Diagnosis and Management of Acute Concussion
Symptoms after mild TBI may be attributable to pathophysiological changes that occur in the brain after injury. Acceleration–deceleration of the brain within the skull results in a stretch and strain upon the white matter and directly to cortical areas. Our knowledge of mTBI pathophysiology derives primarily from studies in animal models, as well as from clinical studies of severe human TBI using invasive monitoring. Animal models characterizing pathological changes and functional correlates, particularly behavioral and cognitive impairments, include fluid percussion, controlled cortical impact, and weight drop injuries. In addition, there are newer models of repeat mTBI/concussion that focus on functional impairment with minimal histological injury. After impact occurs, a cascade of intracellular and extracellular processes occurs including neurotransmitter release, alteration in cerebral blood flow, mitochondrial dysfunction, and free-radical formation. Neuronal cell membrane disruptions and axonal stretching occur, with resulting indiscriminate movement of ions and neurotransmitters across the disturbed membrane. Glutamate is released from presynaptic terminals and activates N-methyl-D-aspartate (NMDA) receptors, further exacerbating these ion shifts. Potassium is released extracellularly, and the Na/K ATP-dependent pump attempts to re-establish ionic equilibrium with resulting depletion of energy stores. Extracellular potassium increases lead to further neuronal depolarization. Calcium accumulation occurs intracellularly, leading to mitochondrial calcium overload with resulting mitochondrial dysfunction and oxidative stress. This calcium accumulation has been shown in animal models to correlate with persistent cognitive deficits as detected on Morris water maze testing.
In addition to the ionic and neurotransmitter dysregulation that occurs, changes in cerebral glucose metabolism have also been shown both in animal and human studies. There is an initial rapid increase in glucose uptake, which is followed by prolonged glucose metabolic depression. This increase may be secondary to cellular energy needs to restore ionic balance. Increased cerebral glucose metabolism is followed by a period of decreased glucose metabolism, and is proportional in magnitude and duration to injury severity in rat models as well as in TBI patients. This glucose metabolic depression may be due to multiple reasons, including decreased cerebral blood flow, reduced demand, and impaired glucose transporter function. Animal studies have shown a decrease in cerebral blood flow during the acute phase after injury, with a resultant mismatch between needs and glucose availability. Additionally, there may be decreased expression of the GLUT1 transporter.
Increased free-radical production may occur after injury, which causes free-radical scavengers to be overwhelmed, leading to oxidative damage. This free-radical production may be the result of intracellular calcium accumulation that activates free-radical-producing enzymes concomitantly with decreased availability of reducing equivalents. The combination of increased intracellular calcium and reactive oxygen species leads to mitochondrial dysfunction, which in turn reduces energy production, thus potentially initiating cell death through apoptotic and necrotic pathways.
In addition to the chemical changes occurring throughout the brain, stretching and shearing of axons throughout the white matter leads to diffuse axonal injury (DAI), particularly in the brainstem, corpus callosum, and frontal lobes. Cell membrane permeability, membrane potential, and cytoskeletal disruption occurs, with axonal transport disturbance. Buildup of transport organelles leads to edema, and secondary axotomy may occur leading to "retraction balls." However, there is some debate as to whether DAI may or may not be the primary mechanism of symptomatology behind postconcussive symptoms.
More recently, use of multimodal magnetic resonance imaging (MRI) techniques such as 1H-magnetic resonance spectroscopy (MRS) has furthered the understanding of metabolic changes that occur after mTBI. N-acetylaspartate (NAA) diminishes after mTBI, and may represent neuronal and/or mitochondrial dysfunction; however, its exact function is not completely understood. MRS studies have shown that this decrease in NAA can recover 30 days after injury. However, the temporal range of decreased NAA has been shown to range from days to months to years after injury. Interestingly, postconcussion reductions in NAA are exacerbated (greater reductions and longer duration—45 days) after repeated concussions.
The pathophysiology of military-related TBI may be different than other TBI sustained from falls, blunt trauma, and sports-related concussions. In a retrospective study of inpatient admission from OIF, Bell et al found that of the 1,513 consultations made by the neurosurgery population, blast injury accounted for almost 60% of military-related TBI. However, other estimates maintain that mTBI sustained in the military looks mechanistically and demographically like sport-related concussion. Many characteristics of the blast determine the resulting effects, including the distance from the blast, whether the blast occurred in an open or closed space, pressure waves that may be reflected off surrounding surfaces, and characteristics of the improvised explosive device (IED). Blast injury results from the transmitted acoustic wave through the brain (primary blast wave) and accompanying blast winds. Vascular damage with hemorrhage and sometimes vasospasm may be triggered, which can lead to ischemia and further clinical deterioration.
Pathophysiology
Symptoms after mild TBI may be attributable to pathophysiological changes that occur in the brain after injury. Acceleration–deceleration of the brain within the skull results in a stretch and strain upon the white matter and directly to cortical areas. Our knowledge of mTBI pathophysiology derives primarily from studies in animal models, as well as from clinical studies of severe human TBI using invasive monitoring. Animal models characterizing pathological changes and functional correlates, particularly behavioral and cognitive impairments, include fluid percussion, controlled cortical impact, and weight drop injuries. In addition, there are newer models of repeat mTBI/concussion that focus on functional impairment with minimal histological injury. After impact occurs, a cascade of intracellular and extracellular processes occurs including neurotransmitter release, alteration in cerebral blood flow, mitochondrial dysfunction, and free-radical formation. Neuronal cell membrane disruptions and axonal stretching occur, with resulting indiscriminate movement of ions and neurotransmitters across the disturbed membrane. Glutamate is released from presynaptic terminals and activates N-methyl-D-aspartate (NMDA) receptors, further exacerbating these ion shifts. Potassium is released extracellularly, and the Na/K ATP-dependent pump attempts to re-establish ionic equilibrium with resulting depletion of energy stores. Extracellular potassium increases lead to further neuronal depolarization. Calcium accumulation occurs intracellularly, leading to mitochondrial calcium overload with resulting mitochondrial dysfunction and oxidative stress. This calcium accumulation has been shown in animal models to correlate with persistent cognitive deficits as detected on Morris water maze testing.
In addition to the ionic and neurotransmitter dysregulation that occurs, changes in cerebral glucose metabolism have also been shown both in animal and human studies. There is an initial rapid increase in glucose uptake, which is followed by prolonged glucose metabolic depression. This increase may be secondary to cellular energy needs to restore ionic balance. Increased cerebral glucose metabolism is followed by a period of decreased glucose metabolism, and is proportional in magnitude and duration to injury severity in rat models as well as in TBI patients. This glucose metabolic depression may be due to multiple reasons, including decreased cerebral blood flow, reduced demand, and impaired glucose transporter function. Animal studies have shown a decrease in cerebral blood flow during the acute phase after injury, with a resultant mismatch between needs and glucose availability. Additionally, there may be decreased expression of the GLUT1 transporter.
Increased free-radical production may occur after injury, which causes free-radical scavengers to be overwhelmed, leading to oxidative damage. This free-radical production may be the result of intracellular calcium accumulation that activates free-radical-producing enzymes concomitantly with decreased availability of reducing equivalents. The combination of increased intracellular calcium and reactive oxygen species leads to mitochondrial dysfunction, which in turn reduces energy production, thus potentially initiating cell death through apoptotic and necrotic pathways.
In addition to the chemical changes occurring throughout the brain, stretching and shearing of axons throughout the white matter leads to diffuse axonal injury (DAI), particularly in the brainstem, corpus callosum, and frontal lobes. Cell membrane permeability, membrane potential, and cytoskeletal disruption occurs, with axonal transport disturbance. Buildup of transport organelles leads to edema, and secondary axotomy may occur leading to "retraction balls." However, there is some debate as to whether DAI may or may not be the primary mechanism of symptomatology behind postconcussive symptoms.
More recently, use of multimodal magnetic resonance imaging (MRI) techniques such as 1H-magnetic resonance spectroscopy (MRS) has furthered the understanding of metabolic changes that occur after mTBI. N-acetylaspartate (NAA) diminishes after mTBI, and may represent neuronal and/or mitochondrial dysfunction; however, its exact function is not completely understood. MRS studies have shown that this decrease in NAA can recover 30 days after injury. However, the temporal range of decreased NAA has been shown to range from days to months to years after injury. Interestingly, postconcussion reductions in NAA are exacerbated (greater reductions and longer duration—45 days) after repeated concussions.
The pathophysiology of military-related TBI may be different than other TBI sustained from falls, blunt trauma, and sports-related concussions. In a retrospective study of inpatient admission from OIF, Bell et al found that of the 1,513 consultations made by the neurosurgery population, blast injury accounted for almost 60% of military-related TBI. However, other estimates maintain that mTBI sustained in the military looks mechanistically and demographically like sport-related concussion. Many characteristics of the blast determine the resulting effects, including the distance from the blast, whether the blast occurred in an open or closed space, pressure waves that may be reflected off surrounding surfaces, and characteristics of the improvised explosive device (IED). Blast injury results from the transmitted acoustic wave through the brain (primary blast wave) and accompanying blast winds. Vascular damage with hemorrhage and sometimes vasospasm may be triggered, which can lead to ischemia and further clinical deterioration.
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