Elsevier

Pathophysiology

Volume 20, Issue 1, February 2013, Pages 49-57
Pathophysiology

Review
Mechanisms and consequences of acquired brain injury during development

https://doi.org/10.1016/j.pathophys.2012.02.006Get rights and content

Abstract

The brain of the infant and young child is a developing, dynamic, structure subject to functional remodelling under the influence of factors responsible for optimal neuronal development and synaptogenesis. It exhibits age dependent variation in metabolic rate, blood flow, and ability to tolerate oxidative stress. It is also characterized by an exuberance of neurotransmitter activity, particularly in the first few years of life. The dynamic evolution and adaptability of early brain function permits the organization of neuronal networks to be influenced by environmental stimulation, and, to reduce the functional impact of injury. However, these same processes may also exacerbate the harm sustained by the brain following an acquired brain injury (ABI). The developing neurons are susceptible to excitotoxicity, oxidative stress, and, inflammation, often leading to cellular necrosis and apoptosis. Despite being immunologically privileged via the blood brain barrier, the developing brain is susceptible to injury from systemic inflammation through alteration of normally protective cerebrovascular endothelial cell function. Finally, many of the therapeutic agents currently employed in post-ABI hospital care may also compromise ABI outcome via non-intended pharmacological effects. These agents include analgesic, sedative and anti-convulsant medications. This review emphasizes those physiological considerations in the developing brain which may impact the outcome after ABI, including, the cellular mechanisms of neuronal and cerebrovascular endothelial cell injury, ABI outcome and future therapeutic directions.

Highlights

► We highlight the vulnerability of the developing brain to injury. ► Up-regulation of normal mechanisms of brain development exacerbates neuronal injury. ► Neuro-depressant medication may be particular deleterious to the infant brain. ► Therapeutic approaches in the injured immature brain are currently sub-optimal.

Section snippets

Background

It is generally accepted that when subjected to an acquired brain injury (ABI) of similar severity, infants and young children will exhibit a functional outcome superior to that observed in the adult. This concept (“Kennard Principle”) holds that in patients a negative linear correlation exists between the age at which ABI is sustained and the functional outcome, and, has been attributed to the morphological and functional plasticity demonstrated by the developing brain in early life [1].

Features of normal childhood brain development and function

Fetal life is characterized by a redundancy in neuron production. Subsequently, neurons are culled through apoptosis, thereby regulating the number and arrangement of neurons in the developing brain. Likewise, post-natal synaptic development is characterized by exuberant proliferation, followed by pruning of the nascent neural network in a pattern determined, at least in part, by the utilization history of the synaptic pathways – “use it, or lose it”. The period of florid synaptogenesis occurs

Physiological considerations in the brain injured child

Trauma is the most common ABI in children, and for young children falls are the most common mechanism of injury [6]. Among the major determinants of traumatic brain injury (TBI) severity are the mechanical characteristics of the cranium. In children the developing skull exhibits characteristics with regard to its’ size, shape and biomechanical properties that render the infant and young child at an increased vulnerability to TBI. The height of the skull of a newborn is disproportionately longer

Mechanisms of neural injury

Although injury to the developing brain has multiple aetiologies (e.g. trauma, hypoxia–ischaemia, infection and neoplastic), many of the pathophysiological mechanisms they elicit are common to them all. Excitotoxicity, oxidative stress and inflammation may all be incited and interact following ABI, often working synergistically to precipitate necrotic and apoptotic neuronal loss.

The primary excitatory neurotransmitter in the developing brain is glutamate, which acts on both inotropic and

Mechanisms of cerebrovascular endothelium injury

A key feature of brain microcirculation is the blood brain barrier (BBB), which had, until recently, been regarded as an effective isolator of brain tissue from systemic immune responses. This model now appears to be simplistic and the BBB is now recognized as an active participant in neuroinflammatory processes. The luminal aspect of the BBB is lined with cerebrovascular endothelial cells (CVECs) whose unique morphology (lack of vacuoles and fenestration) coupled with the presence of highly

ABI exacerbation by therapeutic interventions

Many of the drugs routinely utilized as sedative, analgesic or anti-epileptic therapy in children with an ABI, have been shown to up-regulate “pathological” apoptotic mechanisms and increase neuronal loss in animal laboratory studies involving immature animals. Many of these agents have a common putative action of suppressing neuronal activity, and include NMDA receptor antagonists (ketamine [80], [81]), gamma-aminobutyric-acid-A (GABAA) receptor agonists (benzodiazepines, barbiturates [82])

ABI outcome

The outcome of paediatric ABI depends largely on the etiology, extent of injury, and available specialized care. Further, aggressive and goal-directed neurorehabilitation is paramount in optimizing ABI outcome [86], [87]. The ideal speed and timing of rehabilitation practices following paediatric ABI is still unknown, but it might be crucial to pair active post-ABI rehabilitation with periods of “brain growth spurt” [3], thereby taking advantage of age-dependent plasticity mechanisms.

Future directions

Sedative agents are frequently required in children with an ABI, but these agents often have the potential to exacerbate the injury, hence new agents which possess clinically useful depressant effects on the brain but avoid enhancing pro-apoptotic mechanisms are being sought. Dexmedetomidine (the d-enantiomer of medetomidine), is a potent, specific, and highly selective alpha-2-adrenoceptor agonist. It possesses sedative, anxiolytic and analgesic properties which make it a desirable agent for

Conclusions

ABI remains the major cause of mortality and neurological morbidity in infants and children, and yet, despite growing knowledge of the mechanisms involved, few effective therapeutic interventions have been identified. The ongoing problem of deciphering the neuroprotective versus neurotoxic actions of the known pathophysiological mechanisms, and identifying the appropriate pharmacological intervention required post-ABI, remain. Nonetheless, in view of some of the age-related changes to the

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