Review

Diagnosis, prognosis, and clinical management of mild

traumatic brain injury
Harvey S Levin, Ramon R Diaz-Arrastia

Concussion and mild traumatic brain injury (TBI) are interchangeable terms to describe a common disorder with Lancet Neurol 2015
substantial effects on public health. Advances in brain imaging, non-imaging biomarkers, and neuropathology during Published Online
the past 15 years have required researchers, clinicians, and policy makers to revise their views about mild TBI as a March 20, 2015
http://dx.doi.org/10.1016/
fully reversible insult that can be repeated without consequences. These advances have led to guidelines on
S1474-4422(15)00002-2
management of mild TBI in civilians, military personnel, and athletes, but their widespread dissemination to clinical
Michael E. DeBakey Veterans
management in emergency departments and community-based health care is still needed. The absence of unity on Affairs Medical Center,
the definition of mild TBI, the scarcity of prospective data concerning the long-term effects of repeated mild TBI and Houston, TX, USA
subconcussive impacts, and the need to further develop evidence-based interventions to mitigate the long-term (Prof H S Levin MD);
Departments of Physical
sequelae are areas for future research that will improve outcomes, reduce morbidity and costs, and alleviate delayed
Medicine and Rehabilitation,
consequences that have only recently come to light. Neurology, Neurosurgery,
Pediatrics, and Psychiatry and
Introduction contribute 15%. This survey was done between 2002 and Behavioral Sciences, Baylor
College of Medicine, Houston,
Traumatic brain injury (TBI) is usually classified as mild, 2006 and collected data from 426–445 hospitals in the
TX, USA (Prof H S Levin); and
moderate, or severe, on the basis of the initial Glasgow USA. Although these emergency room visits were not Center for Neuroscience and
coma scale (GCS)1 score recorded in the emergency room, identified as mild TBI, the exclusion of patients who Regenerative Medicine,
the duration of loss of consciousness, and duration of were admitted to hospital, died, or transferred to another Department of Neurology,
Uniformed Services University
post-traumatic amnesia2 (ie, loss of memory of events hospital indicates that the majority had sustained mild
of the Health Sciences,
after the injury). Age groups at high risk of TBI are TBI. Mild TBI is estimated to account for 80–90% of all Bethesda, MD, USA
children 4 years or younger, young adults 15–19 years of cases of TBI in both civilian3 and military populations.7 (Prof R R Diaz-Arrastia MD)
age, or elderly people older than 65 years. Every year in the In view of the high incidence and prevalence of mild Correspondence to:
USA alone, about 1·7 million people are assessed in an TBI, the resulting aggregate of economic and social Prof H S Levin, Baylor College
of Medicine, Department of
emergency room after sustaining TBI of any severity, of burden is substantial.8 On the basis of incidence and cost
Physical Medicine and
whom 52 000 die of TBI and other contributory injuries data from 1985, Max and colleagues9 concluded that 44% Rehabilitation, Baylor College
and another 275 000 are admitted to hospitals and survive.3 of the total lifetime costs associated with TBI were due to of Medicine, Houston,
By comparison, 1·4 million people with TBI are seen in mild TBI. TX 77030, USA
hlevin@bcm.edu
emergency rooms in England and Wales every year.4 Mild TBI can result from any type of mechanical force
Estimates indicate that in the USA, an additional impacting on the cranium.3 Mild TBI and concussion are
84 000 patients with TBI are seen annually in hospital interchangeable terms, wherein sports concussion is a
outpatient departments, and 1·08 million patients with subtype of mild TBI. Concern about the long-term
TBI are seen by office-based physicians and in community sequelae of mild TBI sustained by civilians and military
health clinics. Thus, about 3 million patients with TBI personnel and widely cited reports linking chronic
seek medical attention in the USA annually.5 These traumatic encephalopathy with repetitive mild TBI and
estimates still do not include a large number of exposure to subconcussive head impacts in contact
concussions that occur in sporting events and never result sports make this a clinically important topic. However,
in an encounter with the medical-care system. Injuries mild TBI has been relatively understudied for several
cared for in military, federal, and Veterans Affairs hospitals reasons. First, most patients with mild TBI make a
are also not included in the US Centers for Disease seemingly complete recovery, and early identification of
Control and Prevention (CDC) Injury Prevention and mild TBI patients who are likely to have persistent
Controls’ figures. Military personnel are at especially high symptoms or develop neuropsychological deficits is
risk of sustaining TBI. TBI is reported in 8–22% of difficult. Second, because mortality and functional
military personnel participating in combat operations6 dependence are rare in mild TBI, the outcome
and is also common during participation in non-combat assessments that are traditionally used in more severely
activities, such as martial training, and activities in injured patients are insufficiently sensitive to assess the
dangerous environments. subtle cognitive and behavioural sequalae that most
According to a CDC survey3 of emergency room visits often result from mild TBI.10 The cognitive and
for TBI, falls account for 38% of cases, primarily in psychiatric consequences of TBI are nonspecific and
children and elderly people. Road traffic accidents (which often occur in people with pre-existing emotional
include motor vehicle collisions, motor vehicle– disorders.11–13 Furthermore, many of the long-term
pedestrian collisions, motorcycle, or bicycle accidents) results of TBI manifest years after the trauma, and
contribute 16% of TBI cases, blunt trauma to the head might not be ascribed to a brain injury from which there
accounts for 20%, assaults for 11%, and other causes was an apparently complete recovery.14 For example, TBI

www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2 1

 Review
early in preschool years might alter the developmental
potential of the young brain and cause problems, such
as substance misuse, mood disorders, and conduct
disorders, that manifest during adolescence and young
adulthood.15 Repetitive mild TBI might also accelerate
ageing effects on cognition years after the injury.16
In this Review, we will assess advances in brain
imaging and other biomarkers that can aid diagnosis
and clinical decision making, and discuss approaches to
diagnosis and management of mild TBI. The
pathophysiology and secondary disorders pertaining to
mild TBI and new information relating to the high
incidence and effects of sports concussion are also
reviewed. Finally, we provide our thoughts on the
direction for future research and clinical services.
Diagnosis
When acknowledging the absence of unity on the
definition of mild TBI, the International Collaboration
on Mild Traumatic Brain Injury Prognosis17 have
recommended use of the American Congress of
Rehabilitation Medicine (ACRM)18 definition of mild TBI,
as revised by the WHO Collaborating Centre Task Force
on Mild Traumatic Brain Injury.19 The ACRM defines mild
TBI as a traumatically induced physiological disruption of
brain function resulting from the head being struck or
striking an object or the brain undergoing an acceleration
and deceleration movement, as manifested by at least one
of the following: any period of loss of consciousness up to
30 min; post-traumatic amnesia not exceeding 24 h; any
period of confusion or disorientation; transient
neurological abnormalities, including focal signs,
seizures, and intracranial lesions not requiring surgery; a
GCS score of 13–15 (ie, ranging from confusion to normal
consciousness on examination within 30 min after
presentation). The WHO Task Force stipulated that none
of these manifestations can be due to alcohol, recreational
drugs, medications, systemic illness, or extracranial
injures. However, the ACRM18 and WHO Taskforce19 did
not specify minimum durations of loss of consciousness,
post-traumatic amnesia, and disorientation,17 nor did they
specify how to differentiate overwhelming stress after a
traumatic event from confusion due to head trauma.
Servadei and colleagues’20 definition of mild TBI restricted
the GCS score to 14–15 because outcomes of patients with
a GCS score of 13 are more similar to those of moderate
TBI. Reliance on recall of the event and subjective report
of loss of consciousness, post-traumatic amnesia, and
symptoms affect the diagnostic accuracy of mild TBI and
introduce selection bias,17,21 particularly in cases of
unwitnessed trauma or when the reporting of symptoms
is influenced by potential secondary gain, such as the
desire to return to play in athletes or involvement in
accident-related litigation.
Post-concussion symptoms are common after mild
TBI. The ACRM18 states that post-concussion symptoms
include: physical symptoms of brain injury (eg, nausea,
2 www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2
dizziness, headache, blurred vision, fatigue, and sleep
disturbance that cannot be explained by peripheral
injury or other causes); cognitive deficits (eg, poor
memory, attention, and executive functions) that cannot
be explained by emotional state or other causes; and
behavioural or emotional changes (eg, depression,
irritability, anxiety-related disorders, and emotional
lability) that cannot be accounted for by a psychological
reaction to physical or emotional stress or other causes.
Although the ACRM does not include post-concussion
symptoms in the definition of mild TBI, the diagnostic
criteria for sports concussion include acute or delayed
onset of these symptoms.22
Variability across studies in whether patients with acute
neuroimaging findings, such as contusions, haematomas,
and haemorrhage, are included23 or excluded12,24 is another
indicator of the poor definition of mild TBI. The
classification of TBI as mild, moderate, or severe relies
primarily on the GCS and does not include
pathophysiology,25 which is otherwise increasingly used
in clinical practice and research.26 Consistent with the
findings of the International Collaboration on Mild
Traumatic Brain Injury Prognosis, the US Department of
Defense further defines mild TBI as injuries that do not
result in abnormalities on CT or MRI, or both.27 However,
the neuroimaging-based criterion is vague, as it does not
specify the modality used or the time after injury at which
the imaging was obtained.
Prognosis
The typical clinical course of uncomplicated mild TBI (ie,
no brain lesions found by CT scans) diagnosed in the
emergency room is the clearing of confusion within 24 h.
Post-concussion symptoms, including somatic (eg,
headaches, dizziness), cognitive (eg, poor attention and
memory), and emotional symptoms (eg, irritability,
depression), gradually resolve in most patients with mild
TBI during the following 12 weeks. However, in a
prospective, longitudinal study,13 29 (30%) of 62 patients
with mild TBI had new onset or intensification of at least
one post-concussion symptom 3 months after injury.
Findings of this and another prospective, longitudinal
study12,13 indicate that a pre-injury neuropsychiatric
disorder is strongly related to persistence of symptoms
for 3 months or longer after mild TBI. The trajectory of
recovery from concussion in athletes seems to be more
rapid than recovery from mild TBI in the general
population, and differences in the loss of consciousness,
comorbidities, and pre-injury disorders suggest that
sports concussion might be a distinct type of mild TBI.
Because sub-acute symptoms after mild TBI do not
consistently differ from those of trauma controls (ie,
patients with acute injury to a body region other than the
head), the term post-traumatic symptoms has been
proposed to replace post-concussion symptoms.11 However,
results of a prospective, longitudinal study showed that
complaints of sadness and fatigue were more common

in patients 3 months after mild TBI than in healthy
controls.12 In comparison with patients with mild TBI
presenting to emergency rooms, post-concussion
symptoms in 80–90% of adult athletes typically resolve
within 7–10 days after their first concussion.22
Although functional recovery improves over 3 months,
patients with mild TBI frequently take 1 month or longer
to return to work, and unemployment at 3 months could
be as high as a third of patients.28 However, employment
should be seen in relation to pre-injury work status, and
the rate of unemployment at 3–6 months does not differ
from that of general trauma patients.12,28 When returning
to work, patients with mild TBI have reported that they
expend greater effort and become more fatigued relative
to pre-injury.27
Initial impairment of memory, slow information
processing, and executive dysfunction are common
findings on neuropsychological tests within the first
2 weeks after injury.29 Whereas cognitive recovery by
3 months has been documented in prospective,
longitudinal studies,12 confirmatory research is needed to
characterise the timecourse and identify any persistent
cognitive deficit that is attributable to mild TBI.29
Prognosis for recovery from mild TBI has been
reviewed by the International Collaborating Group on
Mild Traumatic Brain Injury Prognosis.11,29 Cognitive
deficits affecting attention, processing speed, and
memory are frequently present during the first week to
a month.29 Despite favourable recovery in an estimated
80–85% of patients within 3–6 months after sustaining
an isolated mild TBI (depending on case definition,
follow-up interval, outcome measure, and comparison
group), a subgroup of patients with mild TBI might be
left with residual deficits or symptoms that impair
their ability to fulfil their work, school, or family
responsibilities.11,29 However, post-concussive symptoms
such as fatigue are nonspecific,17 and the normal
variability in scores that occurs in healthy persons
across a series of cognitive tests could be misattributed
to mild TBI.29 With few prospective, controlled
longitudinal studies extending beyond 6 months, the
evidence that cognitive deficits persist longer than
6 months is weak.29 Carefully designed longitudinal
research is needed to characterise the time course for
cognitive and functional recovery and to differentiate
persistent deficits and symptoms due to mild TBI from
the effects of pre-injury neuropsychiatric disorder and
other non-mild TBI factors.11–13,29
Pathology found in imaging analysis contributes to
the prediction of outcome in patients with GCS scores
of 13–15.23 For example, in patients with a GCS score of
13–15, intracranial pathology detected by CT within 24 h
after injury (ie, complicated mild TBI), such as
parenchymal lesions, intracerebral and extra-axial
haemorrhage, brain swelling, shear injury, and depressed
or basilar fractures, is associated with a worse outcome,
compared with patients for whom no intracranial
www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2
Review
pathology is detected by CT scan (ie, uncomplicated mild
TBI).19,30 The International Collaboration on Mild
Traumatic Brain Injury Prognosis29 identified positive CT
findings as an evidence-based indication of poor
outcome, regardless of surgical relevance, but noted that
confirmatory studies are needed.
New methods to assess mild TBI
Imaging of structural abnormalities
Concussion, according to the present definition, is
synonymous to mild TBI. Concussions were traditionally
conceived as purely physiological injuries, resulting
from metabolic dysfunction of the brain due to changes
in ionic gradients, dysfunction of sodium, potassium,
and calcium channels, neurotransmitter imbalance, and
inflammation.31 This view is supported by metabolic or
functional imaging studies in humans32,33 and animal
models.31 However, studies using advanced structural
neuroimaging techniques, such as susceptibility-
weighted imaging and diffusion tensor imaging, have
identified subtle structural abnormalities in white
matter and cerebral microvasculature in a substantial
fraction of patients with mild TBI, particularly in those
who had post-concussion symptoms, disability, or both,
3 months after injury (figure).32–34
On the basis of histopathological findings in isolated
cases of mild TBI who died from concomitant injuries,
diffuse axonal injury is thought to be the predominant
pathologic mechanism underlying mild TBI.35,36 Advanced
neuroimaging studies, particularly those using diffusion
tensor imaging, support this view. Diffusion tensor
imaging is used to measure the diffusion of water along
the axis of white matter tracts and can detect disruption of
diffusion within 2 weeks of sustaining mild TBI in
patients with normal MRI.37,38 Although diffusion tensor
imaging metrics (eg, fractional anisotropy and mean
diffusivity) are potential biomarkers of mild TBI (figure),
inconsistencies across studies in the direction of altered
diffusion; between centre variations in imaging protocols,
quality assurance, and analysis techniques; and the
scarcity of normative data applicable across centres have
to be resolved before clinical application is an option.
Diffuse microhaemorrhages are another pathology
underlying mild TBI. Although diffuse microhaemorrhages
have long been recognised as a pathology of severe TBI,
abnormalities in cerebral blood flow and cerebrovascular
reactivity have also been shown in mild TBI, particularly in
patients who have sustained multiple mild TBIs and
have persistent post-concussive symptoms.39,40 Findings
from neuroimaging studies23 using T2*-weighted gradient
echo imaging, which is sensitive to microhaemorrhages
(figure), identified diffuse vascular injury in the deep white
matter in 23 (24%) of 98 patients with mild TBI presenting
to trauma centres.
Other abnormalities identified in mild TBI using
CT and high-resolution MRI techniques include focal
contusions, traumatic subarachnoid haemorrhage, and
3
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extra-axial haematomas (including epidural haematomas
and subdural haematomas). As expected, MRI is far
more sensitive than CT for the identification of subtle
abnormalities. Results of a multicentre study23 showed
that 27 (28%) of 98 patients presenting to trauma centres
after a mean interval of 12 days after injury with CT-
negative scans had abnormal MRI results. In this study,
subarachnoid haemorrhage found by CT scans and four
or more foci of haemorrhagic axonal injury on MRI
analysis were associated with greater disability 3 months
after injury.
In the weeks following mild TBI, alterations in the
pattern of brain activation and functional connectivity in
resting state or performing a cognitive task have been
found by functional MRI (fMRI). Alterations of task-
related and resting-state fMRI have been reported even
when patients perform well on cognitive tests and are
allowed to return to regular activities, including
participation in contact sports.32,33,41
Quantitative electroencephalogram has also been
used to identify physiological dysfunction after mild
TBI and shows evidence of persisting neuronal
dysfunction days or weeks after resolution of clinical
symptoms.42 Although these advanced imaging and
electroencephalogram techniques seem to be more
sensitive than clinical assessments, their use is mainly
in research at present.
Biomarkers
The diagnosis of acute mild TBI can be complicated if the
injury is not witnessed, no evidence of external trauma
exists, CT scan is normal, or the assessment was delayed
for longer than 24 h. To aid the diagnosis of mild TBI and
reduce dependence on self-report, biomarkers in the
blood, saliva, urine, and CSF are under investigation.43
Serum is the most frequently studied source of
biomarkers.44 The most widely studied blood biomarkers
are glial fibrillary acidic protein (GFAP) and ubiquitin
C-terminal hydrolase-L1 (UCH-L1). Receiver operating
characteristic analysis finds area-under-curve higher

A B C

D E

Figure: MRI findings in patients with mild traumatic brain injury

In each patient cranial CT scan was normal. MRI was obtained within 48 h of injury. (A) Fluid-attenuated inversion recovery (FLAIR) image showing left frontal cortical
region of oedema, indicating non-haemorrhagic contusion. (B) FLAIR image, showing region of oedema in splenium of corpus callosum, indicating diffuse axonal
injury (DAI); the splenium is often affected in DAI because its location close to the falx makes it vulnerable to shearing forces. (C) Susceptibility-weighted image
showing diffuse microhaemorrhages in left temporal and left frontal regions. (D) T1-weighted image, before (left) and after (right) administration of gadolinium-
diethylenetriamine pentaacetic acid (DTPA), indicating blood–brain barrier breakdown associated with non-haemorrhagic surface contusion in the right frontal lobe.
(E) Diffusion tensor imaging (DTI) of patient with mild TBI and diffuse axonal injury. Voxel-based analysis indicates regions where fractional anisotropy is lower than
pooled controls (p<0·01, false discovery rate=0·05; left). Pink and red areas denote areas of white matter tracts with fractional anisotropy that differs from that of a
comparison group without TBI. Tract-based spatial statistics analysis of same patient (right). DTI is more sensitive than FLAIR for detecting the multifocal nature of
diffuse axonal injury.

4 www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2


than 0⋅87 for both GFAP and UCHL1.45 The high
sensitivity and specificity of these biomarkers mean that
they can discriminate between mild TBI and healthy
controls (0⋅87, 95% CI 0⋅83–0⋅90, and 0⋅91, 95% CI
0⋅88–0⋅94, for GFAP and UCHL1, respectively) and
differentiate between patients with mild TBI who have an
abnormal CT scan and those with normal CT scan (0⋅71,
95% CI 0⋅64–0⋅78, and 0⋅88, 95% CI 0⋅84–0⋅93, for
GFAP and UCHL1, respectively).45,46 However, the
sensitivity and specificity is inadequate for the prediction
of good recovery from complicated mild TBI at 6 months.45
Professional hockey players who had biomarkers
measured before the game season and again after a
concussion had raised concentrations of microtubule-
associated tau protein in plasma after a concussion,
and the magnitude of this rise in tau concentration
correlated with duration of post-concussive symptoms
(Spearman correlation coefficient 0⋅60, 95% CI
0⋅23–0⋅90; p=0⋅002).47 Despite progress in animal and
human studies and evidence that biomarkers can
potentially aid diagnosis of mild TBI, further validation
is needed. With the heterogeneity of pathological
mechanisms implicated in mild TBI, development of a
panel of biomarkers might be required to achieve
sufficient sensitivity and specificity for broad clinical
application.45
Clinical management
Acute management
Patients with mild TBI require immediate assessment at
the scene of injury to identify those at risk of serious
damage. These patients require transport to the nearest
trauma centre4 with the resources to manage TBI and
other injuries appropriate to the patient’s age.4 Medical
management of acute serious TBI in the UK is organised
in regional neuroscience centres, whereas so-called
level 1 in the USA designates centres that provide the
highest level of trauma care.
Delayed onset of an intracranial haematoma is a
major threat to a patient with apparent mild TBI. This
complication accounted for 72 (62%) of 116 avoidable
deaths in a necropsy series of patients who “talked and
died”.48,49 Delayed onset of brain swelling was the second
most frequent cause of avoidable death. Rose and
colleagues49 found that failure to promptly recognise
neurological deterioration or arrange transport to a
neurosurgical centre were frequent factors for mortality,
whereas the distance travelled was rarely a factor. These
findings were confirmed in a three-country study50 of
severe TBI, in which 86 (13%) of 680 patients were
completely lucid before neurological deterioration due to
delayed haematoma. Evidence-based factors,4,51 which
should prompt community health-care providers to refer
patients for assessment and CT scan, are listed in panel 1.
These factors follow the recommendations by a committee
organised jointly by the American College of Emergency
Physicians and the CDC on neuroimaging and decision
www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2
Review
making.52 Panel 1 also includes the National Institute for
Health and Care Excellence (NICE) 20144 guidelines for
the management of mild TBI in adults and children. A
decision to repeat CT scans should probably be guided by
changes in the patient’s neurological status, including
GCS score, pupillary response, and focal neurological
findings. Routine repeat of the CT scan within 24 h after
admission to hospital for patients with an intracranial
haematoma on their first CT scan but normal neurological
findings did not lead to any change in conservative
neurosurgical management, during which a haematoma
Panel 1: Evidence-based factors that affect the decision for patient referral to a
specialised treatment centre
Children (<16 years)
• Age <5 years: GCS <14 on initial examination in emergency room4
• Age <1 year: GCS <15 on examination in emergency room4
• Age ≥1 year: GCS<15 within 2 h after the injury4
• Age <1 year: bruise, swelling, or laceration larger than 5 cm4
• Seizure without a history of epilepsy4
• Prolonged loss of consciousness (>2 min)4
• Focal neurological deficit4
• Suspected open or depressed skull fracture or tense fontanelle4
• Any sign of basal skull fracture (haemotympanum, ‘panda’ eyes, CSF leakage from the
ear or nose, Battle’s sign)4
• Decrease in sensorium (responsiveness) after an initial lucid interval4
• Dangerous mechanism of injury (eg, pedestrian-vehicle collision, fall from great height)4
• Prolonged confusion or post-traumatic amnesia (>30 min)4
• Severe headache4
• Taking anticoagulants4
• Suspicion of non-accidental injury4
Adults (≥16 years)
• Age>60 years4,51 *
• GCS <14 on initial assessment in emergency room or GCS <15 within 2 h after injury
on assessment in the emergency room 52
• More than one episode of vomiting52
• Post-traumatic seizure4,50†
• Loss of consciousness4,51
• Focal neurological deficit4,51
• Suspected open or depressed skull fracture4,52
• Any sign of basal skull fracture (haemotympanum, ‘panda’ eyes, CSF leakage from the
ear or nose, Battle’s sign)4,51
• Decrease in sensorium after an initial lucid interval, extreme drowsiness, weakness,
inability to walk, slurred speech, restlessness, or agitation4
• Dangerous mechanism of injury (eg, pedestrian-vehicle collision, fall from great
height)51
• Comorbid medical illness, such as cirrhosis, diabetes, immunosuppression4
• Pregnancy
• Severe headache4,51
• Taking anticoagulants50
• Systemic injuries requiring hospital assessment
NICE 2014 guideline recommends that CT scans be performed within 1 h after identification of the risk factor. These risk factors
reflect NICE 2014 and 2008 American College of Emergency Physicians (ACEP)/ US Centers for Disease Control and Prevention
(CDC) policy statement. *Recommended age 55–65 years, dependent on the specific guideline. †Not supported as a univariate
predictor of intracranial lesions by ACEP/CDC Panel (2008) and New Orleans rule.52,53
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is surgically evacuated only in the case of neurologic
deterioration or increased size of hematoma seen on the
repeat CT scan, and there were no cases of neurological
deterioration in a prospective study.53
NICE 20144 also recommended a cervical CT scan for
mild TBI patients aged 65 years or older who have GCS
scores less than 13, have been intubated, have been
injured by a dangerous mechanism of injury (panel 1),
have a focal peripheral neurological deficit, paresthesia
of the lower or upper extremities, or for whom there is
clinical suspicion of a cervical injury.
The NICE 20144 guidelines recommend CT scans in
children within 1 h of the identification of more than
one of the following factors: witnessed loss of
consciousness for longer than 5 min; abnormal
drowsiness (ie, progressive drowsiness in a child who is
initially conscious); three or more episodes of vomiting;
involvement in a dangerous mechanism of injury (eg,
high speed road traffic accident as pedestrian, cyclist, or
passenger, fall from a height of more than 3 m, high-
speed injury from a projectile or other object); or
amnesia (anterograde or retrograde) lasting longer than
5 min. A provisional written report of the CT findings
made available within 1 h after scanning was also
recommended.
In the emergency room, a careful but focused history
and physical examination is the initial step in the
assessment of TBI. Although this clinical examination
might be compromised by intoxication with alcohol,
recreational drugs, or prescribed drugs in 13% of patients
with mild TBI,54 the guidelines for acute CT scans are not
substantially changed by these cofounders.54 Brain
imaging and neurological signs, which are robust to
intoxication, can aid diagnosis and differentiate mild TBI
from more severe injuries. Brain imaging can show the
presence and size of a haematoma and whether it is
causing shift of midline structures. Brain imaging can
also show intracranial haemorrhage and brain swelling.
Unequal response of the two pupils can suggest that a
lesion is present and the patient is at risk for neurological
deterioration. Both CT scanning and pupillary response
to light are robust, whereas the verbal component of the
GCS score is affected because the score depends on
whether the patient is oriented or confused.
Cranial CT scan is the neuroimaging modality of
choice in the emergency room, as it can readily identify
the small subset of patients who require prompt
neurosurgical intervention.4 However, fewer than 10% of
patients with mild TBI have abnormalities detected on
the acute CT scan,55 and only about 1% of these lesions
need neurosurgery.52,55–57 Many studies have addressed
clinical criteria that physicians can use to determine
whether a patient with mild TBI should undergo head
CT scan. In North America, the two most widely used
clinical criteria for the indication of a CT scan are the
New Orleans criteria (one or more risk factors, including
headache, one episode of vomiting, older than 60 years,
6 www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2
intoxication, visible injury above the clavicle, and a
seizure) and the Canadian CT head rule (one or more
risk factors, including GCS score <15 2 h after
presentation, suspected open fracture, signs of basal
fracture, more than one episode of vomiting, and older
than 64 years).52,55 These criteria were validated in patients
who had loss of consciousness or anterograde amnesia,
or both, and were not taking anticoagulants, which could
increase the risk of an intracranial lesion such as
haemorrhage. The primary outcomes used in the
validation studies were detection of an intracranial lesion
and detection of a neurosurgical lesion.
Follow-up studies have assessed the effectiveness of
these and other criteria in terms of sensitivity and
specificity for the identification of clinically significant
intracranial injury in adults. On the basis of the data
available from these studies, the American College of
Emergency Physicians and the CDC issued a joint
clinical policy statement51 in 2008 on indications for
obtaining head CT scans in adults with head trauma,
including adults with loss of consciousness or post-
traumatic amnesia, or both, and those with no loss of
consciousness or post-traumatic amnesia.
The factors that affect the decision to obtain a CT scan
and transport the patient to a trauma centre (panel 1) are
based on these recommendations and the NICE 2014
guidelines, which apply to patients with GCS scores of
13–15 within 1 h after arriving at the emergency room.
Results of studies have supported the sensitivity of the
New Orleans and Canadian criteria to detect intracranial
lesions and the subgroup of lesions that need
neurosurgery, but the specificity of these criteria for the
detection of lesions requiring neurosurgery is low. The
Canadian and New Orleans criteria both had 100%
sensitivity in identifying lesions for which surgical
evacuation was indicated, but a specificity of 76⋅3% (95%
CI 74–78) versus 12⋅1% (95% CI 11–14), respectively.52,55,58,59
Observation for 6–8 h in the emergency room or brief
admission to the hospital can probably be used as an
alternative to CT scans in patients without altered mental
status or signs of skull fracture.60 Additional factors that
might play a part in the decision to observe a patient
instead of CT scan include the absence of factors and
worsening symptoms (panel 1) and an age of 12 months
or younger. Infants are most difficult to examine, need a
paediatric version of the GCS,61 and have an increased
incidence of both asymptomatic intracranial
haemorrhages and other injuries. Home observation is
another option for patients with a normal mental status,
normal neurological examination, and the availability of
a companion.4
Panel 2 presents recommendations from NICE4 for
instructions to patients when they leave the emergency
room.
Post-acute management
Symptom levels and stress 3 months after injury might

be reduced in patients who receive educational material
explaining the most common post-concussion symptoms,
the likely time course for resolution, gradual resumption
of activities, and coping strategies.62 In addition to
information and reassurance, evidence exists that
cognitive behavioural therapy for patients with sub-acute
mild TBI can reduce symptoms within 1–6 months.63,64
Although early behavioural intervention shows promise
in mitigating secondary disorders, definitive, randomised
trials are needed to confirm the results of previous studies
that had methodological limitations.64 Panel 3 summarises
the interventions to improve outcome and reduce
morbidity after mild TBI, organised by the level of
evidence to support their effectiveness.
Persistent post-concussion symptoms
Patients with persistent post-concussion symptoms
3 months after sustaining mild TBI, including headaches
and cognitive complaints, might benefit from treatment.
Pre-injury history of psychiatric disorders, previous TBI,
and level of social support contribute to, or moderate, the
persistence of post-concussion symptoms.12,13 Post-acute
interventions include symptomatic treatment of
headaches,71 sleep disturbance, cognitive behavioural
therapy,64 and cognitive rehabilitation.72 Although some
evidence suggests the efficacy of cognitive behavioural
therapy in the treatment of post-concussion symptoms,
this is insufficient to justify the inclusion of this
intervention as a guideline.64 Mindfulness training and
other self-management techniques might be useful for
symptom reduction, but again the evidence for these
approaches is marginal.64 A letter to teachers or employers
requesting gradual resumption of demands might mitigate
secondary disorders and enhance recovery.
Pharmacological and non-pharmacological therapies
are useful for treatment of post-concussive symptoms in
the post-acute period. A comprehensive discussion is
beyond the scope of this review, and the US Department
of Veterans Affairs has published a useful review.73
Nonetheless, we include a brief discussion of the
principles underlying the most common therapies. Post-
traumatic headaches most frequently have features of
migraine headaches, followed in frequency by those of
tension headaches.71,74,75 Although definitive clinical trials
have not been done specifically for post-traumatic
headache, drugs to relieve symptoms and prophylactic
antimigraine treatments are widely used. However,
results of a 12 month follow-up study71 showed that
patients with mild TBI frequently self-managed their
headaches with over-the-counter drugs, which provided
complete relief in only 11 (26%) of 43 cases with the
migraine phenotype and 12 (70%) of 17 cases with tension
headaches. Of 53 patients who were receiving drugs for
migraine headaches at 12 months post-injury, only 4 (8%)
were treated with triptans, and 29 (27%) of 108 patients
used non-pharmacological therapy at 12 months post-
injury. A combination of pharmacological and non-
www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2
Review
Panel 2: Post-discharge follow-up4
When a patient with any degree of head injury is discharged
from an emergency room or observation ward, verbal and
printed discharge advice should be given to the patient,
their family, and caregivers; follow recommendations in
Patient experience in adult NHS services (NICE guideline For the NICE guideline [CG138]
[CG138]) about provision of information in an accessible see http://www.nice.org.uk/
guidance/cg138
format; printed advice should be age-appropriate and include
the following:
• details of the nature and severity of the injury
• recommendation that a responsible adult should stay
with the patient for the first 24 h after injury
• details of the recovery process, mentioning the fact that
some patients might appear to make a quick recovery, but
later have difficulties or complications
• contact details of community and hospital services in case
of delayed complications
• information about the return to everyday activities,
including school, work, sports, and driving
• details of support organisations
pharmacological treatments is usually needed for
maximum efficacy. Disordered sleep is also very common
in patients with mild TBI patients; 1 week after injury,
43% of uncomplicated patients with mild TBI reported
sleeping more than before injury, compared with 14% of
trauma controls, a clinically significant difference that
was not present at 3 months.12 Counselling about good
sleep hygiene is fundamental and often helpful.
Treatment of post-traumatic depression is empirical, and
a combination of pharmacological and behavioural
approaches is widely used.
Despite these recommendations, the results of a national
survey76 of emergency rooms in the USA showed that of
67 269 patients who received a pain assessment at the
emergency room, 56 161 (84%) reported pain, and a pain
assessment was documented in only 29 463 (44%) patients,
despite the high rate of headaches in this population, and
that 57 113 (38%) of 49 563 patients with mild TBI were
discharged without recommendation for follow-up.
Repetitive mild TBI, sub-concussive impacts,
and chronic traumatic encephalopathy
An association between repetitive mild TBI or sub-
concussive head impacts,68 or both, and chronic traumatic
encephalopathy (a progressive neurodegenerative disorder
with primarily tau pathology) has been found in
neuropathology studies.68 The neurological deterioration is
similar to that of dementia pugilistica, which was described
in retired boxers,77 but chronic traumatic encephalopathy
has also been confirmed in athletes participating in other
contact sports and in military veterans.68 Although
the latent period for onset of chronic traumatic
encephalopathy symptoms is estimated to last 8–10 years,
few prospective longitudinal studies have assessed at-risk
7
 Review
Panel 3: Post-acute management
Beneficial
No return to play on day of sports concussion to allow recovery of putative brain
metabolic disturbance and associated susceptibility to subsequent injury22,65
Likely to be beneficial
• Triage for follow-up if pre-injury history of neuropsychiatric disorder is noted or if severe
acute anxiety or depression are present in emergency room; follow-up to mitigate
persistent post-traumatic symptoms and secondary psychiatric disorders 12,66
• Educational intervention on discharge from emergency room, including written
checklist or instructions for early and late risk factors, time course for recovery, and
contact information (in case of complications) to prevent and reduce posttraumatic
symptoms62,64
• Gradual return to full-time work or school and guidance to mitigate stress, prevent
anxiety and depression, as patients might have to expend more effort to maintain
concentration27
• Sleep hygiene counselling if sleep disturbance is present62
• Assess and treat symptoms and depression if these intensify between initial
emergency room visit and 1 month or longer after injury66,67
• Cognitive behavioural therapy for anxiety-related post-concussion symptoms or
depression63,64,66
• For athletes engaged in contact sport, neurological examination, neuropsychological
assessment, and MRI after repetitive concussions associated with persistent
symptoms;22,65 counselling to review results and consider retirement from contact
sports to prevent or slow progression of neurodegenerative disease, such as chronic
traumatic encephalopathy68
• MRI within 2 weeks of mild TBI if risk factors for important neurosurgical lesion (ie, a
lesion that might cause delayed or persistent effects or require surgical evacuation)
are present;23 MRI can identify haemorrhagic axonal injury not seen on CT scans
• Cognitive rehabilitation therapy for memory problems persisting for at least 3 months69
Uncertain benefits
• Medication to treat sleep disturbance70
• Triptans for headaches with features of migraine71
• Non-pharmacological interventions other than cognitive behavioural therapy and
cognitive rehabilitation therapy64
individuals. Accelerometers in the helmets of football and
hockey players have provided a cumulative record of the
force of head impacts.78 Results of post-season tests of
American football players showed a decline from pre-
season scores in their ability to learn a word list, but this
decline did not occur in athletes engaged in a non-contact
sport. Post-season performance on a measure of attention
(reaction time) was also impaired in players who had a
high exposure to head impacts. Although repetitive mild
TBI or head impacts, or both, in American football players
have been investigated in neuropathological studies of
chronic traumatic encephalopathy and post mortem
interviews with next-of-kin,68 the scarcity of prospective,
longitudinal imaging and neurobehavioural data obtained
from athletes engaged in contact sports has been a
confounding factor in identifying the causal link between
exposure to mild TBI and chronic traumatic
encephalopathy. Other factors, such as genotype, are also
likely to play a part in development of chronic traumatic
8 www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2
encephalopathy.79 Moreover, a review by the International
Collaboration on Mild Traumatic Brain Injury Prognosis
concluded that little evidence exists to support an
association between single or repetitive mild TBI and later
development of dementia.80 The International
Collaboration on Mild Traumatic Brain Injury Prognosis
recommended prospective longitudinal studies, including
appropriate comparison groups, to assess the long-term
consequences of these injuries.81 Relatedly, the threshold of
exposure to head impacts or repetitive mild TBI to trigger
chronic traumatic encephalopathy is also unknown.
Secondary disorders
The most frequent psychiatric disorders that develop after
mild TBI are depression and anxiety disorders, including
post-traumatic stress disorder (PTSD). Findings in an
Australian study showed that the increased prevalence of
psychiatric disorders in mild TBI relative to non-brain
traumatic injury was restricted to PTSD, phobias, and
panic disorder.67,82 By contrast, in a study66 of 559 patients
with mild TBI who had brain abnormality on CT,
297 (53%) of the patients had major depressive disorder
in the first year following mild TBI, and 130 (41%) of the
321 patients without a history of major depressive
disorder had their first onset during the year following
the mild TBI. Age, sex, and pre-injury history of
depression were predictive of major depressive disorder.
However, investigators of a prospective, longitudinal
comparison of CT-negative patients with mild TBI with
patients who had sustained mild traumatic injury to other
body regions reported no between-group difference in
depression 3 months after injury.12
PTSD is a comorbidity that can be diagnosed at 1 month
or longer after mild TBI. It occurs more frequently in
civilians following assault than from other injury
mechanisms and is directly related to combat exposure
in military personnel with mild TBI. In civilians, PTSD
3 months after injury was found to occur in 50 (12%) of
425 patients with mild TBI and was thus more prevalent
than in trauma controls, for whom PTSD occurred in 40
(8%) of 532 patients.82 On the basis of interviews, which
were validated as the criterion for diagnosis83 for military
personnel, PTSD comorbid with deployment-related
mild TBI 3 months post-deployment was reported in
about 15% of 285 military personnel. This rate of PTSD
was twice that of military personnel exposed to a high
intensity of combat without sustaining TBI.83 By
comparison with clinician-diagnosed PTSD, the rate of
clinically significant PTSD symptom levels measured by
self-report instruments is much higher in military
personnel and veterans with mild TBI. Clinically
significant, comorbid PTSD symptoms were present
6 months post-deployment in 54 (43%) of 123 US military
returnees, as measured by a self-report survey.6
Concomitant injury to other body regions complicates
recovery from mild TBI in civilians84 and military
personnel,21 but the presence and severity of non-brain

injuries are not consistently reported in studies.
Depending on the severity of non-brain injury, pain,
depression, and disability might be accentuated as
compared with isolated mild TBI.67,82,84
The criteria for diagnosis of post-concussive disorder
according to Diagnostic and Statistical Manual of Mental
Disorders IV (DSM-IV) are more stringent than the criteria
for diagnosis of post-concussive syndrome according to
the International Statistical Classification of Disease-10.
DSM-IV specifies an injury severity threshold for post-
concussive disorder as including loss of consciousness for
a minimum of 5 min, at least three symptoms present for
3 months, disruption of occupational or social activities,
and impaired attention or memory on cognitive testing.
Both diagnostic formulations have been criticised19
because of the scarcity of evidence to support the severity
threshold, the non-specificity of the symptoms (eg,
headaches are common in the general population), and
the potential for litigation or for compensatory or other
secondary gain. The rates of post-concussion syndrome
and post-concussion disorder vary considerably across
studies, depending on the diagnostic criteria used for mild
TBI and these secondary disorders. Pre-injury psychiatric
disorder, but not mild TBI, has been shown to be predictive
of post-concussion syndrome at 3 months, and the rate of
post-concussion syndrome did not differ between mild
TBI and trauma controls.12,13 Ponsford and colleagues12
found that onset of acute stress disorder within 5 days
after injury was predictive of post-concussion syndrome at
3 months in both mild TBI and trauma control groups.
Women show a higher rate of post-concussion syndrome
than men,13 but the mechanism for this effect is unknown.
Screening with a reliable and valid psychiatric interview
can identify patients with a positive psychiatric history
who are at greater risk of post-concussion syndrome or
post-concussion disorder early after injury. Brief screening
could also inform triage for follow-up of patients at high
risk for persistent morbidity after mild TBI.
Management of sports concussion
Athletes generally recover from sports concussion within
days to weeks, with resolution of symptoms and
improved cognitive performance.22,65,81 Risk factors for
delayed recovery include young age (<16 years), acute
onset of migraine-type headaches, dizziness, slowed
reaction time, memory deficit, or a history of
concussion.22,81 Sports concussion is managed by physical
and mental rest until the athlete is asymptomatic. This
initial phase is followed by graded increases in physical
exertion before return to play.22 The clinician monitors
post-concussion symptoms and cognitive performance
relative to the player’s report of symptoms and test scores
on a pre-season examination, if this baseline was
obtained. Recovery to pre-season level is one of the
criteria used by clinicians to decide when the player can
return to play. During the rest phase, premature physical
exercise might intensify post-concussion symptoms,
www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2
Review
thus lending credence to this management strategy.65
Experimental evidence shows that mild TBI is followed
by an interval of heightened susceptibility to a second
insult. Investigators of experimental and clinical studies
have reported a rapid rise in cerebral glucose metabolism
immediately after TBI, followed by a sustained period of
depressed cerebral glucose metabolism, which might be
a biomarker of susceptibility to a second injury.22,28 After
mild TBI, rodents were found to have decreased parietal
and hippocampal glucose metabolism and impaired
memory, which was resolved 3 days after injury; a second
mild TBI 24 h after the first injury produced further
declines in cerebral glucose metabolism and memory,
but not if it was delayed until 120 h after first injury.85
Results of imaging studies have shown preliminary
evidence for a period of cerebral dysfunction in conscious
patients following mild TBI. This dysfunction includes
reduced cerebral glucose metabolism on PET in patients
with complicated mild TBI (defined by abnormalities on
CT scan or MRI) during a period of 2–28 days after
injury.86 Results of fMRI studies suggest that functional
connectivity of brain networks in athletes might not fully
recover despite resolution of symptoms,33 but the clinical
implications of this finding are not clear.
Despite a rationale based on laboratory research and
clinical observations, few randomised clinical trials are
available to support the approach of cognitive and
physical rest for treating concussed athletes, including
the optimum duration of rest, ie, the number of days and
criteria for termination of rest, and type of rest.65 Rest can
be refrainment from physical activity or cognitive activity,
including operating a computer, attending classes, or
completing homework. A review of an athlete’s mild TBI
(number of concussions, their severity, the persistence of
symptoms, and the effects on everyday activities
including cognitive performance), history, comorbidities
(eg, depression), and neurological and neuropsychological
findings can inform return-to-play decisions. MRI
acquired with appropriate protocols might provide useful
information.23 If return-to-play is recommended,
decisions about the frequency and intensity of play
should consider the current guidelines, which, although
based on little evidence,65 are under development.22
Counselling for players about retirement from contact
sports is guided by clinical judgment.
Conclusions and future directions
Advances in mild TBI research during the past 20 years
have at least preliminarily characterised the time
course for cognitive and functional recovery and the
resolution of symptoms, and studies have identified
prognostic factors, such as pre-injury neuropsychiatric
disorder and specific fi ndings on early post-injury
brain imaging. Animal models and brain imaging
have elucidated mechanisms and shaped clinical
management of mild TBI and recovery. It is now
evident that mild TBI encompasses a range of severities,
9
 Review
Panel 4: Directions for future research and clinical services
for mild traumatic brain injury
• Develop a precise consensus definition to improve
accuracy and reliability of diagnosis17
• Improve application of MRI, diffusion tensor imaging,
susceptibility-weighted imaging, and other advanced
imaging techniques and specify rules for referral,
optimisation, and standardisation of imaging protocols
to detect pathology and guide treatment, while
assuring reproducibility of results across and within
centres
• Research on the neural mechanisms, diagnosis, and
treatment of mild traumatic brain injury (TBI) in young
children and older adults
• Development and validation of non-imaging biomarkers
that have sensitivity and specificity to detect mild TBI and
guide clinical management
• Validate treatment guidelines for triage to follow-up,
management of headaches, and other postconcussion
symptoms
• Research on the neural mechanisms of sports concussion
to develop and validate more rigorous clinical guidelines
for return to play, retirement from contact sports, and
health-care policy in sports medicine
• Randomised clinical trials of pharmacological and
non-pharmacological treatments for sequelae of mild TBI
• Prospective longitudinal studies of repetitive mild TBI and
subconcussive impacts, including multimodal imaging
and biomarkers for early detection of neurodegenerative
disorders and monitoring of the effects of treatment
Search strategy and selection criteria
We searched personal files and PubMed for the period Jan 1,
2004, to Dec 31, 2014,for papers published in English, with
the terms “mild traumatic brain injury”, “animal models”,
“brain imaging”, “pathophysiology”, “biomarkers”, “post-
concussion symptoms”, “depression”, “post-concussion
disorder”, “post-concussion syndrome”, “post-traumatic
stress disorder”, “sports concussion”, “repetitive mild
traumatic brain injury”, “chronic traumatic encephalopathy”,
and “clinical management”.
as determined by the acute effects on consciousness,
and early symptoms, such as headache, initial cognitive
performance, and brain pathology. Progress in the
development of clinical guidelines for transfer of
patients to a neurological trauma centre, triage to acute
CT scan, and management of concussion has been
considerable, but implementation varies across centres
and geographical region. Although diff usion tensor
imaging, other advanced brain imaging, and non-
imaging biomarkers hold promise to improve diagnosis
and monitoring of mild TBI, further research is needed
10 www.thelancet.com/neurology Published online March 20, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00002-2
for clinical application (panel 4).
Contributors
Both authors did the literature review, wrote and revised the report, and
approved the final version.
Declaration of interests
We declare no competing interests.
Acknowledgments
Our work is supported by the US National Institutes of Health, the
Department of Veterans Affairs, Chronic Effects of Neurotrauma
Consortium, the Center for Neuroscience and Regenerative Medicine, and
Department of Defense. Our funding sources had no role in the literature
review, interpretation of data, writing of this Review, or in the decision to
submit for publication. The contents of this paper are solely the
responsibility of the authors and do not represent the official views of the
National Institutes of Health, the Department of Veterans Affairs, Chronic
Effects of Neurotrauma Consortium, the Center for Neuroscience and
Regenerative Medicine, and Department of Defense. We thank James
Montier (Baylor College of Medicine) for his assistance in the preparation
of this Review. We thank Lawrence Latour (National Institute of
Neurological Disorders and Stroke, Bethesda, MD, USA) for panels A–D
of the figure, and we thank Carlos Marquez de la Plata (University of
Texas at Dallas, Dallas, TX, USA) for panel E of the figure.
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