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Pathophysiology of traumatic brain injury
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- 2. an impact, penetrationor rapid movement of the brain within the skull that results in altered mental state. DEFINITION
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- 4. Primary injury: consequenceof direct impact.( coup/ countercoup) Secondary injury: due to subesquent events.
- 5. Why?????? Common than anyother neurological disease or event Poor prognosis High morbidity and mortality
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- 9. CEREBRAL BLOOD FLOW Significantalteration in CBF In experimental animal models -mild to moderate TBI, showed a significant drop off in blood flow (70-80% of normal) , and with more severe injury the drop off neared ischemic levels.
- 10. Some association withstroke. Morphological injury hypotension in the presence of autoregulatory failure inadequate availability of nitric oxide or cholinergic neurotransmitters, potentiation of prostaglandin-induced vasoconstriction.
- 11. Cerebral hyperemia –canpresent in the initial stage leading to cerebral edema and raised ICP.
- 12. Cerebrovascular autoregulation andCO2- reactivity Hyperemia in a setting of impaired autoregulation is generally associated with intractable increases in intracranial pressure and ultimately, poorer cerebral perfusion and worse outcome.(breakthrough phenomenon) CO2 reactivity –may be preserved.
- 14. CEREBRAL VASOSPASM Seen inone third patients Post traumatic day 2-5 Endothelial dysfunction, decreased NO.
- 15. BBB DYSFUNCTION Due tomechanical damage Becomes permeable to blood borne factors Activation of coagulation cascade- thrombus- ischemic injury Pro-inflammatory mediators, activation of cell adhesion molecules Vasogenic and cytotoxic edema
- 17. IONIC FLUX ANDGLUTAMATE Redistribution of ions and neurotransmitters, altering the membrane potential GLUTAMATE K+,Ca2+
- 18. 18 Potassium release into ECS Excitoxicity, precipitatedby the neurotransmitter glutamate Failure of presynaptic membrane ion pumps Initial depolarisation dependant release of GLUTAMATE Conventional Theory RecentOpinion Release of CALCIUM Trauma-induces changes to postsynaptic Glutamate receptor - pharmacology, kinetics and composition AMPA receptor NMDA Receptor AMPA - -amino-3-hydroxy-5-methyl-4-isoxazleproprionic acid NMDA - N-methyl-D-aspartic acid • Increased current response to AMPA-receptor agonists • Reduction in expression of receptors containing the GluR2 subunit (I.e. more permeable to Ca) • Thought to be mediated by TNF- Release of CALCIU M • Generation of neuronal nitric oxide (a free radical) • Increased production of of free radicals (due to high mitochondrial Ca) mixes with NO to form Peroxynitrite • Nitration • Lipid peroxidation • DNA fragmentation CELLULAR DAMAGE
- 19. 19 Protease NO synthas e Phospolipas e A2 Endonuclease s Protein kinases phosphatas es Cytoskeleto n breakdown Mitochondr ialdamage Lipid peroxidation membrane damage DNA fragmentatio n “Secondary” genes Apoptosis Free radicals Notric oxide Arachidon ic acid CA2+ INFLUX LEADING TO DESTRUCTIVE CASCADE
- 21. Cerebral glucose metabolismin TBI Initial phase of hyperglycolysis followed by decraesed glucose metabolism This initial increase in CMRglc is due to an increased requirement of cellular energy to restore the ionic balance and neuronal membrane potential.
- 22. Hyperglycolysis has beenobserved within the first 8 days after severe human head injury. Increase in glucose metabolism may or may not be accompanied by increase in the CBF, leading to uncoupling of the CMRO2/CBF ratio
- 23. Activation of anaerobicpathways followed by accumulation of lactate. Increase in the lactate levels in CSF, altered lactate/ pyruvate ratio and negative A-V difference in the lactate levels.
- 24. Decreased glucose uptake- decreasedCBF(uncoupling) defects in glucose transporter function decreased metabolic demand for glucose.
- 25. Adult rat studieshave shown decreased neuronal glucose transporter (GLUT1) immunoreactivity 2-4 hours after FP injury 18F-DG kinetic changes following moderate to severe TBI in humans have determined that hexokinase activity was globally decreased, with glucose transport impairments occurring specifically within the contusion sites.
- 26. Inhibition of theglycolytic pathway: Increased activity of pentose phosphate pathway Decreased NAD+ levels Decreased activity of PDH POST TBI ENERGY CRISIS
- 28. Reactive molecules withunpaired electrons. ROS and RNS. ˙OH , ONOOˉ, O2˙ˉ, H2O2, NO˙ Scavengers- superoxide dismutase(SOD), glutathione peroxidase, vit E, C, catalase. FREE RADICALS IN TBI
- 30. Lipid peroxidation ofpolyunsaturated fatty acids Oxidation or nitration of proteins Activation of DNA repair enzymes (PARP)
- 31. ROLE OF MITOCHONDRIA Twomechanisms Ca2+ influx Free radical damage Apootosis vs necrosis
- 33. NEUROINFLAMMATION More with contusionsand hemorrhages Surge for pro-inflammatory mediators Followed by increased synthesis of chemokines and cell adhesion molecules (ICAM -1, V-CAM 1) leading to influx of inflammatory cells, though the direct invasion of WBC,s is not there.
- 34. Target – bymonoclonal antibodies. Upregulation of IL-1, TNF-ß within hours after the injury Affects the normal tissue, leading to scar formation.
- 37.