Pathophysiology of Traumatic Brain Injury

Original Editor - Anna Ziemer

Top Contributors - Naomi O'Reilly, Kim Jackson, Lucinda hampton, Rachael Lowe, Tony Lowe, Stacy Schiurring and Simisola Ajeyalemi  

Introduction

A traumatic brain injury (TBI) causes brain damage via primary and or secondary injury mechanisms.

"Primary injury causes local brain damage, while secondary damage begins with inflammatory activity followed by disruption of the blood–brain barrier (BBB), peripheral blood cells infiltration, brain edema, and the discharge of numerous immune mediators including chemotactic factors and interleukins."

Primary traumatic brain injury insult triggers complex cellular and molecular processes leading to further neuronal dysfunction and death (secondary injury). The variety of processes involved contributes to the traumatic brain injury complexity but also creates various therapeutic targets. Multiple factors contribute to those pathophysiological mechanisms of secondary injury and their contribution to the severity of the secondary injury might vary.

Pathophysiology of Secondary Cerebral Damage after Traumatic Brain Injury. A schematic view of the pathophysiology of secondary cerebral damage after traumatic brain injury that supports the concept of optimizing cerebral blood flow, the delivery of oxygen and the adequate supply of energy substrates.

General pathophysiological features of traumatic brain injury and mechanism following primary onset might include:

• Diffuse axonal injury
• Degradation of the cytoskeleton
• Cortical and subcortical neuronal injury/death
• Vascular-related changes (barrier breakdown, vasospasm, oedema)
• Haemorrhage 
• Ischemia
• Glutamate excitotoxicity
• Changes in neurotransmitters
• Seizures
• Physiological disturbances
• Free radical generation 
• Disruption of calcium homeostasis
• Mitochondrial disturbances 
• Metabolic disturbances
• Altered brain metabolism 
• Altered gene expression
• Pro-inflammatory state

These pathophysiological events impair cell function impacting movement, memory and learning ability as well as potentially causing damage to white matter structure. They are described in more detail below.

Vascular Autoregulation

The normal brain vascular autoregulation includes a pressure and volume monitoring mechanism allowing continuous cerebral blood flow (CBF) and optimal oxygen supply. The main mechanism involved in maintaining consistent cerebral pressure in response to changing systemic arterial pressure are vasoconstriction and vasodilatation of brain vessels. Traumatic brain injury impairs or even abolishes cerebrovascular autoregulation immediately after the trauma or over time. 

Multiple factors can initiate these vasodilation or vasoconstriction cascades, including;  

• Systemic arterial pressure 
• Systemic blood volume 
• Blood viscosity 
• Oxygen level delivery 
• Metabolism 
• Hypo / hypercapnia 
• Pharmacologic agents  

Autoregulatory vasoconstriction is more problematic than autoregulatory vasodilation and leads to greater brain tissue sensitivity to decreased cerebral perfusion pressure.

Vasodilation and Vasoconstriction Cascade in the Cerebral Blood Volume and Intracranial Pressure Regulation.  Vasodilation and vasoconstriction cascade in the cerebral vasculature. This cascade model was first described by Rosner in the 1990s (see references 22, 23). A cascade of this type is often trigged by changes in CPP. Any step in the cascade, however, can be triggered as the starting point. There are many triggering factors such as dehydration, vascular volume, systemic metabolism, CMRO2, blood viscosity, systemic oxygen delivery, PaCO2, or certain pharmacologic agents. SAP systemic arterial pressure, CPP cerebral perfusion pressure, ICP intracranial pressure, CBV cerebral blood volume, CMRO 2 cerebral metabolic rate for oxygen.

Following an initial insult, an ischemia like stage of traumatic brain injury triggers a cascade of processes characterised by direct brain tissue damage and cerebral blood flow (CBF) regulation impairment as well as metabolism impairment.  This cascade might result in oedema formation, increase of intracranial pressure (ICP), and decreased cerebral perfusion pressure (CPP).

Cerebral Perfusion Pressure 

Cerebral perfusion pressure is the difference between the systemic arterial pressure and the intracranial pressure. The normal range of this difference is between 50 and 70 mmHg.

The following clinical mechanisms contribute to the dysregulation of the mechanisms that usually maintain volume and pressure:

• Depolarisation and disturbance of ionic homeostasis 
• Neurotransmitter release (e.g. glutamate excitotoxicity)
• Mitochondrial dysfunction 
• Neuronal apoptosis
• Lipid degradation
• Initiation of inflammatory and immune responses

Cerebral blood flow (CBF) disruption can also be caused by mechanical displacement of brain structures, stretching and distorting brain vessels, arterial hypotension, vasospasm, changes in cerebral microvasculature.

Both hypoperfusion and hyperperfusion is related to the difference between cerebral blood flow and cerebral metabolism and oxygen consumption. Therefore, decreased CBF with a normal metabolic rate creates ischemic conditions. 

Ischemia

Cerebral ischemia is a state of decreased blood supply of the brain (hypoperfusion) and leads primarily to metabolic stress and ionic perturbations. Coexisting traumatic damage such as structural injury of cell bodies, astrocytes and microglia, cerebral vascular and endothelial damage intensify the brain tissue damage. The factors involved in post-traumatic vasospasm and contributing to resultant ischaemia include:

• Morphological damage due to mechanical displacement, i.e.vessel distortion
• Hypotension
• Depletion of nitric oxide and or cholinergic neurotransmitters 
• Vascular smooth muscle depolarisation related to potassium channel reduced activity
• Potentiation of prostaglandin induced vasoconstriction
• Free radicals formation

TBI frequently leads to focal or global cerebral ischemia and its presence points towards poor clinical outcome like persistent vegetative state or death.

Oedema

The mechanism responsible for oedema formation and intracranial pressure increase is hyperaemia. Due to reduced proximal cerebrovascular resistance and increased cerebral blood volume and vessel dilatation the impaired brain blood barrier causes an excess of fluids to reside in vascular bed. This pathology is equally detrimental to brain tissue as ischemia causing an increase in intracranial pressure. Oedema is a common result of traumatic brain injury and can be vasogenic or cytotoxic and can cause ICP increase and secondary ischemia. 

• Vasogenic brain oedema is caused by endothelial cells damage. The ion and protein flow through vascular walls to interstitial space causing an increased volume in extracellular space.
• Cytotoxic oedema results from intracellular water accumulation related to increased cell membrane permeability.

Cerebral Metabolic Dysfunction

Cerebral metabolic disfunction relates to oxygen and glucose depletion as well as reduced cerebral energy state at the period of post traumatic hypermetabolic demand. Hypermetabolism is pathophysiological phenomenon following TBI and occurs as a result of transmembrane ionic influx leading to overexcitation and uncoupling with cerebral blood flow. The extent of primary injury is reflected by the extent of pathophysiological processes like mitochondrial dysfunction related to decreased respiratory rates and ATP production, depletion of the nicotinic co-enzyme pool, intramitochondrial accumulation of calcium ions leading to metabolic failure. The overload of excitatory amino acid neurotransmitters results in overstimulation of ionotropic and metabotropic glutamate receptors with consecutive calcium, sodium and potassium ions flow triggering brain blood barrier breakdown and cellular compensatory ATPase activity increase resulting in aggravated metabolic demand. The cascade of mismatched processes of overflow and metabolism creates excitotoxicity. TBI metabolic failure is also related to imbalance between oxygen supply and oxygen consumption and leads to hypoxia. The extent of the hypoxia and its duration determines the clinical outcome. Therefore, measuring brain oxygenation is one of the standard measurements along with ICP and CPP. The oxidative stress related to imbalance of free radicals and endogenous antioxidants availability can lead to immediate cell death or inflammatory processes or apoptosis.

Neuroinflammation

Damage to blood vessel endothelium following TBI triggers a neuroinflammation process with a release of cytokines, free radicals, prostaglandins and complements mobilising an active response from immune system to eliminate the damaged cells and format scar tissue. Proinflammatory enzymes like interleukin-1, interleukin -6 intensify the activity within the first hours from initial insult. The leucocytosis increasing cell debris and phagocytosis response may further increase the inflammatory response and tissue destruction affecting undamaged tissue extending the injury and decomposing dead tissue. 

Cell Death

Categories of biochemical, cellular, and molecular mechanisms involved in the evolution of secondary damage after ischemic or traumatic brain injury. Three major categories of secondary mechanisms include: 1) Ischemia, excitotoxicity, energy failure, and cell death cascades; 2) Cerebral Swelling; and 3) Axonal Injury 4) A fourth category, inflammation and regeneration, influences each of these cascades.

Cell death and axonal injuries contribute to the extent of the traumatic brain injury. The main death processes are known as necrosis and apoptosis. Apoptotic and necrotic neurons are present even in mild injuries and can be found in areas distant from the injury impact area. Degenerating oligodendrocytes and astrocytes are present in the white matter of primary injury area.

Necrosis (cell death) occurs after the first few hours following an insult to brain tissue, mechanical or hypoxic, and is related to cell membrane damage and uncontrolled release of cell death products. The blood brain barrier becomes impaired and white matter injury usually increases. The resulting detritus is interpreted as an ‘antigen’ and triggers inflammatory process and scaring.

Apoptosis is a naturally programmed cell death and affects undamaged neurons. The imbalance of pro and anti-apoptotic proteins triggers the cell death mechanism hours post primary insult. Apoptosis is triggered by cell surface receptor engagement, growth factor withdrawal and DNA damage. 

Several groups of proteins and biochemical transitional pathways are involved in cell death mechanisms and their tracking might create new therapeutic opportunities limiting neurodegeneration and resulting disabilities especially with apoptosis providing the window of opportunity for therapy due to its delayed nature. 

Axonal Damage

Morphologically, axons with their long structure are at significant mechanical risk during the impact of external forces. Sheering or stretching of axons results in primary axotomy or when damage incomplete they trigger secondary axon degeneration. There are some localities of the brain with greater vulnerability such as the junction of grey and white matter. Myelination might provide some protective features and enhance recovery. The pathophysiological mechanisms involved in axonal damage also include swelling of intact axons and “retraction bulbs”.

Cytoskeletal Organization in Growth Cones versus Retraction Bulbs. (a) Growth cones display three distinct regions. The center (C-domain, grey stripped area) contains microtubules which emerge from the axonal shaft. In the periphery (P-domain, dark grey area), a dense network of actin filaments controls the progression of microtubule toward the axon tip and excludes vesicles and organelles from the P-domain. This obstacle occurs at the border between the C-domains and the P-domains, the transition domain (T-domain, yellow arc).  (b) Regeneration failure is associated with the formation of a retraction bulb at the tip of the injured axon. The separation between C-domain, T-domain and P-domain is lost. In addition, microtubules are depolymerized to a large extent. The remaining ones are disorganized and do not reach the axon tip.

Axonal damage due to deafferentation interrupts established pathways and can cause focal and diffused injury immediately after or even after several years from the primary insult. The extent of deafferentation in mild to severe injuries and axonal damage impacts the ability of synaptic sprouting of undamaged axons. The more severe the injury with extensive secondary damage, the less possible axonal reconnection and function recovery. 

Diffuse Axonal Injury

The primary insult of axonal injury leads to disconnection and/or neuron connections malfunction resulting in functional areas impairment. Mechanically disrupted axons present cytoskeletons malfunction resulting in proteolysis, swelling, and other microscopic and molecular changes to the neuronal structure. Neurological presentation of Diffuse Axonal Injury includes bilateral neurological examination deficits frequently affecting the frontal and temporal white matter, corpus callosum, and brainstem. 

The Adams Diffuse Axonal Injury Classification:

Grade 1:

A mild diffuse axonal injury with microscopic white matter changes in the cerebral cortex, corpus callosum, and brainstem

Grade 2

A moderate diffuse axonal injury with gross focal lesions in the corpus callosum

Grade 3

A severe diffuse axonal injury with finding as Grade 2 and additional focal lesions in the brainstem.

The Diffuse Axonal Injury is a severe form of brain injury and is usually diagnosed after a traumatic brain injury with Glasgow Coma Scale (GCS) < 8 for more than six consecutive hours. Diffuse Axonal Injury features in Computed Tomography (CT) and present as small punctate haemorrhages to white matter. However, CT Head has a low yield in detecting Diffuse Axonal Injuries and Magnetic Resonance Imaging (MRI), specifically Diffuse Tensor Imaging (DTI), is the imaging modality of choice for diagnosis of diffuse axonal injury.