Neuropathology

Anatomy
1. Brain
  1. Grey Matter (Outside)
    1. Cerebral & Cerebellar cortex
      1. Contains neuronal cell bodies
  2. White Matter (Inside)
    1. Contains axons, myelin sheaths, astrocyte fibers
  3. Nuclei
    1. Foci of grey matter also occur w/in the white matter
      1. Ex. Olivary, red, cuneate, etc.
  4. Meninges
    1. Protect CNS
      1. Encase CSF
        Support blood vesels
    2. Dura (Outside -thick (Packy)) -> Arachnoid -> Pia Matter (Inside - thin (Lepto))
      1. Sunbarachnoid space (Blood vessels)
2. CNS Cell Types
  1. 1) Neurons
    1. Response to Injury
      1. Extremely vulnerable to injury
        High metabolic rate
        Little NRG storage
        An Axon to care for
        Axon has no Nissl (ribosomes)
        Can't make protein
        Can't dispose of own waste
        Neurons CANNOT regenerate
      2. Acute Necrosis
        Most common response
        Ischaemia
        O2 required for oxidative phosphorylation
        Cell's ATP drops & ion channels leak
        Ca 2+ enters cells => membrane damage
        Increased intracytoplasmic Ca2+ =>
        ATPase => Decreased ATP
        Phospholipase => Decreased phospholipids
        Protease => Disruption of membrane & cytoskeletal proteins
        Endonuclease => Nucleus chromatin damage
        Red dead cells (Red cytoplasm)
        Pyknosis
        Hypoxia
        Hypoglycaemia (toy breed puppies -> seizures)
        Nutritional Deficiency (e.g. thiamine deficiency)
        Toxins (e.g. Pb & Hg)
        Laminar cortical necrosis
        Polioencephalomalacia
        Outer cortex "Melting" => Gelatinous material
        Ruminants
        Acute neuronal necrosis in a distinct pattern
        Causes:
        Salt poisoning (Pigs)
        Water deprivation
        Pb & Hg toxicity
        Polioencephalomalacia
        Polioencephalomalacia
        Cerebrocortical necrosis (CCN)
        Pathogenesis unclear
        Thiamine deficiency vs. sulfide toxicity
        Thiamine required for glucose metabolism => Hypoglycaemia
      3. Chromatolysis
        Swelling of the Neuron
        Powdery appearence => Nissel substances dispersed ( unraveling ER)
        NOT necrosis => Adaptive change
        Dissolution of Nissel bodies
        Ex. Equine dysautonomia (grass sickness)
      4. Wallerian degeneration
        Response of Axon to injury (Normally seen in white matter)
        Healing => Axoplasm (Myelinated - built up at point of injury => swollen axon)
        Neuroma => conglomeration of axons, axoplasm ("abortive attempt" at repair)
        Ex. tail dock neuroma
        No renegeration of basal lamina, inefficent clearance of debris & re-myelination (oligodendrocyte), inhibits axonal sprouting => Chances of repair low
        Breakdown of the nerve fiber DISTAL to the point of initiating injury
        Myelin sheath breaks up
      5. Vacuolation
        Transmissable spongioform encephalopathies (BSE, scrapie)
        Common artefact (Not fixed properly)
        Normal finding
        Lysosomal storage disease
        Early cell injury
        Some toxins
  2. 2) Glial cells (Neural glue)
    1. Astrocytes
      1. " Star-shaped", multiple dendritic extensions
      2. CNS equivalent of fibroblast
      3. Functions:
        Support
        Insulating synapses
        Detoxification
        BBB
        Produces cytokines
      4. Response to Injury
        Necrosis
        Astrocytosis (astrocyte hyperplasia)
        Astrogliosis (astrocyte hypertrophy & hyperplasia)
        Starting to produce glial fibers ("Fibrosis")
    2. Oligodendrocytes
      1. Look like circular nuclei (Circular cells), Myelinate axons
      2. Inefficient at re-myelinating in response to injury
      3. Myelinate axons
        Oligodendrocyte injury => De-myelination
    3. Microglial cells
      1. " Macrophage"
    4. Ependymal cells
      1. Line the ventricles
    5. Choroid plexus epithelial cells
      1. Produce CSF
  3. Order of vulnerability to injury:
    1. Neurons > Oligodendrocytes > Astrocytes > Microglia > Blood vessels
General Responses to Injury (CNS & PNS)
1. Oedema
  1. Vasogenic
    1. Most common form in animals
    2. Follows vascular injury
    3. Breaches BBB -> Increased permeability
    4. Fluid is extracellular
    5. Ex. Oedema disease in Pigs
      1. E.coli (bacterial infection of GI tract)
        Bacteria produce toxins in the intestine (endotoxaemia)
        Toxin enters bloodstream => Brain => Vasculitis, Leaky vessels
  2. Interstitial
    1. Usually follows hydrocephalus
    2. Ventricles dilate & increased hydrostatic pressure => Fluid forced into parenchyma
    3. Fluid is Extracellular
  3. Cytotoxic
    1. ATP deficit & Failure of Na+/K+ pump => Na+ & H2O build up in cell
    2. Fluid in Intracellular
    3. Hypoxia, Ischaemia, toxins (anything that inhibits ATP production)
    4. => Hydrophobic degeneration in other cells
  4. Consequences
    1. Brain swells, becomes compressed => Herniation
      1. 1) Through the Foramen Magnum
        Most common
        2) At Cingulate gyrus under the falx
        3) Transtentorial herniation
      2. Ex. Cerebellar herniation
        Compresses Medulla (Resp. centers) => Sudden death
2. De-myelination
  1. Primary: Myelin forms normally & then is selectively destroyed
    1. Impaired maintenance (i.e. infectious destruction of oligodendrocytes)
      1. Nutritional (Cu, Vit. B12)
        Toxins (Cyanide)
        Cytotoxic oedema
        Immune mediated (i.e. multiple sclerosis, canine distemper (Most common))
        Proposed Pathogenesis:
        Oligodendrocytes die as a result of immune response against viral Ag on their surface
        Molecular mimicry
        Incorporation of neural elements into the virus during assembly resulting in anti-self response
  2. Secondary: Loss of Myelin following axonal damage (i.e. Wallerian degeneration)
  3. Vs. Dysmyelination => Myelin doesn't form properly in first place
3. Vascular Disturbances
  1. Reduced blood flow (or complete blockage) leads to ischaemia
  2. Consequences of ischaemia depend on:
    1. It's degree & duration
      1. Size & type of vessel involved
        Relative susceptibility of tissue to hypoxia
  3. Consequences of ischaemia:
    1. Neuronal necrosis
    2. Vasogenic oedema
      1. The ischaemia is not a direct cause of the oedema, but the two could occur together if the ischaemia was the result of vascular damage
    3. Infarct(s)
      1. Necrosis of a tissue following obstruction of a supplying blood vessel
      2. Often well demarcated
      3. Causes:
        Thrombosis/thromboembolism (Uncommon in the CNS of animals, can see with DIC or sepsis)
        Emboli: FCEM (fibrocartilaginous embolic myelopathy), bone marrow embolism following fracture
        Vasculitis: Classical swine fever (hog cholera - pestivirus), MCF (malignant catarrhal fever -herpesvirus), Oedema disease (vasculitis caused by E.coli toxin)
    4. Malacia
      1. Grossly: appreciable softening of brain/spinal cord (usually resulting from necrosis)
      2. Histologically: Necrosis
      3. Occurs in infarcts, but there are other causes (toxicosis, hypoxia, nutritional, infectious or metabolic disease)
      4. The pattern & location of Malacia are often more Dx helpful than the lesion itself
        Symmetrical Malacia:
        Nutritional, Toxic, Metabolic, Genetic
        Asymmetrical Malacia:
        Vascular, Infectious, Traumatic
Inflammation of the Nervous System
1. Defence (against infection)
  1. Skin
    1. Skull/vertebrae
      1. Meninges & CSF
        Barriers (CSF/ECF, CSF/blood, BBB)
        Microglia (monocyte/ macrophage system)
        Immunologic responses (innate & adaptive)
        BBB
        Endothelial cell
        Not fenestrated
        Tight junctions
        Fewer transporting vesicles
        P glycoprotein
        Astrocytes
        Pericytes
2. Inflammation is usually the result of infection
  1. Bacteria, Fungi, Parasites (protozoa)
  2. Main Routes of Entry
    1. Haemotogenous (most common)
    2. Direct
      1. Spread from adjacent structure (inner ear, skull sinuses)
      2. Injection
    3. Penetrating trauma
    4. Via peripheral nerves
    5. Leukocyte trafficking ("Trojan horse")
3. Sites of Inflammation
  1. Epidural or subdural space
    1. Tends to result in abscess (Uncommon)
  2. Meninges
    1. Leptomeninges - Pia & Arachnoid Matter (Leptomeningitis)
      1. Suppurative:
        Most common
        Bacterial (E.coli, Streptococcus, Haemophilus)
        Swollen brain, meninges opaque, OFTEN NO GROSS LESIONS
        Neutrophils predominate initially
        Usually fatal
        Usually of haemotogenous origin
      2. Eosinophilic meningoencephalitis:
        Porcine salt poisoning/ H2O deprivation
        Perivascular eosinophilic cuffing in the cerebrum & meninges
      3. Lymphocytic:
        Usually viral
      4. Granulomatous:
        Fungal disease & mycobacteriosis
        Idiopathic forms (Mainly Dogs)
    2. Pachymeninges - Dura matter (Pachymeningitis)
  3. Parenchyma
    1. Encephalitis
      1. Inflammation of the cerebral parenchyma)
      2. Classified based on nature of Exudate:
        Suppurative
        Fibrinous
        Granulomatous
        Lymphoplasmacytic
        Eosinophilic
        Haemorrhagic
      3. Bacterial:
        Typically result in Abscesses (Suppurative inflammation - i.e. localized collections of neutrophils)
        Single or multiple depending on route
        Vary in size with a central, liquefied cavity
        Ex. E.coli, Streptococcus, Stapyhlcoccus, Pasteurella & Fusobacterium necrophorum
        Listeria monocytogenes (Listeriosis)
        Sheep, cattle goats
        3 forms (CNS, abortion, sepsis)
        Compared to other bacteria, pathogenesis in CNS disease is a little different
        Oral mucosa -> Trigeminal nerve -> Trigeminal ganglion in brain
        Source: Silage (pH > 5.4 allows bacterial growth)
        Sxs: Circling, Facial nerve paralysis (unilateral), Drooling, Pharyngeal paralysis, Recumbancy, paddling, death
        Usually NO GROSS lesions
        White/grey matter junction predisposed
      4. Viral:
        Lymphoplastic inflammation
        Haematogenous & neural routes mainly
        Hallmark lesions (regardless of virus type):
        1) Neuronal necrosis
        2) Gliosis (glial nodules)
        3) Vascular changes -lymphoplasmacytic cuffing
        Types of Virus:
        Neurtropic
        Viruses which can overcome innate immunity of brain
        Rabies (rhabdovirus)
        Encephalomyelitis & ganglionitis
        Lesions are macroscopic
        Intracytoplasmic, oval, pink inclusion bodies (Negri bodies)
        Aujesky's disease (Herpesvirus)
        Visna (Ovine lentivirus)
        Endotheliotropic
        EHV1 (Equine herpesvirus type 1)
        Classical swine fever (pestivirus)
        Infectious canine hepatitis (canine adenovirus)
        Endothelial cell damage leads to vascular injury & secondary parenchymal necrosis & haemorrhage
        Pantropic
        Canine distemper (morbillivirus)
        Infectious bovine rhinotracheitis (Bovine herpesvirus type 1)
        Respiratory, urogenital & CNS
        Virus can be latent in nerve ganglia
      5. Prion Diseases:
        Transmissable spongiform encephalopathies (TSEs)
        BSE, scrapie, chronic wasting disease
        A group of fatal neurodegenerative diseases which occur in a number of species
        Proteinaceous infectious particle
        Abnormal isoform of prion protein (PrP) in the brain -> PrPsc (common to all cases)
        PrPsc accumulates in nervous tissue as amyloid fibrils
        Long incubation period, difficult to Dx (no immune response)
        Agent is highly resistant
        Alpha helix -> beta pleated sheet
        No gross lesions; Characteristic microscopic lesions
        Spongioform change, Amyloid plaques, Astrogliosis
      6. Fungal/ Protozoa:
        Cryptococcus
        Opportunistic -Aspergillus
        Neospora
        Toxoplasma gondii
    2. Myelitis
Trauma
1. Less common in animals than man
  1. Less risk, Better protection
2. Main forms of injury
  1. Concussion
  2. Contusion
    1. Pathogenesis:
      1. Head is moving, but suddenly stopped by solid object
        1st point of impact = where object hits the head
        Head stops, brain doesn't
        Brain strikes inside of skull at first point of impact (Coup)
        Brain moves in cranium, stretching & tearing vessels & nerves on the opposite side to the original impact (Contrecoup)
  3. Laceration
  4. Haemorrhage
    1. Locations:
      1. a) Epidural
        b) Subdural
        c) Leptomeningeal
        d) Subpial
        e) Intramedullary
Response of Spinal Cord to Injury
1. Like the brain, can be affected by infectious, inflammatory, toxic, nutritional & neoplastic disease, & lesions can occur in its parenchyma
2. Traumatic injuries:
  1. Concussion, contusion, haemorrhage & Compression
    1. Compression
      1. May arise within (Intra-medullary) or outside (Extra-medullary) the spinal cord
      2. Causes:
        Neoplasia
        Abscess
        Extradural
        Vertebral
        Intervertebral
        Fracture: Traumatic or pathological
        Vertebral bodies (e.g. due to abscess, metabolic disease, neoplasia)
        Invertebral disk disease (IVDD)
        Prolapsed disk can cause acute or chronic compression
        Chrondrodystrophic
        Nucleus pulposus replaced by chondroid tissue
        Degeneration of annulus fibrosus is 2ndary
        Young Dogs
        Non-chrondrodystrophic
        Degeneration begins in annulus fibrosis
        Nucleus undergoes fibrosis
        Middle aged dogs (TL)
        Age-related & not breed dependent
        Malformations (esp. vertebral)
        Wobbler horses (stenotic myelopathy): Vertebral canal narrows due to malformation & malarticulation of the cervical vertebrae (usually C3-C4)
        Cervical vertebral malformation-malarticulation (Dogs) - similar pathogenesis to wobbler horses
        Alantoaxial subluxation of toy Dogs (Hypoplastic dens leads to subluxation)
      3. Lesions are similar regardless of the cause
        Gross: Spinal cord may be indented or flattened
        Histologically: Myelin sheath ballooning in all funiculi w/ axonal swelling/loss, Myelin digestion chambers, Neuronal loss, gliosis, malacia (due to vascular damage), oedema
Congenital Malformations
1. Abnormal development of neural tube
2. May involve Spinal cord, Brain, Calvaria, Meninges &/or Vertebral column
3. Morphological
  1. Hydrocephalus
    1. Increased accumulation of fluid within the cranial cavity
    2. Types:
      1. Internal (fluid w/in ventricles)
        Congenital form:
        Obstruction NOT found
        Common in brachycephalic dogs (mesenphalic aqueduct may be stenotic)
        Sporadic in cattle
        Acquired form:
        Causes: Obstruction due to inflammation (of meninges &/or ependymal cells) or space occupying lesions compression (neoplasms, abscesses & cholesteatomas)
        Common
      2. External (w/in arachnoid space)
        Communicating (w/in both locations)
        Hydrocephalus ex vacuo (ventricles dilate 2ndary to replace lost tissue)
  2. Others
    1. Anencephaly (absence of brain)
    2. Lissencephaly (normal in mice, rats, rabbits & birds)
      1. Meningoencephalocoele
        Spinal: spina bifida, hydromyelia & syringomyelia
  3. Cerebellar Defects
    1. Cerebellar hypoplasia
      1. Common
      2. Inherited: (Arab foals, Jersey cows, Chows, Corriedale sheep)
        Acquired: Environmental teratogens attack germinal cells in external granular layer of cerebellum (source of neurons)
        Ex. Bovine virus diarrhea (BVD), feline parvovirus, CSF (hog cholera), canine parvovirus, schmallenberg virus
    2. Cerebellar Abiotrophy
      1. Premature degeneration of nervous tissue elements after they have formed (form of atrophy) - probably inherited
4. Functional (biochemical abnormalites - ex. lysosomal diseases or leukodystrophies)
5. Causes:
  1. Inherited
  2. Environmental (most common)
    1. Toxic
      1. Infectious
        Nutritional
        Radiation
CNS Neoplasia
1. Primary
  1. Meninges
    1. Meningioma
      1. Most frequent in Dogs & Cats
      2. Compressive, space-occupying lesion (seldom invades)
  2. Glial cells
    1. Astrocytoma
      1. Most common glial tumor
        Brachycephalic breeds
        Solid, firm, grey-white (sometimes mottled red w/ areas of necrosis/haemorrhage)
    2. Oligodendroglioma
      1. Most common in Dogs (brachycephalic breeds)
        Soft, grey to pink/red & often gelatinous
    3. Ependymoma
      1. Mainly in ventricles (primarily lateral)
      2. May spread in the ventricular system via CSF
      3. Expansile, but can be invasive & destructive
    4. Choroid plexus tumors
      1. Rare, mainly Dogs, 4th ventricle
  3. Neurons (very rare)
2. Secondary (Metastatic)
  1. Haemangiosarcoma
    1. Mammary or Pulmonary Carcinoma
      1. Lymphoma
        Pituitary tumors
        Vertebral osteosarcoma
Idiopathic Diseases
1. Idiopathic Epilepsy
  1. Small group of neurons periodically & spontaneously depolarize
    1. Structural : Neoplasma, inflammation, trauma
      1. Biochemical: Hypocalcemia, Hypoglycemia, Hepatic encephalopathy
        Idiopathic: No cause identified (indiviuduals have a low seizure threshold)
Diseases of Peripheral Nerves
1. Dorsal & Ventral roots, spinal ganglia, spinal & peripheral nerves, cranial nerves & peripheral components of the ANS
2. Trauma
  1. Nerves are predisposed to injury because of:
    1. Superficial position
      1. Proximity to bone
        Proximity to injection sites
  2. Laceration
    1. Avulsion ("pull out" - usually at roots)
      1. Transection
        Compression & stretching (following fracture or dislocation)
        => Wallerian degeneration
3. Infectious
  1. Some infectious agents involve peripheral nerves as well as CNS
  2. Ex. Rabies, Aujesky's disease, Neospora caninum, Toxoplasma gondii
  3. Neospora caninum
    1. Dorsal roots (Dog)
    2. Equine Guttural Pouch mycosis
      1. Inflammation in the recurrent laryngeal nerve -> vocal cord hemiplegia
      2. Macaw Wasting Disease (Proventricular dilation syndrome)
        Non suppurative inflammation around myenteric ganglia => gastric dysfunction (wasting, anorexia, depression) => neurological signs (ataxia, seizures)
        Borna disease virus ?
4. Idiopathic/ Immune mediated
  1. Coonhound paralysis
    1. Polyradiculoneuritis (racoon bites) => Quadriplegia
      1. Lesions in ventral roots of spinal nerves & in peripheral nerves
5. Neuropathies
  1. Often breed related -> Inherited pathogenesis
6. Degenerative
  1. Equine laryngeal hemiplegia ("roarers")
    1. Common
    2. Pathogenesis:
      1. Degeneration of left recurrent pharangeal nerve -> Atrophy of the left dorsal cricoarytenoid muscle -> Inability to abduct arytenoid cartilage & vocal fold => Airways partially obstructed on inspiration
      2. Cause:
        Idiopathic/ inherited, 2ndary to guttural pouch mycosis, Trauma
    3. 95% cases on Left
7. Toxic
  1. Uncommon
  2. Heavy metals (Pb, Hg, Thallium)
    1. Pb -> damages Schwann cells -> peripheral degeneration
      1. Hg -> Targets neuronal cell bodies -> 2ndary axonal degeneration in peripheral nerves
8. Neoplastic
  1. Uncommon
  2. Dogs
  3. Peripheral nerve sheath tumors (Benign/ Malignant)
9. Nutritional/metabolic
  1. Vitamin A & B, Pantothenic acid & Cu deficiency => Neuropathy
    1. Cu deficiency: Swayback (New born lambs) & enzootic ataxia (older lambs)
  2. Metabolic: Diabetes mellitus, Hypothyroidism

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Neuropathology

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	Created by melian.yates over 10 years ago