H. Volk
Department of Small Animal Medicine and Surgery, University of Veterinary Medicine—Hannover, Hannover, Germany
Most texts will describe epilepsy as a pure seizure disorder. However, epilepsy is far more. Epilepsy is a brain disease1 with seizures being the clinically most prominent sign. Most will recognise a generalised tonic-clonic convulsion, but relatively few will be able to spot focal motor or sensory seizures (ictal behaviour changes). However, apart from the seizures other clinical signs of epilepsy, which are increasingly recognised affecting the interictal period, are changes in cognition and behaviour.2-4 It is thought that there are shared pathophysiological pathways explaining the bidirectional relationship between neurobehavioural disorders and epilepsy;5 for example in human medicine, a patient with depression is more likely to develop epilepsy and a patient with epilepsy depression6,7. It is yet unknown if this bidirectional relationship exists in our veterinary patients.
Neurobehavioural comorbidities are been taken more and more serious in human patient, as they can have a bigger impact on health related QoL (HRQoL) than seizures. This is the case especially for interictal anxiety and depression.8 Only few studies have studied interictal behaviour changes in dogs with epilepsy. In the first study, around two-thirds of dogs developed a behaviour change during the course of their idiopathic epilepsy.9 Drug-resistant dogs were found to have greater amount of unfavourable behavioural changes than drug responders in the same study,9 a finding also been seen in rodent models of epilepsy, where drug-resistant rats had greater behaviour changes10. Not surprisingly, anxiety is the main behaviour change reported in dogs with IE,9,11 and in two more recent studies changes in impulsivity and other clinical signs comparable with attention deficits hyperactivity disorder in people have been noted12,13. An increasing level of evidence also exists that dogs with idiopathic epilepsy might have changes in trainability, spatial memory and accelerated memory loss.3,14,15 As such, epilepsy management should in the future not only focus on reducing seizures, but also consider on reducing the effects of potential behavioural comorbidities.16
In human medicine, certain antiseizure drugs have recognised anxiogenic and anxiolytic effects.16 As in veterinary medicine, most drug studies in human medicine have focused to study seizure suppressing effects rather than also looking at the effects of the medication on cognition and behaviour. A recent systematic review and meta-analysis of antiseizure drug’s tolerability and safety in dogs with epilepsy showed that every 10th canine patient treated with primidone had anxiety documented as side effect, but there were no reports of increased anxiety in dogs being managed with phenobarbital, potassium bromide, levetiracetam, zonisamide or felbamate.17 Interestingly, our veterinary antiepileptic drug blockbuster phenobarbital and potassium bromide have become less used in human medicine due to their behavioural side-effects.16 One of the more promising anxiolytic drugs used in people are gabapentin/pregabalin,16 but these drugs have limited evidence in regards of seizure suppressing activity in dogs with idiopathic epilepsy18. The trials available have only studied these drugs as add-on but not as the sole agent.
The new kid on the block for seizure control imepitoin showed promising anti-seizure and anti-anxiety effects in rodent models19 and in a seizure beagle model20. Charalambous and colleagues17 systematic review found that in one of ten studies where imepitoin was used reported reversible and dose-dependent anxiety. In a questionnaire-based study no anxiogenic or anxiolytic effects of imepitoin was reported in dogs treated for idiopathic epilepsy.21 However, in “non-epileptic” patient imepitoin was used successfully in the management of sound related fears.22
In 2011, the International League Against Epilepsy (ILAE) provided guidance notes for the management of neurobehavioural comorbidities.23 The ILAE recommendation is to use selective serotonin reuptake inhibitors (SSRIs) as first-line drug for the management of anxiety in people with epilepsy. SSRIs appear to be well tolerated and have no to minimal impact on the seizure threshold. Other drugs which are safe to use in these patients are benzodiazepines, azapirones, antihistamines and pregabalin (ADCE).24 There is only anecdotal evidence for the use of the SSRI fluoxetine in dogs with epilepsy. Fluoxetine could impact the metabolism of phenobarbital so that close drug monitoring is indicated. Sertraline has been suggested as a safer substitute, which has been described for the usage of dogs with anxiety.16 SSRIs are thought to take around four weeks to show an effect. Tricyclic antidepressant and monoamine oxidase inhibitor are usually not recommended as there could be an effect on seizure threshold or stimulating certain behaviours.16
An interesting alternative to medication is the use of diet to modify behaviour. A significant reduction in chasing behaviour (a potential indicator of canine ADHD-like behaviour) was documented with a medium-chain fatty acid enriched diet.25 Furthermore, a reduction in stranger-directed fear was noted in the same trial, which may indicate anxiolytic properties of the MCT.
In conclusion, epilepsy is a complex disease which might need more complex management solutions. Management needs to better tailored to the individual patient and the focus should be not only on getting better seizure control.
References
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25. Packer RMA, Law TH, Davies E, Zanghi B, Pan Y, Volk HA. Effects of a ketogenic diet on ADHD-like behavior in dogs with idiopathic epilepsy. Epilepsy Behav. 2016;55:62–68.