Scientific Papers

Investigation of side effects to treatment and cause of death in 63 Scandinavian dogs suffering from meningoencephalitis of unknown origin: a retrospective study | Acta Veterinaria Scandinavica

This study aimed to investigate cause of death and side effects in a Scandinavian population of dogs with MUO, as well as to compare survival between dogs receiving different treatment regimens. The study population closely resembles those of previous studies with regard to age and weight but included a larger proportion of Chihuahuas and Yorkshire terriers [19, 26], likely due to the geographical localization of the two animal hospitals in areas dominated by apartment-dwelling owners. Dogs presented with a wide variation of neurological signs, mirroring the fact that the umbrella term MUO covers both GME, NME and NLE, known to affect different localizations of the brain [1]. Many of the included dogs presented with multifocal localizations on initial neurological examination (34/63, 54.0%), which is in agreement with previous publications [34, 39]. A significant proportion of the included dogs (27/63, 42.9%) either had a history of recent seizures (focal or generalized), or presented in ongoing seizure activity, indicating forebrain pathology. This is also in line with previous literature in which 37.9–47% presented with seizures as part of their history [39, 40].

The MST in the total study population was 714 days (range 0-1678 days). There was no statistically significant difference when comparing survival for dogs treated with CS monotherapy (MST 716 days, range 5-911), CS + Ci combination therapy (MST 916, range 35-1678), or dogs receiving other combination therapies in the current study population (MST 1186, range 121–1640 days) (P = 0.31). However, the limited sample size of all three investigated groups must be kept in mind, and a potential bias towards more severely affected animals in the two subgroups with dogs receiving combination therapy should be considered. In the current study, dogs with more severe clinical signs or an insufficient response to treatment were more likely to receive combination therapy; this is especially true for the dogs included at the UHCA (41/63 dogs), since CS monotherapy in general was the treatment of choice during the five-year study period. On the other hand, dogs receiving combination therapy may be representative of more dedicated owners, as these dogs may need more clinical check-ups and are more costly; this could potentially bias data towards longer survival in this group. A clinical trial with a randomized allocation of dogs to treatment groups with or without add-ons (case control) at the time of diagnosis could be useful. However, this approach may not be ethically acceptable. Alternatively, already existing retrospective raw data could be pooled from multiple locations with sufficient knowledge and diagnostic equipment. This would allow for a larger study population, as well as representation of different treatment regimens since preferred treatment regimens likely differ between different animal hospitals – strict alignment of inclusion and exclusion criteria, as well as standardization of data registration would, however, need to be applied.

Direct comparison to available retrospective studies of MUO survival in regards to treatment regimens is challenging due to differences in study set-ups and inclusion and exclusion criteria. Further, Kaplan-Meier survival curves, which are used in a variety of studies to calculate survival in regards to treatment of MUO [16,17,18, 20, 22, 23, 25, 26, 33, 41,42,43,44,45,46,47], do partially censor study subjects that are still alive at the end of the study period [48]. Even though Kaplan-Meier survival analysis is likely to be the best approach for calculation of survival, disadvantages must be kept in mind. In the current study, cut-off for survival, death or lost to follow-up was made at 1 month, 3 months and 12 months, in order to supplement data that would not be visible on a Kaplan-Meier survival curve, as well as to allow comparison to studies previously made and, in the future, where another approach for calculating MST is used.

In a study by Paušová et al. [15], 182 dogs treated with CS monotherapy had a MST of 570 days (range 2-3540), and a one-year survival of 55.6%. Median survival time was, however, not calculated using Kaplan-Meier survival curves, and even though a 10-year follow-up allowed for exact survival time for most dogs, some long-term survivors were censored from calculations of MST, making direct comparison difficult, as this presumably affects MST negatively. However, the resulting one-year survival in Paušová’s study [15] is longer than the one seen in the current study for the overall population (44.1%), as well as for the CS group (42.3%). However, a substantial number of the dogs in our study were lost to follow-up (17.5% in the overall population and 23.1% in the CS group). One-year survival in our study was similar to Paušová’s study [15] for the CS + Ci group. Around 20% in this group were also lost to follow-up. Survival was higher in the three other combination groups (CS + CA: 60%, CS + 2: 60%, CS + Le: 100%), but small group size needs to be taken into account.

The combination of CS + Ci for treating MUO was investigated in a retrospective study by Brady et al. [47], where a survival of 1345 days (range 38–2044) from diagnosis was reported (n = 40). These results seem very convincing in demonstrating a longer survival than the one shown in the overall population of our study, and when compared to our CS + Ci group. However, in Brady’s study, dogs were only included if they tested negative for infectious diseases at initial presentation or, in the absence of testing (5/40), were still alive one year after diagnosis. This way of inclusion potentially introduces a bias towards a longer survival, and results should be interpreted with caution.

Cytosine arabinoside have been investigated for treating MUO in several studies [19, 41, 43, 45, 46] with results indicating a great potential. In a study by Lowrie et al. [41], a 90% survival (n = 41) was seen at the 3 months mark from diagnosis, if CA was given as a constant rate infusion (CRI) initially, followed by SC injections, and combined with corticosteroids. Dogs that survived the first 3 months, were all alive after 1 year. A lower survival of 44% (n = 39) was seen after 3 months when CA was exclusively given as SC injections in Lowrie et al. [19]. However, none of the dogs that were alive at 3-months died before the 1-year mark. In our study, 73.0% (46/63) were alive after 3 months, but only 44.4% (28/63 dogs) were alive after one year. Survival in Lowrie et al. [41] and Lowrie et al. [19] seem superior to our study, especially if dogs survive the first 3 months. However, continuous treatment with CA can be a challenge, as it needs to be administered at an animal hospital, raising cost when compared to other alternatives. Interestingly, when looking at the challenges related to continuous treatment with CA, Stee et al. [44] compared dogs treated only with CA CRI (n = 42) to a group of dogs (n = 42) receiving both an initial CRI of CA, and subsequent SC treatment. No statistical difference was found between groups, and success rate were almost identical. Since it seems that dogs suffering from MUO can benefit just as much from receiving only the initial CRI infusion, CA could be a viable treatment option in most cases. Only five dogs in our study were treated with CA; due to the small size of this treatment group, statistical evaluation of this group alone was not possible. However, all five dogs were alive at the 3-month mark, as opposed to the CS group (20/26 dogs alive) and CS + Ci group (13/15 alive). In line with current literature, CS + CA seems to be an effective treatment with a good long-term survival overall.

Little is published regarding treatment of MUO with Le. In Gregory et al. [21] Le and its effect on different supposedly immune mediated diseases were investigated. The study included five dogs with either multifocal nonsuppurative encephalitis or meningomyelitis [21]. All five dogs had a good to excellent improvement in neurological status, and two dogs had a partial resolution of cortical lesions on follow-up MRI scans. In regards to side effects, a case series including 14 dogs suffering from immune-mediated polyarthritis, deemed the drug both safe and effective, with only one dog lacking a clinical response to treatment. One dog was reported to have anorexia and vomiting, two dogs had a mild leukopenia, and one dog had a mild thrombocytopenia [49]. In our study, three dogs were treated with Le, and were alive at the one-year mark. However, studies investigating larger populations receiving Le are warranted before any conclusions can be drawn.

Other immunomodulatory drugs that have been investigated in the attempt to treat dogs with MUO includes MMF [18, 23, 42] and azathioprine [22]. None of the dogs included in our study received either of these drugs, but studies investigating their effect may be of interest, and especially the combination of CS and azathioprine, showed promising results in a study by Wong et al. [22], who reported a MST of 1836 days (range 50–2051 days) in 40 dogs with MUO. However, azathioprine is characterized as carcinogenic in humans [50]. An alternative to immunomodulary drugs and the side effects related to this could be radiation therapy, which shows promise in treating MUO [51].

When looking at the primary cause of death in the current population, the main cause of death or euthanasia was relapse (15/35 dogs, 42.9%), followed by a lack of response to treatment (9/35, 25.7%). It is important to keep in mind that the decision to euthanize is often complex, and several factors may affect the decision of the owner, as well as recommendations to euthanize by the responsible veterinarian. However, relapse in dogs suffering from MUO has also previously been described to correlate with a shorter survival time [22]. Preventing relapse and examining whether some treatment regimens have a lower relapse rate than others, would be of great interest to prolong survival. An important focus for future studies investigating different treatment regimens could potentially be the relapse rate.

Not surprisingly, the nature of the observed side effects was similar in all treatment groups and characteristic for CS, as CS was used in all treatment regimens. These included polyphagia (37/47 dogs, 78.7%), gastrointestinal signs (diarrhea in 29/47 dogs, 61.7%, vomiting in 17/47 dogs, 36.2%), and PU/PD (37/47 dogs, 78.7%). Due to the retrospective nature of this study, it was not possible to grade side effects objectively, nor to assess if side effects decreased as CS was tapered, or if tapering was done faster for the dogs receiving add-on drugs. A prospective study investigating possible correlations between CS dosage and side effects is warranted, as has been done for dogs suffering from SRMA [31]. Interestingly, in the present study only 2/63 dogs were euthanized as a direct result of side effects, but side effects might indirectly have led to euthanasia in two more dogs. Counting all four dogs as ‘death or euthanasia related to side effects’, they account for 6.3% of the total population, and 11.4% of the dogs that died during the study period, which should cause some concern.

Many unspecific side effects were reported during treatment with CS, and for some dogs, it may therefore be difficult to discriminate side effects from ordinary disease events that might have occurred anyway. For instance, corneal ulcers were seen in five dogs; however, they were all brachycephalic breeds (four pugs and one Chihuahua), which are known to have abnormal cranial conformation and buphthalmos, predisposing to corneal ulcers [52]. It is also worth noting that add-on drugs introduced to reduce side effects from CS-treatment have side effects of their own. For instance, vomiting, diarrhea, anorexia, weight loss, gingival hyperplasia, papillomatosis, hypertrichosis and excessive shedding have been described in a case report using Ci as monotherapy [53].

Due to its retrospective nature, this study has several limitations. Side effects were not recorded in a systematic manner in the medical records and may be underreported. In addition, recording the exact dosage at which specific side effects were seen was not done, and treatment protocols were not standardized, leading to different dosages and time of initiation of add-on drugs, as well as the timing of check-ups. Since data collection went back five years, a group of dogs were lost to follow-up despite attempts to contact owners, and clinical status for these dogs were therefore unknown.

The fact that dogs were recruited from two different hospitals allowed inclusion of a larger population; however, it also led to differences in methods of CSF analysis, and the use of different types of MRI and CT machines, as well as differences in preferred treatment protocols. We did also include dogs with a CT examination, but no MRI examination, which may have led to inclusion of dogs with an unclear diagnosis. Larger, multicentric studies might be necessary in order to include sufficient cases, but care should be taken to reduce the methodological differences between places.

limitation to this study was the lack of histopathological confirmation of the presumed diagnosis of MUO – however, as brain biopsies are rarely performed ante mortem, studies including only histologically confirmed MUO cases are usually strongly biased towards a short MST. However, we acknowledge the risk of misdiagnosis in the present study of dogs with presumed MUO, and that this may affect study data. For example, there is a risk that dogs with neoplastic lesions may have been included, affecting outcome negatively. Due to the lack of specific biomarkers for MUO, however, even prospective studies may be challenging in this matter.

When investigating treatment of MUO, a lack of knowledge of the underlying disease mechanisms poses a great challenge. Current treatment protocols aim at general immune suppression. Investigations of the underlying pathophysiology and identification of specific drug targets might aid in better treatment options with less side effects, as also suggested by Jeffery & Granger [54].

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