Full Cellular Mechanisms of TBI PDF

When Cells Face trauma: the Basis of Brain damage Dr. Alvarez Explain how mechanical trauma leads to primary and secondary brain injury at the cellular level. Describe key cellular mechanisms involved in TBI, including ion imbalance, excitotoxicity, oxidative stress, and...

When Cells Face trauma: the Basis of Brain damage Dr. Alvarez Explain how mechanical trauma leads to primary and secondary brain injury at the cellular level. Describe key cellular mechanisms involved in TBI, including ion imbalance, excitotoxicity, oxidative stress, and inflammation. Relate cellular injury mechanisms to common clinical features and outcomes of TBI, such as diffuse axonal injury, cerebral edema, and increased intracranial pressure. A 68-year-old woman is brought to the emergency department 45 minutes after falling down a flight of stairs and hitting the left side of her head. Witnesses report that she briefly lost consciousness but later regained awareness and was alert for about 15 minutes before becoming confused. During transport, she vomited once and developed a 2-minute generalized tonic-clonic seizure. Upon arrival, she is drowsy and non- responsive to commands. Physical examination reveals flaccid paralysis of the right arm and leg. TBI arises due to any exterior mechanical force that leads to a temporary or permanent impairment of physical, psychological, and cognitive function along with an altered state of consciousness One of the leading causes of disability - worldwide Resulting damage includes a combination of focal contusions and hematomas, as well as shearing of white matter tracts (diffuse axonal injury [DAI]) along with cerebral edema and swelling. TBI related terms Concussion: traumatically induced transient disturbance of brain function usually loss of conciousness at the moment of impact DAI: Shearing of axons cause traumatic coma more that 6 hours caused by multiple small lesions in the white matter tracts. This typically involves the gray-white junction in the hemispheres, with more severe injuries affecting the corpus callosum and/or midbrain. >24 h: severe diffuse axonal injury Typical clinical scenario: Immediate or delayed loss of consciousness (coma or persistent vegetative state)  Subdural Hematoma: Parenchymal Hematoma: Epidural Hematoma: Crescent-shaped, hyperdense Irregular, hyperdense regions within Biconvex (lens-shaped), hyperdense (acute) on CT brain parenchyma on CT lesion on CT Crosses suture lines Direct damage to small penetrating Does not cross suture lines Rupture of bridging veins between arteries → rupture → localized Common cause: rupture of middle dura and arachnoid -- accumulating bleeding and tissue destruction meningeal artery -- arterial blood venous blood. Clinical scenario: Sudden onset of accumulation between skull and dura Clinical scenario: Gradual onset of focal neurological deficits (e.g., Clinical scenario: Brief loss of headache, confusion, and hemiparesis, aphasia), headache, consciousness followed by a lucid drowsiness (acute cases can and vomiting interval and then rapid deterioration progress rapidly) Primary Injury: Direct trauma causing mechanical disruption (e.g., coup-contrecoup injury, skull fracture). Secondary Injury: Processes triggered by the primary injury, occurring hours to days later (molecular events). Ischemia Excitotoxicity (Ca²⁺ overload) Inflammatory cascade Cytotoxic and vasogenic edema Oxidative stress  Liquefactive Necrosis: The Brain’s Distinctive Response to Injury The brain primarily exhibits liquefactive necrosis in response to ischemia, trauma, or infections. Unlike most organs that undergo coagulative necrosis in ischemic injury, the brain’s high lipid content and the enzymatic activity of lysosomes lead to rapid tissue digestion and the formation of a soft, cystic cavity filled with necrotic debris.  TBI Primary (mechanical trauma) Cell membrane damage Disruption of ion homeostasis (Na+, Ca+ in, K+ out) overload Immediate neural cell death (necrosis), ischemia, blood caspases brain barrier damage apoptosis Adapted from: Front. Toxicol 4:910972. By Alvarez-Palazuelos TBI Secondary exc ito toc ity BBB damage release of Glu Calclum influx Mitochondrial ATP ROS Caspases and damage calpains Lipid peroxidation TNF-α, IL-1β, IL-6 Cytochrome C Cytoskeletal release microglial activation release vasogenic, cytotoxic Apoptosis edema *upregulation of AQP1, & 4 increased intracranial pressure Permanent deficits paralylis, seizures, cognitive disturbance Adapted from: Front. Toxicol 4:910972. By Alvarez-Palazuelos A 68-year-old woman is brought to the emergency department 45 minutes after falling down a flight of stairs and hitting the left side of her head. Witnesses report that she briefly lost consciousness but later regained awareness and was alert for about 15 minutes before becoming confused. During transport, she vomited once and developed a 2-minute generalized tonic-clonic seizure. Upon arrival, she is drowsy and non-responsive to commands. Physical examination reveals flaccid paralysis of the right arm and leg. New: CT reveals a biconvex, hyperdense collection of blood R L biconvex hematoma = epidural What is the most likely explanation for the initial brief loss of consciousness followed by the lucid interval? A) Excessive glutamate release from cell damage B) Compression of the contralateral motor cortex C) Arterial bleeding between the skull and dura mater D) Rupture of bridging veins E) Global cerebral hypoperfusion Mechanism: The patient falls and hits her head, likely resulting in a temporal bone fracture. Pathophysiology: The fracture causes rupture of the middle meningeal artery, leading to arterial bleeding between the skull and dura mater. The combination of head trauma, brief loss of consciousness, and a lucid interval is classic for an epidural hematoma due to rupture of the middle meningeal artery. Which of the following molecular mechanisms most likely triggered the seizure during transport? A) Excessive activation of NMDA receptors B) Decreased extracellular potassium levels C) Increased dopamine release in the frontal cortex D) Rupture of axonal microtubules E) Decreased intracellular calcium levels Answer: A. The expanding epidural hematoma exerts pressure on cortical neurons, causing excessive glutamate release into the synaptic cleft. Glutamate overstimulates NMDA receptors, leading to a sustained influx of Ca²⁺. This results in prolonged depolarization, abnormal electrical activity, and subsequent seizure onset. B) Decreased extracellular potassium levels: Incorrect. Elevated, not decreased, potassium in the extracellular space can contribute to seizures. C) Increased dopamine release in the frontal cortex: Incorrect. Dopamine dysregulation is more associated with psychiatric conditions or movement disorders, not acute seizure onset in TBI. D) Rupture of axonal microtubules: Incorrect. This event contributes to diffuse axonal injury but does not directly cause seizures. E) Decreased intracellular calcium levels: Incorrect. Seizures are triggered by excessive intracellular Ca²⁺ influx, not a decrease. Which of the following is the first molecular event directly responsible for the neuronal dysfunction and motor impairment observed in this patient? A) ATP depletion from mitochondrial failure B) Cytochrome c release from mitochondria C) Excessive intracellular calcium influx D) Caspase activation and neuronal apoptosis E) Oxidative damage to neuronal proteins C) is Correct The expanding hematoma exerts mechanical pressure on cortical neurons, leading to glutamate release and NMDA receptor activation. NMDA receptor overactivation causes calcium influx, which is the immediate, primary molecular event that triggers downstream damage. This calcium overload disrupts key cellular processes, including: Activation of calpains (proteases that degrade the cytoskeleton). Activation of phospholipases (causing membrane breakdown). Disruption of mitochondrial function (leading to downstream ATP depletion). Calcium influx is upstream and triggers most of the subsequent events in neuronal injury, making it the first molecular event.  Protocol of action 1. Stabilize airway, breathing, and circulation. 2. Perform a rapid neurological exam 3. Perform a non-contrast head CT to detect intracranial hemorrhage or fractures. 4. Monitor intracranial pressure (ICP) for severe TBI (GCS ≤ 8) or abnormal CT findings. 5. Maintain systolic blood pressure above 100-110 mmHg with IV fluids or vasopressors. 6. Provide oxygenation, ensuring normocapnia using supplemental oxygen or mechanical ventilation. 7. Administer antiepileptic drugs for seizure prophylaxis within the first 7 days. 8. Maintain normothermia to prevent fever-induced neuronal damage. 9. Initiate early enteral feeding within 48 hours to support metabolic demands. 10. Perform timely surgical interventions (e.g., craniectomy or hematoma evacuation) if indicated Type of event Pathophysiology Therapeutic Interventions Sedation (Benzodiazepines, Excessive glutamate release → NMDA receptor activation → Ca²⁺ Excitotoxicity Levetiracetam), NMDA receptor influx antagonists (Experimental) Oxygen therapy, Calcium channel blockers Mitochondrial Dysfunction Ca²⁺ overload → ATP depletion → ROS production (Nimodipine), Antioxidants (N- acetylcysteine, Vitamin E) Excessive ROS and RNS → Lipid peroxidation, protein/DNA Antioxidant therapy (Edaravone, N- Oxidative Stress damage acetylcysteine), Therapeutic hypothermia Minocycline (Experimental): Inhibits Neuroinflammation Microglial activation → Cytokine release (TNF-α, IL-1β) microglial activation Increased Intracranial Osmotic therapy (Mannitol, hypertonic Edema and hematoma expansion → Increased ICP → Reduced Pressure (ICP) saline), Elevate head (30°), Monitor ICP, cerebral perfusion Decompressive craniectomy Cytoskeletal Breakdown Caspase inhibitors (Experimental), Protease activation → Cytoskeletal breakdown → Apoptosis and Apoptosis Rehabilitation for neuroplasticity Current Diagnosis and Treatment in Neurology: Head Trauma. Chapter 14. Robbins & Kumar Basic Pathology. Chapter 1 Med Clin N Am 104 (2020) 213–238 [email protected]