CH29- Pathogen CNS

Question 1

• What is gray matter? What is white matter? (402)

Answer 1

• Gray matter- high density of neuronal cell bodies;
• Spinal cord = butterfly in the middle (LMN cell bodies and sensory neurons)
• Brainstem = scattered nuclei
• Brain/cerebellum = external layer
• White matter- axons and associated glial cells
• Spinal cord = funiculi (ascending sensory fibers and descending motor)
• Brainstem = intervening tracts
• Brain/cerebellum = internal layer

Question 2

• What are white matter compartments called to within the spinal cord? (402)

Answer 2

• Funiculi

Question 3

• Describe the flow of CSF, and where (3) are obstructions most common to occur?

Answer 3

• Lateral ventricles -> interventricular foramina -> third ventricle -> mesencephalic aqueduct -> fourth ventricle (ventral to cerebellum) -> EITHER lateral apertures to the subarachnoid space OR continues caudally through central canal
• Interventricular foramina, mesencephalic aqueduct, and lateral apertures are narrowed, obstruct easily

Question 4

• What are the 3 layers of the meninges - PAD

Answer 4

• Pia matter - intimate contact with neuronal tissue
• Arachnoid - close contact with the dura
• Dura matter - outer most layer

Question 5

• Name the spaces in between the meninges and what they contain (3)

Answer 5

• Subarachnoid space - contains CSF
• Between arachnoid and pia matter
• Subdural space - contains blood vessels
• Between the dura and arachnoid
• Epidural space - fat-filled space between the spinal cord and vertebral column
• ONLY IN SPINAL CORD

Question 6

• Name the structures that (1) separate the cerebral hemispheres and (1) separate the cerebellum from cerebrum

Answer 6

• Falx cerebri
• Tentorium cerebellum

Question 7

• Name the 3 types of brain herniation:

Answer 7

• Caudally and ventral -> tentorium (ie caudal transtentorial)
• Caudal -> foramen magnum
• Laterally -> ventral to the falx cerebri (rare)

Question 8

• Name the connective tissue layers surrounding the spinal cord and associated potential spaces:

Answer 8

• Pia mater (intimate contact with neural tissue)
• Arachnoid mater (close contact with outer dura)
• Dura mater (outermost, fused with periosteum of skull)
• *Leptomeninges = pia + arachnoid
• *Pachymeninges = dura + arachnoid
• Spaces:
• Subarachnoid = between arachnoid and pia, contains CSF
• Subdural - between dura and arachnoid, where blood vessels pass (potential space)
• Epidural space - surrounding dura mater in vertebral column, fat filled. NOT present in skull

Question 9

• What is the main mode of dysfunction in the brain? Spinal cord?

Answer 9

• Brain = increased pressure that causes herniation
• Spinal cord = compression

Question 10

• How is an axon potential generated?

Answer 10

• APs arise at the axon hillock, excitatory/inhibitory impulses generated by afferent input to the neuron are integrated; sum of them sufficient to cause depolarization = ALL OR NOTHING
• Signals cause voltage gated Na channels to open
• Influx of Na ions through voltage gated Na channels = depolarization
• Membrane repolarized -> closure of Na channels and efflux of K through open K channels
• Resting membrane restored
• Na actively extruded from cell in exchange for K, and K uptake performed by astrocytes
• Resting membrane potential is -80mV

Question 11

• What are 4 components to successful conduction of APs?

Answer 11

• Na-K ATPases
• Appropriate intra/extracell ion concentrations
• Ion channel function
• Myelin
• *impairment of any of these = impairment of impulse conduction

Question 12

• What are the components of a neuron? What is myelin?

Answer 12

• Myelin: fatty envelope produced by oligodendrocytes which allow for fast conduction because the APs move in a saltatory manner from one node to the next (nodes are interruptions in the sheath)

Question 13

• What systemic blood pressures can CNS successfully autoregulate and how? (404)

Answer 13

• Autoregulation (constant CPP) b/w MAP 50-160 mmHg.
• Vasodilation during hypotension
• Vasoconstriction during hypertension

Question 14

• What cells affect metabolic autoregulation in CNS?

Answer 14

• Astrocytes - they detect changes in the chemical milieu and change the BF with the connections to vessels in their feet
• Discuss this image Autoregulation of Blood Flow As PaCO2 increases the arterial vessels dilate causing increase perfusion and the venules constrict. The same response occurs when PaO2 declines below 50 mmHg. This maintains a blood pressure between 50-160 mmHg. As MAP increases the arterioles constrict and the venules dilate to maintain constant pressure and perfusion.

Question 15

• How does PaCO2 affect CBF?

Answer 15

• Hypercapnia (increase PaCO2) = vasodilation = increased perfusion
• Hypocapnia (decrease PaCO2) = vasoconstriction = decreased perfusion
• 1 mmHg change in PaCO2 causes a 5% change in perfusion

Question 16

• How does PaO2 affect CBF?

Answer 16

• Less sensitive to PaO2
• PaO2 < 50mmHg blood flow will markedly increase

Question 17

• How do blood gases affect cerebral perfusion?

Answer 17

• Linear CBF/PaCO2 relationship b/w PaCO2 20-60 mmHg - vasodilation w/ incr PaCO2, vasoconstriction w/ decr PaCO2
• 1 mmHG change in PaCO2 leads to 5% change in cerebral perfusion
• If PaO2 < 50 mmHg than CNS perfusion markedly increased -> PaCO2 more important than PaO2 for CPP changes/autoregulation

Question 18

• Explain how CBF can become dysfunctional in brain injury that causes decreased respiratory drive. How about with increased respiratory drive?

Answer 18

• Brain injury = decreased respiratory drive = HYPERcapnia (increased PaCO2) -> vasodilation -> Increased CBF -> increased pressure and volume -> Increased volume and pressure ->herniation
• Brain injury = increased respiratory drive -> decreased PaCO2 < 25 -> vasoconstriction -> possible ischemia
• Brain injury -> reduced ventilation, increased PaCO2 = increased perfusion following vasodilation of cerebral vessels, increased intracranial volume = increased pressure = increased risk of herniation

Question 19

• What is Cerebral Perfusion Pressure (CPP) equation?

Answer 19

• CPP = MAP - ICP (mean arterial pressure - Intracranial pressure)
• Increase in ICP or decrease in MAP impairs CPP

Question 20

• What is the Cerebral Ischemic Response?

Answer 20

• If there is a decrease in MAP (hypotension) or increase in ICP then the CPP decreases causing ischemia in the brain. The body’s response is massive vasoconstriction (increase vasomotor tone) to increase MAP causing decreased blood flow to other organs such as the kidneys.

Question 21

• What is Cushing’s Response?

Answer 21

• When there is a decrease in CPP causing massive vasoconstriction the result is hypertension. As a response to hypertension the baroreceptors will be activated causing reflex bradycardia.
• Cushings = hypertension + bradycardia

Question 22

• What is brain-heart syndrome? 405

Answer 22

• If CPP drops and is not compensated by vasoconstriction then there is a massive catecholamine release (up to 1000 fold) which can result in myocardial ischemia and ventricular arrhythmias.

Question 23

• What part of the brain sustains ischemic injury to lead to the massive increase in systemic vasomotor tone, and what is this reflex called?

Answer 23

• Marked hypotension OR elevation in ICP -> reduction CPP enough to cause ischemic injury to neurons in medulla
• CPP = MAP - ICP
• Cushings reflex - ischemia to medulla, low CPP -> systemic vasoconstriction -> hypertension -> baroreceptors cause reflex bradycardia

Question 24

• Which cell is responsible for metabolic autoregulation?

Answer 24

• Astrocytes- foot processes in chemical milieu, large number of signalling molecules -> dilation and constriction of pressure likely mediated via relaxing factor and endothelin (endothelial derived factors)

Question 25

• What is normal value for ICP? When should you treat?

Answer 25

• ICP = 8-15 mmHg • Treat at ICP > 15mmhg - 20mmhg

Question 26

• List 3 mechanisms that are meant to accommodate increased intracranial volume?

Answer 26

• Move CSF to subarachnoid space • Reduction of CSF production • Decreased cerebral blood flow

Question 27

• Describe this image

Answer 27

• This is the ICP and volume relationship. As the volume increases by increased CSF or vasodilation causing increase CBF the brain can compensate by 3 mechanisms (moving CSF, decreasing CSF production and decreasing CBF). At a certain volume the mechanisms are overwhelmed and small increases in volume become large increases in ICP and there is a risk of herniation.

Question 28

• What can happen with gradual increases in ICP? What are the clinical signs? 405

Answer 28

• Transtentorial herniation and foramen magnum herniation • No clinical signs (if slow/chronic enough)

Question 29

• What surgical mechanisms decrease ICP? How much decrease in %?

Answer 29

• Durotomy = 65% • Craniotomy = 15%

Question 30

• What are the components of the BBB? (5)

Answer 30

• Tight junctions between endothelial cells, • astrocyte foot processes, • basal lamina • pericytes • perivascular microglia

Question 31

• What 2 structures within the CNS do not have a BBB, and therefore may undergo similar inflammatory processes as peripheral tissues?

Answer 31

• Meninges • Choroid plexus

Question 32

• What is the blood-csf barrier and where is it located? 405

Answer 32

• Barrier formed between the choroid and the blood vessels at the choroid plexus.

Question 33

• *What antibiotics can move through the BBB? 406

Answer 33

• Minimal Drugs Rapidly Find My CNS Space • Minocycline • Doxycycline • Rifampin • Fluoroquinolones • Metronidazole • Chloramphenical • Sulfas/TMS

Question 34

• Which two zones of the brain contain neural stem cells?

Answer 34

• Subventricular zone/olfactory system • Dentate gyrus of hippocampus

Question 35

• What are the 6 lesion categories that can occur in the CNS (407)

Answer 35

• Contusion • Compression • Inflammation • Vascular • Metabolic/toxic • Degenerative

Question 36

* What are the primary injuries (ie describe focal vs dynamic vs diffuse injuries) that occur in Contusion - brain and spinal cord (407)

Answer 36

Brain * Focal injury -> static loading * Dynamic injury -> impact causing the brain to move within the calvarium * Diffuse brain injury --> Widespread damage to gray and white matter caused by swelling, hypoxia and diffuse axonal injury (caused by damage to the cell membrane and influx of Na) = Leads to coma and death Spinal Cord * Ranges in severity from IVDD to transection

Question 37

• When does most cell necrosis occur (407)

Answer 37

• Within 24 hours of injury but can last weeks

Question 38

• What causes the secondary events to be set in motion in Contusion?

Answer 38

• Direct injury to neuronal, axonal and glial cell membranes and blood vessels

Question 39

• What are the secondary injury mechanisms in Contusion (407-410)

Answer 39

• Upregulation of genes causes ongoing hemorrhage • Decreased perfusion of area = reduced energy to cells • Increased cell permeability • Cytotoxic edema • Influx of Na, Ca and Cl causing cell to swell • Excitotoxicity • Increased neuronal release of glutamate and aspartate and decreased uptake by astrocytes causes increase Na and Ca uptake into the cell causing neuron and oligodendrocyte death • Increases intracellular calcium • Increased in mitochondrial membrane permeability causes intracellular changes • Decreased perfusion • Inflammatory response in the tissue

Question 40

• What substrates lead to elevated Na and Ca intracellularly, leading to neuron/oligodendrocyte death?

Answer 40

• Glutamate and aspartate (lesser extent)

Question 41

• Injury to what cell leads to elevated extracellular levels of glutamate?

Answer 41

• Astrocytes • Traumatic injury initiates a series of biochemical and metabolic changes leading to neuronal and glial cell injury. Over what time course does most cell necrosis occur after traumatic injury, and over what time does apoptotic cell death continue for? • 24 hours - necrosis • Weeks - apoptosis • Mitochondrial membranes become permeable after ischemic injury which leads to what 3 consequences? • Release of pro-apoptotic factors -> also activate caspase cascade • Reduces energy production • Escape of free radicals into cytosol = further membrane damage -> progressive ischemia

Question 42

• List 6 consequences of decreased perfusion to an injured region of CNS.

Answer 42

• Mechanical damage to vasculature • Free radical damage to vasculature • Increased expression of TRMP4 -> transient membrane protein involved in ongoing hemorrhage. • Increased parenchymal pressure due to edema • Vasospasm (from increased intracellular Ca) • Release of vasoactive chemicals

Question 43

• List 3 consequences of elevated intracellular Ca (secondary to glutamate effect on several receptors following tissue injury)

Answer 43

• Activates proteases intracellular ie calpains and caspases, initiates programmed cell death • Activates phospholipase A2 -> generates eicosanoids, = initiates inflammatory response • Binds intracell phosphates = further depletion of energy

Question 44

• Describe the inflammatory response initiated by contusion (410)

Answer 44

• Injury causes MMP 9 release which initiates inflammatory response • Hours • Microglial cells -> Release IL-1 and TNF-a and toxic chemicals • Influx of neutrophils • 5-7 days • Influx of macrophages • Secondary demyelination and loss of axons

Question 45

• Define CIDS and why it may be important in treatment of acute spinal injury (410)

Answer 45

• CNS injury induced immunodepression • Circulating lymphs/macs depressed for several days after acute spinal cord injury; lymph function depressed for several months • Associated with elevations in serum ACTH, catecholamines, and elevated urine cortisol • May not want to use corticosteroids due to immunosuppression

Question 46

• What components lead to clinical signs associated with compression of CNS?

Answer 46

• Demyelination* • Prominent feature, particularly in chronic compression -> v sensitive to excitotoxic effects of glutamate, also have high energy requirements to maintain myelin and ischemia may lead to death • Edema • Axonal degeneration • Neuronal necrosis

Question 47

• What type of edema is associated with compression and why? How is it treated?

Answer 47

• Vasogenic, due to obstruction of venous drainage and changes in blood vessel permeability • *anti-inflammatory dose of steroids may be helpful in reducing VASOGENIC edema (not indicated for use in other types of edema) and can dramatically improve CS

Question 48

• What occurs in chronic compression (410)

Answer 48

• Necrosis and apoptosis of glial cells (oligodendrocytes and astrocytes), neurons and axons • Excitotoxicity from excess glutamate and decrease astrocyte uptake • Demyelination because oligodendrocytes are dying from ischemia leads to exposure of channels along the axon resulting in blockage of AP

Question 49

• What are 2 reasons for rapid improvement following surgical decompression, and 2 sources of clinical deterioration following surgical decompression?

Answer 49

• Relief of physical deformation, and rapid increase in blood flow • Sx iatrogenic injury, reperfusion injury

Question 50

• What are the physical causes (2) of vascular obstruction in the CNS? (412)

Answer 50

• Local formation of a thrombus • Embolization

Question 51

* What is the injury to the CNS with vascular occlusion? (412)

Answer 51

* Ischemia or infarct= Causes lack of energy, same secondary consequences as contusion * Increased cell permeability = Cytotoxic edema = Influx of Na, Ca and Cl causing cell to swell = Excitotoxicity * Increased neuronal release of glutamate and aspartate and decreased uptake by astrocytes = increase Na and Ca uptake into the cell causing neuron and oligodendrocyte death * Increases intracellular calcium * Increased in mitochondrial membrane permeability causes intracellular changes * Decreased perfusion, Inflammatory response in the tissue

Question 52

• List 3 most common sources of vascular occlusion injury in dogs and cats?

Answer 52

• FCE (dogs) • Feline ischemic encephalopathy (Cats) • Cuterebra that release vasoactive toxins that cause cerebral vessel spasm • Thrombotic stroke (dogs)

Question 53

• List 5 regions where hemorrhage may occur in the brain/spinal cord.

Answer 53

• Extradural • Subdural • Subarachnoid • Intraventricular • Intraparenchymal

Question 54

• What are the consequences of hemorrhage in the CNS? (412)

Answer 54

• Decreased perfusion = decreased energy • Compression • Vasospasm • Inflammation • Secondary response to decreased energy as described in contusion • Hemoglobin released into the tissues produces free radicals causing damage to vascular, glial and neuronal cells

Question 55

• List the primary causes (6) of hemorrhage. (412)

Answer 55

• Neoplasia • Bleeding disorder • Congenital malformations • Trauma • Hypertension (Cats) • Vasculitis

Question 56

• How can an immune response occur in the CNS without a break in BBB? (412)

Answer 56

• Activated lymphocytes can cross BBB

Question 57

• How does inflammation cause dysfunction of the CNS? (412)

Answer 57

• Inflammatory mediators directly affect neuronal cells • NO, leukotrienes and prostanoids have an effect on microcirculation, integrity of BBB and compromise neural function • Activation of microglia results in release of products that affect a variety of cells • Cytokines affect conduction of the nerve cells and astrocytes causing imbalance in homeostasis Congenital Malformations

Question 58

• List 5 congenital malformations that cause injury to the CNS (413)

Answer 58

• Hemivertebrae -> compression • Primary malformation of CNS • Malformation of mesencephalic aqueduct -> increased ICP and obstructive hydrocephalus • Myelodysplasia ->failure of fusion of midline of spinal cord leading to disruption in circuitry • Abnormal neuronal death -> cerebellar hypoplasia, degenerative myelopathy • Degenerative disease -> ion channelopathies, abnormal protein aggregation, lysosomal storage disease

Question 59

• List 4 types of metabolic/toxic disease processes and how they cause damage to CNS.

Answer 59

• Hepatic encephalopathy -> neurotoxins and imbalance of excitatory and inhibitory neurotransmitters • Uremic encephalopathy -> changes in BP and neurotoxins • Insulinoma -> hypoglycemia • PSS ligation -> can lead to seizures

Question 60

• What are the direct and indirect categories of injury caused by neoplasia? (413)

Answer 60

• Direct -> infiltration and necrosis • Indirect -> compression, damage to blood supply and decrease perfusion

Question 61

• Dysfunction from neoplasms within CNS are result of what? (list 4)

Answer 61

• invasion/destruction of tissues • Vascular compromise • compression • Vasogenic edema

Question 62

• Which non-primary neoplasm is associated with sensory neuropathy in dogs? (413)

Answer 62

• Pancreatic beta cell neoplasia

Question 63

* What are 3 types of edema found in the CNS and where? What injury is each edema associated with? 413

Answer 63

Cytotoxic * BBB intact * Failure of ion channels causes influx of Na and H2O into the cell causing it to swell * Associated with ischemia and hypoxia * Diseases: contusion, vascular, metabolic/toxic, seizures * Most commonly occurs in astrocytes * Treat underlying cause Vasogenic * Caused by leaky blood vessels causing accumulation of extracellular fluid * Found in white matter * Causes: contusion, inflammatory, vascular and compressive, neoplasia * Treatment: corticosteroids for peritumoral edema Interstitial * Extracellular edema caused by abnormal flow of CSF through the CNS causing elevated intraventricular pressure = hydrocephalus

Question 64

* What are the 3 types of IVDD? What are the most common breeds? What is the injury related to each? (414)

Answer 64

Hansen 1 * Chondroid degeneration causes mineralization of disc -> extrusion into canal * Chondrodystrophic breeds (daschund, frenchie, cocker, lab, doberman, chow) * Contusion and compression * Young: 5-8 yrs Hansen 2 * Dehydration and fibrosis (fibrous degeneration) of nucleus resulting in bulging of annulus into canal -> protrusion * Contusion and compression * Large non-chondrodystrophic breeds: GSD, Doberman, Chihuahua, yorkie, maltese * Older dogs Type 3 - Acute Noncompressive Nucleus Pulposus Disc Extrusion (ANNPE) * Peracute rupture of the annulus with spread of normal nucleus propulsus * Athletic dogs * Tearing of the dura, hemorrhage, malacia

Question 65

• What are 2 types of injury sustained to spinal cord following NP extrusion, type 2 IVDD?

Answer 65

• Compression, contusion • Contusion likely more impt

Question 66

• What type of injury sustained to spinal cord following type 1 IVDD?

Answer 66

• Compression

Question 67

• What is hydrocephalus, hydromyelia and syringomyelia? (415)

Answer 67

• Hydrocephalus -> fluid accumulation in ventricles • Hydromyelia -> fluid accumulation in the central canal of the spinal cord • Syringomyelia -> fluid accumulation in the tissue of the spinal cord

Question 68

* What occurs in recovery phase following CNS injury (4)

Answer 68

* Plastic alterations in circuitry due to Synaptic plasticity * Collateral sprouting and synaptogenesis * Behavior change * Ie: spinal walking, adapt pattern of motor activation to achieve goal directed behavior

Question 69

• What is synaptic plasticity?

Answer 69

• Alteration in synapses within the brain, occurring continuously in response to variation of nature of the input • Ie- upregulation of NT receptors = heighted cell response to that = “supersensitivity” • Change TYPE of postsynaptic receptor • Change reliability of transmission • “Gain of response” in post synaptic cells • Convert silent synapse -> active ones (less common)