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

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.

Necrotizing Meningoencephalitis (NME)

Necrotizing meningoencephalitis (NME) is a world-wide disease originally recognized in the US in the 1970's in pug dogs as a breed specific disease colloquially known as "pug dog encephalitis". Since 1989 based on morphologically defined lesion patterns and histology, NME has been recognized in other small breed dogs including Maltese, Chihuahua, Pekingese, Boston terrier, Shih Tzu, Coton du Tulear and Papillon breeds.

The pathogenesis or etiology remain obscure. NME has both a characteristic anatomic distribution pattern and unique histological lesions not previously seen in other canine encephalitides of known etiology. Clinically the disease occurs in either sex but intriguingly so far only in small breed dogs. Gross lesions occur as asymmetrical, multifocal bilateral areas of either acute encephalitis or chronic foci of malacia, necrosis and collapse of hemispheric grey and white matter decreasing in intensity rostro-caudally. Histologically there is a unique combination of focal meningitis and polio- and leucoencephalitis of adjacent white matter. The lesions are intensely inflammatory with meningitis and parenchymal histiocytic, microglial infiltrates with perivascular cuffing with lymphocytes and plasma cells. Coexisting with chronic lesions can be an acute non-suppurative encephalitis in the hippocampus, septal nuclei and thalamus. Usually there are minimal inflammatory lesions in the cerebellum, brainstem and spinal cord.

Clinical signs are variable, and dependent on the region of the brain affected. When the forebrain is affected, dogs have abnormal mentation, seizures, blindness, circling, and behavior changes. When the brainstem is affected, clinical signs such as cranial nerve deficits, changes in mentation, and difficulty walking may occur.

The diagnosis is based in history, signalment, clinical signs, as well as the findings on MR imaging, CSF analysis, and PCR and/or serology for infectious disease. Characteristic findings on MR imaging include asymmetric, bilateral (often multifocal) lesions in the forebrain (+/- brainstem), that are hyper-intense on T2 and FLAIR weighted MR images. These lesions variably enhance with intravenous contrast administration. Cystic areas may be present in areas of the brain that are necrotic. On CSF evaluation there is usually a mild to moderate increase in nucleated cells and protein. The majority of the nucleated cells usually are lymphocytes.

The prognosis is poor even with aggressive anti-inflammatory, immunosuppressive and/or chemotherapy. Most dogs die or are euthanized within 6 months of the start of their clinical signs. Treatment is as with GME, although is more aggressive, with immunosuppressive dosages of corticosteroids administered for longer periods of time and additional immunomodulatory drugs started earlier in the course of therapy.

Necrotizing Encephalitis (NE)

Necrotizing encephalitis, first described in 1993 in Yorkshires and now in the French Bulldog, has a pattern and histological type of the lesions that is strikingly different from those of NME. Grossly the large focal asymmetric bilateral malacic necrotizing brownish lesions are confined to hemispheric white matter. There is an intense histiocytic, microglial and macrophage cell infiltrate with loss of white matter and thick perivascular lymphocytic cuffing. Other areas have acute exudation, severe edema, necrosis and eventual cyst formation with a dramatic gemistocytic astrogliosis, histiocytes and gitter cells intermixed with thick perivascular lymphocytic cuffing. Characteristically the overlying cortex and meninges are not involved. In the midbrain and brainstem including the cerebellum are multifocal intense inflammatory cell infiltrates of macrophages with dramatically thick perivascular lymphocytic cuffing.

Thus the classical lesions in NME and NE are distinctively different based on both distribution pattern and microscopic lesions. As with NME limited immuno-phenotyping restricted to paraffin- embedded lesions (CD3, CD11d, CD18, CD20 and CD79a) is consistent but not diagnostically useful. As with NME the neuro-imaging features, neurological signs, and CSF analysis, vary with intensity and location of lesions, but allow only a differential clinical diagnosis with a lack of scientifically-based therapeutic strategies.

"Non-Conforming" NME and NE

Two cases will be presented, a Pug dog and a Yorkshire terrier, each with a "non conforming" encephalitis that shares features of some of the major morphological boundaries currently applied for the diagnostic distinction between NME and NE, respectively. Whether these cases thus represent a much wider emergent spectrum of a single disease adds to the diagnostic dilemma presented by these encephalitides, and underlines the urgent need for a comprehensive reevaluation to establish guidelines and to foster clinical research into the underlying disease biology.

Steroid Responsive Meningitis-Arteritis (SRMA)

Steroid responsive meningitis-arteritis occurs commonly in young, medium to large breeds of dog. The etiology is unknown, but an immune-mediated cause is suspected as an infectious agent has not been identified, and dogs improve when treated with corticosteroids. Some researchers suggest that repeated vaccinations may cause the disease by sensitizing the dog to viral antigens. This may account for the incidence of the disease in young dogs.

Affected dogs are young, usually between 7 and 16 months of age. Clinical signs include reluctance to move, arched back, stiff gait, cervical and/or thoracolumbar pain, fever, muscle rigidity, pain on opening the mouth, and, less commonly, neurologic deficits such as decreased proprioceptive positioning, paraparesis, or tetraparesis. Polyarthritis may also be present. Clinical signs may be acute in onset and progressive, or may be chronic with a waxing and waning course over a period of weeks or months.

The majority of affected dogs have a mature neutrophilia in their peripheral blood. The CSF white blood cell count may be normal, or may range from 50 to more than 3000 cells/ul, with predominantly mature neutrophils. Bacteria or fungi are not seen within white blood cells. CSF Protein concentration is usually increased. Bacterial (aerobic and anaerobic) and fungal cultures of the CSF, urine, and blood are negative.

Diagnosis is based on history, signalment, and the finding of increased white blood cells in CSF, failure to isolate an infectious agent from CSF, and response to therapy with corticosteroids. Initially, immunosuppressive dosages of prednisone are (prednisone 2.0 to 4.0 mg/kg/day). Steroids are reduced slowly over several months to the lowest dose necessary to maintain a remission of clinical signs. Maintenance treatment using every other day dosage is preferred. Approximately 50 per cent of affected dogs have recurrence of clinical signs following discontinuation of therapy. Therapy for up to 6 months may be necessary to prevent recurrence of clinical signs. Dogs should be serially examined and CSF should be monitored at regular intervals. Ideally, CSF analysis results should be within normal limits, prior to cessation of therapy. Prognosis for resolution of clinical signs is excellent. Treatment with antibiotics may be indicated initially if the diagnosis is uncertain and bacterial meningitis is suspected.