BRAIN INJURY
AND HAZARDOUS
ALCOHOL DRINKING
IN TRAUMA PATIENTS
OLLI
SAVO LA
Department of Neurology,
University of Oulu
OULU 2004
OLLI SAVOLA
BRAIN INJURY AND HAZARDOUS
ALCOHOL DRINKING IN TRAUMA
PATIENTS
Academic Dissertation to be presented with the assent of
the Faculty of Medicine, University of Oulu, for public
discussion in the Auditorium 8 of Oulu University
Hospital, on June 11th, 2004, at 12 noon.
O U L U N Y L I O P I S TO, O U L U 2 0 0 4
Copyright © 2004
University of Oulu, 2004
Supervised by
Professor Matti Hillbom
Reviewed by
Professor Kaija Seppä
Docent Jukka Turkka
ISBN 951-42-7378-8 (nid.)
ISBN 951-42-7379-6 (PDF) http://herkules.oulu.fi/isbn9514273796/
ISSN 0355-3221
OULU UNIVERSITY PRESS
OULU 2004
http://herkules.oulu.fi/issn03553221/
Savola, Olli, Brain injury and hazardous alcohol drinking in trauma patients
Department of Neurology, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu,
Finland
2004
Oulu, Finland
Abstract
Head injury is the leading cause of death and disability in trauma patients, and alcohol misuse is often
associated with such injuries. Despite modern diagnostic facilities, the extent of traumatic brain injury
(TBI) is difficult to assess and supplementary diagnostic tools are warranted. The contribution of
alcohol misuse to traumas also needs to be elucidated, as the role of different patterns of alcohol
drinking in particular has received less attention.
We investigated the clinical utility of a novel serum marker of brain damage, protein S100B, as a
tool for assessing TBI in patients with trauma. We also investigated the patterns of alcohol drinking
among trauma patients and the trauma mechanisms in relation to blood alcohol concentration (BAC),
with special emphasis on head traumas. Finally, we studied the early identification of hazardous
drinkers among trauma patients.
Serum protein S100B was found to be a feasible supplementary method for assessing TBI, as the
latter was shown to elevate its levels significantly, the highest values being found in patients with
severe injuries. S100B was also found to be elevated in patients with mild head injury, where it was
associated with an increased risk of developing post-concussion symptoms (PCSs). Extracranial
injuries also increased S100B values in patients with multitrauma. Accordingly, S100B was not
specific to TBI. The more severe the extracranial injury, the higher the S100B value that was found.
Binge drinking was found to be the predominant pattern in trauma patients. Alcohol intoxication
on admission and hazardous drinking patterns were more often present in patients with head injury
than in those with other types of trauma. The risk of sustaining a head trauma significantly increased
with increasing BAC. The results also demonstrated that BAC on admission is the best marker of
alcohol misuse in trauma patients. The BAC test depicts hazardous alcohol drinking better than
conventional biochemical markers of alcohol misuse such as gamma-glutamyl transpeptidase (GGT),
aspartate aminotransferase (AST), carbohydrate-deficient transferrin (CDT), or mean corpuscular
volume (MCV) of erythrocytes.
The findings support the use of S100B as a supplementary method for assessing TBI and the use
of BAC as a marker of alcohol misuse in trauma patients.
Keywords: alcohol misuse, brain injury, laboratory markers, patterns of alcohol drinking,
post-concussion symptoms, serum protein S100B
To my family and friends
Acknowledgements
The present study was carried out at the Department of Neurology, University of Oulu,
during the years 1998–2004.
While I am very grateful to everyone who has contributed to this work, I would like to
thank the following persons in particular.
First I wish to express my most sincere gratitude to my supervisor, Professor Matti
Hillbom, Head of the Department of Neurology, who introduced me to the subject and
gave his support and scientific guidance at all stages in the work. His criticism and endless enthusiasm for medical science have made this research very pleasant. I am also very
grateful to Professor Onni Niemelä for his guidance. His broad knowledge of alcoholism
has made a great impression during these years.
I am very grateful to my co-authors Professor Juhani Pyhtinen, Tuomo K. Leino,
M.D., Ph.D. and Simo Siitonen, M.D., Ph.D. for their collaboration and encouragement
during the research.
I owe particular thanks to Professor John Koivukangas, Head of the Department of
Neurosurgery, and Professor Esa Heikkinen for allowing me to use the facilities of that
department, and Docent Juhani Valkama and the whole staff of the Accident and Emergency Department of Oulu University Hospital for their excellent co-operation.
I also owe particular thanks to Professor Kaija Seppä and Docent Jurkka Turkka, who
reviewed the manuscript of this thesis and provided constructive criticism and advice. I
would similarly like to thank Mr Malcolm Hicks for revising the English language of the
manuscript.
My warm thanks are also due to Professor Kari Majamaa for his advice in scientific
drawing. I also wish to thank all my colleagues and the whole staff of the Department of
Neurology for their sympathetic support during my work. I am especially indebted to
Maarit Näppä, Merja Halonen, Mirja Kouvala, Marika Hämeenaho and Ilona Huovinen
for their practical assistance. I am also very grateful to Risto Bloigu for his statistical
advice.
My special thanks go to my colleagues in Professor Hillbom’s research group, Vesa
Karttunen, Veli Tuomivaara, Satu Winqvist and Pertti Saloheimo. I will never forget the
great conversations, more or less scientific, that we have had.
I would also like to express my sincere thanks to the patients and their relatives who
participated in this study.
My warm thanks go to my family and friends, especially to my parents and my sister
Kaisa, for their support and care during these years.
Finally, I wish to express my dearest thanks to my wife Kaisa-Marja, for her great support and love during my years of study, and to our children Isla and Nikla, who were born
during this project.
The work was supported financially by the Oulu Medical Research Foundation.
Oulu, April 2004
Olli Savola
Abbreviations
ALT
AST
AUDIT
BAC
CDT
CT
DAI
EDH
EEG
GCS
GGT
GOS
LOC
MAST
MCV
MHI
MRI
NMDA
NSE
PCSs
PTA
RGA
SAAST
SDH
SMAST
SPECT
TBI
alanine aminotransferase
aspartate aminotransferase
Alcohol Use Disorders Identification Test
blood alcohol concentration
carbohydrate-deficient transferrin
computed tomography
diffuse axonal injury
epidural haematoma
electroencephalography
Glasgow Coma Scale
gamma-glytamyl transpeptidase
Glasgow Outcome Scale
loss of consciousness
Michigan Alcohol Screening Test
mean corpuscular volume (of erythrocytes)
mild head injury
magnetic resonance imaging
N-methyl-D-aspartate
Neuron-specific enolase
post-concussion symptoms
post-traumatic amnesia
retrograde amnesia
Self-Administered Alcoholism Screening Test
subdural haematoma
Short Michigan Alcohol Screening Test
single photon emission computed tomography
traumatic brain injury
List of original publications
This thesis is based on the following articles, which are referred to in the text by their
Roman numerals:
I
Savola O & Hillbom M (2003) Early predictors of post-concussion symptoms in
patients with mild head injury. Eur J Neurol 10: 175–181.
II
Savola O, Pyhtinen J, Leino TK, Siitonen S, Niemelä O & Hillbom M (2003) Effects
of head and extracranial injuries on serum protein S100B levels in trauma patients. J
Trauma, in press.
III
Savola O, Niemelä O & Hillbom M (2004) Binge drinking as a major risk factor for
head trauma. Submitted for publication.
IV
Savola O, Niemelä O & Hillbom M. (2004) Blood alcohol is the best indicator of
hazardous alcohol drinking in young adults and working-age patients with trauma.
Alcohol and Alcoholism, in press.
Reprints are included with the permission of the publishers: Blackwell Science Ltd (I),
Lippincott Williams & Wilkins (II) and Oxford University Press (IV).
Contents
Abstract
Acknowledgements
Abbreviations
List of original publications
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 Review of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1 Epidemiology of head injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Classification of head injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1 Mild head injury (MHI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1.1 MHI without brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1.2 MHI with mild brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2 Head injury with moderate brain injury . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.3 Head injury with severe brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3 Clinical features of brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.1 Diffuse axonal injury (DAI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.2 Cerebral contusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.3 Intracerebral haematoma (ICH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.4 Epidural haematoma (EDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.5 Subdural haematoma (SDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.6 Subarachnoid haemorrhage (SAH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.7 Secondary brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.8 Skull and facial bone fracture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4 Diagnosing brain injury in patients with head injury . . . . . . . . . . . . . . . . . . . .
2.4.1 Clinical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.2 Skull radiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.3 Computed tomography (CT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.4 Magnetic resonance imaging (MRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.5 Single photon emission computed tomography (SPECT) . . . . . . . . . . . .
2.4.6 Electroencephalography (EEG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.7 Biochemical markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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2.4.7.1 Neuron specific enolase (NSE) . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.7.2 Protein S100B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.8 Neuropsychological assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5 Treatment of head injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6 Outcome after head injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.1 Mild head injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.1.1 Post-concussion symptoms (PCSs) . . . . . . . . . . . . . . . . . . . . . .
2.6.2 Moderate-to-severe head injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7 Alcohol and head injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7.1 General aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7.2 Alcohol drinking as a risk factor for trauma . . . . . . . . . . . . . . . . . . . . . .
2.7.3 Alcohol drinking as a risk factor for head injury . . . . . . . . . . . . . . . . . .
2.7.4 Alcohol and trauma morbidity and mortality . . . . . . . . . . . . . . . . . . . . .
2.7.5 Alcohol and traumatic brain injury morbidity and mortality . . . . . . . . .
2.8 Identification of hazardous alcohol drinking . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.1 Tools for identifying hazardous alcohol drinking . . . . . . . . . . . . . . . . . .
2.8.1.1 Questionnaires and interviews . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.1.2 GGT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.1.3 AST & ALT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.1.4 CDT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.1.5 MCV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.1.6 BAC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.2 Detecting hazardous alcohol drinking . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.2.1 In patients with trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.2.2 In patients with head injury . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.9 Alcohol interventions as means of preventing injuries . . . . . . . . . . . . . . . . . .
Aims of the research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Subject and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1 Clinical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1.1 Emergency room . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1.2 Alcohol data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1.3 Follow-up interviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.2 Laboratory procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.3 Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1 Protein S100B as a predictor of PCSs in MHI patients (paper I) . . . . . . . . . . .
5.2 Effects of extracranial injuries on S100B levels (paper II) . . . . . . . . . . . . . . .
5.3 Binge drinking as a risk factor for head trauma (paper III) . . . . . . . . . . . . . . .
5.4 Laboratory markers of hazardous alcohol drinking in trauma patients
(paper IV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1 PCSs in patients with mild head injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2 Protein S100B as a marker of brain damage . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3 Alcohol and trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.1 Hazardous alcohol drinking in patients with trauma . . . . . . . . . . . . . . . .
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6.3.2 Alcohol as a risk factor for head trauma . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.3 Identification of alcohol misuse in patients with trauma . . . . . . . . . . . .
6.4 Strengths and weaknesses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References
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1 Introduction
Head injury is a serious health burden, being a leading cause of death and disability
among teenagers and young adults, and resulting in enormous financial costs for society
(Alexander 1995, Thorhill et al. 2000, Thompson et al. 2001). Alcohol is a major cause
of traumas of this kind, and alcohol misuse and its consequences are currently one of the
major health problems world-wide (Lieber 1995, Hadfield et al. 2001).
Despite modern diagnostic and monitoring methods, it remains difficult to assess the
extent of primary brain damage after head injury and the development of secondary damage (Raabe et al. 1999b). Most of the diagnostic process nowadays is based on neuroimaging techniques such as computed tomography (CT) and magnetic resonance imaging
(MRI), although in practice only CT is often available in the acute stage. CT is sensitive
for detecting fresh blood inside the skull, but has a low sensitivity for diffuse axonal
injury (DAI) (Bešenski 2002). There is a major need for supplementary diagnostic tools
in cases of acute head injury, e.g. a simple biochemical marker of brain damage.
The protein S100B is the most promising candidate for a biochemical marker of brain
damage to date (Ingebrigtsen & Romner 2002), having been found to correlate with the
extent of brain damage and the outcome after severe head injury (Raabe 1999b). It has
also been shown to be elevated in approximately 20–38% of patients with mild head
injury (MHI) (Ingebrigtsen et al. 1995, Ingebrigtsen et al. 2000b). Its clinical utility
among such patients is unresolved, however. S100B is also expressed in non-nervous tissues, and extracranial injuries may confound its use as a specific marker of brain damage
(Haimoto et al. 1987, Anderson et al. 2001). The contribution of extracranial injuries to
the elevation in S100B levels observed after head injury also remains to be elucidated.
Most patients with MHI recover well (Binder 1997), although a small but significant
proportion develop persistent post-concussion symptoms (PCSs) that may prevent optimal recovery and impair return to work and psychosocial functioning (Alexander 1995,
Bernstein 1999). Routine follow-up of all patients with MHI is not warranted (Wade et al.
1997), but it might be beneficial and cost-saving to follow up subjects who are likely to
develop PCSs. After identification of these patients, appropriate rehabilitation services
could prevent the condition from becoming chronic and avoid financial costs and social
and human suffering. No methods have been proposed to date for the early detection of
patients at risk of developing PCSs.
18
Alcohol and injuries are closely linked (Rivara et al. 1993a, Corrigan 1995, Porter
2000). Approximately 50% of trauma patients have alcohol in their blood on admission,
and even higher proportions have been reported in series consisting specifically of
patients with head injuries (Brismar et al. 1983, Rivara et al. 1993a, Dikmen et al. 1995).
Chronic alcohol misuse is also common in trauma patients, approximately 45% of whom
have been reported to be misusers (Nilssen et al. 1994). The prevalence of chronic alcohol misuse among head injury patients has varied from 16% to 66% (Corrigan 1995).
Little is known of the different patterns of alcohol drinking in patients with trauma,
and more attention should be paid to binge drinking in particular, because the dangers of
alcohol are not restricted to regular drinking. The social, health and economic costs of
acute alcohol-related problems may even exceed those due to chronic drinking
(Chikritzhs et al. 2001). It would be important to know the prevalence of different patterns of alcohol drinking and their contribution to traumas, and whether a certain drinking pattern is associated specifically with head injuries.
There have been several reports of a positive effect of brief alcohol intervention as
means of reducing alcohol intake and injury recurrence (Walsh et al. 1991, Fleming et al.
1997, Gentilello et al. 1999), but there continues to be a lack of attention paid to alcohol
misuse in accident and emergency departments, so that patients with alcohol misuse tend
to escape specific treatment. This is likely to be due to the lack of practical tools for identifying the optimal target group for alcohol interventions. Laboratory tests such as
gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), carbohydratedeficient transferrin (CDT) and mean corpuscular volume (MCV) of erythrocytes have
been suggested to help the physician to detect alcohol misusers on admission (Mihas &
Tavassoli 1992), but their clinical utility remains to be elucidated. In particular, no
attempt has been made to correlate laboratory markers of alcohol consumption with patterns of alcohol consumption in trauma patients.
The present study was aimed at assessing the clinical utility of S100B as a specific
marker of brain damage and as a factor that predicts poor recovery after MHI, and also at
elucidating the role of different drinking patterns in trauma patients and how alcohol
drinking increases the risk of head trauma. Methods were sought for identifying hazardous drinkers among trauma patients, in the hope that improved identification and assessment of brain damage and alcohol misuse may lead to a better understanding of the risks
of injury and of a poor outcome after injury and may help us to develop treatments and
preventive medical and social policies.
2 Review of the literature
2.1 Epidemiology of head injury
The annual incidence of head injury is estimated to be between 150–300 per 100 000 of
population (Annegers et al. 1980, Jennett & MacMillan 1981, Klauber et al. 1981, Kraus
et al. 1984, Tiret et al. 1990, Durkin et al. 1998, Marshall 2000). Men have approximately twice as high a rate as women (Kraus et al. 1984, Lundar & Nestvold 1985), and the
highest age-specific incidence is found among young adults (Kraus 1993).
These incidence figures are based on studies of hospital discharges after diagnoses of
brain injury or at least skull fracture (Klauber et al. 1981, Kraus 1993), and are likely to
be underestimated. Thornhill et al. (2000) reported that 20% of all head injury patients
admitted to hospital were not recorded in the health service statistics, and found the total
incidence of such admissions to be 326 per 100 000 of population. McGuire et al. (1995)
reported an incidence of 607 per 100 000 of population when all medically treated head
injury patients were taken into account, but according to an extensive survey by Fife
(1987), approximately 10% of patients who reported having had a head injury were never
treated for it medically. Finally, Segalowitz & Lawson (1995) found that approximately
one third of high school and university students had a history of at least one head injury,
and only one fifth of them had been admitted to hospital.
MHI explains approximately 80–90% of all head injuries, while moderate and severe
head injuries explain the rest (McGuire et al. 1995, Thornhill et al. 2000). The annual
incidence of fatal head injuries is consistently found to be between 17–30 per 100 000 of
population (Kraus et al. 1984, Sosin et al. 1989, Tiret et al. 1990). Almost 60% of all fatal
trauma cases admitted to hospital are due to head injury (Gennarelli et al. 1989), and traffic accidents account for approximately 60% of all severe head injuries (Sosin et al. 1989,
Tiret et al. 1990), while falls and assaults are the most common causes of milder head
injuries (Thornhill et al. 2000).
Disability due to head injury is a poorly studied entity. Kraus (1993) estimated the rate
of disability, i.e. severe or moderate disability according to the GOS (Jennet & Bond
(1975), to be 33 to 45 per 100 000 of population/year, but a recent study from Glasgow
20
area has reported the annual incidence to be much higher, 154 per 100 000 of population
(Thornhill et al. 2000).
The financial costs associated with head injury are enormous. Max et al. (1991)
assessed the total costs per year in the US as exceeding $38 billion. Thompson and her
co-workers (2001) suggested that the estimate presented by Max et al. (1991) is conservative, capturing only part of the total costs, and estimated that the figure may well exceed
$62 billion. In fact, the true financial costs due to head injuries are probably incalculable,
as family members may develop physical and mental symptoms, for example, and the
overall financial impact is unknown (Thompson et al. 2001).
2.2 Classification of head injuries
Head injuries are traditionally classified as mild, moderate or severe (Vos et al. 2002), the
purpose being to evaluate the risk of complications and assess the probable outcome
(Ingebrigtsen et al. 2000a, Thornhill et al. 2000). In practice, the classification is often
performed by assessing the level of impaired consciousness on the Glasgow coma scale
(GCS), which is based on eye opening and motor and verbal responses, as presented in
Table 1 (Teasdale & Jennett 1974). MHI is defined as a state with scores of 13 to 15,
whereas moderate and severe head injuries are defined by scores of 9 to 12 and 3 to 8,
respectively. In addition, the presence and duration of post-traumatic amnesia (PTA) are
often used as tools for classifying head injuries (Russell & Smith 1961, Kurup et al.
2000), and a head CT scan-based classification has also been developed especially for
moderate-to-severe head injuries (Marshall et al. 1991).
Table 1. The Glasgow Coma Scale.
Aspect of behaviour
Eye-opening (E):
Spontaneous
To voice
To pain
No response
Best motor response (M):
Obeys commands
Localizes
Withdraws (flexion)
Abnormal flexion (posturing)
Extending (posturing)
No response
Verbal response (V):
Oriented conversation
Confused, disoriented
Inappropriate words
Incomprehensible sounds
No response
Glasgow Coma Scale score = E + M + V
Response score
4
3
2
1
6
5
4
3
2
1
5
4
3
2
1
21
The International Classification of Diseases (ICD) (1992) can also be used for classifying head injuries. This includes diagnoses indicating the clinical features of head and
brain injury, but does not classify them in terms of severity. Its clinical utility is thus limited when assessing the possible outcome, for example. The ICD classification has proved
to be practicable for epidemiological studies, however (Sosin et al. 1989). Head injuries
can also be classified in other ways, into impact versus deceleration/acceleration injuries
(Elson & Ward 1994, Aikuisiän aivovammojen käypä hoito 2003), or penetrating versus
closed head injury (Bayston et al. 2000).
2.2.1 Mild head injury (MHI)
MHIs constitute a significant medical problem for several reasons. Firstly, approximately
80 to 90% of all head injuries are mild (McGuire et al. 1995, Thornhill et al. 2000). Secondly, 0.01 to 3% of patients initially assessed as having MHI will develop life-threatening complications requiring immediate neurosurgical intervention (Dacey et al. 1986,
Stein & Spettell 1995). Thirdly, great attention and financial resources have to be spent
on the evaluation of these patients because of this minimal risk of possible intracranial
complications (Stiell et al. 2001a). Fourthly, a small proportion of MHI patients do not
achieve a good recovery (Thornhill et al. 2000) and may be left neuropsychologically
impaired (Binder et al. 1997) or develop long-lasting PCSs (Alexander 1995).
2.2.1.1 MHI without brain injury
Although there certainly exist head injuries without brain injury, the terms MHI and mild
TBI are often used synonymously (de Kruijk et al. 2001b). This confusion is due to the
fact that there are no specific measures available for detecting the presence of negligible
brain damage or for separating head injury patients with mild TBI from those without
(Bernstein 1999). In two current articles, head injury patients without TBI are characterised as having a GCS score of 15 and no loss of consciousness (LOC), PTA, focal neurological deficits, or physical symptoms such as headache, dizziness or vomiting (de Kruijk
et al. 2001b, Vos et al. 2002).
2.2.1.2 MHI with mild brain injury
MHI with mild brain injury applies to a subset of patients with MHI in whom brain damage is evident but mild. These patients have a GCS score of 13 to 15 on admission to hospital and may also have one or more symptoms and/or signs of TBI. The presence of PTA
(duration < 24 hours) and unconsciousness (duration < 30 minutes) are such signs (Rimel
et al. 1981, Alexander 1995, Bernstein 1999, Aikuisiän aivovammojen käypä hoito
22
2003), and the most frequent symptoms are headache, nausea, vomiting and dizziness (de
Kruijk et al. 2001a, de Kruijk et al. 2001b). Patients having a focal neurological deficit or
structural damage visible in a head CT scan or MRI are assessed as having more severe
TBI (Williams et al. 1990, Alexander 1995, Aikuisiän aivovammojen käypä hoito 2003).
The terms commotio cerebri and cerebral concussion, which are often used in clinical
work to denote mild TBI, were initially defined as referring to a state of functional disturbance of the brain due to trauma without any tissue damage (Ward 1966). Controversy
exists, however, over whether diffuse brain dysfunction can occur without structural damage, because it has become clear that brain damage is often present in patients with cerebral concussion (Ommaya & Gennarelli 1974, Vos et al. 2002). It is currently suggested,
therefore, that the severity of TBI forms a continuum from negligible to clinically significant, and there is simply less brain damage in mild TBI than in more severe cases (Alexander 1995, Ingebrigtsen 1998).
Mild TBIs can be further subclassified into several grades (Dacey et al. 1993, Ingebrigtsen et al. 2000, Kurup et al. 2000, Vos et al. 2002) in order to assess the risk of
intracranial complications and to predict the outcome (Ingebrigtsen et al. 2000, Vos et al.
2002). These grades are also frequently used in sports medicine as a guide to when it is
appropriate to return to action (Kurup et al. 2000).
2.2.2 Head injury with moderate brain injury
Russell & Smith (1961) proposed a four-grade scale of TBI severity based on the duration
of PTA, moderate TBI being defined as a state with PTA between 1 and 24 hours. After
the introduction of the GCS, moderate TBI has been defined as a GCS score of 9 to 12 on
admission (Teasdale & Jennett 1974, Rimel et al. 1982). A current Finnish guideline
defines moderate brain injury as a GCS score of 9 to 12 and/or PTA between 24 hours
and seven days (Aikuisiän aivovammojen käypä hoito 2003).
Moderate TBI patients may have focal deficits in clinical examination (Aikuisiän aivovammojen käypä hoito 2003), one third actually have structural lesions in the brain visible on a head CT scan, and MRI may reveal some additional lesions (Rimel et al. 1982,
Kelly et al. 1988, Stein & Spettell 1995, Ingebrigtsen et al. 2000a). Moderate TBI
patients without a lesion in the brain are considered to have diffuse axonal injury (DAI)
(Rimel et al. 1982). Approximately one tenth of patients with moderate TBI need a neurosurgical operation (Rimel et al.1982).
2.2.3 Head injury with severe brain injury
Patients are deemed to have severe TBI if they have an admission GCS score of 8 or less
(Teasdale & Jennett 1974), although some who “talk and deteriorate” may have a GCS
score of over 8 initially or at some moment (Lobato et al. 1991). Severe TBI can also be
characterised by a duration of PTA of at least 7 days (Aikuisiän aivovammojen käypä
hoito 2003). Some investigators recognise a separate group of critical brain injuries (Vos
23
et al. 2002) consisting of patients who have a GCS score of 3 to 4 and evident brain stem
damage, characterised by diminished or no pupillary reactions and decerebrate motor
posturing, or an absence of pupillary and motor reactions (Vos et al. 2002).
Approximately 5 to 30% of patients with severe TBI have a normal head CT scan initially (Lobato et al. 1986, Eisenberg et al. 1990, Stein & Spettell 1995) with lesions frequently seen later, or else brain atrophy may develop during the subsequent months, indicating that the initial trauma type had been DAI (Lobato et al. 1986).
2.3 Clinical features of brain injury
2.3.1 Diffuse axonal injury (DAI)
Brain injuries are commonly divided into focal and diffuse injuries (Gennarelli 1993).
Diffuse brain injury is a widespread or global disruption of brain tissue and often involves
only microscopically visible lesions (Adams et al. 1989). Typical microscopic findings
are small focal brain lesions, clusters of microglia in the white matter, axonal bulbs, and
axonal swelling and degeneration (Adams et al. 1989). This is called diffuse axonal injury (DAI) (Povlishock et al. 1983, Maxwell et al. 1997).
Strich originally reported two autopsy studies of closed head injury patients, all of
whom had died in a comatose condition (Strich 1956, Strich 1961). Her postmortem findings showed that there were only a few lesions visible to the naked eye, mostly in the corpus callosum or in one or both of the superior cerebellar peduncles. The cerebral cortex
appeared normal. In contrast, Strich (1961) found a widespread diffuse degeneration of
the white matter in all cases, and concluded that this was due to mechanical stresses and
strains which lead the nerve-fibres to tear and degenerate.
More recently, DAI has been found to be a common type of brain damage both in
experimental studies of primates (Jane et al. 1985, Xiao-Sheng et al. 2000) and in studies
dealing with humans (Adams et al. 1982). DAI is often present in cases of severe TBI,
Adams et al. (1989) reporting that 122 out of 434 non-missile head injury patients autopsied had some evidence of DAI, although in 24 cases the DAI could be found only after
microscopic examination. Oppenheimer (1968) also found DAI in five autopsied mild
TBI patients, although the majority of the evidence for an association between mild TBI
and DAI has come from experimental studies (Gennarelli et al. 1982, Jane et al. 1985).
Povlishock et al. (1983) demonstrated that mild TBI does not always disrupt the axons
mechanically but can lead to axonal swelling, it is currently thought that this non-disruptive axonal injury may result in secondary DAI some hours after injury, and that such a
situation may be more common than was previously appreciated (Maxwell et al. 1997).
Although small lesions in the white matter, corpus callosum, or brain stem can be
detected in the head CT scan in some cases of more severe DAI (Zimmerman et al. 1978,
Levi et al. 1990), CT is in general insensible for detecting DAI, whereas MRI may be
more sensitive (Bagley 1999). Thus Mittl et al. (1994) found some evidence of DAI in
30% of MHI patients with normal CT scans, and it is likely that there are a lot of head
24
injury patients with DAI who do not have any detectable CT lesions (Adams et al. 1989,
Bagley 1999), although neuroimaging may reveal diffuse brain atrophy during follow-up
(Ito et al. 1997).
2.3.2 Cerebral contusion
Cerebral contusions are bruises and lacerations of the brain tissue which may either be
limited to the cortex or extend into the white matter and typically include haemorrhage,
infarction, necrosis and oedema (Adams 1975, Levin et al. 1988). Cerebral contusions
have traditionally been described as a result of coup (at the site of impact) or contracoup
injuries (opposite the site of impact, where the brain strikes the skull) (Jallo & Narayan
2000). Cerebral contusions are frequent in patients with TBI, and are mostly found in the
temporal and frontal regions of the brain (Mattson & Levin 1990, Gentry et al. 1988a,
Stiell et al. 2001b), the areas especially prone to injury being the anterior and inferior
portions of the temporal and frontal lobes, where the brain contacts the rough surfaces of
the sphenoid wings, the petrous ridges, the cribriform plate and the planum sphenoidale
(Bagley 1999), although cerebral contusions regularly occur in other regions of the brain
as well (Hesselink et al. 1988). Cerebral contusions may swell and cause increased intracranial pressure (Bullock et al. 1991).
Contusions are characterised in head CT scans by areas of hypodensity, hyperdensity
and oedema (Bešenski 2002). If there are haemorrhagic components, CT may be slightly
more sensitive for detecting cerebral contusions than MRI (Hesselink et al. 1988),
whereas MRI is more sensitive in depicting non-haemorrhagic contusions (Gentry et al.
1988b, Hadley et al. 1988), contusions in the brain stem (Gentry et al. 1988b) and contusions at the subacute and chronic stages (Groswasser et al. 1987, Kelly et al. 1988).
The prognosis for patients with cerebral contusions varies according to the localization and size of the lesions. MHI patients with a small frontal lobe contusion may have
only minor neuropsychological disturbances (Mattson & Levin 1990), whereas mortality
among patients with multiple or extensive contusions may exceed 40%, which is the overall mortality for severe TBI patients (Murray et al. 1999).
2.3.3 Intracerebral haematoma (ICH)
Traumatic ICH, bleeding in the brain parenchyma (Jallo & Narayan 2000), may develop
primarily as a result of trauma or secondarily within the subsequent days after injury
(Clifton et al. 1980, Soloniuk et al. 1986, Mertol et al. 1991). Cerebral contusions and
traumatic intracranial haematomas represent a continuum, so that if there is a clear blood
clot present this is called an intracranial haematoma (Jallo & Narayan 2000). There are
also non-traumatic ICHs, which may be spontaneous or due to bleeding from vascular or
arterial abnormalities (Caplan 1988).
As with contusions, most traumatic ICHs are located in the temporal and frontal lobes
(Adams 1975). Traumatic ICH is seldom found alone, but is often associated with contu-
25
sions, other haematomas and oedema (Caroli et al. 2001). Siddique et al. (2002) found
that only 90 out of 5686 head injury patients had isolated ICH. A head CT scan is sensitive for detecting intracranial haematomas, and it also works as a tool for assessing the
need for surgical treatment (Bullock et al. 1989). An unfavourable outcome after ICH is
associated with the presence of other brain lesions, a prolonged increase in intracerebral
pressure and more advanced age (Caroli 2001, Siddique et al. 2002), and mortality following traumatic ICH still remains high, varying from 11 to 50% (Soloniuk et al. 1986,
Mertol et al. 1991, Caroli et al. 2001).
2.3.4 Epidural haematoma (EDH)
The most common locations for EDH, bleeding between the skullbone and dura (Adams
1975), are the temporal and frontal areas of the skull, often with the middle meningeal
artery as the source (Reale et al. 1984). The typical patient with EDH is a young adult
male (Reale et al. 1984, Miller et al. 1990). Skull fractures significantly increase the risk
of EDH (Miller et al. 1990), which usually develops rapidly after trauma. Some patients
may also have delayed EDHs, however, and most of the recurrent haematomas following
craniotomy for traumatic intracranial mass are EDHs (Bullock et al. 1990).
The classic symptoms of EDH include dilatation of the pupil on the haematoma side
and hemiparesis of the opposite side. EDH is currently diagnosed from a head CT scan,
by the typical appearance of a high-density, biconvex, lentiform, extra-axial mass, often
bounded by suture lines (Bagley 1999). It may have underlying oedema, contusions, and
other haematomas associated with it. Large EDHs may also have a mass effect, characterised on a CT scan by sulcal effacement, midline shift and compression of the ventricular
system, and in the most severe cases herniation occurs due to increasing intracerebral
pressure (Adams 1975, Stieg & Kase 1998).
Since EDH may develop even after rather low-energy trauma (Stein & Spettell 1995),
considerable attention and financial resources have been devoted to the identification of
cases that are likely to develop a haematoma after MHI. Ninety-eight per cent of head CT
scans of MHI patients are negative for EDH (Stiell et al. 2001a). The primary therapy for
acute EDH is urgent surgery (Reale et al. 1984, Miller et al. 1990), and the outcome is
related to the severity of concomitant brain injuries, neurological status at the time of surgery, age and the interval between injury and surgery (Reale et al. 1984, Servadei 1997).
Mortality due to EDH varies between 16 and 40% (Reale et al. 1984).
2.3.5 Subdural haematoma (SDH)
SDH, a collection of blood under the dura, is usually attributed to the rupture of small
bridging veins, ruptured vessels at the site of contusions, or tearing of small branches of
the cerebral arteries, particularly the middle cerebral artery (Adams 1975). SDHs are
divided into acute, subacute and chronic types.
26
Acute SDH is present in approximately one fifth of patients with severe TBI, and
almost 60% of all primarily evacuated traumatic mass lesions among these patients are
SDHs (Marshall et al. 1991a). The majority of patients with acute SDHs have concomitant focal lesions such as contusions and ICHs or DAI (Tandon 2001).
Subacute subdural haematoma is found between a few days and 2 weeks after injury,
whereas chronic SDH may be found weeks or even months afterwards (Adams 1975).
Fogelholm & Waltimo (1975) reported the incidence of chronic SDH to be 1.72 per
100 000 of population, increasing with age to 7.35 per 100 000 of population at 70–79
years. The most frequent additional risk factors for chronic SDH are coagulopathy and
alcoholism (Chen & Levy 2000).
The diagnostic examination of choice for SDHs is a head CT scan. An acute SDH is
typically visible as a high-density, crescentic collection with concave inner borders which
is not confined by the cranial sutures (Bagley 1999). Acute hyperdense blood becomes
isodense within 4 to 7 days and hypodense within 1 to 2 weeks, after which the density
increases again within 3 to 12 weeks because of fresh haemorrhage, until a reduction in
X-ray attenuation is brought about during the subsequent healing process (Stoodley &
Weir 2000). Subacute SDHs may occasionally be of mixed density. Isodense SDHs may
be difficult to diagnose on an unenhanced CT, and such haematomas are best detected
with MRI (Stieg & Kase 1998).
Surgery is the primary treatment for SDHs, being indicated when the thickness of the
blood clot exceeds 10 mm. Chronic SDHs can often be drained through a burrhole,
whereas craniotomy is favoured in acute cases (Tandon 2001). Mortality from acute SDH
is high. In a series of 1150 patients with severe head injuries, 101 had acute SDH, and
mortality among these exceeded 66% (Wilberger et al. 1991). The extent of the underlying brain injury is nevertheless thought to be more important than the SDH clot itself in
dictating the outcome (Wilberger et al. 1991).
2.3.6 Subarachnoid haemorrhage (SAH)
SAH can occur in various clinical contexts, the most common of which are head trauma
and spontaneous rupture of an intracranial aneurysm (Stieg & Kase 1998). Traumatic
SAH results from the disruption of small subarachnoidal vessels or direct extension into
the subarachnoidal space by a contusion or haematoma.
Traumatic SAH is usually diagnosed by means of a head CT scan, and it is often
present in patients with severe TBI, the proportion varying from 33% to 39% (Eisenberg
et al. 1990, Kakarieka et al. 1995, Servadei et al. 2002). The presence of traumatic SAH
is often associated with a poor outcome. Eisenberg et al. (1990) reported that head injury
patients with SAH had a two-fold increase in the risk of death relative to those without
SAH, and other investigators have arrived at similar findings, suggesting that the poor
outcome may be attributed to vasospasm due to the haemorrhage (Kararieka et al. 1995).
Servadei et al. (2002) have recently reported a similar incidence of SAH among patients
with head injury, a similar risk of death and a generally poor outcome, but showed in
addition that death among patients with traumatic SAH was related to the severity of the
initial mechanical brain damage rather than to the effects of delayed vasospasm and sub-
27
sequent secondary brain damage. Patients with traumatic SAHs more often had ICHs and
multiple parenchymal lesions than did those without SAH (Servadei et al. 2002).
2.3.7 Secondary brain injury
Traumatic brain injuries can be divided into primary and secondary types. Secondary
brain injury is important because much can be done to minimise it, whereas primary injury is unavoidable (Bullock et al. 1996, Maas et al. 1997).
Secondary brain injury may occur at any time after the initial impact, and can be either
systemic or intracranial (Maas et al. 1997). The causes of intracranial secondary brain
injury are infection, cerebral ischaemia, and seizures (Maas et al. 1997, Lindsay & Bone
2001), while the systemic insults are hypoxaemia, hypotension, hypercapnia, hypocapnia, hyperthermia, hyperglycaemia, hypoglycaemia, and hyponatraemia (Maas et al.
1997).
Cerebral ischaemia, which is the leading cause of secondary brain damage after TBI
(Graham et al. 1989, Maas et al. 1997), may be due to systemic hypoxia or hypotension
or impaired cerebral perfusion due to increased intracranial pressure (Maas et al. 1997).
Mass lesions, brain swelling and oedema are all able to raise intracranial pressure.
Increased intracranial pressure may not only lead to cerebral ischaemia but also to tonsillar or tentorial herniation (Lindsay & Bone 2001). Brain swelling is thought to be due to
increased intravascular blood within the brain, whereas brain oedema refers to a specific
situation in which there is an increase in extravascular brain water (Gennarelli 1993).
Mass lesions such as EDHs, SDHs and ICHs may develop secondarily within minutes to
hours after trauma, but also within the next few days (Bullock et al. 1990, Mertol et al.
1991). Infections may develop after a dural tear, which provides a route for infection into
the brain (Bayston et al. 2000). Meningitis and cerebral abscess are the clinical features of
secondary infection.
2.3.8 Skull and facial bone fracture
Brain injuries are often associated with skull fractures, either linear or depressed, or fractures of the facial bones. The incidence of skull fractures in MHI patients varies from 3%
to 11% (Dacey et al. 1986, Stiell et al. 2001b), while Rimel et al. (1982) reported that
24% of their patients with moderate TBI had a skull fracture. Correspondingly, Shapiro et
al. (2001), reviewing all trauma admissions during an 11-year period at a level I trauma
centre, found that 11% of the patients had a facial bone fracture.
Skull or facial bone fracture does not directly mean brain injury. Williams et al. (1990)
even suggested that TBI patients with a depressed skull fracture without an underlying
lesion can be classified as mild. Patients with a skull fracture have an increased risk of
intracranial haematoma, however (Mendelow et al. 1983), and it has been estimated that
approximately one out of every four head injury patients with a skull fracture has an
28
intracranial haematoma and half of the patients who develop a haematoma have a fracture
(Ingebrigtsen et al. 2000a).
Basal skull fractures can be suspected if the patient has nasal cerebrospinal rhinorroea,
bilateral periorbital haematoma, subconjunctival haemorrhage, bleeding through a torn
tympanic membrane, or bruising over the mastoid (Lindsay & Bone 2001). Most skull
and facial bone fractures are diagnosed by skull radiography or a head CT scan, is the latter currently being a modality of choice if a skull fracture is suspected (Hofman et al.
2000, Salvolini 2002, Vos et al. 2002).
2.4 Diagnosing brain injury in patients with head injury
2.4.1 Clinical examination
A clinical neurological examination forms the basis for assessing head injury patients on
admission, as this can reveal brain injury and help the physician to estimate the outcome
(Maas et al. 1997, Vos et al. 2002).
Although typical symptoms such as headache, neck pain, nausea, dizziness and vomiting symptoms are frequent among TBI patients shortly after trauma, they are not specific
to brain injury, as they may be due to a mixture of brain injury, peripheral vestibular
injury and injury to the soft and bony tissues of the head or neck (de Kruijk et al. 2001b).
The relationship between amnesia and unconsciousness in patients with TBI is
depicted in Figure 1. The assessment and follow-up of impaired consciousness and amnesia plays an important role in such cases as these features are known to correlate with the
severity of TBI (Russel & Smith 1961, Murray et al. 1999, van der Naalt et al. 1999). The
GCS (Table 1) is currently the most widely used tool among clinicians and investigators
for assessing coma and impaired consciousness (Teasdale & Jennett 1974), but as it was
initially developed for patients with severe head injury, there is a wide heterogeneity in
the severity of TBI among patients with an admission GCS score of 13 to 15 (Williams et
al. 1990, Ingebrigtsen et al. 2000a). It has been suggested that the length of PTA may correlate better with the outcome among moderate-to-mild TBI patients (van der Naalt et al.
1999), and there are few validated questionnaires available to assess the length of PTA
(Fortuny et al. 1980, Shores et al. 1986, King et al. 1997). In any case, both GCS and
PTA have their limitations, since they are vulnerable to confounding factors such as alcohol intoxication (Galbraith et al. 1976, Wrightson & Gronwall 1981, Jagger et al. 1984).
Absence of the pupillary light reflex and/or oculocephalic reflex was also found to be
associated with a poor outcome after severe head trauma (Attia et al. 1998). Expanding
intracranial lesions such as EDH may be revealed by the absence of a pupillary light
reflex (Lindsay & Bone 2001). Basal skull fractures can also be identified by clinical
examination if the patient has nasal cerebrospinal fluid rhinorroea, bilateral periorbital
haematoma, subconjunctival haemorrhage, bleeding through a torn tympanic membrane,
or bruising over the mastoid.
29
Fig. 1. Relationship between amnesia and loss of consciousness in patients with TBI.
2.4.2 Skull radiography
Skull radiography can detect linear skull fractures, depressed fractures, fluid in the paranasal sinuses and air inside the skull. The skull fractures diagnosed in this way carry an
increased risk of intracranial haematoma (Mendelow et al. 1983), but skull radiography
does not detect intracranial haematoma as such, nor does it reveal brain damage, and it
has been concluded in a recent meta-analysis that skull radiography is of little value for
the initial assessment of patients with head injury (Hoffman et al. 2000).
2.4.3 Computed tomography (CT)
A head CT scan is considered the gold standard for the detection of intracranial abnormalities in head injury patients (Vos et al. 2002), as it enables extra-axial haematomas
such as EDHs, SDHs, and SAHs, intra-axial lesions such as cerebral contusions and some
DAIs, and secondary lesions such as brain oedema and herniation to be detected (Bešenski 2002).
A head CT scan has several important purposes when examining patients with head
injury. Firstly, it is an objective method for documenting scalp, bone and brain damage
(Bagley 1999), secondly, initial management decisions can be based on the CT findings
(Stieg & Kase 1998), thirdly, the presence of CT abnormalities and their type can assist in
assessing the severity of brain injury (Marshall et al. 1991b), and fourthly, acute head CT
30
findings provide a baseline from which to monitor changes in TBI over time (Bešenski
2002).
If all head trauma patients with an initial GCS score of 13 to 15 are examined, the
presence of traumatic intracranial findings in the head CT scan varies from 2 to 11%
(Moran et al. 1994, Nagy et al. 1999, Haydel et al. 2000, Livingston et al. 2000, Stiell et
al. 2001b), but if we take those with an admission GCS score of 9 to 12, the presence of
intracranial abnormality exceeds 30% (Rimel et al. 1982), and for those with a GCS score
of 8 or less it may even exceed 94% (Eisenberg et al. 1990).
A normal head CT scan on admission has been found in two large multicentre studies
to be good for excluding the need for neurosurgical intervention (Livingston et al. 2000,
Shackford et al. 1992). The series considered by Shackford et al. (1992) included 2766
head injury patients with an admission GCS at or above 13, among whom none of those
who had a normal neurological examination and normal head CT scan needed neurosurgical intervention (negative predictive value 100%). Livingston et al. (2000) studied 2152
head injury patients with an admission GCS score of 14 to 15 and reported that a normal
initial head CT scan excluded the need for a neurosurgical operation with an accuracy of
99.7%. They therefore concluded that MHI patients with a normal initial head CT scan
can safely be discharged from the emergency department without observation (Livingston et al. 2000).
On the other hand, the use of a head CT scan is not efficient, since almost 80% of the
scans ordered on account of MHI are negative (Stiell et al. 2001a). It is regarded as mandatory for patients with moderate-to-severe head injury (Ingebrigtsen et al. 2000a), but
the indications for imaging in the case of patients who are initially assessed as having
MHI are controversial.
Two large prospective studies have validated a set of clinical criteria for identifying
MHI patients who need to undergo head CT scanning on admission (Stiell et al. 2001b,
Haydel et al. 2000). Haydel et al. (2000) studied 1411 consecutive MHI patients with an
admission GCS score of 15 and found that if all those with risk factors (headache, vomiting, seizure, PTA, drug or alcohol intoxication, or age over 60) were imaged, all the traumatic intracranial abnormalities could be identified (sensitivity 100%, 95% CI 95 to
100%). On their criteria, 78% of MHI patients should undergo a head CT scan (Haydel et
al. 2000).
Stiell et al. (2001b) reported two sets of clinical criteria for ordering head CT scans for
MHI patients, based on a series of 3121 consecutive patients with an admission GCS
score of 13 to 15. The first set of criteria included five risk factors for predicting the need
for neurosurgical intervention (GCS score <15 at 2 h after injury, suspected open or
depressed skull fracture, any sign of basal skull fracture, two or more episodes of vomiting, and age at or over 65). These enabled all such complications to be identified (sensitivity 100%, 95% CI 92 to 100%), and implied that only 32% of MHI patients would need
to undergo a head CT scan. The second set of criteria, which included two risk factors
(amnesia before impact > 30 minutes and a dangerous mechanism of injury, such as a
pedestrian struck by a motor vehicle, an occupant ejected from a motor vehicle, a fall
from >five stairs), predicted 98% (95% CI 96 to 99%) of all intracranial lesions depicted
by a CT scan. The use of these risk factors would lead to the ordering of a CT in 54% of
cases (Stiell et al. 2001b). It may be concluded that not all MHI patients need to undergo
31
head CT scanning and that imaging resources can be directed to those with significant
risk factors, leading to a reduction in total costs (Stiell et al. 2001b, Haydel et al. 2000).
A head CT scan can also be used as a tool for predicting the outcome after head injury.
Marshall et al. (1991b) reported a scale based on CT findings that, together with age and
the best motor GCS score, predicted mortality with a sensitivity of 59% and a specificity
of 87%. The CT is negative in some patients with severe head injury, however, the proportion being 6% according to Eisenberg et al. (1990), although Lobato et al. (1986) had
reported earlier that approximately one half of such patients develop lesions during follow-up and that brain atrophy, associated with a poor outcome, often developed within
the next few months (Lobato et al. 1986). The findings of Lobato et al. (1986) and Eisenberg et al. (1990) may be explained by the fact that head CT scanning is insensitive for
detecting DAI, and a more sensitive imaging method, such as MRI, is warranted for such
patients (Bešenski 2002).
2.4.4 Magnetic resonance imaging (MRI)
MRI is more sensitive than a head CT scan for all types of traumatic brain lesions except
skull fractures and SAHs (Bešenski 2002), but it has some limitations. Firstly, the equipment is not as common as for CT, and secondly, the scanning time is longer and problems may be experienced in imaging an unstable trauma patient and organising monitoring outside the magnetic resonance field.
Most studies dealing with MRI and TBIs are small and concentrate on severe brain
injuries using images obtained with only T1 and T2-weighted sequences. Acute MRI has
been found to depict traumatic intracranial pathology in 25 to 57% of MHI patients and in
10% of those with a normal head CT scan (Ingebritsen et al. 1999, Voller et al. 1999,
Hofman et al. 2001). In cases of more severe head injuries the presence of intracranial
lesions in MRI has varied from 60 to 92%, but the image were often obtained at the
chronic stage (Hadley et al. 1988, Levin et al. 1988, Fiser et al. 1998).
DAI is the most common type of brain injury seen in MRI of TBI patients, but head
CT scans detected only 19% of non-haemorrhagic DAIs (Gentry et al. 1988a). For the
haemorrhagic subset of DAIs, however, MRI was not superior to CT (Gentry et al.
1988b). Cortical contusions without haemorrhagic components are also better depicted by
MRI, but if haemorrhage is present, CT may reveal all the contusions (Gentry et al.
1988b, Hesselink et al. 1988). If a contusion is located in the brain stem, MRI can detect
it more sensitively (Gentry et al. 1988b). SDHs are also best detected with MRI (Gentry
et al. 1988b, Kelly et al. 1988) and finally, the method is superior to a head CT scan for
detecting all types of brain injury in the subacute and chronic stages (Groswasser et al.
1987, Kelly et al. 1988).
Despite its better sensitivity, MRI does not alter the clinical management of imaged
TBI patients in the acute stage (Fiser et al. 1998, Kelly et al. 1988). An acute MRI is recommended, however, if the CT is normal but the presence of TBI is suspected, and if a
patient is to be imaged in the subacute and chronic stages (Aikuisiän aivovammojen
käypä hoito 2003).
32
New magnetic resonance-based imaging methods have been developed within the last
few years, e.g. diffusion-weighted imaging, perfusion-weighted imaging, proton magnetic
resonance spectroscopy and fluid-attenuated inversion-recovery sequences (Ashikaga et
al. 1997, Cecil et al. 1998, Ingebrigtsen 1999, Garnett et al. 2001, Sinson et al. 2001,
Hammound & Wasserman 2002). Although these have not been validated in large groups
of TBI patients, their use may be indicated in certain situations, at least in the chronic
stages, because they may reveal some undetected small traumatic lesions (Aikuisiän aivovammojen käypä hoito 2003).
2.4.5 Single photon emission computed tomography (SPECT)
Unlike static neuroimaging techniques such as CT or MRI, SPECT produces functional
rather than structural images of the brain. Using radionuclides, the cerebral blood flow is
imaged and reconstructed as a visual data set which also indirectly describes the cerebral
metabolism (Umile et al. 1998).
SPECT is generally more sensitive than CT and MRI for detecting abnormalities after
TBI (Ichise et al. 1994, Ito et al. 1997, Hofman et al. 2001). Ichise et al. (1994) examined
29 patients with different degrees of head injury and found SPECT abnormalities in 66%,
whereas MRI detected abnormalities in 45% and CT in 34%. SPECT detects more lesions
in the acute stage than in the later stages (Abdel-Dayem et al. 1998), and the majority of
SPECT abnormalities are found in the frontal and temporal regions of the brain (AbdelDayem et al. 1998). Some investigators have also found a correlation between neuropsychological tests and SPECT abnormalities (Ichise et al. 1994, Hoffman et al. 2001).
SPECT has many limitations. Firstly, there are limited resources for performing it routinely, and secondly, although it can detect many lesions which cannot be seen on CT or
MRI, it remains to be elucidated whether these really represent traumatic lesions (Davalos
& Bennett 2002). Depression may reduce perfusion and cause false positive lesions in
SPECT, for example (Umile et al. 1998).
2.4.6 Electroencephalography (EEG)
The use of EEG for the acute assessment of TBI patients has become rare. EEG describes
the functional response of the brain to insult, EEG abnormalities are often seen in head
injury patients. Geets & Zegher (1985) studied 400 MHI patients and found abnormalities in 27%, whereas Voller et al. (1999) found MRI abnormalities in 25% of MHI
patients but none showed EEG abnormalities. Thatcher et al. (1991) examined 162 closed
head injury patients, most of whom had moderate-to-severe head injuries, and found that
EEG was better at predicting the outcome than the GCS score or head CT scans (Thatcher
et al. 1999). However, Attia & Cook (1998), in their review of all studies dealing with
EEG and the outcome in patients with TBI, concluded that it is still unclear how much
incremental information on clinical examination is added by EEG for predicting the outcome.
33
2.4.7 Biochemical markers
Despite significant progress in cerebral monitoring, it is still difficult to quantify the
extent of primary and ongoing secondary brain injury after head trauma. Thus, there is a
major need for a supplementary diagnostic test to follow CT and MRI, such as a biochemical marker of brain damage (Ingebrigtsen & Romner 2002).
Bakay & Ward (1983) defined an ideal biochemical serum marker of brain damage as
one with high sensitivity to brain injury and high specificity for the brain tissue. It should
also be released into the serum rapidly and only after irreversible brain damage, and it
should have adequate clinical relevance.
Numerous potential biochemical markers of brain damage have been studied in
patients with head injury, including creatine kinase BB (Nordby & Urdal 1985), myelin
basic protein (Thomas et al. 1978), neuron specific enolase (Raabe et al. 1999a) and protein S100B (Townend et al. 2002). Glial fibrillary acidic protein has also been suggested
as a potential marker of brain damage, but there are no studies dealing with it in the context of TBI (van Geel et al. 2002). The most promising markers are neuron specific enolase and protein S100B.
2.4.7.1 Neuron specific enolase (NSE)
NSE is a dimeric protein with a molecular mass of 78 kDa, the and isoforms of which are
mainly expressed in neurons and peripheral neuroendocrine tissues (Cooper 1994). NSE
is located in the cytoplasm of the neurons, and it is considered a possible marker of neuron damage. There are many limitations on its use, however. It is expressed in erythrocytes, for example, and is known to increase in serum due to haemolysis (Johnsson 1996).
Serum values of more than 10 µg/L are considered pathological in studies dealing with
head injuries (Woertgen et al. 1997).
de Kruijk et al. (2001c) measured NSE in 104 MHI patients, but failed to find any significant association between the marker and the length of PTA, reported LOC, or acute
symptoms due to trauma. They did not report the number of patients above the cut-off
level of 10 µg/L, but the 90th percentile of NSE was 14.4 in the patients with MHI and
13.3 in healthy controls (de Kruijk et al. 2001c).
Woertgen et al. (1997) reported that all their patients with severe head injury had elevated levels of NSE, but still had to admit that NSE neither predicted the outcome
(Woertgen et al. 1997, Raabe et al. 1999a) nor correlated with head CT scan findings
(Raabe 1998). Herrmann et al. (2001) found a trend between increased concentrations of
NSE and neurospychological deficits at two weeks after trauma, but not at six months, in
patients with moderate-to-mild head injury, which led Ingebritsen & Romner (2002) to
conclude that despite some promising findings, the sensitivity of NSE is inadequate and
its clinical value as a marker of traumatic brain damage is questionable.
34
2.4.7.2 Protein S100B
Protein S100 is a dimeric protein with a molecular mass of 21 kDa (Zimmer et al. 1995).
It was first described by Moore (1965) and its name is derived from its solubility in 100%
saturated ammonium sulphate at neutral pH. Its two isoforms, ββ and αβ, referred to as
S100B, have been studied as a biochemical marker of acute brain damage (Ingebrigtsen
& Romner 2002).
S100B is expressed in most human tissues, but the highest concentrations are found in
the astroglial cells of the central nervous system (Hidaka et al. 1983, Kato & Kimura
1985, Haimoto et al. 1987, Zimmer DB & van Eldik 1987). The second highest tissue
concentration has been found in adipose tissue, where it is consistently approximately one
third to one fourth of that found in brain tissue (Hidaka et al. 1982, Zimmer & van Eldik
1987). The median serum value of S100B in healthy people has been found to be 0.01 µg/
L with an upper 97.5% cut-off level of 0.13 µg/L (Anderson et al. 2001). Excretion into
urine is the major route for its elimination and its half-life in serum is thought to be short,
between 25 and 113 minutes (Usui et al. 1989, Jönsson et al. 2000, Ytrebø et al. 2001).
Damage to glial cells and a reduced integrity of the blood brain barrier may lead to
increased serum S100B concentrations (Nygaard et al. 1997), and consistent with this,
elevated S100B levels have been found in patients with TBIs of varying severity. Ingebrigtsen et al. (1995) initially reported that S100B was at or above 0.50 µg/L in 20% of
their MHI patients who had normal head CT scans on admission, while in a later study
that included 182 MHI patients 35% had S100B values at or above 0.20 µg/L (Ingebrigtsen et al. 2000b).
Elevated S100B levels in patients with MHI have been found to be associated with
prolonged hospitalisation and the presence of neuropsychological dysfunctions (Ingebrigtsen et al. 1997, Waterloo et al. 1997, Ingebrigtsen et al. 1999, Ingebrigtsen et al.
2000b, Herrmann et al. 2001), and also to predict the presence of intracranial lesions seen
on a head CT scan in cases initially assessed as having MHI (Ingebrigtsen et al. 1999,
Ingebrigtsen et al. 2000b, Biberthaler et al. 2001). Even more importantly, normal or low
S100B has been shown to exclude the presence of intracranial abnormalities in a head CT
scan with a high accuracy, since a cut-off level of 0.20 µg/L has been found to predict a
normal CT scan with an accuracy of 99%.
In patients with moderate-to-severe head injury, increased S100B values have been
associated with lower GCS scores shortly after trauma (Herrmann et al. 2000, Romner et
al. 2000), traumatic lesion size as seen in a head CT scan (Raabe et al. 1998, Romner et
al. 2000) and ongoing secondary brain injury (Raabe et al. 1999b, Woertgen et al. 1997).
They have also been found to predict a poor outcome in these patients. Woertgen et al.
(1997), examined 30 patients with severe head injury (GCS score of 8 or less), and found
that an unfavourable outcome on discharge was associated with higher S100B values than
was a favourable outcome, and later the same authors included 44 patients with severe
head injury in their analysis and found that the S100B serum levels on admission predicted the outcome better than either the GCS or the Marshall Computed Tomographic
Classification (Woertgen et al. 1999). Raabe et al. (1999b) included 84 patients with
severe head injury in their series and found that 58% of the patients who died had a peak
S100B value of at least 2 µg/L shortly after the trauma. S100B was also found to be an
independent prognostic factor for survival, even when age, GCS score, intracranial pres-
35
sure and head CT scan findings were taken into account (Raabe et al. 1999b). Townend et
al. (2002), studying 118 patients with an initial GCS score of 4 to 15, found that a serum
S100B concentration above 0.32 µg/L predicted an unfavourable outcome at one month
post injury with a sensitivity of 93% and a specificity of 72%, while a good recovery at
the same point (extended GOS ≥7) was best predicted with a cut-off of 0.27 µg/L, giving
a sensitivity of 76% and a specificity of 69% (Townend et al. 2002). In conclusion,
S100B measured shortly after trauma has been shown to correlate with the severity of
TBI and predict the outcome even when other prognostic factors such as the GCS score,
CT findings, intracranial pressure level and age are taken into account.
Anderson et al. (2001) reported on a series of 17 trauma patients with severe extracranial injuries without evident head injury, all of whom had elevated S100B levels on
admission (0.19 to 10.2 µg/L). Their observations suggest that the S100B measured in
serum could also be of extracranial origin, but further research is required to demonstrate
the extents to which different types of extracranial trauma contribute to the elevation in
S100B.
2.4.8 Neuropsychological assessment
Neuropsychological and neurobehavioural dysfunctions often complicate the outcome
after TBI. In fact, outcome studies dealing with severe TBIs have shown that chronic disability and the burden imposed on the family are primarily attributable to neuropsychological and neurobehavioural deficits, whereas motor and sensory deficits are less consequential (Levin 1993).
Neuropsychological assessment plays an important role in determining the extent and
severity of the sequelae of head trauma, and the healing process after TBI can also be followed up with neuropsychological tests. A recent Finnish guideline recommends neuropsychological assessment for all TBI patients who are still suspected of having some neuropsychological or neurobehavioural deficits at one month post injury (Aikuisiän aivovammojen käypä hoito 2003). The results of neuropsychological tests are not specific to
TBI, however, but are vulnerable to many confounding variables such as alcohol abuse
and psychotropic drug effects (Mearns & Lees-Haley 1993). Thus, a comprehensive
assessment performed by a professional neuropsychologist is the key factor in obtaining a
reliable test result (Mearns & Lees-Haley 1993, Aikuisiän aivovammojen käypä hoito
2003).
In patients with MHI, information processing speed, memory and attention are the
most common impaired functions, and deficits are often seen during the first weeks after
trauma (Gronwall & Wrightson 1981, Levin et al. 1987, Stuss et al. 1989). In a recent
meta-analysis, the prevalence of impaired neuropsychological performance among this
group of patients was found to vary from 1.4 to 7.4%, and the most common single deficit
was attributed to the measures of attention (Binder et al. 1997). The authors concluded,
however, that neuropsychological assessment is likely to have a positive predictive value
of less than 50% in patients with mild head injury, and that clinicians should exercise considerable caution before diagnosing TBI based on the findings (Binder et al. 1997).
36
The prevalence of neuropsychological impairments increases sharply in patients with
more severe head injury. Herrmann et al. (2001), studying patients with mild-to-moderate head injury, found that 74% showed impairment at two weeks post injury and 69%
still displayed disorders at six months. Typical dysfunctions were attributed to measures
of attention, executive functions and memory performance (Herrmann et al. 2001). Neurospychological impairments practically always complicate the outcome for patients with
severe head injury (Levin 1993). Recovery is rapid within the first year after trauma
(Levin et al. 1987, Levin 1993), but subtle changes in memory, attention and behavioural
adaptation may continue for up to 2 years after injury, although the patient’s overall cognitive capacity may already have reached a plateau (Stuss et al. 1985, Levin 1993).
2.5 Treatment of head injury
Although there is very little firm scientific evidence on which to base the acute management of head injury patients (Young A & Willatts 1998, Thornhill et al. 2000), current
evidence suggests that the aims must differ according to degree of the injury (Maas et al.
1997, Ingebrigtsen 2000a). The management of those who are initially evaluated as
having MHI should be focused on assessing the risk of traumatic intracranial haematoma
and preventing persistent PCSs (Williams et al. 1990, Stein & Spettell 1995, Ingebrigtsen et al. 2000a, Viola et al. 2000, Servadei et al. 2001, Vos et al. 2002), whereas the management of patients with moderate-to-severe head injury must be directed at minimising
secondary brain damage (Menon 1999).
Three recent guidelines summarising the acute management of patients with MHI
maintain that this should be based on the risk for intracranial complications (Ingebrigtsen
et al. 2000a, Servadei et al. 2001, Vos et al. 2002). In the scheme shown in Table 2, MHI
patients are divided into three risk groups: low-risk patients, having an admission GCS
score of 15 without LOC, PTA or additional risk factors, medium-risk patients, having an
admission GCS score of 15 with a history of brief LOC or amnesia, and high-risk
patients, who initially have a GCS score <15. If any of the listed additional risk factors is
present, the patient must be included in the high-risk group (Table 2). If a head CT scan
reveals intracranial pathology with or without a need for intervention, then consultation or
transfer to a neurosurgical centre is recommended. The observation stage can also be performed in a local trauma or medical centre. Instructions should always be given to
patients who are sent home (Ingebrigtsen et al. 2000a).
37
Table 2. Complication rates and management of MHI patients by risk of intracranial lesions.
Severity category
Approximate risk of lesions (%)
Management
Intracranial
Surgical
Low risk
Almost zero
Almost zero
Send home with instructions
Medium risk
<10
1–3
CT; If none, observe for 12 h
High risk
15–20
3–6
CT mandatory; observe for 12 h
Additional risk factors: prolonged unconsciousness or amnesia, anticoagulation or haemophilia, demonstrated
or suspected skull fracture, post-traumatic seizures, neurological deficit, multi-injuries, age > 60 years, vomiting ≥ 2 episodes. Modified from Ingebrigtsen et al. 2000a, Haydel et al. 2000, Servadei et al. 2001, Vos et al.
2002, Stiell et al. 2001b
Inconsistent findings exist as to whether a routine follow-up and counselling should be
given for every patient with MHI and whether this can prevent persistent PCSs. Some
reports support reassurance and counselling (Relander et al. 1972, Alves et al. 1993, Ponsford et al. 2002), whereas others do not (Wade et al. 1997). Bed rest after head trauma
has not been shown to prevent PCSs (de Kruijk et al. 2002b).
Moderate-to-severe head injuries have to be treated in trauma centres, since this has
been shown to reduce overall mortality among such patients (The Brain Trauma Foundation 2000a). Two recent guidelines summarising the acute management of severe head
injury patients (Bullock et al. 1996, Maas et al. 1997) both point out that management
should be focused on preventing secondary brain damage. The preventable causes of such
injury can be divided into systemic ones such as hypoxaemia, hypotension, hypercapnia,
hypocapnia, hyperthermia, hyperglycaemia, hypoglycaemia and hyponatraemia, and
intracranial ones such as mass lesions, brain swelling, oedema, seizures and infection
(Maas et al. 1997). The systemic causes can be monitored and treated by maintaining the
physiological conditions of the body (Menon 1999), while there are five interventions
available to treat and prevent intracranial causes, namely hyperventilation, mannitol
administration, cerebrospinal fluid drainage and the use of barbiturates or corticoids, but
all of these have failed to reduce death or disability in controlled trials (Roberts et al.
1998). There is general agreement, however, that cerebral perfusion pressure has to be
adequate in patients with head injury, between 60 and 70 mmHg, the accepted methods
for maintaining it being ones which either lower the intracranial pressure or raise the
mean arterial blood pressure (Menon 1999). It is accepted that all the aforementioned
interventions except for corticoids either lower the intracranial pressure or raise the mean
arterial pressure and thus maintain an adequate cerebral perfusion pressure (Maas et al.
1997). The indications for surgical treatment in cases of head injury are also generally
accepted. If an extra-axial haematoma of thickness over 10mm or an intra-axial haematoma volume of over 25–30 ml is observed, or if a clot appears to have raised the
intracranial pressure, surgery is indicated (Maas et al. 1997).
The use of prophylactic anticonvulsants in the acute stage is likely to prevent the
occurrence of early post-traumatic seizures, but there is no reliable evidence to support
their use for preventing late post-traumatic seizures (The Brain Trauma Foundation.
2000b). Early enteral feeding should be favoured, since it seems to be associated with a
trend towards a better outcome in terms of survival and disability (Yanagawa et al. 2002).
38
2.6 Outcome after head injury
The Glasgow Outcome Scale (GOS) introduced by Jennett & Bond (1975) for assessing
the outcome after head injury divides patients into five groups: dead, persistent vegetative state, severely disabled, moderately disabled and good recovery. This is a widely
used method to describe the overall outcome after head injury, but as it is likely to be
insensitive to mild disabilities, the authors later introduced an amendment called the
extended GOS, in which the three highest categories of the original version are divided
into better and worse levels (Jennett et al. 1981). Although the GOS and its amended version have been found to correlate with the emotional and cognitive consequences in
patients with severe head injury (Wilson et al. 2000), there has been a need for a practical outcome scale, especially for MHI patients, who often suffer from subjective symptoms rather than objectively measurable deficits. Consequently, King et al. (1995) introduced the Rivermead Post Concussion Symptoms Questionnaire, which is now widely
used for assessing PCSs attributable to mild head trauma (Ingebrigtsen et al. 2000b).
2.6.1 Mild head injury
Recovery from MHI is usually good and disability unusual. Binder (1997) concluded
after reviewing 17 studies dealing with 2660 MHI patients (GCS ≥ 13) that 86% returned
to their previous work and 7–8% had persistent PCSs. In fact, the prevalence of disability
after MHI is clearly attributable to the definition of what is called “mild”. Thornill et al.
(2000) studied head injury patients with an admission GCS of 13 to 15 and found that
they were moderately or severely disabled (GOS: severely disabled or moderately disabled) just as often as those who were initially assessed as having a more severe head
injury (GCS ≤ 13). Thus one should not pool all MHI patients with an admission GCS
score of 13 to 15 together but define those with intracranial lesions in CT or MRI or with
a PTA over 24 hours as having at least moderate brain injury (Williams et al. 1990,
Aikuisiän aivovammojen käypä hoito 2003).
MHI patients have also been reported to have approximately a 1.5 times higher risk of
epileptic seizures than healthy persons, a situation that can last for up to 4 years after
trauma (Annegers et al. 1998).
2.6.1.1 Post-concussion symptoms (PCSs)
MHI may result in a subjective symptom complex known as PCSs (Alexander 1995,
Bernstein 1999), to be found both in children and adults (Lundar & Nestvold 1985, Ingebrigtsen et al. 1998). The most common PCSs are headache, fatigue, dizziness, depression, poor concentration and irritability (Szymanski & Linn 1992). Most patients recover
from these symptoms within a year, but a significant minority, approximately 7–15%,
39
may have persistent symptoms lasting for more than a year after the trauma (Alexander
1995, Binder 1997).
PCSs were assessed earlier with the investigators’ own checklists, but there is now a
standardised questionnaire, known as the Rivermead Post Concussion Symptoms Questionnaire, which includes the sixteen most commonly reported PCSs (King et al. 1995).
There is no consensus as to whether one symptom or a certain number of symptoms lasting long enough should be referred to as the post-concussion syndrome (King 1997), nor
is there any consensus as to whether or not the symptoms should be divided into subgroups such as physical symptoms, cognitive complaints and behavioural and affective
symptoms (Bernstein 1999).
The aetiology of PCSs remains unclear. Demographic, psychogenic and organic factors have all been suggested as playing a role in their development (Lishman 1988,
Gasquoine 1997), and there is some evidence that age could increase their risk (Rutherford et al.1978). Similarly, females have been thought to develop PCSs more often than
males (Rutherford 1977, Bazarian et al. 1999). Psychogenic and behavioural factors such
as depression, emotional distress, alcohol or drug abuse and litigation have also been
thought to increase the risk of PCSs (Miller 1961, Lishman 1988, Bohnen & Jolles 1992,
Karzmark et al. 1995, Cattelani et al. 1996, King 1996). Organic factors have been poorly
studied, however. PTA as a marker of the severity of TBI has been assessed in relation to
PCSs (King 1996, Bazarian et al. 1999), and traumatic brain damage could be an underlying factor, at least in some patients. Mittl et al. (1994) found that 30% of their patients
who had been initially assessed as having MHI with normal CT had abnormalities compatible with DAI in MRI, while Ingebrigtsen et al. (2000b) found a tendency for an
increased frequency of PCSs in patients with an elevated serum S100B concentration.
The relationship between PCSs and neuropsychological deficits is unclear. Although
some investigators have found higher prevalences of specific deficits such as attention
and reaction time tests in neuropsychological tests performed on patients suffering from
PCSs, there have been a number of patients with PCSs without any deficit (Bohnen &
Jolles 1992, Bazarian et al. 1999).
In conclusion, PCSs relatively often complicate recovery after MHI, and in a small but
significant group of patients the symptoms may be persistent. The clinical picture of PCSs
reflects a multifactorial state in which organic, psychological and socioeconomic factors
may play a role (Lishman 1988). Individual symptoms may substitute for each other over
time and thus the association of a single symptom with damage in a certain region of the
brain may be difficult to establish (Bohnen & Jolles 1992). The role of brain injury in the
development of PCSs has been poorly studied, however. In any case, the prevention of
PCSs has been raised as one of the main aims in the management of MHI patients (Ingebrigtsen et al. 2000a).
2.6.2 Moderate-to-severe head injury
Moderate-to-severe head injury often leads to death or chronic disability. The GOS scores
reported after severe head injury, defined by an admission GCS score ≤8, in four large
studies are summarised in Table 3.
40
Table 3. Glasgow Outcome Scale (GOS) at six months post injury. Findings in four large
surveys of the outcome after severe traumatic brain injury.
EBIC core data
survey - severe
cases
International
databank - full
series
USA traumatic
coma databank
UK four centres
study
481
2959
746
976
Dead
40%
49%
36%
39%
Vegetative
4%
2%
5%
1%
Severe disability
16%
13%
16%
17%
Variable
Sample size
GOS
Moderate disability
19%
15%
16%
16%
Good recovery
21%
20%
27%
24%
Unspecified
3%
Modified from Murray et al. (1999)
Murray et al. (1999) also reported data on 273 patients with moderate head injury (admission GCS score 8 to 12) and found the GOS distribution at six months post injury to be
48% good recovery, 21% moderate disability, 14% severe disability, 1% vegetative state
and 16% dead. Similar findings have also been reported at three months (Rimel et al.
1982) and one year after moderate head injury (Thornhill et al. 2000). Thus the contributions of patients with severe and moderate head injury to the classes of severe disability
and moderate disability do not differ much, whereas the occurrence of death is more frequent in those with severe head injury and a good recovery in those with moderate head
injury.
There are a number of prognostic factors which may influence the outcome in patients
with moderate-to-severe head injury. Increasing age, lower GCS motor score, absence of
pupillary light reflex or oculocephalic reflex, and CT findings especially marks of
increased intracranial pressure or SAH, have been consistently found to be associated
with a poor outcome (Choi et al. 1988, Marshall et al. 1991a, Attia & Cook 1998, Signorini et al. 1999, Wardlaw et al. 2002), as also have multiple injuries (Gennarelli et al.
1989), haemostatic abnormalities (Olson et al. 1989), female gender (Farace & Alves
2000), previous head injury (Thornhill et al. 2000), apolipoprotein ε4 genotype (Teasdale
et al. 1997), alcohol abuse (Corrigan 1995) and lower socioeconomic status (Binder
1997, Wagner et al. 2000).
Patients with moderate-to-severe head injury have an increased risk of post-traumatic
epilepsy (Annegers et al. 1998), this being approximately 7% within 1 year after a closed
severe head injury and 12% within 5 years, or approximately 1% and 1.5%, respectively,
after a closed moderate head injury (Annegers et al. 1980, Annegers et al. 1998). The
presence of contusion, SDH, or skull fracture marks a specific type of trauma that
increases the risk of later seizures. In the case of both moderate and severe head injuries,
the increased risk of late seizures lasts for up to approximately ten years after the trauma
(Annegers et al. 1998).
41
2.7 Alcohol and head injury
2.7.1 General aspects
Alcoholism and hazardous alcohol drinking have an enormous impact on the productivity and quality of life in Western countries. It was estimated that the total annual costs of
alcohol misuse in the US in 1985 exceeded $86–100 billion (Rice et al. 1991, Angell &
Kassirer 1994), and ten years later the total costs were estimated to have increased to
$175.9 billion (Rice 1999). Thirty three per cent of all economic costs attributed to
motor-vehicle crashes, for example, have been estimated to be associated with alcohol
(CDC 1993).
In Finland, the annual direct costs arising from alcohol misuse exceed 550–705 million
euros. If all the direct medical care expenditure, indirect costs and the value of lost productivity, including persons who die prematurely due to alcohol misuse, the total annual
costs are estimated to reach 2443–4563 million euros (Päihdetilastollinen vuosikirja
2003).
2.7.2 Alcohol drinking as a risk factor for trauma
Acute hospitalisations are often associated with alcohol, so that Charalambous (2002)
estimated that 2–40% of all accident and emergency department attendances are of this
kind, and alcohol is especially linked to traumas, approximately one half of all trauma
patients being BAC-positive on admission and more than a third having a BAC at or
above 100mg/dL (Rivara et al. 1993a). A high incidence of acute alcohol abuse has also
been found among adolescents, to the extent that Porter (2000) reported that 32% of a
series of 2724 trauma patients aged 12–24 years were BAC-positive on admission.
There is direct evidence that alcohol intoxication increases the risk of trauma (Honkanen et al. 1976, Cherptitel et al. 1995, Rivara et al. 1997, McLeod et al. 1999, Li et al.
2001, Borges et al. 2004). Cherpitel et al. (1995) reported that the risk of injury was
found to increase with an average daily consumption of one drink and with a frequency of
consuming five or more drinks on one day more often than twice a year. The case-control
study by McLeod et al. (1999) showed in a multivariate analysis after adjustment for
demographic variables that the consumption of more than 60 grammes of ethanol (pure
alcohol) in a 6-hour period produced an odds ratio of 3.4 (95% CI 1.8–6.4) on sustaining
an injury. Alcohol intoxication has also been found to be associated with other forms of
risk behaviour for sustaining an injury, such as suicidal ideation and violence (Field et al.
2001).
42
2.7.3 Alcohol drinking as a risk factor for head injury
Alcohol ingestion is often involved in head injuries, the proportion of BAC positives having been found to be over 50% in prospective head trauma series (Rimel et al. 1982, Brismar et al. 1983, Corrigan 1995, Dikmen et al. 1995), while the number of patients with
BAC at or above 100mg/dL has been reported to vary from 35 to 40% (Rimel et al. 1981,
Dikmen et al. 1995). Head injury patients are also often chronic alcohol misusers.
Corrigan (1995) found in a review of seven studies that the prevalence of chronic alcohol
abuse varied from 16% to 66%. Bias was evident in the case of the lowest rates, because
the findings were based on chart reviews (Corrigan 1995). Brismar et al. (1983) found
that psychiatric examination revealed alcohol dependence in 43 out of 100 consecutive
head injury patients. Chronic alcohol misuse among head injury patients also seems to be
associated with many forms of risk behaviour which may compound the risk of head injury. These include lower educational attainment, problems with the law, lower perceived
social support, and greater prevalence of other substance abuse (Cherner et al. 2001).
2.7.4 Alcohol and trauma morbidity and mortality
Ward et al. (1982) reported that mortality after trauma was significantly lower among
those with a positive BAC on admission than in sober counterparts, and suggested that
alcohol may have some protective effects on the consequences of injury (Ward et al.
1982). Patients who died on the scene were not included in the series. It is known, however, that many accidental deaths occur before hospital admission (Klauber et al. 1981),
so that the finding of Ward et al. (1982) may be biased. Waller et al. (1986) later found
after studying more than 1 million drivers involved in motor vehicle crashes that the
drinking drivers more often suffered serious injury or death than the sober ones, and similar findings have also been reported in bicycling injuries (Li et al. 2001). Thus alcohol
ingestion is more likely to potentiate the primary injury than to provide protection from
its consequences. Alcohol intoxication on admission has also been shown to result in an
increased use of invasive diagnostic and therapeutic procedures (Gurney et al. 1992,
Jurkovich et al. 1992, Melnick et al. 2000), and there is evidence that alcohol abusers
often suffer recurrent traumas (Rivara et al. 1993b).
2.7.5 Alcohol and traumatic brain injury morbidity and mortality
The pathophysiological changes associated with acute and chronic alcohol exposure in
the setting of TBI are complex. Alcohol intoxication can cause haemodynamic and respiratory depression, blood-brain barrier disruption and haemostatic impairments (Zink et al.
1993, Kelly 1995). Kelly et al. (1997a) found in an experimental setting involving brain
injury in rats that high-dose acute alcohol ingestion (3g/kg) increased mortality after trauma, whereas better recovery rates were recorded in the low (1g/kg) and moderate (2.5g/
43
kg) alcohol dose groups. Theoretically, alcohol may also be neuroprotective, since it
causes inhibition of N-methyl-D-aspartate (NMDA) receptors (Kelly 1995). On the other
hand, chronic alcohol exposure results in up-regulation of NMDA receptors and downregulation of -aminobutyric acid receptors, and this adaptation may result in hyperexcitability during withdrawal and thus exacerbate TBI (Lovinger 1993, Kelly 1995). There is
no clear experimental evidence that chronic alcohol administration exacerbates TBI, however. Neither 6 weeks nor three months of alcohol ingestion in rats was found to have any
significant exacerbating effects on neurological motor deficits or sizes of morphological
brain lesions (Shapira et al. 1997, Masse et al. 2000).
The contribution of acute alcohol intoxication to the outcome after human head injury
remains to be elucidated. There are studies in which alcohol intoxication on admission
has been found to predict either a favourable (Kraus et al. 1989) or an unfavourable outcome (Brooks et al. 1989, Sparadeo & Gill 1989, Kelly et al. 1997b, Bombardier &
Thurber 1998), and studies in which alcohol has not been found to correlate with the outcome at all, or else the correlation has been lost when other prognostic factors have been
taken into account (Choi et al. 1988, Ruff et al. 1990, Signorini et al. 1999, Wagner et al.
2000). In contrast, chronic alcohol misuse has quite consistently been found to be associated with a poor outcome. Corrigan (1995) concluded after reviewing seven studies dealing with this relationship that only one had failed to find such an association. Separate
associations between alcohol abuse and more severe primary injury, higher mortality rate
and poorer neuropsychological and overall outcome have also been reported (Corrigan
1995).
2.8 Identification of hazardous alcohol drinking
Hazardous alcohol drinking often means frequent drinking aimed at intoxication. The
identification of alcohol misuse has been based on a clinical history, specific questionnaires and various laboratory tests or combinations of tests (Ewing 1984, Skinner et al.
1986, Ross et al. 1990, Mihas & Tavassoli 1992, Hartz et al. 1997). In the case of trauma
patients, the results of clinical histories, questionnaires and laboratory tests of alcohol
misuse have been compared with clinical diagnoses of alcohol dependence (Soderstrom
et al. 1997, Ryb et al. 1999), or with each other (Rivara et al. 1993, Nilssen et al. 1994,
Dikmen et al. 1995, Bombardier et al. 1997b, Cherner et al. 2001), but there have been
no studies dealing with the identification of different patterns of alcohol drinking.
44
2.8.1 Tools for identifying hazardous alcohol drinking
2.8.1.1 Questionnaires and interviews
There are a number of questionnaires designed to identify and assess alcohol misuse and
dependence, of which the most common are the Michigan Alcoholism Screening Test
(MAST) (Selzer 1971), the self-administered Short Michigan Alcoholism Screening Test
(SMAST) (Selzer et al. 1975), the Alcohol Dependence Scale (Skinner & Allen 1982),
the CAGE questionnaire (Ewing 1984), Self-Administered Alcoholism Screening Test
(SAAST) (Hurt et al. 1980) and the Alcohol Use Disorders Identification Test (AUDIT)
(Saunders et al. 1993). Most of these have been validated with materials consisting of
alcoholics and non-alcoholics, and they have been shown to distinguish between them
with high sensitivity and specificity (Davis et al. 1987, Ross et al. 1990).
There is also a structured interview for assessing the amount of alcohol drinking and
its pattern. The Timeline Followback technique is a retrospective survey which includes
memory aids to enhance patient recall and is thought to allow the collection of reliable
information on a period of at least 12 months (Sobell & Sobell 1995, Allen et al. 1997).
2.8.1.2 GGT
Gamma-glutamyl transpeptidase (GGT) is a membrane-bound glycoprotein found in the
membrane fractions of many tissues, including liver, kidney, brain, spleen, pancreas and
heart (Mihas & Tavassoli 1992). Chronic alcohol consumption leads to elevated serum
GGT values, and the sensitivity of GGT for detecting alcohol misuse has been reported to
vary between 34 and 85% (Sillanaukee 1996). The suggested mechanisms for the
increase of GGT in serum due to alcohol ingestion include induction of hepatic GGT,
increased permeability of hepatic plasma membranes and hepatocellular injury. An
increase in GGT calls for heavy drinking for several days or weeks (Rosman 1992, Sillanaukee 1996). Values above 80 U/L (men) and 50 U/L (women) are considered indicative of alcohol misuse. The half-life of GGT in serum is approximately 2–3 weeks.
Elevated serum GGT may also be due to non-alcoholic conditions, however. Non-alcoholic liver diseases, diabetes, obesity, heart failure, the use of anticonvulsants and severe
trauma are such conditions (Sillanaukee 1996).
2.8.1.3 AST & ALT
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are enzymes that
are abundant in the liver, and AST is also found in the heart, muscle, brain, pancreas, kidney and lungs (Mihas & Tavassoli 1992, Rosman 1992). These enzymes may increase in
serum after alcohol-induced liver damage, but also in cases of non-alcoholic liver diseas-
45
es, muscle disorders and myocardial infarction (Sillanaukee 1996). AST values above 50
U/L (men) and 35 U/L (women) are considered indicative of alcohol misuse. The sensitivity of AST for detecting alcohol misuse has varied between 15 and 69%, but the specificity has been low (Sillanaukee 1996). ALT is not as useful as AST as a marker of alcohol misuse, but a ratio of AST to ALT of over two may be useful, and may indicate alcoholic hepatitis (Mihas & Tavassoli 1992).
2.8.1.4 CDT
Transferrin is the iron transport protein, which includes two globular domains and several polysaccharide side chains (Mihas & Tavassoli 1992). When transferrin is exposed to
alcohol, abnormal side chains result and carbohydrate-deficient transferrin (CDT) is produced (Lesch & Walter 1996).
CDT is a promising marker of excessive alcohol use. Serum CDT was found to be
increased after a daily intake of 50–80 grammes of pure alcohol for at least one week and
was normalised slowly during abstinence, with a half-life of approximately 15 days
(Stibler 1991). Values above 20 U/L (men) and 26 U/L (women) are considered indicative
of alcohol misuse.
After pooling approximately 2500 individuals from relevant studies, Stibler (1991)
found that CDT had a sensitivity of 82% and a specificity of 97% for detecting alcohol
misuse. Meerkerk et al. (1998), however, reported that in studies dealing with more general populations the sensitivity of CDT varied from 12% to 45% and the specificity from
87% to 96%. False positive findings have been reported at least in patients with primary
biliary cirrhosis, chronic hepatitis C, hepatic malignancies, a genetic variation in transferrin and certain rare inborn glycoprotein disorders (Sillanaukee 1996). Common chronic
diseases such as hypertension, asthma/bronchitis, diabetes, angina pectoris, depression
and disorders of the digestive tract have not been found to cause unspecificity (Meerkerk
et al. 1998).
2.8.1.5 MCV
The mean corpuscular volume (MCV) of erythrocytes may be elevated as a result of
excessive alcohol consumption, but also in response to many other conditions such as liver disease, folate deficiency and hypothyroidism (Sillanaukee 1996). Values above 96 fL
are considered indicative of alcohol misuse. MCV returns to normal values within 3
months after the beginning of abstinence. Its sensitivity for alcohol misuse is relatively
low, since MCV detects only 30–40% of subjects with a drinking problem (Mihas &
Tavassoli 1992).
46
2.8.1.6 BAC
Blood alcohol concentration (BAC) can be measured directly from a blood sample or be
estimated from breath, saliva or urine measurements. Urine measurements often show
higher concentrations than measurements in blood, whereas breath measurements give an
accurate estimate of the real BAC (Bendtsen et al. 1999).
BAC of at least 150mg/dL without gross evidence of intoxication, 300mg/dL at any
time or 100mg/dL in routine examination are first-level criteria for alcoholism (Criteria
Committee, National Council on Alcoholism, New York 1972).
2.8.2 Detecting hazardous alcohol drinking
2.8.2.1 In patients with trauma
CAGE has been found to be the best questionnaire for predicting chronic alcohol dependence in trauma patients (Nilssen et al. 1994, Soderstrom et al. 1997), where it predicted
life-time alcohol dependence with a sensitivity of 84% and a specificity of 90% (Soderstrom et al. 1997). By contrast, laboratory tests such as GGT, AST, MCV and serum
osmolality seem to lack sensitivity and specificity for detecting alcohol dependence in
trauma patients. Ryb et al. (1999) compared the above four tests in 684 male trauma
patients and found relative low sensitivities (0.51, 0.43, 0.27, and 0.74, respectively) and
specificities (0.78, 0,74, 0.89, and 0.70, respectively) for detecting current alcohol dependence. BAC on admission nevertheless appeared to be associated with recent alcohol
dependence better than any of the conventional biochemical markers (Ryb et al. 1999).
2.8.2.2 In patients with head injury
Although the prevalence of hazardous alcohol drinking may be high in patients with head
injury, the identification of alcohol misuse among such patients has not been studied
greatly (Corrigan 1995). Dikmen et al. (1995) found that 45% of patients with head injury reported 2 or more items on the SMAST, a level considered indicative of problem
drinking. Bombardier et al. (1997b) studied 50 head injury patients admitted to an inpatient rehabilitation programme and found that MAST showed alcohol problems in 74%
of these cases, while Brismar et al. (1983) found that 43 out of 100 consecutive head
injury patients were alcohol-dependent, and GGT was elevated in 37%, AST in 35% and
ALT in 28% of the total series. No relationship between alcohol dependence and biochemical markers was reported (Brismar et al. 1983).
47
2.9 Alcohol interventions as means of preventing injuries
Although alcohol is thought to be a significant cause of trauma, there still continues to be
a lack of attention to hazardous drinking in accident and emergency departments (Soderstrom & Cowley 1987, Schermer et al. 2003), although these could be optimal places for
commencing alcohol interventions and thus reducing its detrimental effects (Charalambous 2002).
Alcohol interventions are aimed at reducing alcohol drinking and alcohol-related
effects such as violence, injuries and illnesses. There are many intervention protocols, but
a brief alcohol intervention is thought to be the most practicable in accident and emergency departments (Dunn et al. 1997). Holder et al. (1991) found a negative relationship
between the effectiveness and costs of alcohol interventions, which further supports the
use of inexpensive, easy methods of alcohol counselling.
Evidence is accumulating that brief interventions are effective in reducing alcohol
drinking and may thereby also reduce the risk of alcohol-related accidents (Antti-Poika I
et al. 1988, Walsh et al. 1991, Fleming et al. 1997, Holder et al. 2000). Two recent metaanalyses have concluded that alcohol interventions may be associated with reductions in
suicide attempts, domestic violence, drinking-related injuries and injury hospitalizations,
and with reductions in deaths ranging from 27% to 65% (Dinh-Zarr et al. 1999, Dinh-Zarr
et al. 2000).
In a study of 2524 consecutive trauma patients, including 1153 who were screened as
positive with respect to alcohol problems, Gentilello et al. (1999) randomised 366
patients to a counselling group (a brief alcohol intervention) and 396 to a control group. A
significant decrease in alcohol consumption was found in the former at 12 months,
accompanied, interestingly, by significant reductions in injuries requiring emergency or
trauma centre admissions (47%) or hospital admissions (48%) within three years of the
original trauma (Gentilello et al. 1999).
Even though hazardous alcohol drinking is a major problem affecting patients with
head injury, there are no studies dealing with a brief alcohol intervention as a means of
reducing alcohol consumption in this group. On the other hand, the consumption of alcohol has been found to decrease after the occurrence of head injury even without structured
interventions (Kreutzer et al. 1991, Dikmen et al. 1995). Dikmen et al. (1995) found that
alcohol consumption had decreased most compared with the pre-injury level at 1 month,
after which it increased significantly, but the patients were not followed-up for more than
12 months. The reduction in alcohol consumption early after trauma may be due to lack
of access to alcohol (still hospitalised), non-structured advice given by health care providers, decreased tolerance of alcohol, or rethinking in the aftermath of a major trauma (Dikmen et al. 1995).
3 Aims of the research
The purpose of the present research was:
1. to find simple clinical measures that predict the development of PCSs in patients with
mild head injury and to validate serum protein S100B as a prognostic marker. (I)
2. to evaluate the clinical utility of protein S100B as a marker of brain damage in patients with multitrauma, and to find out whether its usefulness is confounded by extracranial injuries. (II)
3. to study patterns of alcohol drinking in trauma patients and assess whether there are
specific risk patterns for head trauma. (III)
4. to investigate how hazardous alcohol drinkers among patients with head injuries and
other types of trauma can best be identified on admission. (IV)
4 Subject and methods
The work was carried out in the Department of Neurology, University of Oulu, during the
years 1998–2004. The protocol was approved by the Ethics Committee of the Medical
Faculty, University of Oulu, and carried out according to the principles of the Declaration of Helsinki. All the patients or their relatives gave informed consent before inclusion
in the series.
4.1 Subjects
The series comprised 385 consecutive acute trauma patients aged 16 to 49 years admitted
to the emergency department of Oulu University Hospital between June 1998 and July
2000, comprising 224 having head injuries with or without extracranial injuries and 161
patients having extracranial injuries only. Patients admitted more than 6 hours after the
trauma event were excluded. None of the patients reported suffering from cancer, multiple sclerosis, stroke, or treated epilepsy.
Paper I involved 172 MHI patients, of whom 129 were men and 43 women. These represented the 199 out of the 224 head injury patients who fulfilled the following criteria for
MHI: Glasgow Coma Scale (GCS) score of 13–15 on admission, loss of consciousness
for ≤ 30 minutes, if at all, and no focal deficits in a neurological examination performed
on admission. Twenty-seven of these 199 MHI patients had to be excluded because they
were not reached, so that no interview to determine post-concussion symptoms (PCSs)
could be performed.
Paper II covered a total of 379 trauma patients, of whom 224 were head injury patients
and 155 patients with extracranial injuries only. Fifty-four of the head injury patients had
simultaneous extracranial injuries. Six patients with extracranial injuries only were omitted because they reported PTA, so that the presence of TBI could not be convincingly
excluded. Additionally, we examined whether the exposure of healthy individuals to high
+Gz forces without actual impact on tissues could increase serum S100B values. For this
purpose, we recruited eight flight crew members of the Finnish Air Force, seven of whom
performed two flight missions seated in the back seat of a BA Hawk Mk 51 A aircraft and
50
wearing an extended coverage anti-G suit. The detailed characteristics of the flight missions and management of these subjects have been described elsewhere (Siitonen 2000).
Paper III included all the 385 trauma patients, and paper IV included those who were
interviewed for patterns of alcohol drinking (n=349).
4.2 Methods
4.2.1 Clinical examination
4.2.1.1 Emergency room
The patients included in the series were carefully examined on admission by emergency
room physicians according to a structured checklist designed for this purpose. Clinical
data, including neurological examinations, the presence of clinical symptoms such as
unconsciousness, amnesia, dizziness, headache, neck pain, nausea and vomiting, and the
type and extent of the head and extracranial injuries were carefully recorded. A history of
infections (HIV/AIDS, hepatitis B and C) and other diseases was also recorded. The level of alcohol intoxication was assessed clinically and graded as none, slight, or severe
intoxication. Venous blood samples were obtained from each patient for biochemical
determinations.
The injured body parts of each patient were divided into six categories: head, spine,
thorax, abdomen and upper and lower extremities. The presence of injury was recorded
when there was distinct physical evidence of trauma as assessed by the emergency room
physician. The Injury Severity Score (ISS) was also used as an index of trauma severity
(Baker et al. 1974, Copes et al. 1988), and the GCS to assess the level of consciousness
(Teasdale & Jennett 1974).
The physician decided on admission which of the additional examinations (imaging
modalities) were needed, and the patients were subsequently treated according to the hospital’s routine protocols. Sixty-six head injury patients underwent a head CT scan within
24 hours from the trauma, and the resulting scans were evaluated twice, first as part of the
routine clinical evaluation and later in a re-evaluation of all the scans by a trained neuroradiologist. Thirty-three patients were further examined by skull radiography.
The patients with head injury discussed in paper II were classified on the basis of their
symptoms and signs as follows: 1. 35 patients having head injury without brain injury, 2.
165 patients having head injury with mild brain injury, and 3. 24 patients having head
injury with moderate-to-severe brain injury. The groups fulfilled the following diagnostic
criteria:
1. Head injury without amnesia, unconsciousness, headache, dizziness or vomiting.
2. Head injury with amnesia and/or unconsciousness (duration ≤ 24 hours), headache,
dizziness or vomiting
51
3. Head injury with amnesia and/or unconsciousness (duration > 24 hours), intracranial
lesion visible in the head CT scan or focal deficits in the neurological examination.
The extracranial injuries were divided in paper II into two groups: small (soft tissue
contusions, wounds, sprains, luxations and small fractures) and large (large fractures and
abdominal injuries). Vertebral, pelvic, femoral and brachial fractures and fractures of both
forearm bones were assessed as large and all other extracranial fractures as small.
4.2.1.2 Alcohol data
Blood alcohol concentration (BAC) on admission was determined either from exhaled air
(n=206) or from serum samples (n=179). Personal interviews were conducted with 349/
385 (91%) of the patients by the same interviewer throughout using a structured questionnaire to gather data on their alcohol consumption. The interviews were performed blind
to any knowledge of the determinations of BAC levels or other biochemical markers of
alcohol consumption. The interviews took place within 2–6 weeks of the injury.
The history of alcohol consumption included the following information: how many
drinks of alcohol (one standard drink = 12 g of ethyl alcohol, corresponding to one beer,
one glass of table wine or four centilitres of proof spirit) the patient had consumed during
(i): 24 hours, and (ii): one week preceding the injury. Daily alcohol consumption during a
period of one year prior to the trauma was also assessed using a time-line follow back
technique (Sobell & Sobell 1995, Allen et al. 1997). Based on the resulting data, the
patients were classified into dependent drinkers, binge drinkers, light-to-moderate drinkers and non-drinkers. The dependent drinkers were those who showed clinical evidence of
pathological alcohol use, social impairment and tolerance/withdrawal. Their daily alcohol consumption had exceeded 80 g. Binge drinking (i.e. heavy episodic drinking) was
defined as an intake of 6 or more (men) or 4 or more (women) standard drinks of alcohol
in one session. Binge drinkers were further divided into frequent binge drinkers, who
reported this type of drinking at least once a month, and infrequent binge drinkers, who
reported that it occurred 1–11 times per year. Light-to-moderate drinkers did not drink for
intoxication, but consumed 1–2 standard drinks per day either daily or less frequently.
Non-drinkers had not drunk any alcohol during the year preceding the injury, and
included both life-long abstainers and ex-drinkers. The dependent drinkers and frequent
binge drinkers together made up the group referred to as hazardous drinkers.
4.2.1.3 Follow-up interviews
The follow-up interviews were carried out twice, a face-to-face interview within 2–6
weeks of the trauma, but not before full recovery from amnesia, and a second, telephone
interview 8–30 months after the injury.
The first interview included questions on the trauma, education and employment status, previous diseases, use of medicines, lifestyle factors and a modified Rivermead Post
52
Concussion Symptoms Questionnaire (King et al. 1995) in which the answers were
dichotomized to yes or no. Questions were also added regarding decreased alcohol tolerance and the occurrence of panic attacks. The presence and duration of post-traumatic
amnesia (PTA) at the time of injury was assessed according to the Rivermead Post-Traumatic Amnesia Protocol (King et al. 1997), and educational status was recorded in terms
of the number of years of schooling. The patient was also asked whether he or she had
insurance that covered the accident. Previous diseases such as TBIs, psychiatric illnesses
and contacts and HIV, hepatitis or other liver diseases were also ascertained, and medications were carefully recorded.
The second interview was a telephone interview (8–30 months after the injury), which
aimed at ensuring that the patients with PCSs really fulfilled our criteria (I). This was
done because the first interview had been performed 2–6 weeks after trauma, and according to our definition of PCSs, symptom(s) had to last at least one month post injury before
the criteria were fulfilled.
4.2.2 Laboratory procedures
Venous blood samples were obtained from each trauma patient as soon as possible after
admission, but no later than six hours from trauma. The samples were centrifuged and
stored at –20ºC until analysed, except that the mean corpuscular volume (MCV) of erythrocytes was determined as soon as possible after admission. Protein S100B, serum gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST) and carbohydratedeficient transferrin (CDT) were measured for each patient, whereas MCV was determined in 302/385 cases (78%).
The concentration of protein S100B was measured using a commercially available
monoclonal two-site immunoluminometric assay (LIA-mat® Sangtec® 100; AB Sangtec
Medical, Bromma, Sweden) with a detection limit of 0.02 µg/L. Blood alcohol concentrations were measured on a Vitros 250 clinical chemistry analyser (Johnson & Johnson
Clinical Diagnostics, Rochester, New York), and the ALCO-SENSOR III (Intoximeters
Inc., St. Louis, Mo) was used for the breath analyses. Serum CDT was measured with a
competitive radioimmunoassay after microcolumn separation (CDTect, AxisShield, Oslo,
Norway), and the measurements of MCV, GGT and AST were carried out using standard
clinical chemical methods.
Normalised S100B values for paper I were calculated according to a half-life of 120
minutes as follows: normalised S100B = 2 (time from trauma to blood sampling in minutes / 120
minutes)
x measured S100B. The following cut-off values were used in the analyses for the
diagnostic characteristics of the laboratory tests: in paper I: S100B 0.50 µg/L, in paper IV:
MCV >96 fL for women and men, GGT >50 U/L for women and >80 U/L for men, AST
>35 U/L for women and >50 U/L for men and CDT >26 U/L for women and >20 U/L for
men.
53
4.2.3 Statistical analysis
Categorial variables were compared by means of Fisher’s exact 2-tailed test or the Pearson χ2 test. Continuous variables were compared among groups using Student’s t-test, the
Mann-Whitney U-test, or the Kruskall-Wallis test. Univariate associations of continuous
variables were tested by means of Spearman’s rank correlation coefficients (rs). Receiver
operating characteristic (ROC) curves for the S100B values were also drawn in paper I
for detecting PCSs patients with and without S100B normalisation, and sensitivities,
specificities, positive and negative predictive values, and 95% confidence intervals (CIs)
were calculated for each marker of alcohol consumption in paper IV for detecting hazardous alcohol drinking.
Odds ratios (OR) and 95% confidence intervals (CI) before and after adjustment for
possible confounding variables were calculated by logistic regression for paper I, and the
hypotheses were tested and 95% CI determined using standard error estimates for the
logistic coefficients. Stepwise multiple logistic regression (p<0.1 for entry limit and
p>0.15 for removal limit) was used to test the significant independent risk factors for
PCSs. In paper III, relative risk (RR) estimates and 95% CIs were calculated before and
after adjustment for confounding factors, and in paper II, a two-way analysis of variance
was used to assess the effects of head injuries and other types of trauma on S100B values.
All the analyses in papers I and II were performed using the Statistical Package for the
Social Sciences (SPSS, version 10.0, for Windows, SPSS Inc, Chicago, IL USA), and in
papers III and IV using the CIA statistical software (Gardner & Altman 1989) and SPSS.
5 Results
5.1 Protein S100B as a predictor of PCSs in MHI patients (paper I)
A total of 172/199 (86%) MHI patients were included in this series, 129 men and 43
women, with a mean age of 31.3 years (SD 10, range 10–49) (I; Table 2). Thirty-seven of
them (22%) reported PCSs, i.e. at least one PCS lasting at least one month following the
trauma event. The most common PCSs were depression, dizziness, fatigue and headache
(I; Table 1). Thirty of these patients (81%) had suffered from at least two symptoms, and
the mean number of symptoms amounted to 5.0 (SD 3.6, range 1–14). Thirty-nine of the
172 patients (23%) underwent a head CT scan on admission, and eight had traumatic
intracranial lesions visible. Of the 164 patients who did not have any evidence of intracranial lesions, 32 (20%) reported PCSs.
Significant risk factors for PCSs emerging in univariate analysis were the presence of
skull or facial bone fracture, elevated serum protein S100B (0.50 µg/L), the presence of
dizziness and headache on admission, psychiatric illness in childhood, loss of consciousness and PTA (I; Table 2). There was also a correlation between the number of symptoms
and the S100B values (Spearman correlation, p < 0.001), but no statistically significant
correlation between PCSs and age (as a continuous variable), psychiatric illness in adulthood, use of psychotropic drugs, current smoking, prior use of illicit drugs, or neck pain
on admission.
The ROC curves for S100B in the 172 MHI patients with and without S100B normalisation are presented in Figure 2. Serum protein S100B with a cut-off level of 0.50 µg/L
showed a high specificity for PCSs (93%) but a rather low sensitivity (27%). The sensitivity with a cut-off value of 0.20 µg/L was 68% and the specificity 67%, but the negative
predictive value was as high as 88%.
55
Fig. 2. Comparison of ROC curves for S100B in 172 MHI patients before and after normalisation of S100B values (to correspond to the time of onset of head injury). Sensitivities and specificities at different S100B cut-off levels are shown. Figure from paper I.
Skull fracture, elevated protein S100B (≥ 0.50 µg/L), dizziness and headache on admission and age were identified as independent risk factors for PCSs (Table 4). The model
remained unchanged after normalisation of the S100B values. This model gave ORs of
6.1 (1.9–19.6) for skull fracture, 6.0 (2.3–15.2) for protein S100B, 3.0 (1.1–7.9) for dizziness, 2.3 (0.9–5.9) for headache and 1.05 (1.00–1.10) for age.
Table 4. Multivariate ORs for PCSs in mild head injury patients (n=172). Table from
paper I.
Variable
OR
95% CI
Skull fracture
8.0
2.6–24.6
p value
0.001
Protein S100B ≥ 0.50 µg/L
5.5
1.6–18.6
0.007
Dizziness on admission
3.1
1.2–8.0
0.021
Headache on admission
2.6
1.0–6.5
0.043
Age
1.05
1.01–1.10
0.027
ORs represent comparisons between patients with and without at least one symptom lasting for one month or
more and are adjusted for sex, educational status and the other variables listed in the table.
Loss of consciousness, post-traumatic amnesia, presence of extracranial injury, prior head
injury, employment status, insurance, psychotropic drugs, current heavy drinking, smoking and prior use of illicit drugs were not independent risk factors for PCSs.
56
5.2 Effects of extracranial injuries on S100B levels (paper II)
A total of 379 trauma patients were included in this series, of whom 224 had head trauma and 155 had extracranial injuries only. Fifty-four (24%) of the 224 head trauma
patients also had extracranial injuries.
The median serum concentration of protein S100B among the patients with head
trauma was 0.17 µg/L (0.07–0.36, Q1–Q3), whereas the corresponding value for those
without head trauma was 0.07 µg/L (0.03–0.13, Q1–Q3) (Mann-Whitney U-test: p <
0.001). When the head trauma patients were classified into those with no brain injury,
mild brain injury and moderate-to-severe brain injury, the median levels (n, Q1–Q3) of
S100B were 0.10 µg/L (35, 0.06–0.18), 0.16 µg/L (165, 0.07–0.32) and 1.27 µg/L (24,
0.32–3.3), respectively (Kruskall-Wallis test: p < 0.001). The median S100B concentration (n, Q1–Q3) was 0.35 µg/L (7, 0.20–0.64) for the patients with large extracranial injuries only and 0.07 µg/L (148, 0.03–0.12) for those with small extracranial injuries (MannWhitney U-test: p < 0.001).
The effects of the severity of brain injury and the size of extracranial injury on S100B
levels (logarithmic modification of S100B values) are illustrated in Figure 3. Both brain
injury and extracranial injury independently increased the serum S100B concentrations in
the trauma patients, since two-way analysis of variance showed that the two variables and
their interaction were statistically significant (p < 0.001).
A comparison of S100B cut-off levels showed that there were only a few head trauma
patients without brain injury or patients with extracranial injuries alone above the highest
cut-off level (0.50 µg/L) (II; Table 4), whereas the head trauma patients with moderate-tosevere brain injury exceeded this cut-off in 67% of cases. Likewise, 61% (136/224) of the
head trauma patients and 26% (41/155) of those with extracranial injuries only had
S100B above 0.13 µg/L (Pearson χ2 test: p < 0.001).
Fig. 3. Effects of the severity of brain injury and the size of extracranial injury on S100B levels.
Logarithmic modification of S100B concentrations: Ln (1 + S100B). Figure from paper II.
57
Of the different types of extracranial injuries, large extracranial injuries such as large
fractures and abdominal injuries elevated S100B values significantly (II; Table 3), whereas soft tissue contusions, wounds, sprains, luxations and small fractures (i.e. small extracranial injuries) did so only slightly (II; Table 3). We did not find any significant increase
in serum S100B in healthy individuals after exposure to high +Gz forces, the median
S100B level (Q1–Q3) in blood samples taken 5 and 60 minutes after the 22-minute flight
missions with a maximal acceleration of + 6 Gz being 0.00 µg/L (0.00–0.03).
5.3 Binge drinking as a risk factor for head trauma (paper III)
Eight per cent of the trauma patients were found to be dependent drinkers, 61% frequent
binge drinkers and 17% infrequent binge drinkers (Table 5). Thus a total of 78% of the
patients reported binge-type drinking. The light-to-moderate drinkers and non-drinkers
represented 8% and 6% of the population, respectively. The dependent drinkers tended to
be older than the patients with other drinking patterns, and they also had the highest
BACs on admission (Table 5). The proportion of women among the dependent drinkers
and frequent binge drinkers was found to be low.
Table 5. Characteristics of the patients classified according to the history of alcohol consumption (n = 349).
Pattern of dringing
Dependent drinkers
Patients
n (%)
Women
n (%)
Age
(years)
Mean ±
SD
BAC (mg/
dL)
on admission
Mean ± SD
Clinically
intoxicated on
admission
n (%)
Alcohol consumption during the preceding year, g/day
Mean ± SD,
women/men
26 (8)
0
38 ± 9
210 ± 160
20 (77)
137±45 †
Frequent binge
drinkers
214 (61)
51 (24)
30 ± 10
120 ± 110
124 (58)
16±15 / 27±20
Infrequent binge
drinkers
59 (17)
25 (42)
33 ± 10
20 ± 70
5 (8)
6±3 / 6±6
Light-to-moderate
drinkers
28 (8)
14 (50)
31 ± 12
0 ± 10
1 (4)
2±1 / 4±4
Non-drinkers
22 (6)
7 (32)
30 ± 12
0
0
0/0
BAC, blood alcohol concentration. † Men only
Dependent drinking and frequent binge drinking were found to be common patterns
among the head trauma patients (Table 6), in whom they occurred significantly more
often than in those with other types of trauma (77% versus 59%, RR, 2.38; 95% CI, 1.50
to 3.77).
Fifty-one per cent of all the patients had alcohol in their blood on admission and most
of the intoxicated subjects (86%) had reached a level of 100 mg/dL. When the patients
were classified according to the type of trauma, the incidence of elevated BAC was significantly higher in the head trauma patients than in those with other types (65% versus
32%, RR, 3.92; 95% CI, 2.55 to 6.03). The relative risk of sustaining a traumatic head
58
injury increased sharply with increasing BAC, being significantly higher than that for
other types of trauma above the level of 150 mg/dL (Figure 4). The RRs were as follows:
0 mg/dL (0.51; 95% CI 0.42–0.63), 1–99 mg/dL (0.67; 95% CI 0.32–1.38), 100–149 mg/
dL (0.84; 95% CI 0.40–1.76), 150–199 mg/dL (1.71; 95% CI 0.93–3.17) and > 199 mg/
dL (4.87; 95% CI 2.82–8.40).
Table 6. Drinking patterns of the trauma patients interviewed (n=349), by type of trauma.
Pattern of drinking
All
Head trauma
Other trauma
Dependent drinkers
N=349
N=192
N=157
26 (8%)
24 (12%)
Frequent binge drinkers
2 (1%)
214 (61%)
124 (65%)
90 (57%)
Infrequent binge drinkers
59 (17%)
27 (14%)
32 (21%)
Light-to-moderate drinkers
28 (8%)
8 (4%)
20 (13%)
Non-drinkers
22 (6%)
9 (5%)
13 (8%)
Fig. 4. Crude relative risks for head injury at various level of blood alcohol concentration
(BAC). Above the level of 150 mg/dL, the risk for head injury was greater than the risk for other
types of injury. The bars indicate the 95 % confidence intervals at different BACs, and if the
bar does not cross the level one, it is statistically significant.
The main causes of trauma under the influence of alcohol were assaults, falls on the
ground and biking accidents, so that these together accounted for 68% (135/198) of all
the trauma patients who had alcohol in their blood. Ninety-four per cent of the assault
victims were BAC-positive on admission and most of their traumas (92%) were head
injuries (III; Table 3). The patients injured in falls on the ground and biking accidents also
frequently had alcohol in their blood, 60% and 61%, respectively. The BAC-positive subjects sustained head traumas significantly more often both in falls on the ground (RR,
3.50; 95% CI, 1.32 to 9.26) and bicycling injuries (RR, 8.26; 95% CI, 1.48 to 45.45) than
59
their sober counterparts (III; Table 3), but the BAC-negative bicyclists had injuries to
their extremities (50%, 9/18) significantly more often than the BAC-positive ones (7%, 2/
28) (RR, 12.99; 95% CI, 2.35 to 71.43).
5.4 Laboratory markers of hazardous alcohol drinking in trauma
patients (paper IV)
Sixty-nine per cent (240/349) of the trauma patients interviewed reported hazardous alcohol drinking (i.e. they were dependent drinkers or frequent binge drinkers). BAC (blood/
breath alcohol) proved to be the most sensitive marker of hazardous drinking and a highly specific one (Table 7), so that 137 (57%) of the hazardous alcohol drinkers had a reading above 100 mg/dL. When a cut-off level of > 0 mg/dL was used, the sensitivity for
identifying hazardous drinkers increased to 68% (95% CI, 61 to 73%) with a positive predictive value of 96% (95% CI, 92 to 98%). Thus, 96% of the BAC-positive trauma
patients proved to be hazardous alcohol drinkers.
We further analysed the usefulness of various combinations of biochemical markers.
BAC (>0 mg/dL) together with CDT was the most sensitive combination, correctly identifying 73% of the target population, but even though both CDT and GGT slightly
improved the sensitivity when combined with BAC, the additional effect did not reach
significance.
Table 7. Sensitivities, specificities, positive predictive values (PPV) and negative predictive values (NPV) of markers of alcohol consumption for detecting hazardous alcohol
drinking (including dependent drinkers and frequent binge drinkers) among the trauma
patients (n=349). Table modified from paper IV.
Screening test
Sensitivity
Specificity
PPV
NPV
BAC >0 mg/dL,
(95% CI)
68% (61 to 73%)
94% (87 to 97%)
96% (92 to 98%)
57% (49 to 64%)
BAC >100mg/dL
57% (51 to 63%)
94% (89 to 98%)
96% (91 to 98%)
50% (43 to 57%)
GGT
11% (8 to 16%)
97% (92 to 99%)
90% (74 to 97%)
33% (28 to 39%)
MCV
18% (13 to 24%)
94% (88 to 98%)
88% (75 to 95%)
34% (28 to 40%)
CDT
33% (28 to 40%)
88% (81 to 93%)
86% (78 to 92%)
38% (32 to 44%)
AST
17% (13 to 22%)
94% (89 to 98%)
87% (74 to 94%)
34% (29 to 40%)
BAC = blood alcohol concentration (100 mg/dL = 22 mmol/L); cut-off values: CDT (20/26 U/L, men/
women), GGT (80/50 U/L, men/women), AST (50/35 U/L, men/women), MCV (96 fL, men and women).
MCV was measured for 288 (83%) of the patients interviewed (n = 349).
6 Discussion
6.1 PCSs in patients with mild head injury
The reported incidence rates of PCSs in patients with MHI vary widely, but a significant
minority, approximately 7–15%, may have persistent symptoms lasting more than a year
after trauma (Alexander 1995, Binder 1997). In our series, 22% of the MHI patients had
PCSs one month after the trauma, and if those with intracranial lesions visible in CT are
excluded, the corresponding figure is 20%.
Skull or facial bone fracture, elevated serum protein S100B (≥ 0.50 µg/L), dizziness
and headache on admission were found to be independent predictors of PCSs in the MHI
patients. Elevated serum protein S100B was a significant predictor even when the patients
with intracranial lesions verified by a head CT scan were excluded. The association
between elevated protein S100B serum concentrations on admission shortly after head
injury and PCSs strongly suggests an organic aetiology for PCSs. Serum S100B was elevated on admission in 27% of the MHI patients who developed PCSs, but only in 7 % of
those who did not.
Previous studies have also observed an association between elevated S100B and PCSs
among MHI patients (Ingebritsen et al. 2000b, de Kruijk et al. 2002a), but the association was even more distinct in the present case, possibly because we had a rather low proportion of PCSs patients (22%). Ingebrigtsen et al. (2000b) identified a relatively high
proportion of PCSs among MHI patients (62%), but their timing and methods of interview differed from ours. In a recent study, de Kruijk et al. (2002a) found that elevated
S100B and NSE values on admission predicted more severe PCSs at six months post
injury, and those who had headache, dizziness, or nausea shortly on admission also
reported more severe PCSs (de Kruijk et al. 2002a). Our results are in good accordance
with these findings, since we also found headache and dizziness on admission to predict
the development of PCSs, although we also found skull or facial bone fracture to be an
independent and important risk factor for PCSs.
Our results do not support the notion of an association between heavy alcohol drinking or illicit drug use and PCSs, although it has been suggested that alcohol misuse could
play a role in their development (Lishman 1988), neither did we find significant associa-
61
tions between other possible risk factors such as gender, prior disease, and factors predisposing to malingering (insurance, unemployment, etc.) and PCSs. Litigation is also often
thought to be a risk factor for PCSs (Bernstein 1999, Mickeviciene et al. 2002), but our
findings do not support this hypothesis, although they do not exclude the possibility that
litigation may exacerbate the symptoms.
6.2 Protein S100B as a marker of brain damage
Serum protein S100B has recently been an object of increasing attention in the identification of brain damage because of its high brain tissue specificity. Its clinical utility with
head trauma patients has not yet been fully elucidated, however.
Acute traumatic brain injury has been found to cause a leakage of S100B into the
serum (Ingebrigtsen et al. 1999, Raabe et al. 1999b, II), and the severity of brain injury
has been found to correlate positively with S100B values, the highest levels being
reported in patients with moderate-to-severe injuries (Raabe et al. 1999b, Romner et al.
2000, II). Brain lesions found in head CT scans have also been shown to be associated
with elevated S100B (Raabe et al. 1999b, Ingebrigtsen et al. 2000b). Romner et al.
(2000), studying 278 acute head injury patients with minor, moderate and severe injuries,
found that S100B was elevated (>0.20 µg/L) in 92% of those with intracranial lesions in
their head CT scans and 34% of those without. In fact, serum S100B with a cut-off of
0.20 µg/L was extremely good at excluding intracranial pathology visible in a head CT
scan, since its negative predictive value was as high as 99%.
A positive correlation has also been reported between elevated S100B values and poor
recovery in patients with head injury (Raabe et al. 1999a, Woertgen et al. 1999, Townend
et al. 2002). Townend et al. (2002) studied 119 such patients (with an initial GCS score of
4–15) and found that a serum S100B concentration of > 0.32 µg/L predicted severe disability (extended GOS < 5) at one month after trauma with a sensitivity of 93%, a specificity of 72%, and a negative predictive value of 99%. Thus, patients with a concentration of S100B > 0.32 µg/L and poor recovery at one month post injury must be extremely
rare.
S100B levels have been shown to be elevated in 20–42% of patients with MHI (Ingebrigtsen et al. 2000b, de Kruijk et al. 2001c, de Kruijk et al. 2002a, I, II). In addition, a
poor neuropsychological outcome has been reported to be associated with increased
S100B concentrations in MHI patients (Waterloo et al. 1997, Herrman et al. 2001), and
S100B levels have been shown to be higher in patients who will develop PCSs than in
those who will not (Ingebrigtsen et al. 2000b, de Kruijk et al. 2002a). Furthermore, we
showed in paper I that S100B was an independent and good predictor of PCSs. When a
cut-off value of 0.50 µg/L was used, the sensitivity, specificity and negative predictive
value for PCSs were 27%, 93% and 82%, respectively, while if a lower cut-off value
(0.20 µg/L) was used, the corresponding figures were 68%, 67% and 88%. The MHI
patients with S100B values of < 0.20 µg/L shortly after trauma rarely developed PCSs.
One of our objectives was to study the effects of extracranial injuries on S100B levels
in serum (II). We showed that not only brain damage but also extracranial injuries, includ-
62
ing small ones, increased serum S100B values in patients with multitrauma, although
only large extracranial injuries elevated S100B values significantly, as reported by others
(Andersson et al. 2001). Although small extracranial injuries (i.e. wounds, soft tissue contusions, distensions, luxations and small fractures) also increased serum S100B values,
the effect was not found to be clinically significant (II). Thus it is evident that extracranial
injuries cause some false positive findings related to S100B, at least if a large extracranial injury is present. However, normal S100B values (< 0.20 µg/L) predict the absence of
intracranial damage and good recovery after trauma with a high accuracy. Thus, S100B
can be used as a marker to exclude intracranial pathology (Romner et al. 2000), poor outcome (Townend et al. 2002) and the development of PCSs (I) in patients with head
trauma.
6.3 Alcohol and trauma
6.3.1 Hazardous alcohol drinking in patients with trauma
There is no doubt that alcohol and injuries are closely linked to each other. Approximately one half of all trauma patients are BAC-positive on admission, and more than a third
have a BAC at or above 100mg/dL (Rivara et al. 1993a, III). The proportion of BAC-positive cases among patients with head injury has been found to be over 50%, and the proportion of those with a BAC at or above 100mg/dL has been shown to vary from 35 to
40% (Rimel et al. 1982, Brismar et al. 1983, Corrigan 1995, Dikmen et al. 1995, III).
The methods used to detect heavy alcohol drinking and alcoholism in previous studies
of trauma patients have varied greatly (Corrigan 1995, Nilssen et al. 1994), the lowest
incidences, 16% (Rimel et al. 1982), 25% (Sparadeo & Gill 1989) and 36% (Wong et al.
1993), having been found in studies where the assessments were based on retrospective
chart reviews, while the highest ones, 66% (Kreutzer et al. 1991) and 58% (Kreutzer et al.
1990), have been reported from rehabilitation centres. Nilssen et al. (1994) reported an
approximately 45% incidence of alcohol abuse in trauma patients based on screening with
the CAGE and SMAST questionnaires.
We found that binge-type drinking was the predominant pattern among the trauma
patients. Patterns of alcohol consumption have so far not received much attention. We further showed, however, that a total of two-thirds of our trauma patients reported hazardous
drinking (i.e. they were dependent drinkers or frequent binge drinkers), and hazardous
drinking was found to be more frequent in the patients with head injury that in those with
other types of trauma (III).
The high prevalence of binge drinkers among trauma patients is alarming. It suggests
that more attempts should be made to reduce this type of drinking. If alcohol consumption
is assessed in terms of grammes of ethanol consumed per day, most binge drinkers will be
classified as moderate drinkers and not as hazardous ones (Naimi et al. 2003), but it is
precisely this pattern of binge drinking that is closely associated with alcohol-impaired
driving (Liu et al. 1997), and there is growing evidence that the social, health and eco-
63
nomic costs of acute alcohol-related problems may even exceed those arising from the
chronic effects (CDC 1993, Chikritzhs et al. 1993). The highest prevalence of binge
drinking has been found among young adults, but it is also a frequent and favoured
drinking pattern among adolescents (American Academy of Pediatrics Committee on
Substance Abuse 1995, Naimi et al. 2003). Binge drinking is an increasing problem
worldwide (Mäkelä et al. 2001, Naimi et al. 2003), and the present findings suggest that it
is a substantial, and growing medical hazard, and that more interventions should be
employed in attempts to prevent it.
Fleming et al. (1997) found that brief advice from a physician reduced binge drinking
by approximately 40% in a randomised controlled trial, and the reduction was found to
last for at least 12 months. Thus, if alcohol interventions are to be used, they should be
focused on this group, because most of them are young adults and not heavy drinkers, and
therefore the intervention could come before the patients have reached a stage of severe
alcohol dependence.
6.3.2 Alcohol as a risk factor for head trauma
Previous reports have emphasized the high prevalence of alcohol intoxication among
trauma patients, but not the high frequency of binge drinkers. Our data emphasise the
adverse consequences of binge drinking, which may cause severe intoxication in individuals who are not regular drinkers and who do not have increased alcohol tolerance. Thus
the more frequent binge drinking is, the greater is the risk of trauma. Accordingly, the
lower incidence of trauma observed here in infrequent binge drinkers than in frequent
ones is apparently due to their fewer occasions of alcohol intoxication (III). Where
Mäkelä et al. (2001) found that the mean frequency of binge drinking in Finland was
approximately 11 times a year, 61% of all our trauma patients reported at least 12 such
episodes a year prior to injury. The high binge drinking rate among trauma patients supports the view that this type of drinking is a more significant risk factor for trauma than
has been previously acknowledged.
We showed that the risk of sustaining a head trauma increased as a function of increasing blood alcohol level, and significantly so above the level of 1.5‰ (III). The most common causes of injury among the BAC-positive patients were assaults, falls on the ground
and bicycling injuries. Alcohol is likely to cause deleterious effects on psychomotor skills
and the preventive mechanisms to respond to situational hazards which, in turn, may
favour the occurrence of head trauma. Consistently, BAC-positive patients injured by
falls on the ground or in bicycling accidents injured their head significantly more often
than did their sober counterparts (III). In contrast, sober bicyclists more often avoided
head trauma and injured their extremities (III).
McLeod et al. (1999) reported that consuming more than 60 grammes of alcohol in a
6-hour period conferred an odds ratio of 3.4 (95% CI 1.8 to 6.4) for sustaining an injury
in general, and increased risks of more severe injuries under the influence of alcohol have
also been found in certain specific traumas such as bicycling injuries (Olkkonen & Honkanen 1990, Li et al. 2001), motor vehicle crashes (Waller et al. 1986), motor vehicle-
64
related pedestrian injuries (Rivara et al. 1997), assaults (Martin & Bachman 1997, Kyriacou et al. 1998) and injuries sustained in falls (Honkanen et al. 1976).
6.3.3 Identification of alcohol misuse in patients with trauma
A positive effect of a brief alcohol intervention as a means of reducing alcohol intake and
the adverse health effects has been reported in several studies (Walsh et al. 1991, Fleming et al. 1997, Gentilello et al. 1999, Dinh-Zarr et al. 2000), but there still continues to
be a lack of attention to hazardous alcohol drinking in accident and emergency departments (Soderstrom & Cowley 1987, Charalambous 2002). One apparent reason for this is
that hazardous drinkers usually remain unrecognised by the clinicians. A simple and inexpensive method for the early identification of hazardous drinkers would thus be of the
utmost importance.
Ryb et al. (1999) reported that the BAC test is the best detector of alcohol dependence
in trauma patients, while GGT, AST and MCV are of little value as screening tests. We
also found that the conventional biochemical markers (GGT, MCV, CDT, and AST)
lacked sensitivity and specificity, especially for detecting binge drinkers, but were of the
opinion that the BAC test, performed either on exhaled air or on a blood sample, is the
best method of detecting hazardous alcohol drinking (i.e. dependent drinking and frequent
binge drinking) among trauma patients (IV). BAC not only identifies acute alcohol drinking but also provides a good estimate of chronic patterns of hazardous drinking. BAC (>
0mg/dL) on admission was found to be a sensitive (68%) and specific (94%) marker of
hazardous drinking, and 96% of all the BAC-positive trauma patients turned out to be
hazardous drinkers. Thus, the BAC test can be recommended as a primary screening tool
to guide patients for alcohol interventions without subjecting them to an unacceptable
degree of stigma as problem drinkers and before they have reached a stage of severe
dependence.
6.4 Strengths and weaknesses
The material was collected from the emergency department of a hospital which is the
only trauma centre for Oulu, a city with approximately 120,000 inhabitants. The patients
were recruited consecutively seven days a week and 24 hours a day, but with certain
exclusion criteria applied.
Firstly, patients representing the age range 16–49 were recruited. This was done,
because the highest rates of morbidity, mortality and persistent functional and psychological impairment due to trauma are known to occur in this group. Secondly, many common
diseases such as cardiovascular and neurological diseases are frequent in the elderly, and
little is known about their effect on S100B levels. Additionally, life-style factors such as
alcohol drinking habits are likely to differ between our material and cases of children or
elderly people, and as our material includes acute trauma patients, the results of series
derived from out-patient clinics may differ from ours.
65
The interviews were always performed by the same person. The first interview to place
face to face, and the second, which occurred 8 to 30 months post injury was a telephone
interview aimed at ensuring that the PCSs had lasted long enough to fulfil our criteria (i.e.
one month post injury). The long interval between trauma and the interview may have
caused underestimation of certain symptoms, particularly impairment of cognitive functions.
Of the 385 patients, 349 (91%) were interviewed within 2–6 weeks of the trauma
(including alcohol data) and PCSs data was collected from 86% of the MHI patients (172/
199). Thus, the percentage of patients who were interviewed was high, higher than in
many other studies concerning PCSs or alcohol drinking (Ingebrigtsen et al. 1998, Ryb et
al. 1999, Ingebrigtsen et al. 2000b).
In conclusion, the material represents a good spectrum of consecutive Finnish trauma
patients in a general hospital, excluding children and elderly people. Because the results
concerning protein S100B and the alcohol literature from other countries is quite comparable to ours in this respect, it can be assumed that the results can also be generalised
worldwide.
7 Conclusions
1. PCSs often complicate recovery after mild head injury. Skull or facial bone fractures,
elevated serum protein S100B and headache or dizziness on admission are associated
with an increased risk of developing PCSs. These simple criteria may help the physician on duty to identify patients for counselling and follow-up.
2. Serum protein S100B is a feasible supplementary method for detecting traumatic
brain damage. In particular, normal levels of S100B after head injury predict normal
head CT scan findings, good overall recovery and the absence of PCSs in the followup.
3. In addition to brain injury, extracranial injuries also increase serum S100B levels and
may cause false-positive findings. S100B is not a specific marker of brain injury.
4. Alcohol intoxication indicative of hazardous alcohol drinking (i.e. dependent drinking and frequent binge drinking) is a common finding in trauma patients, and more
common in head injury patients than in those with other types of trauma. Binge drinking is the predominant pattern of alcohol drinking in trauma patients, and particularly in head trauma patients.
5. The risk of sustaining a head injury significantly increases with increasing BAC, and
is significant if BAC exceeds 150 mg/dL.
6. Hazardous alcohol drinkers, i.e. dependent drinkers and frequent binge drinkers, can
best be identified by means of a BAC test on admission. The conventional laboratory
markers of alcohol consumption such as CDT, GGT, AST, or MCV do not offer any
significant benefit in patients with trauma.
7. BAC should be measured, either from exhaled air or blood, in the case of all the
trauma patients on admission. If there is an option for brief alcohol intervention, all
BAC-positives should be guided for such counselling.
8. The results point to the usefulness of the BAC test as a marker of alcohol misuse and
protein S100B as a marker of brain damage in patients with trauma.
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