Different sides of the same coin? Comorbidity and characteristics of canine neurodevelopmental disorders and their impact on animal welfare

Epilepsy is a complex brain disease, in which individuals are predisposed to spontaneous seizures, and is common in both humans and dogs. Epilepsy is estimated to affect 0.6% of dogs, with prevalence markedly higher in some breeds e.g. 17-33% in the Belgian Shepherd. Although seizures may be the signature symptom of epilepsy, epilepsy may have a variety of manifestations, not limited to seizure activity. Co-morbid psychiatric and neurodevelopmental disorders are commonly seen in people with epilepsy, and have been reported to have a greater impact upon the quality of life (QoL) of the individual patient. To date, the behavioural comorbidities of epilepsy in the dog have been little studied, with the main focus in veterinary medicine being upon seizure control (reducing seizure frequency/severity). This approach may leave many dogs vulnerable to the negative effects of undiagnosed comorbid disorders including anxiety, depression, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). This research programme will focus on two recognised neurodevelopmental comorbidities of epilepsy, ADHD and ASD. ADHD is a neurodevelopmental disorder that affects one third of human epilepsy patients, with hallmarks of ADHD including easy distraction, impulsivity, hyperactivity and slow learning. ADHD-like behaviour is seen in rat models of epilepsy and has recently been recognised as a comorbidity of canine epilepsy. ASD is characterised by social deficits and communication difficulties and stereotyped/repetitive behaviours. ASD symptoms occur in 15-35% of children with epilepsy, and ASD-like behaviours are seen in rodent models, but has not yet been considered as a comorbidity of canine epilepsy. Children with these disorders frequently present with overlapping clinical signs of ASD/ADHD, and it is likely that the epilepsy-ASD-ADHD phenotype has a complex and heterogeneous pathogenesis. This research programme will objectively study the behaviour of dogs with epilepsy to identify ASD and ADHD phenotypes, and identify neuroanatomical and electrophysiological processes associated with these phenotypes. We will study a cohort of pet owned Border Collies, recruited through liaison with veterinary surgeons, in a case-control study with half affected by epilepsy, and half healthy controls. Detailed seizure diaries and behavioural/training histories will be taken to explore their influence upon behaviour and the relationship between ASD/ADHD and drug response. Objective behavioural tests combined with owner questionnaires will be conducted to quantify ASD/ADHD-like behaviours and explore whether dogs with epilepsy show increased levels in comparison to healthy controls. Once a behavioural phenotype is established, we will investigate whether it is associated with neuroanatomical and/or neurophysiological markers. Awake and sedated EEG methods will be used to quantify interictal neurophysiological profiles, and magnetic resonance images will be collected to quantify brain volumetrics, to detect differences in brain activity and/or anatomy associated with ASD/ADHD, as are seen in humans with these disorders. Cognitive (judgement) bias tests will be used to measure the effect of ASD/ADHD on the affective state of dogs, and whether they have a negative impact on canine welfare. A validated ASD/ADHD questionnaire tool will be created and deployed as a cross-sectional prevalence survey to estimate how common ASD/ADHD are in the general canine population. This tool could ultimately be used by veterinary surgeons to screen for comorbidities. This approach has the potential to deepen our understanding of the underlying pathophysiology of epilepsy and neurodevelopmental disorders, establish the presence of new co-morbidities in dogs with epilepsy that require further attention (including treatment development) to protect canine welfare, and strengthen the dog as a spontaneously occurring model of epilepsy and its comorbidities.

Idiopathic epilepsy (IE) is a common neurological disease in both man and dogs. Although seizures may be the hallmark of IE, IE may have a variety of manifestations, not limited to seizure activity. Co-morbid psychiatric and neurodevelopmental disorders are prevalent in people with epilepsy, likely resulting from altered neurobiological mechanisms involved in early brain development. These disorders can have a greater impact upon the quality of life (QoL) of the individual patient than seizures. To date, the main focus of epilepsy study in veterinary medicine has been upon seizure control (reducing seizure frequency/severity). This approach may leave many dogs vulnerable to the negative effects of undiagnosed comorbid disorders including anxiety, depression, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). This research programme will focus on two recognised comorbidities of epilepsy, ADHD and ASD, to deepen our understanding of the shared pathophysiology of epilepsy and neurodevelopmental disorders. We will study a cohort of pet owned Border Collies, in an age and sex matched case-control study of dogs with IE and matched healthy control dogs. We will define ASD/ADHD phenotypes in our study population by assessing behaviour in objective tests combined with owner questionnaires. Subsequently we will explore whether neurophysiological and/or neuroanatomical markers are associated with these phenotypes, using awake and sedated EEG to examine brain activity profiles, and MRI to quantify brain volumetrics. Finally, established cognitive (judgement) bias methods will be used to measure the effect of ASD/ADHD on the affective state of dogs. This approach has the potential to significantly improve canine welfare by the identification of co-morbidities that may compromise QoL and require further attention (e.g. treatment development), and will strengthen the dog as a spontaneously occurring, natural model of epilepsy and its comorbidities.

Epilepsy is a major welfare issue in the dog, and of the ~10.5 million dogs kept as companion animals in the UK, 0.6-0.8% are estimated to be affected by epilepsy (approximately 63,000 dogs). Idiopathic epilepsy (IE; where no cause can be found) is a quality of life (QoL) issue for both the affected dog and their owner. Undiagnosed comorbid neurodevelopmental disorders (ADHD/ASD) may lead to further problems for owners, with hyperactivity, impulsivity and repetitive behaviours potentially challenging and distressing for owners to manage. Understanding epilepsy and its comorbidities will have an impact upon more than one species. Epilepsy, ASD and ADHD are prevalent disorders in man, with the Centers for Disease Control and Prevention in the US estimating that 1 in every 26 people are affected by epilepsy, 1 in 68 children affected by ASD, and 1 in 10 children affected by ADHD. As potentially lifelong 'hidden' disabilities, these disorders of societal and financial importance, with epilepsy alone accounting for $15.5 billion in direct costs (medical) and indirect costs (lost or reduced earnings and productivity) each year in the US. Deepening our understanding of these disorders is of high importance, to allow the development of new, more effective therapies to reduce their individual and combined impact upon QoL.
Stakeholders who will benefit include:
- Commercial companies: Pet food, nutraceutical and veterinary pharmaceutical companies have an interest in the treatment of chronic diseases such as IE and behavioural abnormalities. This is a substantial industrial sector, with the pet food industry and related supply and services representing a combined annual turnover of over 24 billion Euros. Increased knowledge of the aetiopathogenesis of IE, ASD and ADHD in dogs will be advantageous in R&D studies of anti-epileptic drug development and drug efficacy, along with the relatively new field of identifying existing or novel therapies (drug/dietary) that improve co-morbid behavioural problems.
- Affected dogs: Neurodevelopmental problems in dogs with IE have been under-studied in veterinary medicine compared to studies of seizure control. Affected dogs may eventually benefit from more accurate diagnoses of their disorder(s), with behavioural abnormalities no longer going undiagnosed and so unmanaged, with new therapies potentially developed for their treatment.
- Veterinary practices: At present there are no guidelines on the diagnosis and/or treatment of behavioural problems co-morbid with epilepsy. Creation of a simple screening tool from this research to detect co-morbid behavioural abnormalities could aid vets in their decision to refer cases to behavioural specialists/pursue further behavioural management themselves. If ASD/ADHD are linked with resistance to AEDs, behavioural markers may aid vets in their treatment decisions and lead to a more 'personalised medicine' approach to epilepsy treatment.
- Dog owners: Owners of dogs with IE are recognised to experience distress due to the management of their dog's condition, which may involve both seizure activity and abnormal behaviours. Owners may eventually benefit from improved therapeutic management of their dog as a result of the accurate phenotyping of ASD/ADHD in this project, and further research into effective therapies.
- Human neurologists, neuroscientists and pharmacologists: If signs of ASD/ADHD are seen in dogs with IE, the dog may offer a naturally occurring model of neurodevelopmental disorders cormorbid with epilepsy. This will offer a better model than current rodent models, as the dog is physiologically more similar to humans, with increased behavioural complexity compared to rodents and the benefit of sharing the same environment. Downstream, this may lead to reductions in the number of rodents used in epilepsy comorbidity research, avoiding the need to induce seizures by using pet-owned animals, who will also benefit from new treatment development.