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Stewart, William

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Stewart, William

  1. 1. The Neuropathological Reality of Diffuse Axonal Injury<br />Dr Willie Stewart PhD FRCPath<br />Consultant and Lead Neuropathologist<br />Honorary Clinical Senior Lecturer<br />Southern General Hospital, UK<br />
  2. 2. The Glasgow TBI Archive<br />unique dataset consisting of:<br /><ul><li>Approx 2000 cases with history of TBI (hours to decades survival)
  3. 3. Accrued between 1970 and 2006
  4. 4. Standardised sampling protocols
  5. 5. Formalin fixed, paraffin embedded
  6. 6. Standardised reporting
  7. 7. Over 150 publications using variety of techniques
  8. 8. Approx 1200 DNA samples from (largely) non-fatal TBI cases in longitudinal studies
  9. 9. Approx 50 fresh frozen TBI cases + age matched controls</li></ul>Clinical cohorts in longitudinal studies of outcome (up to several decades)<br />
  10. 10. The Neuropathological Reality of Diffuse Axonal Injury<br /><ul><li>Historical perspective
  11. 11. Terminology
  12. 12. Pathology
  13. 13. Macroscopic appearances
  14. 14. Histology
  15. 15. Time course
  16. 16. Myths and misunderstandings
  17. 17. Knowledge gaps</li></ul>n = magic number<br />
  18. 18. Diffuse traumatic axonal injury<br /><ul><li>Shearing injury
  19. 19. Diffuse damage to white matter of immediate impact type
  20. 20. Diffuse white matter shearing injury
  21. 21. Inner cerebral trauma
  22. 22. Diffuse axonal injury (DAI)
  23. 23. Traumatic axonal injury (TAI)
  24. 24. Diffuse traumatic axonal injury (dTAI)</li></li></ul><li>Diffuse traumatic axonal injury<br />Diffuse damage to axons in cerebral hemispheres, corpus callosum, brainstem and cerebellum. May be focal (haemorrhagic) lesion in corpus callosum and/ or brainstem.<br />Multifocal rather than diffuse<br /><ul><li>assymetrical involvement
  25. 25. parasagittal white matter
  26. 26. corpus callosum
  27. 27. internal capsule
  28. 28. fornices
  29. 29. cerebellar peduncles
  30. 30. brainstem tracts</li></li></ul><li>Diffuse traumatic axonal injury<br />Grade 1: Widespread axonal damage (stereotypical distribution)<br />Grade 2: Above plus focal lesion in corpus callosum<br />Grade 3: Above plus focal lesion in rostral brainstem <br /><ul><li> Now recognised in majority fatal TBI
  31. 31. Pathology grading system questioned</li></ul> n lucid interval<br />Grade 1 10 2(6)<br />Grade 2 29 9(5)<br />Grade 3 83 6<br />No dTAI 312 ?<br />
  32. 32.
  33. 33. Diffuse traumatic axonal injury<br />Haematoxylin and eosin<br /> axonal swellings and bulbs<br />Silver impregnation (Palmgren)<br />15-18h survival<br />approx 30% fatal TBI<br />Amyloid precursor protein (APP)<br />anterograde transport. Accumulates proximal to injury<br /> sub 1h survival (?)<br /> range of axonal abnormalities (partially) described<br /> time course of pathology (partially) characterised<br /> in majority fatal TBI<br />Synaptophsin, ubiquitin, neurofilament, tau....<br />
  34. 34. H&E<br />
  35. 35. LFB/CV<br />
  36. 36. Palmgren<br />
  37. 37. APP<br />
  38. 38.
  39. 39. Single mTBI<br /><ul><li>69 male
  40. 40. altercation in house
  41. 41. fall
  42. 42. no LOC
  43. 43. lucid and mobile immediately after
  44. 44. next morning found unresponsive
  45. 45. Local hospital- GCS ??
  46. 46. no intervention
  47. 47. died 4/7 after admission
  48. 48. Cause of death ‘bronchopneumonia’</li></li></ul><li>
  49. 49. APP<br />H&E<br />H&E<br />APP<br />
  50. 50. Single mTBI<br />“The third case, which showed a mild degree of white matter change associated with congophilicangiopathy, also had one of the highest”<br />
  51. 51.
  52. 52. Time course axonal APP pathology<br />APP<br />
  53. 53.
  54. 54.
  55. 55.
  56. 56.
  57. 57. Approximately 30% of acute TBI cases have amyloid-βplaques<br /><ul><li>Observed within hours of injury
  58. 58. Observed across the age spectrum
  59. 59. Diffuse in nature
  60. 60. Transient or persist?</li></li></ul><li>Amyloid plaque and NFT pathology is greater in TBI cases w survival >1year v controls<br />Frequent<br />Moderate<br />Sparse<br />Extensive<br />Moderate<br />Minimal<br />P=0.019; ChiSq<br />TBI Control<br />
  61. 61. Multiple mTBI<br />“Punch Drunk Syndrome” /dementia pugilistica / chronic traumatic encephalopathy (CTE)<br />Martland (1928): <br /><ul><li> tremors slowed movement, confusion, and speech problems </li></ul>Corsellis et al (1973) 15 ex-boxers:<br /><ul><li>septal and hypothalamic</li></ul>cavum septum <br />fornix and mammillary bodies atrophied<br /><ul><li>cerebellar</li></ul>tonsillarscarring, <br />reduction in Purkinje cells<br /><ul><li>substantia nigra – loss of pigment
  62. 62. Neurofibrillarytangles (NFTs)
  63. 63. TDP-43 abnormalities</li></li></ul><li>The Neuropathological Reality of Diffuse Axonal Injury<br /><ul><li>Terminology confused
  64. 64. Present in vast majority fatal TBI
  65. 65. Pathology of dTAI in mild requires further work
  66. 66. May persist several years after injury
  67. 67. Association with neurdegenerative pathology
  68. 68. under-estimated by imaging studies (for debate)</li></li></ul><li>The Glasgow TBI Archive<br />unique dataset consisting of:<br /><ul><li>Approx 2000 cases with history of TBI (hours to decades survival)
  69. 69. Accrued between 1970 and 2006
  70. 70. Standardised sampling protocols
  71. 71. Formalin fixed, paraffin embedded
  72. 72. Standardised reporting
  73. 73. Over 150 publications using variety of techniques
  74. 74. Approx 1200 DNA samples from (largely) non-fatal TBI cases in longitudinal studies
  75. 75. Approx 50 fresh frozen TBI cases + age matched controls</li></ul>Clinical cohorts in longitudinal studies of outcome (up to several decades)<br />

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