Lauren R. Talarico,     Fairfax, Virginia

Overview

Among the subtypes of inflammatory CNS disease are granulomatous meningoencephalitis, necrotizing meningoencephalitis, necrotizing leukoencephalitis, and eosinophilic meningoencephalitis, referred to as GME, NME, NLE, and EME, respectively. GME has been reported to affect the spinal cord and cause a subsequent meningomyelitis. Steroid-responsive meningitis-arteritis (SRMA) is another suspected autoimmune disorder that affects primarily the spinal cord; this disorder is not considered here. As a group, these diseases often are referred to as meningoencephalitis of unknown cause because antemortem diagnosis is difficult to achieve in most cases. Given the increasing availability of less invasive stereotactic brain biopsy instruments guided by magnetic resonance imaging (MRI) or computed tomography (CT), we anticipate that definitive diagnoses will become more attainable in the near future.

The disorders NME and NLE sometimes are referred to as pug dog encephalitis and Yorkshire terrier encephalitis, respectively. It is important to realize that dogs of many other breeds can develop NME and NLE and that these disorders are not exclusive to pug and Yorkshire terrier breeds. The author also has diagnosed GME in pug dogs and Yorkshire terriers and therefore advises against using this breed-specific terminology. Furthermore, the majority of the literature contains reports of noninfectious meningoencephalitis (NIME) in small-breed dogs; however, the author has definitively diagnosed GME in several large-breed retriever dogs.

To date, a definitive cause of granulomatous, necrotizing, and eosinophilic meningoencephalitides has not been established. Genetic, infectious, and autoimmune causes have been proposed. A recent study by Barber et al (2010) evaluating the results of polymerase chain reaction testing of brain tissue and cerebrospinal fluid (CSF) demonstrated that Ehrlichia, Anaplasma, Rickettsia, and Borrelia are unlikely to be associated with NIME; however, the role of Bartonella still is uncertain. It is the author’s belief that GME, NME, NLE, and EME are autoimmune in origin, and this constitutes the basis for our therapeutic approach. An underlying genetic predisposition for these diseases also may play a role.

Clinical Signs

The majority of NIME cases are small-breed dogs between 2 and 6 years of age brought in because of peracute- or acute-onset multifocal neurologic signs. Patients with noninfectious CNS inflammatory diseases rarely have extraneural signs, and results of routine blood work usually are unremarkable. The specific deficits found on the neurologic examination reflect the location of the lesion within the brain, meninges, and spinal cord. Typically multiple areas of the brain are affected. Animals with forebrain involvement can have seizures and show behavioral or mentation changes, circling, pacing, head pressing, and central blindness with normal pupillary light reflexes. Signs referable to brainstem involvement can include severe mental depression varying from obtundation to coma; mydriasis; hemiparesis or hemiplegia; tetraparesis or tetraplegia; decreased palpebral, corneal, and gag reflexes; facial and trigeminal paralysis; and central vestibular signs. Cerebellar signs, including intention tremors, titubation, hypermetria or dysmetria, and absent menace response with normal vision often are encountered. Head pain with or without neck pain is likely secondary to inflammation of the meninges. Animals with head pain back away when the examiner attempts to pet the head, and their eyes often appear squinted.

Clinical signs typically are progressive, but the rate of progression varies. It is important to realize that the severity of a patient’s clinical signs at presentation is not correlated with survival time or achievement of disease remission.

Diagnosis

NIME is a histopathologic diagnosis, and a definitive antemortem diagnosis is not often achieved. With the advent of minimally invasive stereotactic MRI- or CT-guided brain biopsy tools at veterinary referral centers and veterinary colleges, definitive antemortem diagnoses are becoming more frequent. Nevertheless, the majority of cases are diagnosed presumptively based on a combination of signalment, clinical signs, MRI, and spinal fluid analysis (CSF tap). Infectious encephalitis, congenital malformations, storage diseases, toxin exposure, and neoplasia are differential diagnoses for multifocal neurologic signs with peracute onset in a young adult animal. A minimum data set consisting of results of a complete blood count, chemistry panel, urinalysis, and thoracic radiographs often is within normal limits.

MRI and CSF analysis provide the most helpful information for making a presumptive diagnosis. MRI typically reveals multifocal infiltrative lesions within the brain parenchyma that are hyperintense on T2-weighted and FLAIR (fluid-attenuation inversion recovery) images and hypointense to isointense compared with the surrounding parenchyma on T1-weighted sequences. Contrast enhancement is variable. The meninges also can be hyperintense on T2-weighted and T1-weighted postcontrast sequences. The lesion and associated edema often are space occupying, causing compression of the surrounding brain parenchyma and a midline shift. In extreme cases, subfalcine and/or transtentorial herniation of the caudal cerebellum through the foramen magnum will occur.

GME tends to have a predilection for the white matter and typically affects both the brainstem and forebrain. There is a focal form of GME that produces a solitary space-occupying mass lesion which can closely resemble a neoplastic process. The majority of NME cases are supratentorial in distribution, predominately affecting both the gray and white matter of the forebrain. NLE is characterized by defacement of the white matter of both the brainstem and cerebral cortex. Additionally, the necrotizing encephalitides (NME and NLE) can be associated with visible areas of necrosis within the brain parenchyma in addition to inflammatory lesions as described earlier. Occasionally the MRI findings are normal and the diagnosis is based solely on the results of CSF analysis.

CNS inflammation is best documented by CSF analysis, consisting of cytologic examination and protein evaluation. GME, NME, and NLE are characterized by mononuclear cell pleocytosis (elevated lymphocytes and monocytes) and elevated protein level. These CSF findings are nonspecific because they cannot discriminate between autoimmune, neoplastic, viral, and protozoal CNS infections. EME is characterized by eosinophilic pleocytosis and elevated protein level. Differential diagnoses for eosinophilic pleocytosis are parasitic, protozoal, autoimmune, and neoplastic diseases. Cell counts and protein level can be quite variable, ranging from zero to several thousand cells per microliter and zero to several hundred grams per deciliter, respectively. The magnitude of the pleocytosis or protein level in the CSF is not prognostic. Occasionally the CSF tap findings can be normal, especially if the patient recently received corticosteroids. It is possible that animals with normal imaging findings but CSF results consistent with NIME are being seen early in the disease process before the formation of brain lesions.