Neuropathology Flashcards
Where are fibroblasts normally found in the CNS?
How do wounds in the CNS heal?
Fibroblasts in the CNS are found in the leptomeninges and in the few outer mm of the CNS. They are pulled into cerebral cortex with blood vessels
Wounds deep in the CNS (abscess) heal by the proliferation of astrocytes/astrocyte processes
Superficial wounds or wounds that extend through the leptomeninges heal by synthesis and deposition of collagen by fibroblasts and by the proliferation of astrocytic foot processes
McGavin
7 microscopic changes that occur in the neuronal cell body
- Central chromatolysis after: axonal injury, degenerative conditions, viral infection or inherited conditions
- Ischemic cell change
- Enlargement of the cell body in lysosomal storage diseases
- Accumulation of lipofuscin pigment in aging
- Accumulation of neurofilaments in certain neuronal degenerative diseases
- Inclusion body formation in certain viral diseases
- Cytoplasmic vacuolation in spongiform encephalopathies
McGavin
4 reasons neurons are vulnerable cells
- Large requirements for energy
- Lack intracellular glucose reserves
- Vulnerable to free radical oxidative stresses
- Vulnerable to excicotoxiticy
- Under normal conditions, astrocytic processes surrounding synapses have efficient uptake systems to remove excitotoxins so neurons are not injured
McGavin
9 causes of acute neuronal necrosis
How long does it take to see histopathologic evidence of necrosis?
Acute neuronal necrosis = acidophilic or ischemic necrosis
- Cerebral ischemia
- Vascular thrombosis
- Cardiac failure
- Inflammatory mediators
- Toxins (CO, cyanide poisoning, bacterial toxins)
- Thermal Injury
- Heavy metals
- Nutritional deficiencies
- Trauma
Conditions that reduce ATP generation via oxidative phosphorylation lead to neuronal degeneration and death
Takes 6-8h
How do cyanide poisoning and CO poisoning cause acute neuronal necrosis?
Cyanide poisoning: interference with cytochrome oxidase activity in mitochondria
CO poisoning: competitive inhibition of O2 uptake
McGavin
Which neurons are the most susceptible to injury? (4)
- Purkinje neurons
- Some striatial neurons
- Neurons of the 3rd, 5th, and 6th cerebral cortical lamina
- Hippocampal pyramidal cells
Also regional: Cerebral cortex and striatum > thalamus > brainstem > spinal cord
What ion abnormality is associated with excitotoxicity?
Increased intracellular calcium:
- CNS injury –> altered mitochondria and endoplasmic reticulum –> increase in the release of normally sequestered intracellular calcium
- Neuronal depolarization –> release of excitatory glutamate –> persistent activation of glutamate receptors –> excitotoxicity and influx of extracellular calcium into cells
- Excitotoxicity is enhanced by ROS effects on cell membranes
- reperfusion of ischemic tissue can enhance the generation of ROS
McGavin
Neuron characteristics on HE stained section:
- Cytoplasm of the cell body is shrunken, eosinophilic, sharply angular to triangular in shape
- Nucleus is reduced in size, triangular, central, pyknotic
- Nucleolus and Nissl substance are not detectable
Ischemic neurons
- Following ishcemia: neurons are removed either by neuronophagia (microglia) or lysis
- there is swelling of perineuronal and perivascular astrocytic processes and eventual replacement of the space left by loss of the neuron cell body by astrocytes and their processes
McGavin
Grossly: atrophy of cerebral gyri and widening of the sulci
Microscopically: diminished numbers of neurons, astrogliosis, atrophy and loss of neurons in functionally related systems
What is the broad term? What are possible causes?
Chronic neuronal loss = simple neuronal atrophy
Causes:
- Cerebral cortical atrophy of aging
- Ceroid lipofuscinosis
- Various selective or multisystem neuronal degeneration
McGavin
What is the difference between spheroids and digestion chambers in Wallerian Degeneration?
What changes are seen in the neuronal cell body with Wallerian Degeneration?
Damage to nerve fiber –> decreased/halted axonal transport –> segmental swellings in the axon = spheroids
Axon’s myelin degenerates –> areas of vacuolation into which macrophages infiltrate and digest necrotic axonal and myelin debris = digestion chambers
Neuronal cell body: Swelling, central chromatolysis
McGavin
How does the rate of development of Wallerian Degneration vary based on the diameter of the axon?
Larger axon - faster rate of degeneration
McGavin
What are astrocytic responses to CNS injury?
What is the difference between astrocytosis and astrogliosis?
What are gemisocytic astrocytes vs. fibrillary astrocytes?
Reaction to CNS injury:
- Swelling (acute response, is reversible or may progress to hypertrophy) = Gemisocyte
- Hypertrophy
- Division
- Laying down intermediate filaments in cell processes
Astrocytosis: Astrocytes have increased size and number in response to injury
Astrogliosis: Somewhat synonymous with hypertrophy. Synthesis of intermediate filaments, increased length, complexity and branching of the astrocytic processes
Gemisocytes (aka plump astrocyte): reactive astrocyte where the nuclei enlarges and cell body becomes visible on HE. Acute injury
- normally the cytoplasm of astrocytes is not visible
Fibrillary astrocyte: chronic reactive astrocyte with large numbers of GFAP containing processes. Also called sclerosis
Pic: arrow = gemisocyte
What are “astrocytic nuclei that tend to be in pairs, triplets, quartets, or occasionally with prominent central nucleoli, surrounded by a clear space of edematous cytoplasm”
Alzheimer type II astrocytes
(hepatic and renal enceephalopathy)
McGavin
What is a network of interlaced astrocytic processes called?
glial scar
- provides a loose barrier that separates the injured brain from normal adjacent tissue
- The astroglia act to reform a glia limitans around the injured region of the CNS in an effort to restore the BBB and re-establish fluid/electrolyte balance
McGavin
Oligodendrocytes swell and hypertrophy around injured neurons - what is this called?
Satellitosis
- Other glial cells can contribute to satellosis
McGavin
5 mechanisms of Primary Demyelination?
- Inherited enzyme defects –> formation of abnormal myelin
- Impairment of myelin synthesis and maintenance (infection, nutritional, toxin, cyanide poisoning, Cuprizone toxicity)
- Loss of myelin as a consequence of cytotoxic edema (status spongiosus)
- Destruction of myelin by detergent-like metabolites (lysolechitin)
- Immunologic destruction of myelin (Coonhound paralysis, marek’s disease (chickens), canine distemper)
McGavin
Nutritional causes of primary demyelination?
- Copper deficiency
- Malnutrition
- Vitamin B12 deficiency
McGavin
If the ventricle is stretched by enlargement –> results in tearing of the ependymal lining, will this lining be repaired?
no
- after 1-2 weeks, astrogliosis occurs in the repaired areas
McGavin
What are the 4 ways that microglia respond to injury?
What is focal proliferation of microglia called?
- Hypertrophy
- Hyperplasia
- Phagocytosis of cellular/myelina debris
- Neuronophagia
Focal proliferation –> glial nodule
Immune functions of microglia (4)
- Express MHC 1 and II
- Serve as antigen presenting cell
- Possess broad adhesion molecules, cytokines, chemokines
- Produce NO, ROS, and chemical mediators of inflammation
McGavin
Embryonic origin of?
- neurons
- astrocytes
- oligodendrocytes
- microglia
Neurons, astrocytes, oligodendrocytes originate from neuroectoderm
- Neurons from neuroblasts
- Astrocytes and oligodendrocytes from spongioblasts
Microglia - mesoderm
ACVIM Proceedings
3 Causes of pseudolaminar cortical necrosis:
- Cerebral hypoxia
- Systemic hypoglycemia
- Polioencephalomalacia from thiamine deficiency (rum), lead poisoning (rum) and salt poisoning (pig)
ACVIM Proceedings
Main type of cells?
Reactive astrocytes - small nuclei with expanded eosinophilic cytoplasm
ACVIM Proceedings
Sato et al found that dogs with progressive myelomalacia after acute thoracolumbar intervertebral disc herniation were more likely to have detectable serum _____________ than dogs with disc herniation but without myelomalacia
Nishida et al. assessed phosphorylated neurofilament subunit NF-H in the serum of dogs with acute intervertebral disk herniation and found differences between dogs with different _____________ as well as higher concentrations in dogs that did not regain ______________
Serum GFAP
Nishida et al. assessed phosphorylated neurofilament subunit NF-H in the serum of dogs with acute intervertebral disk herniation and found differences between dogs with different injury severities as well as higher concentrations in dogs that did not regain the ability to ambulate after surgery
ACVIM Proceedings
What four biomarkers are elevated in dogs with SRMA?
C-reactive protein (CRP)
Serum amyloid A (SAA)
Alpha-1-acid glycoprotein (AGP)
Serum IgA - does NOT vary substantially with effective therapy or relapse
Dogs with SRMA have dramatically elevated serum CRP concentrations which decrease dramatically after effective immunosuppressive therapy. With clinical signs consistent with relapse of the disease, CRP and SAA concentrations are again elevated (even when CSF cytology is WNL)
CRP, SAA and AGP evaluated within the CSF - showed increased concentrations but more variable and less dramatic than changes in serum, not useful for detecting relapses
CSF IgA concentrations are dramatically increased in dogs with SRMA, do not change substantially with therapy or with relapse
ACVIM Proceedings
Miyake et al found that pugs with NME had increased concentrations of ____________ in their serum
GFAP
- such elevations were not found in other CNS diseases or in other breeds with NME
ACVIM Proceedings
What is the utility of CSF GFAP as a marker for NME?
CSF anti-GFAP autoantibodies
Serum GFAP?
Serum GFAP autoantibodies?
Dogs with NME
- CSF GFAP - elevated when compared with healthy controls, noninflammatory CNS diseases, dogs with other inflammatory CNS diseases
- CSF GFAP autoantibodies - highest in dogs with NME (but some of the healthy pugs had high CSF concentrations of GFAP)
- Serum GFAP - only pugs with NME showed elevated serum GFAP concentrations, other breeds with NME did not, did not correlate with survival time
- Serum GFAP autoantibodies - detectable in dogs with NME but “much less discriminatory” as they are increased in dogs with other diseases
ACVIM Proceedings
Biomarker found to be:
- detectable in the plasma of dogs with intracranial tumors
- more likely to be detected in the plasma of dogs with astrocytomas than meningiomas or oligodendrogliomas
VEG-F
- concentrations were greater in dogs with higher-grade tumors
ACVIM Proceedings
Axonal degeneration of the upper and lower motor neurons, axonal degeneration with secondary demyelination and astroglial proliferation in all spinal cord funiculi (most severe in dorsal portion of lateral funiculus and dorsal columns of the middle to lower thoracic region) in the dog - indicates?
Degenerative myelopathy
- Cytoplasmic aggregates that bind anti-SOD1 antibodies are usually present in spinal cord
- late state disease with LMN signs - denervation atrophy in muscle, nerve fiber loss with axonal degeneration and secondary myelin loss in myelinated fibers of peripheral nerves
- thoracic intercostal muscles of dogs with DM indicate that there are significant atrophic changes in these muscles at stages of the disease in which there is no apparent degeneration of the associated motor neurons
- Neuronal cell body degeneration or loss in the ventral horn of the spinal cord is not a prominent histopathologic finding until late in the disease
- Significant sensory neuron degeneration preceded evidence of motor neuron pathology
ACVIM Proceedings
Failure of closure of dorsal aspect of the vertebral foramen in multiple adjacent vertebrae is called?
Failure of the neural tube to close is called?
What is a term for malformation of the spinal cord owing to abnormal interaction of the notochord, paraxial mesoderm, and neural plate during neurulation?
Rachischisis (failure of multiple adjacent vertebral arches to close)
- Most common in the lumbosacral region
Myesoschisis (failure of neural tube to close)
- Usually involves a number of adjacent spinal cord segments
- for this to occur - skin ectoderm remains attached to the borders of the neural plate –> prevents any vertebral arches from forming
- resulting in persistent attachment of the cutaneous ectoderm to the neural plate and inability of the vertebral arches to close around the open neural plate
- ALWAYS results in spina bifida
Myelodysplasia = malformation of the spinal cord owing to abnormal interaction of the notochord, paraxial mesoderm, and neural plate during neurulation
- Almost always occur with vertebral malformations due to interrelated embryologic signs
What condition results when there is destruction of neuroepithelial cells that give rise to the telencephalon?
Multiple cystic cavities that communicate with the lateral ventricle - what is this called?
Hydrancephaly
Porencephaly (similar pathogenesis to hydrancephaly)
(DeLahunta)
Most common cause of hydrancephaly in animals?
Virus induced destruction of germinal cells
- destruction of neuroepithelial cells that give rise to the telencephalon
- Destruction of germinal layer cells –> aplasia; destruction of differentiated neopallial neurons –> atrophy
- Can also occur due to vascular interruptions
- The neopallium is reduced to a thin pial/glial membrane with no associated parenchyma other than a thin layer of ependyma lining the lateral ventricle
- Sometimes concurrent microphthalmia
- Usually the olfactory paeopallium, archipallium (hippocampus), and basal nuclei are spared
- Cerebellar lesions occasionally present
(DeLahunta, braund)
Viral causes of hydrancephaly (5)
- Akabane
- Bluetongue
- Sheep - can be caused by live virus vaccination of dam
- Innoculation 50 - 58d –> necrotizing encpehalitis/hydrancephaly
- 75 - 78d –> porencephaly
- Calves - infection around 125d gestation –> hydrancephaly
- Sheep - can be caused by live virus vaccination of dam
- Bovine viral diarrhea (cerebellum more affected)
- Feline Panleukopenia (cerebellum more affected, can be caused by dam innoculation with MLV)
- Cache valley virus
(DeLahunta)
What is internal vs. external hydrocephalus?
Internal hydrocephalus - ventricular dilation w/ CSF accumulation
External hydrocephalus - CSF accumulation in a dilated SAS (also called hydrocephalus exvacuo)
How does Vitamin A deficiency cause hydrocephalus?
Vitamin A deficiency in calves –> dural fibrosis –> affects arachnoid villi –> decreased CSF absorption –> CSF hypertension
Bacterial hematogenous CNS diseases often start where?
Interface between white and gray matter, and in the cerebral vessels
- Thought to result from abrupt changes in vascular flow or luminal diameter of vessels at the interface - these changes make endothelial cells more susceptible to injury, vasculitis and thrombosis, and predispose the vessels to entrapment of tumor/bacterial emboli
(McGavin)
- Empty cytoplasmic inclusion bodies in the neuronal cell body in the red nucleus in cattle
- Eosinophilic inclusion bodies (pseudo-Negri bodies) in the lateral geniculate body and hippocampus in cats
- Pseudo-negri bodies in the thalamic and cellular Purkinje cells in dogs
- Dark brown melanin granules in the hypothalamus
What is the common significance of these inclusions?
Normal/nonpathologic neuronal inclusions
What are the possible outcomes of Chromatolysis?
Where is there normally dispersion of Nissl substance, which can be confused for chromatolysis?
Possible outcomes - reversible or necrosis
CN nuclei V and VII - normally have a peripheral rim of Nissl substance and centrally placed nucleus
(Vanvelde)
Which 3 neuroanatomic sites are most susceptible to global ischemia/acidophilic neuronal necrosis?
Cerebral cortex
Hippocampus (CA1 and CA2 sectors) - due to dendritic glutamate receptors
Purkinje cells
(Vanvelde)
What pathologic process is characterized by:
- chromatin condensation
- Cytoplasmic blebbing
- nuclear fragmentation
- “bodies”
What molecules regulate this process?
Apoptosis
- Regulated by Bcl2 family and caspases
- Caspase stain can be used to differentiate necrosis from apoptosis
(Vanvelde)
3 Pathologic hallmarks of meningoencephalitis of viral origin??
- Perivascular cuffing
- Neuronal degeneration/necrosis
- Microglial nodules
(Vanvelde)
Axon is traumatized. What happens to its cell body, axon and terminal? What happens to anterograde neurons? Retrograde neurons?
Cell that is injured:
- Cell body - chromatolysis
- Axon distal to injury - axonal necrosis, myelin degeneration
- Terminal degradation
Anterograde neuron- transneuronal degeeration
Retrograde axon - chromatolysis
(Vanvelde)
What are the 4 steps of Wallerian degeneration?
- Axon necrosis/degeneration of the distal segment
- Starts within 24h (focal eosinophilic swellings)
- Dissolution of the distal axon:
- Axonal protease
- Recruitment of hematogenous macrophages (complement C3 important for this)
- Phagocytosis of myelin by macrophages, schwann cells (ellipsoids/digestion chambers)
- Proliferation of Schwann cells - form Bunger’s bands along the course of former axon
- Axon sprouting of the distal stump
- Axon sprouts find their way along the Schwann cell bands
- Sprouting from individual axons is multiple, one sprout is selected for the completion of regeneration
- Regenerated axon is remyelinated in Schwann cells
- New sheath is thinner than the original and nodal length variable and shorter
How does Wallerian degeneration in the CNS differ from PNS? (3)
How is it similar? (2)
What areas of the CNS are most known for having Wallerian degeneration occur? (3)
- Oligodendrocyte is poorly regenerative
- No basal lamina scaffold
- Myelin debris inhibits axonal sprouting
- Initial regressive changes of Wallerian degeneration are similar to the PNS but proceed over a longer time course
- This is because involvement of hematogenous macrophages is slower and less intense in the CNS
- Activated microglial cells take most of the work
- Axonal sprouting and some remyelination can occur
“The poverty of the regenerative response results mostly in the permanent disappearance of the axons, myelin, and oligodendrocyte cell bodies. Some of the myelin debris may be phagocytosed by reactive astrocytes and their processes extend to fill the vacancy - network of astroglial scar tissue”
Wallerian degeneration in the CNS is most commonly seen in the spinal cord, optic tract, and brain stem. Probably the best-known association is with focal compressive myelopathies in horse/dog
Jubb & Kennedy
Histopathologic appearance of Wallerian degeneration? (3)
- Axon spheroids
- Distended myelin sheath
- Bunger’s bands (Schwann cells proliferate within the persisting endoneurial tube forming densely-packed chains)
(Jubb and Kennedy)
3 ways that oligodendrocytes react to injury?
What is satellitosis?
- Swelling
- Hypertrophy
- Degeneration
Satellitosis = oligodendrocytes swell and hypertrophy around injured neurons. Othe glial cells can also contribute to satellitosis
(McGavin)
_______ occurs when oligodendrocytes are damaged, and their myelin internodes undergo degeneration and phagocytosis
_________ occurs when primary axonal necrosis occurs with resultant loss of the myelin sheath
What stains can distinguish between these 2 processes?
Primary demyelination occurs when oligodendrocytes are damaged, and their myelin internodes undergo degeneration and phagocytosis
- Axons remain intact for a long time
- Causes LEUKODYSTROPHY
Secondary demyelination occurs when primary axonal necrosis occurs with resultant loss of the myelin sheath
Luxol fast blue / Holmes silver stain can distinguish between primary and secondary demyelination
- Primary demyelination - absence of blue-staining myelin sheaths (black silver impregnated axons remain intact)
- Secondary demyelination - loss of both axons and myelin sheaths
5 categories of primary demyelination?
- Inherited enzyme defects (inherited leukodystrophy)
- Impairment of myelin synthesis and maintenance (infection, nutritional, toxins, CN poisoning, cuprizone toxicity)
- Loss of myelin as a consequence of cytotoxic edema = status spongiosis (Hexachlorophene poisoning)
- Destruction of myelin by detergent-like metabolites (lysolechitin)
- Immunologic destruction (coohnound paralysis, some stages of canine distemper)
(McGavin)
What type of cells form gitter cells?
Normal and neoplastic ependymal cells will be immunoreactive for what markers?
phagocytic macrophages filled with myelin - microglia or macrophages
vimentin (more consistently), and GFAP
(Vanvelde)
Sequence of pathologic changes secondary to ischemic infarct?
- 1-2h - first microscopic evidence of neuronal injury
- 2h - pale staining of white matter infarct microscopically
- 3-5h - ischemic cell change in most neurons
- 6/8-24h - neutrophilic infiltration, pale myelin, cytoplasm of astrocytes visible, thrombosis, proliferation of endothelium at margin
- 8-48 hours - Initial gross detection of infarct (unless hemorrhagic)
- 1-2d - swelling of axons/myelin, prominent neutrophilic inflammation
- 2d - Loss of neuroectodermal cells, increase gitter cells/fewer neutrophils
- 3-5d - Prominent gitter cells, astrocytic proliferation @ margin of infarct
- 5-7d - Grossly, swelling of infarct reaches maximum
- 8-10d - reduction in gross swelling of infarct, liquefaction necrosis, collagen formation in meninges, astroglial fiber production
- 3 weeks-6 mos - mononuclear cells decreased, astroglial scar fiber density increased, astrocytic proliferation reduced, astrocytes return to normal appearance
- 2-4mos - cystic appearance of infarct with vascular network
(McGavin)
Where does fluid accumulate in vasogenic edema? cytotoxic edema? interstitial edema?
Vasogenic - extracellular accumulation of fluid
Cytotoxic: Accumulation of fluid intracellularly in neurons, astrocytes, oligodendroglia, endothelial cells. Not all cells are involved in all cases of cytotoxic edema. Gray and white matter of the brain are both affected
Causes: early-stage hypoxia/ischemia, intoxication with metabolic inhibitors, severe hypothermia
Interstitial: Elevated ventricular hydrostatic pressure –> Accumulation of fluid in the extracellular space (of the periventricular white matter) –> primary demyelination
(McGavin)
What causes hypo-osmotic edema of the brain?
What is the difference between spongiform change and status spongiosis (according to Dr. Miller)
Overconsumption of water –> dilution of osmolality of the edema –> osmolality of plasma is decreased and water moves from the vasculature into the brain down the osmotic gradient
Spongiform change = morphologic changes in HE stained sections that occur primarily in the gray matter
- Small clear vacuoles of variable sizes that form in the cytoplasm of neuron cell bodies, proximal dendrites and processes of astrocytes related to affected neurons in diseases such as Transmissible spongiform encephalopathies, Rabies encephalitis
Status spongiosus (spongy degeneration)
- Multiple fluid-filled clear spaces in the white matter of HE stained sections of the CNS
- Extracellular of intracellular
- Accumulation of edema fluid in the white matter
4 mechanisms of entry into the CNS
7 Regions of the brain where BBB is absent
- Direct extension (penetrating trauma, middle/inner ear, nasal cavity/sinus)
- Hematogenous entry (
- Leukocyte trafficking
- Retrograde axonal transport - rabies and listeria
BBB:
- Area postrema
- Median eminance
- Neurohypophysis
- Pineal body
- Subfornical organ
- Commissural organ
- Supraoptic crest
Equine:
Grossly: multifocal petechial or ecchymotic hemorrhages in gray and white matter of brain and spinal cord
- Multiple random foci of reddish-gray malacia
Microscopically: primary vasculitis with endothelial cell necrosis and secondary thrombosis, edema, polymorphonuclear cell infiltration, hemorrhages
- Primary vasculitis results in secondary ischemia with perivascular malacia, spheroids
- Multinucleate syncytial cell formation
Herpesvirus
- LACK OF INFLAMMATION is characteristic (except in blood vessels in the meninges)
(Miller)
Combination of which 3 clinical sigs is characteristic of equine herpesvirus?
Diagnostic test? Prevention?
T3-L3 myelopathy + urinary incontinence + mild tail/anal hypotonia
Serum/nasal secretion PCR for viral DNA or antigen
Vaccine for EHV has not been effective against neurologic form
(de Lahunta)
When polioencephalomyelitis is identified on histological examination, which disease has to be on the list?
Rabies!
- Particularly of the brainstem
- No correlation between the severity of clinical signs and the intensity of the inflammatory response
- Polioencephalitis + perivascular mononuclear cuffs and glial nodules
- Spinal cord involvement may be the main sign in horses
(Vanvelde)
Suspicion of rabies can be confirmed by finding typical cytoplasmic inclusion bodies in which 2 locations?
Mechanism of spread/infection?
Hippocampus neurons
Purkinje cells of the cerebellum
- Rabies antigen can be easily demonstrated with IHC in paraffin sections
- intra CYTO plasmic
- Preferred tissue for rabies examination by light microscopy and fluorescent antibody technique include: Hippocampus, cerebellum, medulla, trigeminal ganglion
- First replicates locally at the site of inoculation –> irritation
- Virus binds nicotinic ACh receptors at the NMJ –> enters peripheral nerve terminals OR myocytes (or both)
- If nerve terminals infected – shorter incubation period, if myocytes only are infected – longer incubation period
- Virus moves via fast retrograde axonal transport in sensory OR motor neurons –> CNS
- It is not known whether viral infection and replication in neurons of dorsal root ganglia are essential for infection and replication in neurons of dorsal root ganglia are essential for infection of the CNS
- The virus then moves into the spinal cord –> ascends to the brain using both anterograde/retrograde axoplasmic flow
- During the spread of the virus between neurons in the CNS, there is simultaneous centrigfugal movement via anterograde axonal transport of the virus peripherally from the CNS to axons of cranial nerves
- Results in infection of oral cavity, salivary gland ect
(Vanvelde)
Pathogenesis of CDV?
What determines the severity of disease and areas infected?
- Spread between dogs by aerosol transmission: Trapped in the mucosa of the nasal turbinates –> infects local macrophages –> spread by macrophages (leukocyte trafficking) to regional lymph nodes (retropharyngeal) –> replicates
- Primary viremia –> infects systemic lymph nodes/spleen, and the thymus approximately 48h after exposure
- Infection of the lymphoid system –> immunosuppression can occur
- Secondary bacterial infections (conjunctivitis, rhinitis, bronchopneumonia)
- 4-6 days after primary viremia –> secondary viremia occurs largely via leukocyte trafficking
- CDV spreads from cells of the lymphoid system to infect the CNS and epithelial cells of the respiratory mucosa, urinary bladder mucosa, and gastrointestinal tract
- CNS – trafficking leukocytes form perivascular cuffs and from these cells – CDV disseminated throughout the CNS
- Infects the CP and ependyma –> shed into CSF and spreads through CSF into periventricular zone
- The degree of inflammation in the CNS at this stage is minimal
- Virtually all cells of the CNS including those in the meninges, choroid plexus, neurons and glia are susceptible to infection
- Oligodendrocytes are novel – infection in these cells is usually incomplete
Clinical signs/severity of the disease depends on:
- Age of the dog
- Strain of CDV
- Kinetics of the antiviral immune response
In experimentally infected dogs
- 1/3 died of encephalomyelitis and effects of severe immunosuppression
- 1/3 of dogs developed a timely systemic immune response and CNS disease quickly resolved
- 1/3 developed subacute to chronic inflammatory/demyelinating disease of the white matter (+/- gray matter involvement) because of a delayed and deficient immune response
(Miller)
Canine:
Microscopic lesions of:
- Demyelination
- Status spongiosus, vacuolation of white matter
- Astrocytic, ependymal intranuclear and intracytoplasmic eosinophilic inclusion bodies
Canine distemper virus:
(Vanvelde)
_________ is thought to arise from long-term persistent infection of the CNS with a defective form of CDV
Old dog encephalitis
- Some mild peptide differences between conventional distemper virus and this virus
- The mechanism involved in development of lesions are not known however they result in a proliferation of nonsuppurative inflammatory cells
- Lesions are primarily in the cerebral hemispheres and brainstem
- Microscopic lesions : Microscopic lesions – demyelination with disseminated, nonsuppirative encephalitis
- nuclear and cytoplasmic inclusions positive for distemper in the cerebral cortex, thalamus and brainstem (not cerebellum like conventional distemper)
(Miller)
Regions affected by FIP coronavirus:
Noneffusive form - result in leptomeningitis, chorioependymitis, focal encephalomyelitis, ophthalmitis
Pyogranulomatous vasculitis tends to affect vessels of:
- Leptomeningies, especially sulci and near their entrance into subjacent CNS tissue and around the circle of Willis
- Periventricular white matter – especially around the 4th ventricle
- Uvea, retina, and optic nerve sheath are also commonly involved in FIP
(Miller)
Canine:
Grossly – moderately well demarcated, expansile, yellow-brown foci that displaces and disrupts normal tissue
Microscopically – exudate consists of neutrophils, macrophages (epitheloid type), and multinucleated giant cells
Blastomyces infection (+/- microbes in the cytoplasm)
- Infections with C. immitis or H. capsulatum elicit similar response
- Coccidoides microbes - intra or extracellular spherules containing endospores
- Histoplasmosis - intracellular
(Miller)
T/F: cryptococcus in the CNS of cats often has a significant inflammatory reaction
Special stains for cryptococcus?
False
- Crypto enters CNS by direct extension, leukocyte trafficking
- Leukocyte response varies from sparse to granulomatous - in some infected cats, can be present without an inflammatory response
- Thick mucopolysaccharide capsule + protection from oxidative damage (virulence factors)
Stains: PAS and Gomori’s methenamine silver
(Miller)
Neospora: Who is the definitive host? Who is the intermediate host? How is it transmitted?
What histopathologic lesion is caused by neospora?
Definitive host: dogs
Intermediate host: herbivores
Infection has been recognized in: dogs, cats, cattle, sheep and horses as well as lab rodents
definitive host (dog) ingests tissue from an intermediate host (cow) that contains Neospora cysts
Tissues include Fetal membrane, Aborted fetal tissues
Also transplacental transmission
Gross lesions – involve white and/or gray matter.
Peracute gross lesions may include foci of hemorrhage and necrosis
Acute foci granular in texture and yellow-brown to gray
Chronic larger areas of granular yellow-brown to gray discoloration
Makes white matter indistinguishable from gray matter
Microscopic: multifocal necrotizing lesions with glial nodules and mixed inflammatory infiltrates
Young dogs – ascending polyradiculoneuritis and polymyositis
Adult dogs – clinical signs referrable to CNS lesions complicated by polymyositis, myocarditis and dermatitis
(Miller)
Toxoplasma gondii:
- Definitive and intermediate hosts
- Gross and microscopic lesions
Definitive host: Domestic, feral and wild cats, intermediate: rodents, birds, cats, fish, amphibians, reptiles, birds, humans
- Bird/rodent passes oocysts in feces, sporulate in 5d after passing, cat ingests sporulated oocyst, passes through intracellular intraintestinal life cycle
- OR cat can ingest bradyzoites from tissue cysts
- In utero brain infection is possible
Gross - gray or white matter lesions, foci of hemorrhage and necrosis, then granular yellow/brown foci
Microscopic - neurons and astrocytes are the target cells.
Early - vasculitis, necrosis of adjacent parenchyma, free organisms in the tissue, mixed polymorphonuclear/mononuclear cell response
Subacute/chronic - focal microgliosis becomes more evident, necrosis diminishes, organisms in tissue cysts appear, cellular response more purely mononuclear +/- chorioretinitis
** Occasionally bradyzoites can be observed in normal CNS tissue without an inflammatory or tissue lesion
Which broad category of infections causes the following type of lesions:
- Nonsuppurative inflammatory pattern
- Can also induce a suppurative pattern associated with severe tissue necrosis
- Inflammatory infiltrate sometimes contains significant eosinophils
- Suppurative with variable numbers of eosinophils
- Chronic lesions may develop a granulomatous component
Protozoal
Helminth
(Vanvelde)
Neospora lesions in puppies:
Rapidly progressing myositis
Polyradiculoneiritis - only infects spinal nerve roots in puppies < 12 weeks
(DeLahunta)
Insect larvae that infect the CNS (3)
Cestodes that infect the CNS? (2)
Nematodes that infect the CNS? (5)
Insect larvae:
- Oestrus ovis – nasal cavity of sheep –> ethmoid bone
- H. bovis enter the spinal canal during their migration in the subcutis from the hoof to the dorsal midline
- Cuterebra
Cestodes
- Coenurus cerebralis – larval form of the dog tapeworm Taenia multiceps
- Most commonly infest sheep and occasionally other ruminants
- Cysticercosis in the brain of pigs
Nematodes
- Parelaphostrongylus tenuis – ruminants, camelids
- Strongylus vulgaris – horse
- Elaphostrongylus rangiferi – small ruminants
- Toxocara canis – dogs
- Baylisascaris procyonis – many species
Miller
What are the 4 arboviruses?
What is the histopathologic lesion?
- Togaviridae Western, Venezuelan, Eastern eqine encephalitis
- Bunyaviridae
- Flaviviridae
- Reoviridae
Arbovirus = arthropod-borne virus (ticks and mosquitoes)
Polioencaphalitis with neuronal damage, mononuclear inflammation, gliosis
- WNV - brainstem and spinal cord
- EEE - cerebral cortex
(Vanvelde)
What disease if goat kids causes severe multifocal granulomatous meningoencephalomyelitis (especially brainstem, spinal cord, cerebral white matter)
What infectious disease of horses causes
CAEV (lentivirus)
What are FIV and FeLV lesions of the CNS?
FIV: microglial cells appear to e a primary target of the infection
FeLV: rare complication of chronic FeLV infection is demyelination/axonal damage of the spinal cord white matter (particularly ventromedial and dorsolateral columns) with NO inflammation
- These lesions are associated with infection of endothelial, glial and nerons
(Vanvelde)
What organism causes multifocal, well demarcated hemorrhages on brain surfaces, hemorrhages infiltrated with neutrophils, foci of gram negative bacteria, in cattle brain?
What kind of bacteria is Listeria and how is it spread to the CNS?
Histophilus somni
- normal inhabitant of the respiratory system
- G- coccobacillus
Listeria
- G+, intracellular bacterium
- Spreads from the oral cavity via cranial nerves to the medulla
- Listeric rhombencephalitis
- Invasion of bacteria leads to focal suppuration with microabscesses, then a strong cell-mediated immune response
(Vanvelde)
Salmon poisoning in dogs is characerized by what lesion?
What disease in dogs causes suppurative meningitis, immune-complex necrotizing arteritis, meningeal hemorrhages
Cerebellar meningitis
Steroid-responsive meningitis/arteritis
(Vanvelde)
4 broad categories of neurodegenerative diseases? (and subcategories)
- Axonopathy
- ex/ DM, ENAD
- Neuronopathy
- Motor neuron disease
- Hereditary canine spinal muscular atrophy, multisystem chromatolytic neuronal degeneration, familial motor neuron disease
- Cerebellar Purkinje cell degeneration
- Cerebellar cortical abiotrophy +/- other nuclear degenerative changes
- Other
- Multisystem neuronal degeneration
- Neuronal vacuolation and spinocerebellar degeneration
- Motor neuron disease
- Myelin disorders
- Leukodystrophy
- Necrotizing myelopathy
- Globoid cell leukodystrophy
- Leukoencephalomyelopathy
- Progressive ataxia
- Myelin Dysgenesis
- CNS hypomyelination
- Dysmyelination
- Leukodystrophy
- Other
- Combined encephalomyelopahy and polyneuropathy with neuronal vacuolation
What disease causes degeneration and loss of motor axons in the ventral horns of the spinal cord and axonal degeneration in the ventral spinal nerve rootlets and peripheral nerves?
Specific examples? (3)
Motor neuron diseases
- Motor neurons are chromatolytic + eosinophilic (or drop out)
- Primary lesion = abiotrophy of GSE neurons in the spinal cord ventral gray horn and brainstem nuclei
- Some diseases involve sensory nuclei of the brainstem as well
- Clinical signs evident at a few weeks postnatally, occasionally several mos to year
- Brittany spaniel autosomal DOMINANT - homozygous vs. heterozygous intermediate vs. heterozygous chronic form
- Rottweiler - regurgitation and megaesophagus
- English pointer - autosomal recessive
Examples:
- Equine motor neuron disease (ACQUIRED)
- Shaker calf syndrome in horned Hereford calves, Brown swiss calves
- Hereditary canine spinal muscular atrophy - Brittany spaniel, Swedish Lapland, Rottweiler, English pointer, inherited motor neuron disease in domestic cats
Cerebellar weight < 10% of the brain indicates?
Histopathologic lesions of cerebellar abiotrophy?
4 breeds with late-onset cerebellar abiotrophy?
Cerebellar degeneration
Histopath:
- Degeneration or absence of Purkinje cells, Proximal swelling of Purkinje cell axons
- Variable loss of granule cells
- Cerebellar cortical astrogliosis = BERGMAN astrocytes
- Degeneration of nuclei in the cerebellar medulla
- Symmetrical degeneration of extrapyramidal neurons (olivary nuclei, pontine nuclei, caudate nuclei)
Late onset: American Staffordshire Terrier, Brittany spaniel, Gordon setter, Old English sheepdog
In which breeds is cerebellar cortical abiotrophy associated with ceroid lipofuscinosis?
Striatonigral and cerebello-olivary degeneration is a disease of what 2 breeds?
Staffordshire Terriers/Pitbull terriers
Neuronal storage process predominantly targets the Purkinje cells
Striatonigral and cerebello-olivary degeneration is an AUTOSOMAL RECESSIVE disease in Kerry Blue Terriers and Chinese Crested dogs
- Also called progressive neuronal abiotrophy of Kerry Blue Terriers
- Affects connected neural systems including basal nuclei, the substantia nigra and the cerebellar cortex (caudate nucleus and cerebellar cortex are believed to be the primary sites of involvement)
- Develop signs at 2-5 mos of age - progressive cerebellar ataxia
- Purkinje neurons and caudate nuclei neurons both have receptors for glutamic acid. Excessive accumulation of glutamate in the vicinity of neuronal cell bodies is toxic and causes ischemic degeneration
- Mutation in the SERACI gene - DNA test available
- What breed gets a multisystem neuronal degeneration with nerve cell loss/astrogliosis/axonal swellings in septal nuclei, globus pallidus, subthalamic nuclei, substantia nigra, tectum, medial geniculate bodies, and cerebellar/vestibular nuclei
- Intracytoplasmic neuronal vacuolation and mild spongiform in:
- Cerebellar nuclei
- Extrapyramidal nuclei
- Thalamus
- Ventral and dorsal spinal cord horns
- Spinal ganglia
- Autonomic ganglia
- Cocker spaniel: pathogenesis unknown, progressive over 1st year of life
- Neuronal vacuolation and spinocerebellar degeneration (AKA inherited encephalomyelopathy and polyneuropathy)
- Unknown cause, unknown inheritance
- Spinal cord: bilateral symmetric axonopathy with secondary demyelination, astrogliosis (lat and ventral funiculi) - NOT limited to spinocerebellar tracts
- Neuropathy of recurrent laryngeal and other long nerves
- ROTTWEILER and other breeds
- Unclear if this is primary neuronopathy or axonopathy
2 broad categories of axonopathy
Wallerian-like degenerative axonopathies
- Unknown injury to axon –> distal site undergoes Wallerian-like degeneration
- diffuse axonal and secondary myelin degeneration
- Axon unable to support its metabolism, most distal axon dies first
- Sensory axon - this is in the spinal cord
- Motor axon - this is in the muscle/nerve
- Sensory axon - this is in the spinal cord
Axonopathy with prominent axonal swelling (spheroids)
- Neuroaxonal dystrophy - Axonal changes start at the preterminal portion of the axon and synaptic terminals –> dystrophic axons are found in the nuclei of the gray matter
- Other types
Examples of Wallerian-like axonopathy (7)
- Hereditary ataxia
- Sensory ataxia neuropathy
- Labrador retriever axonopathy
- Peripheral and central axonopathy
- Degenerative myelopathy of large breed dogs
- Degenerative myelopathy of Corgi
- Several in cattle and one in sheep
Canine degenerative disease with:
- Involvement of ventral and lateral columns of the cervical spinocerebellar tracts
- Central auditory pathways (trapezoid body, cochlear nuclei)
- Spinal nerve root degeneration
Breeds? (3)
Hereditary ataxia
- Smooth-haired Fox terrier, JRT/Parson Russell terrier
- Prolonged course of slowly progressive clinical signs of a cerebellovestibular disorder
- Mutation in KCNJ10 - encodes a glial K+ channel that regulates neuronal excitability
- DNA test available
- Izbian hound
- Cerebellarvestibular ataxia at a few weeks of age
- LACK A PATELLAR REFLEX - suggests sensory neuropathy
- Both breeds may have clinical signs that stabilize
- Considered a Wallerian-type degeneration axonopathy
Disease of the dog with:
- Degeneration of central and peripheral axons with proprioceptive fibers most severely affected
- Decrease in mitochondrial ATP production and respiratory chain enzyme activities
- Muscle changes typical of mitochondrial pathology
What cat breed gets a hereditary multisystem degeneration with a distal axonopathy distribution?
Sensory ataxic neuropathy in Golden Retrievers
- Deletion in mitochondrial tRNA Tyr gene is the causative mutation
- Considered a Wallerian-like axonopathy
Birman cats
Which columns/tracts most consistently involved in degenerative myelopathy
Dorsolateral and ventromedial
- Spinocerebellar
- Corticospinal
- Rubrospinal
- Reticulospinal
Degenerative myelopathy is a Wallerian-like axonal degeneration
Which neurodegenerative disease of the Rottweiler starts with hypermetria at 1 year of age, progresses t a full cerebellar syndrome over 1-2 years with sensory systems most affected?
What other breeds get this dz?
Neuroaxonal dystrophy
- Dystrophic axons in the nucleus thoracicus, dorsal horns of the spinal cord, dorsal column nuclei, sensory trigeminal nucleus, cerebellar granular layer, vestibular nuclei and geniculate bodies
- +/- loss of Purkinje cells in vermis and flocculus
Other breeds: Chihuahua and Papillion, Cocker spaniel, Beagles, Border Collie
_____________ is a generalized disorder of cytoplasmic intermediate filaments affecting the PNS primarily, also brain and spinal cord (advanced cases)
Giant axonal neuropathy in GSD
- Giant axons include neurofilaments
- Similar to neuroaxonal dystrophy - mitochondria and organelles also accumulate
- Young adult GSD, progressive TL myelopathy, then LMN PL signs, loss of bark and regurgitation
- Autosoma recessive
- Histo - swollen axons w/ excessive disorganized neurofilaments in the spinal cord (mainly distal long-fiber tracts), also PNS
- Myenteric and sympathetic axons also affected
- ED - decreased amplitude of directed evoked motor potentials and sensory neuron action potentials
- Denervation potentials later in the disease
What is believed to be the cause of progressive axonopathy in Boxer dogs?
- Proximal axonal sswellings + distal hypoplasia of nerves suggests impaired transport of neurofilaments that are major determinants of axon growth
- Immunochemical studies of cytoskeletal proteins (tubulin, neurofilaments, actin, fodrin) confirmed that defects in slow axonal transport are involved
- PL ataxia ~ 3 mos of age
- CNS and PNS both affected
- Spheroids and axon degeneration are prominent in:
- Lateral and ventral funiculi of the spinal cord
- Brainstem nuclei
- Cerebellar white matter
- Optic pathways
- Autonomic nervous system
- PNS - paranodal swellings occur in the extradural spinal nerve roots
Disorder of myelin synthesis and maintenance?
Leukodystrophy
- Affect bilaterally symmetrical areas of white matter + destruction of myelin and eventually axons
- Microscopically - axons lacking sheets, gitter cells, astrocytes
- The distribution pattern of the lesion is often selective or even bizarre and therefore difficult to explain by a general defect at the level of myelin metabolism
Pathologic findings of:
- Bilaterally symmetrical lysis of white matter in the whole circumference of the mid thoracic spinal cord, tapering of lesions cranially and causally
- Occasionally focal involvement of the brainstem
Necrotizing myelopathy
- Autosomal recessive disease described in Afghan hounds, Kooikers, occasionally Miniature Poodles
- AKA afghan hound myelinolysis
- Rapidly progressing signs 7-10 days
- Fasiculus proprius relatively spared
- Same primary demyelination of the axons surrounding the dorsal nucleus of the trapezoid body
- Initial lesion appears to be splitting of the myelin sheath along the intraperiod line
Leukodystrophy that affects Rottweiler and Leonberger dogs is called?
Leukoencephalomyelopathy
- Slowly progressive ataxia between 1.5 - 4y of age
- Bilaterally symmetric white matter lesions in the brain and spinal cord
- Demyelination and remyelination because many axons have very thin myelin sheaths
What is the pathophysiology of globoid cell leukodystrophy?
What are the clinical signs?
How is it tested for?
- Leukodystrophy
- Lack of galactocerebrosidase –> accumulation of psychosine which is toxic to oligodendrocytes and Schwann cells –> PRIMARY demyelination
- Neurons are normal
- Globoid cells are macrophages that are filled with phagocytized myelin remnants
- Clinical signs first occur between 3-7 mos
- TL myelopathy that progresses to involve cervical spinal cord, then cerebellum (OR can start with cerebellar signs –> progress to spinal cord signs)
- PRN test for leukocytes with the gene mutation
Fibrinoid leukodystrophy - What is the other name?
Where are lesions seen?
Alexanders disease
- Cerebral white matter (also other areas…)
- Myelin lesions are associated with Rosenthal fiber formation - string-like depositions of amorphous eosinophilic material perivascularly, especially below the pia and ependyma
White matter spinal cord brainstem lesions of lack of myelin staining in cattle - likely cause?
Progressive ataxia in Charolais cattle
- 1-2 years progressive dz
- higher magnification - finely granular or fibrillar structure can be demonstrated
- Considered a LEUKODYSTROPHY
What malformation results when ewes are exposed to veratrum californicum during pregnancy
Holoprosencephalo - results in failure of the visual area to divide into 2 fields
- Cyclopamine interferes with SHH in the prechordial plate
- One midline optic vesicle develops, single midline telencephalic vesicle develops
- Absence in any nasal portion of the respiratory system and olfactory system
- Also called arhinencephaly
- Reported in a miniature schnauzer with hypodipsia and hypernatremia
- A queen treated with griseofulvin had a kitten with this malformation
(DeLahunta)
Incomplete ossification of the frontoparietal suture is referred to as _________
What is the difference between diplomyelia and diastematomyelia?
Molera or fontanelle
Diplomyelia = duplication of the spinal cord, 1 set of meninges, 1 dural sheath
Diastematomyelia = 2 spinal cords each with own meningeal sheath, each in its own vertebral canal, separated by bony partition
(DeLahunta)
What is the term used to describe when spinal cord segments are smaller than usual?
Segmental hypoplasia.
- Sometimes contain only white matter, no gray matter
What is the inheritance pattern for caudal vertebral hypoplasia or aplasia in the Manx cat?
Caudal vertebral hypoplasia or aplasia is inherited as an autosomal dominant gene and the homozygous state is a lethal factor (Manx cat)
- The clinically affected cats are heterozygotes with variable expression
- The various forms of spinal cord malformation, myelodysplasias, may result in excretory dysfunctions such as urinary and fecal incontinence that is sometimes associated with loss of tone, reflexes, and nociception of the anus and perineal region
- More severe myelodysplasia –> partial or complete inability to stand and walk with PL
- Dr. Miller calls this “anury and brachyury”
(DeLahunta)
Spinal dysraphism is seen in which breed?
What does dysraphism mean?
Weimeraner - this should actually be called myelodysplasia
Spinal cord dysraphism = failure of the neural folds to appose and close
- A number of spinal cord changes occur - hydromyelia, syringomyelia, abberant neuronal migration
- Abberations of the dorsal median septum
- Absence of a ventral median fissure
- Hydromyelia or an absent central canal
- Presence of ventral gray column neuronal cell bodies scattered across midline in the ventral funiculi as a result of their failure to migrate into the ventral gray columns
- These lesions occur in scattered thoracolumbar segments
- NKX2-8 gene on chromosome 8
Hereditary polioencephalomyelopathy of the Australian Cattle Dog
- Age at onset?
- Clinical signs?
- Known cause?
- Pathologic lesions?
- CSF normal/abnormal?
- Age at onset: 5-12 mos
- Clinical signs
- NAD: Multifocal (cervical and lumbar intumescence, medulla/cerebellum, prosencephalon
- Initially seizures, then tetanic contraction of the thoracic limbs
- Slowly progressive
- Known cause: Maternally inherited missense mutation of mitochondrial DNA
- Pathologic lesions:
- Spongiosus and cavitation in cerebellum, brainstem nuclei, spinal cord gray matter (C7/T1 most severe
- EM - abnormally high numbers of swollen mitochondria in astrocytes
- Elev. CSF lactate and pyruvate
What 2 breeds have a mitochondrial encephalopathy secondary to maternally inherited missense mutation of mitochondrial DNA?
Australian Cattle dog and Shetland Sheepdog
- Similar disorder reported in English Springer Spaniel and Yorkshire Terrier
Alaskan Husky encephalopathy - mutation of the ___________ gene results in development of the disease
Clinical signs? Age at onset?
Thiamin transported 2 gene (SLC19A3)
- Therefore NOT a mitochondrial encephalopathy (research has failed to reveal mutations in mitochondrial genes)
- Considered a “secondary mitochondrial disease”
7 mos-6.5 years.
NAD: diffuse involvement of the brain including the cerebrum, brain stem, and cerebellum
- Acute onset of clinical signs, or chronic progressive waxing and waning clinical history.
- Initial onset of seizures
- Cerebellar/vestibular gait
- Hypertonicity in limbs
- Abnormal mentation/behavior
- Abnormal prehension of food, facial hypalgesia
- Euth 2 mos - 1 year after onset of signs
(Miller/deLahunta/Dewey)
Distribution of lesions in Alaskan Husky encephalopathy
Histologic findings?
Bilaterally symmetric foci of encephalomalacia in the:
- Thalamus
- Caudate
- Pons
- Medulla
- Gray-white matter border of the cerebral cortices
Histology - Status spongiosus with variable progression to cavitation/necrosis
Abundance of astrocytes that can be bizarre and vacuolated
MRI - bilateral cavitation from thalamus to medulla, less pronounced degenerative lesions in the caudate nucleus, putamen and claustrum
CSF lactate/pyruvate WNL
(Miller)
5 dog breeds with mitochondral encephalopathy
- Australian cattle dog
- Alaskan husky (really a secondary mitochondrial disorder)
- English Springer Spaniel
- 15-16 mos
- Encephalomyelopathy, Ataxia, disorientation, visual deficits
- Status spongiosus in accessory olivary nucleus, atrophy in optic nerve and tracts, symmetrical spongiosus in the brainstem
- EM - mitochondria with abnormal morphology in neurons
- Yorkshire Terrier
- 4 mos - 1y,
- Cerebellar dysfunction, blindness, Sz, Deaf, Pharyngeal/laryngeal dysfunction
- Bilateral cavitary lesions in thalamus and midbrain
- EM - abnormally-shaped neuronal mitochondria
- CT - bilateral cavitary lesions in thalamus and medulla
- Shetland Sheepdog
- 1-3 weeks, Multifocal CNS/seizures, Maternally inherited missense mutation of mitochondrial DNA
Which molecule conjugates with fatty acids to transport them across the inner mitochondrial membrane, and acts as a buffer for intracellular organic acids?
Carnitine
With organic acidurias, it is common for a secondary carnitine deficiency to develop
(Dewey)
6 Breeds with reported organic aciduria
- Staffordshire Bull Terrier
- West Highland White Terrier
- Maltese
- Standard Poodle
- CKCS
- Labrador Retriever
(Dewey)
Which 2 breeds get L-2-hydroxyglutaric aciduria?
Staffordshire-bull terrier
- Clinical signs: onset 6 mos - 7 years, seizures, ataxia, dementia, head/neck tremors; slowly progressive
West Highland White Terrier
- Visual impairment, dementia, episodic head tremors, tetraparesis with TL hypermetria; slowly progressive
Histopath: Spongy change in the gray matter of the cerebral cortex, thalamus, cerebellum and brainstem
(Dewey, Vanveld)
Which 2 breeds gets malonic aciduria?
Maltese
- onset @ 6 weeks
- Seizures
- Progressive alteration of consciousness
Labrador retriever - methylmalnoic and malnoic aciduria
(Vanvelde, Dewey)
How are organic acidurias diagnosed?
Typical MRI lesions of organic acidurias?
Demonstrating abnormally high levels of specific organic acids in urine, serum, and/or CSF using gas chromatography-mass spectroscopy
MRI - similar to mitochondrial encephalopathies
- bilaterally symmetric lesions of white or gray matter structures that are hyperintense on T2W images
- These lesions tend to be slightly hypontense on T1W images and are noncontrast enhancing
- CSF cytology and protein normal
Treatment of organic acidurias?
Manipulating diet
Adding vitamin supplementation
Goal is to compensate for abnormal metabolic pathway
General recommendations - high-carbohydrate, low-fat (MC triglycerides), low-protein diet and supplementation with L carnitine and B vitamins
Anticonvulsant therapy if necessary
Mutation in TECPR 2 is seen in a neurodegenerative disease of what breed?
Spanish water dog
- Behavior changes
- Gait abnormalities with predominantly sensory deficits
- Histopathology - neuronal loss with spheroid formation seen primarily in the dorsal nuclei of the brainstem and spinal sensory pathways
- Spheroids contain abundant, double-walled, small vacuoles (autophagosomes), few mature lysosomes could be identified
- “The accumulation of autophagosomes within spheroids highlights the role of autophagy in the maintenance of axonal function”
RAB3GAP1 gene mutation identified in which neurodegenerative disease?
Polyneuropathy with ocular abnormalities and neuronal vacuolation = juvenile-onset laryngeal paralysis/polyneuropathy = neuronal vacuolation and spinocerebellar degeneration
- Affected dogs develop laryngeal paralysis, progressive weakness/sensory loss and cataracts at a young age
- Rottweilers also show a prominent cerebellar ataxia
- Gene codes for a protein that plays a role in autophagy and other aspects of membrane processing
- Based on appearance and staining, the vacuoles are unlikely to be lysosomes and are most likely dilated endoplasmic reticulum membranes
(ACVIM 2017)
Mutation in ATG4D contributes to neurodegenerative disease in which breed?
Lagotto Romagnolo
- Progressive cerebellar ataxia and behavioral changes
- Small to large intraneuronal vacuolation and spheroids = abnormal autophagosomes
- Spheroids showed immunoreactivity to autophagy proteins LC3 and p62
- Some of the vacuoles were positive for lysosome markers
(ACVIM 2017)
Mutation in the FAM134B gene identified in which neurodegenerative disease?
Border Collies with hereditary sensory neuropathy
- Ataxia, loss of pain perception, self-mutilation
- FAM134B is expressed in sensory and autonomic ganglia- mediates selective autophagy of the endoplasmic reticulum
(ACVIM 2017)
Mutation in RAB24 gene is associated with which neurodegenerative disorder?
Hereditary ataxia in Old English Sheepdog and Gordon Setter
- RAB24 is thought to play a role in fusion of autophagosome with lysosome
(ACVIM 2017)
Dog
Selective symmetrical encephalomalacia. A. Dog. Alaskan Husky encephalopathy (AHE). Brain: MRI. T2W image with distinctive characteristic bilaterally symmetrical areas of malacia in thalamus. B: Dog. AHE. Corresponding transverse slice through the thalamus with bilateral cystic encephalomalacia.
C: Australian Cattle Dog. Spinal cord. Hereditary polioencephalomyelopathy. There are bilaterally symmetrical areas of myelomalacia. LFB-HE. D: AHE. Histology of the thalamus with malacia, infiltration of gitter cells, neovascular proliferation, mild perivascular mononuclear cell cuffing and marked reactive gemistocytic and fibrillary astrocytosis. Morphologically intact neurons can be found in these lesions. HE.
What is failure of neural tube closure, resulting in persistent attachment of the cutaneous ectoderm to the neural plate and inability of the vertebral arches to close around the open neural plate?
Myeloschisis
(Song et al)
What is “failed separation of the neural tube from the skin ectoderm, causing tubular sacts lined with hair follicles, sweat, and sebaceous glands that typically extends from the dorsal midline to underlying tissues” called?
Dermal sinus tract
- Types I-V depending on the ventral extent of the tubular sac
- Duplication of FGF3, FGF4, FGF19, and ORAOV1 gene mutations responsible for the dorsal hair ridge in Rhodesian and Thai Ridgeback dogs predisposes these breeds
- Differs from dermoid cysts, which are closed epithelium-lined sacs with liquefied substance
- Differs from pilonidal cysts, which are acquired secondary to foreign bodies, such as hair
(Song et al)
What is spina bifida occulta and cystica/manifesta/aperta?
Occulta: no neural tissue involved
Cystica/manifesta/aperta: associated meningocele or myelomeningocele through the vertebral defect
(Song et al)
4 breeds with increased incidence of spina bifida?
- English Bulldog
- German Shepherd
- Rhodesian Ridgeback
- Manx
Song et al
What is tethered cord syndrome?
A syndrome in which excessive stretching and tension on neural tissues occurs owing to abnormal attachments to the vertebrae or skin
May occur in conjunction with MMC and spinal bifida, although may occur in isolation owing to failure of the neuroectoderm to separate from the ectoderm
As a consequence of the abnormal attachments of the neural tissues in NTD, the disproportionate growth of the vertebral column during skeletal maturation in comparison with the neural tissues causes tension on the spinal cord, roots, and/or spinal nerves –> progressive worsening of neurologic deficits (preferable to the lumbar intumescence, conus medullaris, and cauda equina)
(Song et al)
What congenittal abnormalities in dogs and cats can be observed in association or coexistent with NTDs?
Hydrocephalus
Arthrogryposis
Syringomyelia
Cryptorchidism
Cleft palate
(Song et al)
CSF xanthochromia - intensity of the color peaks how long after hemorrhage, lasts for how long after subarachnoid hemorrhage?
Color peaks 24h after hemorrhage, disappears by 4-8 days
Xanthochromia can also be associated with an increase in total protein and hyperbilirubinemia
CSF cell count > ________ is associated with an increase in turbidity
How does the NCC of lumbar CSF compare to cisternal?
NCC > 500 cells/uL (200 WBC/uL or > 700 RBC/uL)
lumbar fluid typically has a lower NCC
(De Terlizzi)
Aside from ablumin, what other proteins are present in CSF?
- Transthyretrin
- Retinol binding proteins
- Transferritin
These are synthesized in the choroid plexi
Also traces of beta/gamma globulin, tau protein, GFAP, and myelin basic protein (synthesized intrathecally)
(De Terlizzi)
How can urine dipstick reagent strip be used to determine CSF protein?
Urine protein reagent strips may be useful for initial preliminary screening of CSF protein concentration
Highly specific for albumin detection, less specific for globulin detection
False positive and false negative test results may occur at dipstick readings of trace or 1+
Dipstick readings of 2+ or above reliably represent a true increase of total protein concentration
Gross and histopathologic lesions of dysmyelination/hypomyelination?
Macroscopically - inadequate myelination/dysmyelination is visible in the white matter assuming a grayish-translucent appearance
Histopathologically - pallor of the white matter
Special myelin stains, thin sections, and electron microscopy help define the defect
PNS is normally myelinated
(Vanvelde)
Cow brain
Spongiform encephalopathy
BSE. A: There is a characteristic gray matter localization of a spongy state (sn, solitary tract nucleus; vn, nucleus vagus; st, solitary tract). HE. B: A higher magnification of the spongiform change with associated astrogliosis. HE. C: Intracytoplasmic neuronal vacuolation in a brainstem nucleus. HE. D: Immunohistochemical visualization of PrPd accumulation with a bilaterally symmetrical pattern of distribution (IV, fourth ventricle). IHC Inset: typical linear PrPd pattern of localization. IHC.
Typical gross appearances of canine oligodendroglioma and astrocytoma.
(A)Canine oligodendroglioma. A well-demarcated, gelatinous gray mass is present in the region of the ventral frontal cortex and basal ganglia (asterisk) associated with areas of hemorrhage and a midline shift.
(B)Canine astrocytoma. A poorly recognizable mass (asterisk) that is of similar color and consistency with the adjacent parenchyma and is associated with a midline shift (arrow)
Koehler et al
Glial tumor with the following features:
- Nuclei - Mostly round, coarse chromatin pattern
- Cytoplasm - Scant to moderate eosinophilic (or lost due to artifact)
- Pseudo-rosettes
- Nuclear rowing
- Myxoid/mucinous matrix +/- lakes
- Branching capillaries
- Mineralization
- Nuclear molding
Oligodendroglioma (if >80% of tumor meets the criteria)
(Koehler et al)
Glial tumor with the following characteristics:
- Nuclei - oval to elongate, open-faced chromatin pattern
- Naked nuclei
- Pleomorphic cells (large nucleoli, multinucleate cells), elongate cells (pilocytic), spindle-cell morphology
- Cytoplasm - eosinophilic, abundant cytoplasm
- Random, disorganized pattern
- Lower degree of cell density
- Rare mucin microcysts
- Mineralization
- Eosinophilic stroma
Astrocytoma
if > 80% of the tumor meets these criteria
(Koehler et al)
How is low vs. high grade glioma determined?
(Infiltration does not matter)
If necrosis +/- microvascular proliferation +/- pseudopalasading –> high grade
- If none of the above, does it have:
- Mitosis in ten 400x fields +/- Overt presence of universal features of malignancy?
- If yes –> high grade
- If no –> low grade
Koehler et al
K9 brain tumor
Pathologic features of undefined canine glioma
(A)A roughly equal proportion of oligodendroglioma-like morphology (top) and astrocytoma-like morphology bottom).
(B)Two distinct populations of neoplastic cells with small, basophilic cells admixed with mucin separated by islands of less dense neoplastic cells that are more astrocytic in morphology.
(C)Regions of basophilic mucin deposition in an undefined canine glioma
Koehler et al
D - Olig2
E - GFAP
F - CNPase
Dog brain tumor
Pathologic features of canine glioma immunohistochemical features
(D)Olig2immunoreactivity in canine oligodendroglioma is characterized by diffuse, intense intranuclear immunoreactivity in virtually all of the neoplastic cells.
(E)GFAP immunoreactivity in canine astrocytoma is often patchy, but intense cytoplasmic immunoreactivity is noted in approximately 30%of the neoplastic cells.
(F)CNPase immunoreactivity in canine oligodendroglioma is diffusely cytoplasmic and specific for the neoplastic cells.
Koehler et al
Features of oligodendroglioma
Koehler et al
Canine brain tumor
Meningothelial meningioma
- Tumor cells form sheets and lobules of meningothelial cells
- Cells are uniform with fine chromatin patterns
- Nuclear inclusions can be seen
- Whorls and psammoma bodies are not common
- Relatively common in the dog, less common in the cat
(Miller)
Canine brain tumor
Fibroblastic meningioma
- Spindle cells forming parallel, storiform, and interlacing bundles and fasicles
- Abundant collagen
- Nuclear features approximate those in the meningothelial variant (fine chromatin pattern, nuclear inclusions can be seen)
- Less common variant in the dog and cat
(Miller)
Canine brain tumor
Transitional meningioma
- Co-evolution of fibroblastic and meningothelial patterns
- Typically interlacing regions of fasicles and tight whorls
- Very common pattern in the dog and cat
(Miller)
Canine brain tumor
Psammomatous
- These tumors contain a predominance of psammoma bodies (>75% sample)
- Typically a background transitional pattern
- Uncommon in the dog, very common in the cat
(Miller)
Canine brain tumor
Atypical meningioma
- Increased mitotic activity (>4 per 400x field) or >3 of the following:
- Increased cellularity
- Small cells with high N:C ratio
- Prominent nucleoli
- Sheet-like growth
- Foci of necrosis (geographic)
- Can occur with any other pattern
- Common in the dog, rare in the cat
(Miller)
Canine brain tumor
Microcystic meningioma
- Abundant intracytoplasmic cysts that may coalesce to form microcysts in tissue
- An uncommon variant but common change seen in many canine meningiomas as a minor component
- Rare in cats
(Miller)
Canine brain tumor
Rhabdoid meningioma
- Plump cells with eccentric nuclei; commonly have eosinophilic cytoplasm
- Similar pattern seen in other tumor types
(Miller)
Canine brain tumor
Papillary meningioma
- Pseudorosettes predominate often along with other features like meningothelial whorls
- Frequency increases with recurrences
- Commonly invade the brain parenchyma
- Uncommon in the dog; extremely rare in the cat
(Miller)
Canine brain tumor
Anaplastic meningioma
- Histologic characteristics of frank malignancy including atypia, markedly elevated mitotic rate (20 per 10), geographic often large regions of necrosis
- Rare in the dog and cat
(Miller)
Canine brain tumor
Choroid plexus tumor
- Papillary and frond-like intraventricular masses, often with invasion into adjacent neuroparenchyma
- Some are most solid with small tubules and trabeculae
- Cells will spread widely in the CSF and lead to carcinomatosis
(Miller)
Ependymoma
- Uncommon/rare intracranial tumors in the dog (< 2-3%)
- Mostly reported in the lateral ventricle; less often in the 3rd and 4th ventricle
- More common in cats
(Miller)
Feline brain tumor
Figure 4.Brain; cat no. 1. Classic ependymoma with numerous pseudorosettes and fewer true rosettes. HE.Inset: Detail of the pseudos-stratified neoplastic cells around a blood vessel in a pseudorosette. HE.
Figure 5. Brain; cat no. 1. Tall columnar neoplastic cells arranged in true rosettes (R) with a core of cell processes. HE.
Figure 6.Brain; cat no. 13. Tanycytic ependymoma. Irregular bundles of neoplastic cells with delicate and elongated (piloid) processes.
(Woolford et al)
Cat brain tumor
Figure 7. Brain; cat no. 15. Area of clear cell differentiation in a papillary ependymoma. Tall columnar to polygonal cells have clear cytoplasm and small round nuclei. Rosettes (R) are present. HE.
** clear cell subtype occurs only in the lateral ventricle
Figure 8.Brain; cat no. 12. Subependymoma. Irregular clusters of tumor cells with prominent nuclei are separated by zones rich in fibrillary cell processes.
Figure 9. Brain; cat no. 17. Glomeruloid microvascular proliferation where the extraventricular ependymoma invades the neocortex. HE.
Figure 10.Brain; cat no. 1. Strong diffuse cytoplasmic GFAP immunoreactivity in a classic ependymoma. Immunohistochemistry with hematoxylin counterstain
(Woolford et al)
Canine brain tumor
Granular cell tumor
- Typically occur as plaque-like masses over the cerebral hemisphere, less commonly in other areas
- Sheets, nodular foci, clusters of neoplastic cells with abundant eosinophilic granular cytoplasm
- Reported to occur in the neurohypophysis
- Sometimes combined with meningiomas
- S100, ubiquitin, and alpha-1-antitrypsin immunoreactive
- Negative GFAP, negative leukocyte and macrophage markers
(Miller)
Canine brain tumor
Suprasellar germ cell tumor (Germinoma)
- Uncommon to rare tumor in the dog
- Consist of sheets of germ–cells, hepatocyte-like cells and epithelial differentiation
- IHC for alpha fetoprotein is diagnostic
(Miller)
Canine brain tumor
Histiocytic sarcoma
- Single or multiple, either parenchymal, meningeal or both
- Either part of systemic disease or primary in the CNS
- Primary variant arises primarily in the meninges and invades the parenchyma
(Miller)
Canine tumor
Nephroblastoma
- Arises between T10 and L2
- Can metastasize within the CNS to form multiple masses
- Seen in young dogs
- Arises intradural but extraparenchymal location
- ICH for wilms tumor 1 is confirmatory
(Miller)
Canine tumor
Malignant nerve sheath neoplasm
Schwannoma
- Most common in nerve roots and cranial nerves (especially 5 and 8)
- expansive and invasive neoplasms. Often track into the parenchyma around perivascular spaces
- Antoni A: Long, bipolar spindle cells with rare palisading Verocay body formation
- Antoni B: Markedly pleomorphic cells embedded in and eosinophilic to myxomatous stroma
- May have cartilage, bone, epithelial, and melanocytic differentiation
- Robustly positive for S100
Neurofibroma
- Mixture of schwannoma features with abundant collagen, fibroblasts, and perineurial cells
- Decreased S100 staining
Perineurioma
- Unique and rare tumor with tight concentric whorls of neoplastic perineurial cells, often around a central axon
(Miller)
Dog brain tumor
Choroid plexus tumors.
A: Comparison of the similar histology of the normal choroid plexus (right side) with that of a papilloma on the left.
B: Surgical biopsy of a choroid plexus carcinoma in the fourth ventricle. There is piling up of epithelial cells, mitotic figures >2 per 400X HPF and some cell sheeting. HE.
C: Low and high MW (Lu5) cytokeratin immunoreactivity in a choroid plexus papilloma. IHC.
D: Neoplastic epithelial cells from a cytospin preparation of CSF from a choroid plexus carcinoma. Wright’s stain.
Paraganglioma.
A: The characteristic packeting of nests of neuroendocrine-like cells formed by a thin fibrovascular stroma. HE.
B: The supporting fibrovascular stroma contains the cells within islands or nests. Reticulin silver stain.
C: Strong cytoplasmic immunoreactivity to chromogranin (illustrated) and to synaptophysin is expected in most cells. IHC
(Vanvelde)
Dog nerve tumor
Schwannoma.
A: Histologically, these tumors are comprised of spindle-shaped cells with elongate nuclei and bipolar cytoplasmic processes, which form patterns of intersecting bundles, streams or whorls.
B: Dog. Neurofibroma. These tumors have very low cell density forming spindle-shaped elongate cells (of Schwann or fibroblast cell origin) with abundant collagen arranged isomorphically.
C: Immunoreactivity to laminin in the pattern of each cell bordered by a thin lamina is confirmation of a schwannoma. IHC
(Vanvelde)
Young dog with neck pain
Steroid-responsive meningitis arteritis (SRMA).
A: Dog. Acute SRMA. Large spinal meningeal artery (partially thrombosed lumen); muscular layer (media, m) with focal acute fibrionoid necrosis (arrows), with intense inflammation in surrounding meninges (arach). HE.
B: Dog. Chronic SRMA. Chronic stenosing arterial lesion. The original structure of the media (m) with concentrically arranged smooth muscle cells is intact. Between the media and the endothelium there is a massive layer of cell infiltration with sub-intimal fibrosis and stenosis of the vascular lumen. There is some non-suppurative inflammatory cell infiltrate in the meninges and perivascularly (arrows). HE
(Vanvelde)
Canine brain
Canine necrotizing meningoencephalitis (NME). Pug dog.
A: Cerebrum.Transverse MRI FLAIR sequence showing massive acute hyperintense bilateral lesions in cerebral cortex and subcortical white matter.
B: Lateral view of the brain. Gross lesion in temporal lobe with multifocal areas of discoloration and underlying cortical necrosis.
C: Histological section of the same dog at the same level as in B. Extensive destruction of cortex on right side and subcortical white matter on left side.
D: Frontal lobe. Severe lymphocytic meningitis and polioencephalitis with necrotizing leukoencephalitis in underlying white matter. HE
Canine brain
Canine necrotizing encephalitis (NE). Dog. Yorkshire Terrier.
A: Transverse MRI FLAIR image at level of basal ganglia. Hyperintense lesions in cerebral white matter. Destructive grey matter lesions on the right side.
B: Similar case. Chronic lesion with cystic malacia and associated cerebral atrophy.
C: Cerebrum. Destructive lesion with intense diffuse infiltration with inflammatory cells and several very prominent perivascular cuffs comprised mainly of lymphocytes. HE.
D: NE. Dog. Yorkshire Terrier. Subcortical white matter. Severe diffuse infiltration with inflammatory cells in parenchyma at the edge of a malacic lesion. HE. E: “Burnt out” cystic lesion with distinctive proliferation of gemistocytic astrocytes and thick lymphocytic perivascular cuffing. HE
(Vanvelde)
Canine nerve
Acute polyradiculoneuritis. Dog. Spinal nerve root. Diffuse lymphocytic infiltration (large arrow), several degenerating axons (arrows) within the fascicle. HE
(Vanvelde)
Horse cauda equina
Cauda equine neuritis. Horse.
A: Massive enlargement of lumbosacral spinal nerves outside of the dura mater.
B: Histologically there is a multifocal fibrosing, granulomatous and necrotizing polyneuritis sometimes with multinucleated giant cells (arrow). HE
(Vanvelde)
Causes of hemorrhagic brain infarcts
- Thrombosis of veins (uncommon)
- Vascular damage of artery, increased leakage of erythrocytes when reperfusion occurs in focal ischemia
- Leads to ring hemorrhages which may coalesce to form larger hemorrhagic lesions
- Hemorrhagic cerebral infarcts must be differentiated from TRAUMA
- Traumatic lesions more likely to have meningeal contact, meningeal hemorrhage, and possibly “contre-coup” lesions in other locations
(Vanvelde)
Cat brain with:
- Hyalinosis of the vessel wall (thickening and leakage of eosinophilic material and its deposition in the vessel wall resulting in hyaline appearance)
- Hyperplastic arteriosclerosis (thickening of the vessel wall due to concentric hyperplasia of spindloid cells)
- Severe vasogenic edema
- Parenchymal and subarachnoid hemorrhages
- Ischemic necrosis w/ influx of phagocytes
Hypertensive encephalopathy
- Develops with an abrupt and prolonged increase of systemic blood pressure that overwhelms the autoregulatory mechanisms of the brain
(Vanvelde)
What vessels supply each colored area?
Red: central (sulcal) branch of the ventral spinal artery
Blue: circumferential branches of the ventral radicular arteries
Green: Circumferential branches of the dorsal spinal artery
(Vanvelde)
Dog spinal cord
Dog. Fibrocartilagenous emboli (FCE).
A: White matter of the cord. Well demarcated area of pallor with edema, acute necrosis and hemorrhage. Embolus occludes the dorsal radicular artery (arrow). HE.
B: Infarcted area with edema, dilation of myelin sheaths, fibrocartilagenous embolus (arrow). HE.
C: A large fibrocartilagenous embolus almost completely occludes a subarachnoidal vein. HE.
D: Fibrocartilagenous emboli stain bright blue with alcian-blue stain
Cat brain
Cat. Feline hypertensive encephalopathy
A: Hyaline changes and thickening of arteriolar walls, secondary proteinaceous exudation, edema and gliosis in the surrounding brain parenchyma. HE.
B: Subarachnoidal arteries showing hyperplastic changes with massive thickening of the wall due to adventitial fibroblast proliferation and subendothelial deposition of hyaline material. HE
(Vanvelde)
Dog brain
Dog with septicemia. Cross-section of forebrain. Multifocal and randomly distributed hemorrhages of varying size in the gray and white matter
(Vanvelde)
Cat brain - what is the lesion?
Previous old trauma. A: Cat. A depressed area of focal, chronic encephalomalacia in the right frontal lobe with loss of tissue. Note yellowish-brown discoloration of the lesion
(Vanvelde)
B: Diagram of common types of dysraphic malformations of the spinal cord associated with spina bifida
a: spina bifida aperta with a lack of closure of the neural tube
b: spina bifida occulta
c. meningomyelocoele
d: meningocoele.
(Vanvelde)
Weimaraner puppy. Spina bifida, absent dorsal arch with a syringomyelic cavity in dorsal columns
Vanvelde
Disorders of neuronal migration and sulcation.
A: 6-month-old Lhaso Apso dog. Brain with agyria (lissencephaly). Note the lack of any hemispheric gyral formation and slight collapse of cerebral hemispheres suggestive of some degree of hydrocephalus.
B: Same dog, transverse section through the cerebral hemispheres with complete lack of gyral formation. Note thickened cortex and and a bilateral midcortical laminar layer of aberrant white matter. The subependymal white matter is relatively thin and there is bilateral slightly asymmetrical hydrocephalus. HE-LFB stain.
C: Newborn goat. Brain. Pachygyria. Normal cortical gyri are replaced by fewer greatly thickened gyral convolutions bilaterally in the cerebral hemispheres. There is also a severe cerebellar hyoplasia.
D: Calf brain. Polymicrogyria. There are multifocal random areas of small disorganized cortex with smaller gyri in the cerebral hemispheres.
(Vanvelde)
Encephaloclastic defects.
A: Dog. Brain. Porencephaly. There is a single, once fluid-filled, cyst in both white and gray matter but without connections to either the ventricle or subarachnoid space.
B: Neonatal calf. Hydranencephaly. This calf was transplacentally infected with modified live bluetongue virus at 60 days’ gestation. The cerebral hemispheres have been essentially destroyed and there are residual cystic meningeal sacs, which have collapsed. The cerebellum and brainstem appear normal
(Vanvelde)
Cat cerebellum - what is the pathology?
Cat. Virus-induced cerebellar hypoplasia.
A: Kitten. Normal neonatal cerebellum including the folial cortex. HE.
B. Kitten with extreme cerebellar hypoplasia and dysplasia from in utero transplacental feline panleukopenia virus infection. HE.
C: Newborn kitten. Cerebellum. Feline panleukopenia virus intranuclear viral inclusion bodies and cytolysis of the subpial neuroblast layer. HE.
D: Kitten. Extreme cerebellar folial dysplasia and hypoplasia with almost non-existent granular layer and dysplastic disorganized Purkinje cells
(Vanvelde)
Neonatal foal. Dandy-Walker syndrome. There is marked vermal cerebellar agenesis with cystic distension of the fourth ventricle
(Vanvelde)
Puppy with quadrigeminal cyst.
A: Sagittal MRI with the T2W image revealing the patent connection between the lumen of the quadrigeminal cyst and the third ventricle. The cerebellar vermis is herniated through the foramen magnum.
B: Gross image of the same puppy as in A. The cyst has collapsed but leaves a markedly enlarged space (arrow) with obvious induced compression of the occipital lobes and cerebellum with cerebellar coning. There is also dilatation of the lateral ventricle
(Vanvelde)
Dog brain tumor cytology
Meningioma
- Exfoliate in variably tight aggregates that may be associated with pink extracellular matrix
- Cells mostly are fusiform to stellate, but can be ovoid and have a moderate volume of pale-blue cytoplasm
- Nuclei are ovoid with finely granular chromatin and multiple prominent nucleoli
- Round prominent structures may be seen in the nucleus (nuclear pseudoinclusions) - represent projection of the cytoplasm into nuclear grooves
- Anisocytosis/anisokaryosis usually are moderate, N/C ratios are variable
(Burton)
Canine brain tumor cytology
Meningioma
- Exfoliate in variably tight aggregates that may be associated with pink extracellular matrix
- Cells mostly are fusiform to stellate, but can be ovoid and have a moderate volume of pale-blue cytoplasm
- Nuclei are ovoid with finely granular chromatin and multiple prominent nucleoli
- Round prominent structures may be seen in the nucleus (nuclear pseudoinclusions) - represent projection of the cytoplasm into nuclear grooves
- Anisocytosis/anisokaryosis usually are moderate, N/C ratios are variable
(Burton)
Canine brain tumor cytology
Psammoma body
(Burton)
Canine brain tumor cytology
Lymphoma
- Lymphoma of the CNS appears similar to that in other organs
- Expanded population of discrete, round cells with round to indented nuclei approximately 2-3 RBCs in diameter
- Finely stippled, immature chromatin
- The chromatin pattern and amount of cytoplasm are most useful in differentiating from lymphoma
- Oligodendroglioma - moderate volume of medium-blue cytoplasm. Nuclei are ovoid and eccentrically placed and have coarsely granular chromatin with prominent nucleoli
(Burton)
Canine brain tumor cytology
Astrocytoma
- Cytologic appearance of astrocytomas varies with degree of differentiation of the neoplastic cells
- Differentiated tumors comprise spindloid cells
- Scant cytoplasm forming long bipolar cytoplasmic processes
- Elongated nuclei
- Finely granular chromatin
- Fine basophilic nucleoli
- Anisocytosis/anisokaryosis are mild to moderate
- N/C ratio high
(Burton)
Canine brain tumor cytology
Oligodendroglioma
- Abundant coursing capillaries
- Neoplastic cells are fragile, bare nuclei may be present
- Cells are ovoid with a moderate volume of medium-blue cytoplasm
- Nuclei are ovoid, eccentrically placed
- Coarsely granular chromatin with prominent nucleoli
- Chromatin pattern, amount of cytoplasm - most useful in differentiating from lymphoma
(Burton)
Dog spinal cord tumor cytology
Primitive neuroectodermal tumor (PNET)
- Exfoliate in loosely cohesive sheets and cells often are seen individually such that they may be difficult to differentiate from lymphoma
- Compared to lymphoma, the cells often aggregate and tend to form vague palisading and acinar-like arrangements
- Ovoid nuclei
- Stippled chromatin
- Variably prominent nucleoli
- Anisocytosis/anisokaryosis are mild to moderate
- NC ratio high
- Many mitotic figures usually present
(Burton)
Dog brain tumor cytology
Histiocytic sarcoma
- Population of large, atypical, discrete cells
- Round with a variable volume of medium-blue cytoplasm that often is vacuolated
- Nuclei are ovoid to ameboid
- Finely stippled chromatin
- Multiple prominent nucleoli
- Anisocytosis/anisokaryosis are marked
- NC ratios are high
(Burton)
Dog brain tumor cytology
Choroid plexus papilloma
- Comprised of cohesive sheets of round cells
- Moderate to abundant amounts of mid blue cytoplasm containing variable number of fine pink granules
- Nuclei round to ovoid, eccentrically placed, have small or inapparent nucleoli
- Anisocytosis/anisokaryosis are mild
- NC ratio are moderate to low
(Burton)
Canine brain tumor cytology
Choroid plexus carcinoma
- Exfoliate in sheets, often palisading in rows
- Cells have a small to moderate volume of mid-blue cytoplasm
- Round nuclei
- Coarsely granular chromatin
- Variably prominent nucleoli
- Anisocytosis/anisokaryosis are mild to moderate
- NC ratios are high
(Burton)
Canine brain tumor cytology
Ependymoma
- Ependymomas exfoliate as tightly cohesive clusters, often acinar-like arrangements
- Moderate volume of medium-blue cytoplasm, may contain clear vacuoles
- Nuclei are round, eccentrically placed
- Granular chromatin
- Single nucleoli
- Anisocytosis/anisokaryosis are mild to moderate
(Burton)
Canine brain lesion cytolog
Encephalitis
- Inflammatory lesions in the CSF are characterized by variable numbers of inflammatory cells
- Type of cells may indicate the underlying cause
(Burton)
Canine CSF
Myelin-like material
- Appears as variably sized-aggregates of pale-pink, foamy material, often with internal circular structures giving a honeycomb appearance
- Mostly incidental finding in CSF
- Larger amounts associated with intervertebral disc disease
- More likely seen in lumbar than cerebellomedullary samples, and in dogs < 10kg
(Burton)
Canine CSF
Surface epithelial cells
- Ependymal, meningeal, and choroid plexus cells possible
- Round, moderate volume of pink granular cytoplasm and eccentric nuclei = ependymal or choroid plexus origin
- Polygonal/spindloid with pale blue cytoplasm and round/ovoid nuclei - meningeal origin
- Anisokaryosis/cytosis are mild
(Burton)
Canine CSF
Lymphotycic pleocytosis
(Burton)
Feline CSF
Mononuclear pleocytosis/reactivity
- Macrophages predominate in normal CSF
- In cases of mononuclear reactivity, these cells are present in normal numbers but have reactive changes including increased volume of vacuolated cytoplasm or increased cytoplasmic basophilia
- Reactive monocytes w/o blood contamination - useful indicator of CNS pathology
- Nonspecific
(Burton)
CSF cat
Feline infectious peritonitis
- Fluid has very high protein content - medium to thick purple background
- Reactive macrophages usually predominate, neutrophils may also predominate
- Small mature lymphocytes often present
(Burton)
Canine CSF
Cryptotoccal meningitis
(Burton)
Canine CSF
Lymphoma
- Lymphoma in the CSF exfoliates as discrete round cells that are large, with nuclei approximately 2-3 red blood cells in diameter
- Nuclei may be round, indented, or have irregular borders
- chromatin is finely granular
- Nucleoli are prominent
- Mitotic figures are common
(Burton)
Canine CSF
Histiocytic sarcoma
- Large cells, marked atypia
- Nuclei vary from ovoid to ameboid
- Multinucleation is common
- Mitotic figures are common
- Anisocytosis/anisokaryosis are marked
- N/C ratios variable
- Frequently accompanied by mixed inflammatory response
- Immunocytochemical stains may be required for definitive diagnosis
(Burton)
Canine CSF
Choroid plexus carcinoma
- May be seen in CSF as cohesive sheets (often palisading rows)
- Individualized cells that are round with moderate volume of mid-blue cytoplasm
- Round eccentrically placed nuclei
- Granular chromatin
- Prominent nucleoli
- CP carcinomas - higher CSF protein than papilloma
(Burton)
Canine spinal cord tumor
Nerve sheath tumor
- Samples are variably exfoliative, cells seen individually and in aggregates that may be associated with a bright-pink extracellular matrix
- Cells are spindloid and plump with a moderate volume of medium-blue cytoplasm
- Forms tendrils and wisps
- May contain clear vacuoles
- Nuclei are ovoid
- Coarsely granular chromatin and prominent nucleoli
- Anisocytosis/anisokaryosis are mild to moderate
- NC ratios are moderate to high
- Can be difficult to differentiate from meningiomas
- Presence of long cytoplasmic wisps is more suggestive of nerve sheath tumors
- Includes Schwannomas, neurofibromas, neurofibrosarcomas
(Burton)
Canine ventral funiculus
Degenerative myelopathy
“This is a longitudinal microscopic section showing a chain of ellipsoids reflecting secondary demyelination and containing axonal fragments”
de Lahunta
Young afghan hound
A microscopic section of the C8 spinal cord segment from a young Afghan hound with myelinolysis.
Note the sparing of the fasciculus proprius and the nerve roots.
(de Lahunta)
“A microscopic section of a midthoracic spinal cord segment of the same Afghan hound with myelinolysis in Fig. 10.27 . Note the bilateral symmetry of the lesion”
5m Doberman Pinscher C4
“Note the normal space around the spinal cord as compared with that in Fig. 10.43. The discoloration of the dorsal funiculi represents the wallerian degeneration of these cranial projecting pathways, which were disrupted by the compression at the level of the C5 spinal cord segment”
(de Lahunta)
Great dane puppies
“Cranial surface of the disarticulated fifth cervical vertebrae from two great dane puppies who were littermates. Number 17 (left) came from a puppy that was allowed to eat ad lib, whereas Number 16 (right) came from a puppy that was fed 25% less than Number 17. Note the failure of bone resorption around the cranial orifice of the vertebra in the puppy fed ad lib.”
(de Lahunta)
Cat brain
at the level of the confluence of the cerebellar peduncles. Note the abnormal basophilic staining associated with the choroid plexus on the left and associated with the parenchyma adjacent to the fourth ventricle on the right of the image. Infection with the feline infectious peritonitis virus caused this choroid plexitis, ependymitis, and associated periventricular encephalitis
(de Lahunta)
Nerve biopsy
2year old male Leonberger dog with inherited polyneuropathy. Note the depletion of large myelinated nerve fibers and endoneurial fibrosis
Toluidene blue stain
(VCNASAP Coates)
What neuropathy causes this?
Sensory neuropathy in English Pointer and Short-Haired Pointer
Absence of substance P
Loss of small myelinated and unmyelinated nociceptive fibers
(VCNASAP Coates)
Feline muscle biopsy
Histopathology of a muscle biopsy specimen from a Norwegian Forest cat with type IV glycogenosis showing the presence of macrophages with stored material in cells of skeletal muscle and in surrounding connective tissue.
Myofiber necrosis also is evident (hematoxylin-eosin stain).
(VCNASAP Coates)
Cerebellum. What is the pathology?
Cerebellar atrophy
Note the marked absence of both the Purkinje neurons and the granule cell neurons in the cortex on both sides of the folial white lamina in the center
Will also see degeneration in the pontine nuclei, olivary nuclei, caudate and substantia nigra
(de Lahunta)
Calf brain
2 week old calf with cerebellar hypoplasia and atrophy caused by in utero infection with bovine viral diarrhea virus
Note the severe lack of cerebellar tissue and its asymmetry
(de Lahunta)
Cerebellum 7m Portugese water dog
GM1 gangliosidosis
Note the swelling of the cytoplasm caused by the accumulation of GM1 ganglioside substrate
(de Lahunta)
Dog brain
Chronic cerebrocortical necrosis post anesthetic hypoxia
“Higher magnification of a microscopic section of the neocortex of two adjacent occipital lobe gyri from a dog with a history similar to that of the boxer dog in Fig. 14.77. Note that the central laminae are most at risk after hypoxia”
The caudal colliculi are also very susceptible
(de Lahunta0
