Conference 22 - 2013 Case: 02 20140409

Signalment:

3-year-old female domestic cat, (Felis cats).The cat had three episodes of seizures with increasing severity during a period of one month. There was loss of proprioception and loss of vision after an episode with cluster attacks, but both proprioception and vision showed some improvement the following days. The cat was dehydrated at admission, but after rehydration the hematocrit was still very high (see below). The cat was euthanized. The differential diagnosis included encephalitis due to dry form of feline infectious peritonitis, Toxoplasma, neoplasia or polycythemia.

Gross Description:

The cat was not macroscopically dehydrated (normal position of eyes in orbits). The heart was moderately rounded in shape and the right side was moderately dilated. Between the atria there was a persistent foramen ovale that measured 8 mm in diameter. The lungs were congested and edematous with moderate amounts of red colored mucus in the bronchi. In the stomach there was one nematode and in the small intestine there was one tapeworm. Colonic contents were moderately increased in amount and drier than normal. The renal cortices contained numerous petechiae on the cut surface. The texture of the cortex was normal. The size of the spleen was normal. Bone marrow was diffusely red. In formalin fixed brain there were bilateral mildly accentuated vascular structures on the cut surface of the hippocampus.

Histopathologic Description:

In the brain there was bilateral and nearly diffuse neuronal necrosis in the hippocampus. The necrosis affected both the dentate gyrus and the pyramidal neurons. There were some segments with intact neurons in the dentate gyrus, but most neurons were necrotic with a shrunken hypereosinophilic appearance with a pyknotic or karyolytic nucleus. There were some mitotic figures probably representing proliferating glial cells. There was mild multifocal rarefaction and vacuolation of the neuropil and proliferation of vessels with hypertrophied endothelial cells. A similar but small focus of necrosis was detected in the pyriforme lobe. Otherwise, the brain was unremarkable, except for one vessel with perivascular infiltrates of lymphocytes in the cerebral cortex laterally to the thalamus.

Other relevant histological findings: In the lungs there was severe congestion and edema. Pulmonary vessels were normal. There was moderate acute congestion in the liver. Although renal cortical petechiae were detected macroscopically, this could not be confirmed histologically, but the glomerular capillaries were engorged with blood. Cell density of bone marrow was moderately increased with mixed cell types but dominated by erythroid cells of mature stages.

Morphologic Diagnosis:

Brain, hippocampus: Neuronal necrosis, subtotal, bilateral, subacute.

Lab Results:

Complete blood count:
	RBC: 20.56 (5-10)
	HGB: 239 (80-150)
	HCT: 0.72 (0.24-0.45)
	MCV: 35.1 (40-52)
	RDW: 18.5 (13-17)
	Lymphocytes: 0.2 (1.5-7.0)

	Conclusion: marked erythrocytosis and marked lymphopenia

Condition:

Feline Hippocampal Necrosis

Contributor Comment:

Feline hippocampal necrosis is a neurological disorder with unknown cause, characterized by generalized or complex-partial seizures of acute onset and rapid progression.(3) Fatzer et al described the findings in 38 domestic cats suffering from the disease.(3) Most cats were between 1-6 years old, and there was no breed or sex predisposition. The typical distribution of the lesions is severe involvement of the hippocampus with sparing of the remaining parts of the brain, except for the pyramidal lobes in some cases.(3,10) Histopathologic findings are acidophilic neuronal necrosis that may be diffuse in severe cases, gliosis, and proliferated vessels with hypertrophied endothelial cells.(3,10) The hippocampal lesions in this case were consistent with the findings described by Fatzer et al.(3) Some cases may have perivascular lymphohistiocytic infiltrates,(3) but this was only present around one vessel in this case and in a location not related to the necrotic lesions.

The polycythemia observed in this cat was interpreted to be an absolute polycythemia (primary or secondary) and not a relative polycythemia due to dehydration, since the cat presented with a high hematocrit (0.72) even after rehydration. The rare disease primary polycythemia (polycythemia vera) must be distinguished from secondary polycythemia which is more common. In primary polycythemia, the bone marrow has a very high cellularity with little remaining fat. Aspirated marrow has a synchronous trilineage hyperplasia with a myeloid:erythroid ratio of near 1.0.(9) This cat had had a moderately cellular bone marrow with a dominance of mature erythroid cells, possibly indicating a secondary polycythemia. Measurement of blood oxygen levels would be helpful differentiating between primary and secondary polycythemia, but this was not performed in this case. A cause of secondary polycythemia is vascular anomalies causing anoxia. This cat had a persistent foramen ovale of 8 mm in diameter, a lesion usually not causing anoxia unless the blood flow through the atrial defect switches from left-right to right-left (Eisenmenger syndrome).(5) Pulmonary hypertension may be the result of heart malformations causing left to right shunting of blood and increased blood flow to the lungs.(1) Vascular lesions in the lungs due to pulmonary hypertension were not detected in this cat; neither acute lesions consisting of endothelial degeneration, fibrinoid necrosis and vasculitis, nor chronic lesions consisting of remodeling of pulmonary arterioles with thickening of the tunica intima and hypertrophy of the media were noted.(1) Interestingly, hypoxia due to patent foramen ovale in the absence of pulmonary hypertension is described in humans.(4) It is not clear to what degree the cardiac and hematological abnormalities contributed to the hippocampal necrosis in this cat. Of the 38 cats described by Fatzer et al, no similar hematological abnormalities were described; however, it is unclear whether hematological examinations were performed on all cats.

JPC Diagnosis:

Cerebrum, hippocampus and piriform lobe: Neuronal necrosis, multifocal, subacute, with edema, gliosis and neovascularization.

Conference Comment:

Conference participants briefly discussed the differential diagnosis for the histological findings, including ischemic encephalopathy, neuronal toxicity and rabies viral infection. Within the central nervous system, neurons and oligodendroglia are the most sensitive to ischemia, while blood vessels are more resistant and may survive in necrotic areas. In general, the grey matter is more sensitive to hypoxia than the white matter; specifically neurons of the hippocampus (especially the CA1 region) and the deeper laminae of the cerebral cortex, as well as Purkinje cells, are the most sensitive to ischemic necrosis.(6) Ischemic necrosis following fibrocartilagenous embolus (FCE) is a possible explanation for the lesions in this case; however, FCE is rare in cats, and when it occurs, it is asymmetric and typically affects the spinal cord, rather than the brain.(2) Feline ischemic encephalopathy (FIE) is quite similar to feline hippocampal necrosis, and has been associated with aberrant migration of Cuterebra spp. larvae. This condition is characterized by severe necrotizing lesions and infarction of areas of the cerebrum supplied by the middle cerebral artery, and thus often involves the hippocampus and piriform lobe; however, in contrast to feline hippocampal necrosis, which is bilateral and symmetric, the lesions in FIE are typically unilateral or asymmetric with spontaneous resolution and often partial to total recovery.(3,6)

Due to its use of glutamate (or possibly aspartate) as an excitatory neurotransmitter, the hippocampus is also particularly vulnerable to neuronal excitotoxicity, which may have played a role in the pathogenesis of this case. Glutamate is toxic to neurons and is normally cleared rapidly by glial cells. Conditions such as ischemia, hypoxia, seizures, and hypoglycemia promote a cascade of unregulated events including endogenous glutamate release, activation of glutamate receptors, decreased clearance of glutamate, and opening of voltage gated calcium channels, ultimately resulting in neuronal degeneration and necrosis; this is known as endogenous neuronal excitotoxicity.(6,8) A comparable neurotoxic condition has been described in marine mammals and seabirds in association with exposure to domoic acid (an analog of L-glutamate) following harmful algal blooms.(8)

In contrast to the microscopic lesions in this case, which are confined to the hippocampus, the lymphoplasmacytic perivascular cuffing, focal gliosis and neuronal intracytoplasmic viral inclusions (Negri bodies) commonly associated with rabies virus tend to be most severe from the pons to the hypothalamus and within the cervical spinal cord.(6) Nevertheless, definitive diagnosis of feline hippocampal necrosis in this case (versus rabies viral infection) was complicated for some participants by identification of scattered eosinophilic, intracytoplasmic rabies-like inclusions. The occurrence of intracytoplasmic neuronal inclusions indistinguishable from Negri bodies is a fairly common incidental finding in older dogs and cats which must be differentiated from true viral inclusions with laboratory diagnostics such as fluorescent antibody testing.(7)

References:

1. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. Vol 2. 5th ed. Philadelphia, PA: Elsevier Limited; 2007:523-654.

2. Coradini M, Johnstone I, Filippich LJ, Armit S. Suspected fibrocartilaginous embolism in a cat. Aust Vet J. 2005;83:550-551.

3. Fatzer R, Gandini G, Jaggy A, Doherr M, Vandevelde M. Necrosis of hippocampus and piriform lobe in 38 domestic cats with seizures: a retrospective study on clinical and pathologic findings. J Vet Intern Med. 2000;14:100-104.

4. Maraj R, Ahmed O, Fraifeld M, Jacobs LE, Yazdanfar S, Kotler MN. Hypoxia due to patent foramen ovale in the absence of pulmonary hypertension. Tex Heart Inst J. 1999;26:306-308.

5. Maxie MG, Robinson WF. Cardiovascular system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. Vol 3. 5th ed. Philadelphia, PA: Elsevier Limited; 2007:1-106.

6. Maxie MG, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. Vol 1. 5th ed. Philadelphia, PA: Elsevier Limited; 2007:284-285, 336-337, 413-416.

7. Nietfeld JC, Rakich PM, Tyler DE, Bauer RW. Rabies-like inclusions in dogs. J Vet Diagn Invest. 1989;1(4):333-338.

8. Silvagni PA, Lowenstine LJ, Spraker T, Lipscomb TP, Gulland FM. Pathology of domoic acid toxicity in California sea lions (Zalophus californianus). Vet Pathol. 2005;42(2):184-191.

9. Valli VEO. Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. Vol 3. 5th ed. Philadelphia, PA: Elsevier Limited; 2007:107-324.

10. Vandevelde M, Higgins RJ, Oevermann A. Metabolic-toxic diseases. In: Veterinary Neuropathology: Essentials of Theory and Practice. Chichester, UK: Wiley-Blackwell; 2012:106-128.