Congenital and Acquired Brain Injury. 1. Epidemiology, Pathophysiology, Prognostication, Innovative Treatments, and Prevention

Article Outline

• Abstract
• 1.1 Educational Activity: To discuss the public health implications of traumatic brain injury epidemiology and its effect on the local community
• Incidence
  • Death
  • Hospitalization
  • Emergency department
• Prevalence
• Severity
• Age
• Survival
• Mechanism of Injury
• Other Demographic Factors
• Economic Impact
• 1.2 Clinical Activity: To counsel the family members of your 17-year-old male patient who has sustained TBI about the need for preventing reinjury and to develop prevention strategies for the entire family
• Transportation-Related Injury Prevention
• Drugs and Alcohol
• Falls
• 1.3 Educational Activity: To discuss the approach to prognosis for a patient recently admitted to inpatient rehabilitation 1 month after a severe TBI
• 1.4 Educational Activity: To discuss the potential pathophysiologic features that explain why an 18-year-old patient remains unresponsive 1 week after TBI in the presence of a normal CT
• 1.5 Educational Activity: To participate in developing the guidelines and options for using innovative treatments in the early management of TBI for your local city health department
• Appendix 2. Definition of Threshold Value
• Appendix 3. Glasgow Outcome Scale
• Appendix 4. Summary of Findings from Studies of Nonpenetrating TBI GCS
  • Coma Duration
  • Posttraumatic Amnesia
  • Age
  • Neuroimaging
• Appendix 5. Guidelines for Prognostication After Severe TBI
• References
• Copyright

Abstract 

Brown AW, Elovic EP, Kothari S, Flanagan SR. Kwasnica C. Congenital and acquired brain injury. 1. Epidemiology, pathophysiology, prognostication, innovative treatments, and prevention.

This self-directed learning module reviews the current epidemiology of traumatic brain injury (TBI), its pathophysiology, prognostication after injury, currently available innovative early approaches to diagnosis and treatment, and effective methods of prevention. It is intended to provide the rehabilitation clinician with current knowledge to accurately inform patients, families, significant others, referring physicians, and payers and to aid in clinical decision making while caring for patients after TBI.

Overall Article Objective

To describe current knowledge in traumatic brain injury epidemiology, pathophysiology, prognostication, acute treatment, and prevention.

Key Words: Diffuse axonal injury, Economics, Guidelines [publication type], Mortality, Preventive measures, Rehabilitation

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1.1 Educational Activity: To discuss the public health implications of traumatic brain injury epidemiology and its effect on the local community 

BRAIN TRAUMA HAS A dramatic social and economic impact on our society. This review provides the context to inform clinical discussions with patients, families, significant others, health care providers, and payers regarding the current epidemiology of traumatic brain injury (TBI) in the United States.

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Incidence 

The most recent estimates indicate that 1,565,000 people experienced TBI in 2003 in the United States, a rate of 538.2 per 100,000 population.¹ Of these injuries, approximately 78% were treated in an emergency department and not hospitalized, 19% were hospitalized, and for 3% the injury was fatal. The overall incidence rate has been stable since 1998,¹ although reported rates underestimate incidence because the reporting of mild injury is incomplete. The estimates reported below are based on reported medically attended injuries.

Death 

Improved acute medical care and injury-prevention strategies have led to a steady decline in the incidence of TBI-related death over the past 30 years, from as high as 24.6 per 100,000 population in 1979² to an estimated 17.5 per 100,000 in 2003.¹ The estimated 30-day mortality after TBI is reported to approximate 21%.³, ⁴ Death rates in 2003 were highest for persons older than 65 years (38.4/100,000).¹

Hospitalization 

The incidence rate for people hospitalized after TBI has remained steady over the past decade, estimated to be 99.9 per 100,000 in 2003.¹ Hospitalization rates for TBI are greatest for persons older than 65 years (234.1/100,000).

Emergency department 

The incidence rate of TBI for people seen in emergency departments and discharged without hospitalization was 420.9 per 100,000 in 2003, over 4 times greater than the overall rate for hospitalization.¹ The rate of emergency department visits is by far the greatest for those between ages 0 to 4 years (1091.2/100,000).¹

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Prevalence 

Although the majority of injuries are mild and cause no lasting impairment, TBI of any severity can lead to significant long-term disability. It is estimated that as many as 5.3 million people are living in the United States with disability related to TBI, approximately 2% of the population.⁴ This compares with the estimated United States breast cancer prevalence of 2.3 million and multiple sclerosis prevalence of 400,000.

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Severity 

Among persons surviving TBI, the vast majority will experience a mild injury, with almost 90% of all injuries categorized as mild in population-based estimates.³ Even for those hospitalized after TBI, state surveillance reports have estimated 75% of hospital discharges were mild based on the Glasgow Coma Scale (GCS) score (initial GCS score of ≥13).⁵

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Age 

In 2003, overall rates of TBI were highest in the very young (age group of 0−4y, 1188.5/100,000) followed by adolescents (age group of 15−24y, 917.5/100,000) and the elderly (age group >65y, 524.3/100,000). Injury rates were lowest for the age group 45 to 64 years (327.3/100,000).

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Survival 

For people surviving TBI for 6 months, 10-year life span does not appear to be shortened compared with the general population, indicating that these people will age with any acquired activity-limiting impairment along with their noninjured peers.³ However, additional long-term mortality has been shown in a subpopulation of persons who survive moderate to severe injury and receive inpatient rehabilitation.⁶

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Mechanism of Injury 

Injury related to falls has been the leading cause of medically attended TBI for over a decade, with estimated average annual incidence rates greatest for 2 groups: those aged 0 to 4 years (594.2/100,000) and those older than 75 years (359.8/100,000).⁷ Incidence rates for injuries related to motor vehicles and traffic (273.1/100,000) and assaults (125.9/100,000) are highest among adolescents age 15 to 19 years. In the United States in 2003, 32% of TBIs were caused by falls, 19% by motor vehicle or traffic collisions, and 18% resulted from the external cause of being “struck by or against,” the category in which sport-related injuries are placed.¹

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Other Demographic Factors 

The risk of TBI for men is still almost twice that for women. American Indian, Alaskan Native, and black men are at highest risk, whereas female members of those same ethnic groups are at the lowest risk. Alcohol intoxication is estimated to be associated with TBI-related hospitalizations greater than 12% of the time, and an estimated 40% to 50% of transportation-related TBIs occur in the absence of personal protective equipment.⁵

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Economic Impact 

The total economic impact of TBI in the United States in 2000 was estimated to be $60.434 billion: $9.222 billion in lifetime medical costs and $51.212 billion in productivity losses. Although TBI ranked eighth out of 9 body regions in injury incidence rate, the estimated medical costs per injury were $14,809, second only to spinal cord injury ($56,080 per injury) and far greater than the next most costly body region (lower limb, $2085 per injury).⁸

Among injuries, it is clear that brain trauma has a dramatic social and economic impact on our society. It is also clear that governmental and other social processes have led to significant progressive declines in incidence rates for all causes of TBI except falls. It appears that advances in acute medical and trauma care and largely preserved life span after TBI will increase the prevalence of those who are aging with an activity-limiting impairment associated with brain injury. Continued aggressive efforts in injury prevention focused on reducing risk for falls and transportation-related injuries as well as vigorous promotion of personal protective equipment and intolerance of driving under chemical influence is essential to further reduce the substantial burden of TBI on our society.

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1.2 Clinical Activity: To counsel the family members of your 17-year-old male patient who has sustained TBI about the need for preventing reinjury and to develop prevention strategies for the entire family 

Prevention efforts can be classified into 1 of 4 areas: passive, active, educational, and legislative.⁹ Passive activities include those in which no direct action is required by the potentially injured host. These include areas such as road safety engineering and airbags. It is in the area of active strategies (eg, using seatbelts and motorcycle helmets, not driving while intoxicated) where family members may most benefit from clinician input.

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Transportation-Related Injury Prevention 

The majority of hospitalizations resulting from TBI are caused by transportation-related events.⁴, ⁹, ¹⁰ Prevention efforts contributed to a reduction in the incidence of TBI-related motor vehicle crash (MVC) deaths by 38% between 1980 and 1994, and fatality rates per 100 million passenger miles traveled dropped from 4.6 in 1970 to 2.3 by 1989.¹⁰ Both active and passive strategies played a role in this decline. These strategies include airbags, the use of seatbelts, raising the legal drinking age, and lowering the acceptable alcohol level.⁹ Seatbelt usage in combination with mandatory airbags has been shown to reduce fatalities by 50%.¹¹

MVCs are the primary source of death for children and adolescents.¹² The front seat is a dangerous place for children under 12 years of age because of their light weight, small size, and potential for injury by airbag deployment.⁹ Total compliance with all child safety laws could result in 500 fewer fatalities and 53,000 fewer child injuries every year.¹²

Motorcycles are the most dangerous form of transportation. Motorcycle fatalities are often linked to driver error, elevated blood alcohol levels, excessive speed, and, particularly, failure to use a helmet. Failure to use a helmet more than doubles the likelihood of head, neck, or facial injury and more than triples the likelihood of fatalities. Rescinding mandatory helmet laws has led to increases in total injuries, head and brain injury fatalities, and an increase in the percent of head injuries occurring when an injury of any kind was sustained.⁹

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Drugs and Alcohol 

Alcohol is perhaps the most important risk factor for sustaining a TBI. More than 50% of people sustaining TBI are intoxicated at the time of injury. A person has twice the risk of a repeat trauma admission within 2 years if he/she is intoxicated at the time of the initial injury. Raising the legal drinking age and lowering the acceptable blood alcohol level for driving have led to a reduction in alcohol-related MVCs.⁹ One third of all teenagers report they would drive with a friend who had been drinking, and 17% reported that they would personally drive after drinking.¹³

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Falls 

Falls are the second most common cause of TBI requiring hospitalization.⁹ In the pediatric population, falls account for 9% of the total trauma related deaths,¹³ and 41% of hospital admissions.¹⁴ For persons over 75 years of age, falls are the most common cause of trauma-related death. Fall-prevention efforts can be very effective in reducing risk. Installation of window guards resulted in a 96% decrease in falls from windows.¹³ Playground-related falls can also be effectively reduced by combining education, parental supervision, and the use of protective surfaces around playground equipment.⁹

Physician input is a critical component of fall prevention in the elderly population. Issues important to address include polypharmacy, abnormalities in gait and balance, postural hypotension, and minimizing the use of sedating medications (appendix 1). Exercise programs to prevent muscle disuse can be beneficial by addressing the factors that directly affect individual risk.⁹ It has been shown that less than $100 of supplies and fewer than 10 hours of unskilled labor can substantially reduce fall risk for elderly persons in their home.¹⁵

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1.3 Educational Activity: To discuss the approach to prognosis for a patient recently admitted to inpatient rehabilitation 1 month after a severe TBI 

Information about prognosis has been identified by families as one of their most important needs after a TBI. Unfortunately, it is a need that often goes unmet. One reason for this is the difficulties that TBI clinicians encounter in trying to extract useful guidelines from the extensive scientific literature published on this topic. Recently, a comprehensive, evidence-based review¹⁶ was performed with the aim of deriving empirically supported, clinically useful guidelines for prognostication after TBI. The results of that review are briefly summarized here.

Traditional methods of presenting prognostic information are often found by patients and families to be confusing and unhelpful (eg, “Your daughter has a 43% chance of being severely disabled, a 36% chance of being moderately disabled, and a 21% chance of having mild deficits”). A better way to provide prognostic information may be through the use of threshold values. These are values of a predictor variable above or below which a certain outcome is especially likely or unlikely (appendix 2). In particular, it was believed that families would be most interested in 2 outcomes: (1) how early can they exclude the possibility of a severe disability and (2) how long can they continue to hope for a good recovery.

In terms of defining these outcomes, the review focused on independent living, return to work, or the analogous outcome categories of the Glasgow Outcome Scale (GOS) (appendix 3). The predictor variables that were chosen included the initial GCS score, length of coma (defined as time to follow commands), duration of posttraumatic amnesia (PTA), age, and results of early neuroimaging (computed tomography [CT] scan or magnetic resonance imaging [MRI]). Reviewed were all studies published from 1983 through 2005 that studied outcome in adults 6 months or later after severe TBI. Of the hundreds of studies reviewed, only 35 met all the inclusion criteria; these studies form the basis of the results (appendix 4) and the final guidelines based on these results (appendix 5).

The studies that met the inclusion criteria were almost unanimous in finding that age, length of coma, duration of PTA, and neuroimaging findings correlated significantly with outcome. Much more important, the review identified threshold values for several of these variables that allow clinicians to make much more refined prognoses in individual cases. Specifically, age, length of coma, and duration of PTA all provide valuable information that the clinician can use to mark milestones after which either a severe disability or a good recovery are unlikely (see appendix 5). The most powerful of these was the duration of PTA, defined as the time after injury before the patient regains day-to-day memory (as measured by the Galveston Orientation and Amnesia Test). Of note, neither the initial GCS score nor the neuroimaging findings were associated with threshold values.

Keep in mind that exceptions to these guidelines can exist (eg, a severe disability may occur even with a PTA lasting less than 2 months). Based on the confidence intervals, up to 10% of patients could have outcomes that are considered unlikely according to these results. This underscores the importance of using terms such as “likely” or “unlikely” rather than, for instance, “always” or “never” in communicating prognoses. In addition to the language one uses, other important aspects are involved in the communication of prognoses, and clinicians should be comfortable with all of them.¹⁶ This review focuses on predictor variables that are easily available to rehabilitation clinicians at the present time. It is possible that technologic advances will allow us to provide even more powerful predictions in the future. These newer modalities are discussed in the final TBI chapter of this study guide.

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1.4 Educational Activity: To discuss the potential pathophysiologic features that explain why an 18-year-old patient remains unresponsive 1 week after TBI in the presence of a normal CT 

Pathologic changes after TBI can be divided into broad categories: focal versus diffuse and primary versus secondary. Focal injuries involve an injury to a localized region of the brain, whereas diffuse injuries are more widely dispersed. Primary injuries occur at the time of impact, whereas secondary injuries occur at some time after the initial blow to the head and may possibly be avoided or minimized by treatment.

Focal injuries include cerebral contusions, localized hemorrhages, and focal ischemic lesions, all of which are easily imaged on standard CT and MRI scans. Contusions usually occur when the brain strikes the rough inner surface of the skull during trauma. These contusions most often involve the inferior frontal lobes and anterior portion of the temporal lobes. Focal regions of ischemia result from either vasospasm after a traumatic subarachnoid hemorrhage or by physical compression of arteries, resulting in a focal region of cerebral infarction. Deep penetrating arteries may be sheared during trauma, causing small hemorrhages in the deeper regions of the brain.

Epidural hematomas typically occur in association with a skull fracture that lacerates the middle meningeal artery. Hematoma expansion is limited by the tight adherence of the dura to the skull. Subarachnoid hemorrhages occur between the pia mater and the arachnoid, predisposing cerebral arteries to vasospasm.

Subdural hematomas (SDHs) arise from shearing of the bridging veins, which may cause both extensive hemorrhages and significant cerebral compression. Rapidly developing SDHs and epidural hematomas manifest with acute neurologic deterioration. However, SDHs may not be clinically evident in the acute stages in older adults or others with cerebral atrophy when hemorrhage expansion is slow, often delaying presentation of neurologic compromise by weeks to months after trauma.

Widespread cerebral injury occurs from diffuse axonal injury (DAI), systemic hypoxia, poor cerebral circulation, apoptosis, abnormal metabolism, and excitotoxicity. Of these, DAI is both unique to TBI and is its leading cause of morbidity, including impairments in cognition, behavior, and arousal¹⁷ by disconnecting injured axons from their targets. DAI, which is initiated at the time of injury and followed by pathophysiologic processes that persist for several days after the trauma, occurs when the brain is exposed to stretch and torque forces, typically occurring in acceleration and deceleration events, such as MVCs. This results in disruption of axonal transport caused by cytoskeletal injury, leading to focal areas of swelling and detachment seen as axonal retraction balls on histopathologic examination. However, recent evidence suggests the extent of axonal disruption has been largely underestimated by traditional methods of examination. Impaired membrane permeability permits influx of extracellular calcium that reverses axonal transport from an anterograde to retrograde direction, precluding localized swelling that in the past was used to determine the extent of injury.¹⁸ With the exception of occasional petechial hemorrhages, standard CT and MRI scans are often unremarkable after isolated DAI in patients with significant cognitive and behavioral problems.¹⁹, ²⁰ However, because fluid attenuated inversion recovery and diffusion-weighted and gradient echo MRI sequences are more sensitive in detecting evidence of DAI than are standard imaging techniques, cerebral atrophy may become apparent on later scans.

Diffuse injury may also result from other pathophysiologic processes, either occurring at the time of injury or shortly thereafter. These include the immediate posttraumatic release of excitatory amino acids, such as glutamate. After excessive glutamate release, calcium influx commences, resulting in the formation of oxygen radicals, lipid peroxidation, mitochondrial injury, and deoxyribonucleic acid (DNA) damage.²¹ Apoptosis, or programmed cell death, has also been implicated in neuronal demise after TBI. This process is likely initiated in the mitochondria, partly in response to calcium influx, oxidative stress, and adenosine triphosphate depletion, resulting in both cytoskeletal and DNA damage. Oxygen radicals are also implicated in damage to the blood brain barrier and in both vasogenic and cytotoxic edema.²¹ Diffuse injury also results from cerebral ischemia, resulting from either globally impaired cerebral circulation in the presence of increased intracranial pressure and/or systemic hypotension or focal areas of cerebral ischemia resulting from traumatically induced alterations of blood flow caused by dysregulation of perfusion. All of these processes are potential targets of intervention that may ultimately lead to treatments aimed at ameliorating their adverse impact on outcomes.

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1.5 Educational Activity: To participate in developing the guidelines and options for using innovative treatments in the early management of TBI for your local city health department 

The early management of TBI begins at the scene of the injury. First responders must understand the signs of TBI so patients can be transported to appropriate centers to receive state-of-the-art care. In a recent study²² of an organized state trauma system, direct transport to a trauma center resulted in significantly lower mortality than indirect transport. Transport mode, air versus ground, and time to admission were not related to mortality, a finding that supports current management guidelines. Hospital-based pathways can be developed to standardize treatment of patients with severe TBI based on clinical guidelines and services available within an institution. The use of a pathway can decrease the length of hospital stay and the need for ventilator support. Consequently, these pathways can result in cost savings to the institution.²³

National guidelines exist for the management of severe TBI. The guidelines from the Brain Trauma Foundation combine published and unpublished data to support recommendations in early TBI. They recommend the use of intraventricular catheters to monitor intracranial pressure in patients with severe injuries and abnormal admission CT scans. The use of prophylactic hyperventilation, once a common practice, should be avoided unless used in the case of acute neurologic deterioration.²⁴ Finally, the use of steroids is not recommended as a strategy to improve outcome or reduce intracranial pressure because the use of methylprednisolone acutely after severe TBI showed an increased risk of death.²⁵ Other commonly used neurocritical care interventions for refractory intracranial hypertension, such as barbiturates and decompressive craniectomy, have not been shown to improve morbidity and mortality, even though they do lower intracranial pressure. Osmotic diuretics, including mannitol and 3% saline solution, are not treatment standards but do have indications for use with increased intracranial pressure.²⁶ Adherence to these guidelines has reduced mortality by 50%. Studies are also currently ongoing in craniectomy and therapeutic hypothermia to delineate subpopulations of TBI in which it might be beneficial.

A recent addition to the management guidelines addresses the use of cerebral perfusion pressure (CPP) to guide interventions after severe TBI. CPP is the pressure gradient that drives cerebral blood flow. Because it is closely related to ischemia, it may have a relationship to secondary injury. It is known that cerebral blood flow is even lower in the areas of posttraumatic contusions and subdural hematomas, putting an injured brain at even further risk. New guidelines recommend maintaining the CPP at greater than 60mmHg in adults. The reduction of CPP under 50mmHg is associated with decreased brain tissue oxygenation and resultant increased morbidity and mortality.²⁷ Brain tissue oxygenation may be directly monitored with 2 commercially available monitors. When continuous tissue monitoring is used to guide interventions in concert with traditional intracranial pressure monitoring, mortality is significantly reduced. In patients who underwent brain tissue oxygenation monitoring, cerebral hypoxia was more frequent in those patients who died than in those who survived.²⁸

Other forms of monitoring are emerging that may have a role in the intensive care setting. Continuous electroencephalography can identify nonconvulsive status epilepticus, a possible cause of reduced mental status. Microdialysis may allow practitioners to follow concentrations of metabolites such as lactate and pyruvate that correlate with amount of ischemia. Single-photon emission CT provides information regarding cerebral blood flow to aid in the placement of oximeters or microdialysis catheters in the area of ischemia. Contrast-enhanced ultrasonography also can measure changes in cerebral blood flow after alterations in the level of the head of the bed or after decompressive craniectomy.²⁹

To date, at least 20 different compounds and therapeutic interventions have been tested in over 50 trials in the acute management of TBI. None was shown to reduce adverse functional outcomes in the treatment groups, despite improvements in intermediate endpoints such as intracranial pressure. Future advances depend on gaining a better understanding of the pathophysiology of injury, identifying an appropriate therapeutic time window, and standardizing treatment between centers.³⁰ Extrapolation from animal models of injury has limited the effectiveness of these trials to date. These models have not fully represented the heterogeneity of clinical TBI, with only 7% of reports in the Journal of Neurotrauma over 5 years addressing secondary insult in the protocol. In contrast, the focus of clinical interventions is to limit secondary injury.³¹

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Appendix 2. Definition of Threshold Value 

A predictor variable’s threshold is that value above or below which a certain outcome is especially likely or unlikely.

Example: If coma lasts more than 1 month, a person is very unlikely to achieve a “good recovery” on the Glasgow Outcome Scale (GOS).

In this example, “coma >1mo is the threshold value for a good outcome as measured by GOS.”

From Kothari.¹⁶ Reprinted with permission.

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Appendix 3. Glasgow Outcome Scale 

From Kothari.¹⁶ Reprinted with permission.

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Appendix 4. Summary of Findings from Studies of Nonpenetrating TBI GCS 

Coma Duration 

Posttraumatic Amnesia 

Age 

Neuroimaging 

From Kothari.¹⁶ Reprinted with permission.

Abbreviations: MRI, magnetic resonance imaging; PTA, posttraumatic amnesia.

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Appendix 5. Guidelines for Prognostication After Severe TBI 

Severe Disability, as determined by the GOS is unlikely when:

Time to follow commands is less than 2 weeks

Duration of PTA is less than 2 months

Good Recovery, as determined by the GOS is unlikely when:

Time to follow commands is longer than 1 month

Duration of PTA is greater than 3 months

Age is greater than 65 years

NOTE. This summary of evidence-based guidelines is from Kothari.¹⁶ Reprinted with permission.

Appendix 1. Fall Prevention in the Elderly

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