Neuropath - edema + ischemia

Differences in CNS lymphatics

• lymphatics limited

• deliver limited amount of fluid to LN for processing

• capacity limited

• swelling increased intracranial pressure → reduced blood flow to brain

4 types of edema in the brain

• vasogenic

• cytotoxic

• intramyelinic

• transependymal

Vasogenic edema

• inflammation, neoplasia, or vascular irritants cause endothelial damage

• fluid spreads in white matter tracts

Cytotoxic edema

• primarily affects astrocytes (most abundant CNS cell type)

• hypoxia, ischemia, or toxins (Bromethalin) damage astrocyte ion pumps (maintenance of water balance)

• rapid reductions in plasma osmolality → astrocyte hyperosmolar to plasma during rehydration → increased astrocyte tissue water content

Bromethalin toxicity

• uncouples oxidative phosphorylation

• damages astrocyte ion pumps, initiates edema cycle

• results in rapid reduction of plasma osmolality, damages BBB, increases fluid into the brain

• causes normal axons surrounded by swollen edematous myelin sheath

Edema cycle

• cytotoxic edema causes vascular compression, altered blood flow, & endothelial injury → vasogenic edema causes vascular compression/tissue swelling & ischemia/hypoxia → cytotoxic edema

• leads to swelling around blood vessels shutting off blood flow (ischemia, worse in deep grey matter)

• can cause death w/spongiosis histologically

Intramyelinic edema

• caused by Bromethalin (rodenticide) - uncouples oxidative phosphorylation

• causes myelin sheath swelling around intact axons

• causes death via increased intracranial pressure

• sharply demarcated vacuoles associated w/vacuoles

Transependymal edema

• obstructed flow of CSF → increased CSF pressure pushing across ependymal cell lining

• enters periventricular white matter

• can occur slowly w/loss of tissue to offset intracranial pressure (dilated ventricles)

  • fluid separates oligodendrocytes from astrocytes → gradual loss of myelin (white matter atrophy)

  • increased intracranial pressure → decreased blood flow to gray matter (gray matter atrophy)

Gross & histologic appearance of CNS edema/increased intracranial pressure

• tissues swollen

• flattened gyri/reduced sulci → cerebral cortical ischemia

• herniation of cerebellum & cerebrum at caudal aspect of calvarium → hemorrhagic infarction

  • causes seizures, head-pressing, circling etc.

Cerebral cortical ischemia

• caused by flattening of gyri w/lack of subarachnoid space

• selective neuronal necrosis (surface grey matter) → pannecrosis (deep)

  • pannecrosis appears grossly as polioencephalomalacia

Polioencephalomalacia

• specific disease (thiamine deficiency in ruminants) & morphologic diagnosis (ischemic necrosis of the cerebrocortical gray matter caused by pannecrosis)

• cortical grey matter pallor

Ddx for polioencephalomalacia in ruminants

• thiamine deficiency

• salt toxicity

• bacterial endotoxins (C. perfringens)

• lead toxicity

Thiamine deficiency in ruminants

• caused by high concentrate diets (rumen acidosis), reduces rumen ability to create thiamine

• cofactor in oxidative energy pathways, essential for endothelial health

• cerebrocortical gray matter highly dependent in ruminants

• vasogenic edema → edema cycle (visible as pallor grossly, highlighted by UV light)

Thiamine deficiency in cats

• usually obtained from food, can occur w/hepatic lipidosis or ingestion of thiaminase rich foods

• affects periventricular gray matter via hemorrhage + necrosis

Salt toxicity

• high salt or concentrate diet w/limited access to water

• occurs when animal gains access to water, rapid change of plasma osmolarity

• causes cytotoxic edema → edema cycle

• consistent across species

Bacterial exotoxins

• consumption of large amounts of new feed → GI stasis → overgrowth of gut bacteria (especially in young ruminants + pigs)

  • pigs: E. coli w/vascular leakage endotoxin

  • lambs: C. perfringens w/epsilon toxin (aka focal symmetrical encephalomalacia @ basal nuclei)

• causes vasogenic edema → edema cycle

Epsilon toxicity

• produced by C. perfringens, damages endothelium

• causes multisystemic edema including the CNS

• may cause bilateral symmetric malacia

Canine lead toxicity

• selective neuronal necrosis w/prominent gitter cell response

• all levels of cortical grey matter affected (uniform & symmetric)

Potential causes of infarction

• vascular compression (may be slow/chronic)

• embolism

• primary vascular Dz

  • atherosclerosis (fibro-fatty build-up in artery walls, seen w/hypothyroidism)

  • vasculitis (inflammation of blood vessels → clot formation)

  • hypertension (burst of small vessels → large hemorrhagic infarct)

• arteriospasm

tissue damage due to physical compression + ischemia

Septic emboli

• often causes focal grey matter hemorrhage due to high vascular density

• causes vasculitis → hemorrhagic infarct

• classically caused by H. somni, grows in vessel walls

Blood supply to the gray matter of the spinal cord

• ventral spinal artery

• little redundancy

Concussion

• transient loss of consciousness following rapid + extreme rotation of calvarium

• stretches white matter tracts → transient disruption of neuronal conduction

• does not cause hemorrhage

Causes of hemorrhage

• contusion

• laceration

• avulsion

Contusion

• bruising when leptomeninges pressed against calvarium

• causes tear or burst of blood vessels + bleeding

Subdural hematoma

• blood pooled leaked from blood vessels between the brain & the dura

• causes increased intracranial pressure/vascular compression → edema cycle

Arteriospasm

• occurs w/hemorrhage contacting sub-arachnoid space

• triggers regional constriction of blood vessels

• can lead to progressively large infarctions (waves) over time

  • blood seeps in from adjacent viable tissue, triggers waves

• greater frequency in the spinal cord (ascending-descending myelomalacia) due to ease of travel in white matter adjacent to meninges

Mechanism of arteriospasm & vessel patency

• non-passive

• arterial patency maintained by EDRF + PGI2 (produced by endothelial cells)

• hemorrhage → oxyhemoglobin → free radicals insult endothelial cells → diminish EDRF + PGI2, produce acute phase proteins (ACh, Bradykinin) → constriction + ischemia

Intervertebral disc degeneration

• affects nucleus pulposus + annulus fibrosus w/chondroid metaplasia

• leads to herniation in cervical + lumbosacral spinal cord (greatest flexion + extension & lack of conjugal ligaments)

• worst case-scenario: leptomeningeal hemorrhage (ascending-descending myelomalacia)

• occurs at accelerated rate in chondrodystrophic breeds (burst vs bulge)

Wallerian degeneration

• deprived blood supply + oxygen (spinal cord ischemia) via compressive lesion leads to distal death of neuron w/myelin debris

  • cylinder + sheath swelling → fragmentation + phagocytosis

• caudal of compression: ventral + ventrolateral funiculi affected, descending axons

• cranial of compression: dorsal + dorsolateral funiculi affected, ascending axons

• change irreversible but can see functional recovery w/time (functional plasticity)