Etiology of CNS inflammation can broadly be subdivided in infectious diseases and non-infectious diseases. The proportion of both may vary significantly between different areas of the world depending on local prevalence of infectious agents and vectors being available for disease transmission, as well as depending on the local climatic conditions. However, diseases with presumed non-infectious etiology represent a significant percentage of inflammatory CNS diseases, and they may actually outweigh by far infectious causes in many areas of the world.

The following non-infectious inflammatory CNS diseases may have to be considered as potential differential diagnoses in certain canine breeds:

 Meningitis: Steroid-responsive meningitis/arteritis

 Encephalitis/meningoencephalitis: Granulomatous meningoencephalitis, necrotizing leukoencephalitis, necrotizing meningoencephalitis, idiopathic eosinophilic meningoencephalitis, idiopathic cerebellitis

Steroid-Responsive Meningitis/Arteritis (SRMA)

Steroid-responsive meningitis/arteritis (SRMA) is the most common canine inflammatory CNS disorder. Usually, young to young adult dogs are affected (6–18 months), but it can be seen in the age range of 4 months to 7 years. The disease can occur in dogs of any breed, but the following are affected more frequently: Beagle, Boxer, Bernese mountain dog, Weimaraner, Nova Scotia duck tolling retriever.

Even though SRMA has been observed in the canine population for several decades, the exact etiopathogenesis is currently still unknown. Detection of activated T-lymphocytes may suggest an infectious etiology. Every attempt, however, to identify any viral or bacterial antigen in those patients has failed so far. Demonstration of autoantibodies may suggest an autoimmune etiology.

Clinical Signs

An acute and a chronic form can be differentiated, with the first being much more common. The chronic form may develop from relapsing intermittent acute disease or from inappropriate treatment of the acute form. Symptoms of acute SRMA include fever, stiff gait, arched back, severe cervical spinal hyperesthesia, depression, lethargy, anorexia. Neurological deficits are rarely seen. Symptoms can sometimes be intermittent and self-limiting. In chronic cases, however, the following signs may be seen in addition: ataxia, paresis, menace deficits and seizures.

Diagnostics

CSF obtained may be blood tinged due to high red blood cell content secondary to arteritis. CSF analysis in acute form usually reveals moderate to severe predominately neutrophilic pleocytosis (up to 10 000 nucleated cells/µl) with a varying number of red blood cells, an elevated total protein, as well as a positive Pandy-reaction (semiquantitative immunoglobulin test). Neutrophils accounting for 50–90% of all nucleated cells may exhibit toxic changes. In addition, monocytes, lymphocytes and macrophages (erythrophages, siderophages) may be seen. Those findings, however, can be seen with bacterial meningitis as well. Therefore, careful screening of all slides for intracellular bacteria is strongly recommended. Bacterial culture can be performed, but does not seem to be necessary in most cases where signalment, clinical signs and CSF findings support the presumptive diagnosis of SRMA.

Suspected diagnosis can be substantiated by measuring the following parameters: IgA in serum and CSF (sensitivity: 91%, specificity: 78%;¹) as well as C-reactive protein in serum and CSF.

Therapy

Even though prednisolone has been accepted as the mainstay of the therapy of SRMA, an ideal and commonly accepted treatment protocol has not been established. Therapy is initiated using prednisolone in an immunosuppressive dose, usually resulting in a dramatic improvement of clinical signs. Following that initial phase, the prednisolone dose is slowly tapered, but how fast and to which level the dose can be decreased is subject to an ongoing debate. We recommend the following protocol: Prednisolone 1.5–2 mg/kg BID for 3–4 days; followed by prednisolone 1 mg/kg BID for 1 more month; followed by prednisolone 1 mg/kg SID for 2 more months. Reevaluation is performed after about 3 months. CSF analysis used to be recommended in order to decide if the treatment can be discontinued. It appears, however, that C-reactive protein in serum might be sufficient to determine if the immune-mediated process has been terminated. Following the decision to discontinue therapy, prednisolone has to be tapered over the next 2–3 months before it can be discontinued completely.

Dogs are usually suffering from severe side effects of chronic prednisolone therapy, especially in cases where relapses require treatment over a prolonged period of time. Therefore, changing to other protocols might be indicated in selected cases. Azathioprine can be used alternatively given at a dose of 2 mg/kg initially daily together with prednisolone and switching to an alternate application after 2 weeks (one day: azathioprine, the other day: prednisolone). Then, the prednisolone might be tapered to the lowest effective dose. Other medications have been used empirically (cyclosporine, lomustine, mycophenolate mofetil).

Prognosis

Prognosis is fair to good. It might be better in Boxers than in Beagles and Bernese Mountain Dogs. Despite following a strict treatment protocol for an appropriate period of time, relapses may occur in 20–30% of cases. Such relapses are rarely seen beyond 3 years of age. The number of relapsing cases may decrease in the future when the decision to terminate medical treatment will be more commonly based on C-reactive protein measurements than on normal CSF findings.

Non-Infectious Encephalitis (GME, NLE, NME, IEME)

Most of those diseases are well known for about 30 years, but the underlying etiology has still to be determined. All attempts to identify an infectious agent in cerebrospinal fluid or tissue samples of those patients have failed so far. Therefore, the term non-infectious encephalitis is often used, whereas others prefer the term encephalitis of unknown etiology to reflect the lack of knowledge of the etiopathogenesis.

Granulomatous Meningoencephalitis (GME)

Granulomatous meningoencephalitis (GME) is historically spoken the oldest disease of those mentioned above. It is characterized by granulomatous inflammatory lesions. Initially, the disease was seen in small terrier breeds. Nowadays however, GME should be considered in any dog of every breed with encephalitis (except giant breeds).

Usually, young adult dogs are affected, most of them being 3 to 6 years old - but GME has been described in the age range between 5 months and 12 years. Typically, GME presents as an acute onset, progressive, multifocal neurologic disease that may be fatal if left untreated. Clinical symptoms can vary significantly depending on the affected region. According to the lesion distribution, 3 different types of GME can be differentiated: focal, disseminated and ocular. In the focal form, small inflammatory lesions may confluence forming large granuloma which may cause unifocal, lateralized clinical signs, similar to neoplastic lesions depending on the location within the brain. The following symptoms can be seen: ataxia, vestibular syndrome, cranial nerve deficits, reduced mentation, restless pacing, circling, visual deficits and in about 20% of dogs seizures. Focal lesions can be restricted to spinal cord in up to 10% of dogs. The more common disseminated form is characterized by diffuse lesions affecting all parts of the brain, resulting in multiple clinical symptoms that are often more severe than in the focal form. The ocular form is restricted to optic disc, optic nerve and retina, but it may progress to the disseminated form. The ocular form manifests with an acute onset of visual impairment, variable pupillary changes, variable degrees of optic disc edema and occasionally chorioretinitis, especially in the non-tapetal fundus.

Necrotizing Leukoencephalitis (NLE)

This variant can be seen in Yorkshire Terriers and French Bulldogs. NLE is characterized by a non-suppurative inflammation, mainly affecting the deep white matter of cerebrum and brain stem. Leptomeningeal involvement is usually mild and therefore, CSF may exhibit mild pleocytosis only. Yorkshire Terriers are affected at an age between 1 and 10 years, with most of them being 1–4 years old. French Bulldogs are usually 1–3 years old. Clinical symptoms reflect lesion localization in forebrain and brainstem with relative sparing of the cerebellum. Signs may include central vestibular syndrome, reduced mentation, visual deficits, conscious proprioceptive deficits and seizures.

Necrotizing Meningoencephalitis (NME)

Necrotizing meningoencephalitis (NME) is most frequently diagnosed in Pugs, but it may be seen in Maltese, Chihuahua, Papillon, Pekingese and Shi Tzu. In Pugs, where the term Pug dog encephalitis is used too, it may affect dogs from 5 months to 7 years, even though it is most frequent in dogs up to 3 years. The predominant presenting clinical signs are seizures, visual deficits and altered mentation, which can be explained by the disease's predilection for the cerebral hemispheres. Unlike NLE, in NME cerebellar, brainstem, and spinal cord involvement is rare.

Affected dogs often present after only a few days of showing clinical disease, whereas other dogs are affected to some degree for several weeks to months before presentation. Symptoms reflect the almost exclusive prosencephalic (cerebrum and/or thalamus) localization and can include lethargy, anorexia, blindness with normal pupillary light reflexes, circling, head pressing, and partial or generalized seizures.

Idiopathic Eosinophilic Meningoencephalitis (IEME)

It is the rarest condition of the once discussed here. The term IEME is used if CSF analysis reveals a percentage of eosinophils of at least 20%. IEME of suspected immune-mediated etiology has been seen in dogs of different breeds in an age range between 6 months and 13 years, with most of them being 3–4 years old.

Though eosinophilic encephalitis can be caused by various infectious agents (i.e., Toxoplasma gondii, Neospora caninum, Cryptococcus neoformans, Baylisascaris procyonis, Prototheca), most of those dogs are diagnosed with the immune-mediated form based on a lack of detection of an infectious agent and response to immunosuppressive therapy.

Diagnostics of GME, NLE and NME

Diagnostics can include CSF analysis, MRI, brain biopsy, as well as additional tests to exclude an infectious etiology.

CSF analysis is required to detect inflammatory changes. However, this test is neither 100% sensitive nor very specific for a certain disease. CSF will reveal inflammatory changes only if the pathological changes of the brain extend to CSF-associated surfaces. Therefore, CSF analysis may reveal only minor changes or it may be completely normal in cases of focal GME with deep seeded granuloma-like lesions or in dogs with NLE where leptomeningeal involvement may be minimal. Therefore, CSF nucleated cell count may be normal in about 10% of dogs with GME. The following nucleated cell counts can be usually seen in dogs with GME, NLE, NME based on our own experience in Leipzig in dogs with histologically confirmed diagnosis (normal: ≤5/µl): GME: 10–1500/µl; NLE: 1–100/µl; NME: 1–500/µl.

In dogs wittics of GME, NLE and NME GME cell differentiation usually reveals a mixed but predominately mononuclear pleocytosis. The percentage of neutrophils rarely exceeds 30%. Sometimes a small number of eosinophils, lymphoblasts as well as mitotic figures can be seen in GME. In dogs with NLE and NME mixed pleocytosis is usually seen; however, percentage of lymphocytes may be higher than in GME, whereas the number of neutrophils rarely exceeds 15%.

Total protein concentration is typically elevated in most dogs; it may, however, be normal in a certain percentage of dogs with NLE (30%) or NME (15%). In rare cases, CSF analysis may be completely normal (normal nucleated cell count and normal total protein concentration) in dogs with NLE and NME.

MRI is the imaging modality of choice to detect inflammatory brain lesions, whereas CT may miss a significant number of cases. However, MRI might be completely normal in about 25% of dogs with encephalitis. Therefore combining CSF analysis and MR brain imaging is necessary in order maximize diagnostic yield.

MRI findings in GME are rather nonspecific. The most common MRI findings for the disseminated form include multiple hyperintensities on T2-weighted or fluid attenuated inversion recovery (FLAIR) sequences distributed throughout the CNS white matter. These lesions typically assume an infiltrative appearance and have irregular margins. Despite the predilection of the GME for white matter, MRI lesions often are distributed throughout both grey and white matter. The lesions are of variable intensity on T1-weighted images and have variable degrees of contrast enhancement. Vasogenic edema in the white matter is commonly seen on T2-weighted images and appears hyperintense to cerebral parenchyma. Meningeal enhancement is not commonly apparent. The focal form of GME may be identified on CT or MRI as a nonspecific single-space occupying mass lesion with homogenous contrast enhancement and perilesional edema. Therefore, focal GME can be misinterpreted as neoplastic lesion.

Typical MRI lesions associated with NME include asymmetric, multifocal prosencephalic lesions affecting the grey and white matter, with variable contrast enhancement on T1-weighted imaging. In Pugs, lesions are most severe in parietal and occipital lobes. Complete loss of grey/white matter distinction also may be discernible. Lesions appear hyperintense on T2-weighted images and isointense to slightly hypointense on T1-weighted images. Contrast enhancement is rather mild and patchy within the parenchymal lesions with additional leptomeningeal enhancement.

In NLE, multiple, asymmetric bilateral prosencephalic lesions, mainly affecting the subcortical white matter and thalamus, have been described. The NLE lesions are hyperintense on T2-weighted and FLAIR images and often include cystic areas of necrosis. These lesions are hypointense or isointense on T1-weighted images and contrast enhancement is variable and may be ring-like around necrotic areas. Those findings are highly suggestive of NLE. In Yorkshire Terriers, such findings have to be differentiated from similar looking lesions in dogs with subacute necrotizing encephalopathy. In that condition, however, lesions are usually bilaterally symmetric.

Therapy and Prognosis in GME, NLE and NME

Therapy is immunosuppressive. Traditionally, prednisolone has been used with an initial dose of 2–4 mg/kg daily and slowly tapering to the least effective dose. Those patients suffer from significant side effects of long-term prednisolone therapy. Therefore, other medications have been used to reduce prednisolone dose or even to completely replace prednisolone (azathioprine, cyclosporine, cytosine arabinoside, lomustine, procarbazine). Unfortunately, most of those alternatives have been investigated in dogs with presumptive diagnosis without histological diagnoses only. Therefore, clear recommendations regarding the most effective therapy cannot be made.

The treatment protocol employed at the University of Leipzig combines prednisolone and lomustine. Lomustine is a long-acting, immunosuppressive, alkylating nitrosurea compound with good CNS penetration. Therapy is initiated using prednisolone at a dose of 4 mg/kg daily for 3–4 days. At the same time lomustine is given at 50–60 mg/m² orally every 6 weeks. In case of improvement of clinical symptoms, the prednisolone is reduced to 2 mg/kg daily for the following 6 weeks.

Lomustine may cause significant leukopenia and less commonly anemia and thrombocytopenia. The nadir of the leukocyte count is reached about one week after lomustine application. Lomustine dose should be reduced by 25% if the leukocyte concentration drops below 3.5 G/l.

In cases of complete resolution of neurological deficits, the prednisolone dose is reduced every 6 weeks by 25% up to the least effective dose. Prednisolone can be discontinued completely in about 30% of dogs. Blood cell count as well as liver enzymes should be checked one week following every lomustine application.

Using the treatment protocol described above, the following median survival times can be achieved: GME: 641 days (range: 2–1836); NLE in Yorkshire Terriers: 453 days (range: 112–880); NLE in French Bulldogs: 622 days (range: 313–880); NME in Chihuahua: 587 days (range: 424-629 (n=3); NME in Pugs: 53 days (range: 1–334).

References

1.  Maiolini A, Carlson R, Schwartz M, Gandini G, Tipold A. Determination of immunoglobulin A concentrations in the serum and cerebrospinal fluid of dogs: an estimation of its diagnostic value in canine steroid-responsive meningitis–arteritis. Vet J. 2012;191:219–224.