History
A 4-year-old 7.3-kg (16-lb) castrated male Pug was evaluated because of a sudden onset of rapidly progressive neurologic abnormalities. Four days prior to referral evaluation, the owner perceived the dog to have right forelimb lameness. The following day, a neurologic examination by the primary care veterinarian revealed ambulatory tetraparesis with decreased conscious proprioception in all limbs. Clinical signs were refractory to empirical fluid therapy administered SC and an NSAID administered orally.
Clinical and Gross Findings
At the referral evaluation, the dog had markedly diminished mentation. Physical examination revealed nonambulatory tetraparesis, vertical nystagmus of the right eye, rotary nystagmus of the left eye, and facial muscle fasciculation. Forelimb and hind limb reflexes were intact. The dog was afebrile. Neuroanatomical localization of neurologic deficits indicated an intracranial lesion. Owing to the rapid deterioration of the dog's neurologic status and a grave prognosis, the owner elected to euthanize the dog by IV administration of euthanasia solution without pursuing further antemortem diagnostic testing.
At postmortem examination, the brain appeared grossly normal in size and symmetry with no meningeal abnormalities. In transverse fixed sections of the cerebral cortex, there were extensive, coalescing malacic lesions of the periventricular white matter that extended into subcortical white matter and some cortical gray matter (Figure 1). Dorsolateral thalamic lesions were found. Of the 2 hemispheres, the right was more dramatically affected. No gross midbrain or hind-brain lesions were identified. The cervical portion of the spinal cord had a 0.3-cm-wide dorsal furrow beginning at the C3 vertebra and extending 3.0 cm caudally. Transverse sections of this region of the spinal cord had evidence of profound dorsal malacia and cavitation. No gross abnormalities in other viscera were found.
Photograph of a transverse brain section from a 4-year-old dog that was evaluated because of sudden-onset, progressive, neurologic disease. Neurologic abnormalities included vertical nystagmus in the right eye, rotary nystagmus in the left eye, facial muscle fasciculation, and nonambulatory tetraparesis. Notice coalescing regions of malacia in the left and right hemispheres (arrows). Bar = 1.0 cm.
Citation: Journal of the American Veterinary Medical Association 248, 4; 10.2460/javma.248.4.377
Photograph of a transverse brain section from a 4-year-old dog that was evaluated because of sudden-onset, progressive, neurologic disease. Neurologic abnormalities included vertical nystagmus in the right eye, rotary nystagmus in the left eye, facial muscle fasciculation, and nonambulatory tetraparesis. Notice coalescing regions of malacia in the left and right hemispheres (arrows). Bar = 1.0 cm.
Citation: Journal of the American Veterinary Medical Association 248, 4; 10.2460/javma.248.4.377
Photograph of a transverse brain section from a 4-year-old dog that was evaluated because of sudden-onset, progressive, neurologic disease. Neurologic abnormalities included vertical nystagmus in the right eye, rotary nystagmus in the left eye, facial muscle fasciculation, and nonambulatory tetraparesis. Notice coalescing regions of malacia in the left and right hemispheres (arrows). Bar = 1.0 cm.
Citation: Journal of the American Veterinary Medical Association 248, 4; 10.2460/javma.248.4.377
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page →
Histopathologic Findings
Histologic evaluation of sections of the cerebrum revealed extensive histiocyte infiltration, perivascular lymphoplasmacytic cuffing, and astrocytosis within the periventricular and subcortical white matter. Inflammation was most severe in the internal capsule and extended cranially along the corona radiata, with some extension into cortical gray matter (Figure 2). Similar lesions extended from the internal capsule medially across the external medullary lamina into the dorsolateral thalamus. Inflammation often surrounded coalescing regions of necrosis and cavitation. The only histologic change observed in midbrain and hindbrain regions was rare, sporadic axonal vacuolation. The cervical portion of the spinal cord had lymphoplasmacytic, histiocytic perivascular infiltrates, multifocal necrosis, and prominent loss of myelin, which were more prominent in the dorsal aspect of the cord (Figure 3). Necrosis effaced the dorsal white matter and gray horns in the spinal cord regions corresponding to the dorsal furrow. Meningitis was minimal, except for mild lymphocytic infiltrates in regions overlying the caudal cerebrum.
Subgross histologic image (A) and photomicrographs (B and C) of a transverse section of the right hemisphere from the brain of the dog in Figure 1. A—Notice extensive necrosis and edema within the right cerebral periventricular white matter, which has progressed along the internal capsule into the subcortical white matter (arrowheads). H&E stain; bar = 1.0 cm. B—Magnified image of the area within the black box in panel A. Grossly evident malacia is characterized histologically by abundant edema and necrosis. H&E stain; bar = 100 μm. C—Magnified image of the area within the dashed box in panel A. This region near the junction of the internal capsule and thalamus is markedly hypercellular because of infiltrates of histiocytes and lymphocytes. H&E stain; bar = 25 μm.
Citation: Journal of the American Veterinary Medical Association 248, 4; 10.2460/javma.248.4.377
Subgross histologic image (A) and photomicrographs (B and C) of a transverse section of the right hemisphere from the brain of the dog in Figure 1. A—Notice extensive necrosis and edema within the right cerebral periventricular white matter, which has progressed along the internal capsule into the subcortical white matter (arrowheads). H&E stain; bar = 1.0 cm. B—Magnified image of the area within the black box in panel A. Grossly evident malacia is characterized histologically by abundant edema and necrosis. H&E stain; bar = 100 μm. C—Magnified image of the area within the dashed box in panel A. This region near the junction of the internal capsule and thalamus is markedly hypercellular because of infiltrates of histiocytes and lymphocytes. H&E stain; bar = 25 μm.
Citation: Journal of the American Veterinary Medical Association 248, 4; 10.2460/javma.248.4.377
Subgross histologic image (A) and photomicrographs (B and C) of a transverse section of the right hemisphere from the brain of the dog in Figure 1. A—Notice extensive necrosis and edema within the right cerebral periventricular white matter, which has progressed along the internal capsule into the subcortical white matter (arrowheads). H&E stain; bar = 1.0 cm. B—Magnified image of the area within the black box in panel A. Grossly evident malacia is characterized histologically by abundant edema and necrosis. H&E stain; bar = 100 μm. C—Magnified image of the area within the dashed box in panel A. This region near the junction of the internal capsule and thalamus is markedly hypercellular because of infiltrates of histiocytes and lymphocytes. H&E stain; bar = 25 μm.
Citation: Journal of the American Veterinary Medical Association 248, 4; 10.2460/javma.248.4.377
Subgross histologic images (A and B) and photomicrograph (C) of transverse sections of the cervical portion of the spinal cord from the dog in Figure 1. A—Multifocal regions of inflammatory infiltrate and demyelination have caused loss of the distinction between the white matter and gray matter horns. H&E stain; bar = 2.5 mm. B—Notice the marked loss of dorsal white and gray matter, leading to dorsal collapse of the cord and formation of a dorsal furrow. H&E stain; bar = 2.5 mm. C—Magnified image of the dorsal aspect of the spinal cord section in panel B. The residual white and gray matter dorsal to the central canal is markedly hypercellular as a result of histiocyte and lymphoid cell infiltration. H&E stain; bar = 250 μm.
Citation: Journal of the American Veterinary Medical Association 248, 4; 10.2460/javma.248.4.377
Subgross histologic images (A and B) and photomicrograph (C) of transverse sections of the cervical portion of the spinal cord from the dog in Figure 1. A—Multifocal regions of inflammatory infiltrate and demyelination have caused loss of the distinction between the white matter and gray matter horns. H&E stain; bar = 2.5 mm. B—Notice the marked loss of dorsal white and gray matter, leading to dorsal collapse of the cord and formation of a dorsal furrow. H&E stain; bar = 2.5 mm. C—Magnified image of the dorsal aspect of the spinal cord section in panel B. The residual white and gray matter dorsal to the central canal is markedly hypercellular as a result of histiocyte and lymphoid cell infiltration. H&E stain; bar = 250 μm.
Citation: Journal of the American Veterinary Medical Association 248, 4; 10.2460/javma.248.4.377
Subgross histologic images (A and B) and photomicrograph (C) of transverse sections of the cervical portion of the spinal cord from the dog in Figure 1. A—Multifocal regions of inflammatory infiltrate and demyelination have caused loss of the distinction between the white matter and gray matter horns. H&E stain; bar = 2.5 mm. B—Notice the marked loss of dorsal white and gray matter, leading to dorsal collapse of the cord and formation of a dorsal furrow. H&E stain; bar = 2.5 mm. C—Magnified image of the dorsal aspect of the spinal cord section in panel B. The residual white and gray matter dorsal to the central canal is markedly hypercellular as a result of histiocyte and lymphoid cell infiltration. H&E stain; bar = 250 μm.
Citation: Journal of the American Veterinary Medical Association 248, 4; 10.2460/javma.248.4.377
Morphologic Diagnosis and Case Summary
Morphologic diagnosis: severe, multifocal-to-coalescing, histiocytic and lymphoplasmacytic, necrotizing meningoencephalomyelitis.
Case summary: nonsuppurative, necrotizing meningoencephalomyelitis in a dog.
Comments
Idiopathic meningoencephalitides are common inflammatory disorders of the accounting for nearly 21% of histologically assessed cases of meningoencephalitis in that species.1 Many types of idiopathic meningoencephalitis are known and are histologically delineated by the cellular nature and distribution of inflammatory infiltrates within the neuroparenchyma and meninges. Definitive causes for these encephalitides have remained elusive; current theories focus on multifactorial origins involving genetic, autoimmune, environmental, and possible viral factors.2–5 Nonsuppurative entities, such as granulomatous meningoencephalitis (GME), necrotizing meningoencephalitis (NME), and necrotizing leukoencephalitis (NLE), comprise 60% to 84% of reported idiopathic cases.1,6 The hallmark histopathologic feature shared by these 3 nonsuppurative meningoencephalitides is the presence of predominantly histiocytic and lymphoplasmacytic inflammation; thus, their classification as separate clinical entities is largely based on distinct lesion distributions.2,3,7 Antemortem differentiation between the nonsuppurative encephalitides is a diagnostic challenge because of overlap in reported historical features, neurologic abnormalities, and diagnostic findings.2,6,7
Granulomatous meningoencephalitis is the most common canine idiopathic inflammatory encephalopathy. Granulomatous meningoencephalitis is characterized by angiocentric granulomatous lesions that are multifocally distributed throughout the white matter and, to a lesser extent, the gray matter of the cerebrum, cerebellum, brainstem, and cervical portion of the spinal cord.2,3,7 Severe leptomeningitis of the cerebellum, brainstem, and spinal cord is commonly present with relatively mild inflammation within cerebral meninges.3 Despite extensive histologic lesions, gross changes may be less pronounced than in the necrotizing encephalitides.7
Necrotizing meningoencephalitis was first described in a cohort of Pugs in 1989.4 Unlike GME, nonsuppurative inflammation is predominantly restricted to the cerebral hemispheres in cases of NME.2,4 Cortical gray matter and subcortical white matter are most affected; loss of demarcation between gray and white substance is a common gross abnormality.2 Multifocal to coalescing regions of profound necrosis, appearing grossly as malacia or cavitation, are another feature of NME.2,4,7 Marked cerebrocortical leptomeningitis is usually present.3,4 Despite extensive pathological changes within the cerebral cortex, lesions of the noncerebral neuroparenchyma are rare. Between 85% and 100% of affected animals have predominantly lymphocytic pleocytosis and high total protein concentration in CSF samples.4,8 Evaluation of anti-glial fibrillary acid protein antibody titers in CSF is a potentially useful antemortem diagnostic test, with an elevated titer having a sensitivity of 91% and specificity of 73% for NME.9 The serum concentration of glial fibrillary acid protein may also be increased in NME; a concentration > 0.1 ng/mL is 67% sensitive and 100% specific for the condition.10
Necrotizing meningoencephalitis develops most commonly in Pugs, although cases in other toy breeds including the Maltese, Papillon, Shih Tzu, Chihuahua, and Pekingese have been reported.2,3 Neurologic abnormalities are referable to intracranial disease. Clinical signs include abnormal mentation, seizure, blindness, ataxia, vestibular derangements, and aberrant cranial nerve findings.4,8 Onset of clinical disease is often acute, with > 50% of dogs having neurologic signs of < 2 weeks' duration at the time of diagnosis.4 A chronic variant of NME, with which animals have clinical abnormalities for up to 6 months, has been documented.4 Affected Pug dogs are often young (median age of onset, 18 months), and a sex predisposition is suspected, as 40 of 60 (67%) Pugs with NME were female in 1 study.8 Clinical disease is rapidly progressive, with a mean survival time of 93 days.8 Administration of anticonvulsant medications may marginally prolong survival time.8
Another idiopathic canine encephalitis predominantly observed in toy breeds is NLE, which was first described in Yorkshire Terriers.2,5,11 Similar to NME, marked neuroparenchymal necrosis with lymphoplasmacytic and histiocytic inflammation is observed with NLE.2,3 Lesions are mainly present within the periventricular cerebral white matter, including the thalamus.2,3 Pathological changes may extend caudally into the mesencephalon, cerebellum, and spinal cord, but subcortical white matter, cortical gray matter, and meninges are commonly spared.2,3 Interestingly, neurons within affected gray matter may remain intact despite marked, adjacent inflammation.5 Gross malacia and neuroparenchymal cavitation are often more dramatic with NLE than with NME.2
In the case described in the present report, the neurologic signs and lesion distributions did not strictly conform to the classic patterns reported for GME, NME, and NLE. Given the extensive white matter involvement, mild degree of meningitis, and neuroparenchymal cavitation, the pathological changes most closely resembled NLE. However, the dog's signalment and rapid progression of clinical disease were more typical of NME. There are other reports of nonsuppurative, necrotizing meningoencephalomyelitis in small-breed dogs where the histopathologic findings are not completely consistent with a defined clinical entity.2,6 These cases could be breed-related variants or reflect a continuum of the classic nonsuppurative encephalitides.6
References
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2. Talarico LR, Schatzberg SJ. 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.
3. Park ES, Uchida K, Nakayama H. Comprehensive immunohistochemical studies on canine necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalomyelitis (GME). Vet Pathol 2012; 49: 682–692.
4. Cordy DR, Holliday TA. A necrotizing meningoencephalitis of Pug dogs. Vet Pathol 1989; 26: 191–194.
5. Tipold A, Fatzer R, Jaggy A, et al. Necrotizing encephalitis in Yorkshire Terriers. J Small Anim Pract 1993; 34: 623–628.
6. Granger N, Smith PM, Jeffery ND. Clinical findings and treatment of non-infectious meningoencephalomyelitis in dogs: a systematic review of 457 published cases from 1962 to 2008. Vet J 2010; 184: 290–297.
7. Suzuki M, Uchida K, Morozumi M, et al. A comparative pathological study on canine necrotizing meningoencephalitis and granulomatous meningoencephalomyelitis. J Vet Med Sci 2003; 65: 1233–1239.
8. Levine JM, Fosgate GT, Porter B, et al. Epidemiology of necrotizing meningoencephalitis in Pug dogs. J Vet Intern Med 2008; 22: 961–968.
9. Toda Y, Matsuki N, Shibuya M, et al. Glial fibrillary acidic protein (GFAP) and anti-GFAP autoantibody in canine necrotising meningoencephalitis. Vet Rec 2007; 161: 261–264.
10. Miyake H, Inoue A, Tanaka M, et al. Serum glial fibrillary acidic protein as a specific marker for necrotizing meningoencephalitis in Pug dogs. J Vet Med Sci 2013; 75: 1543–1545.
11. Kuwamura M, Adachi T, Yamate J, et al. Necrotising encephalitis in the Yorkshire terrier: a case report and literature review. J Small Anim Pract 2002; 43: 459–463.
