15-year-old, male, neutered, domestic shorthair, feline (Felis catus).This 15-year-old castrated male domestic shorthair cat had a history of diabetes mellitus since two years of age; it was well controlled. The cat was diagnosed with mild to moderate hypertrophic cardiomyopathy. The cat presented due to acute onset of seizures and obtundation. There was severe white matter swelling/edema of unknown etiology found on an MRI. The blood pressure was 174 mmHg. There was partial cerebellar herniation. Treatment included prednisone and mannitol that resulted in clinical improvement for a period of approximately two weeks prior to reoccurrence of the clinical signs. Despite aggressive medical management with mannitol, hypertonic saline, steroids and antibiotics the cat's condition worsened and the owner elected euthanasia.
Grossnecropsyfindingsreportedbythe submitting veterinarian were confined to partial herniation of the cerebellum. There was partial herniation of the cerebellum.
There is marked diffuse edema of the white matter. Clear space and small eosinophilic lakes of edema fluid separate nerve fibers. Astrocytes in the white matter often have increased amounts of eosinophilic cytoplasm. In the meninges, arteries exhibit changes characterized by either myointimal hyperplasia and adventitial proliferation or fibrinoid necrosis. Around vessels with fibrinoid necrosis there are perivascular and mural infiltrates of neutrophils along with a few macrophages. The tunica media contains many pyknotic nuclei. A few of the vessels have concentric layers of proliferating fibrocytes in the tunica adventitia. Mild to moderate white matter edema is also present in the pons, medulla and cerebellar white matter. There are no vascular changes in those regions.
1. Edema, diffuse, severe, cerebral white matter.
2. Fibrinoid necrosis and adventitial hyperplasia, multifocal, arteries, meninges.
The white matter edema and the vascular changes are consistent with hypertensive encephalopathy. This condition has been reported in cats with chronic renal disease and following renal transplantation.1 However, any condition that results in hypertension could theoretically cause the brain pathology.2 These conditions include hyperthyroidism, primary hyperaldosteronism, diabetes mellitus, pheochromocytoma and erythropoietin therapy. About 20% of cases of hypertension in cats have no identifiable cause (i.e. idiopathic hypertension). Thecathadahistoryofdiabetesmellitusthat could have caused the hypertension. However, a full necropsy was not performed and the other conditions could not be entirely ruled-out.
The pathogenesis of hypertensive encephalopathy is thought to involve the development of vasogenic edema as a result of sudden increases in blood pressure that exceed the autoregulatory capacity of the vasculature in the brain resulting in endothelial injury and breakdown of the blood- brain barrier.2 The edema is primarily in the white matter where it results in separation of axons and myelin sheaths and pallor of the tissue. There is sometimes increased perivascular space around white matter vessels. Vascular changes, usually in the pia, are consistent with hypertension and include onion-skinning of the vessels (hyperplastic arteriosclerosis) and, occasionally, fibrinoid or hyaline change (hyaline arteriosclerosis).
1. Brain,cerebrum,whitematter:Edema, diffuse, moderate, with reactive astrocytosis.
2. Brain, meninges: Hyaline vascular necrosis, multifocal, moderate with perivascular sclerosis.
Almost all conference participants observed the histologic lesions confined to the white matter of the cerebrum and interpreted the findings as consistent with edema; but only a few noted and diagnosed the vascular lesions. When evaluating nervous tissue, the differentiation of edema and preparation artifact is often difficult. Rough handling and autolysis often exacerbates the degree of artifact seen in tissue sections. In the tissue sections of this case, in addition to the physical separation of nerve fibers by clear space, many astrocytes are enlarged with increased eosinophilic cytoplasm, presumably as the result of edema. Recognizing the vascular lesions and their association with feline hypertension provides an identifiable explanation for diffuse white matter edema in this cat.
In general, there are four mechanisms of edema:(4)
- Increased microvascular permeability (e.g. vasculitis secondary to endotoxemia)
- Increased intravascular hydrostatic pressure (e.g. pulmonary hypertension)
- Decreased intravascular osmotic pressure (e.g. protein-losing nephropathy/enteropathy)
- Decreased lymphatic drainage (e.g. intestinal lymphangectasia)
McGavin and Zacharys Pathologic Basis of Veterinary Disease expands the mechanistic list by including hydrostatic (interstitial) and hypo-osmotic types of brain edema. Briefly, hydrostatic edema is characterized by extracellular periventricular fluid accumulation as a result of increased hydrostatic pressure within the ventricles. Hypo- osmotic edema occurs with water and salt intoxication in which the differences in osmotic pressure between the brain and the plasma results in movement of fluid from the vasculature into the brain.(5)
In this case, partial herniation of the cerebellum through the foramen magnum (colloquially referred to as cerebellar coning) was noted at necropsy. In addition to the foramen magnum, there are two other potential locations of herniation during brain swelling. The occipital cortex may herniate caudally beneath the tentorium cerebelli or, in cases of unilateral swelling, the cingulate gyrus of the unaffected hemisphere may be forced laterally under the falx cerebri.(4)
Participants also discussed the differential diagnosis for white matter spongiosis, which can be broadly classified as either idiopathic or toxic/metabolic. A more detailed discussion of the various idiopathic spongiform myelinopathies is available within the selected references.(3,4) Toxic and metabolic causes of status spongiosis include, but are not limited to, hepatic encephalopathy, renal encephalopathy, branched chain α-ketoacid decarboxylase deficiency (i.e. maple syrup urinary disease), hexachlorophene toxicosis, halogenated salicylanilide toxicosis, bromethalin toxicity and several plant species.(3)
| ||Vasogenic Edema ||Cytotoxic Edema|
|Pathogenesis||Damage to cerebral vasculature → fluid and proteins leave vessel under hydrostatic pressure → edema||Glial cell injury → disturbed cellular osmoregulation → acute cell swelling with maintenance of vascular integrity|
|Gross findings||Flattened gyri and narrowed sulci Herniation (i.e. cerebellar coning) Edematous swelling of the white matter||Similar to findings in vasogenic edema with possible displacement May be grossly normal|
|Distribution of the edema||White matter; may affect grey matter if severe||Grey matter
|Histologic findings||Generalized pallor
Swelling and necrosis of astrocytes
Eosinophilic lakes of edema fluid
White matter spongiosis (if oligodendrocytes affected)
Intracellular fluid accumulation
1. Brown CA, Munday JS, Mathur S and Brown SA. Hypertensive encephalopathy in cats with reduced renal function. Vet Pathol. 2005;42:642-649.
2. Kent M. The cat with neurological manifestations of systemic disease; key conditions impacting on the CNS. Journal of Feline Med Surg. 2009;11:395-407.
3. Maxie MG, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. 5th ed., vol. 1. Philadelphia, PA: Elsevier Ltd; 2007:385-388.
4. Summers BA, Cummings JF, de Lahunta A. Principles of neuropathology. In: Veterinary Neuropathology. St. Louis, MO: Mosby; 1995:36-36.
5. Zachary JF. Nervous system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 4th ed. St. Louis, MO: Elsevier; 2007:862-865.