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Inflammatory brain disorders of dogs: GME, NME, NE and SRMA (Proceedings)

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Apr 01, 2009

Inflammatory central nervous system (CNS) diseases are a group of diseases that affect the brain, or brain and spinal cord, in the absence of an (apparent) infectious cause. These inflammatory CNS diseases affect dogs worldwide.

The four most clinically relevant inflammatory CNS diseases of dogs are Granulomatous Meningoencephalomyelitis (GME), Necrotizing Meningoencephalitis (NME), Necrotizing Encephalitis (NE), and Steroid Responsive Meningitis-Arteritis (SRMA). In this lecture, we will discuss the most current clinical aspects of all four diseases, including the signalment, history, clinical signs, diagnosis, differential diagnosis, and therapy.

Most of the CNS inflammatory diseases are characterized by an acute onset with a progressive course; some are chronic progressive. Diffuse or multifocal involvement is characteristic of most of the diseases in this group, but localized signs also may occur. A minimum database may provide evidence of systemic disease, although most primary CNS inflammatory diseases usually do not produce a systemic response.

Diagnosing CNS inflammatory disease is achieved by a combination of findings on history, signalment, and clinical findings, as well as advanced imaging and results of CSF analysis. While CSF analysis is useful for establishing the diagnosis of inflammatory disease, it often is not specific with regard to etiology. Advanced imaging also may be very useful in the diagnosis of inflammatory disease of the CNS, although a definitive diagnosis cannot be made on advanced imaging alone. Cytology and/or histopathology of the lesion (via biopsy) are necessary for a definitive diagnosis.

Granulomatous Meningoencephalomyelitis (GME)

Canine granulomatous meningoencephalitis (GME) is the current term for an idiopathic disease probably first described in 1936 and still attracting a confusing and lengthy number of synonyms (inflammatory reticulosis, lymphoreticulosis, neoplastic reticulosis, etc.) reflecting changes only in immunological terminology. The term reticulosis in humans was introduced by 1950 and then essentially discarded in human neuropathology by 1980 with the identification as a primary CNS B cell lymphoma. But in the dog reticulosis has persisted "ghost-like" despite any similarities to the human lesion. GME has world wide distribution, has no defined breed or gender specificity, and is characterized by a unique angiocentric granulomatous encephalitis currently described with three major patterns of lesion distribution in brain and spinal cord.

Histologically there is a perivascular accumulation of macrophages often admixed with lymphocytes and plasma cells. In the common disseminated form, most intense lesions occur in the upper cervical spinal cord, brainstem and midbrain, often with less severe extension rostrally into hemispheric white matter. Secondly there is a disseminated form with angiocentric expansion forming multiple coalescing mass lesions. Lastly there is a focal form in which single discrete mass lesions occur in either the spinal cord, brainstem, midbrain, thalamus, optic nerves, or in the cerebral hemispheres without dissemination. It remains contentious whether the latter is a neoplastic rather than an immunoproliferative process.

Preliminary immunophenotyping studies (e.g., Thy-1, MHC class II, B7.1, B7.2, TCR αβ,γδ, CD1 b,c, CD3, CD4 a,b, CD 8 a,b, CD11 b,c,d, CD20, CD45, CD 45R, CD79a), and MIB-1 staining, on each of these disease patterns suggests that both disseminated forms exhibit similar phenotypic profiles. However the focal form appears to be of neoplastic histiocytic dendritic cell phenotype.

The pathogenesis of GME remains obscure, though an autoimmune encephalitis induced by anti-GFAP antibodies in CSF or a T cell mediated delayed hypersensitivity mechanism have been suggested. PCR-based screening for viral DNA (e.g., herpes, adeno or parvoviruses) has been negative. Findings from neuro-imaging, neurological examination, and CSF analysis, will be discussed against the modifying background of the spectrum of gross and microscopic lesions.

The prognosis for dogs with GME is poor, and most dogs eventually die or are euthanatized. Some survive only a short time, while others have a more prolonged clinical course, from 6 months to rarely, even years. Therapy is based on the use of corticosteroids or other immunomodulatory drugs at immunosuppressive or anti-inflammatory doses.

A tentative diagnosis of GME is based on signalment, clinical signs and the presence of focal or multifocal lesions on magnetic resonance (MR) imaging or computed tomography (CT). Dogs with GME typically have an elevated nucleated cell count and protein in the CSF, predominantly composed of lymphocytes. Since the CSF usually is inflammatory, dogs are tested for infectious disease with serology or PCR analysis for the presence of infectious agents. Histopathology is required for definitive diagnosis. CNS tissue may be collected by CT-guided brain biopsy or surgery (craniotomy or laminectomy).

The prognosis is poor, and most dogs eventually succumb to the disease over a variable period of time despite therapy. The most common therapy is corticosteroids. Other forms of immunomodulatory therapy (e.g., cytosine arabinoside [Cytosar®], cyclosporine) may be used if the dog does not tolerate corticosteroids, for some dogs if a lower dosage of corticosteroids is used, or if there is inadequate clinical response. Whole brain irradiation has been utilized on occasion. Since at this point in time double blinded, placebo-controlled clinical trials do not exist to help us to choose the best therapy for our patients with GME, most of the information we have is anecdotal. Determining the "best" therapy is therefore, based on our best assessment of the literature, experience, and response of our individual patients.

At UC Davis, initially we start treatment with immunosuppressive doses of prednisone. Usually this therapy is continued for at least the first month, during which time we may add in cytosine arabinoside (Cytosar®), which is continued at monthly intervals. The dosage of prednisone may be reduced over time in some dogs. Serial physical and neurological examinations, blood work, and CSF taps are done to closely monitor affected dogs. Most dogs require therapy for the remainder of their lives.