Demographic and injury characteristics
Demographic and injury characteristics in the present study of a TBI cohort aged 16-55 years admitted to the Trauma Referral Centre with acute TBI are comparable to those of other TBI populations [8, 13]. All subjects from East Norway with moderate-to-severe TBI (GCS 3-12) in need for acute neurosurgical check-up and care are referred to this Trauma Referral Centre. Participants in this study were representative of their cohort; the refusal rate was about 20% as in existing literature , and the substance use at the time of injury did not differ between participants and non-participants.
The level of consciousness might be obscured in acute settings due to substance use at the time of injury, medical sedation or paralysis . In this study, the mean GCS score did not differ significantly between the substance-positive and substance-negative groups of patients, agreeing with results reported by Sperry . In contrast, assessment of structural brain damage by neuroimaging is not influenced by state of consciousness. Therefore, we defined the severity of TBI in this study by structural brain damage as shown on CT scans. There is evidence that the CT scan can assist in discriminating less severe from more severe TBI using the Marshall scores as a standard measure of anatomical classification of severity . Fifty-five percent of patients in this study had injuries that could be categorised as more severe.
In this study, almost half of the patients showed substance use upon admission to the hospital. The proportion of patients found to be under the influence of alcohol was 35%, which is higher than in previous Norwegian studies [28, 29]. A trend towards increasing alcohol consumption in the general Norwegian population during the last decades  as a result of the increased number of regular drinkers  as well as higher consumption in Oslo/Eastern Norway than in other regions may explain this result . Norway is, however, in the lower range of international statistics on alcohol consumption as compared to other Western countries . This could be explained by limitation in availability of alcohol, as well as the high taxation on alcoholic beverages in Norway. The alcohol consumption rate shown in this study was within the range of those reported in a recent review of TBI epidemiology in Europe (24-51%)  and other international studies [3, 4]. This study also confirms that alcohol is the most common substance used in the TBI population [4, 8].
The use of other psychoactive substances was found in 12% of the total TBI sample. This rate is lower than those presented in international studies , and is biased by clinical routines on admission and the clinical definition of substance use. In agreement with studies on illicit drug use in TBI populations , cannabis was the most frequently detected drug. It is well known that cannabis is the most frequently used illegal drug in the general population in Norway . The proportion of patients that use substances while driving motor vehicles was more than five times higher in the present study than in a recent study on the prevalence of alcohol and illicit drugs among motor vehicle drivers (aged ≤ 54 years) in South-Eastern Norway . Our findings may indicate that persons who sustain TBI are not representative of the general population. However, a considerably lower proportion of traffic injury cases in this study were alcohol-influenced than in older TBI literature . This may represent the reduction of the legal limit for BAC from 0.5 to 0.2 mg/g in 2001 , effectiveness of campaigns and programmes for reducing drinking and driving, and a decrease in the incidence of traffic-related TBI during the last decades .
The proportion of patients with substance use was significantly higher in the less severe Marshall group. Falls and other injuries were the main causes of injury in this severity group. The percentage of patients under the influence of alcohol on admission and injured by falls or assaulted was in agreement with other Nordic studies [9, 29]. Northern European countries are often characterised as nations with infrequent but heavy episodes of drinking ("dry" culture), with higher tolerance toward excessive drinking, and higher frequencies of alcohol-related injuries than Southern European countries where alcohol use is more integrated into everyday life ("wet" culture) .
As hypothesised previously, we expected that substance use on admission could have a potentiating effect on anatomical brain injury, as measured by findings on the "worst" head CT scan within 24 hours of injury . Contrary to expectation, substance use tended to decrease the probability of more severe intracranial injury in the adjusted logistic regression (OR = 0.39). However, strong conclusion should not be drawn due to insufficient statistical power in the analysis (power 0.58, alpha 0.05) . Cunningham's results  showing that alcohol potentiated the severity of TBI among victims of motor vehicle crashes were not replicated in this study.
It has been reported that acute alcohol intoxication exerts both detrimental and beneficial effects on the injury severity and outcome of TBI, although mechanisms have not been determined. The hypothesis that alcohol-inebriated victims injured by falls on stairs sustain more severe intracranial injuries because of delayed reaction time and inadequate protection reflexes was not supported . Smink et al.  could not demonstrate a relationship between alcohol concentration and the severity of traffic accidents. Furthermore, alcohol and methamphetamine use was found to be associated with decreased mortality in a retrospective study of severe TBI . Ruff et al.  also found that alcohol intoxication at the time of injury "was not associated with poor outcome in those who survived long enough to reach hospital". Based on experimental research, Kelly  reported that acute alcohol intoxication may have neuroprotective effects in traumatic brain injuries as a result of "ethanol-induced inhibition of N-methyl-D aspartate receptor-mediated (NMDA) excitotoxicity". Dose-dependent effects are also reported, with a better outcome in animals obtained with low and moderate ethanol doses as compared to no- and high-ethanol groups . According to Tien et al. , low to moderate BAC may be beneficial in patients with severe brain injury from blunt head trauma, while high BAC seems to have a deleterious effect on in-hospital death in these patients. Although the focus of our study was not to assess whether BAC levels impact the severity of structural brain injury, the mean BAC level was found to be similar in both severity groups.
The considerable number of patients with substance use in the present study shows that the use of alcohol and drugs is a major risk factors for TBI [3, 9, 39]. Health-related and psycho-social consequences of TBI, as well as the economical burden of these injuries underline the importance of preventive efforts targeting at-risk populations.
Pre-injury substance misuse
Screening by the CAGE questionnaire showed that 26% of patients reported pre-injury substance abuse (problems with alcohol and/or other substances). Around two-thirds of these patients misused alcohol. This study shows a lower proportion of pre-injury substance misuse than in TBI literature (40-55%) reviewed from 1994-2004 . This rate is also slightly lower than that reported in a recent study on a TBI population from Australia (21% alcohol and 9% drug dependence) . In our study, we omitted patients with pre-existing substance abuse disorders, which could explain these lower rates. Lower sensitivity of the CAGE-drug questionnaire as compared to the CAGE-alcohol questionnaire  is a methodological limitation, as the cut-off score used. If we include patients with a CAGE score of one (8 patients, 9%), those omitted due to pre-diagnosed severe substance abuse disorders (14 patients, 14%) and the pre-injury substance misuse group (26%), a total proportion of 49% reached the range of estimates presented in the literature [4, 10]. We based our findings on self-reports from the patients (the CAGE interview), thus possibly under-reporting illicit drug use, since patients may be unwilling to report engagement in illegal activities . Prior history of substance abuse is less often found in persons treated in Trauma Referral Centres than in rehabilitation populations . However, the occurrence rate of pre-injury substance abuse in this study is higher than in a Danish study , where 5.8% of the intracranial lesions group were diagnosed with substance misuse by the ICD-9 criteria. In our study, 26% of all patients with ICD-10 diagnoses of intracranial lesions had a positive CAGE screening for pre-injury substance problems.
CAGE positivity is usually equivalent to being a heavy drinker . When we extracted results of patients with positive CAGE-alcohol, the proportion shown was more than two times higher than the rate of heavy drinkers found in a Norwegian survey in 1998 . One population at risk of pre-injury substance misuse in this study was a male, younger than 35 years of age, with a lower education level (≤12 years). The other population was single males, older than 35 years, with a high school education. It has previously been reported that drinking serves an important social function for young people , and that increased consumption of alcohol is found in subjects with a higher level of education and higher income [30, 32].
We found in the adjusted regression analysis that patients with pre-injury substance problems showed significantly increased probability of more severe TBI as compared to their counterparts (OR 4.05). Chronic alcohol use has consistently been found to be associated with more severe traumatic brain injuries. Ronty et al.  reported that pre-injury alcohol abuse precipitated the development of more severe structural traumatic brain damage on CT examinations. A strong association between history of excessive alcohol use and poor outcome for all types of intracranial diagnoses and greater prevalence of mass lesion was reported by Ruff at al. . Several other studies have reported an association between alcohol abuse and greater severity of TBI as measured by posttraumatic amnesia, neuropsychological tests and global functioning [3, 4, 14]. According to previous experimental studies, chronic alcohol exposure may exacerbate TBI, probably as the "effect of imbalance of up-regulation of NMDA receptor activity and down-regulation of gamma-aminobutyric acid (GABA) receptor function resulting in excitotoxicity" .
The association shown in this study between pre-injury substance abuse and more severe intracranial injuries underlines the importance of identifying persons at risk who would benefit from intervention related to substance abuse. A routine alcohol and psychoactive substance screening of TBI patients at the emergency admission may pinpoint this population .
In the adjusted regression analyses, female gender tended to have increased probability of more severe intracranial injury, in agreement with a previous study on females under 50 years of age . Older age tended to increase the probability of more severe intracranial injuries. Other studies have reported that increasing age is related to poorer outcome after TBI . Of all patients with severe intracranial injuries, 20% were young adults living with parents and attending secondary school. School education programmes about the effects and dangers associated with alcohol consumption and drug use are "a key component in preventing substance abuse in this population" .
This study has several important limitations that should be addressed. It is a selected cohort study describing a TBI population aged 16-55 years. The study assesses the severity of anatomical brain injury as shown on CT at a fixed point of time (within 24 hours of injury). The clinical course and outcome of TBI were not evaluated in this study. Our results should be interpreted with caution because no standard protocol to obtain blood samples and urine tests for substance exists (25% of patients were classified by clinical judgment), as well as the small number of participants. Therefore, we made no distinction between the types of substances used when analysing the probability of more severe TBI. The frequency of pre-injury substance problems is slightly underestimated due to the exclusion criteria which resulted in omission of 14 patients with previously diagnosed severe substance abuse. Ten of these suffered from severe TBI supporting the association between pre-injury substance abuse and severe structural brain injury shown by the study. Self-reported screening instruments might under-report pre-injury use of alcohol and, especially, of illicit drugs. Limitations of the CAGE questionnaire are described above. Clinical interviews based on the DSM-IV diagnostic criteria may provide a reliable measure of substance abuse disorders. However, a replication of the study is needed before the present findings can be considered as a verified hypothesis.