Diffuse Axonal Injury

Traumatic Axonal Injury

1. Diffuse Axonal Injury Ade Wijaya, MD – September 2019

2. Introduction Traumatic brain injury (TBI ) is one of the leading cause of death in young people A process of widespread axonal damage in the aftermath of acute or repetitive TBI, leading to deficits in cerebral connectivity that may or may not recover over time One of the most common pathologies in all closed-head trauma Su E, Bell M. Diffuse axonal injury. Translational research in traumatic brain injury. 2016 Apr 21;57:41.

3. Pathological findings (Adam classification) Grade I (Mild DAI) Microscopic changes in white matter of cerebral cortex, corpus callosum, brainstem, and occasionally the cerebellum Grade II (Moderate DAI) Grossly evident focal lesions in the corpus callosum Grade III (Severe DAI) Additional focal lesions in the dorsolateral quadrants of the rostral brainstem (involving superior cerebellar peduncle) Su E, Bell M. Diffuse axonal injury. Translational research in traumatic brain injury. 2016 Apr 21;57:41.

4. Clinical features Meyers C.A. et al. Early versus late lateral ventricular enlargement following closed head injury. J Neurol Neurosurg Psychiatry. 1983;46(12 ): 1092–1097. Wilson J.T. et al. Early and late magnetic resonance imaging and neuropsychological outcome after head injury. J Neurol Neurosurg Psychiatry. 1988;51(3):391–396. Meythaler J.M. et al. Current concepts: Diffuse axonal injury-associated traumatic brain injury. Arch Phys Med Rehabil. 2001;82(10):1461–1471. Richmond E, Rogol A.D. Endocrine. 2013. Traumatic brain injury: Endocrine consequences in children and adults.

5. INITIAL INJURY AND PRIMARY AXOTOMY Stretch and shear injuries Distortion of the axonal cytoskeleton subsequently disrupts normal axonal transport mechanisms, leading to accumulation of transport products in injured regions and alterations in neuronal homeostasis I ncreased axolemmal permeability, mitochondrial swelling, and cytoskeletal compaction damaging microtubule and neurofilament structures Shearing of axonal fibers leading to complete disconnection after trauma, or primary axotomy, can cause a more pronounced accumulation of transport products in the injury referred to as an “axonal bulb” Singleton R.H. et al. Traumatically induced axotomy adjacent to the soma does not result in acute neuronal death. J Neurosci. 2002;22(3):791–802 . Pettus E.H. et al. Traumatically induced altered membrane permeability: Its relationship to traumatically induced reactive axonal change. J Neurotrauma. 1994;11(5):507–522 . Farkas O, Povlishock J.T. Cellular and subcellular change evoked by diffuse traumatic brain injury: A complex web of change extending far beyond focal damage. Prog Brain Res. 2007;161:43–59 . Chen X.-H. et al. A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. Brain Pathol. 2009;19(2):214–223.

6. SECONDARY AXOTOMY AND DISRUPTED NEURONAL HOMEOSTASIS Multiple injury cascades from oxidative, excitotoxic, and inflammatory pathways S tretch disrupts membrane permeability and precipitates depolarization R elease of excitatory neurotransmitters such as glutamate D ysfunction of normal glutamate reuptake processes Glutamate  f urther damage to the axonal cytoskeletal as well as ion channel structures   Secondary axotomy is a process of rapidly progressive axonal deterioration, breakage, and retraction occurring following but not at the time of injury Su E, Bell M. Diffuse axonal injury. Translational research in traumatic brain injury. 2016 Apr 21;57:41.

7. NEUROINFLAMMATION M ediated by microglia IL-1 family, IL-6, IL-10, and TNF-α The leukocyte adhesion molecule ICAM-1 is another potential mediator of post-DAI secondary injury in that it is upregulated following DAI Oehmichen M, Theuerkauf I, Meissner C. Is traumatic axonal injury (AI) associated with an early microglial activation? Application of a double-labeling technique for simultaneous detection of microglia and AI.   Acta Neuropathol. 1999;97(5):491–494. Lu K.-T. et al. Extracellular signal-regulated kinase-mediated IL-1-induced cortical neuron damage during traumatic brain injury. Neurosci Lett. 2005;386(1):40–45 Rancan M. et al. Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats. J Neurosci Res. 2001;63(5):438–446 . Rhodes J.K.J, Sharkey J, Andrews P.J.D. The temporal expression, cellular localization, and inhibition of the chemokines MIP-2 and MCP-1 after traumatic brain injury in the rat. J Neurotrauma. 2009;26(4):507–525.

8. Special considerations Blast injuries Chronic traumatic encephalopathy Abusive head trauma Su E, Bell M. Diffuse axonal injury. Translational research in traumatic brain injury. 2016 Apr 21;57:41.

9. Biomarkers C alcium -D ependent  P roteolysis and  αII S pectrin  B reakdown  P roducts N eurofilament  M arkers G lial  F ibrillary  A cidic  P rotein M yelin  B asic  P rotein S-100 β N euron -S pecific  E nolase U biquitin  C arboxy -T erminal  H ydroxylase   L1 Su E, Bell M. Diffuse axonal injury. Translational research in traumatic brain injury. 2016 Apr 21;57:41.

10. NEUROIMAGING Head CT: frequently does not identify pathology associated with DAI MRI: Microhemorrhages Punctate areas of T 2  signal hyperintensity in the white matter and at gray-white matter junctions in the frontal or occipital lobes Laalo J.P, Kurki T.J, Tenovuo O.S. Interpretation of magnetic resonance imaging in the chronic phase of traumatic brain injury: What is missed in the original reports? Brain Inj. 2014;28(1):66–70 . Provenzale J.M. Imaging of traumatic brain injury: A review of the recent medical literature. AJR Am J Roentgenol. 2010;194(1):16–19. Imaizumi T. et al. Dynamics of dotlike hemosiderin spots associated with intracerebral hemorrhage. J Neuroimaging. 2003;13(2):155–157. Viswanathan A. Cerebral microhemorrhage. Stroke. 2006;37(2):550–555

11. Other Imagings D iffusion  W eighted  I maging  (DWI)  and  D iffusion  T ensor  I maging  (DTI) M agnetization  T ransfer  I maging M orphometric and  V olumetric  A nalysis Functional MRI Su E, Bell M. Diffuse axonal injury. Translational research in traumatic brain injury. 2016 Apr 21;57:41.

12. Treatment C alcineurin  M odulators S tem  C ell  T herapy R ecombinant  H uman   E rythropoetin D ocosahexanoic  A cid Su E, Bell M. Diffuse axonal injury. Translational research in traumatic brain injury. 2016 Apr 21;57:41.

13. Summary A complex process S tretching and shearing of axons Persistent syndrome of cerebral disconnection and longstanding functional impairment Biomarkers Neuroimaging Future therapies

14. Thank you