Chapter 29: Pathogenesis and Physiology of CNS injury Flashcards
Descirbe the distribution of the grey matter in the spinal cord, brainstem and cerebral cortex
Spinal cord: butterfly shape in the central cord, divivding the surrounding white matter into funiculi
Brainstem: forms scattered nuclei with intervening tracts of white matter
Cerebral cortex: External layer of grey matter with white matter underneath connecting the cortex to other regions of the CNS
What is grey matter and white matter?
Grey matter: high density of neuronal cell bodies
White matter: Axons and associated glial cells
Describe the ventricles of the CNS:
Where is CSF produced and how does it flow through the brain?
One lateral ventricle within each hemisphere
Third ventricle within diencephalon
Fourth ventricle ventral to the cerebellum
CSF is formed within ventricles via the choroid plexus
- Flows from lateral ventricles, through interventricular foramina into 3rd, through mesencephalic aqueduct into 4th and then through lateral apertures into subarachnoid space or continues caudally into central canal
What are the leptomeninges?
Arachnoid mater and pia mater
What are the pachymeninges?
Dura mater and arachnoid mater
What are the two forms of brain herniation?
Transtentorial
Foramen magnum
What is the normal resting potential of neuronal cell membranes?
-80mV (inside of cell negative with respect to the outside)
How are action potentials generated?
Rapid depolarization of the membrane due to an influx of Na through voltage-gated Na-channels
- Electrolyte concentrations are returned to resting levels by active extrusion of Na from the cell in exchange for K, and K uptake by astrocytes
What cell produces myelin?
Oligodendrocytes
What is required for maintenance of a resting potential and generation/conduction of action potentials?
- Energy (Na-K/ATPase)
- Appropriate intra- and extracellular electrolyte concentrations
- Ion channel function
- Myelin
What are the 2 forms of CNS perfusion autoregulation?
Pressure autoregulation: remains constant with MAP between 50-160mmHg via vasodilation during hypotension and vasoconstriction during hypertension
Metabolic autoregulation: astrocytes match blood flow to neuronal activity (NO, CO, K, adenosine, glutamate, arachidonic acid)
How does PaCO2 alter CNS perfusion?
Very sensitive!
- Hypercapnia increases perfusion
- Hypocapnia decreases perfusion
- For every 1mmHg change in PaCO2, there is a 5% change in cerebral perfusion
- PaCO2 < 25mmHg causes severe hypoperfusion and potential ischemia
How is cerebral perfusion pressure defined?
CPP = Mean arterial blood pressure (MAP) - intracranial pressure (ICP)
Reduction in MAP or increase in ICP can therefore impair cerebral perfusion
What is normal intracranial pressure?
8-15mmHg
- > 15mmHg requires treatment, > 30mmHg causes significant reduction in cerebral perfusion*
What are some mechanisms for accomodating for gradual increases in intracranial volume?
- Moving CSF into subarachnoid space
- Reducing CSF production
- Decreasing cerebral bloodflow
How much is ICP decreased by a craniotomy? and by adding a durotomy?
Craniotomy alone 15%
+ Durotomy 65%
What forms the blood-brain barrier?
Endothelial cell tight junctions
Astrocyte foot processes
Basal lamina
Pericytes
Perivascular microglia
What antibiotics have good penetration of the blood brain barrier?
Timid DOgs Rarely MElt CHeese (For 3 Cents)
Why is the CNS said to be ‘immunologically privileged”?
- Relatively isolated from the immune system by the BBB
- Immunosuppresive parenchymal environment
- Poorly developed lymphatic drainage
(meninges and choroid lack BBB and can get inflamed)
What protective immunologic mechanisms limits entry of pathogens and other exogenous material into the CNS?
- Expression of major histocompatibility complex molecules and coexpression of costimulatory molecules (B7) are necessary for cells to act as antigen-presenting cells. Endothelial cells do not express these.
- Cell adhesion molecules are expressed only at low levels on endothelial cells (can be rapidly upregulated)
What are the resident immune and phagocytic cells of the CNS?
Microglial cells
Where are the 2 stem cell populations within the CNS?
- Subventricular zone/olfactory system
- Dentate gyrus of the hippocampus
What are the main categories of CNS injury?
- Contusion
- Compression
- Inflammation
- Vascular
- Metabolic/toxic
- Degenerative
What causes diffuse brain injury?
Widespread damage to white and/or grey matter caused by brain swelling, hypoxia and diffuse axonal injury.
DIffuse axonal injury results from inertial forces causing membrane damage to axona, allowing unregulated Na entry and depolarization, initiating secondary effects
What is the broad definition of secondary neural injury?
A series of metabolic and biomechanical changes that cause neuronal and glial cell death.
What gene is upregulated in secondary neural injury and plays a central role in ongoing hemorrhage?
- Trmp4 (transient membrane potential)
List the mechanisms by which contusion causes secondary injury:
- Decreased perfusion -> decreased energy to cells -> Ion pump failure (increased intracellular Ca, Na, Cl causing swelling)
- Mechanical damage to neurons -> increased release and decreased astrocytic uptake of glutamate. Glutamate interaction with NMDA and AMPA receptors cause rapid increases in intracellular Na and Ca (more gradually)
- Mitochondrial membranes become permeable due to ischemia and apoptosis-inducing factor is released as well as free radicals and further decreases energy production
- Rapidly initiates a inflammatory response with initial influx of neutrophils and peak macrophages in 5-7days which coincides with demyelination
What is the result of increased intracellular Ca?
- Activates intracellular proteases (calpains, caspase), which destroy the cytoskeleton and initiate programmed cell death
- Activates phospholipase A2, initiating an inflammatory response
- Binds intracellular phosphates, further depleting energy sources
What cytokines and toxic chemicals are released by microglial cells after injury?
- Cytokines: IL-1, TNF-a
- Chemicals - H2O2, NO, proteinases
How does CNS injury effect an animal’s susceptibility to infection?
- Circulating lymphocyte and monocyte numbers are depressed for several days
- Lymphocyte function is depressed for several months after spinal cord injury and stroke.
What are the pathologic changes associated with compression?
- Demyelination
- Edema
- Axonal degeneration
- Neuronal necrosis (oligodendrocytes, astrocytes, neurons and axona)
What are the main forms for disease causing vascular obstructive lesions?
- FCE
- Feline ischaemia encephalopathy (FIE)
- Thrombotic “stroke” in dogs
What are the 5 broad localizations of CNS hemorrhage?
- Extradural
- subdural
- subarachnoid
- intraventricular
- intraparenchymal
Secondary injury due to compression and also similarly to contusion due to decreased energy supply
How does the inflammatory response cause CNS dysfunction?
- Inflammatory mediators can directly affect neural function
- Nitric oxide, leukotrienes and prostanoids have profound effects on the microcirculation and the integrity of the BBB
What substance is a powerful blocker of conduction?
Nitrous oxide
List some metabolic diseases of the CNS
- Hypoglycemia secondary to insulinoma
- Hepatic encephalopathy
- Uremic encephalopathy
- PANS (post-attenuation neuro signs in PSS)
What are the most common neoplasms to metastasize to the brain?
- Hemangiosarcoma
- melanoma
- carcinoma
What is the difference between cytotoxic edema, vasogenic edema and interstitial edema?
- Cytotoxic edema - intracellular swelling in the presence of a normal BBB as a result of ion pump failure
- Vasogenic edema - Increased vascular permeability causing the accumulation of extracellular fluid, particularly within the white matter tracts
- Interstitial edema - Abnormal flow of CSF through the CNS associated with elevated intraventricular pressure
What is Hansen Type 1 disc degeneration?
Progressive decrease in proteoglycan content of the nucleus pulposus with consequent dehydration and mineralization. Leads to loss of ability to withstand pressure and causes secondary degeneration and tearing of the annulus
What is Hansen Type II disc degeneration?
Progressive dehydration of the nucleus and replacement with fibrinoid tissue leading to an increase in stress transfer to the annulus. Annulus undergoes wear-and-tear degeneration with rupture of fibers over months-to-years and progressive protrusion
Which cells of the CNS can be regenerated readily?
Glial cells (astrocytes and oligodendrocytes)
For unknown reasons, remyelination does not always occur spontaneously
Define hydrocephalus, hydromyelia
and syringomyelia.
What cause syringomyelia?
Hydrocephalus - accumulation of fluid within the ventricles
Hydromyelia - fluid within the central canal
Syringomyelia - within the parenchyma of the spinal cord. Caused by diseases which alter the CSF flow such as arachnoiditis, Chiari-like malformation and elevated ICP
What is synaptic plasticity?
Alteration in synapses within the brain in response to variation in the nature of their input.
- upregulation of neurotransmitter receptors
- alterations in type of postsynaptic receptors and in reliability of transmission
- Can change the types of ion channels expressed
- Formation of new synapses - may be influenced by rehab
What is collateral sprouting?
A repair mechanism where a partially denervated cell will become reinnervated by branches from a functioning nerve
How can fasting aid in CNS recovery?
Reduced caloric intake is associated with
- reduction in reactive oxygen species and lipid peroxidation
- Increase in neuroprotective molecules such as BHB and antiapoptotic proteins
