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- Materials and Methods
Background: Marked eosinophilic meningitis or meningoencephalomyelitis (EME) is rarely reported in dogs and the cause is usually undetermined. Long-term prognosis for dogs with cerebrospinal fluid (CSF) eosinophilia is variable.
Animals: Twenty-three client-owned dogs.
Methods: Retrospective case series. Dogs with eosinophilic CSF, defined as total nucleated cell count (TNCC) >3 cells/μL with >20% eosinophils, were identified by a computerized search of all dogs having cisternal and/or lumbar CSF analyzed as part of the diagnostic workup between 1992 and 2007.
Results: TNCC in CSF ranged from 4 to 4,740 cells/μL (median 84 cells/μL, reference range ≤3 cells/μL), with 22 to 95% (median 78%) eosinophils in the differential count. An infectious agent was identified on necropsy in 4 of 23 (17%) dogs (Cryptococcus neoformans [n = 2], Neospora caninum [n = 1], and Baylisascaris procyonis [n = 1]). Each of these dogs had progressive neurologic deterioration. Sixteen dogs had idiopathic EME. Magnetic resonance imaging (MRI) findings were abnormal in 7 of 13 dogs with EME; 2 dogs had focal lesions and 5 dogs had multifocal lesions. Clinical signs in 12 of 16 (75%) dogs with idiopathic EME resolved with prednisone treatment. Three dogs with acute intervertebral disc herniations recovered after decompressive surgery alone.
Conclusions: Idiopathic EME is a common cause of eosinophilic pleocytosis in dogs. MRI findings are variable. Infectious causes of EME were less common and had a poor prognosis.
Eosinophils are rarely identified in the cerebrospinal fluid (CSF) of dogs and other species. When the percentage of eosinophils in the CSF is only mildly increased (<5%), this finding is considered nonspecific and is associated with a variety of diseases, including infectious and noninfectious inflammatory disease as well as neoplasia, infarction, shunt placement, and spinal cord compression.1–4 It is recommended that an eosinophilia of 10% of the total white cells in the CSF should be used as a minimum criterion for the diagnosis of eosinophilic meningitis in people.2
CSF eosinophilia in animals is classically associated with migrating helminth infection in dogs, sheep, horses, llamas, goats, foxes, and primates.5–13 Diseases with a predominantly eosinophilic CNS infiltrate in the nervous tissue include Dirofilaria immitis migration in a cat, Cuterebral myiasis in a cat, Toxoplasma gondii infection in horses, amebic infection in a sheep, and Hypoderma bovis migration in a horse.14–18 Eosinophilic meningitis occurs in acute lead poisoning in calves and salt poisoning in swine and idiopathic eosinophilic meningoencephalitis is described in 2 cows and a cat.19–22
Marked CSF eosinophilia associated with an infectious etiology is rarely reported in dogs. Angiostrongylus infection is a cause of eosinophilic meningomyelitis in Australian dogs but is rarely reported in other countries.12,13 Eosinophilic CSF occurs in association with Neospora sp., Prototheca sp., and Cryptococcus sp. infection in dogs.1,12,13,23,24 Eosinophils occur in the CSF of dogs with canine distemper virus (CDV), rabies virus, bacterial encephalitis, and toxoplasmosis, although not in a high enough percentage to be considered as eosinophilic pleocytosis.1 Eosinophilic meningitis/meningoencephalitis/meningoencephalomyelitis (EME) of undetermined etiology (idiopathic EME) is reported in 11 dogs.23,25,26 The purpose of this study was to describe the presentation, CSF analysis, magnetic resonance imaging (MRI), and clinicopathologic findings in 23 dogs with eosinophilic pleocytosis.
Materials and Methods
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- Materials and Methods
A computerized medical record search from 1992 to 2007 was performed for dogs presenting for neurologic signs to the University of California Davis, Veterinary Medical Teaching Hospital (UCD VMTH) with eosinophilic CSF. Dogs were included if they had a CSF pleocytosis (>3 nucleated cells/μL, UCD VMTH Clinical Pathology Laboratory reference range ≤3 cells/μL), with ≥20% eosinophils in the differential count. Given that 10% CSF eosinophils is recommended as a minimum criterion for eosinophilic meningitis, we reasoned that ≥20% eosinophils in CSF was unequivocal evidence of specific recruitment of eosinophils into the CNS and constituted marked CSF eosinophilia and eosinophilic meningitis.2
Signalment, clinical history, physical, and neurologic examination findings were recorded for all dogs. Results of diagnostic tests, including CBC, serum biochemical panel, urinalysis, thoracic radiographs, and abdominal ultrasound, were recorded. The total nucleated cell count (TNCC), percentage of eosinophils in the differential count, and protein concentration for the initial CSF analysis and all subsequent CSF analyses were recorded for all dogs. Results of advanced imaging, including myelography, computed tomography (CT), and MRI, were also reviewed by the authors (RCW, BKS). All CT and MR images were acquired with settings considered optimal for imaging the CNS. Infectious disease testing on serum, CSF, or both included Cryptococcus latex agglutination Cryptococcal antigen test (n = 14; 7 CSF, 5 serum, and 2 CSF and serum), T. gondii IgG and IgM antibody (n = 10; 3 serum, 6 CSF, and 1 CSF and serum), Neospora caninum immunofluorescent antibody test (IFA) (n = 8; 4 serum, 2 CSF, and 2 CSF and serum), Coccidiodomycosis immunodiffusion (n = 8; 6 serum, 1 CSF, 1 CSF and serum), PCR panel for CDV, West Nile virus, N. caninum and hughesi, Rickettsia rickettsia, Ehrlichia canis, Borrelia burgdorferi, and T. gondii (n = 7), D. immitis antigen (n = 7), E. canis/E. equi antibody (n = 7 serum), CDV IgG and IgM antibody (n = 4; 2 CSF, 1 serum, and 1 serum and CSF), Babesia canis antibody (n = 2 serum), and Brucella canis rapid slide agglutination test (n = 2). CSF culture and fecal culture and sedimentation were performed in 2 dogs each.
Reported response to treatment and overall outcome was determined. Necropsy findings were examined if available.
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- Materials and Methods
Eosinophilia is an uncommon finding in the CSF of dogs with neurologic disease. It can be associated with meningitis, encephalitis, and myelitis and occurs mainly in young to middle-aged large breed dogs. MRI findings in dogs with idiopathic EME vary considerably and focal mass lesions and cranial nerve involvement may be identified. Neurologic signs resolve in the majority of dogs with idiopathic EME most likely attributable to anti-inflammatory or immunosuppressive prednisone therapy.
Of the 23 dogs with marked CSF eosinophilia in this study, an idiopathic cause was diagnosed most frequently (13/23) with infectious and noninfectious inflammatory causes occurring less commonly. This is also the first report of intracranial nematode migration causing eosinophilic pleocytosis in the CSF. This probably reflects the rarity of the disease because B. procyonis infection is characterized by large deposits of eosinophils along necrotic migration tracks and cerebral blood vessels.28 Although there is no canine immunologic assay currently available to detect antibodies to B. procyonis, as is the mainstay of diagnosis B. procyonis in humans, fecal analyses including flotation and sedimentation techniques should be performed in all dogs with EME to look for parasites with migratory potential.
Variable CSF analyses have been reported in dogs with neosporosis and cryptococcosis, although most have a mixed, histiocytic, or neutrophilic pleocytosis.29–40 CSF eosinophilia is rarely reported in dogs with Neospora, with eosinophils typically constituting <5% of the TNCC.36,37,41 In both dogs with cryptococcosis and the dog with neosporosis in this report, few eosinophils were identified in CNS tissues collected at necropsy despite the high percentage of eosinophils in the CSF. Eosinophilic inflammation may have initially localized to the meninges in these dogs whereas granulomatous or histiocytic infiltrates predominated in the brain parenchyma.
In a majority of the dogs with eosinophilic CSF in this report, an underlying infectious agent was not identified. Idiopathic EME has been reported previously in 11 dogs; however, MRI findings were available in only 1 dog.23–26 MRI findings in the 13 dogs with idiopathic EME in this report were variable. Focal mass lesions were reported in 4 dogs, suggesting that EME, similar to GME, may present focally in some dogs. Three dogs with mass lesions responded to treatment with prednisone and had no recurrence of clinical signs when prednisone was discontinued, with a follow-up time of 2–3 years, making neoplasia unlikely. One dog with masses in the olfactory bulb and pyriform lobe died at home and necropsy was not performed. Prominence of the sulci, suggestive of cortical thinning or atrophy, was present in 1 dog, which is similar to the MRI findings in another report of a dog with idiopathic EME.26 Patchy regions of T2 hyperintensity and/or T1 postcontrast enhancement were seen in several dogs, indicating more diffuse parenchymal disease. Cranial nerve V, VII, and VIII involvement was seen clinically and on MRI in 1 dog, which has not previously been reported with EME. An underlying neoplastic process such as lymphoma infiltrating the cranial nerves was considered, but the lack of recurrence of clinical signs after corticosteroid treatment was tapered would be unusual for lymphoma. Diffuse meningeal enhancement was identified in 1 dog with an extremely high TNCC (3,880 cells/μL), which may have reflected severe meningitis. MRI indicated no intracranial abnormalities in 4 dogs, including 2 dogs with a marked CSF pleocytosis. Small or very diffuse meningeal and/or intraparenchymal lesions may be difficult to detect on MRI.
Dogs with idiopathic EME had a much better long-term prognosis than dogs with an infectious etiology. Only 4 (25%) dogs with idiopathic EME died or were euthanized. This compares to previous reports where 6 of 11 (55%) dogs with idiopathic EME died or were euthanized.23,25,26 Of those 6 previously reported dogs, 3 were euthanized without treatment and 3 died despite treatment with corticosteroids. In the 5 previously reported cases where clinical signs resolved, 4 dogs received corticosteroids.23,25 Necropsy findings in 5 previously reported cases of idiopathic EME include meningeal discoloration (n=3), spongiosis (n=2), demyelination (n=2), gliosis and astrocytosis (n=2), malacia (n=2), cortical atrophy (2), neuronal necrosis (n=1), hemorrhage (n = 1), and opaque exudate within sulci (n=1).23,25,26 The wide variety of pathologic findings described in these dogs may reflect pathologic processes of different etiologies or temporally associated factors in a continuum of the same disease.
In 3 dogs in this report, including 1 dog with 78% eosinophils in the CSF, eosinophilic CSF was associated with acute IVD extrusion. Although infectious disease testing was not performed in these dogs, all recovered without immunomodulatory treatment. It is possible that eosinophilic CSF in these dogs may have reflected an allergic or hypersensitivity reaction to IVD material or, less likely, that they had concurrent idiopathic EME that resolved without corticosteroid therapy.
It is unclear why idiopathic EME is diagnosed in a majority of the dogs with marked CSF eosinophilia whereas an infectious agent is more commonly identified in other species. It is possible that infectious causes of canine EME are not properly diagnosed. Fecal examination is the primary diagnostic tool for identifying intestinal parasites with migratory potential in dogs. If fecal floatation had been performed in all dogs in this study, it is possible that other parasitic organisms would have been identified. However, in humans, parasitic infections including Toxocara and Gnathostomiasis are commonly diagnosed with serology rather than with fecal floatation because ova from the parasites are often not identified in the feces.42–44 Therefore, it is possible that even with fecal analysis, parasitic causes of EME in dogs go undiagnosed without more thorough serologic testing. Eosinophilic meningoencephalitis has been reported in association with viral infection in humans and it is possible that some dogs with EME suffer from a transient undiagnosed viral infection.45 Two dogs in this report recovered without treatment, which may support a self-limiting viral etiology. Some cases of idiopathic EME may represent another form of pathogen-free steroid responsive inflammatory CNS disease, which is common in dogs but rare in other species. The often dramatic response to corticosteroids in many dogs with idiopathic EME supports an inflammatory process that may or may not be associated with (or preceded by) underlying allergy or infection. However, corticosteroids can also reduce blood and tissue eosinophil numbers directly via many mechanisms, including induction of apoptosis.46
Similar to other reports, a majority of the dogs in this study were young to middle aged. However, idiopathic EME was diagnosed in 2 dogs ≥10 years of age. All 4 dogs with infectious EME and a majority of the dogs with idiopathic EME (69%) were large breed dogs. Unlike GME and necrotizing encephalitis, which occur more commonly in small breed dogs and typically require life-long immunosuppressive therapy, many cases of EME in this report occurred in large breed dogs and responded to a tapering dose of prednisone, following a clinical picture more similar to steroid responsive meningitis.
Peripheral eosinophilia was identified in only 1 dog in this report (dog with B. procyonis migration). In 8 of 13 (62%) previously reported cases of EME, concurrent blood eosinophilia was noted, although there was no correlation between the magnitude of blood and CSF eosinophilia.23–26 Similarly, there is often no correlation between eosinophilia in the peripheral blood and the CSF in humans with EME.3,47
Necropsy findings in dogs with idiopathic EME are variable in distribution and severity and may suggest different underlying etiologies or the effects of temporally associated factors in a continuum of the same disease. Prognosis for infectious EME is poor and, as such, thorough infectious disease evaluation including fecal analysis and serum and CSF immunology is required to rule out known infectious causes. Pathologic examination of all euthanized dogs that fail to respond to treatment will be crucial in better characterizing the underlying etiology of idiopathic EME.