Ch 29 Pathophysiology of CNS dz and injury

Question 1

Descirbe the distribution of the grey matter in the spinal cord, brainstem and cerebral cortex

Answer 1

Spinal cord - butterfly shape in the central cord, divivding the surrounding white matter into funiculi

Brainstem - forms scattered nuclei with intervening tracts fo white matter

Cerebral cortex - external later of grey matter with white matter connecting the cortex to other regions of the CNS

Question 2

What is grey matter and white matter?

Answer 2

Grey matter - high density of neuronal cell bodies
cord: somatic & visceral LMN, sensory input from afferent fibers via dorsal roots

White matter - Axons and associated glial cells
carries ascending sensory & descending motor

Question 3

ventricles of the CNS

Answer 3

lateral ventricle > each hemisphere
Third ventricle > diencephalon
Fourth ventricle ventral to the cerebellum

CSF 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 aperatures into subarachnoid space or continues caudally into central canal

Question 4

Meninges – and space between

Answer 4

• Pia mater – intimate with neural tissue
• Arachnoid mater – in close contact with…
• Dura mater – outermost
   Spaces – subarachoid (has CSF); subdural (potential, has blood vessels); epidural (surrounds dura around cord; over brain dura fused to periosteum)

Question 5

tisue separting brain componeents?

Answer 5

• Falx cerebri – conn. tissue separates hemispheres
• Tentorium cerebelli – separates cerebellum from cerebrum
  o Both help minimize excess movement, skull protects

Question 6

Name the two forms of brain herniation

Answer 6

Transtentorial
Foramen magnum

Question 7

What is the normal resting potential of neuronal cell membranes?

Answer 7

-80mV (inside of cell negative with respect to the outside)

Question 8

How are action potentials generated?

Answer 8

Rapid depolarisation of the membrane due to an influx of Na through voltage-gated Na-channels
ELectrolyte oncentrations are returned to resting levels by active extrusion of Na from the cell in exchange for K, and K uptake by astrocytes

Question 9

What cell produces myelin?

Answer 9

Oligodendrocytes

fatty envelope – high resistance and low conductance; allows AP conduction in ‘saltatory’ manner, ie it ‘jumps’ node to node (gaps in the myelin)

Question 10

What is required for maintenance of a resting potential and generation/conduction of action potentials?

Answer 10

Energy (Na-K/ATPase)
Appropriate intra and extracellular electrolyte concentrations
Ion channel function
Myelin

Question 11

What are the 2 forms of CNS perfusion autoregulation?

mechanisms to protect CNS from fluctuations in BP, hypoxia, hypercapnia

Answer 11

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, arichadonic acid)

Question 12

How does PaCO2 alter CNS perfusion?

Answer 12

hypercapnia leads to increased CNS perfusion

Decreases during hypocapnia

For every 1mmHg change in PaCO2, there is a 5% change in cerebral perfusion

PaCO2 less than 25mmHg causes vasoconstriction and potential ischaemia

Question 13

CPP = MAP - ICP

Answer 13

Reduction in MAP or increase in ICP can therefore impair cerebral perfusion

marked hypotension or elevation in intracranial pressure may reduce cerebral perfusion enough to cause ischemia of neurons in the medulla

Question 14

cushings reflex

brain heart syndrome” profound catecholamine release

Answer 14

increased ICP reduce cerebral perfusion > ischemia of neurons in the medulla.

causes increase in systemic vasomotor tone > increase MAP and therefore CPP.

ensuing systemic hypertension activates baroreceptors, causing a reflex bradycardia (Cushing’s reflex)

also resuls in systemic vasoconstriction (can damage organs) The

Question 15

What is normal intracranial pressure?

Answer 15

8-15mmHg

Over 15 required treatment, over 30 causes significant reduction in cerebral perfusion

Question 16

What are some mechanisms for accomodating for gradual increases in intracranial volume?

Answer 16

Moving CSF into subarachnoid space
Reducing CSF production
Decreasing cerebral bloodflow

Question 17

How much is ICP decreased by a craniotomy and by a durotomy?

Answer 17

Craniotomy alone 15%
Durotomy 65%

Question 18

Question 19

What forms the blood-brain barrier?

Answer 19

Endothelial cell tight junctions
Astrocyte foot processes
Basal lamina
Pericytes
Perivascular microglia

electively permeable, and free diffusion dependent on lipid solubility, ionization, and size.

Meninges and choroid plexuses don’t have BBB so can see inflamm

Question 20

What ABx have good penetration of the BBB?

Answer 20

Question 21

Why is the CNS said to be ‘immunologically previledged”

Answer 21

Relatively isolated from the immune system by the BBB

Immunosuppresive parenchymal environment

Poorly developed lymphatic drainage

Microglial Cells = resident immune and phagocytic cells of CNS

Question 22

What protective immunologic mechanisms limits entry of pathogens and other exogenous material into the CNS?

Answer 22

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)

Perivascular macrophages and microglial cells DO express major histocompatibility complex and participate in the immune response

Question 23

What are the resident immune and phagocytic cells of the CNS?

Answer 23

Microglial cells

Question 24

Where are the 2 stem cell populations within the CNS?

Answer 24

Subventricular zone/olfacotry system
Dentate gyrus of the hippocampus

Question 25

categories of CNS injury? 6

Answer 25

Contusion
Compression
Inflammation
Vascular
Metabolic/toxic
Degenerative

Question 26

CONTUSION

Answer 26

Hansen type I intervertebral disc herniation

Vertebral fractures/luxations

Vertebral column instability

Impact to head

Extreme flexion/extension of vertebral column

Question 27

COMPRESSION

Answer 27

Neoplasia

Hansen type I and II intervertebral disc herniation

Vertebral fractures/luxations

Congenital vertebral column malformation

Degenerative vertebral column changes (e.g., cervical spondylomyelopathy)

Localized hemorrhage

Question 28

INFLAMMATION

Answer 28

Microbial infection

GME and necrotizing encephalitis

Contusion/vascular disease

Neoplasia

Question 29

VASCULAR

Answer 29

FCEM/FIE

Neoplasia

Contusion

Vasculitis

Bleeding disorder

Question 30

METABOLIC/TOXIC

METABOLIC/TOXIC

Answer 30

Hepatic encephalopathy

Hypoglycemia (beta islet cell neoplasm)

Uremic encephalopathy

Seizures post portosystemic shunt ligation

Question 31

DEGENERATIVE

Answer 31

Degenerative myelopathy

Cerebellar abiotrophy

Lysosomal storage diseases

Hypomyelinating/demyelinating diseases

Motor neuron diseases

Question 32

• Primary mechanical damage

Answer 32

mechanical damage form trauma results in contusion / compression/ shearing/ laceration

casues physcial disruption of cell membrane leadind to heamorrhage abd subseuquent ischaemia

results in neuron and glial cell injury

disc/haemoatoma/bone causes ongoing compression
- affects cord perfusion by limting arterial supply and venous drainage
- causes direct damage to myelin and axons

Question 33

sedondary injury (5)

vascular changes

Answer 33

traumatic and ischaemic injury initiates biomechancial and metabolic cahnges that end in nueron and glial cell death

vascular changes
1. damage blood vessels results in hameorrhage
3. haem products toxic to neurons = mass effec of heamorrhage increased interstital P and reduces perfusion
4. upregulation of gene Trpm4 invoved in sexondary vascula damge
5. reduced perfusion due to free radical damge’inc interstitial pressure dt cytotoxic and vasogenic oedema

Tx: hypotenision ad hypoxaemia
prompt decompression nay cuase reperfusion
experimental evidencec suggest prognsois imprvoed
compartent syndrome (swelling under meninges > consdier DUROTOMY

Question 34

excitotoxicity

Answer 34

Decreased perfusion and therefore energy to neurons and glial cells cause Ion pump failure (increased intracellular Ca, Na, Cl causing swelling)

decreased astrocytic uptake of glutamate. Glutamate interaction with NMDA and AMPA receptors cause rapid increases in intracellular Na and Ca

Na+ results in cytotoxic oedema
Ca2+ deplete energy > cell death

Tx: none proven

Question 35

free radiacal damage

Olby 2016 -

Answer 35

ROS produced by ischamic conditions / inc Ca2+ / haem/inflammation

lipid peroxidtaion of membrane causes death of -glial + neuron + endothial-

Ros peaks 12hr

Tx: methyl pred trials in dogs experimental failed to demonstrate effect
RCCT MPSS no benefit (olby 2016)

Question 36

inflammatory reaction

Answer 36

-microglial cells produce TNFa ad IL-1B
increase MMPs
reduce BBB, results in NO and recruit WBC (neutropils invade witin hrs)

macoiphages casue axon los ad demyelination

Tx: no evidece to use CCS

Question 37

apoptosis

Answer 37

neurons die by necrosis, difficutl to reverse ocne started
oligodendoryte death by apoptosis

contribute to demyelination and reduced FUNCTION

Question 38

secondary injury - chornic phase

Answer 38

axons try to regenerate
glial scar forms > worse if menignes disrupted and fibroblasts invade

inability dt poor intrinsic response (low cyclic AMP produced by mature neurons) and nonpermissve environment (myelin and astrocytes inihibit axon extension)

result: preistence pf demyelinated axons accross lesion site

Tx: no evidence for stem cell therapy

Question 39

How does CNS injury effect an animals susceptibility to infection?

Answer 39

Circulating lymphcyte ad monocyte numbers are depressed for several days
Lymphocyte function is depressed for several months after spinal cord injusry and stroke

Question 40

What are the pathologic changes associated with compression?

Answer 40

Demyelination
Oedema
Axonal degeneration
Neuronal necrosis (oligodendrocytes, astrocytes, neurons and axona)

Question 41

White mater tracts (UMN)

Answer 41

Ascending sensory
- cell body in dorsal root
- prorioception (fascicilus)
- superfiical pain (spinothalamic) myelinated fibres
-deep/nocieption (propriospinal) non-myelinated, close to grey matter
bladder filling (spinothalamic)

descending motor
- VMF (corticospinal + reticulospinal)
- fine motor control (rubrospinal)
- posture/balance (vestibulosponal)
voluntary bladder empty (reticulospinal)

Question 41

effects of compression

Answer 41

White matter tracts
- proprioception largest and myelinated
- motor middle size and myelinated
- pain sensation smallest and non-myelinated

large diameter fibre increased susceptible to injury, smaller more resistant
progression of CS with severity of cord damage explained by this as well as position of the tracts
> proprioception more superficial and ore susceptible to compression
> deep pain more deeply positioned

therefore, lesion must inovlve most of diameter of spinal cord for patient to lose deep pain
> as pain fibres also more resistantm loss of deep pain is a sign of lesion severity

Question 42

LMN

Answer 42

LMN (reflex arc) cell body lies within the ventral horn of gray matter

Question 43

What are the main forms for disease causing vascular obstructive lesions?

Answer 43

FCE
Feline ischaemia encephalopathy (FIE)
Thrombotic “stroke” in dogs

• Gray matter affected more than white matter
• Energy failure causes secondary injury to happen

Question 44

What are the 5 broad localisations of CNS haemorrhage?

Answer 44

Extradural
subdural
subarachnoid
intraventricular
intraparenchymal

Secondary injusy due to compression and also similarly to contusion due to decreased energy supply

Question 45

How does the inflammatory response cause CNS dysfunction?

meningitis, myelitis

Answer 45

Inflammatory mediators can directly affect neural function

NO, leukotrienes and prostanoids have profound effects on the microcirculation and the integrity of the BBB

Question 46

List some metabolic diseases of the CNS

Answer 46

Hypoglycaemia secondary to insulinoma
Hepatic encephalopathy
Uraemic encephalopsthy
PANS

Question 47

• Malformations usually lead to compression injuries

Question 48

What are the most common neoplasms to metastasise to the brain?

Answer 48

HSA
melanoma
carcinoma

Question 49

primary neoplasia

Answer 49

parenchyma itself (gliomas)

Tissues surrounding the central nervous system (e.g., meningiomas, sarcomas, round cell neoplasms)

infiltration and necrosis of adjacent normal tissue or by indirect effects through compression and damage to the blood supply

Neurologic dysfunction results from compression, vasogenic edema, invasion and destruction of tissue, and vascular compromise.

Question 50

What is the difference between cytotoxic oedema, vasogenic oedema and interstitial oedema?

Answer 50

Cytotoxic oedema - intracellular swelling in the presence of a normal BBB as a result of ion pump failure
Vasogenic oedema - Increased vascular permeability causing the accumulation of extracellular fluid, particularly within the white matter tracts
Interstitial oedema - Abnormal flow of CSF through the CNS associated with elevated intraventricular pressure

periventricular edema associated with hydrocephalus

Question 51

cytotoxic oedema occurs with?

Answer 51

ischemia and hypoxia (both of which can occur with contusion, vascular disease, and other diseases that can affect energy balance, such as repeated seizures),

Question 52

Vasogenic edema

Answer 52

contusion, inflammatory disease, vascular disease, and compressive diseases such as neoplasia.

Question 53

What is Hansen Type 1 degeneration?

o Chondroid degeneration

Answer 53

Progressive decrease in proteoglycan content of the nucleus pulposus with consequant dehydration and mineralisation. Loead to loss of ability to withstand pressure and causes secondary degeneration and tearing of the annulus

o Less able to withstand pressure, tearing of annulus, then disc extrusion occurs (dorsally usually bec annulus thinner dorsally) causing contusion and compressive injury

small, yoounger, chondrodystrophic breeds

Question 54

What is Hansen Type II degeneration?

fibroid metamorphisis

Answer 54

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

causing compression

older, larger nonchondro breeeds

Question 55

ANNPE

Answer 55

-when vertebae and IVD subject to supraphysiologic forces (acitivy.trauma) structural integrity may fail - small tear in AF results in acute extrusion of hydrated NP
- causes continuion injury wthour compression (unless haemorrhage/clot)
-CS: peracute, often severe, non-progressive after 24hr
90% lateralised
vocalise at onset and moderate hyperaesthesia
lareg breed, older C1-C5
-DX: CT/myelo to rule out IVDD
MRI: T2W focal intramedullary hyperintenity
over IVD and lateralised
reduced T2W intesity IVD/narrow
minimal to no cord compression
-Tx: no evidence for nueroprotective tx for acute SCI
supportive (restrict, nurse, physio)
Px: 67-100% recovery (fenn 2016)
poor px: severity, length on T2W transvers vs cord area
if >90% (sens 86 spec 96%)

Question 56

HNPE

Answer 56

welll hydrated extradural disc mateiral remains within canal > compression
pa> pathophys unknwon, most minimally dehydrated
> susect 2nd to sudden cahnges in IVD preossure and biomechanicas
> CS: cervoval, central, non-painful, any bredd
> >Dx: MRI (beltran 2012(
T2W hyperintense NP dorsal to IVD
seagull appearance
IVD narrow with less disc material
> CT with contrast (91% sen, 100% spec) lesion dorasl to IVD
> Tx: ideal unknown, decompression if severe
> some reposnde t medical
> Px: dependednt on severity
> no diff btw Sx and medical Borlace
> good outcomes reported

Question 57

Which cells of the CNS can be regenerated readily?

Answer 57

Glial cells (astrocytes and oligodendrocytes)
For unknown reasons, remyelination does not always occur spontaneously

Question 58

Define hydrocephalus, hydromyelia
syringomyelia.
What cause syringomyelia?

Answer 58

Hydrocephalis - accumulation of fluid within the ventricles

Hydromyelia - 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

Question 59

What is synaptic plasticity?

Answer 59

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

Question 60

What is collateral sprouting?

Answer 60

A repair mechanish where a partially denervated cell will become reinnervated by branches from a functioning nerve

Question 61

Anatomic description and clinical relevance
of the meningovertebral ligament in dogs
Marc Kent 2019

Answer 61

Cadaveric specimens from 6 neurologically normal dogs and 2 dogs with
vertebral neoplasms that extended into the epidural space and MRI sequences
and cytologic preparations from 2 dogs with compressive hydrated
nucleus pulposus extrusion that underwent decompressive surgery

anatomic barrier within the ventral epidural space and causes pathological
lesions to adopt a bilobed shape regardless of the pathogenic process

Question 62

Central cord syndrome: clinical features,
etiological diagnosis, and outcome in 74 dogs
** Ros 2022**

Answer 62

lesions affecting the cervical intumescence (C6-T2 spinal cord segments) cause lower motor neuron (LMN) signs in the TLs and upper motor neuron (UMN) signs in the PLs

lesions involve mainly the gray matter of the cervical intumescence

C1-C5 spinal cord segments in 65 of 74 (88%) dogs and C6-T2 in 9 (12%) dogs. Neurolocalization did not correlate with the imaging findings in 43 (58%) dogs.The most common condition was Hansen type I disk herniation in 27 (36%) dogs and hydrated nucleus pulposus extrusion in 16 (22%) dogs.

Outcome was favorable in 69 (93%) dogs. Hypoventilation was associated with death.

Question 63

myelomalacia

Almost exclusively occurs in dogs but has been reported in humans

Answer 63

fatal sequela of acute disc extrusion

euthanasia, before it affects the phrenic nucleus in the cervical region (causing suffocation)

Unpredictable onset in the days after the inciting injury, though many already starting at presentation and most dogs are euthanised within 3 days

Histopathology > severe liquefactive necrosis of the spinal cord that extends over several segments
PICTURE > softened and haemorrhagic cord, leukomalacia with loss of distinction between grey and white matter

Question 64

PMM pathogenesis

ACVIM consensus statement on diagnosis and management
of acute canine thoracolumbar intervertebral disc extrusion
Natasha J. Olby

Answer 64

Acute SCI involves primary mechanical damage caused by the disk herniation
and secondary damage

Proposed mechanisms:
* > dominated by phagocytic microglia/macrophages causing persisting axonal damage
* > microenvironment with dysregulation of cytokines and MMPs
* > cranial and caudal propagation of necrotic debris along the central canal could cause further haemorrhagic lysis
* > Endothelin overexpression (vasoconstrictor that disrupts the blood spinal cord barrier)
* > Physiological defence systems are unable to terminate the progression of oxidative injury

Increased pressure might play a role in longitudinal propagation of damage elevated intraspinal pressure > swollen cord is compressed against dura.

Question 65

PMM
prevelence?
risk factors (4)?

Answer 65

Prevalence
~ 2%, depending on clinical grade up to 25%
One study: 0% G1-2
0.6% G3
2.7% G4
14.5% G5

Risk factors (RETROSPECTIVE studies)
G5
Lesion location – L4-S3
French Bulldogs (fenchies vs dachi: not controlled for location of injury and the higher prevalence of lumbar IVDE in French bulldogs)
MRI T2W hyperintensity

Question 66

PMM
CS and diagnosis?

Answer 66

Gold standard: histopathology

Ascending paralysis, loss of segmental spinal reflexes (so for T3-L3 lesion that would LMN to HLs and FLs), cranial migration of the Cutaneous trunci Reflex, decreased abdominal tone, inability to remain sternal, Horner syndrome, dull mentation, hypoventilation and possibly increased pain.

MRI
hyperintense signal >6 x length of L2 on sagittal T2-weighed > though 1 study saw this only in 45% of PMM cases
presence of a CSF signal loss on HASTE compared to L2 is reported to have higher sensitivity/ 60-100% and specificity 80-90

Recent 2023 paper: MRI features can support the diagnosis in dogs with clinical evidence of PMM, and absence of these features supports absence of PMM at time of imaging.
However, their absence NOT preclude imminent progressive myelomalacia

protein markers in research, such as from astrocytes, that are shown to increase with PMM

Question 67

PMM treatment?

EHLD: Nakamoto 2019, Durotomy: Takahashi 2020, Jeffery 2020

Answer 67

TIMING
DPN: current literature does not generally demonstrate improved neurologic outcome in deep pain negative dogs with early surgical intervention, often surgery within 24 h,

DPN and PMM: one study found (Castel) an association between delay of decompression beyond 12 h and increased risk PMM, but literature overall lacking

SURGERY Emerging evidence > focal or extensive hemilaminectomy and durotomy might decrease the risk PMM in dogs DPN and
may improve survival in dogs with CS of PMM
2 Japanese retrospective studies reported a 91-100% survival rate with extensive hemi and durotomy, though most remained paralysed, including the FL if affected.
1 prospective study reported a reduced occurrence of PMM following extended durotomy (4 vertebrae) in G5 dogs

AVCIM consensus suggests that extensive hemilaminectomy with durotomy can be considered for dogs with suspected PMM
however, long-term morbidity (such as spinal instability) and how much surgery require further investigation

Medical (no current evidence to show nsaid or CCS provide benefit)