Applied Pathophysiology: Mechanisms of Disease

Applied Pathophysiology: A Conceptual Approach to the Mechanisms of Disease

• This lecture series covers the mechanisms of disease in the nervous system.
• Specific topics within this series are alterations of neuronal transmission, alterations in CNS functions, and alterations in PNS functions.

Processes of Neuronal Injury

• Mature neurons do not divide. New neurons do not replace damaged neurons.
• Loss of neurons leads to impaired neurologic transmission.
• Impaired neurologic transmission leads to neurologic disorders.
• Cell damage can occur from aging, injury site, and functions under control.
• Manifestations reflect the site of injury.

Result of Injury at the Cellular Level

• Chromatolysis is part of apoptosis; it involves the swelling of a neuron and the dissolution of chromophil substance in neurons.
• This can happen in certain pathological conditions or following injury to a neuron or its axon.
• Atrophy is the decrease of cell size.
• Neuronophagia is the process of phagocytosis and inflammatory responses caused by a dead neuron damaging neighboring cells.
• Intraneuronal inclusions are distinctive structures formed in the nucleus or cytoplasm of a neuron.

Neuronal Injury

• The response to injury depends on the specific cell type involved and mirrors the cell's properties.
• Injury responses of support cells often involve astrogliosis, a process where astrocytes proliferate in response to local tissue injury which forms a glial scar.
• Uncontrolled astrogliosis can lead to tumors such as gliomas, which are types of brain cancer.
• Microglia, an immune response cell, also respond to injury through reactive changes, expanding their nucleus to form "rod cells" and join with astrocytes to produce microglial nodules.
• Ependymal damage in the central nervous system can result from infection or hemorrhage in ventricles, and this can interfere with CSF production and transfer.
• Injury responses of neurons can involve neuropathy resulting from nerve damage or destruction that leads to muscle weakness and numbness.
• Axonal degeneration involves the breakdown of distal parts of the axons, which is caused by necrosis and leads to inflammatory responses that lead to phagocytosis of cell debris, removing dead material.
• Demyelination in neurons is caused by myelin damage causing nerve conduction interruption.
• Ependymal cell damage can cause issues with CSF (cerebrospinal fluid) alterations.

Central and Peripheral Nervous System Neuronal Injury

• Mechanisms of injury in the central nervous system (CNS) can include traumatic CNS injuries (e.g., traumatic brain injury (TBI), traumatic spinal cord injury (SCI)).
• Mechanisms of injury in the peripheral nervous system (PNS) can include traumatic peripheral nerve injuries.

Traumatic Central Nervous System Injury

• Impaired neurologic function can stem from local or systemic causes.
• Injury in a specific area produces a local effect, whereas injury affecting the regions responsible for integrating impulses to multiple distant sites causes a systemic effect.
• Causes of TBI include automobile accidents, falls, sports-related injuries, and shaken baby syndrome, which presents in two categories: closed and open traumatic injuries.

Traumatic Brain Injury: Closed Head Injury

• A coup injury refers to the acceleration injury when the brain moves inside the skull.
• A contrecoup injury refers to the deceleration injury from the brain striking the opposite side of the skull.

Traumatic Brain Injury: Lacerations and Contusions

• Brain tissue can be subject to contusions and lacerations as a result of forces caused by the head impact.

Traumatic Brain Injury: Open Traumatic Injury

• Injuries to central nervous system structures (meninges and brain) can be exposed during open traumatic injuries.
• There is a risk of infection.

Traumatic Brain Injury: (Diagnosis and Treatment)

• Diagnosing traumatic brain injuries involves imaging (CT, MRI), examining brain activity (EEG), performing lumbar punctures (spinal tap) to check for CSF and blood content (intracranial hemorrhage), and other procedures.
• Treatment for traumatic brain injuries focuses on specific injuries, including surgical removal of hematomas or foreign materials, reducing ICP, using pain control, administering anticonvulsant medications, providing respiratory support, and administering antibiotics for infection prevention.

Traumatic Spinal Cord Injury (SCI)

• Most common causes of SCI include fractures, contusions, spinal column compression (trauma to the head or neck), and pulling, twisting, or severing of the spinal cord tissue.
• SCI damage can manifest from mild paresthesia (abnormal sensations) to paralysis in all four extremities. The level and severity of the injury contribute to neurologic deficits.

Spinal Cord Injury: Diagnosis

• Diagnostic tools for SCI include X-rays for fractures, neurological examination to identify deficits, lumbar puncture to assess cerebrospinal fluid, and imaging methods (CT, MRI).

Spinal Cord Injury: Treatment

• Treatment often involves initial immobilization, followed by corticosteroid therapy to reduce inflammation. Further treatments such as traction and surgery may be undertaken.

Ischemic Central Nervous System Injury:

• Inadequate perfusion to the CNS causes tissue necrosis.
• Causes of ischemia include local ischemia (occlusion of blood supply by thrombus or embolus) and global ischemia (inadequate blood supply).
• Global ischemia leads to hypoxia, which can be triggered by cardiac arrest or severe hemorrhage.

Central Nervous System Pressure Injury

• Increased intracranial pressure (ICP) can result from excessive cerebrospinal fluid (CSF) volume, cerebral edema, or space-occupying lesions (tumors).
• Increased intracranial pressure (ICP) leads to reduced blood flow (ischemia), death of brain cells, and brain tissue damage.

Excitation Injury

• Neurons that easily depolarize or hyperpolarize can cause altered transmission and lead to excitation injury.
• The pathologic consequences of increasing impulse frequency, especially in intense excitation, lead to cascade effects involving glutamate (the main excitatory neurotransmitter).
• Prolonged action potentials may stimulate protein breakdown and formation of free radicals leading to DNA damage.
• This can lead to metabolic demand inability and tissue sensitivity to hypoxia, resulting in permanent damage to the hippocampus, cerebral cortex, and reduction in higher order cognitive (cognitive and memory) functions.

Peripheral Nervous System Injury

• Peripheral nerves are vulnerable due to the lack of protection compared to the CNS.
• Injury commonly results from trauma, pressure, or compression, leading to limited responses when compared to the CNS as nerves have limited regenerative capacity.

Traumatic Peripheral Nerve Injury

• Crushing or cutting a nerve causes the section of the severed nerve to degenerate (Wallerian degeneration).
• Traumatic injury can induce inflammatory processes. Also, Chromatolysis—the reaction of nerve cell bodies to damage—occurs in the neuron.
• The severity of the sensory symptoms can depend on the number of axons involved.
• Peripheral nerve regeneration is dependent on the level of injury, and a shorter injury has a better recovery prognosis than a longer injury.

Peripheral Nervous System Pressure Injury

• Nerve compression can result from edema in constricted spaces, such as carpal tunnel syndrome.
• Nerve trauma can contribute to edema impinging the nerve plexus and potentially lead to brachial plexus palsy.

Neuronal injury summarized

• Neuronal injury can be caused by a number of different mechanisms, such as trauma, ischemia, excitation, and pressure.
• The type of injury, its location, and the affected part of the nervous system (central or peripheral) determine the resultant manifestations including mental status alterations, impaired movement, sensor disorders, etc.