AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

NERVOUS SYSTEM

February 2017

N-M26

 

Signalment (JPC 140798):  11-year-old Jack Russell terrier.

 

HISTORY:  This dog had a 3-week history of severe behavioral changes.  CSF analysis showed elevated WBC count.  There were no gross lesions.

 

HISTOPATHOLOGIC DESCRIPTION:  Cerebrum with lateral ventricle:  Multifocally expanding the meninges and Virchow-Robin space,  primarily within the white and, to a lesser extent, grey matter are numerous perivascular cuffs composed of many macrophages (occasionally epithelioid), lymphocytes, and fewer plasma cells which form concentric layers around vessels.  There are few mitotic figures and individualized necrotic cells within this population.  Inflammatory cells infiltrate the adjacent spongiotic neuropil, and are admixed with increased numbers of reactive astrocytes with large vesiculate nuclei and fewer microglial cells with rod-shaped nuclei (microgliosis).  Diffusely, endothelial cells are hypertrophied (reactive) and vessel walls are often transmigrated by previously described inflammatory cells. 

 

MORPHOLOGIC DIAGNOSIS:  Cerebrum: Meningoencephalitis, perivascular and coalescing, lymphohistiocytic, multifocal, moderate, with spongiosis, Jack Russell terrier, canine.

 

CONDITION:  Granulomatous meningoencephalitis / meningoencephalomyelitis (GME)

 

SYNONYMS:  Inflammatory reticulosis, granulomatous reticulosis

 

GENERAL DISCUSSION: 

·         Granulomatous meningoencephalitis (GME) is a relatively common, progressive, invariably fatal, neurologic disease of unknown origin that produces multifocal, often coalescing perivascular cuffs of mononuclear cells or of granulomatous inflammation, predominantly within the white matter

·         Historically referred to as inflammatory or granulomatous reticulosis a subtype of reticulosis

·         Proliferation of differing concentrations of blood-derived macrophages, lymphocytes, plasma cells occasionally admixed with neutrophils and/or multinucleated giant cells

·         Occurs most commonly small toy breed dogs (poodles, terrier breeds), 1-6 years of with a higher prevalence in females

·         GME is further classified into three morphologic forms:

o   Focal GME:  Single space-occupying mass composed of multiple coalescing perivascular cuffs found most commonly in the brainstem

o   Disseminated GME:  Multifocal CNS lesions predominantly within the cerebrum, caudal brainstem, cerebellum and cervical spinal cord

o   Ocular GME:  Optic neuritis with visual impairment with lesions primarily within the retina or post retinal portion of the optic nerve

 

PATHOGENESIS: 

·         Unknown

·         Inflammatory lesions consist primarily of CD3+ T lymphocytes and activated macrophages with MHC II expression suggesting T-cell-mediated delayed-type        hypersensitivity with organ specific autoimmune disease

·         Histomorphological similarities to viral encephalitis (rabies, distemper), but no conclusive link to these or other viral diseases has been proven

 

TYPICAL CLINICAL FINDINGS: 

·         Signs vary with location and severity of lesion

·         Mature dog with progressive neurologic dysfunction often suggestive of a multifocal lesion

·         CSF evaluation often reveals marked elevated protein (mostly globulin) and marked leukocytosis, predominantly lymphocytes and plasma cells

·         CBC, CHEM and UA are usually WNL since the disease is not usually multisystemic

·         Ocular signs if optic neuritis, including blindness and abnormal pupillary light reflexes

 

TYPICAL GROSS FINDINGS: 

·         Variable, often no gross lesions

·         If lesions coalesce there may be a grossly evident, gray-white mass, that is granular to gelatinous, with irregular, well defined margins

·         Lesions predominate in the white matter of the cerebellomedullary region

Optic nerves may be enlarged

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

·         Patchy in distribution, ranging from very few foci to dissemination

·         Mixed perivascular/meningeal accumulations selectively in white matter of well differentiated lymphocytes, macrophages and plasma cells, +/- epitheloid macrophages, +/- giant cells, +/- low numbers of neutrophils

·         Perivascular aggregates expand in concentric pattern and displace surrounding parenchyma

·         Whorled perivascular pattern; may evolve into granulomas that mimic space occupying masses and compresses adjacent parenchyma

·         Prominence of reticulin fibers

·         Astrogliosis predominately in the white matter

·         Nonsuppurative inflammatory infiltrates and granuloma formation within the optic nerve, retina or choroid

 

ADDITIONAL DIAGNOSTIC TESTS: 

·         CSF analysis:  Protein level and cellular composition

·         Immunohistochemistry:  CD3, 43, 45R (T-cells); IgG, IgM (B cells); lysozyme and DH82 (macrophages)

·         CD163-positive macrophages/microglia accumulation

·         Expression of IFN-γ and IL-17 from T-cells and macrophages are marked in NME and GME

 

DIFFERENTIAL DIAGNOSIS: 

Clinical, gross and microscopic:

·         Canine distemper encephalitis:  Mononuclear perivascular cuffing; predilection for white matter; viral antigen in tissue with IHC

Fungal or protozoal encephalitis:  Perivascular and parenchymal changes; identification of organisms in tissue

Microscopic (GME diagnosis is supported by the exclusion of neoplastic, infectious and inflammatory diseases):

·         Lymphoma:  Previously classified as neoplastic reticulosis

o   A monomorphic population of cells that generally do not infiltrate the surrounding white matter parenchyma

·         Central malignant histiocytosis:  Previously classified as neoplastic reticulosis

o   Lesions are focal to multifocal and most often in the cerebrum

o   Similar to GME with whirling of neoplastic cell around blood vessels; however, meninges are diffusely involved and neoplastic nodules may form in the parenchyma, away from blood vessels

o   Typically less differentiated with high mitosis and variable numbers of lymphocytes and macrophages that may mimic an inflammatory lesion

·         Necrotizing meningoencephalitis of Pug and other small breeds

o   “Pug dog encephalitis” also commonly reported in Maltese, Pekingese, Shih Tzu and Chihuahua

o   Predominately within the cerebral cortex gray matter often bilateral  but asymmetric

o   Similar inflammatory component to GME but more extensive necrosis with fewer histiocytes

·         Necrotizing leukoencephalitis of Yorkshire terriers

o   Similar histopathologic lesions but more necrotic and affects brainstem and cerebrum

 

COMPARATIVE PATHOLOGY: 

·         GME–like lesions that are unrelated to infectious agents are rare in other animal species but have been described occasionally in horses, rats and cats

 

REFERENCES: 

  1. Adamo PF, Adams, WM, Steinberg, H. Granulomatous meningoencephalomyelitis in dogs. Compend Contin Educ Vet. 2007;29(11):678-690.

2.     Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Ltd; 2016:393-394

  1. Kipar A, Baumgartner W. Immunohistochemical characterization of inflammatory cells in brains of dogs with granulomatous meningoencephalitis. Vet Pathol. 1998;35:43-52.
  2. Klang A, Leschnik M, Schmidt P, Pakozdy A.Bilateral hippocampal malformation and concurrent granulomatous meningoencephalitis in a dog with refractory epilepsy. J Comp Pathol. 2013 Dec 6. [Epub ahead of print]
  3. Koestner A, Bilzer T, Fatzer R, Schulman FY, Summers BA, Van Winkle TJ. Histological Classification of Tumors of the Nervous System of Domestic Animals. Vol V. 2nd series, Washington, DC: Armed Forces Institute of Pathology; 1999;31.
  4. Munana KR, Luttgen PJ. Prognostic factors for dogs with granulomatous meningoencephalomyelitis: 42 cases (1982-1996). J Am Vet Med Assoc. 1998;212:1902-1906.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(4):682-692    
  5. Park ES, Uchida K, Nakayama H. Th1-, Th2-, and Th17-related cytokine and chemokine receptor mRNA and protein expression in the brain tissues, T-cells, and macrophages of dogs with necrotizing and granulomatous meningoencephalitis. Vet Pathol, 2013;50(6):1127-1134.
  6. Summers BA, Cummings JF, de Lahunta A.  Inflammatory diseases of the central nervous system. In: Veterinary Neuropathology. St. Louis, MO: Mosby Year Book; 1995:110-113.
  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(11):1233-1239.
  8. Suzuki M, Uchida K, Morozumi M, et al. A comparative pathological study on granulomatous meningoencephalomyelitis and central malignant histiocytosis in dogs. J Vet Med Sci. 2003;65(12):1319-1324.
  9. Zachary JF. Nervous system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2016:894.

 

 

 


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