AFIP SYSTEMIC PATHOLOGY

 

JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

April 2017

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 lymphocytes, plasma cells, fewer Mott cells, epithelioid macrophages, and few 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 (necrosis) with replacement with variable amounts of eosinophilic proteinaceous fluid. Multifocally, the ependymal lining of the lateral ventricle and third ventricle is disrupted by the previously described cellular infiltrate with areas of loss. The third ventricle is filled with eosinophilic proteinaceous fluid and few of the previously described inflammatory cells. Within the adjacent neuroparenchyma there is a 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: Meningoencephalitis 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:

·       FIP is a group 1 coronavirus that has two subtypes, 1a and 1b

·       The best documented example of generation of coronavirus species through homologous recombination is present in group 1a coronavirus, which is the generation of FCoV [also called feline infectious peritonitis virus (FIPV) in some publications] type II strains by double recombination between FCoV (FIPV) type I strains and canine coronavirus (CCoV)

·       Feline Infectious Peritonitis (FIP): fatal, systemic disease associated with feline coronavirus (FCoV) infection; infects domestic and wild felids

·       FIP causes a fibrinous to granulomatous serositis, protein-rich effusions in body cavities, and granulomatous inflammatory lesions in several organs

·       Family Coronaviridae, genus Coronavirus; enveloped, single-stranded RNA virus

·       Predisposing factors: young (< 3 years old) cats; immunosuppression; multi-cat households

·       Prevalence of FCoV infection: high (up to 90%), but only 5% develop FIP; mortality in cats with FIP is up to 100%

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

·       Prominent in catteries that breed Devon Rex, British shorthair, Birman, Burmese and Abysinnian

 

PATHOGENESIS:

·       Transmission is via oronasal via feces; rarely saliva, mutual grooming, close contact, sharing food bowl, grooming tools; transplacental is uncommon

·       There are two proposed mechanisms for the development of vasculitis based on multiphasic nature of disease

·       Type III immune mediated disease (chronic necrotizing vasculitis)

·       Activation of viral infected macrophages, resulting in release of cytokines and alterations in endothelial junctional complexes and vascular leakage (acute phlebitis)

·       Target cells are monocytes and macrophages; FCoV-infected circulating monocytes are thought to be responsible for viral dissemination

·       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

·       Cats infected with nonmutated FCoV > virus replicates in enterocytes > asymptomatic infection or diarrhea > shed virus intermittently or continuously

·       Key event in FCoV becoming virulent is spontaneous viral genetic mutation during replication in the infected host

·       At present, 3 key features have been identified as essential prerequisites for the development of FIP lesions:

·       1. Systemic infection with virulent FCoV (ie, FIPV)

·       2. Effective and sustainable FIPV replication in monocytes, and

·       3. Activation of FIPV-infected monocytes:

·       The monocytes strongly express cytokines, such as tumor necrosis factor (TNF)–a and IL-1b, and adhesion molecules, such as CD18, that allow their interaction with activated endothelial cells and express enzymes, such as matrix metalloproteinase-9, which dissolve the vascular basement membrane at sites of monocyte emigration

·       The endothelial cells appear systemically activated, and the restrictive distribution of vascular lesions (ie, affecting veins and only in selected organs) is likely a consequence of selective responsiveness of the endothelium

·       Cats with FIP show increased vascular endothelial growth factor (VEGF) transcription in (virus-infected) monocytes and increased serum VEGF levels

·       Furthermore, peritoneal exudate cells of cats with FIP exhibit high TNF-a mRNA levels and were previously shown to release IL-1b and IL-6, and even alveolar macrophages collected by bronchoalveolar lavage from FIP cats show significant upregulation of TNF-a, GM-CSF, granulocyte (G)–CSF, IL-6, and other B-cell differentiation factors, all suggesting strong generalized monocyte/macrophage activation in response to FIPV

·       Two recognized biotypes:

·       Feline enteric coronavirus (FECV) > minimal disease

·       Feline infectious peritonitis virus (FIPV) > severe systemic immune-inflammatory disorder

·       2 clinical forms of FIPV

·       “Effusive” (Wet) – intracavity effusions and abdominal distension

·       “Dry” parenchymatous form – “neurological” or “brain and eye” form

·       Clinical signs and pathologic findings are due to vasculitis and phlebitis and organ failure resulting from damage to blood vessels that supply them

·       Host cell mediated immune response determines severity of FIP lesions

·       Strong cell-mediated immunity (CMI) > viral replication terminated

·       Partial CMI > non-effusive (dry) form

·       No CMI > effusive (wet) form

·       Antibody-dependent enhancement is enhanced form of FIP may occur in cats with preexisting antibodies

 

TYPICAL CLINICAL FINDINGS:

·       Neurologic signs

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

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

·       Other clinical findings

·       Nonspecific: chronic fever, weight loss, anorexia, lethargy; stress leukogram

·       Ascites, thoracic and/or pericardial effusion

·       Dyspnea, tachypnea, muffled heart sounds

·       Abdominal masses on palpation (omental/visceral adhesions; mesenteric lymphadenopathy)

·       Chronic diarrhea, vomiting, obstipation, thickened intestines on palpation

·       Eyes: anterior uveitis; retinal changes – occasional granulomatous inflammation, cuffing of retinal vasculature, +/- hemorrhage, detachment

·       In-utero infections: stillborn or clinically affected kittens

·       Clin path:

·       Lymphopenia

·       Mild to moderate regenerative anemia

·        Hyperproteinemia due to hypergammaglobulinemia

·       Other laboratory parameters, such as liver enzymes, bilirubin, urea, and creatinine, might be helpful, but high values merely reflect organ damage, which is most likely a consequence of FIP lesions

·       FIP effusions typically have a very high protein content (>35 g/l) but a low cellularity (<5000 nucleated cells/ml), with a dominance of macrophages and neutrophils; when sufficient cells are present, the demonstration of viral antigen in macrophages confirms the diagnosis with a very high PPV

·        Acute phase protein, a1 acid glycoprotein (AGP):

·       Serum levels are highly elevated in cats with FIP (>3 mg/ml) but are also high in other inflammatory conditions or neoplastic diseases, such as lymphoma

·       Furthermore, AGP levels may also rise  in asymptomatic FCoV carriers, especially from households with endemic infection

·       However, when interpreted alongside pretests (ie, epidemiological factors, clinical information, and FCoV serology), moderate AGP increases are useful discrimination parameters when the probability of FIP is high, whereas with low FIP probability, only very high AGP levels support the diagnosis of FIP

 

TYPICAL GROSS FINDINGS:

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

·       Other gross findings

·       FIP lesions are common in peritoneum, kidney, and uvea

·       Fibrinous pleuritis, peritonitis, and/or pericarditis with thoracic, abdominal, and/or pericardial effusion

·       Multifocal granulomatous lesions in various organs, including eyes, CNS, and intestine - lesions commonly found only in ileocecocolic junction, but may be present in other areas (e.g. colon or small intestine)

·       Mesenteric lymphadenopathy

·       Eyes are not routinely examined, but will have lesions

·       Anterior uveitis – may be subtle depending on time of diagnosis

·       Keratic precipitates - (important clinical hallmark)

·       Retinal changes – occasional granulomatous inflammation, cuffing of retinal vasculature, +/- hemorrhage, detachment

 

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, interstitial nephritis, 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)

 

ULTRASTRUCTURAL FINDINGS:

·       FIP virus present in macrophages in lesions

·       Pleomorphic, spherical enveloped virions; 60-120nm 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 immunoflourescence 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)

·       Pseudorabies (Porcine herpesvirus-1, alphaherpesvirus)

·       Toxoplasma gondii, Cryptococcus neoformans

·       Identification of Bartonella henselae in two cats with pyogranulomatous myocarditis and diaphragmatic myositis

·       Leukoencephalomyelopathy in cats similar to spontaneous outbreaks by feeding a gamma-irradiated dry diet with elevated peroxide and reduced vitamin A concentrations

 

COMPARATIVE PATHOLOGY:

·       Cheetahs are highly susceptible to developing FIP; possibly due to genetic deficiency in cellular immunity

·       Few reports of lions in captivity

 

Emerging coronaviral diseases in animals include:

  • Epizootic catarrhal enteritis and feline infectious peritonitis (FIP)–like systemic disease in ferrets
  • A fatal systemic disease in dogs
  • Mink epizootic catarrhal gastroenteritis.

 

Coronaviruses in other species:

·       Avian: Infectious Bronchitis (chickens); Coronaviral enteritis of turkeys (Bluecomb disease)

·       Bovine: Bovine coronavirus

·       Canine: Canine coronavirus

·       Ferrets: ferret systemic coronavirus

·       Mice: Mouse Hepatitis Virus

·       Rats: Sialodacryoadenitis virus

·       Porcine: Transmissible gastroenteritis virus; Hemagglutinating encephalomyelitis virus; Porcine respiratory coronavirus; Porcine epidemic diarrhea (corona-like virus)

 

References:

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  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.
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  9. Miller AD, Zachary JF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2016:896-897.
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  11. Oliveira LB, Susta L, Rech RR, Howerth EW. Pathology in practice. Effusive FIP with fibrinous epicarditis in a cat. J Am Vet Med Assoc. 2014;245(8):899-901.
  12. Pesavento PA, Murphy BG. Common and emerging infectious diseases in the animal shelter. Vet Pathol. 2013;50(6):1–14.
  13. 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.
  14. Varanat M, Broadhurst J, Linder KE, Maggi RG, and Breitschwerdt EB. Identification of Bartonella henselae in two cats with pyogranulomatous myocarditis and diaphragmatic myositis. Vet Pathol;2012;49(4):608-611.
  15. Wilcock, BP, Njaa BL.  Special senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier; 2015:90.

 

 

 

 

 


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