Adult-Onset Spongiform Leukoencephalopathy in 2 Ragdoll Cats

A 6-year-old neutered male Ragdoll cat was presented for acute ataxia, inappetence, and vomiting. Initial examination findings were ataxia, absent oculovestibular reflex, hypermetric gait, and wide-head excursions. The onset of signs coincided with discontinuation of prednisonea (unknown dose) used to treat an upper respiratory infection. Serum chemistry abnormalities included increases in ALT 152 U/L (28–76 U/L), creatinine phosphokinase 987 U/L (64–440 U/L), and glucose 189 mg/dL (70–154 mg/dL), and hypokalemia 3.1 mEq/L (3.9–5.3 mEq/L). CBC abnormalities were a leukocytosis of 27,900 cells/μL (4,200–15,600 cells/μL) with a mature neutrophilia of 21,762 cells/μL (2,500–12,500 cells/μL). Total T4 was normal. On presentation to the Veterinary Neurological Center, clinical abnormalities included ataxia, wide-based stance, wide-head excursions, and delayed oculovestibular reflex. Transverse T1-weighted spin echo and T2-weighted fast spin echo magnetic resonance (MR) (1.0 Tb) images were obtained followed by transverse and sagittal T1-weighted images after IV administration of gadopentetate dimegluminec (0.1 mmol/kg). On the transverse T2-weighted images, there was bilaterally symmetric increased signal intensity within the internal capsule and corona radiata in all lobes, but most pronounced in the frontal lobes (Fig 1). On the transverse T2-weighted image of the cerebellum located at the level of the lateral apertures (Fig 2A), there were small bilaterally symmetric, crescent-shaped areas of increased signal intensity within each hemisphere approximately 4–5 mm dorsal to the plane of the lateral apertures. There was a similar appearing area within the culmen of the vermis approximately 7 mm dorsal to the floor of the 4th ventricle. The location of these lesions corresponded to the white matter just dorsal to the deep cerebellar nuclei. An additional lesion was noted more dorsally within the vermis. On the T1-weighted transverse images, the lesions had a corresponding decrease in signal intensity and no abnormal contrast enhancement. On the sagittal T1-weighted postcontrast images, there was pronounced gray to white matter distinction believed to be created by the abnormally low signal intensity of the white matter corpus medullare. Case 1. Transverse T2-weighted image of the cerebrum at the level of the frontal lobes. There is bilaterally symmetric increased signal intensity within the internal capsule and corona radiata (arrows). Case 1. (A) Transverse T2-weighted image of the cerebellum at the level of the lateral apertures. There are small, symmetric, crescent-shaped areas of increased signal intensity within each hemisphere and within the vermis each located just dorsal to the deep cerebellar nuclei. An additional lesion is noted more dorsally within the culmen of the vermis. Compare this image to the corresponding transverse T2-weighted image from a cat with no clinical evidence of cerebellar disease (B). Note the lack of hyperintensities in (B). Cisternal cerebral spinal fluid (CSF) analysis and brainstem auditory evoked response test were normal. The cat's neurological status reportedly declined and was euthanized 2 weeks after the onset of signs. A complete necropsy was performed at Veterinary Pathology Services in Phoenix, AZ. The brain appeared grossly normal. Histopathologic evaluation revealed marked variable vacuolar changes and mild gliosis within all sections of the brain. The most striking vacuolar change was in the cerebellar white matter tracts, with additional vacuolar change in the midbrain, pons, thalamus, and white matter of the cerebrum. The findings were consistent with severe spongiform encephalopathy. A 13-year-old neutered male Ragdoll cat was examined for ataxia, inappetence, and lethargy of 1 week. Initial examination findings were ataxia, horizontal nystagmus, and circling to the left. Prednisonea (0.5 mg/kg PO q12h) was administered, and the cat's neurological status remained unchanged. Previous medical history included upper respiratory infections, enteritis, and hyperthyroidism, for which the cat was treated with iodine-131 2 years before. Clinicopathologic abnormalities included increases in serum creatinine phosphokinase 670 U/L (64–440 U/L) and leukocytosis of 20,100 cells/μL (4,200–15,600 cells/μL) with an absolute eosinophilia of 2,412 cells/μL (0–1,500 cells/μL). Clinical abnormalities included wide-head excursions, altered mentation, wide-based stance, ataxia, intention tremors, circling to the left, positional vertical nystagmus, and mucoid discharge of the left eye. On the transverse T2-weighted images, there was bilaterally symmetric increased signal intensity within the internal capsule and corona radiata, similar to that seen in Case 1 (Fig 3). On transverse T2- and T1-weighted images, there were cerebellar lesions appearing nearly identical to Case 1 except the dorsal vermal lesion was absent. As in Case 1, the crescent-shaped areas of T2 and T1 prolongation were located within the white matter just dorsal to the deep cerebellar nuclei. On the midsagittal postcontrast T1-weighted image, there was pronounced gray to white matter distinction created by the abnormally low signal within the corpus medullare, as noted in Case 1. On the midsagittal T2-weighted image (Fig 4A, not obtained in Case 1), the cerebellum was subjectively enlarged, and the normally low signal white matter was markedly hyperintense, resulting in a striking reversal of signal characteristics when compared with the cerebellum of a normal cat (Fig 4B). Other magnetic resonance imaging (MRI) findings included fluid and soft tissue filling of the nasal cavity and paranasal sinuses compatible with severe rhinitis and sinusitis, consistent with previous medical history. Case 2. Transverse T2-weighted image of the cerebrum at the level of the frontal lobes. Similar to Case 1, there is bilaterally symmetric increased signal intensity within the internal capsule and corona radiata (arrows). Case 2. (A) Midsagittal T2-weighted image. When compared with a cat with no clinical evidence of cerebellar disease (B), the cerebellum appears subjectively enlarged, and the normally low signal white matter is markedly hyperintense, resulting in a striking reversal of signal characteristics when compared with the normal cerebellum. Cisternal CSF analysis was normal. Treatment included amoxacillin-clavulanic acidd (15 mg/kg PO q12h) for the rhinitis and sinusitis and prednisonea (0.5 mg/kg PO q12h) was continued. One week later, the cat was again examined for inappetence and open mouth breathing. There was bilateral mucoid ocular and purulent nasal discharges, hypothermia (97.8°F), and lethargy. Neurological examination was unchanged. Deterioration was attributed to sinus infection. Treatment was declined and the cat was euthanized. Gross abnormalities at postmortem examination included green, gelatinous exudate in the nasal cavity and frontal sinuses, and a subjectively swollen cerebellum with prominent folia. Histopathologic evaluation of formalin-fixed brain was performed at the University of Missouri Veterinary Medical Diagnostic Laboratory, Columbia, MO. Brain cross-sections were prepared for histopathological examination and were stained by standard methods with hematoxylin and eosin and luxol fast blue (LFB). Cresyl violet and periodic acid Schiff (PAS) were used as counter stains for LFB. Histopathologic findings were dominated by widespread vacuolation in the white matter, predominantly of the cerebellum, pons, cerebral cortex, internal capsule, corpus callosum, and white matter of the centrum semiovale with minimal sparing of U fibers (Fig 5). Within the cerebellum, vacuolar change was most severe in the white matter around the cerebellar nuclei and peduncles (middle peduncle was examined histologically), but extended into the cerebellar folia. White matter vacuolar change was apparent in the pons region around the facial nerve. Less severe changes were apparent near the cochlear nucleus and in ascending and descending white matter tracts in the medulla. Stains for myelin (LFB) demonstrated a general reduction in staining intensity with elongate vacuoles situated along axons in longitudinally situated white matter tracts (Fig 6). Immunohistochemical staining was done to detect axons by staining for phosphorylated neurofilament proteins. These demonstrated relative preservation of axons in areas of vacuolation, consistent with a primary demyelinating process (Fig 7), although axonal displacement was noted secondary to vacuolar change. Immunohistochemical staining to detect microglia and other leukocytes by cluster of differentiation (CD) 18 antibody did not reveal increased microglial density in affected tissue. Case 2. Composite photomicrograph of the internal capsule and cerebral white matter, demonstrating loss of myelin staining and vacuolar change. Luxol fast blue-cresyl violet stain. This corresponds to the abnormalities seen on magnetic resonance imaging in Figure 3. Magnification: Scale bar=1 mm. Case 2. Longitudinal vacuoles in the facial nerve in the pons show the distribution of large vacuoles along axonal pathways. Luxol fast blue-periodic acid Schiff stain. Magnification: Scale bar=50 μm. Case 2. This step section of the area shown in Figure 6 was stained immunohistochemically to detect phosphorylated neurofilament (SMI34 antibody, 1 : 6,000). DAB chromogen, hematoxylin counter stain. Magnification: Scale bar=50 μm. Scattered positive PAS staining bodies, consistent with glycosaminoglycan bodies, were observed throughout the neuropil rather than within cells. Large numbers were in the cuneate, gracilis, and dorsal vestibular nuclei of the medulla (Fig 8). Testing for prion protein (PrPSC) was negative. Case 2. Periodic acid Schiff (PAS) positive bodies, consistent with glycosaminoglycan bodies, scattered throughout the neuropil in the medulla. Luxol fast blue-PAS stain. Magnification: Bar=30 μm. We report acquired spongiform encephalopathy affecting the white matter in Ragdoll cats. In both cats, neurologic signs localized to the cerebellum or brainstem, whereas MRI and histopathological changes were more widespread. Descriptions on the use of MRI for the clinical diagnosis of cerebellar spongiform encephalopathy in animals are rare. In reports of two Bull Mastiff puppies1 and a Labrador Retriever puppy,2 MRI lesions consisted of bilaterally symmetric T2 hyperintensities within the cerebellar nuclei in both breeds and the thalamic nuclei in the Labrador Retriever. Hydrocephalus in the Bull Mastiffs, and poor gray to white matter distinction on proton density-weighted images in the Labrador Retriever, were also described. Although consistent with a neurodegenerative disorder, the predominant MRI features in these dogs corresponded to vacuolar changes within the nuclei,1,2 a feature not present in our cats. Reports of spongiform changes in young animals suggests an underlying congenital disorder in Samoyeds,3 Silky Terriers,4 Labrador Retrievers,2,5,6 and cattle.7 The disease occurs in Egyptian Mau,8 Birman,9 domestic short-hair,10 and Persian11 cat breeds. Acquired status spongiosis in cats occurs as a result of hexachlorophene12 or experimental bromethalin13 toxication and feline spongiform encephalopathy (FSE).14 The MR images in the cats were compared with scans from 25 cats having no clinical evidence of cerebellar or brainstem disease (age- and breed-matched controls were not available). Abnormalities, only present in our Ragdoll cats, consisted of symmetric T1 and T2 prolongation in the internal capsule and corona radiata of the cerebrum and the corpus medullare of the cerebellum (the latter appearing diffusely but more intensely within the crescent-shaped lesions dorsal to the cerebellar nuclei). Lesion location and appearance were nearly identical, with the exception of an additional lesion in the dorsal vermis in Case 1. Histopathologically, white matter vacuolation within the cerebrum and cerebellum correlated with the MR images, although the brainstem lesions were not definitely identified on MRI. Unfortunately, histologic sections precisely corresponding to the transverse MR images of the cerebellum were not made. Nevertheless, in Case 2, white matter vacuolation was most severe around the deep cerebellar nuclei, likely accounting for the crescent-shaped hyperintensities seen dorsal to the nuclei on the transverse cerebellar images. Vacuolation was present in the cerebellar white matter extending from the deep nuclei to the folia and correlated with T2 and T1 prolongation of the corpus medullare on the sagittal images. This resulted in a striking reversal of arbor vitae signal characteristics on the midsagittal T2-weighted images of Case 2 in comparison with a cat with no cerebellar disease. The normally low signal white matter was markedly hyperintense because of T2 prolongation. Prolongation of T2 and T1 relaxation, and the resultant increase and decrease in signal intensity on conventional T2- and T1-weighted spin echo images, respectively, occurs with an increase in water proton mobility. This can occur with edema, necrosis, inflammation, or neoplasia associated with an increase in intra-, extracellular-free, or both (unbound) water molecules. Although most neurodegenerative diseases have myelination alterations that can be elucidated by MRI,15 the mechanism of signal changes in myelin containing structures is perhaps more complex. As with other pathologic responses, demyelination is associated with prolonged T2 and T1 relaxation on conventional MR images.15 Vacuolation, 1 light microscopic characteristic of demyelination, can occur in 2 ways. One is separation of the myelin lamellae at the intraperiod line, causing vacuolation by reopening of the extracellular space associated with presumed accumulation of fluid between the external aspects of the oligodendrocyte processes.16 The second involves intracellular swelling of oligodendrocyte processes and separation at the major dense line.16 Ultrastructural examination would be required to determine where in the myelin sheath the vacuolation and intramyelinic edema is occurring. Likewise, the close relationship between myelin and axons makes it impossible to distinguish between primary axonal abnormalities and primary myelin pathology (and their respective edema components) with conventional MRI alone.15 Based on MRI and histopathologic findings, an underlying etiology could not be identified; however, a metabolic disorder such as an in-born error of metabolism primarily affecting white matter17 or a toxic neurodegenerative disorder was considered most likely. Recently, cats consuming irradiated food developed white matter vacuolation of the spinal cord and optic nerve,18,19 and a leukoencephalopathy in adult cheetahs was also suspected to be food related.20 MRI abnormalities in the cheetahs were limited to the cerebral white matter, and were characterized by a diffuse, symmetric T2-weighted hyperintensity and T1-weighted hypointensity and contrast enhancement. These findings correlated with axonal and myelin degeneration on histopathologic examination. Exposure to a common toxin in our cats was unlikely because the disease developed in each cat 2 years apart. Both cats had a history of upper respiratory infections, but to the authors' knowledge, there are no published reports correlating spongiform changes to upper respiratory infections. In Case 2, histopathologic findings included glycosaminoglycan bodies and spongiform changes. Glycosaminoglycan bodies can be associated with mucopolysaccharide storage disease; however, spongiform change is not an expected associated microscopic finding17 and typical clinical signs were absent in our cat. A more likely explanation for the glycosaminoglycan bodies is an age-related change, as reported in other metabolic disorders.21 Vacuolar change can also be age related.17 However, age-related vacuolation is not consistent with the severity of lesions seen on the MRI or demonstrated histopathogically in Case 2. Clinically, neurodegenerative disorders such as adult onset cerebellar abiotrophy, which has been reported in cats,22 could not be ruled out. Recently, MRI morphometry assessment of relative cerebellar size and CSF space was used to distinguish affected from nonaffected American Staffordshire Terriers with cerebellar cortical degeneration (CCD).23 In affected dogs, the relative cerebellar size was significantly smaller and the relative CSF space was significantly larger than in normal dogs,23 unlike our cats, in which the cerebellums were considered subjectively normal or enlarged. Furthermore, the signal intensity alterations seen in our cats were not identified in dogs with CCD.23 PrPSC was negative in Case 2. Although testing was not done in Case 1, suspicion for FSE was low. In reports of FSE, histopathologic changes include spongiform change in the gray matter and neuronal vaculation,14 features not present in our cats. aUnknown manufacturer bGeneral Electric, Signa LX, Milwaukee, WI cMagnevist, Berlex Laboratories, Wayne, NJ dClavamox, Pfizer Animal Health, Exton, PA

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