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