Urinary neurotransmitter analysis and canine behavior assessment.

Behavioral problems are highly prevalent in domestic dogs, negatively affecting the quality of life of dogs and their owners. In humans and dogs, neuropsychological or neurobehavioral disorders can be associated with deviations in various neurotransmitter systems. Previous evidence has revealed correlations between urinary neurotransmitters and various behavioral disorders; however, a causal relationship has not yet been conclusively demonstrated. Non-invasive urinary neurotransmitter analysis may identify specific biomarkers, which enable a more differentiated assessment of canine behavioral disorders in the future and contribute to more effective neuromodulatory treatment decisions and monitoring. This approach could offer new insights into underlying pathomechanisms of canine neurobehavioral disorders. This study assessed urinary neurotransmitter levels and the descriptive behavior profile of 100 dogs using established rating scales (Canine Behavioral Assessment and Research Questionnaire, Attention Deficit Hyperactivity Disorder Rating Scale, Dog Personality Questionnaire, Canine Cognitive Dysfunction Rating Scale), and explored relationships between these variables. No correlation was found between urinary neurotransmitters and the assessed behavior profiles; however, age-, sex- and neuter-related influences were identified. The lack of correlation could be explained by the many confounding factors influencing both behavior and urinary neurotransmitter excretion, including age, sex and neuter status effects, and methodological issues e.g., low discriminatory power between anxiety and aggression in the descriptive behavior evaluation. Urinary neurotransmitter testing could not be validated as a tool for canine behavior evaluation in this study. However, reliable assessment methods with low susceptibility to human biases could be valuable in the future to support behavioral-phenotype diagnoses.

Metabolic fingerprinting of dogs with idiopathic epilepsy receiving a ketogenic medium-chain triglyceride (MCT) oil.

Consumption of medium-chain triglycerides (MCT) has been shown to improve seizure control, reduce behavioural comorbidities and improve cognitive function in epileptic dogs. However, the exact metabolic pathways affected by dietary MCT remain poorly understood. In this study, we aimed to identify changes in the metabolome and neurotransmitters levels relevant to epilepsy and behavioural comorbidities associated with the consuming of an MCT supplement (MCT-DS) in dogs with idiopathic epilepsy (IE). Metabolic alterations induced by a commercial MCT-DS in a population of 28 dogs with IE were evaluated in a 6-month multi-centre, prospective, randomised, double-blinded, controlled cross-over trial design. A metabolic energy requirement-based amount of 9% MCT or control oil was supplemented to the dogs' stable base diet for 3 months, followed by the alternative oil for another 3 months. A validated, quantitative nuclear magnetic resonance (NMR) spectroscopy platform was applied to pre- and postprandially collected serum samples to compare the metabolic profile between both DS and baseline. Furthermore, alterations in urinary neurotransmitter levels were explored. Five dogs (30%) had an overall reduction in seizure frequency of ≥50%, and were classified as MCT-responders, while 23 dogs showed a ≤50% reduction, and were defined as MCT non-responders. Amino-acid metabolism was significantly influenced by MCT consumption compared to the control oil. While the serum concentrations of total fatty acids appeared similar during both supplements, the relative concentrations of individual fatty acids differed. During MCT supplementation, the concentrations of polyunsaturated fatty acids and arachidonic acid were significantly higher than under the control oil. ß-Hydroxybutyric acid levels were significantly higher under MCT supplementation. In total, four out of nine neurotransmitters were significantly altered: a significantly increased γ-aminobutyric acid (GABA) concentration was detected during the MCT-phase accompanied by a significant shift of the GABA-glutamate balance. MCT-Responders had significantly lowered urinary concentrations of histamine, glutamate, and serotonin under MCT consumption. In conclusion, these novel data highlight metabolic changes in lipid, amino-acid and ketone metabolism due to MCT supplementation. Understanding the metabolic response to MCT provides new avenues to develop better nutritional management with improved anti-seizure and neuroprotective effects for dogs with epilepsy, and other behavioural disorders.

Oral Palatability Testing of a Medium-Chain Triglyceride Oil Supplement (MCT) in a Cohort of Healthy Dogs in a Non-Clinical Setting.

The oral palatability of functional foods such as medium-chain triglycerides (MCT) play a crucial role in owner and patient compliance when used as an adjunct in the management of health conditions such as epilepsy. Despite the promising benefits, the palatability of MCT has not undergone a more recent evaluation in dogs. The aim of this study was to assess the palatability and tolerance of short-term, daily supplementation of a 10% metabolic energy based MCT oil volume compared to a tasteless control oil in healthy dogs. An at-home, randomized, double-blinded, controlled single-bowl palatability test with three five-days phases was conducted. Data were collected from nineteen healthy dogs via study visits, feeding diary and eating questionnaires. No difference in the average food intake or intake ratio between food with and without oil supplementation or between the two oil groups was found. The mean food intake time was longer under MCT. In conclusion, MCT oil given as a short-term supplement is well tolerated and palatable in a healthy canine population, with only some changes in eating behaviour. Our results support earlier evidence that MCT oil is a well-tolerated additive in the nutritional management of different diseases such as epilepsy or dementia in dogs.

Owner reported management of interictal anxiety behaviours in canine epilepsy.

BACKGROUND: Idiopathic epilepsy (IE) is the most common chronic neurological condition in dogs, and can be associated with interictal (between seizure) anxiety (IIA). It is unclear how owners manage their pet's IIA, including how much veterinary support they receive for it. METHODS: An international online questionnaire collected data on IIA prevalence, management of IIA and perceived levels of veterinary support for IIA from owners of dogs diagnosed with IE. RESULTS: Valid responses were available from n = 220 owners. IIA was reported by 83.6% of owners. Common management strategies were behavioural or training techniques, reported by 90.4% of owners, whilst 34.4% reported use of behavioural products. Only 28.5% of owners felt fully supported by their vet in managing IIA. Owners who felt unsupported were less likely to have received advice on behavioural management or training from their vet (p = 0.003). CONCLUSION: Access to veterinary support for the management of IIA is needed for owners of dogs with IE.

Research priorities for idiopathic epilepsy in dogs: Viewpoints of owners, general practice veterinarians, and neurology specialists.

BACKGROUND: Epilepsy is the most common chronic neurological disease in dogs that adversely affects the quality of life (QoL) of affected dogs and their owners. Research on epilepsy in dogs is expanding internationally, but where best to focus limited research time, funds, and expertise to achieve better outcomes for affected dogs and their owners has not been studied. OBJECTIVE: To explore idiopathic epilepsy (IE) research priorities of owners of dogs with IE, general practice veterinarians, and veterinary neurologists. METHODS: An international online survey was conducted in 2016 and repeated in 2020. Participants rated the absolute importance and relative rank of 18 areas of IE research, which were compared between groups and time points. RESULTS: Valid responses were received from 414 respondents in 2016 and 414 respondents in 2020. The development of new anti-seizure drugs (ASD) and improving the existing ASD management were considered the most important research priorities. Areas of research with increasing priority between 2016 and 2020 included non-ASD management, with the greatest potential seen in behavioral and dietary-based interventions. Disagreements in priorities were identified between groups; owners prioritized issues that impacted their and their dog's QoL, for example, adverse effects and comorbidities, whereas general practitioner vets and neurologists prioritized clinical issues and longer-term strategies to manage or prevent IE, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Ensuring that voices of owners are heard in the planning of future research should be a broader goal of veterinary medicine, to target research efforts toward areas most likely to improve the QoL of the dog-owner dyad.

Medium-chain triglycerides dietary supplement improves cognitive abilities in canine epilepsy.

OBJECTIVE: Cognitive impairments (CI) have recently been identified in canine epilepsy patients. A medium-chain triglyceride (MCT) enriched diet has been demonstrated to improve cognition in aged dogs and seizure control in canine epilepsy. This study evaluates the short-term effects of MCT-oil consumption on cognitive abilities in dogs with epilepsy, a naturally occurring animal model. METHODS: A 6-month multicenter, prospective, randomized, double-blinded, controlled cross-over diet trial was conducted comparing dietary supplementation (DS) of MCT oil to a control oil. Allocation to dietary oil supplements, consisting of 9% total caloric intake, was block-randomized and supplemented into each dogs' diet for 3 months followed by a respective switch of DS-oil for a further 3 months. Noninvasive cognitive tests and a validated psychometric tool were utilized to evaluate cognitive function and perturbations associated with dietary intervention. RESULTS: Twenty-nine dogs completed the trial, of which 18 completed noninvasive cognitive testing. Spatial-working memory (P = 0.008), problem-solving ability (P = 0.048), and owner-reported trainability (P = 0.041) were significantly improved during MCT-oil supplementation compared to control-DS. SIGNIFICANCE: MCT-oil DS improves cognition in dogs with epilepsy when compared to a control-DS. MCT supplementation may represent a promising option to address CI associated with epilepsy.

Clinical reasoning in canine cervical hyperaesthesia: which presenting features are important?

BACKGROUND: To evaluate whether clinical features from the history, presentation, physical and neurological examination of dogs with cervical hyperaesthesia are statistically predictive of the underlying diagnosis. METHODS: Two hundred and ninety-eight dogs presenting with cervical hyperaesthesia between January 2010 and October 2018 were investigated. Only neurologically normal dogs with cervical hyperaesthesia on examination were included, while those with concurrent neurological deficits including gait abnormalities and proprioceptive deficits were excluded. Univariate analysis of clinical variables was performed, and those associated with each diagnosis were retained for multivariable binary logistic regression models. RESULTS: Ninety-five per cent of cervical hyperaesthesia presentations were represented by eight conditions that included steroid-responsive meningitis arteritis (SRMA; n=100), intervertebral disc extrusion (n=78), syringomyelia (SM; n=51), intervertebral disc protrusion (n=30), neoplasia (n=8), cervical spondylomyelopathy (n=7), immune-mediated polyarthritis (n=5) and meningoencephalomyelitis of unknown aetiology (n=5). Younger age (P=0.003), pyrexia (P=0.003) and haematology abnormalities (P=0.03) comprising leucocytosis, neutrophilia or monocytosis were associated with a diagnosis of SRMA. CONCLUSIONS: Easy-to-recognise clinical features can be used to identify the most likely differential diagnosis in neurologically normal dogs with cervical hyperaesthesia, which may aid the decision making of veterinary surgeons evaluating dogs with this presentation.

Investigating the potential for seizure prediction in dogs with idiopathic epilepsy: owner-reported prodromal changes and seizure triggers.

BACKGROUND: Canine idiopathic epilepsy (IE) is characterised by recurrent seizure activity, which can appear unpredictable and uncontrollable. The purpose of this study was to investigate the potential for seizure prediction in dogs by exploring owner-perceived seizure prediction abilities and identifying owner-reported prodromal changes (long-term changes in disposition that indicate forthcoming seizures) and seizure triggers (stimuli that precipitate seizures) in dogs with IE. METHODS: This is an online, international, cross-sectional survey of 229 owners of dogs diagnosed with IE, meeting the International Veterinary Epilepsy Task Force tier I diagnostic criteria. RESULTS: Over half (59.6 per cent) of owners believed they were able to predict an upcoming seizure in their dog, of whom nearly half (45.5 per cent) were able to do so at least 30 minutes before the seizure commenced. The most common 'seizure predictors' were preseizure behavioural changes including increased clinginess (25.4 per cent), restlessness (23.1 per cent) and fearful behaviour (19.4 per cent). Nearly two-thirds of owners reported prodromal changes (64.9 per cent), most commonly restlessness (29.2 per cent), and nearly half (43.1 per cent) reported seizure triggers, most commonly stress (39.1 per cent). CONCLUSIONS: The relatively high prevalence of owner-reported prodromal changes and seizure triggers shows promise for utilising these methods to aid seizure prediction in dogs, which could open a window of time for pre-emptive, individualised drug interventions to abort impending seizure activity.

Behavioural changes in dogs with idiopathic epilepsy.

BACKGROUND: Breed-specific and broader cohort studies have shown behavioural changes in dogs following the onset of idiopathic epilepsy (IE). METHODS: A cross-sectional, case-control questionnaire study was carried out to strengthen this body of evidence. Owners of eight breeds of dog completed an online questionnaire about their dogs' behaviour; once for control dogs and twice for dogs with IE, for both pre-IE and post-IE onset behaviour. RESULTS: Ninety-six (24.74 per cent) dogs with IE and 292 (75.26 per cent) age and breed-matched control dogs met the inclusion criteria. Control dogs had significantly higher 'Trainability' scores than dogs with IE (P=0.04). After IE, dogs had significantly higher 'Dog-Directed Fear or Aggression' (P=0.02), 'Non-Social Fear' (P=0.01), 'Attachment/Attention-Seeking Behaviour' (P=0.04), 'Attention-Deficit' (P=0.02) and significantly lower 'Trainability' (P=0.02) than prior to the onset of IE. Medication status did not significantly affect any behavioural factor, but drug-resistant dogs had significantly less 'Trainability' than drug-responsive (P=0.04) and partially drug-responsive dogs (P=0.03). CONCLUSION: Behavioural differences related to cognitive function are seen between dogs with IE and controls. Behavioural changes related to anxiety, attention and cognition are seen in dogs following the onset of IE. The ability to clinically define and diagnose behavioural comorbidities in dogs is much needed from both a clinical and research perspective.

A double-blinded randomised dietary supplement crossover trial design to investigate the short-term influence of medium chain fatty acid (MCT) supplement on canine idiopathic epilepsy: study protocol.

BACKGROUND: Epilepsy is the most common brain disease in dogs. Recently, diets have been reported to have a positive impact on seizure activity and behaviour in various species including dogs with idiopathic epilepsy (IE). Historically, classic high fat ketogenic diets (KD) and medium chain triglycerides (MCT) KD have been successfully used to manage drug-resistant epilepsy. Similarly, an MCT enriched diet has been shown to improve seizure control and behavioural comorbidities in some dogs with IE. However, it is unknown whether an MCT dietary supplement (DS) may provide similar positive effects. METHODS: A 6-month prospective, randomised, double-blinded, placebo-controlled, crossover, multicentre dietary trial is designed comparing a 9% metabolic energy based calculated medium-chain triglyceride (MCT) oil supplement to a conventional 'control' DS. Only dogs which will have an International Veterinary Epilepsy Task Force Tier II level like diagnosis of IE which satisfied the following inclusion criteria are included: age between 6 months and ≤ 12 years; weighing between 4 and ≤ 65 kg; unremarkable interictal neurological examinations; no clinically significant findings on routine laboratory diagnostics; unremarkable brain MRI scan; have had at least 3 seizures in the previous 3 months prior to enrolment; treated with at least one ASD and being classified as resistant. All dogs are fed initially for 90 ± 2 days with either the control oil or the MCT oil alongside their normal diet, followed by 97 ± 2 days with the other supplement including a 7-day washout period. Overall, the aim is to recruit thirty-six patients at five different centres and to investigate the effect of MCTs as DS on seizure activity, tolerability, behavioural comorbidities and quality of life (QoL). DISCUSSION: Dietary interventions are rarely studied in a standardised form in veterinary medicine. The background diet, the cohort of animals and ASD received is standardised in this prospective diet trial to ensure representative data about the potential effect of MCT DS. If the study data confirms former findings, this would provide further evidence for the efficacy of MCTs as a management option for canine epilepsy. This publication should offer a repository of trial conditions and variable description with forecasted statistical analysis.

Investigating owner use of dietary supplements in dogs with idiopathic epilepsy.

Epilepsy is the most common chronic neurological disorder in dogs. Some diets have been shown to have a positive impact upon the seizure activity in dogs with idiopathic epilepsy (IE), while other diets and dietary supplements (DS), although marketed as providing health benefits, lack conclusive scientific evidence on their actual beneficial effects. A web-based owner questionnaire was designed to assess how and why owners of dogs with IE use different dietary regimes and DS. The study cohort, with 297 valid responses, consisted mainly of pure-breed (82.5%) male neutered (52.9%) dogs. Over two-thirds of owners (67.7%) changed their dog's diet after their dog received a diagnosis of IE. Nearly half of the owners (45.8%) reported giving DS, the most common being coconut oil or derived medium-chain triglyceride oil (71.3%). Some owner justifications of DS use included improvement of seizure frequency (88.2%), seizure severity (61.8%) and protection from potential drug side effects (62.5%). Many owners give DS to their dog with IE. The pharmacokinetic properties of anti-epileptic drugs, such as efficacy, absorption and clearance can be influenced by other medications, diets and possibly by DS. We propose that use of DS should be considered and monitored by veterinary surgeons in epilepsy management.

Preliminary assessment of cognitive impairments in canine idiopathic epilepsy.

In humans, epilepsy can induce or accelerate cognitive impairment (CI). There is emerging evidence of CI in dogs with idiopathic epilepsy (IE) from recent epidemiological studies. The aim of our study was to assess CI in dogs with IE using two tests of cognitive dysfunction designed for use in a clinical setting. Dogs with IE (n=17) were compared against controls (n=18) in their performance in two tasks; a spatial working memory task and a problem-solving task. In addition, owners completed the Canine Cognitive Dysfunction Rating (CCDR) scale for their dog. The groups did not differ statistically with respect to age and breed. Dogs with IE performed significantly worse than controls on the spatial working memory task (P=0.016), but not on the problem solving task (P=0.683). CCDR scores were significantly higher in the IE group (P=0.016); however, no dogs reach the recommended threshold score for CCD diagnosis. Our preliminary data suggest that dogs with IE exhibit impairments in a spatial working memory task. Further research is required to explore the effect of IE on other cognitive abilities in dogs with a larger sample, characterising the age of onset, nature and progression of any impairments and the impact of anti-epileptic drugs.

Clinical reasoning in feline epilepsy: Which combination of clinical information is useful?

We sought to identify the association between clinical risk factors and the diagnosis of idiopathic epilepsy (IE) or structural epilepsy (SE) in cats, using statistical models to identify combinations of discrete parameters from the patient signalment, history and neurological examination findings that could suggest the most likely diagnosis. Data for 138 cats with recurrent seizures were reviewed, of which 110 were valid for inclusion. Seizure aetiology was classified as IE in 57% and SE in 43% of cats. Binomial logistic regression analyses demonstrated that pedigree status, older age at seizure onset (particularly >7years old), abnormal neurological examinations, and ictal vocalisation were associated with a diagnosis of SE compared to IE, and that ictal salivation was more likely to be associated with a diagnosis of IE than SE. These findings support the importance of considering inter-ictal neurological deficits and seizure history in clinical reasoning.