Signalment:  

4.5-year-old female spayed Yorkshire terrier, (Canis familiars).A 4.5 year-old, spayed female Yorkshire terrier dog was referred to the University of Illinois Veterinary Teaching Hospital for neurologic evaluation. The animal had become blind and was circling to the right six months prior to presentation to the hospital. One week prior to presentation, the animal had become ataxic and unable to right itself after falling.

On initial neurologic examination, the animal had a left head turn and tilt, thoracolumbar kyphosis and extensor rigidity of the pelvic limbs. The animal was tetraplegic but could move all limbs when supported ventrally. The animal would alligator roll to the left when attempting to stand. Placing responses and hopping were absent in all four limbs. Muscle tone was increased in all four limbs, most markedly in the pelvic limbs. Spinal reflexes were increased in the pelvic limbs (with a crossed extensor). Menace response was absent in both eyes and there was a resting ventrolateral strabismus in the left eye. Pain could be elicited on palpation over the calvarium and cervical spine. Complete blood count, chemistry profile and preprandial and postprandial bile acids testing showed no significant abnormalities.

The animals neurologic status improved somewhat after treatment with prednisone, and the animal was no longer painful. Two weeks after starting the steroid medication, a neurologic examination showed no change to the cranial nerve deficits and a continued head tilt and turn; however, the animal was able to walk again (with tetraparesis and tetrataxia). The animal continued to show improvement on steroids for six weeks but then began to show worsening neurologic symptoms. At final examination, the animals demeanor was dull, and it was unable to stand with or without support. Proprioception was decreased to absent in all four limbs. In addition to previously observed cranial nerve symptoms, the animal now had mild anisocoria (left > right) and positional slow rotary nystagmus. The owner elected euthanasia.

Gross Description:  

On necropsy, the animal was in fair to poor nutritional condition, with mottled dark pink to red lungs (congestion), mild tonsillar atrophy, and moderate cardiomegaly. On opening of the calvarium, the right hemisphere of the brain was fluctuant. The exterior of the cerebral cortex was moderately to markedly thinned, and partially translucent. On coronal incision into the cerebral hemispheres, a large amount of clear, slightly yellow fluid was released from the markedly distended ventricles. There were multiple, 1 mm to 8 mm in diameter, gray to pink, depressed foci in the periventricular areas and within the cortical white matter. Extending from the frontal to the occipital cerebral cortex, these white matter lesions were irregular, bilateral but non-symmetrical, and often associated with thinning of the cortical grey matter. Lesions were more severe in the right hemisphere than the left. There was a focal, 1 mm in diameter cavitation in the left metencephalon. Other areas of the brain (i.e. cerebellum, retina, optic nerve) were not affected.

Histopathologic Description:

The cerebral white matter was severely affected by bilateral but asymmetric white matter degeneration. Loss of white matter ranged from 75% to nearly 100%, generally decreasing in a cranial to caudal direction through the cerebral hemispheres. Degeneration was characterized by loss of tissue substance with formation of pseudo-cysts delineated by numerous reactive astrocytes (gemistocytes) admixed with foamy macrophages (gitter cells) and few lymphocytes. The ventricles were markedly enlarged (compensatory hydrocephalus). Staining with GFAP for astrocytes revealed a marked gliosis throughout the affected areas. The Virchow-Robin space of occasional blood vessels was expanded by a mild infiltrate of lymphocytes, plasma cells, and occasional macrophages. The loss of white matter was verified by an almost complete lack of staining for myelin with Luxol fast blue within affected areas. In less severely affected white matter areas, like the corpus callosum, marked and abrupt areas of demyelination were often noted. Within the brain stem, similar multifocal loss of white matter was identified in the dorsal thalamus, geniculate area, and mesencephalon. One focal area of cavitation was noted in the metencephalon. The occasional neurons encountered within degenerate areas appeared unaffected. No histopathologic lesions were noted within gray matter adjacent to areas of white matter degeneration.

Morphologic Diagnosis:  

Brain, cerebrum: Severe, necrotizing, leukoencephalitis with marked astrogliosis and compensatory hydrocephalus.

Lab Results:  

CBC:

	Value	Reference Range	Units
HCT	55.8%	35-52%
MCHC	31.3	32.0-36.0	g/dL
Eosinophils	0.081x103	0.1-1.0 x103	/μL

• Anisocytosis: 1+
• Polychromasia: rare
• Target cells: 4+

Chemistry:

	Value	Reference Range	Units
Globulin	2.6	2.7-4.4	g/dL
Alb/Glob ratio	1.3	0.6-1.1
ALT	93	8-65	U/L
Total T4	14.3	15.0-48.0	nmol/L
Bile acids (preprandial)	15.5	0.0-7.5	nmol/L
Bile acids (postprandial)	16.0	0.0-25.0	nmol/L

Microbiology:

Aerobic culture:

• Brain: Pasteurella multocida few
• Brain: Alpha strep non-Enterococcus rare
• Brain: Escherichia coli - rare

Anaerobic culture:

• Brain: Clostridium perfringens - v. few
• Brain: Prevotella - few

Condition:  

Necrotizing leukoencephalitis of Yorkshire terriers (NLE)

Contributor Comment:  

Necrotizing leukoencephalitis of Yorkshire Terriers (NLE) is a rare, idiopathic, inflammatory disease of the central nervous system. It is characterized by infiltration by inflammatory cells into the white matter of the cerebrum and brainstem, with consequent widespread cavitation necrosis, demyelination, perivascular lymphoplasmacytic cuffing and glial scarring. Active lesions are characterized by marked lymphohistiocytosis, glial activation, and infiltration by numerous gitter cells and gemistocytes. Quiescent, chronic lesions are characterized by marked cavitation, advanced gliosis, and a relative paucity of inflammatory and gitter cells.(11) Lymphoplasmacytic cuffing in the case under discussion was relatively mild, but in other reported cases of NLE, perivascular lymphoplasmacytic exudate has been marked and extensive.(4,7,11) NLE is relatively sparing of the cerebral cortex and meninges, and predominantly affects periventricular cerebral white matter, including the centrum semiovale, thalamocortical fibers, internal capsule and thalamus.(7)

NLE is commonly grouped with Necrotizing Meningoencephalitis (NME) or pug dog encephalitis(7) in veterinary literature. While breed predilection and lesion topography vary between the two diseases (NME affects gray and white matter primarily in the cerebral cortex, hippocampus and thalamus,(4) while NLE affects the cerebra and brainstem), the hallmark of both diseases is lymphoplasmacytic meningoencephalitis and bilateral, asymmetric, cerebral necrosis.(7) There is some debate as to whether these diseases are two distinct entities or one disease with a similar pathogenesis but histopathologic differences as a result of minor genetic differences between breeds, modifying genes and/or variations in antigenic exposures.(7)

NLE was first described in Yorkshire terriers in 1993,(9) and has since been diagnosed in French bulldogs as well.(6,8) It primarily affects young adult dogs, with a mean age of onset of 4.5 years (range, 4 months to 10 years old).(8) It appears to affect male and female dogs equally.(9) Clinical signs on initial presentation are referable to the location of the cerebral lesions, and commonly include visual deficits or blindness, depression, seizures, circling, ataxia and head tilt.(6) Conventional treatment is with immunosuppressive doses of glucocorticoids. Survival after diagnosis varies between 3 and 18 months(2) and the disease is invariably progressive and fatal.

The etiology of NLE is poorly understood. No infectious agents have ever been identified in association with NLE; PCR screening in dogs with histopathologic diagnoses of NLE and NME for the presence of degenerate herpesvirus, adenovirus, and canine parvovirus viral proteins have revealed no viral proteins,(1) and IHC staining for Toxoplasma gondii and Neospora caninum are routinely negative. However, negative PCR results for viruses does not rule out the possibility of a viral trigger for the disease via molecular mimicry, or the possibility that a pathogen is present at undetectable levels in the presence of a self-perpetuating immune response, a phenomenon that has been described for flavivirus infections.(7) Genetics may play a role in pathogenesis, as the disease is breed specific, and a strong familial inheritance pattern was detected in pugs with NME.(7) There is likely an immune-mediated component to NLE, as evidenced by the variable but generally positive response of the disease to treatment with glucocorticosteroids. In one case report of NLE, major infiltration of necrotic areas by cytotoxic T-lymphocytes, IgG producing plasma cells, macrophages and microglial cells was identified, suggesting a possible delayed T-cell immune response in the pathogenesis of the disease.(3) It is most likely that NLE is a multifactorial disorder caused by an as yet unknown combination of the factors above.

Diagnosis of NLE can be made on a combination of factors: age, breed affected, clinical signs that can be localized to the cerebra and brainstem, and a chronic, progressive course should all be considered when making a diagnosis. MRI imaging can be a very helpful diagnostic tool, and allows the diagnosis of NLE with a high degree of suspicion based on lesion localization, lesion appearance in different sequences and contrast enhancement.(11) Protein levels and cell counts in the CSF may also be increased in cases of NLE,(5,6) but this is a non-specific finding and should only be used in conjunction with the factors above in making a diagnosis.

JPC Diagnosis:  

Cerebrum, frontal cortex: Leukoencephalitis, necrotizing, multifocal, severe with hydrocephalus ex vacuo and numerous gemistocytic astrocytes.

Conference Comment:  

Small/toy breeds are susceptible to several potentially overlapping, idiopathic encephalitides which are poorly understood. Necrotizing leukoencephalitis (NLE) of the periventricular cerebral white matter (and brainstem) is described in Yorkshire terriers and occasionally French bulldogs and is discussed comprehensively by the contributor. Necrotizing meningoencephalitis (NME) is a similar syndrome, known historically as pug dog encephalitis, that is reported in various toy breeds including the pug, Maltese terrier, chihuahua, Yorkshire terrier, Pekingese, West Highland white terrier, Boston terrier, Japanese spitz, and miniature pinscher. In contrast to NLE, NME typically affects the leptomeninges, cerebral hemispheres and subcortical white matter, with loss of the anatomic demarcation between gray and white matter.(7) Granulomatous meningoencephalitis (GME) is a progressive, generally fatal neurologic disease of unknown origin that typically affects toy and terrier breeds; it is characterized by focal (mass-like) or disseminated perivascular accumulations of histiocytes, lymphocytes and plasma cells, primarily within the white matter of the brain, spinal cord and the optic nerve.(4,7) Due to considerable overlap in the clinical presentation of these conditions, some researchers suggest that the terminology meningoencephalitis of unknown etiology (MUE) may be preferable for an antemortem diagnosis of idiopathic meningoencephalitis without concurrent histopathology. Although the etiopathogeneses for these disorders remain elusive, immunosuppressive therapy is the mainstay of treatment, suggesting that an aberrant immune response directed against the CNS may play a role in the development of idiopathic canine meningoencephalitis.(7) A similar, fatal condition, known as Alaskan husky encephalopathy (AHE) affects young huskies, and is characterized by bilateral thalamic necrosis and cavitation. AHE is thought to be similar to Leigh syndrome, which is a group of diseases in humans attributed to mutations in either nuclear or mitochondrial DNA. A recent study found a mutation in the gene encoding a thiamine transporter protein (SLC19A3.1) plays a critical role in the pathogenesis of AHE.(10)

The microscopic lesions in this case, particularly their cavitating nature and specific location within the white matter, are most consistent with the condition known as necrotizing leukoencephalitis of Yorkshire terriers (NLE). Conference participants speculated that the mild perivascular and leptomeningeal inflammation was likely a reactive change secondary to marked necrosis and that the presence of hydrocephalus ex vacuo was probably due to the filling of the large pseudocysts with CSF. 

References:

1. Jung D, Kang B, Park C, Yoo J, Gu S, Jeon H, et al. A comparison of combination therapy (cyclosporine plus prednisolone) with sole prednisolone therapy in 7 dogs with necrotizing meningoencephalitis. J Vet Med Sci. 2007;69(12):1303-1306.

2. Kuwamura M, Adachi T, Yamate J, Kotani T, Ohashi F, Summers B. Necrotising encephalitis in the Yorkshire terrier: a case report and literature review. J Small Anim Prac. 2002;43:459-463.

3. Lezmi S, Toussaint Y, Prata D, Lejeune T, Ferreira-Neves P, Rakotovao F, et al. Severe necrotizing encephalitis in a Yorkshire terrier: topographic and immunohistochemical study. J Vet Med Assoc. 2007;54:186-190.

4. Park E, Uchina K. Nakayama H. Comprehensive immunohistochemical studies on canine necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalitis (GME). Vet Pathol. 2012;49(4):682-692.

5. Schatzberg S, Haley N, Barr S, de LaHunta A, Sharp N. Polymerase chain reaction screening for DNA viruses in paraffin-embedded brains from dogs with necrotizing meningoencephalitis, necrotizing leukoencephalitis, and granulomatous meningoencephalitis. J Vet Intern Med. 2005;19:553-559.

6. Spitzbarth I, Schenk H, Tipold A, Beineke A. Immunohistochemical characterization of inflammatory and glial responses in a case of necrotizing leukoencephalitis in a French bulldog. J Comp Path. 2010;142:235-241.

7. Talarico L, Schatzberg S. Idiopathic granulomatous and necrotising inflammatory disorders of the canine central nervous system: a review and future perspectives. J Small Anim Pract. 2010;51:138-149.

8. Timmann D, Konar M, Howard J, Vandevelde M. Necrotizing encephalitis in a French bulldog. J Small Anim Pract. 2007;48:339-342.

9. Tipold A, Fatzer R, Jaggy A. Necrotizing encephalitis in Yorkshire terriers. J Small Anim Pract. 1993;34:623-628.

10. Vernae KM, Runstadler JA, Brown EA, et al. Genome-wide association analysis identifies a mutation in the thiamine transporter 2 (SLC19A3) gene associated with Alaskan husky encephalopathy. PLOS One. 2013;8(3):e57195.

11. von Praun F, Matisek K, Grevel V, Alef M, Flegel T. Magnetic resonance imaging and pathologic findings associated with necrotizing encephalitis in two Yorkshire terriers. Veterinary Radiology & Ultrasound. 2006;47(3):260-264.

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1-5. Cerebrum

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