Ch 29 Pathophysiology of CNS dz and 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 fo white matter
Cerebral cortex - external later of grey matter with white matter connecting the cortex to other regions of the CNS
What is grey matter and white matter?
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
ventricles of the CNS
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
Meninges – and space between
- 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)
tisue separting brain componeents?
- Falx cerebri – conn. tissue separates hemispheres
- Tentorium cerebelli – separates cerebellum from cerebrum
o Both help minimize excess movement, skull protects
Name 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 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
What cell produces myelin?
Oligodendrocytes
fatty envelope – high resistance and low conductance; allows AP conduction in ‘saltatory’ manner, ie it ‘jumps’ node to node (gaps in the myelin)
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?
mechanisms to protect CNS from fluctuations in BP, hypoxia, hypercapnia
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)
How does PaCO2 alter CNS perfusion?
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
CPP = MAP - ICP
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
cushings reflex
brain heart syndrome” profound catecholamine release
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
What is normal intracranial pressure?
8-15mmHg
Over 15 required treatment, over 30 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 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
electively permeable, and free diffusion dependent on lipid solubility, ionization, and size.
Meninges and choroid plexuses don’t have BBB so can see inflamm
What ABx have good penetration of the BBB?
Why is the CNS said to be ‘immunologically previledged”
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
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)
Perivascular macrophages and microglial cells DO express major histocompatibility complex and participate in the immune response
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/olfacotry system
Dentate gyrus of the hippocampus
categories of CNS injury? 6
Contusion
Compression
Inflammation
Vascular
Metabolic/toxic
Degenerative
CONTUSION
Hansen type I intervertebral disc herniation
Vertebral fractures/luxations
Vertebral column instability
Impact to head
Extreme flexion/extension of vertebral column
COMPRESSION
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
INFLAMMATION
Microbial infection
GME and necrotizing encephalitis
Contusion/vascular disease
Neoplasia
VASCULAR
FCEM/FIE
Neoplasia
Contusion
Vasculitis
Bleeding disorder
METABOLIC/TOXIC
METABOLIC/TOXIC
Hepatic encephalopathy
Hypoglycemia (beta islet cell neoplasm)
Uremic encephalopathy
Seizures post portosystemic shunt ligation
DEGENERATIVE
Degenerative myelopathy
Cerebellar abiotrophy
Lysosomal storage diseases
Hypomyelinating/demyelinating diseases
Motor neuron diseases
- Primary mechanical damage
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
sedondary injury (5)
vascular changes
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
excitotoxicity
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
free radiacal damage
Olby 2016 -
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)
inflammatory reaction
-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
apoptosis
neurons die by necrosis, difficutl to reverse ocne started
oligodendoryte death by apoptosis
contribute to demyelination and reduced FUNCTION
secondary injury - chornic phase
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
How does CNS injury effect an animals susceptibility to infection?
Circulating lymphcyte ad monocyte numbers are depressed for several days
Lymphocyte function is depressed for several months after spinal cord injusry and stroke
What are the pathologic changes associated with compression?
Demyelination
Oedema
Axonal degeneration
Neuronal necrosis (oligodendrocytes, astrocytes, neurons and axona)
White mater tracts (UMN)
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)
effects of compression
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
LMN
LMN (reflex arc) cell body lies within the ventral horn of gray matter
What are the main forms for disease causing vascular obstructive lesions?
FCE
Feline ischaemia encephalopathy (FIE)
Thrombotic “stroke” in dogs
- Gray matter affected more than white matter
- Energy failure causes secondary injury to happen
What are the 5 broad localisations of CNS haemorrhage?
Extradural
subdural
subarachnoid
intraventricular
intraparenchymal
Secondary injusy due to compression and also similarly to contusion due to decreased energy supply
How does the inflammatory response cause CNS dysfunction?
meningitis, myelitis
Inflammatory mediators can directly affect neural function
NO, leukotrienes and prostanoids have profound effects on the microcirculation and the integrity of the BBB
List some metabolic diseases of the CNS
Hypoglycaemia secondary to insulinoma
Hepatic encephalopathy
Uraemic encephalopsthy
PANS
- Malformations usually lead to compression injuries
What are the most common neoplasms to metastasise to the brain?
HSA
melanoma
carcinoma
primary neoplasia
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.
What is the difference between cytotoxic oedema, vasogenic oedema and interstitial oedema?
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
cytotoxic oedema occurs with?
ischemia and hypoxia (both of which can occur with contusion, vascular disease, and other diseases that can affect energy balance, such as repeated seizures),
Vasogenic edema
contusion, inflammatory disease, vascular disease, and compressive diseases such as neoplasia.
What is Hansen Type 1 degeneration?
o Chondroid degeneration
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
What is Hansen Type II degeneration?
fibroid metamorphisis
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
ANNPE
-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%)
HNPE
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
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
syringomyelia.
What cause syringomyelia?
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
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 mechanish where a partially denervated cell will become reinnervated by branches from a functioning nerve
Anatomic description and clinical relevance
of the meningovertebral ligament in dogs
Marc Kent 2019
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
Central cord syndrome: clinical features,
etiological diagnosis, and outcome in 74 dogs
** Ros 2022**
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.
myelomalacia
Almost exclusively occurs in dogs but has been reported in humans
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
PMM pathogenesis
ACVIM consensus statement on diagnosis and management
of acute canine thoracolumbar intervertebral disc extrusion
Natasha J. Olby
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.
PMM
prevelence?
risk factors (4)?
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
PMM
CS and diagnosis?
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
PMM treatment?
EHLD: Nakamoto 2019, Durotomy: Takahashi 2020, Jeffery 2020
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)
