Conference 16 - 2016 Case: 2 20170125

Signalment:

Six-month-old, male, Tonkinese cat, (Felis catus).The cat presented for further investigation of a vestibular ataxia, head tremors, inappetence, and lethargy. The cat was in poor body condition compared to its littermate and had previously been found to be pyrexic. Neurological examination findings were consistent with a central vestibular syndrome. MRI of the brain revealed marked dilatation of the third and fourth ventricles and mild dilatation of the lateral ventricles. There was marked contrast enhancement of the ependymal lining and meninges, consistent with feline infectious peritonitis and obstructive hydrocephalus. Cerebellar herniation was present with caudal displacement of the cerebellar vermis through the foramen magnum, consistent with elevated intracranial pressure. A provisional diagnosis of feline infectious peritonitis (FIP) was made. Due to a grave prognosis, the cat was euthanized and submitted for necropsy examination.

Gross Description:

An increased volume of clear fluid drained from the cranium as the brain was removed and there appeared to be diffuse flattening of the cortical gyri. The brain was dissected following fixation and there was moderate dilation of the third, fourth and lateral ventricles.

Histopathologic Description:

Brain: Sections of forebrain, midbrain, cerebellum and brainstem are examined. Variably within the examined sections the meninges, choroid plexus and ependyma are multifocally and extensively expanded by dense infiltrates of lymphocytes, plasma cells, macrophages and rare viable and degenerate neutrophils. There is prominent perivascular cuffing, predominantly targeting veins, of periventricular and meningeal blood vessels by lymphocytes, macrophages, plasma cells and occasional viable and degenerate neutrophils. The inflammatory infiltrate extends into both vascular walls and beyond the Virchow-Robin spaces into the adjacent neuropil. There is a mild to moderate gliosis within the adjacent neuropil and periventricular white matter contains variably-sized extracellular clear spaces (edema). Ependymal cells lining the ventricles appear mildly elongate with disruption and increased spacing between cells. Multifocally, there is necrosis of the ventricular lining with deposition of fibrin.

Immunohistochemistry
Immunohistochemical labeling for feline coronavirus antigen identified scattered, large, foamy round cells (macrophages) which labeled positively for Coronavirus antigen within the lesions in the brain tissue.

Morphologic Diagnosis:

1. Brain: multifocal, marked, pyo-granulomatous and lymphoplasmacytic meningoencephalitis with vasculitis and perivasculitis, ventriculitis, choroiditis and ependymitis 2. Brain: moderate acquired hydrocephalus

Lab Results:

Feline coronavirus antibody titer was extremely high; CSF (post mortem) showed a marked, mixed pleocytosis with neutrophilic predominance and markedly increased protein con-centration.

Condition:

Pneumonia/Acanthamoeba spp

Contributor Comment:

Feline corona-viruses (FCoVs) are enveloped, single-stranded, positive-sense RNA viruses that belong to the Coronaviridae family, Alphacoronavirus genus and exist as two pathotypes, feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FECV).^1,3 Despite FCoVs being ubiquitous in the environment, with a prevalence of more than 90% of cats in multicat households, feline infectious peritonitis (FIP) is sporadic, with young, entire male, purebreed cats most commonly affected¹. Feline enteric coronavirus is generally considered avirulent, however, can be associated with hemorrhagic enteritis and diarrhoea and affected cats may become persistently infected and continue to shed virus. In contrast, FIPV results in severe, systemic disease and is a common cause of neurologic disorders in young cats. Feline coronavirus is generally transmitted via the fecal-oral route following which it infects enterocytes, eventually being restricted to the caecum and colon.¹ Analysis of FECVs and FIPVs suggests a complex scenario involving several gene mutations to result in increased virulence^1,3. Feline infectious peritonitis viruses appear to have an increased ability to replicate in macrophages and monocytes and result in systemic disease.¹ Virus-infected macro-phages localize to small and medium sized veins within the serosa and damage endothelial cells with the subsequent immune response resulting in a vasculitis. A strong cell-mediated response is protective against FIP, whereas a weak cell-mediated response results in the dry form of the disease. The wet form of disease results from a lack of cell-mediated immune response to the virus. Both type III and type IV hypersensitivity responses have been implicated in the pathogenesis of FIP.⁵

Feline infectious peritonitis is often distinguished by a wet or effusive form and a dry non-effusive form with a proportion of cases showing a combination of the two. Typical gross findings associated with the effusive form of FIP include a fibrinous and granulomatous peritonitis, protein rich effusions and visceral granulomatous inflammatory foci. In 60% of non-effusive cases of FIP there is involvement of the eyes and/or CNS with or without granulomatous lesions in the thoracic and abdominal viscera and frequently in the absence of a grossly apparent peritonitis². Gross lesions in the brain are often unapparent, however may include thickening and opacity of the meninges, and an obstructive hydrocephalus, as seen in this case. Proteinaceous material within the ventricular system may be visible as grey-blue gelatinous material.⁴

Clinical signs associated with FIP are often vague and include pyrexia, lethargy and inappetence with additional changes dependent on the distribution of tissues affected.² The characteristic microscopic findings associated with FIP include a vasculitis and perivasculitis, predominantly affecting small to medium sized venules. A high proportion of macrophages alongside variable numbers of neutrophils, lymphocytes and plasma cells infiltrate and surround vessels. Vascular necrosis with thrombosis and infarction may also occur.² Feline infectious peritonitis may be suspected based on the signalment, compatible clinical signs, and identification of pathognomonic gross and histologic lesions. Identification of viral antigen in lesions using immuno-histochemistry or real time RT-PCR is confirmatory for a diagnosis of FIP.³

JPC Diagnosis:

Cerebrum, brainstem: Meningoencephalitis, lymphoplasmacytic and histiocytic, perivascular, diffuse, moderate to marked with lympho-plasmacytic and histiocytic choroiditis and phlebitis, Tonkinese cat, Felis catus.

Conference Comment:

Although there is some moderate slide variability, we thank the contributor for providing an excellent example and review of feline infectious peritonitis (FIP), a disease that is caused by a mutated feline enteric coronavirus (mutated FCoV). Given the history provided by the contributor, this case is likely more consistent with the non-effusive form of FIP with lesions restricted to the central nervous system, although the distinction between the wet and dry form is somewhat arbitrary and the disease likely represents a continuum rather than two distinct clinical forms.³ As mentioned by the contributor, neurologic signs due to encephalitis or meningitis are present in approximately 60% of all FIP cases.^4,5 Chronic ventriculitis, choroiditis, and ependymitis causes outflow obstruction of the cerebrospinal fluid from the ventricular system of the brain leading to marked dilation of the ventricles.⁵ This dilation of the ventricles leads to a compression atrophy of the proximate neuroparenchyma because of the lack of expansibility within the skull. The resulting increased intracranial pressure then results in both hydrocephalus and caudal displacement and herniation of the cerebellum through the foramen magnum, present in this case. FIP remains as one of the most common causes of infectious death in cats with Bengals, Birmans, Himalayans, ragdolls, and Rexes significantly overrepresented for the development of the disease.³

A recent publication in Veterinary Pathology by Kiper and Meli¹ outlined three key features as prerequisites for the development of FIP: a) systemic infection with virulent mutated FCoV, b) effective viral replication in circulating monocytes, and c) activation of mutated FCoV-infected monocytes.¹ Although avirulent FCoV is readily transmitted via the fecal-oral route, most believe that the mutated virulent form is not transmitted horizontally, but is rather the result of spontaneous mutation within each cat that develops FIP. The hallmark lesion of FIP is granulomatous or lymphohistiocytic phlebitis, present in this case, which is mediated by activated circulating monocytes during viremia.

Activated monocytes upregulate adhesion molecules such as CD18, and produce pro-inflammatory cytokines such as TNF-α, IL-1b, GM-CSF, and IL-6, in addition to matrix metalloproteinases (MMP-9), and vascular endothelial growth factor (VEGF). Endothelial cells appear to be selectively responsive and activated by the cytokine storm generated, which limits the distribution of lesions to veins within select organs. The trigger for the massive monocyte activation and selectivity of lesion location is not currently known.¹

Conference participants discussed the nature of the immune response by the host as a determining factor for which form of the disease the animal will have. As mentioned by the contributor, mutated FCoV-infected circulating monocytes are likely responsible for viremia. The conference moderator instructed that cats with a strong cell-mediated immune (CMI) response do not develop FIP.^1,3,5 Alternative, a weak CMI and strong humoral response results in the effusive, or wet form of the disease. This form is characterized by vasculitis, peritonitis and profound thoracic and peritoneal effusion as a result of deposition of antigen-antibody complexes (type III hypersensitivity).^3,5 In addition, these cats are hypergammaglobulinemic due to the overproduction of ineffective antibodies. In contrast, the noneffusive dry form of the disease is associated with a moderate CMI response with pyogranulomatous inflammation (type IV hypersensitivity) and develop clinical signs based on the organs affected, such as the brain in this case. However, as noted above, the different forms represent a continuum and most cases are likely a mix of the two extreme forms of the disease. ^1,3,5

References:

1. Kipar A, Meli ML. Feline infectious peritonitis: still an enigma? Vet Pathol. 2014; 51(2):505-526.
2. Pedersen NC: A review of feline infectious peritonitis virus infection: 1963-2008. J Feline Med Surg. 2009; 11(4):225-258.
3. Uzal FA, Plattner BL, Hostetter JM. Alimentary System. In: Maxie MG, ed. Jubb, Kennedy and Palmer's Pathology of Domestic Animals. Vol 2. 6^th ed. Missouri: Elsevier; 2016:253-254.
4. Vandevelde M, Higgins RJ, Oevermann A. Veterinary Neuro-pathology: Essentials of Theory and Practice. Oxford: Wiley-Blackwell; 2012.
5. Zachary J, McGavin M. Nervous system. In: Pathologic Basis of Veterinary Disease. 5^th ed. Missouri: Elsevier; 2012:860-861.