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InFocus

A spotlight on the treatment of non-infectious meningoencephalomyelitis in dogs

Non-infectious meningoencephalomyelitis remains a challenging group of inflammatory central nervous system diseases to diagnose and treat, with prognosis often remaining poor

Non-infectious meningoencephalomyelitis forms a group of conditions causing severe and progressive dysfunction of the central nervous system in dogs. The aetiology is unknown but thought to be immune-mediated. A presumptive diagnosis is obtained from the signalment, disease history, cerebrospinal fluid analysis and advanced imaging. Currently, there is no distinct treatment protocol, but a rather large choice of medications; a prognosis remains guarded to poor.

The conditions under the umbrella of non-infectious meningoencephalomyelitis are characterised by severe (suspected autoimmune) inflammation of the meninges, brain and spinal cord. Lesion location is variable, leading to a diverse range of neurological signs. Definitive diagnosis requires histopathological recognition of the lesions in the nervous system, which is rarely achieved ante-mortem. Therefore, clinicians rely on a presumptive diagnosis established by their clinical suspicion, cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI). The treatment goal is to establish immune suppression, either with glucocorticoids relayed or not with immunosuppressant drugs.

Clinicians rely on a presumptive diagnosis established by their clinical suspicion, cerebrospinal fluid analysis and magnetic resonance imaging

This review aims to give a brief overview of non-infectious meningoencephalomyelitis and an update on treatment options.

Meningoencephalomyelitis of unknown origin

FIGURE (1) A two-year-old male castrated Maltese that presented with sudden onset bilateral blindness. Note the dilated pupil in the right eye (this dog lacked pupillary light reflexes), typically seen in the optic form of GME: optic neuritis

The umbrella term of “meningoencephalomyelitis of unknown origin” (MUO) corresponds to the branch of immune-mediated diseases causing inflammation of the meninges, brain and spinal cord. It is the term coined when no definitive diagnosis is reached. It mainly encompasses granulomatous meningoencephalomyelitis (GME), necrotising meningoencephalitis (NME) and necrotising leukoencephalitis (NLE). It specifically excludes those of infectious origin (bacterial, protozoal – Toxoplasma, Neospora; viral – distemper; fungal – Cryptococcus), as well as steroid-responsive meningitis and eosinophilic meningoencephalitis.

Each disease has distinct histopathological abnormalities; however, there can be a great overlap in the clinical presentation between the various forms. In addition, Nessler et al. (2022) recently reported that GME can be found concurrently with NLE or NME.

Using the five fingers approach to neurological cases (Cardy et al., 2015), MUO characteristics are broadly:

  • Signalment: small-breed dogs, females higher risk, middle age
  • Onset: acute to subacute
  • Progression: progressive
  • Symmetry: non-symmetrical
  • Pain: can be painful
  • Localisation: commonly multifocal, including optic neuritis (Figure 1), but also seen as focal, brainstem alone or diffuse

Clinical signs can be varied, and seizures can occur. In a recent study of 61 dogs with MUO, 23 percent developed post-encephalitis epilepsy; these cases are younger, often have seizures at the start of the disease and have a shorter survival (Kaczmarska et al., 2020).

Unfortunately, clinical signs only reflect the localisation of the lesions and are, therefore, in themselves not specific. Table 1 proposes typical neurolocalisations of each of the subtypes of MUO and their associated clinical signs.

Breeds affectedMean age of onset (years)NeurolocalisationClinical signs
GMEToy breeds and small breeds, in particular Miniature Poodles, Maltese, Dachshunds, West Highland Terriers and ChihuahuasFour to eightDisseminated – multifocal; cerebrum, cerebellum, brainstem or spinal cord



Disseminated – multifocal signs



Focal – any central nervous system localisation (including spinal cord)Focal – reflecting the site affected
Ocular – optic nerve, optic chiasm +/- central nervous systemOcular – visual impairment, dilated pupils, absent pupillary light reflexes (Figure 1)
NMEPugs, Yorkshire Terriers, Maltese, Chihuahuas and Boston TerriersUnder fourForebrainSeizures, altered mentation, ataxia/tetraparesis, blindness
NLEYorkshire Terrier and French BulldogFour and a halfBrainstem
+/- forebrain
Central vestibular signs, blindness and seizures
Table (1) Summary of the three main types of meningoencephalomyelitis of unknown origin in dogs

Granulomatous meningoencephalitis (GME)

Small-breed dogs such as Miniature Poodles, Maltese, Dachshunds, West Highland Terriers and Chihuahuas predominate the population of GME (Muñana and Luttgen, 1998; Adamo et al., 2007; Talarico and Schatzberg, 2010), but toy breeds and small-breed dogs in general are over-represented. They are most affected between four and eight years old, but some cases have been reported from six months old.

Perivascular mononuclear infiltrates are either generalised, focal or home into the optic nerve and chiasm. This results in three broad categories of disseminated, focal and ocular-only forms, respectively (Cuddon and Smith-Maxie, 1984; Muñana and Luttgen, 1998; Summers et al., 1995).

Necrotising meningoencephalitis

NME is characterised by inflammation of the subcortical white matter (ie in the forebrain), leading to necrosis. Forebrain lesions commonly result in seizures, circling, ataxia, blindness and mentation changes.

Also known as “Pug dog encephalitis” (Cordy and Holliday, 1989), it typically affects Pugs, Yorkshire Terriers, Maltese, Chihuahuas and Boston Terriers (as well as other less common breeds) under the age of four (Talarico and Schatzberg, 2010; Cooper et al., 2014). A genetic test is available for NME in Pugs (Laboklin).

Necrotising leukoencephalitis (NLE)

Known as “necrotising encephalitis of the Yorkshire Terrier”, this disease is morphologically characterised by periventricular white matter and brainstem inflammation and necrosis. Therefore, these dogs present with cranial nerve deficits reflecting caudal brainstem dysfunction in addition to forebrain signs.

The mean age of onset is four and a half years, and Yorkshire Terriers are predominantly affected (Kuwamura et al., 2002). A genetic test is available in this breed (Laboklin). French Bulldogs have also been reported with NLE (Timmann et al., 2007; Spitzbarth et al., 2010). (Note that NME and NLE can occur in other breeds.)

Diagnosis

A presumptive diagnosis is obtained from the signalment, history and clinical signs, but needs to be backed up by MRI scans and CSF cytology. The CSF usually shows a mononuclear pleocytosis (Granger et al., 2010). These results are not exclusive to MUO and can also occur in infectious cases. Additionally, the results may also appear normal (Menaut et al., 2008; Granger et al., 2010).

The findings of inflammatory CSF should lead to testing for infectious diseases. Toxoplasma and Neospora are diagnosed through serology or polymerase chain reaction (PCR) tests on blood and CSF. Both Toxoplasma and Neospora typically affect multiple organs and are visible through routine biochemistry; in particular, creatinine kinase and aspartate aminotransferase were found to be increased in Neospora cases (Jones and Harcourt-Brown, 2021). Distemper is diagnosed through PCR on CSF.

MRI can show regions of hyperintensity (Figure 2), contrast uptake (Figure 3) and meningeal enhancement, and can differentiate white- from grey-matter lesions and map the disease. It offers a superior yield compared to computed tomography, which is not recommended for MUO diagnosis, but still only 60 percent of lesions are visible on MRI (Granger et al., 2010).

Stereotactic biopsy has a diagnostic accuracy of 82 percent (Flegel et al., 2012) and is safe if the target is chosen carefully (Flegel et al., 2012; Troxel and Vite, 2008). It provides a histological diagnosis ante-mortem; however, this significantly increases cost of diagnosis and requires an experienced neuropathologist to read the specimens.

Treatment

Treatment for MUO is generally given for months to years. There is no consensus regarding which drug and dosage provide distinctly improved survival. We remain unable to determine whether some dogs can be cured with a few months of immunosuppressive therapy and whether others need lifelong medication.

Direct comparison of treatments is difficult due to the lack of randomised controlled trials, and most papers report retrospective case series reflecting clinical experience in various hospitals

Direct comparison of treatments is difficult due to the lack of randomised controlled trials, and most papers report retrospective case series reflecting clinical experience in various hospitals. A major issue is the fact that most cases received corticosteroids in parallel to other medications. The authors briefly present the possible immunosuppressant therapies used in dogs with MUO below.

Glucocorticoids

Historically, glucocorticoids have appeared as a good first-line treatment, later combined with immunosuppressant drugs. Prednisolone is used at an immunosuppressive dose (2mg/kg/day) for three to four weeks and then tapered down over three to six months. Glucocorticoids lead to polyphagia, weight gain, polyuria, polydipsia and iatrogenic hyperadrenocorticism. Therefore, their dosage is tapered down, and adjunctive therapies are often used for dogs requiring long-term immunosuppression.

A recent review found a range of 28 to 357 days median survival time with glucocorticoids alone (Jeffery and Granger, 2023). However, treatment with glucocorticoids did not predict the development of post-encephalitis epilepsy (Kaczmarska et al., 2020).

Mycophenolate

Mycophenolate (20mg/kg/bid) inhibits T- and B-cell proliferation. Gastrointestinal side effects, infections and haematological abnormalities led to treatment withdrawal in many cases.

Median survival times reported a range from 118 days (Lujan Feliu-Pascual et al., 2008) to 731 days. However, the latter was associated with a multidrug combination of mycophenolate, glucocorticoids, cytarabine and cyclosporin (Woolcock et al., 2016).

Cytosine arabinose (cytarabine)

There is some controversy around the ideal method of administration (eg duration versus concentration) of cytarabine in dogs with MUO. For many years now, referral centres have used a 24-hour constant-rate infusion or subcutaneous injections over 48 hours, given monthly, but recent studies dispute these methods and their efficacy (Cornelis et al., 2019; Joong-Hyeon Yu et al., 2020; Lowrie et al., 2016; Stee et al., 2020).

The lack of side effects in dogs also suggests that the doses used are too low (Keegan et al., 2019). Twenty-four-hour infusions are associated with a high cost and the need for hospitalisation, meaning that clients may drop the treatment. In people, cytarabine is typically administered over five to seven days to reach effective serum levels.

Lomustine

Lomustine is a chemotherapy agent that works by alkylating DNA and RNA, which stops protein synthesis and, thus, immune cell proliferation.

Flegel et al. (2011) found a survival time of 457 in dogs with GME and 329 in dogs with NME using a concentration of 60mg/m2 every six weeks. Some dogs had side effects of anaemia and leucopenia. Two other studies found survival times of 287 (Uriarte et al., 2008) and 335 days (Flegel et al., 2008). All three studies gave glucocorticoids alongside lomustine.

Ciclosporin

Ciclosporin acts by suppressing T-lymphocyte activation and proliferation.

A median survival time of 1,345 days was found in a study using a combination of prednisolone, IV dexamethasone and ciclosporin (3 to 5mg/kg bid) (Brady et al., 2020). No adverse effects were reported.

Azathioprine

Azathioprine acts by inhibiting protein synthesis and, thus, the production of immune cells.

Wong et al. (2010) administered prednisolone (2mg/kg/day) and azathioprine (2mg/kg/day) and reported a median survival time of 1,834 days. No adverse effects due to the treatment were seen.

Radiation therapy

Radiation therapy has been trialled for its anti-inflammatory effects, showing a mean survival time of 404 to 476 days (Muñana and Luttgen, 1998; Sisson et al., 1989; Beckmann et al., 2015).

Faecal transplant

It is now thought that the microbiota in MUO cases differs from the normal population, with diminished Prevotellaceae; it is currently unknown whether this is a trigger for MUO or a resulting factor (Jeffery et al., 2017). Potentially restoring the microflora back to normal could be a novel treatment for MUO in the near future.

Follow-up

Relapses are common for MUO cases, which require regular monitoring. There is no consensus on the frequency of rechecks and whether repeat CSF and/or MRI have a role to play in the early detection of recurrence and survival. But these certainly come at a cost and are invasive. We tend to suggest a recheck every other month and to monitor haematological and biochemical changes for myelosuppression and organ toxicity where applicable. Costs could be reduced by performing manual blood smears to check for platelet counts and leukocyte numbers rather than full haematology profiles.

It is also important to bear in mind that immunosuppression in MUO cases renders patients susceptible to infection and, therefore, not to confuse the recurrence of signs with the appearance of an infection. This distinction can be difficult to make and requires careful clinical examination and use of blood work and imaging.

It is also important to bear in mind that immunosuppression in MUO cases renders patients susceptible to infection and, therefore, not to confuse the recurrence of signs with the appearance of an infection

Seizures are a common presenting sign of relapse; however, this may not correlate to worsening/relapsing of the meningoencephalomyelitis, and corresponds to post-encephalitis epilepsy. Kaczmarska et al. (2020) found that only 3 of 14 dogs with MUO and post-encephalitis epilepsy developed drug-resistant epilepsy. Standard epilepsy treatment can be used in case of seizures.

If neurological signs are controlled but glucocorticoid side effects are not tolerated, it might be useful to further wean down the glucocorticoid dose and replace these with an immunosuppressant drug.

It is undeniable that the cost and unpredictability of MUO cases can be challenging for the client, and this may deter from “trial treating” with relatively unpredictable survival times and prognoses. However, these cases can deteriorate quickly and, without intervention, have rapid death. Some cases unfortunately die or are euthanised before treatment commences, whereas some studies have shown promising mean survival times of 1,345 days post-diagnosis (Brady et al., 2020). In addition, choosing medication that can be administered orally from home may be economically beneficial.

Conclusion

MUO remains a challenging group of inflammatory central nervous system diseases to diagnose and treat, carrying a guarded to poor prognosis. Previous reviews (Granger et al., 2013; Jeffery and Granger, 2023) concluded that there is no distinct treatment choice that generates prolonged survival. This fact is becoming more and more accepted and means that clinicians may engage in conducting randomised controlled trials that would allow scientific comparison of treatment protocols.

The use of clinical scoring, rather than death, could also help better define treatment success. Perhaps future research should focus on identifying MUO triggers, for example by better describing the body’s immune response for the various forms of MUO and within breeds.

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