JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2023

N-V17

 

Signalment (JPC #1948535): 8-month-old spayed female lilac-point Himalayan cat 

 

HISTORY: This cat exhibited ataxia, anterior uveitis, and chorioretinitis. The clinical course deteriorated to the point where the cat was euthanized. Grossly, there were bilateral corneal protrusions with central (2-3 mm) erosions, a faintly mottled liver with gray-white foci, and nodules on the left kidney.

 

HISTOPATHOLOGIC DESCRIPTION: Cerebrum and diencephalon: Multifocally expanding Virchow-Robin space up to 2-5 times normal and infiltrating the perivascular and periventricular neuroparenchyma, as well as the choroid plexus, are numerous epithelioid macrophages, lymphocytes, plasma cells, and fewer Mott cells and neutrophils. Vessel walls (primarily venous) are often obscured or disrupted by previously described inflammatory cells (phlebitis) or are lined by hypertrophied (reactive) endothelial cells. There is periventricular rarefaction and loss of the neuroparenchyma (liquefactive necrosis) with replacement by variable amounts of eosinophilic proteinaceous fluid. Multifocally, the ependymal lining of the lateral ventricle and third ventricle is lost and replaced by the previously described cellular infiltrate. The third ventricle is filled with eosinophilic proteinaceous fluid and few of the previously described inflammatory cells.  Within the adjacent neuroparenchyma there is mild to moderate gliosis composed of scattered reactive and gemistocytic astrocytes, gitter cells, and microglia, with vacuolation of the neuroparenchyma (spongiosis). Occasionally, myelin sheaths are dilated and rarely contain swollen, hypereosinophilic axons (spheroids).  

 

MORPHOLOGIC DIAGNOSIS: Cerebrum and diencephalon: Encephalitis, perivascular and periventricular, granulomatous and lymphoplasmacytic, diffuse, marked, with necrosis, phlebitis, ventriculitis, and choroiditis, Himalayan cat, feline.

 

ETIOLOGIC DIAGNOSIS: Coronaviral encephalitis

 

CAUSE: Feline infectious peritonitis virus (Feline coronavirus – FCoV)

 

CONDITION: Feline Infectious Peritonitis (FIP)

 

GENERAL DISCUSSION: 

• Family Coronaviridae, genus Alphacoronavirus - enveloped, single-stranded, positive-sense RNA viruses; has two biological pathotypes: Feline infectious peritonitis virus (FIPV) and Feline enteric coronavirus (FCoV)
• Feline infectious peritonitis (FIP) is a worldwide, invariably fatal, sporadic, low prevalence viral disease of domestic and wild felids caused by FIPV which is a mutated form of FCoV

 

PATHOGENESIS:

• Fecal-oral transmission and possibly by inhalation of FCoV > replication in enterocytes / lymphoid system > leukocyte trafficking to Peyers patches > spontaneous viral genetic mutation during replication in infected host (FCoV > FIPV) that enables the virus to replicate in macrophages > secondary macrophage associated viremia and macrophages are activated> dissemination to multiple organs and vessels (systemic infection) > host immune response > granulomatous inflammation with vasculitis (phlebitis)
• Transmission is oronasal via feces; rarely saliva, mutual grooming, close contact, sharing food bowl, grooming tools; transplacental is uncommon
• The progression of disease depends on the cat’s immune response:

• Strong cell-mediated immune response: Results in activation of macrophages, FIP virus replication is terminated, and cleared  
• Weak or ineffective cell-mediated response: Delayed (Type IV) hypersensitivity response; noneffusive (dry form) syndrome ensues, with a less florid macrophage response in tissue and reduced virus production; this form has a more prolonged clinical course (1-6 months) 
• No/ineffective cell-mediated immunity: Antibody is produced, but there is a failure to generate a cell-mediated response and cats develop effusive disease (wet form); vasculitis results from both Type III hypersensitivity response [primary immune complex] and activation of macrophages; this syndrome has a rapid clinical course, progressing to death in 1-12 weeks 

• FCoV likely uses proteins such as the spike (containing S1 and S2 subunits) protein, and potentially other glycoproteins such as S2, M, and E, to attach and bind to feline aminopeptidase-N, a cell membrane receptor on monocytes and macrophages 
• Two serotypes; both serotypes may cause FIP, most commonly Type I

• Type I: Cytopathic
• Type II: Non-cytopathic

 

TYPICAL CLINICAL FINDINGS:

• Clinical signs and pathologic findings are due to vasculitis and phlebitis and organ failure resulting from damage to blood vessels that supply them
• Cats 3 months to 3 years old; purebreds; young intact males
• Neurologic signs:

• Behavioral changes, dullness, coma, paresis, ataxia, paralysis, seizures
• If FIP lesions affect peripheral nerves or spinal column then lameness; progressive ataxia; tetraparesis, hemiparesis, or paraparesis

• Noneffusive (dry parenchymatous form): Granulomatous inflammation, localized in the lymph nodes, kidneys, uvea, meninges, ependyma, and choroid plexus of the brain and spinal cord

• Insidious onset, vague signs of dullness, weight loss, and anorexia  
• Ocular lesions: Uveitis, chorioretinitis, panophthalmitis 
• CNS signs (ataxia, nystagmus, seizures) 
• Clinicopathological Features: 

• Lymphopenia
• Neutrophilia with left shift
• Nonregenerative anemia ([HCT] <30%; anemia of chronic disease)
• Cerebral spinal fluid elevated protein levels (56-348 mg/dl with normal <25 mg/dl) and pleocytosis (100-10,000 nucleated cells/ml)

• Effusive (wet form): Ascites, pleural and pericardial effusion, weight loss,

dyspnea, tachypnea, mild pyrexia, icterus, scrotal enlargement, palpable abdominal masses (from adhesions); rapid clinical course- death within a few weeks   

• Clinicopathological Features: 

• Plasma proteins typically elevated because of hypergammaglobulinemia (may be polyclonal or monoclonal) due to chronic inflammation and antibody production 
• Effusion is a high protein exudate or modified transudate
• Serum Albumin:globulin ratio less than 0.8 (albumin level remains normal or falls slightly and globulin levels increase)

 

TYPICAL GROSS FINDINGS:

• CNS lesions: Plaques in cerebral sulci; mild to moderate hydrocephalus with accumulation of a fibrinous protein-rich exudate; cerebellar herniation
• Noneffusive form – Grey-white nodules that are often perivascular and track along vessels in the serosa and mesentery  

• Brain: Hydrocephalus with gelatinous foci resembling cryptococcosis possible in cats with neurologic involvement
• Abdominal and thoracic lymph nodes: Lymphadenopathy 
• Kidneys (U-V06): Enlarged with vasculocentric pyogranulomas
• Eye (S-V03): ‘Keratic precipitates’ in anterior chamber, hypopyon, hyphema, corneal edema, cuffing of retinal vasculature, retinal detachment

• Serosal surfaces covered with small (1-2 mm) white plaques of fibrin with a granular appearance; large amounts of fibrin can result in adhesions on visceral and peritoneal surfaces
• Orchitis and periorchitis (reported, but uncommon) - scrotal swelling and enlarged testicles

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Granulomatous to necrotizing phlebitis and periphlebitis
• Neurologic lesions: 

• Noneffusive form usually causes leptomeningitis, chorioependymitis, focal encephalomyelitis, and ophthalmitis
• Effusive form usually causes a pyogranulomatous vasculitis in the vessels of the leptomeninges, periventricular white matter (around the fourth ventricle), and choroid plexus

• Additional lesions: 

• Cell/protein-rich exudates or effusions
• Interstitial pneumonia (P-V15); interstitial nephritis (U-V06); splenic and lymph node histiocytosis, lymphoid hyperplasia/depletion; enteritis; panophthalmitis, anterior uveitis, keratic precipitates (large globular accumulations of macrophages and neutrophils adherent to the corneal endothelium) (S-V03)

 

ULTRASTRUCTURAL FINDINGS:

• FIP virus present in macrophages in lesions
• Pleomorphic, spherical enveloped virions; 80-160 nm in diameter (average 100 nm)
• Virions appear in dilations of endoplasmic reticulum and matrix of large vacuoles
• Characteristic petal-shaped surface projections (peplomers) responsible for crown-like ("corona") appearance of virus

 

ADDITIONAL DIAGNOSTIC TESTS:

• Histopathology (if pathognomonic lesions present); detection of intracellular FCoV antigen (immunofluorescence or immunohistochemistry); RT-PCR
• There are no pathognomonic laboratory changes

• CSF in many cats with neurologic signs associated with FIP have normal CSF taps; positive anti-coronavirus IgG titer; elevated protein (50-350 mg/dL); pleocytosis
• Effusion is modified transudate or exudate; clear to yellow, viscous fluid, fibrin; variable cellularity (2000-6000 nucleated cells/ml); increased protein content (>4g/L), LDH (>300IU/L), alpha-amylase (pancreatic involvement)
• Positive Rivalta test

 

DIFFERENTIAL DIAGNOSIS:

• Causes of meningitis and encephalitis in cats: 

• Feline leukemia (Type C Retrovirus, Retroviridae)
• Feline immunodeficiency virus (Lentivirus, Retroviridae)
• Rabies (Lyssa virus, Rhabdoviridae; N-V06)
• Pseudorabies (Porcine herpesvirus-1, alphaherpesvirus; N-V07)
• Toxoplasma gondii (N-P02, P-P01), Cryptococcus neoformans (N-F02)
• Leukoencephalomyelopathy in cats similar to spontaneous outbreaks by feeding a gamma-irradiated dry diet with elevated peroxide and reduced vitamin A concentrations

 

COMPARATIVE PATHOLOGY:

CORONAVIRUSES

Disease	Species	Comments
Bovine coronavirus (winter dysentery)	Bovine	Gastroenteritis, thought to be a coronavirus – still some debate
Canine coronavirus  (D-V03)	Canine	Enteritis
Feline coronavirus (FIP)	Feline	Peritonitis, pneumonia, meningoencephalitis, panophthalmitis; granulomatous vasculitis
Feline enteric coronavirus	Feline	Diarrhea in kittens
Mouse hepatitis virus (MHV, D-V04)	Mouse	Hepatitis, enteritis, encephalomyelitis; syncytia formation
Porcine transmissible gastroenteritis (TGE,  D-V06)	Porcine	Gastroenteritis
Porcine hemagglutinating encephalomyelitis virus	Porcine	Vomiting, wasting and encephalomyelitis (usually no diarrhea)
Porcine epidemic diarrhea virus (PEDV)	Porcine	Gastroenteritis (western Europe, similar to TGE)
Rat coronavirus	Rat	Rhinitis, tracheitis, pneumonitis in young
Rat sialodacryoadenitis virus (D-V05, S-V02)	Rat	Sialodacryoadenitis, porphyrin released from damaged harderian gland, squamous metaplasia of ducts
Avian infectious bronchitis	Chickens	Tracheobronchitis, nephritis, wrinkled egg
Bluecomb (turkeys)	Turkeys	Enteritis, cyanosis of the comb, “Bluecomb”
Rabbit coronavirus	Rabbits	Enteritis, myocarditis
SARS-CoV-1	Humans	Severe Acute Respiratory Syndrome
SARS-CoV-2	Humans	COVID-19
Ferret enteric coronavirus; ferret systemic coronavirus	Ferrets	Enteritis;  Ferret systemic coronavirus infection (Similar to dry form of FIP; no effusion, icterus, or increased bilirubin, see Doria-Torra, Vet Pathol. 2016)

 

References:

1. Boes KM. Body cavity fluids. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:250-252
2. Cheville NF. Ultrastructural Pathology: The Comparative Cellular Basis of Disease. 2nd ed. Ames, IA: Wiley-Blackwell; 2009:370-373, 875.
3. De Lorenzi D, Pintore L. Nervous system. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:523.
4. Doria-Torra G, Vidaña B, Ramis A, Amarilla SP, Martínez J. Coronavirus infection in ferrets: Antigen distribution and inflammatory response. Vet Pathol. 2016;53(6):1180-1186.
5. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1432.
6. Levine GJ, Cook JR. Cerebrospinal Fluid and Central Nervous System Cytology. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:217-218. 
7. Malbon AJ, Meli ML, Barker EN, Davidson AD, Tasker S, Kipar A. Inflammatory Mediators in the Mesenteric Lymph Nodes, Site or a Possible Intermediate Phase in the Immune Response to Feline Cronavirus and the Pathogenesis of Feline Infectious Peritonitis?. J Comp Pathol. 2019;216:69-86.
8. Miller AD, Porter, BF. Nervous System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:982-983.
9. Rissi DR. A retrospective study of the neuropathology and diagnosis of naturally occurring feline infectious peritonitis. J Vet Diagn Invest. 2018;30(3):392-399.
10. Robinson WF, Robinson NA.  Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier, Inc; 2016:90.
11. Sangl L, Felten S, Matiasek K, Dörfelt S, Bergmann M, Balzer HJ, et. al. Detection of feline coronavirus RNA, spike gene mutations, and feline coronavirus antigen in macrophages in aqueous humor of cats in the diagnosis of feline infectious peritonitis. J Vet Diagn Invest. 2020 Jul;32(4):527-534.
12. Stanton JB, Zachary JF. Mechanisms of Microbial Infections. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:263-264.
13. Spagnoli ST, Gelberg HB. Alimentary System and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:485. 
14. Stranieri A, Giordano A, Paltrinieri S, Giudice C, Cannito V, Lauzi S. Comparison of the performance of laboratory tests in the diagnosis of feline infectious peritonitis. J Vet Diagn Invest. 2018;30(3):459-463.
15. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013: 844, 861. 
16. Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:755.
17. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier, Inc; 2016:253-255.
18. Valenciano AC, Rizzi TE. Abdominal, Thoracic, and Pericardial Effusions. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:239. 
19. Wilcock, BP, Njaa BL.  Special senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier, Inc; 2016:453.
20. Wronski JG, de Cecco BS, Raiter J, Henker LC, de Lorenzo C, Bandinelli MB, et. al. Ophthalmic and immunopathological characterization of systemic infectious diseases in cats. Vet Pathol. 2023 Mar 4:ePUB ahead of print. 
21. Ziolkowska, et al. Feline Infectious Peritonitis: Immunohistochemical Features of Ocular Inflammation and the Distribution of Viral Antigens in Structures of the Eye. Vet Pathol. 2017;54(6):933-944. 

 

 

 

 

 

 

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