Revamping Our Understanding of Epilepsy
World Small Animal Veterinary Association Congress Proceedings, 2019
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.


1.  Berendt M, Farquhar RG, Mandigers PJ, et al. International veterinary epilepsy task force consensus report on epilepsy definition, classification and terminology in companion animals. BMC Vet Res. 2015;11:182.

2.  Packer RM, Volk HA. Epilepsy beyond seizures: a review of the impact of epilepsy and its comorbidities on health-related quality of life in dogs. Vet Rec. 2015;177(12):306–315.

3.  Winter J, Packer RMA, Volk HA. Preliminary assessment of cognitive impairments in canine idiopathic epilepsy. Vet Rec. 2018;182(22):633.

4.  Packer RMA, McGreevy PD, Salvin HE, Valenzuela MJ, Chaplin CM, Volk HA. Cognitive dysfunction in naturally occurring canine idiopathic epilepsy. Plos One. 2018;13(2):e0192182.

5.  Kanner AM. Depression in epilepsy: prevalence, clinical semiology, pathogenic mechanisms, and treatment. Biol Psychiatry. 2003;54(3):388–398.

6.  Forsgren L, Nystrom L. An incident case referent study of epileptic seizures in adults. Epilepsy Res. 1990;6:66–81.

7.  Hesdorffer DC, Hauser WA, Annegers JF, Cascino G. Major depression is a risk factor for seizures in older adult. Ann Neurol. 2000;47:246–249.

8.  Johnson EK, Jones JE, Seidenberg M, Hermann BP. The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. Epilepsia. 2004;45(5):544–550.

9.  Shihab N, Bowen J, Volk HA. Behavioral changes in dogs associated with the development of idiopathic epilepsy. Epilepsy Behav. 2011;21(2):160–167.

10.  Gastens AM, Brandt C, Bankstahl JP, Löscher W. Predictors of pharmacoresistant epilepsy: Pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsy. Epilepsia. 2008;49(10):1759–1776.

11.  De Risio L, Newton R, Freeman J, Shea A. Idiopathic epilepsy in the Italian spinone in the United Kingdom: prevalence, clinical characteristics, and predictors of survival and seizure remission. J Vet Intern Med. 2015;29(3):917–924.

12.  Packer RM, 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.

13.  Jokinen TS, Tiira K, Metsahonkala L, et al. Behavioral abnormalities in lagotto romagnolo dogs with a history of benign familial juvenile epilepsy: A long-term follow-up study. J Vet Intern Med. 2015;29(4):1081–1087.

14.  Packer RMA, McGreevy PD, Pergande A, Volk HA. Negative effects of epilepsy and antiepileptic drugs on the trainability of dogs with naturally occurring idiopathic epilepsy. Appl Anim Behav Sci. 2018;200:106–113.

15.  Packer RMA, McGreevy PD, Salvin HE, Valenzuela MJ, Chaplin CM, Volk HA. Cognitive dysfunction in naturally occurring canine idiopathic epilepsy. PLoS One. 2018;13(2):e0192182.

16.  Watson F, Rusbridge C, Packer RMA, Casey RA, Heath S, Volk HA. A review of treatment options for behavioural manifestations of clinical anxiety as a comorbidity in dogs with idiopathic epilepsy. Vet J. 2018;238:1–9.

17.  Charalambous M, Shivapour SK, Brodbelt DC, Volk HA. Antiepileptic drugs tolerability and safety—a systematic review and meta-analysis of adverse effects in dogs. BMC Vet Res. 2016;12:79.

18.  Charalambous M, Brodbelt D, Volk HA. Treatment in canine epilepsy—a systematic review. BMC Vet Res. 2014;10(1):257.

19.  Rundfeldt C, Löscher W. The pharmacology of imepitoin: the first partial benzodiazepine receptor agonist developed for the treatment of epilepsy. CNS Drugs. 2014;28(1):29–43.

20.  Löscher W, Potschka H, Rieck S, Tipold A, Rundfeldt C. Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. Epilepsia. 2004;45(10):1228–1239.

21.  Packer RM, Volk HA. Study on the effects of imepitoin on the behaviour of dogs with epilepsy. Vet Rec. 2015;177(5):132.

22.  McPeake KJ, Mills DS. The use of imepitoin (Pexion™) on fear and anxiety related problems in dogs—a case series. BMC Vet Res. 2017;13(1):173.

23.  Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia. 2011;52(11):2133–2138.

24.  Kwon OY, Park SP. Depression and anxiety in people with epilepsy. J Clin Neurol. 2014;10(3):175–188.

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.


Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

H. Volk
Department of Small Animal Medicine and Surgery
University of Veterinary Medicine Hannover
Hannover, Germany

MAIN : Neurology : Revamping Our Understanding of Epilepsy
Powered By VIN