on the order of symptoms within each factor, which might however be approached by a Rasch analysis. In a study by Eyres et al. [25] of the internal construct validity of RPQ by fit to the Rasch Measurement model, two underlying constructs were demonstrated, arguing against a summation of all symptoms scores. However, there was only partial overlap between the constructs observed in that study and the factors observed in this study. One construct comprised headaches, dizziness and nausea and thus overlapped with factor 1 in this study, but this factor also comprised sleep disturbance and fatigue. The observation of a strong common factor as well as the parallel occurrence of symptoms belonging to each factor would support that total sum scores are meaningful. An analysis of the fit of these data to the Rasch Measurement model would be of interest also in this respect. The observed RPQ symptom structure does not allow any conclusions about specificity or about aetiological mechanisms, since corresponding data from control groups were not available. Several previous studies have demonstrated that symptoms reported by patients after MTBI are not specific but reported also by patients with chronic pain [15 17],

6 218 M. Lannsjö et al. whiplash injuries [33] and low back pain [18]. However, the factor structure of symptoms reported by patients with these conditions is not known. Smith-Seemiller et al. [16] reported that cognitive symptoms are more prominent in patients with MTBI as compared with patients with chronic pain, indicating that symptoms after MTBI might have some differentiating characteristics. It is also not known if any of the previously identified or suggested prognostic factors, such as prior psychiatric or somatic disease, co-morbidities [7, 17, 34], female gender [7, 17, 30, 35], expectations [36 38] or financial incentives [39 41] relate to the symptom sub-groups after MTBI. In summary, this study of a national cohort of patients with MTBI shows that a significant minority reports multiple symptoms to persist at 3 months post-injury and that there is a strong common factor for all RPQ symptoms but also sub-groups of symptoms. Further studies, relating possible aetiological factors to sub-groups of symptoms, might help to clarify mechanisms behind symptom persistence and guide intervention studies. Acknowledgements This study was supported by grants from the Swedish insurance company AFA and Centre for Research and Development Uppsala University/ County Council of Gavleborg. 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. Carroll LJ, Cassidy JD, Peloso PM. Prognosis for mild traumatic brain injury: Results of the WHO collaborating Centre Task Force on Mild Traumatic Brain Injury. Journal of Rehabilitation Medicine 2004;43(Suppl): Iverson GL. Outcome from mild traumatic brain injury. Current Opinion in Psychiatry 2005;18: Boake C, McCauley SR, Pedroza C, Levin HS, Brown SA, Brundage SI. Lost productive work time after mild to moderate traumatic brain injury with and without hospitalization. Journal of Neurosurgery 2005;56: Nolin P, Heroux L, Caplan B. Relations among sociodemographic, neurologic, clinical and neuropsychologic variables, and vocational status following mild traumatic brain injury: A follow-up study. Journal of Head Trauma Rehabilitation 2006;21: Cassidy JD, Carroll LJ, Peloso PM, Borg J, Holst H, Holm J, Kraus J, Coronado VG. Incidence, risk factors and prevention of mild traumatic brain injury: Results of the WHO collaboration centre task force on mild traumatic brain injury. Journal of Rehabilitation Medicine 2004;43(Suppl): Bazarian JJ, McClung J, Shah MN, Cheng YT, Flesher W, Kraus J. Mild traumatic brain injury in the United States, Brain Injury 2005;19: Ponsford J, Willmott C, Rothwell A, Cameron P, Kelly A.-M, Nelms R, Curran C, Ng K. Factors influencing outcome following mild traumatic brain injury in adults. Journal of the International Neuropsychological Society 2000;6: World Health Organization. The ICD-10 classification of mental and behavioural disorders: Clinical descriptions and diagnostic guidelines. Geneva: World Health Organization; World Health Organization. The ICD-10 classification of mental and behavioural disorders: Diagnostic criteria for research. Geneva: World Health Organization; American Psychiatric Association. 4th ed. Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychiatric Association; Crawford S, Wenden FJ, Wade DT. The Rivermead head injury follow up questionnaire: A study of a new rating scale and other measures to evaluate outcome after head injury. Journal of Neurology, Neurosurgery & Psychiatry 1996;60: Lundin A, de Boussard C, Edman G, Borg J. Symptoms and disability until 3 months after mild TBI. Brain Injury 2006;20: Ingebrigtsen T, Waterloo K, Marup-Jensen S, Attner E, Romner B. Quantification of post-concussion symptoms 3 months after minor head injury in 100 consecutive patients. Journal of Neurology 1998;245: Iverson GL, Lange RT. Examination of post-concussionlike symptoms in a healthy sample. Applied Neuropsychology 2003;10: Iverson G, McCracken LM. Postconcussive symptoms in persons with chronic pain. Brain Injury 1997;11: Smith-Seemiller L, Fow NR, Kant R, Franzen MD. Presence of post-concussion syndrome symptoms in patients with chronic pain vs mild traumatic brain injury. Brain Injury 2003;17: Meares S, Shores EA, Taylor AJ, Batchelor J, Bryant RA, Baguley IJ, Chapman J, Gurka J, Dawson K, Capon L, et al. Mild traumatic brain injury does not predict acute postconcussion syndrome. Journal of Neurology, Neurosurgery & Psychiatry 2008;79: Gasquoine PG. Postconcussional symptoms in chronic back pain. Applied Neuropsychology 2000;7: King NS. Post-concussion syndrome: Clarity amid controversy? The British Journal of Psychiatry 2003;183: Boake C, McCauley SR, Levin HS, Pedroza C, Contant CF, Song JX, Brown SA, Goodman H, Brundage SI, Diaz- Marchan PJ. Diagnostic criteria for postconcussional syndrome after mild to moderate traumatic brain injury. Journal of Neuropsychiatry & Clinical Neurosciences 2005;17: McCauley SR, Boake C, Pedroza C, Brown SA, Levin HS, Goodman HS, Merritt SG. Postconcussional disorder: Are the DSM-IV criteria an improvement over the ICD-10? The Journal of Nervous and Mental Disease 2005;193: Kashluba S, Casey JE, Paniak C. Evaluating the utility of ICD-10 diagnostic criteria for postconcussion syndrome following mild traumatic brain injury. Journal of the International Neuropsychological Society 2006;12: 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: Potter S, Leigh E, Wade D, Fleminger S. The Rivermead post concussion symptoms questionnaire a confirmatory factor analysis. Journal of Neurology 2006;253:

7 25. Eyres S, Carey A, Gilworth G, Neumann V, Tennant A. Construct validity and reliability of the Rivermead postconcussion symptoms questionnaire. Clinical Rehabilitation 2005;19: Geijerstam JL, Oredsson S, Britton M. Medical outcome after immediate computed tomography or admission for observation in patients with mild head injury: Randomised controlled trial. British Medical Journal 2006;333: Norlund A, Marke LA, af Geijerstam JL, Oredsson S, Britton M. Immediate computed tomography or admission for observation after mild head injury: Cost comparison in randomised controlled trial. British Medical Journal 2006;333: Teasdale GM. Head injury. Journal of Neurology, Neurosurgery & Psychiatry 1995;58: Stålnacke B.-M. Thesis: Detection and outcome of mild traumatic brain injury in patients and sportsmen. Department of Community Medicine and Rehabilitaton, Rehabilitaton Medicine, Umeå University, Sweden; King NS. Emotional, neuropsychological, and organic factors: Their use in the prediction of persisting postconcussion symptoms after moderate and mild head injuries. Journal of Neurology, Neurosurgery & Psychiatry 1996;61: Stålnacke B.-M. Community integration, social support and life satisfaction in relation to symptoms 3 years after mild traumatic brain injury. Brain Injury 2007;21: Alves W, Macciocchi SN, Barth JT. Postconcussive symptoms after uncomplicated mild head injury. Journal of Head Trauma Rehabilitation 1993;8: Haldorsen T, Waterloo K, Dahl A, Mellgren SI, Davidsen PE, Molin PK. Symptoms and cognitive dysfunction in patients with the late whiplash syndrome. Applied Neuropsychology 2003;10: Prevalence and structure of symptoms after MTBI McCauley SR, Boake C, Levin HS, Contant CF, Song JX. Postconcussional disorder following mild to moderate traumatic brain injury: Anxiety, depression and social support as risk factors and comorbidities. Journal of Clinical and Experimental Neuropsychology 2001;23: Bazarian JJ, Wong T, Harris M, Lehay N, Mookerjee S, Dombovy M. Epidemiology and predictors of post-concussive syndrome after minor head injury in an emergency population. Brain Injury 1999;13: Mittenberg W, DiGiulio DV, Perrin S, Bass AE. Symptoms following mild head injury: Expectation as aetiology. Journal of Neurology, Neurosurgery & Psychiatry 1992;55: Gunstad J, Suhr JA. Expectation as aetiology versus the good old days : Postconcussion syndrome reporting in athletes, headache sufferers and depressed individuals. Journal of the International Neuropsychological Society 2001;7: Ferrari R, Constantoyannis C, Papadakis N. Cross-cultural study of symptom expectation following minor head injury in Canada and Greece. Clinical Neurology and Neurosurgery 2001;103: Binder LM, Rohling ML. Money matters: A meta-analytic review of the effects of financial incentives on recovery after closed head injury. The American Journal of Psychiatry 1996;153: Mickeviciene D, Schrader H, Nestvold K, Surkiene D, Kunickas R, Stovner LJ, Sand T. A controlled historical cohort study on the post-concussion syndrome. European Journal of Neurology 2002;9: Mickeviciene D, Schrader H, Obelieniene D. A controlled prospective inception cohort study on the post-concussion syndrome outside the medicolegal context. European Journal of Neurology 2004;11: