Modulating effects of physiological, genetic, and biochemical factors on the sequelae of childhood traumatic brain injury
Lo, Tsz-Yan M.
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Brain trauma occurs frequently in children and its consequences cause significant health and financial burden to the patients, their carers and society. This thesis assessed the modulating effects of physiological, genetic, and biochemical factors on the sequelae of childhood brain trauma. Primary brain injury from the mechanical forces of trauma and secondary brain insults consequent on the primary injury are determinants of brain trauma outcome. The most important secondary insults recognised are reduced cerebral perfusion pressure (CPP) and raised intracranial pressure (ICP). CPP is governed by the mean arterial blood pressure and the ICP. During childhood these physiological measures change with age. With continuous physiological recordings, ‘critical’ age-related minimum CPP thresholds for children aged 2-6, 7-10 and 11-15 years were defined as 48, 54 and 58mmHg respectively. Utilising these thresholds and a novel cumulative pressure-time index (PTIc), we have demonstrated that CPP insult still remains a feature in 80% of the severe brain trauma patients and significantly relates to global outcome. Brain trauma and cerebral ischaemia are stimuli to the inflammatory cascade leading to further brain damage. Serum adhesion molecule levels after brain trauma indicate injury severity and predict outcome better than brain specific proteins. Predictability is improved using more than one serum biomarker level. Neuro-inflammatory pathways involving adhesion molecules may have a strong modulating effect on brain trauma outcome but warrants further investigations in relation to CPP insult. Genetic factors such as Apolipoprotein E (APO E) genetic polymorphisms may additionally influence outcome, but it was not known whether genetic factors lessen the quantity of CPP insult or the cellular response to it. We demonstrated that the e4 carriers who had unfavourable outcome had 22 times less CPP insult than the non-e4 carriers, while the e3 homozygous who had good recovery had 26 times more CPP insult than the non-e3 homozygous. This suggests that APO E polymorphisms may affect the patient’s cerebral ischaemic tolerance differently, indicating especially the need to prevent CPP insult among e4 carriers. Cerebral ischaemia may, therefore, be a common pathway through which physiological and genetic factors modulate outcome after brain trauma.