ReviewMechanisms and consequences of acquired brain injury during development
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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