Traumatic Brain Injury in Children

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Chapter 74 Traumatic Brain Injury in Children

Jason T. Lerner, Christopher C. Giza

Introduction and Background

Epidemiology of Pediatric Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of death and disability in the pediatric population and has been identified as a significant public health problem in the United States and worldwide [Engberg and Teasdale, 1998; Murgio et al., 1999; Thurman et al., 1999; Tsai et al., 2004; Weiner and Weinberg, 2000]. Age-related incidence rates for TBI in children have been estimated to be as high as 670 per 100,000 when head injuries of all severities are included [McCarthy et al., 2002]. When limited to TBI resulting in hospitalization, the reported incidence has declined over the past 15 years, most likely due to injury prevention measures and improved motor vehicle safety. None the less, TBI is responsible for the majority of trauma-related death and hospitalization. The incidence rate of TBI-related hospitalization remains significant, consistently around 75–80/100,000 [McCarthy et al., 2002; Reid et al., 2001]. Childhood TBI results in an estimated 3000 deaths, 29,000 hospitalizations, and 400,000 emergency department visits annually in the U.S. (children 0–14 years old) [Thurman et al., 1999]. TBI is six times more likely to cause death in childhood than AIDS/HIV infection, and 20 times more likely than asthma [Centers for Disease Control and Prevention, 2000]. Moderate and severe pediatric TBI has been associated with long-standing cognitive, neurological, and behavioral impairments [Fay et al., 1994; Massagli et al., 1996a], and the cost of these disabilities is often carried over the person’s lifetime. Fortunately, the majority of all TBI is considered mild in severity; however, recent studies suggest that even mild pediatric TBI may have adverse long-term functional consequences [Hawley et al., 2004]. There is also increasing evidence that repeated mild TBI, as commonly occurs in a sports-related setting, results in chronic cognitive impairment [Collins et al., 1999; Matser et al., 1999], and may even predispose to early memory disturbances and dementia in some individuals [Guskiewicz et al., 2005; McKee et al., 2009; Omalu et al., 2006]. Despite these facts, no specific treatment standards exist for pediatric TBI, either acutely or during recovery. A recent review of guidelines for pediatric TBI management concluded that acute supportive therapies are often administered inconsistently or simply extrapolated from adult TBI protocols, not taking into account the unique physiology of the immature brain [Adelson et al., 2003b].

The peak incidence of pediatric TBI occurs in the adolescent and young adult, with a secondary peak in infancy [Kraus and McArthur, 2000]. The etiology of TBI varies with age (Figure 74-1). Adolescents sustain most head injuries in motor vehicle accidents, as well as sports-related concussions and assaults. Pre-adolescent children are also frequent victims of motor vehicle accidents, but more often as a pedestrian or while riding a bicycle. Those under the age of 5 years are more prone to falls [Thurman, 2001], while infants are particularly vulnerable to repeated severe TBI in the form of abusive head trauma (AHT, previously inflicted TBI or nonaccidental trauma).

Fig. 74-1 Etiology of pediatric traumatic brain injury by age group.

(From Thurman D, for the Centers for Disease Control and Prevention. Traumatic brain injury in the U.S.: Assessing outcomes in children, Appendix B. Available at: http://www.cdc.gov.)

Traumatic brain injury is about twice as common in boys than girls overall, with this gender distinction becoming increasingly evident in the childhood and adolescent years [Kraus and McArthur, 2000; Rivara, 1994]. In the U.S. annually, it is estimated that about 30,000 pediatric patients incur permanent disability as a result of TBI. These sequelae include headaches, post-traumatic epilepsy, motor disturbances, learning disabilities, cognitive impairment, and behavioral problems. Furthermore, the vast majority of children suffering TBI, even those surviving moderate or severe injury, fail to receive adequate medical, rehabilitative, or psychosocial follow-up upon hospital discharge [Armstrong and Kerns, 2002; Hawley et al., 2004]. Finally, given the magnitude of recurrent head trauma as a problem of youth, it is increasingly noted that health-care providers should take every opportunity to provide important information and education to patients and their families, particularly with regard to potential sequelae of repeated injuries, as well as effective injury prevention.

In this chapter, we will discuss injury mechanisms and biomechanics, cellular and molecular pathophysiology of TBI, and recovery, and provide a framework for the clinical evaluation and initial treatment of head trauma in children. We will emphasize critical distinctions between traumatic injury in the developing brain as compared to the adult brain. Specific acute syndromes of pediatric head injury will be described individually in detail, followed by a discussion of appropriate management, a review of published treatment guidelines, and an overview of determining prognosis following severe pediatric TBI. Finally, this chapter will describe the chronic clinical syndromes and sequelae associated with pediatric head injury.

Anatomy

To understand the mechanisms and types of TBI best, knowledge of the basic anatomy of the brain and its coverings is essential (Figure 74-2). The scalp is the outermost covering and is highly vascular, tending to bleed profusely when lacerated. Under the scalp is a tendinous sheath, extending from the frontal to occipital regions, called the galea aponeurotic. The potential space beneath this is the subgaleal compartment, an occasional site of significant bleeding following head injury. The skull is next, with the periosteum covering its outer surface. The skull itself is composed of three layers, the bony outer and inner tables, separated by the diploic space, which is more vascular. Between the inner table of the skull and the dura mater is the epidural space, another potential space that is a significant site for arterial bleeding, particularly after skull fracture. The dura is the tough outer protective layer covering the brain itself. Below the dura is the subdural space, which is crossed by small veins that drain into the venous sinuses, which provides another site for post-traumatic hematomas. The next layer of brain coverings is the arachnoid, and under this, the subarachnoid space, which contains cerebrospinal fluid (CSF), and into which post-traumatic bleeding is also fairly common. The subarachnoid space is contiguous with the basal cisterns and the ventricular system, and CSF normally flows from its site of production at the choroid plexus within the ventricles, out into the basal cisterns, over the convexities of the cerebrum and into the venous drainage of the brain via the arachnoid villi. Subarachnoid blood can impair the flow of CSF after trauma and occasionally result in hydrocephalus. The last layer is the pia mater, which lies directly over the brain surface itself.

Fig. 74-2 Schematic representation of the brain, skull, scalp, and pathologic entities related to head trauma.

(From Rosman NP et al. Pediatr Clin North Am 1979;26:707.)

The vascular supply of the brain originates in the great arteries of the neck (carotid and vertebral). These enter the skull through foramina at its base, and then arborize in fairly consistent vascular distributions. Venous drainage from the brain is routed through deep-draining veins or through small penetrating veins that traverse the subdural space. In either circumstance, venous blood then enters the venous sinuses, leaving the intracranial space via the jugular veins.

One important developmental aspect of brain and skull anatomy is the rigidity of the skull itself. Intracranial pressure is determined by the three main contents of the skull: namely, the brain itself, blood, and CSF. In infancy, the skull is more pliable, with flexible sutures and open fontanels. These features provide a mechanical outlet for elevated intracranial pressure (ICP) that is not present once the sutures fuse. In older infants and children, as in adults, post-traumatic brain swelling can be accommodated only by displacement of blood and CSF from the intracranial space, followed in severe cases by downward herniation of brain contents through the foramen magnum.

Biomechanics

Trauma is a unique form of brain injury, whereby a biomechanical force is imparted to the brain. In general, the forces applied to the brain may be described as linear or rotational. The clinical significance to identifying these forces is that they are often associated with particular mechanisms and types of injury. Linear forces refer to acceleration or deceleration forces in a straight line. As the brain “floats” in the CSF, these forces often result in compression of the brain at the site of contact (termed the “coup” injury). This injury can take the form of local hemorrhage or contusion, accompanied by overlying soft-tissue swelling and occasionally skull fracture. As the intracranial contents are shifted toward the point of contact, however, a relatively low-pressure area evolves in a location opposite to the coup injury. Injury in this area is termed “contre-coup,” and can often be larger and more serious than the coup injury. Because of the relative irregularity of the skull floor in the anterior and middle cranial fossae, there is a propensity for focal traumatic injuries to occur in the frontal and temporal lobes. This is an important consideration when evaluating a child for neurological and cognitive impairment post-injury, as memory, attention, impulse control, judgment, and personality are all behavioral functions that may be localized in these brain regions, and that are undergoing rapid change during brain maturation.

Because the brain parenchyma is itself soft and deformable and brain regions are connected by fiber tracts, the brain is also prone to injury from rotational forces. These are the forces imparted when one part of the brain is twisted in relation to another part. In these circumstances, the underlying white-matter tracts are subjected to significant shearing forces that can result in stretch injury and microhemorrhages seen clinically [Tong et al., 2004] and in experimental models [Huh et al., 2008; Raghupathi and Margulies, 2002]. This type of damage following trauma is referred to as diffuse axonal injury (DAI), and can result in significant clinical disability. By its nature, DAI can occur throughout the brain, with a propensity for regions with major fiber tracts (corona radiata, corpus callosum, brainstem, etc.). While the developing brain has been shown to have remarkable resilience to focal injuries such as strokes or surgical resection, its ability to recover from diffuse injuries may be much more limited.

Linear forces can play a role in straightforward collisions or falls, although it is generally difficult to separate them completely from rotational forces. Severe rotational forces are common in motor vehicle accidents where collisions are offset or at an angle, or when the child is thrown from or struck by the vehicle. Rotational forces can be seen in sports concussion, a milder but much more common form of injury in older children and adolescents.

Penetrating trauma, while less common, often results in tremendous biomechanical forces, as well as physical disruption of tissue along the path of the foreign object. While the tissue destruction, with surrounding necrosis, hemorrhage, and edema, is a major factor in determining long-term disability, the transmitted forces from the passage of the projectile to more distant parts of the brain can result in immediate death, presumably by affecting respiratory and autonomic centers [Carey, 1995]. One large series reported that younger age was associated with worse outcome from gunshot wounds [Levy et al., 1993].

Injury Types

While specific injury types will be discussed in greater detail later in the chapter, an overview of the types of injuries commonly seen in the pediatric population ranges from superficial injuries to the scalp to severe diffuse cerebral edema with herniation. Scalp injuries are very common, and include contusions, lacerations, and hematomas. While many scalp injuries may occur with little, if any, evidence of underlying brain injury, careful history and examination should be undertaken in each case to rule out the possibility of concussion or, more rarely, intracranial injury. Concussion has been redefined as any trauma-induced transient disturbance of neurological function, even in the absence of unconsciousness [American Academy of Neurology, 1997]. A large scalp hematoma may conceal a skull fracture, and, in infants, can result in significant blood loss. Skull fractures are reported following 20 percent of childhood TBI [Harwood-Nash et al., 1971], and while simple linear fractures are generally benign, the presence of any fracture greatly increases the risk of intracranial hemorrhage [Lloyd et al., 1997]. Post-traumatic intracranial bleeding may occur in the form of cerebral contusion, cerebral laceration, and epidural, subdural, or subarachnoid hemorrhage, individually or often in combination. DAI represents stretch and shearing of white-matter tracts and can have profound clinical consequences, with prolonged unconsciousness and poor outcome. Traumatic injury, at its most severe, can lead to cerebral swelling and elevated ICP. While this problem may be accommodated to some degree by flexible sutures and open fontanels in infants, all ages are vulnerable to cerebral herniation, a displacement of cerebral contents within or outside of the intracranial space. Based on location of edema or focal lesions, distinct types of herniation can occur (Figure 74-3). Each of these injury types will be discussed in greater detail later in this chapter.

Fig. 74-3 Different forms of brain herniation.

1, Cingulate. 2, Uncal. 3, Cerebellar tonsillar. 4, Upward cerebellar. 5, Transcalvarial.

(From Fishman RA. Cerebrospinal fluid in diseases of the nervous system. Philadelphia: WB Saunders, 1980.)

While all of the above types of injury are associated with clinical syndromes of primary TBI, it is important to be aware that, inextricably intertwined with the primary injury, are the effects of so-called secondary injuries. Secondary injuries may be additional pathological insults independent of the original TBI, such as hypotension due to systemic hemorrhage, hyperthermia due to concomitant infection, or airway occlusion by a foreign body resulting in hypoxia or systemic hyper-/hypoglycemia. In many individuals, a secondary injury may be directly or indirectly related to the original brain injury, but occurs after the initial TBI. Thus, the spectrum of secondary injury encompasses entities such as cerebral edema with reduced brain perfusion, intracranial hemorrhage, early post-traumatic seizures, respiratory compromise of neurologic origin resulting in hypoxia, and post-traumatic hydrocephalus. More general etiologies of secondary injury include on-going excitotoxicity, free radical generation, oxidative stress, and inflammation. Clinical secondary injuries, such as hypotension, hypoxia, hydrocephalus, edema, hypoglycemia, and seizures, are of great medical significance, as they are generally treatable in the intensive care unit setting, and are often independent predictors of poor outcome [Chesnut et al., 1993a; Chiaretti et al., 2002].

Pathophysiology of Traumatic Brain Injury

Distinctions of Injury to the Developing Brain

Biomechanical Factors

Clearly, the physics of TBI in a child is different than in an adult. The relatively large head size, reduced muscular strength in the neck, and increased flexibility of the neck may promote a greater range of biomechanical force imparted to the head. On the other hand, there is less CSF space around the brain, and the prominent bony ridges of the anterior and middle cranial fossae are less developed. These factors may contribute to a lower occurrence of focal lesions in pediatric TBI [Berney et al., 1994; Bruce et al., 1979; Levi et al., 1991; Luerssen et al., 1988].

The physical properties of the developing skull also confer advantages and disadvantages. It is thinner, and thus more prone to diffuse deformation [Margulies and Thibault, 2000]. Some authors have reported a higher risk of skull fracture in children [Berney et al., 1994], although this finding is not universal [Levin et al., 1992]. However, the open fontanels and flexible sutures may serve to dampen traumatic forces, as well as to accommodate a greater degree of intracranial swelling. The brain itself, particularly in infants and young children, has a higher water content and is incompletely myelinated [Holland et al., 1986; Paus et al., 2001]. The higher water content tends to make the brain less compressible and less compliant than in the adult. Thus, the physical properties of the immature brain may provide both unique benefits and potential vulnerabilities to TBI, a theme that will be repeated when considering other developmental distinctions.

Changes in Cerebral Metabolism

It is well known that cerebral metabolism changes during maturation. The primary source of energy for the brain changes from lactate in the perinatal period, to ketone bodies while nursing, to glucose after weaning, and on through to adulthood [Nehlig, 2004; Vannucci and Vannucci, 2000]. The ability to use alternative fuels may have important consequences for acute energy metabolism in the injured brain at different ages [Prins et al., 2004].

Even after the brain has switched to predominantly glucose metabolism, the levels of this metabolic activity continue to change throughout the developing years. Basal glucose metabolism rates peak at around 6 years of age, correlating with the time of maximal synaptogenesis. As synaptic pruning and dendritic rearrangement occur throughout childhood and adolescence, cerebral glucose metabolism declines, although it still remains elevated compared to the adult brain [Chugani and Phelps, 1986]. Also, the brain does not mature uniformly, and cerebral metabolic rates for glucose and other substances have different time courses regionally.

Distinct Neurovascular Regulation

Neurovascular control may also differ in the young brain. Early studies suggested a propensity for diffuse cerebral swelling in children following closed-head injury, occurring 2–5 times more often than in adults [Aldrich et al., 1992; Lang et al., 1994]. Recent studies report that normal children have higher baseline cerebral blood flow (CBF) than adults, with significant variation across narrow age groups [Suzuki, 1990; Zwienenberg and Muizelaar, 1999]. At birth, CBF is lower than in adults, but increases rapidly to peak by age 5 years. CBF then appears to decline through adolescence to adult levels [Suzuki, 1990]. The effect of these developmental differences on injury-induced changes in CBF and the mechanism(s) of these differences are not yet well understood. Certainly, molecular mediators of neurovascular tone, such as nitric oxide synthase, have differential expression patterns in the immature brain [Keilhoff et al., 1996; Ohyu and Takashima, 1998], and these may play a role in age-dependent changes in blood flow and response to injury.

Increased Excitatory Neurotransmission

As mentioned earlier, the number of synapses in the human brain appears to peak in early childhood, and is associated with a peak in cerebral glucose metabolism. Levels of excitatory transmitter receptors are higher in the immature brain [Fosse et al., 1989; Insel et al., 1990; Miller et al., 1990a]. The occurrence of early post-traumatic seizures is also noticeably higher in children, and particularly in infants and younger children [Annegers et al., 1980; Berney et al., 1994].

Because excessive release of excitatory neurotransmitters can result in neuronal injury and death (excitotoxicity), the fact that the developing brain is more active might suggest that blocking excitatory transmission would be neuroprotective. However, early in development, neuronal activation also plays a critical role in both survival of immature neurons and in proper wiring of cerebral circuitry. In fact, in animal models, use of glutamate antagonists early in postnatal development (while protective against some degrees of excitotoxic insult) resulted in a large degree of programmed cell death (apoptosis) [Bittigau et al., 1999; Ikonomidou et al., 1999; Pohl et al., 1999]. Such evidence suggests that optimal recovery from brain injury may require a proper balance of excitation and inhibition, and may also account for the relative ineffectiveness of glutamate antagonists following human brain injury [Biegon et al., 2004; Hardingham et al., 2002; Ikonomidou and Turski, 2002].

On-Going Cerebral Maturation

In the past, the developing brain was generally felt to recover better after many types of brain injury, including stroke, TBI, and surgical resection. Developmental plasticity does confer some advantage when the brain must recover from a focal lesion [Kennard, 1942; Kolb et al., 2000; Villablanca and Hovda, 1999], if the lesion occurs at a specific age (see chapter 13). However, more recent work clearly indicates that the very young brain may be particularly vulnerable to diffuse injuries like TBI [Anderson et al., 2005; Babikian and Asarnow, 2009]. One mechanism for this vulnerability can be explained by post-traumatic impairment in experience-dependent neuroplasticity, which is the complex task of responding to environmental stimuli and rearranging neuronal network that results in enhanced function. In a mature brain, the consequences of such impairment might be overcome with time; in the young brain, it is likely that reduced responsiveness at a critical window of development will result in long-term dysfunction [Giza et al., 2009]. As a result, studies looking at post-TBI brain development, both in experimental animals and in children, must necessarily take into account the normal trajectory of brain maturation.

The Post-Traumatic Neurometabolic Cascade

Traumatic brain injury results in an immediate release of glutamate, widespread ionic changes, fluctuating cerebral glucose metabolism (initially elevated, then reduced), and dynamic changes in blood flow. Later, axonal damage and disconnection, reduced responsiveness to physiological stimuli, impaired neurotransmission, and apoptosis occur [Giza and Hovda, 2001]. For an overview of post-traumatic pathophysiology at the cellular level, see Figure 74-4. Specific components of the brain’s response to traumatic injury will be discussed below.

Fig. 74-4 Neurometabolic cascade after traumatic injury.

Cellular events: 1, Nonspecific depolarization and initiation of action potentials. 2, Release of excitatory neurotransmitters. 3, Massive efflux of potassium. 4, Increased activity of membrane ionic pumps to restore homeostasis; 5, Hyperglycolysis to generate more adenosine triphosphate (ATP); 6, Lactate accumulation; 7, Calcium influx and sequestration in mitochondria, leading to impaired oxidative metabolism; 8, Decreased energy (ATP) production; 9, Calpain activation and initiation of apoptosis. Axonal events: A, Axolemmal disruption and calcium influx; B, Neurofilament compaction via phosphorylation or sidearm cleavage; C, Microtubule disassembly and accumulation of axonally transported organelles; D, Axonal swelling and eventual axotomy. ADP, adenosine diphosphate; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; Glut, glutamate; NMDA, N-methyl-d-aspartate.

(From Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train 2001;36:230).

Glutamate Release and Ionic Flux

Following a traumatic brain injury, there is an immediate and indiscriminate release of the excitatory neurotransmitter, glutamate [Bullock et al., 1998; Katayama et al., 1990]. This can occur due to widespread triggering of action potentials, synaptic neurotransmitter release, and membrane disruption. This flood of glutamate results in a massive efflux of potassium into the extracellular space [Katayama et al., 1990; Nilsson et al., 1993], and an influx of sodium and calcium [Nilsson et al., 1996; Osteen et al., 2001]. While hyperacute measures of extracellular glutamate are obviously unobtainable in human patients, microdialysis or CSF samples from severely injured patients (including children) in the days after injury have demonstrated glutamate elevations and have been associated with secondary injury and poorer outcomes [Bullock et al., 1998; Ruppel et al., 2001; Vespa et al., 1998].

Dynamic Changes in Cerebral Metabolism

As the injured cells attempt to restore ionic equilibrium post-trauma, membrane pumps such as the Na⁺-K⁺ ATPase are activated. An increase in cerebral glucose uptake, termed hyperglycolysis, is seen early after experimental TBI and has been postulated as a mechanism of providing additional substrate to generate the energy necessary to drive these membrane ionic pumps [Kawamata et al., 1992; Yoshino et al., 1991]. Acute studies of cerebral glucose metabolism using positron emission tomography (PET) in adult patients have also shown evidence for increased cerebral glucose uptake [Bergsneider et al., 1997]. Interestingly, there is increasing laboratory evidence that injured neurons are capable of utilizing alternative fuels to glucose [Magistretti et al., 1999; Pellerin and Magistretti, 2004; Prins et al., 2004], and it is well known that the capacity to use alternative fuels in uninjured neurons is age-specific [Vannucci and Vannucci, 2000].

After the acute period of hyperglycolysis, there is a prolonged period of diminished glucose uptake by the brain. This hypometabolism is seen in both adult and immature rats, although it lasts longer in adults (7–10 days) than in rat pups (3 days) [Yoshino et al., 1991; Thomas et al., 2000]. In traumatically injured adult patients, the period of reduced glucose metabolism has been shown to last weeks or months [Bergsneider et al., 2001].

Cerebral Blood Flow: Hyperemia? Hypoperfusion?

Blood flow also undergoes dynamic changes after injury and the pattern these changes take may depend on the type of injury and its severity. A pattern of diffuse cerebral swelling has been reported more often in children than adults [Aldrich et al., 1992; Lang et al., 1994]. This phenomenon was originally attributed to hyperemia [Bruce et al., 1981], but subsequent studies suggest that the incidence of post-traumatic hyperemia has been overestimated [Muizelaar et al., 1989]. In the earlier studies of post-TBI CBF in children, flow values were compared with normal values from a young adult control group. When CBF has been measured in normal children, however, it appears that blood flow values change dramatically across development, and are generally much higher in young children than in adults [Chiron et al., 1992; Suzuki, 1990; Zwienenberg and Muizelaar, 1999]. Subsequent studies of CBF in children suffering TBI, when compared to age-appropriate control values, have failed to show clear hyperemia [Adelson et al., 1997a; Sharples et al., 1995b]. In an experimental model of TBI, there is evidence for dramatically increased cerebral blood flow adjacent to a traumatic contusion, and this focal hyperemia was most pronounced in immature animals [Biagas et al., 1996]. While clinically it is important to recognize that diffuse cerebral swelling is more common in children, the mechanism of this swelling does not appear to be solely attributable to hyperemia.

The relation between CBF and outcome appears to depend upon the state of cerebral autoregulation. In the presence of intact autoregulation, increased CBF has been associated with better perfusion and improved outcome in children and young adults [Kelly et al., 1996; Vavilala et al., 2004]. However, after very severe injuries, in which autoregulation is dysfunctional and cerebral vasculature is pressure-passive, increased CBF can result in intractable elevations of ICP and worse outcome.

Beyond the acute phase of head injury, CBF generally declines. Post-TBI CBF can decline below normal, and it is important to monitor for ischemia, as this is associated with worse outcome [Bouma et al., 1991; Vespa et al., 2003]. Investigations are still under way to determine whether neurovascular coupling is intact during this period of reduced flow.

Altered Neurotransmission

Reductions in excitatory neurotransmitter systems have been reported after TBI in experimental animals, including impairments in glutamatergic [Giza et al., 2006; Miller et al., 1990b; Osteen et al., 2004; Sihver et al., 2001], noradrenergic [Fujinaka et al., 2003; Krobert et al., 1994], and cholinergic transmission [Gorman et al., 1996]. These changes may correlate with the injury-induced reduction in cerebral metabolism described above. Furthermore, these changes may be an underlying mechanism for post-TBI deficits in neuronal activation [Dietrich et al., 1994; Ip et al., 2003; Sanders et al., 2000], diminished activity-dependent molecular responsiveness [Giza et al., 2002; Griesbach et al., 2004], and impaired experience-dependent plasticity in developing animals [Fineman et al., 2000; Giza et al., 2005; Ip et al., 2002]. Activation studies using functional magnetic resonance imaging (fMRI), even after relatively mild TBI, have shown reduced or aberrant activation patterns in traumatically injured teenagers and young adults [Jantzen et al., 2004; McAllister et al., 1999].

Axonal Disconnection

Mechanical stretch can disrupt axonal membranes, resulting in calcium influx and microtubule and neurofilament disruption. Damage to these important cytoskeletal components impairs normal axonal transport, endangering distal axonal segments and synapses. Over time, disrupted axonal transport leads to an accumulation of transported proteins and organelles at the injury site, causing axonal blebs and, eventually, disconnection [Pettus and Povlishock, 1996; Povlishock and Christman, 1995; Povlishock and Pettus, 1996]. This type of damage is seen following experimental TBI in both immature [Raghupathi and Margulies, 2002] and adult animals [Povlishock and Pettus, 1996]. In postmortem human specimens, evidence of axonal blebbing and damage has been reported long after injury [Maxwell et al., 1997], and MRI can clearly show abnormalities of diffuse axonal injury, in pediatric and adult TBI patients [Tong et al., 2004]. Newer imaging modalities, such as diffusion tensor imaging (DTI) and MR spectroscopy, have shown white-matter abnormalities that correlate with functional impairments after pediatric TBI, even in brain regions without overt structural lesions [Ashwal et al., 2006; Babikian et al., 2009a; Ewing-Cobbs et al., 2008; Wilde et al., 2008].

Cell Death: Necrosis and Apoptosis

Mechanisms of post-TBI cell death occur across a spectrum from necrosis to apoptosis. Necrosis represents acute energy failure, inability to maintain ionic homeostasis, cell swelling, and eventual disruption of the plasma membrane. This type of cell death occurs when energy is depleted and does not require protein synthesis. Necrosis is seen as a direct result of traumatic injury, generally occurs acutely, and evolves in regions experiencing profound energy failure. When cells rupture, there is release of intracellular contents and a significant destructive inflammatory response.

Apoptosis is characterized by nuclear condensation, DNA fragmentation, and preservation of the cell membrane. Apoptosis requires energy and protein synthesis, and triggers an acute inflammatory response that may be distinct from that seen with necrosis (see chapter 14). Usually, apoptotic cell death takes longer to evolve after injury, and studies have demonstrated that apoptosis can continue to occur long after experimental trauma [Conti et al., 1998; Wilson et al., 2004]. While apoptosis is seen after TBI, it is also part of the brain’s normal maturational program. Thus apoptotic pathways are more active in the immature brain, and apoptotic cell death appears more prominently after experimental injury to the developing brain [Bittigau et al., 1999; Pohl et al., 1999].

Impaired Plasticity

An important aspect of injury in the young brain is the effect of this injury on normal neuronal responsiveness and on developmental plasticity (see chapter 13). As mentioned earlier, increased plasticity in the immature brain results in significantly better recovery than in the adult following a focal lesion, and this has been well described in rats [Kolb and Tomie, 1988], cats [Burgess and Villablanca, 1986; Villablanca and Hovda, 1999], primates [Kennard, 1938], and humans [Hogan et al., 2000; Trauner et al., 1993]. However, the benefits of youth are less apparent when the injury is more diffuse and/or occurs at a critical window of brain development. Environment enrichment (EE) is an experimental model of enhancing brain development, and animals reared in EE grow up to have larger brains [Bennett et al., 1964; Diamond et al., 1964; Rosenzweig and Bennett, 1996], increased dendritic arborization [Faherty et al., 2003; Greenough et al., 1973; Juraska, 1984; Volkmar and Greenough, 1972], and superior performance on neurobehavioral tasks [Tees et al., 1990; Venable et al., 1988; Williams et al., 2001]. While injured rat pups show less overt cell death and less behavioral impairment than adults [Gurkoff et al., 2006; Prins et al., 1996; Prins and Hovda, 2003], they do lose the ability to benefit from EE rearing. Specifically, they show a loss of EE-induced experience-dependent plasticity; cortical thickening is blocked [Fineman et al., 2000], expansion of dendritic arbors is inhibited [Ip et al., 2002], and EE-induced cognitive enhancements are absent [Giza et al., 2005]. These studies of altered developmental plasticity are also supported by the findings of Prins and colleagues using a different model [Prins et al., 2003]. Following a lesion, regrowth of entorhinal cortical axons in a nontraumatically injured brain occurs in a well-characterized fashion. In juvenile rats subjected to experimental TBI, this normal pattern of axonal regrowth was markedly disturbed, with evidence of disruption down to the synaptic level.

Studies of developmental plasticity in traumatically injured children are difficult, as the effects of both age at injury and age at assessment must be considered in the control groups. However, there is growing evidence that pediatric TBI results in severity-dependent altered trajectories of brain development [Babikian and Asarnow, 2009; Catroppa et al., 2008]. First, although children generally have better outcome from TBI than adults, those injured at the earliest ages (i.e., in infancy) actually have worse outcomes [Anderson et al., 2005; Levin et al., 1992; Luerssen et al., 1988]. Some of this may be due to different mechanisms of injury, including nonaccidental trauma, which has a very poor developmental prognosis and is predominantly an etiology seen in infancy. It is also possible that the very young brain is decidedly more vulnerable to injury, as suggested by experimental studies using hypoxia-ischemia [Ikonomidou et al., 1989] and TBI [Bittigau et al., 1999; Pohl et al., 1999]. Second, there are rare anecdotal reports of neonates with head trauma that appear to have resulted in abnormal cortical development that was subsequently confirmed pathologically after epilepsy surgery for intractable seizures [Lombroso, 2000; Marin-Padilla et al., 2002]. Third, studies of severe pediatric TBI show more persistent cognitive deficits when the injury was diffuse rather than focal [Levin et al., 2000]. Lastly, in studies of repeated, mild sports-related TBI sustained during adolescence or early adulthood, subtle but significant cognitive impairments are detected [Collins et al., 1999; Matser et al., 1999].

Patient History

The clinical approach to pediatric TBI differs, based on whether the presentation is acute (emergency department, urgent care clinic, etc.) or delayed (persistent post-TBI symptoms in a regular clinic). For an acutely injured child, history taking and initial assessment begin rapidly and simultaneously. Elements of the history should be obtained from parents, witnesses, and emergency personnel. Essential information includes mechanism of injury (pedestrian struck by motor vehicle, fell 10 feet out of a tree, bicycle crash, etc.), protective factors (helmet, seatbelt, etc.), any loss of consciousness (and duration), any post-traumatic amnesia (and duration), seizure activity (with duration and description), current medications (including allergies), and any persistent neurological signs (confusion, focal deficit, etc.). Examination, monitoring for ABCs (airway, breathing, circulation, spine), and initial management are begun simultaneously. Additional components of the history that may be relevant are sought once the patient is stabilized and include premorbid cognitive and behavioral development, prior head injuries, prior neurosurgical procedures, history of epilepsy or other neurological disorder, and other pertinent medical conditions (coagulopathy, asthma, etc.). In older children or teenagers, the possibility of drug or alcohol use should be considered. In infants and toddlers, inconsistencies in the history and presence of associated injuries should raise suspicion of child abuse.

For patients presenting in clinic with persistent neurological problems after (presumably) milder head injury, the same historical information is sought. In addition, the child and parent should be asked about the nature of post-traumatic symptoms, including headache, neck pain, nausea, vomiting, dizziness, ataxia, visual disturbances, cognitive impairment, behavioral changes, and any focal neurological deficits. Pain should be localized, if possible. The duration of constant symptoms should be ascertained, along with alleviating or exacerbating factors. Episodic symptoms should also be carefully investigated, including triggers, duration, pattern of episodes, and actions that result in symptom resolution.

Examination

For the acutely and severely brain-injured child, the physical and neurological examination must be done expediently, with the aim of identifying immediately life-threatening signs that would direct initial management. The presence of secondary insults is a strong independent predictor of poor TBI outcome, so careful assessment of airway and breathing are of paramount importance. The pattern of breathing should be noted (irregular, tachypneic, etc.). Adequate circulation and perfusion are also critical; examination of skin color, pulses, blood pressure, capillary refill, and excessive bleeding is critical. In a hypotensive patient, bodily injuries that result in internal bleeding, such as hemothorax, liver or splenic lacerations, and pelvic and long bone fractures, should be identified as soon as possible, although they may not be evident from the examination. In infants, massive scalp hematomas may result in hypotension and shock. Spinal cord or cardiac injury can also result in hypotension. In patients who are or were unconscious, careful stabilization of the spine is necessary.

The patient’s Glasgow Coma Scale (GCS) score should be determined. The GCS is a quick, reproducible means of rating the severity of the patient’s neurological injury (Table 74-1) [Teasdale and Jennett, 1976]. There are three components to the GCS score:

1. eye opening (ranging from 1 to 4)

2. best verbal response (1–5)

3. best motor response (1–6)

The total GCS score ranges from 3 (worst) to 15 (normal). There are obvious limitations to this scale in the setting of pediatric trauma, such as how to determine verbal score in infants and young children. Several GCS modifications have been proposed to make it more usable in this age group, and one modified scale is shown in Table 74-1. By convention, mild TBI is defined by a GCS score of 13–15, moderate by 9–12, and severe by 8 or less. A patient with a GCS of 13–15 but having an intracranial lesion would generally be classified as having a moderate TBI [Malec et al., 2007] (see chapter 73).

Table 74-1 Glasgow Coma Scale and Modification for Children

Assessment of the patient’s mental state should be made, including alertness, orientation, confusion, combativeness, or unresponsiveness. Use specific descriptions of mental status (“able to follow simple commands but becomes quiet and sleepy if unstimulated”) rather than vague words such as “lethargic” or “obtunded.” Inspection of the head can reveal lacerations, contusions, and hematomas. Careful examination is warranted to identify stepoffs (palpable uneven edges of a skull fracture), foreign bodies, fractures, or penetrating injuries that may underlie more superficial damage. In infants, the open fontanel can be assessed quickly to screen for elevated ICP. Periorbital ecchymosis (“racoon eyes”) and/or rhinorrhea raise concern for a fracture of the anterior skull base. Retroauricular ecchymosis (“Battle sign”), hemotympanum, and/or otorrhea are signs indicative of a basilar skull fracture involving the temporal bone. Ophthalmoscopic examination to detect retinal hemorrhage is very important, particularly in cases of suspected nonaccidental trauma.

Patients rendered unconscious by the injury, or those who retained consciousness but report post-traumatic neck pain, should have their cervical spine immobilized until it can be assessed and neurosurgically and radiologically cleared of any significant fracture or dislocation. Initially, with the head in neutral position, the cervical spine should be carefully palpated, noting any angulation, stepoff, crepitus, or point tenderness.

The post-trauma neurological examination is, by necessity, short and directed; it should be performed in just a few minutes. Cranial nerve (CN) testing offers rapid, objective evaluation of brainstem functions. The pupillary response tests integrity of CN II and CN III. Fixed midposition pupils suggest symmetric midbrain dysfunction. A unilateral fixed dilated pupil in conjunction with declining mental status is a sign of impending transtentorial herniation, usually due to a mass lesion ipsilateral to the abnormal pupil, and warrants immediate intervention. Bilateral pinpoint pupils raise the possibility of opiate ingestion or severe pontine injury. Bilateral fixed dilated pupils are evidence of widespread injury, but can also be due to systemic effects of resuscitation drugs. A pupil that fails to constrict under direct light (but does so when light is presented to the opposite eye) is indicative of an afferent pupillary defect (APD), a sign of ipsilateral optic nerve injury due to fracture of the orbit.

Integrity of nerves innervating the extraocular muscles (CN III, CN IV, CN VI) and their brainstem connections can be tested in three ways. First, simply observe the eyes for spontaneous conjugate roving movements. Second is the oculocephalic response (doll’s-eye maneuver), performed by turning the child’s head rapidly to one side. A normal response is for the eyes to move conjugately in the direction opposite the head turning. This is rarely used acutely following trauma because it is not generally safe to move the head/neck until the cervical spine has been cleared. If it is absolutely necessary to assess these specific nerves, the third method is to test the oculovestibular reflex (calorics). Prior to caloric testing, one must check for a non-occluded ear canal, an intact tympanic membrane and the absence of either hemotympanum or otorrhea. Then, with the head positioned 30 degrees above horizontal, 30–60 mL of ice-cold water is irrigated rapidly into the ear. An intact response is tonic eye deviation toward the irrigated ear. After a few minutes, the response may be tested in the opposite ear.

An intact corneal response demonstrates function of CN V and CN VII. If, upon corneal stimulation, the globe rotates upward but the eye does not close, this suggests an intact afferent limb but impaired motor output. Other evidence of a CN VII palsy, as might be seen in a basilar skull fracture. Tickling the inside of the nose with a wisp of cotton or administering a noxious stimulus may elicit a facial grimace, which should be observed for symmetry.

Sensorimotor examination can also be done quickly, starting with the best motor response elicited on GCS testing. Limb posture and muscle tone should be examined, and particular note should be made of any asymmetry. If the patient is unable to follow commands, then sensorimotor responses may be assessed by application of a peripheral noxious stimulus (e.g., nail bed pressure) in each limb. If no response occurs, then the site of noxious stimuli can be moved centrally (e.g., sternal rub, supraorbital pressure) to distinguish between afferent versus efferent impairment. Application of painful stimulus centrally also allows one to observe more easily whether the child can localize pain (distinction between a 4 and 5 for best motor score). If the child is awake, coordination should be assessed by observation of posture, spontaneous movements, and directed movements when the child reaches for an object or mimics the examiner. Deep tendon reflexes should be checked for asymmetry, hyperreflexia/clonus or areflexia. Flaccid paresis with no reflexes should immediately raise suspicion of a spinal injury. An outline of the rapid trauma examination is provided in Box 74-1.

Box 74-1 Rapid Pediatric Trauma Examination

1. ABCs, brief history – mechanism of injury, loss of consciousness, amnesia, seizure, persistent neurological symptoms

2. Glasgow Coma Scale score

3. Physical examination, particularly head and neck

a. Scalp – depressions, stepoffs, fluid collections, lacerations

b. Other signs of skull fracture – otorrhea, hemotympanum, rhinorrhea, raccoon eyes, Battle sign

c. Cervical spine – deformity, point tenderness

d. Associated severe bodily injuries – thoracic, abdominal, long bone

4. Mental status – describe succinctly, avoid ambiguous terms

5. Cranial nerves

a. Pupillary response (cranial nerve II, III)

b. Oculocephalic “doll’s-eye” response (cranial nerve III, IV, VI)

c. Oculovestibular “caloric” response (cranial nerve III, IV, VI, VIII)

d. Corneal response, facial grimacing (cranial nerve V, VII)

e. Gag response (cranial nerve IX, X)

6. Sensorimotor – asymmetry, abnormal muscle tone, coordination (if possible), movement (spontaneous, to command), movement to pain (withdrawal, decorticate, decerebrate, no movement)

7. Reflexes – asymmetry, areflexia, hyperreflexia/clonus, upgoing toes

In the mildly injured child who is conscious at the time of initial evaluation, the neurological examination can be conducted less urgently and more completely. In instances, mental status testing can be more extensive, starting with observation and possibly digit span recall to assess the child’s attention. This can be followed by evaluation of orientation, language, memory (both anterograde – for new items, and retrograde – for past events, including events surrounding the injury), and behavior. Cranial nerve, motor, coordination, and sensory examinations can include voluntary responses to the examiner’s commands, as well as subjective reports of sensory input (visual fields, tactile stimulation). Gait should be observed for signs of unsteadiness or ataxia. As with the more severely injured child, deep tendon reflexes and plantar responses should be checked. Aspects of the neurological examination are reviewed in detail in Chapters 1–4 and 73.

In either setting, neurological reassessment is mandated based on the severity of the injury. Mental status should be recorded in distinct descriptive wording, such as “awake but mumbling incoherently and unable to follow commands” or “crying when approached but consolable by parent.” Deterioration of the neurological examination may be a sign of progression of the underlying injury (e.g., cerebral edema, expansion of a subdural hematoma, etc.) or may represent a new complication (hemorrhagic transformation of a contusion, seizure), and should be evaluated immediately so that appropriate treatment may be instituted.

Immediate Management

Initial management of the child suffering from moderate or severe TBI centers on implementation of the ABCs and avoidance of secondary insults (see chapter 76). Early management will occur concomitantly with initial evaluation and examination. The airway must be secured and supplemental oxygen provided. In circumstances where the child is unable to maintain his/her airway adequately, then endotracheal intubation should be performed. Appropriate noninvasive monitors should be placed, including cardiac, respiratory, temperature, blood pressure, and those for pulse oximetry. Intubated patients should also have an end tidal CO₂ monitor. Intravenous access must be established immediately and fluid resuscitation begun. Blood should be drawn for serum electrolytes, glucose, renal and hepatic function, complete blood count, prothrombin time (PT)/partial thromboplastin time (PTT), type and cross for blood transfusion, and, if appropriate, alcohol or drug screens.

Acute Clinical Syndromes

As TBI is a heterogenous disorder with multiple manifestations, acute syndromes may occur in isolation but are often overlapping. For example, nonaccidental trauma is a particular etiology of infantile head trauma that can include subdural hematomas, other intracranial hematomas, cerebral edema, diffuse axonal injury, cerebral contusion, skull fracture, and early post-traumatic seizures. Epidural hematomas are often associated with skull fractures. Concussion can occur alone or as a repeated injury; it can be associated with acute seizures, and rarely, with malignant cerebral edema, second impact syndrome, herniation, and death. Fortunately, concussion can also, and almost always does, last briefly and be symptomatically self-limited.

Herniation Syndromes

Herniation is the displacement of brain tissue from one intracranial compartment to another. This can occur as a result of a space-occupying lesion in one region, diffuse swelling of both cerebral hemispheres, or hydrocephalus (see Figure 74-3 and chapter 73) [Fishman, 1980; Plum and Posner, 1980]. The Cushing response is a paradoxical bradycardia with hypertension and slow irregular respiration that can be seen in the setting of elevated ICP and impending herniation. Definitive treatment for herniation requires surgical removal of the offending mass, if present. In cases where herniation is triggered by edema, positioning the head so it is slightly elevated and in the midline is indicated (to facilitate venous drainage), as well as immediately initiating first-tier measures (see the section on management below) to control elevated ICP: sedation, hyperventilation, and hyperosmolar therapy. Ventriculostomy with CSF drainage should be instituted as soon as possible. Infants can tolerate some elevation of ICP better due to unfused sutures and an open fontanel. These properties also allow for additional physical examination clues to the presence of increased ICP, such as a tense or bulging fontanel or a steadily increasing head circumference (if chronic).

In lateral transtentorial herniation, a hemispheric mass, such as an epidural or subdural hematoma, can displace the medial temporal lobe structures across the tentorial notch. This displacement compresses the midbrain, resulting in impaired consciousness, ipsilateral CN III palsy with pupillary dilatation, and contralateral hemiparesis. A unilateral dilated pupil in the setting of an awake patient cannot be the result of herniation. Occasionally, this type of herniation compresses the posterior cerebral artery, resulting in an ipsilateral occipital lobe cerebral infarction and contralateral homonymous hemianopia.

A unilateral mass can also result in translocation of brain tissue across the midline. At first, the falx cerebri will simply be displaced away from the side of the mass. This is termed a “midline shift” and can be readily seen on an acute computed tomography (CT) scan. When more severe, the cingulate gyrus will actually be pushed under the falx cerebri, resulting in subfalcine herniation. This herniation syndrome is associated with compression of the anterior cerebral artery(s), with resultant infarction of the medial frontal lobe(s).

Diffuse bilateral cerebral edema or bilateral mass lesions can cause symmetric herniation of the supratentorial contents into the posterior fossa. This is termed central transtentorial herniation and is more common than the lateral syndrome. Physical examination findings consistent with the early stage of this syndrome include impaired mental status, fixed midposition pupils, impaired upward gaze, hyperventilation (central neurogenic hyperventilation), and posturing. The latter will first take the form of decorticate posturing (arms flexed, legs extended), but as herniation progresses, decerebrate posturing (arms and legs extended) will be seen. In these later stages of central herniation, pupils may become symmetrically constricted and respirations may become irregular.

Cerebellar tonsillar herniation occurs when the posterior fossa contents are pushed down through the foramen magnum. This form of herniation usually is seen in the setting of a posterior fossa mass. Because the infratentorial compartment is smaller than the supratentorial compartment, critical pressure effects can occur rapidly and with much smaller space-occupying lesions. Tonsillar herniation can cause head tilt, neck stiffness, and lower cranial neuropathies, or can present relatively abruptly with cardiorespiratory compromise. Posterior fossa masses can also cause herniation of cerebellar contents upward through the tentorium.

All of these herniation syndromes can lead to ischemic and hemorrhagic complications (e.g., Duret hemorrhages in the brainstem). The final stages of herniation occur as medullary centers are compressed, resulting in apnea, cardiac collapse, and death.

A final type of brain herniation can occur through a traumatic or surgical defect in the skull. Transcalvarial herniation occurs when brain swelling is relieved by extrusion of brain tissue out of the cranial cavity through a fracture, burr hole, or craniotomy. In some circumstances, this type of herniation may alleviate disastrous brainstem consequences of downward herniation syndromes.

Diffuse Cerebral Swelling

Since trauma, particularly closed head trauma, is by nature a diffuse process, bilateral swelling can occur even in the absence of discrete focal lesions. In fact, diffuse cerebral swelling is more common in children [Aldrich et al., 1992; Lang et al., 1994], while focal cerebral damage, such as contusions, is more common in older adolescents and adults. The etiology of this swelling was originally postulated to be due to hyperemia [Bruce et al., 1981]. However, as previously discussed, original reports of post-traumatic hyperemia in children overestimated the frequency of this phenomenon by comparing CBF values with those of uninjured young adult controls rather than uninjured children [Muizelaar et al., 1989; Zwienenberg and Muizelaar, 1999]. It is more likely that severe degrees of cerebral edema are related to the severity and nature of the injury, and particularly to the degree of cytotoxic and vasogenic edema formation. Cytotoxic edema occurs as a result of injured neurons undergoing energy failure, with loss of membrane ionic gradients and a rapid increase in intracellular water. In contrast, vasogenic edema results from fluid seeping into the extracellular space across a damaged or dysfunctional blood–brain barrier. Cytotoxic edema is felt to predominate after traumatic injury. Diffuse edema can occur as a direct response to trauma, but can also be due to a post-traumatic secondary insult, such as hypotension or hypoxia. At its extreme, diffuse edema can result in central transtentorial herniation and death.