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Read-Only Case Details Reviewed: May 2008
AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2020

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 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 Coronavirus - 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 (1-3%) viral disease of domestic and wild felids caused by FIPV which is a mutated form of FCoV

 

 

·      Predisposing factors: young (<2 years) cats; immunosuppression; multi-cat households (common in catteries that breed Devon Rex, British shorthair, Birman, Burmese, and Abyssinian)

·      FIP is a common cause of neurologic disorders in cats; 13% of cats with FIP develop neurologic signs

 

PATHOGENESIS:

·      Fecal-oral transmission and possibly by inhalation of FCoV > replication in enterocytes / lymphoid system > 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

·      Two serotypes; both serotypes may cause FIP, most commonly Type I

·      Type I: Cytopathic

·      Type II: Non-cytopathic

·      Host cell ligands:

·      Both serotypes can use ‘‘dendritic cell (DC)–specific intercellular adhesion molecule (ICAM) grabbing nonintegrin’’ (DC-SIGN, CD209), a C-type lectin, which recognizes high-mannose oligosaccharides as ligands, to infect monocyte-derived dendritic cells

·      Co-localization and binding inhibition studies confirmed that DC-SIGN and not APN is involved in the entry process of serotype I FCoV in monocytes, whereas for serotype II FCoV, both APN and DC-SIGN play a role in the infection of monocytes

·      Specifically, for serotype II, binding is mediated by APN, but DC-SIGN is important for either internalization or a subsequent step

 

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

·      Neurologic signs:

·      Ataxia, nystagmus, seizures, incoordination, intention tremors, hyperesthesia, behavioral changes, cranial nerve deficits, head tilt

·      If FIP lesions affect peripheral nerves or spinal column then lameness; progressive ataxia; tetraparesis, hemiparesis, or paraparesis

·      Noneffusive (dry parenchymatous form, think brain and eye): Typically, a granulomatous inflammation, localized in the lymph nodes, kidneys, uvea, meninges, ependyma, and choroid plexus of the brain and spinal cord

·     Often vague signs of dullness, weight loss, and anorexia 

·     Ocular lesions: iritis (manifest in color change in iris)

·     CNS signs (ataxia, nystagmus, seizures) in 12.5% of cases

·     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) 

·     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

·       Albumin:globulin ratio less than 0.8 and typically 0.45 or less (albumin level remains normal or falls slightly and globulin levels increase, possibly through stimulation of B cells by IL-6)

·       Elevated Alpha1-acid glycoprotein (AGP) >1500 ug/ml

·       Neutrophilia with left shift

 

TYPICAL GROSS FINDINGS:

·      CNS lesions: meninges thickened and opaque; mild to moderate hydrocephalus with accumulation of a protein-rich exudate

·      Noneffusive form – Granulomatous lesions in various organs (on surface and throughout)

  • Brain: Hydrocephalus with gelatinous foci resembling cryptococcosis possible in cats with neurologic involvement
  • Colon: Thickened with a gross appearance similar to alimentary lymphoma
  • 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

·      Effusive form – Pleural effusion and effusive peritonitis

  • The surfaces of abdominal and/or thoracic contents 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 and the periventricular white matter (around the fourth ventricle)

·      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; low cellularity (<1000 nucleated cells/ml); increased protein content (>35g/L), LDH (>300IU/L), alpha-amylase (pancreatic involvement)

·      Most consistent finding is increase in total serum protein concentration due to increase in globulins (monoclonal or polyclonal hypergammaglobulinemia), but only reflects chronic antigenic stimulation

·      Intracellular FCoV Ag by immunofluorescence or immunohistochemistry (CCV2-2 is more sensitive than FIPV3-70)

 

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.    Addie DD. Feline coronavirus infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 4th ed. St. Louis, MO: Elsevier; 2012:92-107.

2.    Cheville NF. Ultrastructural Pathology: The Comparative Cellular Basis of Disease. 2nd ed. Ames, IA: Wiley-Blackwell; 2009:370-373, 875.

3.    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.

4.    Dubielzig RR, Ketring KL, McLellan GJ, Albert DM. Veterinary Ocular Pathology: a Comparative Review. Philadelphia, PA: Saunders Elsevier; 2010:268-269.

5.    Felten S, Hartmann K, Doerfelt S, Sangl L, Hirschbeger J, Matiasek K. Immunocytochemistry of mesenteric lymph node fine-needle aspirates in the diagnosis of feline infectious peritonitis. Jour Vet Diagn Invest. 2019;31(2):210-216.

6.    Kipar A and Meli ML. Review feline infectious peritonitis: Still an enigma? Vet Pathol. 2014: 51(2): 505-526.

7.    Labelle P. The eye. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1317-1318.

8.    MacLachlan NJ, Dubovi EJ. Coronaviridae. In: MacLachlan NJ, Dubovi EJ, eds Fenner’s Veterinary Virology. 5th ed. London, UK: Academic Press; 2017: 446-448.

9.    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?. Jour Comp Pathol. 2019;216:69-86.

10. Miller AD, Zachary JF.  Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:896-897.

11. Mwase M, Shimada K, Mumba C, Yabe J, Squarre D, Madarame H.  Positive immunolabelling for feline infectious peritonitis in an African lion (Panthera leo) with bilateral panuveitis. Jour Comp Pathol. 2015;152(2-3):265-8.

12. Pesavento PA, Murphy BG. Common and emerging infectious diseases in the animal shelter. Vet Pathol. 2013;50(6):1–14.

13. Rissi DR. A retrospective study of the neuropathology and diagnosis of naturally occurring feline infectious peritonitis. Jour Vet Diagn Invest. 2018;30(3):392-399.

14. 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.

15. 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.

16. Vandevelde M, Higgins RJ, Oevermann A.  Inflammatory diseases. In: Vandevelde M, Higgins RJ, Oevermann A, eds. Veterinary Neuropathology: Essentials of Theory and Practice. 1st ed. Ames, IA: Wiley-Blackwell: 2012:59-60.

17. 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.

18. Zachary JF. Mechanisms of microbial infections. In: Zachary, JF ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017; 217-218.

19. 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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