Introduction

The last decade in the UK has seen improvements in the way that traumatic brain injury (TBI) is managed, with the implementation of Major Trauma Networks. Enhanced pre-hospital approaches, excellent leadership, standardised care and governance are some of the reasons a patient is 30% more likely to survive major trauma today in the UK.¹

The recent Lancet Neurology Commission on TBI highlighted the scope and considerable public health challenge of TBI. It estimated that 50% of the world’s population will experience one or more traumatic brain injury in their lifetime.² The Commission particularly highlighted the urgent need for the development, validation and implementation of prognostic models in TBI, particularly less severe TBI; 80–90% of all TBI cases fall into less severe classifications.³

The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study is a European Commission funded observational study that began in 2013. It aims to characterise TBI, identify best practices, develop precision medicine and improve outcomes via comparative-effectiveness studies. The CENTER-TBI study is closely linked with the US Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study and forms part of a franchise of studies making up the International Initiative for Traumatic Brain Injury Research (InTBIR). Therefore the findings of CENTRE-TBI will be greatly amplified by analyses across the InTBIR studies.

Early neurorehabilitation in TBI has been shown to shorten overall hospital stay, reduce the likelihood of being discharged into a care setting and improve functional outcomes at one year.⁴ The development of TBI neurorehabilitation facilities collocated within Major Trauma Centres should therefore be a priority in ongoing TBI service redesign.

Facilitating individualised management of TBI to optimise diagnosis, track disease progression and improve outcome prediction is the pathway of the future for TBI. There is therefore an unmet medical need for rapid blood-based biomarker tests, as an adjunct to imaging studies.

Substantial scientific advances in the past decade have resulted in identification of blood-based protein biomarkers that are relevant to different phases of TBI.^{5, 6} Ongoing research efforts are yielding new classes of biomarkers, including metabolic and lipid markers, microRNAs and exosomes.^7–9 These hold potential for diagnosis, prognosis and therapeutic stratification, but are not yet in advanced clinical development.

Epidemiology

Approximately 50 million people worldwide each year sustain a TBI, and the cost is estimated as being 0.5% of global economic output.¹⁰ The incidence, including the whole range of TBI severity from minor to very severe injuries, varies in different countries, from 60 cases per 100,000 inhabitants up to numbers 12 times higher.¹¹ This reflects local variations, varying diagnostic criteria and methodologies. There are an estimated one million A&E attendances in the UK each year due to TBI.¹² TBI is the single largest cause of death and disability in the under 40-year-old age group.

The number of TBI admissions in the UK in 2015 had increased by 6% compared to 2005–2006, and males were 1.6 times more likely to sustain a TBI than females.¹³ Calls to the Headway charity nurse-led helpline also increased by 60% between 2010 and 2014. Of particular note, the data showed a 61% increase in the incidence of TBI in the female population, when compared to 2000–2001. This may be due to multiple factors such as increased life expectancy, increased alcohol consumption and potentially increased risk-taking behaviour in the female population.

It is estimated that TBI costs £15 billion per year in the UK through direct and indirect costs.¹⁰ TBI is known to reduce life expectancy and is also a risk factor for premature death and suicide.¹⁴ It doubles the risk of developing a mental health disorder,¹⁵ and it is estimated that 50% of adults and 33% of young offenders in prison have a history of a TBI.¹⁶ In addition to the impact of TBI on the individual and their family, the societal costs can be substantial. In the UK, health and social care costs for people with TBI have been estimated at £71.1 million for the 18–25-year-old age group alone.¹⁷

Figures regarding the prevalence of people living with the consequences of TBI are less well documented. It has been estimated, however, that millions of people (approximately five million in the USA and seven million in Europe) were living with TBI-related disability in 2014.¹⁸

Epidemiological studies also show increased mortality rates even after a mild traumatic brain injury. One large cohort study showed that 15 years after the injury, the mortality rate in young patients with a mild TBI was higher than the rate in matched controls.¹⁹ Patients with mild TBI had higher mortality rates than those with other types of injury, so the findings were not due to nonspecific lifestyle factors associated with those exposing themselves to potential injury.

Classification

Severity classification in TBI has been of interest due to its relationship to outcome and post-acute medical care.²⁰ TBI severity can be classified both for clinical and research purposes using single indicators, such as duration of post traumatic amnesia (PTA),²¹ duration of loss of consciousness,²² and Glasgow Coma Scale (GCS),²³ or a combination of the above (see Table 3.1).

Although these measures are well established, they may be influenced by other factors such as sedation, intoxication and psychological shock. Whilst neuroimaging provides an objective anatomical indicator of severity,²⁴ it is often not obtained in the less severe cases.

With the advent of neuroimaging, it has become increasingly possible to classify TBI in a clinical setting on a pathoanatomic basis, where the features and location of traumatic abnormalities can be defined both from clinical features and radiological appearances. Pathoanatomic features may be a more important determinant of long-term neuropsychological outcome than classifications based on severity, as defined by clinical factors alone.

Different imaging modalities are available to classify TBI, with CT being most commonly used in the acute traumatic presentation. MRI is used further down the line of recovery to guide prognosis and diagnosis of pathologies, such as diffuse axonal injury. This is often difficult to diagnose on initial CT imaging.²⁵ Other imaging modalities such as diffusion tensor imaging,²⁶ functional MRI²⁷ and PET imaging²⁸ are currently promising research tools but are not widely used in day-to-day clinical practice.

Acute Management

The ideal management of patients with an acute TBI allows accurate and timely diagnosis of the complex problems which occur both immediately and less acutely post-TBI. It should also provide rapid and accurate treatment, and it should be focused on pathological and impairment based diagnostics and therapeutics.

Stroke services are now organised into Hyper Acute Stroke Units and Stroke Units, with all stroke patients being cared for by a Stroke Consultant on a dedicated and specialist stroke ward. This is currently not the case for TBI patients in many countries. Cohorting patients who have suffered a stroke has been shown to increase cohesion of the care pathway, improve patient flow, reduce preventable disability and reduce length of stay.²⁹

Major Trauma Networks were developed in order to get the right patient to the right place at the right time. Progress has been made in identifying and treating, in a timely fashion, secondary insults to the brain including hypoxia, hypotension, seizures and intracranial haematomas.

Pre-hospital TBI care has greatly improved over the past few decades.³⁰ This care has emphasised rapid, safe extrication of the trauma victim, stabilisation of the spine, aggressive resuscitation to prevent hypotension, immediate airway management and rapid, safe transport to an appropriate trauma centre. The most important key feature of current paediatric and adult head injury protocols is the aim to decrease all potential secondary brain insults.

The early detection of an intracranial haematoma would allow focusing of the trauma pathway on the needs of the individual patient. Therefore, access to better monitoring at the roadside is desirable. If patients survive the first few minutes, there is a therapeutic window of opportunity to intervene and prevent further death of brain tissue.

Currently, TBI is managed uniformly. The pre-hospital data field does not specify the type of brain injury, if any. Hence all such patients receive the same treatment (usually intubation and transfer to a neurosurgical unit). On-scene diagnosis of injury would permit more directed therapies to be initiated. It is vital to dispatch resources appropriate for the presumed severity of injury. Currently pre-hospital dispatch criteria are often based on ‘mechanism of injury’ (e.g. fall > 2 floors, ejected from car) and interrogation of emergency line callers.

Different types of traumatic intracranial bleeding (haematomas) exist, all of which can compress the brain and can be life-threatening. Timely surgery can be life-saving, but this depends on rapid patient transfer to a centre with neurosurgical facilities. Initial neurosurgical treatment of TBI can be either causally directed (e.g. to remove space-occupying intracranial haematomas)³¹ or symptomatic (e.g. to decrease pressure on the brain to prevent or minimise damage to important structures and prevent life-threatening herniation events). Symptomatic approaches include insertion of an external ventricular drain for drainage of cerebrospinal fluid^{32, 33} and decompressive craniectomy, which can be performed in the same setting as the evacuation of a haematoma, or later to treat diffuse brain swelling that is refractory to conservative medical management.

Substantial variation exists in neurosurgical practice, owing to an inadequate evidence base for international guidelines on surgical indications.^34–36 Additionally, at the level of individual patients, there is debate among clinicians regarding which patients might benefit from some procedures, such as surgical treatment for traumatic intracranial lesions and for raised intracranial pressure (ICP), and uncertainty regarding the optimum timing of surgery.

Surgery might be life-saving and preserve neurological function in some patients,³⁷ but others might survive with an unfavourable functional outcome, ranging from severe neurological and cognitive deficits to a vegetative state.^38–40 Conversely, surgery might not always be necessary. A substantial proportion of patients who are managed conservatively have favourable outcomes.^41–45

Therefore, when deciding whether to operate, medical therapies that might be effective in achieving the same physiological goals as surgery should also be considered. Surgical indications that are too liberal could lead to increased survival with complications of unnecessary surgery in patients with less severe injury, or severe disabilities in those with devastating TBI.

Conversely, inappropriate conservative management might result in unnecessary death and disability. The decision to operate is based not only on medical but also on ethical considerations. Patients’ and relatives’ views of a meaningful quality of life might be different from the medical perception of a favourable outcome. These differences could depend on several factors, including cultural and religious considerations. If discussion of the expected outcome with relatives is possible, past views expressed by patients on an acceptable quality of life should be taken into consideration.⁴⁶

Accumulating evidence provides useful support for such decision making. An illustrative example is the use of decompressive craniectomy for intracranial hypertension. Although the procedure can be life-saving by lowering ICP, it is often associated with surgical complications, and structural distortions associated with removal of a portion of the skull might cause additional brain injury in some patients.⁴⁷ Initially used over a century ago, the intervention has come back into use over the past two decades, but given the need to balance risks and benefits, a clear definition of its role has been difficult.^48–50

Two important randomised control trials (RCTs) have provided useful guidance in this context. The DECRA (Decompressive Craniectomy) trial showed that very early use of decompressive craniectomy for modest rises in ICP in patients with diffuse injuries was associated with worse outcomes.⁵¹ More recently, the RESCUEicp (Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure) trial showed that, when used for refractory severe intracranial hypertension, decompressive craniectomy could save lives, but resulted in a 9% increase in survival with severe dependence at 6 months.⁵² However, by 12 months, there were 13% more survivors who were at least independent at home. As the intervention is not uniformly beneficial, individual wishes of patients and their families should be taken into consideration.

Other studies have addressed similar surgical dilemmas. A recent study suggested that in patients with a traumatic acute subdural haemorrhage, early evacuation was associated with better outcome than a more conservative approach.⁵³ Similar trends were noted in the STITCH (Surgical Trial In Traumatic intraCerebral Haemorrhage) study⁵⁴ which reported better outcomes with early surgical management in patients with traumatic intracerebral haemorrhage. However, the results of the STITCH trial were not statistically significant owing to an inadequate sample size caused by premature discontinuation of the trial by the funding agency.⁵⁵ The RESCUE-ASDH (Randomised Evaluation of Surgery with Craniectomy for patients Undergoing Evacuation of Acute SubDural Haematoma) trial is currently ongoing. Clinical decision making could be greatly improved by the identification of patient subgroups most likely to benefit from the intervention and, importantly, patients who are not likely to benefit.

The consequences of TBI either arise as a primary consequence of the trauma (through direct contact and/or through acceleration–deceleration forces) or secondary to subsequent nontraumatic consequences. The injuries may be focal, diffuse, or both. Focal injuries include skull fractures, haemorrhage and contusions. Diffuse injuries include diffuse axonal injury (DAI) and/or vascular injury.⁵⁶

Intraparenchymal haemorrhage or intracerebral haemorrhage refers to significant bleeding within the brain parenchyma. Pathologically, contusions and intraparenchymal haematomas exist along the same continuum. In a contusion, blood is intermixed with brain tissue.⁵⁷ Radiologically, a contusion becomes an intraparenchymal haematoma once two thirds or more of the lesion is blood.⁵⁸

Up to one third of all contusions enlarge in the subacute phase and so the extent of damage may be underestimated or missed on scans conducted immediately after the initial injury. A metabolic reaction is triggered in adjacent tissue, which peaks approximately 5 days after the injury. Mechanically, the inferior surfaces of both the frontal and temporal lobes are particularly vulnerable to contusional injury following TBI, due to the irregular bony surface floor of the frontal and middle cranial fossa. Injuries to the parenchyma in these regions can lead to persistent focal neuropsychological deficits.

The prognosis associated with extradural and subdural haemorrhages is improved if the injury is not associated with significant pressure effects, if there is no oedematous or inflammatory response in the underlying parenchyma and if the haemorrhage does not require surgical management.

However, the risk of morbidity and mortality increases significantly if the bleed requires surgical intervention, particularly if this is delayed.⁵⁹ Mass effects are better tolerated in some brain regions than others. Figure 3.1 shows a large acute extradural haemorrhage requiring urgent neurosurgical intervention.

Figure 3.1 An acute left sided extradural haematoma with midline shift and uncal herniation requiring urgent neurosurgical intervention.

Intraventricular haemorrhage can occur as a result of trauma, most commonly developing from a primary traumatic subarachnoid bleed. When associated with raised intracranial pressure, survivors of such injuries are at high risk of being left with significant and widespread cognitive difficulties.

Secondary injuries refer to the cerebral damage caused by events following the primary injury. These may occur as a direct consequence of the pathophysiological cascade triggered by the primary injury, or they may be the neurological consequences of other physical injuries sustained in the trauma. Secondary injuries can result from hypoxia, raised ICP, hypercarbia, hyponatraemia and seizures. The presence of any of these processes significantly increases the likelihood of developing long-term neurological sequelae following a TBI. The impact is cumulative, with the more injuries sustained by the brain, the less likely the patient is to make a full neurological recovery.

Cognitive deficits post-TBI commonly include reduced speed of cognitive processing, difficulties in memory and attention,^{60, 61} language and executive functions.⁶² Behavioural alterations such as impulsivity and aggression,⁶³ in addition to neuropsychiatric consequences, including depression and apathy, are commonly encountered.⁶⁴ There is also an increased rate of relationship breakdown amongst families coping with the effects of TBI.⁶⁵ Other areas that are frequently affected are social reintegration and life satisfaction,⁶⁶ educational attainment⁶⁷ and vocational outcome.⁶⁸

The resolution of confusion or PTA immediately post-TBI is often commonly followed by a constellation of symptoms including dizziness, fatigue, headaches, reduced concentration, memory impairment, sleep disturbance, irritability, photophobia, phonophobia, depression and blurred vision.

Most patients sustaining a mild TBI should be expected to recover within the first three months.⁶⁹ There are well documented factors that may cause this period of recovery to lengthen.⁷⁰ Up to one third of such patients report symptoms lasting up to six months.⁷¹ The presence of a more severe initial injury, older age, female sex, previous head injuries and pre-existing psychological problems all make symptoms more likely to be persistent.⁷²

Following the initial traumatic event, patients go through a long and complex process of functional recovery. There is a general trend for patients to experience an initial stage of rapid improvement, gradually plateauing over a period of two years.^{73, 74}

Neurorehabilitation consists of a series of interventions tailored to the individual’s unique bio-psycho-social needs, in order to optimise recovery and maximise functional outcomes. The ultimate aim of neurorehabilitation is to enhance community reintegration. In the UK, TBI hyper-acute neurorehabilitation may start following admission to intensive care, continuing into the community and vocational settings.

The point at which to commence intensive neurorehabilitation is a matter of ongoing debate. Introducing neurorehabilitation when patients remain in PTA with reduced physical and cognitive tolerance of therapy may be considered a misallocation of resources, but intervening too late may also have a negative impact on recovery.

Early (<35 days post injury) TBI rehabilitation admission leads to a significant reduction in length of intervention and total hospital stay, thus decreasing the associated cost of care.⁷⁵

A prospective randomised study of a specialist multidisciplinary domiciliary outreach team showed that treatment increased independence and lessened care needs significantly when compared to standard care.⁷⁶ Residential neurorehabilitation for patients with neurobehavioural disorders after TBI improves functional outcomes and is estimated to result in lifetime savings of up to £1.13 million.⁷⁷

PTA length can be used as an indicator of injury severity and has been shown to have prognostic value for long-term functional outcomes.^{78, 79} There have been attempts to influence the length of PTA in order to improve TBI outcomes has been attempted.^{80, 81} However, there is limited evidence for the effectiveness of early intervention in patients with PTA.⁸²

A recent survey identified that fewer than 20% of neurotrauma centres have evidence-based guidance on the characteristics of intensive rehabilitation.⁸³ It is likely that progress in this domain has been hindered by the difficulties associated with conducting rigorous trials on complex interventions, particularly where doing so would involve delaying access to necessary interventions. Whilst recent progress has been made in quantifying the clinical and cost-effectiveness of parameters such as the number of disciplines involved and intervention intensity, evidence on optimal timing of neurorehabilitation is still scarce.^{84, 85}

Long-term sequelae of TBI can include post traumatic headaches, seizures and neurodegeneration. There is an increased incidence of Parkinson’s disease⁸⁶ Alzheimer’s disease,⁸⁷ and chronic traumatic encephalopathy.⁸⁸

Prevention

Most TBIs are preventable, and the demographics are changing. Whilst TBI from high velocity injuries in young males still occur, the burgeoning elderly population with TBIs from falls from standing is increasing considerably.⁸⁹ The global ageing population is increasing in size dramatically. Altered physiology, anatomy, comorbidity and medications can influence the response to trauma and its medical management. There are also more TBIs occurring in several developing countries due to increased motorisation.

According to the World Health Organization (WHO), road traffic accidents are the number one cause of death among those aged 15–29 years, killing almost 1·3 million people of all ages each year. Approximately half of those killed are pedestrians, cyclists and motorcyclists.⁹⁰ Ninety percent of all TBI-related deaths occur in low and middle income countries.⁹¹ Road traffic accident and trauma-related TBIs are increasing in these countries.

Only 28 countries, representing 449 million people (7% of the world’s population), have adequate laws that address all of the top five risk factors for injury and premature death: seat belt use, child restraint use, speeding laws, drink driving laws and the use of a protective helmet. Road traffic injuries are currently estimated to be the ninth leading cause of death globally, and they are predicted to become the fifth leading cause of death by 2030.⁹⁰

Among the people most at risk of sustaining a TBI are those using powered two-wheel vehicles. Mandatory helmet use has decreased the number and severity of head injuries among both motorcycle⁹² and bicycle users.^93–95 In Taiwan, introduction of the motorcycle helmet law in 1997 reduced motorcycle-related head injuries by 33%, and injuries that did occur were less severe and were associated with shorter hospital stays.⁹⁶ Despite strong evidence that helmets reduce the severity of injuries from motorcycle crashes and increase the likelihood of survival, helmet laws are not universally implemented.⁹⁷

The impact is greatest in low and middle income countries, where helmet wearing rates are only slightly above zero. Child passengers rarely wear helmets and those who do often wear adult helmets, offering inadequate protection. Where mandatory helmet laws are enacted, strong enforcement has yielded a 40% reduction in the risk of death.⁹⁰

In high income countries, recent attention has focused on the risks incurred by distracted drivers.⁹⁸ The likelihood of a safety critical event occurring while driving has been reported to be six times higher for drivers dialling a mobile phone and 23 times higher for those texting. Although campaigns aimed at influencing drivers’ behaviour remain relevant, technological solutions should also be considered. There have been suggestions to develop smart solutions to recognise and block nonhands-free mobile phone use whilst driving.

Annually, more than 600,000 individuals worldwide die from falls, the majority from TBI. The US Centre for Disease Control and Prevention reported that, in 2013, nearly 80% of all TBI-related Accident and Emergency department visits, hospital admissions, and deaths in adults aged 65 years and older were caused by falls.^{99, 100}

The incidence of falls in low and middle income countries is likely to be underreported, and therefore, the global incidence of fall-related TBI is likely to be much higher than suggested by current estimates.

Crucial to improving TBI outcomes are pre-hospital emergency care at the scene of the injury, acute hospital inpatient care and post-acute care. The latter of these is rarely available in low resource settings. While 85% of high income countries have an emergency specialty for doctors, a recent WHO systematic review of emergency care in 59 low and middle income countries reported that only 28% of facilities had Consultant-level Physicians available full-time; 18% were staffed by specialty trained Accident and Emergency Physicians, and in only 4% were these available at all times.¹⁰¹

Therefore General Practitioners, Medical Practitioners and nurses, often without proper training, are often left to manage acute trauma. Furthermore, many patients with TBI require emergency neurosurgical intervention that is frequently non existent. In many countries in Africa, for example, the ratio of neurosurgeons to members of the population in 2005 was roughly 1 to 9 million.¹⁰²

The UN has developed Sustainable Development Goals (SDGs), and SDG 3.6 aims to halve global deaths and injuries from road traffic accidents and ensure universal health coverage, by 2030.

Prevention initiatives can be applied at a population level with legislation, improvements in infrastructure, vehicle safety design, trauma care and workplace safety measures. Alternatively, prevention measures can focus on high risk subgroups. Examples include the targeting of drivers and cyclists to prevent alcohol impaired driving, speeding and distracted driving: promotion of seat belt, child restraint and helmet use; a focus on elderly people living alone and at risk of falls (see Figure 3.2) and strategies aimed at children at risk of abuse.

Figure 3.2 Falls in the elderly population are usually multifactorial.

Prevention strategies need to take account of changing epidemiological patterns, which show increases in fall-related TBI in older individuals.^103–105 Frail elderly people are more likely to fall, more likely to suffer a TBI when a fall occurs and more likely to suffer long-term adverse effects even from a seemingly mild TBI.¹⁰⁶

It might also be possible to specifically target individuals to address their patterns of risk-taking behaviour.¹⁰⁷ Irrespective of the target population, information campaigns should employ a range of measures to raise awareness of key issues in prevention and care for TBI. The potential of broad education and awareness campaigns, also using social media, is exemplified by the success of the ThinkFirst National Injury Prevention Foundation, established in the USA in 1990.¹⁰⁸

Several studies have identified increased age as a factor prognostic of mortality following TBI.^109–111 Adults aged 65 years and over made more than 3.5 million visits to Accident and Emergency departments in England during the financial year 2012–2013.¹⁰⁰ Attendances by this age group formed 19% of the 18.3 million Accident and Emergency department attendances in England that year.

Professional sports organisations are increasingly obliged to remove any player with a suspected TBI from play immediately, thus setting an example for amateur athletes and, in particular, young players. Such decisions should not be taken by interested parties (e.g. coaches), but rather by a neutral party such as an independent healthcare professional. The English Rugby Football Union has developed the widely publicised ‘Headcase’ project, and the SCAT 3 is used as a pitch side concussion detection programme.¹¹²

Various international efforts have been initiated to develop, refine and implement rational guidance for players, parents and coaches about the time that needs to be spent away from training and contact sport following a mild TBI.¹¹³ However, further refinement in diagnosis is needed, as is guidance on action required when a mild TBI is reliably diagnosed.^{114, 115}

In children and adolescents, there are additional concerns about the cumulative effects of multiple mild TBIs on brain development and learning, and the consequent cognitive and behavioural sequelae.¹¹⁶ Children and young adults are also at increased risk of second impact syndrome.^{117, 118}

Sport-related TBIs have received significant media coverage in recent years, in part due to an increased body of scientific literature and growing concern surrounding their long-term effects. The major focus is on mild TBI, as these account for 80% of TBI related visits to Accident and Emergency departments.

With the development and application of advanced mild TBI assessment tools, including neuropsychological testing, neuroimaging and balance and gait assessments, there is a rising tide of data that is driving changes in clinical practices and the management of patients with mild TBI.