History
A 4-year-old 1.18-kg (2.6-lb) spayed female Yorkshire Terrier was referred to the University of Illinois Veterinary Teaching Hospital for neurologic evaluation. The dog had been losing vision and circling to the right for 6 months. The dog became ataxic and unable to right itself after falling 1 week prior to referral.
Clinical and Gross Findings
On neurologic examination, the dog had a left head turn and tilt, thoracolumbar kyphosis, and extensor rigidity of the pelvic limbs. The dog was nonambulatory and tetraparetic and would twist and roll (ie, alligator roll) to the left when attempting to stand. Placing responses and hopping were absent, but muscle tone was increased in all 4 limbs. Menace response was absent bilaterally, and there was a resting ventrolateral strabismus of the left eye. Signs of pain could be elicited on palpation over the calvaria and cervical portion of the vertebral column. A CBC, serum biochemical analysis, and evaluation of serum preprandial and postprandial bile acids concentrations revealed no remarkable abnormalities. The owner declined additional diagnostic assessment, and the dog was sent home to be treated with clindamycin, doxycycline, and gabapentin.
Six days later, the neurologic status of the dog had further deteriorated; antimicrobial administration was discontinued, and treatment with prednisone was initiated (1 mg/kg [0.45 mg/lb], PO, q 24 h). With prednisone treatment, the dog regained the ability to walk (albeit with tetraparesis and tetrataxia) and no longer had signs of pain on palpation of the calvaria and cervical portion of the vertebral column, but there were no improvements in cranial nerve deficits or the head tilt and turn. The prednisone dosage was increased 13 days later (1.3 mg/kg [0.59 mg/lb], PO, q 24 h).
After 6 weeks of prednisone treatment, neurologic signs suddenly worsened. The dog had dull mentation, appeared confused, and was unable to stand with or without support. Proprioception was decreased to absent in all 4 limbs. In addition to the previously noted cranial nerve deficits, the dog had mild anisocoria (left pupil more affected than right pupil) and positional slow rotary nystagmus. The owner elected euthanasia.
On necropsy, there were no gross lesions except in the brain. On opening of the calvaria, the right hemisphere of the brain was fluctuant (Figure 1). On coronal incision into the cerebral hemispheres, a large amount of slightly yellow to brown fluid was released from the distended ventricles. There were multiple gray to pink depressed areas in the cortical white matter and in the periventricular areas. Extending from the frontal to the occipital cerebral cortex, white matter lesions were irregular, bilateral but nonsymmetric, and often associated with thinning of the cortical gray matter. There was a focal 1-mm-diameter cavitation on the left side of the pons. Other brain areas (ie, cerebellum and optic nerves) were not affected.
Photographs of the unfixed (A–C) and fixed (D) brain of a 4.5-year-old spayed female Yorkshire Terrier that was evaluated because it had been losing vision and circling to the right for 6 months and had then become ataxic and unable to right itself after falling 1 week prior to referral. Six weeks after initiation of treatment with prednisone, the dog was euthanized because of its deteriorating condition. Notice that the right cerebrum is partially collapsed (A) and there are gray to pink depressed areas in the white matter (B; arrow) and in the periventricular areas (C; arrow). The section through the fixed brain (D) illustrates the severity and distribution of lesions in the cortex and thalamus (T).
Citation: Journal of the American Veterinary Medical Association 247, 4; 10.2460/javma.247.4.361
Photographs of the unfixed (A–C) and fixed (D) brain of a 4.5-year-old spayed female Yorkshire Terrier that was evaluated because it had been losing vision and circling to the right for 6 months and had then become ataxic and unable to right itself after falling 1 week prior to referral. Six weeks after initiation of treatment with prednisone, the dog was euthanized because of its deteriorating condition. Notice that the right cerebrum is partially collapsed (A) and there are gray to pink depressed areas in the white matter (B; arrow) and in the periventricular areas (C; arrow). The section through the fixed brain (D) illustrates the severity and distribution of lesions in the cortex and thalamus (T).
Citation: Journal of the American Veterinary Medical Association 247, 4; 10.2460/javma.247.4.361
Photographs of the unfixed (A–C) and fixed (D) brain of a 4.5-year-old spayed female Yorkshire Terrier that was evaluated because it had been losing vision and circling to the right for 6 months and had then become ataxic and unable to right itself after falling 1 week prior to referral. Six weeks after initiation of treatment with prednisone, the dog was euthanized because of its deteriorating condition. Notice that the right cerebrum is partially collapsed (A) and there are gray to pink depressed areas in the white matter (B; arrow) and in the periventricular areas (C; arrow). The section through the fixed brain (D) illustrates the severity and distribution of lesions in the cortex and thalamus (T).
Citation: Journal of the American Veterinary Medical Association 247, 4; 10.2460/javma.247.4.361
Histopathologic Findings
Extending from the frontal to the occipital cortex, the white matter was severely and irregularly replaced by fluid-filled pseudocysts (Figure 2). Multifocally, the cortical gray matter was severely atrophied and the ventricles were markedly enlarged by compensatory hydrocephalus. The affected white matter was replaced by numerous reactive astrocytes (gemistocytes) admixed with perivascular gitter cells and few lymphocytes (Figure 3). The perivascular space of occasional blood vessels was expanded by a mild infiltrate of lymphocytes, plasma cells, and macrophages. In the brainstem, similar lesions were identified in the dorsal aspect of the thalamus, geniculate area, and midbrain. One focal area of cavitation was noted in the pons. The hippocampus and cerebellum were not affected.
Photomicrograph of a section of the right hemisphere of the brain of the dog in Figure 1. The cerebral cortex (CC), hippocampus (H), and thalamus (T) are visible. Severe degeneration of the white matter (arrows) is evident; there is marked dilation of the ventricle (V). H&E stain; bar = 5 mm.
Citation: Journal of the American Veterinary Medical Association 247, 4; 10.2460/javma.247.4.361
Photomicrograph of a section of the right hemisphere of the brain of the dog in Figure 1. The cerebral cortex (CC), hippocampus (H), and thalamus (T) are visible. Severe degeneration of the white matter (arrows) is evident; there is marked dilation of the ventricle (V). H&E stain; bar = 5 mm.
Citation: Journal of the American Veterinary Medical Association 247, 4; 10.2460/javma.247.4.361
Photomicrograph of a section of the right hemisphere of the brain of the dog in Figure 1. The cerebral cortex (CC), hippocampus (H), and thalamus (T) are visible. Severe degeneration of the white matter (arrows) is evident; there is marked dilation of the ventricle (V). H&E stain; bar = 5 mm.
Citation: Journal of the American Veterinary Medical Association 247, 4; 10.2460/javma.247.4.361
Photomicrographs of sections of the brain of the dog in Figure 1. A—The affected white matter is replaced by numerous reactive astrocytes (gemistocytes [arrow]) and gitter cells (arrowhead). H&E stain; bar = 50 μm. B—A blood vessel in the white matter is surrounded by mild numbers of lymphocytes, plasma cells, and occasional macrophages. H&E stain; bar = 50 m. C—Marked glial scarring is present around a blood vessel. Immunohistochemical stain for glial fibrillary acid protein; bar = 50 μm. D—In the corpus callosum, an abrupt zone of demyelination (lack of blue staining) is visible. Luxol fast blue stain; bar = 200 μm.
Citation: Journal of the American Veterinary Medical Association 247, 4; 10.2460/javma.247.4.361
Photomicrographs of sections of the brain of the dog in Figure 1. A—The affected white matter is replaced by numerous reactive astrocytes (gemistocytes [arrow]) and gitter cells (arrowhead). H&E stain; bar = 50 μm. B—A blood vessel in the white matter is surrounded by mild numbers of lymphocytes, plasma cells, and occasional macrophages. H&E stain; bar = 50 m. C—Marked glial scarring is present around a blood vessel. Immunohistochemical stain for glial fibrillary acid protein; bar = 50 μm. D—In the corpus callosum, an abrupt zone of demyelination (lack of blue staining) is visible. Luxol fast blue stain; bar = 200 μm.
Citation: Journal of the American Veterinary Medical Association 247, 4; 10.2460/javma.247.4.361
Photomicrographs of sections of the brain of the dog in Figure 1. A—The affected white matter is replaced by numerous reactive astrocytes (gemistocytes [arrow]) and gitter cells (arrowhead). H&E stain; bar = 50 μm. B—A blood vessel in the white matter is surrounded by mild numbers of lymphocytes, plasma cells, and occasional macrophages. H&E stain; bar = 50 m. C—Marked glial scarring is present around a blood vessel. Immunohistochemical stain for glial fibrillary acid protein; bar = 50 μm. D—In the corpus callosum, an abrupt zone of demyelination (lack of blue staining) is visible. Luxol fast blue stain; bar = 200 μm.
Citation: Journal of the American Veterinary Medical Association 247, 4; 10.2460/javma.247.4.361
Glial fibrillary acid protein immunohistochemical analysis revealed marked gliosis throughout the affected tissue areas (Figure 3). Loss of white matter was verified by an almost complete lack of staining for myelin within affected areas. In less severely affected white matter areas, such as the corpus callosum, marked and abrupt areas of demyelination were often evident.
Morphologic Diagnosis and Case Summary
Morphologic diagnosis: severe, bilateral, necrotizing leukoencephalitis (NLE) with marked astrogliosis and compensatory hydrocephalus.
Case summary: NLE in a Yorkshire Terrier.
Comments
Necrotizing leukoencephalitis is a rare, idiopathic, inflammatory disease of the CNS. It is characterized by infiltration of inflammatory cells into the white matter of the cerebrum and brainstem, with consequent widespread demyelination, cavitation necrosis, perivascular lymphoplasmacytic cuffing, and glial scarring. Active lesions are characterized by extensive infiltration with lymphocytes and macrophages, associated with a marked glial reaction. Quiescent or chronic lesions are characterized by marked cavitation, advanced gliosis, and a relative paucity of inflammatory and gitter cells.1 In the case described in this report, lymphoplasmacytic cuffing was relatively mild, but in other reported cases2–4 of NLE, perivascular lymphoplasmacytic cuffing has been marked and extensive. Necrotizing leukoencephalitis usually spares the cerebral cortex and meninges and predominantly affects the periventricular cerebral white matter, including the centrum semiovale and internal capsule and thalamus.5
Necrotizing leukoencephalitis was first described in Yorkshire Terriers in 19936 and has since been diagnosed in French Bulldogs.4,7 It primarily affects young adult dogs (mean age, 4.5 years; range, 4 months to 10 years old) of either sex.3,6 Clinical signs are associated with the location of the cerebral lesions and commonly include visual deficits or blindness, signs of depression, seizures, circling, ataxia, or head tilt.2,6,8 In the dog of this report, severe occipital white matter degeneration was likely responsible for the observed blindness and ataxia, and paraparesis was the result of the brainstem cavitation. For affected dogs, survival time after diagnosis of NLE ranges between 3 and 18 months, and the disease is invariably progressive and fatal.3
Necrotizing leukoencephalitis is commonly grouped with necrotizing meningoencephalitis (NME [also known as Pug encephalitis]).5 Although breed predilection and lesion topography vary between the 2 diseases (NME affects gray and white matter primarily in the cerebral cortex, hippocampus, and thalamus,9 whereas NLE affects the cerebral white matter and brainstem), the hallmark of both diseases is lymphoplasmacytic meningoencephalitis and bilateral, asymmetric, cerebral necrosis.5
The cause of NLE is poorly understood. No infectious agents have ever been identified in association with NLE. In dogs with NLE or NME, results of screening for the presence of herpesvirus, adenovirus, morbillivirus, rabies virus, or parvovirus viral proteins by means of PCR assays as well as results of immunohistochemical staining for Toxoplasma gondii or Neospora caninum are routinely negative.1,2,8,10 Genetics may play a role in pathogenesis, given that the disease is breed specific and a strong familial inheritance pattern has been detected in Pugs with NME.5 There is likely an immune-mediated component to NLE, as evidenced by the variable but generally positive response to treatment with glucocorticosteroids. Some reports2,9 have suggested that this condition is autoantibody mediated or T-cell mediated because of the presence of numerous T lymphocytes, some cytotoxic T lymphocytes, B lymphocytes, and macrophages and the production of IgG and interleukin-17. Although autoantibodies against glial fibrillary acid protein have been detected in samples of CSF from many dogs with NME,11 the role of such autoantibodies in the physiopathology of the disease remains controversial. It is most likely that NLE is a multifactorial disorder caused by an as yet unknown combination of these factors.
Interestingly, NLE bears a striking resemblance to Marburg's variant and the Schilder type of multiple sclerosis in humans, which are rapid, progressively fatal conditions characterized by well-demarcated zones of extensive demyelination and necrosis of white matter; marked infiltration by reactive astrocytes, macrophages, and microglia; and lymphoplasmacytic perivascular cuffing.12 In some forms of multiple sclerosis, autoantibodies against aquaporin 4 and myelin oligodendrocyte glycoproteins have been implicated in development of demyelination, and further research may implicate similar autoantibodies in the pathogenesis of NLE.13
Diagnosis of NLE in dogs can be made from a combination of factors including age, breed, clinical signs that localize to the cerebra and brainstem, and evidence of chronic, progressive disease. Magnetic resonance imaging is a helpful diagnostic tool and provides a high degree of suspicion of NLE on the basis of lesion localization, lesion appearance in different image sequences, and findings of no contrast enhancement to ringlike contrast enhancement patterns following contrast agent administration.1 Protein concentration and cell counts in samples of CSF may also be high in cases of NLE,1,10 but this finding is nonspecific and should only be used in conjunction with other factors in making a diagnosis.
Immunosuppressive doses of glucocorticoids are the standard treatment for dogs with NLE.5 Recent work has suggested that combining glucocorticoids with cyclosporine, cytosine arabinoside, or procarbazine not only may allow reduction in dosage of glucocorticoids needed to effect a response (thereby ameliorating the systemic adverse effects associated with long-term steroid administration5), but also may significantly increase survival time.5,10
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11. Shibuya M, Matsuki N, Fujiwara K, et al. Autoantibodies against glial fibrillary acidic protein (GFAP) in cerebrospinal fluids from Pug dogs with necrotizing meningoencephalitis. J Vet Med Sci 2007; 69: 241–245.
12. Sobel RA, Hickey WF, Seilhean D. Primary diseases of the white matter. In: Gray F, De Girolami U, Poirier J. Escourol and Poirier manual of basic neuropathology. 4th ed. Oxford, England: Butterworth-Heinemann, 2004; 157–167.
13. Reindl M, Di Pauli F, Rostásy K, et al. The spectrum of MOG autoantibody-associated demyelinating diseases. Nat Rev Neurol 2013; 9: 455–461.
