A Sole prednisolone therapy in canine meningoencephalitis of unknown etiology

Meningoencephalitis of unknown etiology (MUE) is a frequently diagnosed and often fatal disease in veterinary neurology. The aim of this retrospective study was to assess the efficacy of three different sole prednisolone treatment schedules in dogs diagnosed with MUE. The dogs were diagnosed clinically with MUE based on previously described inclusion criteria, and treated with a three-, eightor eighteen-week-tapering prednisolone schedule. Thirty eight dogs were included in the study. Seventeen, fifteen and six dogs received the three-, eightand eighteen-week tapering schedule, respectively. Overall, 37% of the dogs died or were euthanized because of MUE, and a significant difference in survival time was seen between the three treatment schedules. Surprisingly, the highest number of dogs that died because of MUE was seen in the eightweek treatment schedule (56%), followed by the three-week (26%) and eighteen-week (0%) treatment schedule. Based on the results of this study, no definitive conclusions can be drawn regarding the ideal prednisolone dosing protocol for dogs diagnosed with MUE. However, a more aggressive and immunosuppressive treatment protocol might lead to a better outcome.


Meningoencephalitis of unknown etiology (MUE) is a frequently diagnosed and often fatal
disease in veterinary neurology. The aim of this retrospective study was to assess the efficacy of three different sole prednisolone treatment schedules in dogs diagnosed with MUE. The dogs were diagnosed clinically with MUE based on previously described inclusion criteria, and treated with a three-, eight-or eighteen-week-tapering prednisolone schedule. Thirty eight dogs were included in the study. Seventeen, fifteen and six dogs received the three-, eight-and eighteen-week tapering schedule, respectively. Overall, 37% of the dogs died or were euthanized because of MUE, and a significant difference in survival time was seen between the three treatment schedules. Surprisingly, the highest number of dogs that died because of MUE was seen in the eightweek treatment schedule (56%), followed by the three-week (26%) and eighteen-week (0%) treatment schedule. Based on the results of this study, no definitive conclusions can be drawn regarding the ideal prednisolone dosing protocol for dogs diagnosed with MUE. However, a more aggressive and immunosuppressive treatment protocol might lead to a better outcome.

INTRODUCTION
Meningoencephalitis of unknown etiology (MUE) is a group of non-infectious central nervous system diseases with a likely multifactorial pathogenesis (Coates et al., 2014). Making a definitive diagnosis requires histopathological examination of central nervous tissue, but a presumptive antemortem clinical diagnosis can be achieved based on a combination of neurological examination results, magnetic resonance imaging (MRI) findings and cerebrospinal fluid (CSF) abnormalities (Coates et al., 2014). The exact etiology and pathophysiology of MUE are currently unknown, but immunosuppressive drugs are considered to be the cornerstone of the medical treatment of the disease. Several treatment protocols with different associated long-term survival times have been reported, whereby treatment with glucocorticosteroids only is generally associated with shorter survival times (Munana and Luttgen, 1998;Jung et al., 2007;Granger et al., 2010;Flegel et al., 2011) than combination therapy with other immunosuppressive therapies, including cytosine arabinoside, cyclosporine, leflunomide, lomustine, azathioprine, mycophenolate mofetil or radiation therapy (Munana and Luttgen, 1998;Jung et al., 2007;Coates et al., 2007;Granger et al., 2010;Flegel et al., 2011;Beckmann et al., 2015;Barnoon et al., 2016). However, in a clinical setting, adding more expensive immunosuppressive therapies to the glucocorticoid protocol might be financially impossible. In a recently published prospective trial in dogs with MUE, an overall median survival time of 602 days has been reported for dogs receiving immunosuppressive doses of glucocorticosteroids starting at a dose of 1mg/kg twice daily, supporting the use of monotherapy with glucocorticosteroids in the treatment of MUE (Mercier and Barnes Heller, 2015). Therefore, the aims of this study were to retrospectively evaluate the efficacy of three different prednisolone treatment protocols that were historically used (three-, eight-and eighteen-weektapering schedule) in dogs diagnosed with MUE. In the study, it was assumed that a longer survival time would be achieved with a longer and more immunosuppressive treatment protocol.

MATERIALS AND METHODS
The electronic medical database of Ghent University, Small Animal Department was searched between March 2006 and September 2014. Owner contact was performed in October 2014. Adapted inclusion criteria were used (Granger et al., 2010), considering dogs suitable for inclusion if the following data were available: (1) signalment, (2) localization by neurological examination, (3) inflammatory CSF analysis, (4) intracranial MR and/or CT imaging results, (5) negative infectious disease testing, and (6) long-term follow-up through research of medical records or through telephone contact with the owner or referring veterinarian. Neurological status was recorded at the time of admission and further on a daily basis. The results were recorded daily in a computer program, if the dog was hospitalized. The outcome was defined as successful if dogs were not showing the previously reported neurological signs or if improvement was seen according to the owner or referring veterinarian. An unsuccessful outcome was defined as death or euthanasia because of disease progression or if no change in neurological signs was seen. Relapse was defined as a sudden deterioration of the neurological status after an initial improvement after diagnosis and initiation of treatment. All dogs were only receiving glucocorticosteroids as immunomodulating therapy, and a tapering prednisolone treatment schedule consisting of three, eight or eighteen weeks was used (Table 1). The dogs treated with the three-, eight-, eighteenweek schedule were diagnosed between March 2006 and March 2010, January 2009 and August 2012, and January 2010 and September 2014, respectively. The eighteen-week treatment schedule was started with an immunosuppressive dose of prednisolone, being 3 mg/ kg/day, whereas the eight-week schedule was started at an immunosuppressive dose of 2 mg/kg/day. The three-week tapering schedule was started with an antiinflammatory dose of 1 mg/kg/day. It was recorded whether dogs survived their initial treatment protocol and whether a relapse in neurological signs (sudden deterioration after initial improvement) was seen during treatment together with the associated changes made to the prednisolone schedule. Survival time (ST)

Three weeks
Eight weeks Eighteen weeks 1 week 1 mg/kg q24h 2 weeks 1 mg/kg q12h 3 weeks 1.5 mg/kg q12h 1 week 0.5 mg/kg q24h 2 weeks 0.5 mg/kg q12h 6 weeks 1 mg/kg q12h 1 week 0.25 mg/kg q24h 2 weeks 0.5 mg/kg q24h 3 weeks 0.5 mg/kg q12h 2 weeks 0.25 mg/kg q24h 3 weeks 0.5 mg/kg q24h 3 weeks 0.25 mg/kg q24h was defined as time from diagnosis to death or euthanasia. A semiparametric cox model (hazard analysis) was fitted to the data to detect differences in survival time between the three treatment groups. All statistic tests were performed using S-Plus. For all analyses, a value of P < 0.05 was considered significant.
Seventeen (45%), 15 (39%), and 6 (16%) dogs received the three-, eight-, and eighteen-weeks prednisolone treatment schedule, respectively. In eight dogs (21%), this therapy was combined with phenobarbital for treatment of seizures. There was a significant difference in ST between the three treatment groups (P=0.028) (Figure 1). Overall, 24 dogs (63%) had a successful outcome, 22 of those dogs were alive at the time of data capture. The remaining two dogs were euthanized because of other reasons 730 and 1167 days after their diagnosis, respectively, and both dogs were not receiving any immunomodulating medication at the time of euthanasia. Fourteen dogs (37%) had an unsuccessful outcome, and died or were euthanized because of MUE. The median survival time (MST) could not be calculated for the group of dogs receiving the three-week and eighteen-week tapering prednisolone schedule, as more than 50% of those dogs were alive at the time of data capture. The MST for the dogs treated with the eight-week tapering schedule, was 180 days. Five dogs died or were euthanized (one in the three-week group en four in the eight-week group) during their treatment schedule. No changes were made to their schedules. Ten dogs (26%) showed a relapse in neurological signs. Four of those dogs did so after terminating their three-week tapering schedule, three dogs after terminating their eight-week treatment schedule, two dogs during their eight-week schedule (after three and six weeks), and one dog after terminating the eighteen-week schedule. If the relapse was seen after termination of the treatment schedule, the same schedule was initiated again (n=7), and the dose was increased again to the starting dose if a relapse was seen before termination of the tapering schedule (n=3). There was no significant difference in relapse rates between the three treatment schedules (P=0.886). An overview of the results can be found in Table 3.

DISCUSSION
Thirty-eight dogs diagnosed with MUE received oral prednisolone therapy in three different tapering schedules. Overall, 37% of dogs were euthanized because of MUE. The survival curves for the three treatment schedules were significantly different. Surprisingly, the highest mortality rate was seen in the eight-week (immunosuppressive) treatment group (56%), followed by the three-week (anti-inflammatory) (28%) and the eighteen-week (immunosuppressive) treatment (0%) schedule. Possible explanations might be that (1) all dogs at the institution historically received the three-week treatment protocol when a suspicion of non-infectious encephalitis was made. However, as a possibly immune-mediated origin has recently been reported in the literature, dogs diagnosed with MUE admitted with severe neurological signs may have received a longer, more immunosuppressive (eight-week) treatment schedule and (2) the eighteen-week tapering schedule was only introduced in the last four years of inclusion, so the recently included cases in the present study might still have deceased in the following weeks to months, probably having falsely (positively) influenced the results.
In the literature, the MST in dogs diagnosed with MUA and receiving sole prednisolone therapy ranges from 28 -357 days (Granger et al., 2010), 91 -329 days (Flegel et al., 2011) and 602 days (Mercier and Barnes Heller, 2015). As more than 50% of the dogs were alive or censored for outcome calculations at the time of data capture, no overall MST could be calculated in the presented study. However, the MST was 180 days in the eight-week treatment group, which appears to be the group with the highest percentage of deceased and relapsed dogs. Further prospective studies should be performed, including more dogs receiving the more immunosuppressive treatment schedules, although comparing immunosuppressive and anti-inflammatory treatment protocols for a presumed immune-mediated disease can cause ethical dilemma.
Pitfalls in the current study are the lack of histopathological confirmation of all cases, the low number of cases and the relatively high percentage of dogs that was diagnosed using CT imaging (34%). However, 18% of the dogs had no visible lesion on CT or MR imaging, which is comparable to the 7% for MRI and 14% for CT described previously (Granger et al., 2010). Prednisolone therapy is associated with common side effects. In order to overcome these effects, other immunosuppressive drugs can be added to the protocol. Looking at the side effects of the prednisolone treatment was beyond the scope of this article, as not all of them were systematically recorded; moreover, these effects are difficult to trace back through telephone contact with the owner or referring veterinarian.
To conclude, the overall prognosis for dogs diagnosed with MUE and treated with sole prednisolone therapy is guarded. Almost 40% of dogs will succumb due to the disease. A long and immunosuppressive treatment schedule is advised, although side effects might be significant.