Epilepsy is a challenging multifactorial disorder with a complex genetic background. Our current understanding of the pathophysiology and treatment of epilepsy has substantially increased due to animal model studies, including canine studies, but additional basic and clinical research is required. Drug-resistant epilepsy is an important problem in both dogs and humans, since seizure freedom is not achieved with the available antiseizure medications. The evaluation and exploration of pharmacological and particularly non-pharmacological therapeutic options need to remain a priority in epilepsy research. Combined efforts and sharing knowledge and expertise between human medical and veterinary neurologists are important for improving the treatment outcomes or even curing epilepsy in dogs. Such interactions could offer an exciting approach to translate the knowledge gained from people and rodents to dogs and vice versa. In this article, a panel of experts discusses the similarities and knowledge gaps in human and animal epileptology, with the aim of establishing a common framework and the basis for future translational epilepsy research. 

Translational veterinary epilepsy: A win-win situation for human and veterinary neurology.

Background Paroxysmal gluten-sensitive dyskinesia is a subtype of movement disorder classified as canine paroxysmal dyskinesia (cPD), which until now has only been described in Border Terriers (BT). Objectives Our aim was to report cPD with positive gluten serology in dog breeds other than BT. Animals Thirty-one client-owned dogs with suspected cPD were examined in this study. Methods The hospital records of the dogs where the serum was tested for modified gliadin peptide immunoglobulin G (gliadin IgG) and tissue transglutaminase-2 immunoglobulin A (transglutaminase-2 IgA) were studied. A total of 31 dogs were presented to the clinic with cPD. A work-up consistent with Tier 1 or Tier 2 confidence levels for canine epilepsy was undertaken in all dogs. The dogs' diets and episode descriptions or videos in 16/31 cases were additionally studied. A follow-up was held to inquire about the dogs' wellbeing and response to the diet changes. Results Fourteen of the 31 dogs tested positive for gluten sensitivity with either gliadin IgG or transglutaminase-2 IgA or both ratios elevated. In seven dogs, serology was classified as questionable with gliadin IgG or transglutaminase ratios mildly elevated. Ten dogs tested negative. According to the owners' reports, five of the dogs that tested positive had no more episodes after changing to a strictly gluten-free diet, with one of the dogs relapsing twice after being fed treats containing gluten. Three dogs had a reduction in episode frequency of >50%, and two dogs had shorter and less intense episodes. Conclusion A considerable subset of dog breeds presented for presumed cPD showed laboratory signs of gluten sensitivity and responded to a gluten-free diet.

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Gluten serological testing in various dog breeds with paroxysmal dyskinesia

Simple Summary Epilepsy is the most common neurological disorder in dogs. It is increasingly recognized that ketogenic diets enriched with medium chain triglycerides (MCT) have a positive impact on dogs with idiopathic epilepsy by reducing the frequency and severity of seizure activity. Significant evidence points towards a relationship between gut microbiota and epilepsy, and that the MCT diet may alter this microbiota. The current study examined the effects of a MCT diet administered for one month on the fecal microbiota in dogs with IE and non-epileptic beagles. The diet reduced Actinobacteria in all dogs while reducing seizure frequency in epileptic ones. Different baseline microbiota patterns were found in dogs with drug-sensitive epilepsy (DSE) and dogs with drug-refractory epilepsy (DRE). The baseline microbiota pattern of dogs with DSE was similar to that of non-epileptic dogs. In them, the MCT diet decreased the relative abundance of bacteria from the Firmicutes phylum and increased that of the Bacteroidetes and Fusobacteria phylum. The opposite effect was found in dogs with DRE. These results suggest that the MCT diet could help reduce gut microbiota differences between dogs with DRE or DSE. Abstract Ketogenic diets have been successfully used in people and dogs with idiopathic epilepsy. This study examined the effect of a ketogenic medium chain triglycerides (MCT)- enriched diet administered for one month on the fecal microbiota of epileptic (n = 11) (six with drug-sensitive epilepsy, DSE; five with drug-refractory epilepsy, DRE) and non-epileptic beagle dogs (n = 12). A significant reduction after diet in the relative abundance of bacteria from the Actinobacteria phylum was observed in all dogs. Epileptic dogs showed a higher relative abundance of Lactobacillus compared with non-epileptic dogs at baseline but these differences disappeared after diet. Epileptic dogs also showed a significantly higher abundance of Negativicutes and Selenomonadales after dietary intervention. Baseline microbiota patterns were similar in non-epileptic beagles and dogs with DSE but significantly different from dogs with DRE. In non-epileptic and DSE groups, the MCT diet decreased the relative abundance of Firmicutes and increased that of Bacteroidetes and Fusobacteria, but the opposite effect was observed in dogs with DRE. These results suggest that the MCT diet effect would depend on individual baseline microbiota patterns and that ketogenic diets could help reduce gut microbiota differences between dogs with DRE and DSE.

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Effect of a Ketogenic Medium Chain Triglyceride-Enriched Diet on the Fecal Microbiota in Canine Idiopathic Epilepsy: A Pilot Study

In the last decade, nutrition has gained interest in the management of canine idiopathic epilepsy (IE) based on growing scientific evidence. Diets can serve their functions through many pathways. One potential pathway includes the microbiota-gut-brain axis, which highlights the relationship between the brain and the intestines. Changing the brain's energy source and a number of dietary sourced anti-inflammatory and neuroprotective factors appears to be the basis for improved outcomes in IE. Selecting a diet with anti-seizure effects and avoiding risks of proconvulsant mediators as well as interference with anti-seizure drugs should all be considered in canine IE. This literature review provides information about preclinical and clinical evidence, including a systematic evaluation of the level of evidence, suggested mechanism of action and interaction with anti-seizure drugs as well as pros and cons of each potential dietary adaptation in canine IE. 

The role of nutrition in canine idiopathic epilepsy management: Fact or fiction?

Abstract Background Epilepsy is the most common chronic neurological disease in dogs. More than two-thirds of these patients suffer from associated behavioural comorbidities. The latter could have their origin in partially overlapping pathomechanisms, with the intestinal microbiome as a potential key link between them. The current arsenal of drugs for epilepsy management remains limited. Most canine patients continue to have seizures despite treatment and the occurrence of comorbidities is not sufficiently addressed, limiting quality of life of affected dogs and owners. Therefore, novel additional epilepsy management options are urgently needed. The microbiome-gut-brain axis may serve as a new target for the development of innovative multimodal therapeutic approaches to overcome current shortcomings in epilepsy management. Methods A six-month prospective, randomised, double-blinded, placebo-controlled, crossover, dietary trial was designed to investigate the potential of the psychobiotic Bifidobacterium longum on behavioural comorbidities in canine epilepsy. Seizure semiology will be evaluated as a secondary outcome measure. Thirty-four privately owned dogs are planned to be included in the ongoing study meeting the following inclusion criteria: Dogs displaying increased anxiety/fear behaviour since the start of the idiopathic epilepsy. Tier II confidence level of the International Veterinary Epilepsy Task Force for the diagnosis of idiopathic epilepsy, with a maximum seizure interval of 3 month and a minimum of three generalised seizures within that period and chronically treated with at least one antiseizure drug without improvement in seizure frequency Each dog will receive the allocated supplement (probiotic vs. placebo) alongside its normal diet for a 3-month period. After a three-week wash out period, the second phase starts by administering the respective other supplement for another 3 months. Discussion The current study considers modern high-quality standards for epilepsy medication trials. Common biasing effects should be limited to a possible minimum (regression-to-the mean effect, placebo effect, observer effect), ensuring a high validity and accuracy of the acquired results, thus enabling a representative nature of the efficacy of Bifidobacterium longum as add-on supplement for dogs suffering from epilepsy and its comorbidities. This publication should provide a description of the study procedure and data acquisition methods, including prognosed statistical analysis. 

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A six-month prospective, randomised, double-blinded, placebo-controlled, crossover, dietary trial design to investigate the potential of psychobiotics on seizure semiology and comorbidities in canine epilepsy: study protocol

Phenobarbital (PB) is one of the most important antiseizure drugs (ASDs) to treat canine idiopathic epilepsy (IE). The effect of PB on the taxonomic changes in gastrointestinal microbiota (GIM) and their functions is less known, which may explain parts of its pharmacokinetic and pharmacodynamic properties, especially its antiseizure effect and drug responsiveness or drug resistance as well as its effect on behavioral comorbidities. Fecal samples of 12 dogs with IE were collected prior to the initiation of PB treatment and 90 days after oral PB treatment. The fecal samples were analyzed using shallow DNA shotgun sequencing, real-time polymerase chain reaction (qPCR)-based dysbiosis index (DI), and quantification of short-chain fatty acids (SCFAs). Behavioral comorbidities were evaluated using standardized online questionnaires, namely, a canine behavioral assessment and research questionnaire (cBARQ), canine cognitive dysfunction rating scale (CCDR), and an attention deficit hyperactivity disorder (ADHD) questionnaire. The results revealed no significant changes in alpha and beta diversity or in the DI, whereas only the abundance of Clostridiales was significantly decreased after PB treatment. Fecal SCFA measurement showed a significant increase in total fecal SCFA concentration and the concentrations of propionate and butyrate, while acetate concentrations revealed an upward trend after 90 days of treatment. In addition, the PB-Responder (PB-R) group had significantly higher butyrate levels compared to the PB-Non-Responder (PB-NR) group. Metagenomics of functional pathway genes demonstrated a significant increase in genes in trehalose biosynthesis, ribosomal synthesis, and gluconeogenesis, but a decrease in V-ATPase-related oxidative phosphorylation. For behavioral assessment, cBARQ analysis showed improvement in stranger-directed fear, non-social fear, and trainability, while there were no differences in ADHD-like behavior and canine cognitive dysfunction (CCD) scores after 90 days of PB treatment. While only very minor shifts in bacterial taxonomy were detected, the higher SCFA concentrations after PB treatment could be one of the key differences between PB-R and PB-NR. These results suggest functional changes in GIM in canine IE treatment.

The effect of phenobarbital treatment on behavioral comorbidities and on the composition and function of the fecal microbiome in dogs with idiopathic epilepsy

Lisa F. Becker

Papers

The effect of phenobarbital treatment on behavioral comorbidities and on the composition and function of the fecal microbiome in dogs with idiopathic epilepsy