7 Antiepileptic Therapy in Dogs

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Disclosures

è FINANCIAL DISCLOSURE: • Grant/Research Support – Purina, Boehringer Ingelheim, BBSRC, Wellcome Trust, AKC Canine Health Foundation Department of Small Animal Diseases • Consulting and Speaker Engagement – Purina, Boehringer Ingelheim. è UNLABELED/ UNAPPROVED USES DISCLOSURE: Antiepileptic Therapy in Dogs - Fundamentals • I will discuss results of clinical trials in which antiepileptic drugs were used which are either not licensed for the specie or are only licensed in certain countries. Please and Cases check local authorities before use.

Prof. Holger A. Volk DipECVN, PhD, PGCAP, FHEA, MRCVS Head of Department, Tierärztliche Hochschule Hannover RCVS & EBVS® European Specialist in Veterinary Neurology Past-President of the European College of Veterinary Neurology Treasurer of the European Board of Veterinary Specialisation Honorary Senior Lecturer -UCL Institute of Neurology Honorary Professor of Veterinary Neurology and Neurosurgery -Royal Veterinary College

Outcome in individual patients: impact on seizures

How does success look like? Therapeutic success

Outcome in individual patients: impact on seizures Thank you Marios Charalambous

Evaluate short-term & long-term success.

Term drug-resistant combined with drug information. (e.g. PHB resistant)

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International Veterinary Epilepsy Task Force

1. International Veterinary Epilepsy Task Force consensus report on epilepsy definition, classification and terminology in companion animals (chaired by Prof. Mette Berendt) 2. International Veterinary Epilepsy Task Force Consensus Proposal: Diagnostic approach to epilepsy in dogs (Chaired by Drs. Luisa De Risio and Sofie Bhatti) 3. International Veterinary Epilepsy Task Force current understanding of idiopathic epilepsy of genetic or suspected genetic origin in purebred dogs (Chaired by Dr. Velia-Isabel Hülsmeyer) 4. International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe (Chaired by Drs. Sofie Bhatti and Luisa De Risio) 5. International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy (Chaired by Profs. Heidrun Potschka and Andrea Fischer) 6. International Veterinary Epilepsy Task Force recommendations for a veterinary epilepsy-specific MRI protocol (Chaired by Drs. Clare Rusbridge and Sam Long) 7. International Veterinary Epilepsy Task Force recommendations for systematic sampling and Berendt M; Bhatti SFM; De Risio L; Farquhar RG; Fernández-Flores F; Fischer processing of brains from epileptic dogs and cats (Chaired by Profs. Kaspar Matiasek and Martí Pumarola Batlle).

A, Hasegawa D; Hülsmeyer VI; Jokinen-Pääkkönen T; Jovanovik E; Löscher W, www.ivetf.org Lohi H; Long S; Mandigers PJJ; Matiasek K; Milne M; Muñana K; Packer, RMA; – Pakozdy A; Patterson EE; Penderis J; Platt S; Podell M; Potschka H; Pumarola MB; Rosati M; Rusbridge C; Saito M; Stein VM; Tipold A; Volk H; Wagner E. IVETF

ACVIM consensus statement - Panel Members

Scenario

Which drug would you use? A 5 years old 17 kg German Shepherd intact male dog manifested single generalized tonic- clonic seizures one year ago. The dog is normal in-between the episodes. You wonder what the best treatment would be. 1. Phenobarbitone 2. Imepitoin 3. Potassium bromide 4. Levetiracetam 5. Gabapentin 6. Zonisamide

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Scenario

A 5 years old 17 kg German Shepherd intact male dog manifested single generalized tonic- clonic seizures one year ago. In the last two months the dog manifested five episodes. The dog is normal in-between the episodes, idiopathic epilepsy is suspected. You wonder what the best treatment would be.

Scenario Which drug would you use first line? A 5 years old 17 kg German Shepherd intact male dog manifested single generalized tonic- clonic seizures one year ago. In the last two months the dog manifested cluster seizures. 1. Phenobarbitone The dog is normal between the episodes, idiopathic epilepsy is suspected. You wonder 2. Imepitoin what the best treatment would be. 3. Potassium bromide 4. Levetiracetam 5. Gabapentin 6. Zonisamide

How high is the placebo effect if you are a surgeon or a medic? Which drug would you use first line?

1. Phenobarbitone J Vet Intern Med 2010;24:166–170 2. Imepitoin Placebo Effect in Canine Epilepsy Trials

3. Potassium bromide K.R. Mun˜ ana, D. Zhang, and E.E. Patterson

4. Levetiracetam Background: The placebo effect is a well-recognized phenomenon in human medicine; in contrast, little information exists on the effect of placebo administration in veterinary patients. 5. Gabapentin Hypothesis: Nonpharmacologic therapeutic effects play a role in response rates identiﬁed in canine epilepsy trials. Animals: Thirty-four dogs with epilepsy. Methods: Meta-analysis of the 3 known prospective, placebo-controlled canine epilepsy trials. The number of seizures per 6. Zonisamide week was compiled for each dog throughout their participation in the trial. Log-linear models were developed to evaluate seizure frequency during treatment and placebo relative to baseline. Results: Twenty-two of 28 (79%) dogs in the study that received placebo demonstrated a decrease in seizure frequency compared with baseline, and 8 (29%) could be considered responders, with a 50% or greater reduction in seizures. For the 3 trials evaluated, the average reduction in seizures during placebo administration relative to baseline was 26% (P 5 .0018), 29% (P 5 .17), and 46% (P 5 .01). Conclusions and Clinical Importance: A positive response to placebo administration, manifesting as a decrease in seizure frequency, can be observed in epileptic dogs. This is of importance when evaluating open label studies in dogs that aim to assess efﬁcacy of antiepileptic drugs, as the reported results might be overstated. Findings from this study highlight the need for more placebo-controlled trials in veterinary medicine. Key words: Clinical trials; Dog; Epilepsy; Statistical modeling.

he placebo effect is a well recognized, but poorly un- placebo-controlled studies are considered necessary to Tderstood phenomenon that involves a nonspecific gauge the true efficacy of a novel intervention, and are psychological or physiological therapeutic effect of a the basis for drug evaluation and approval in human medical intervention that lacks specific activity for the medicine. condition being treated.1 Early medical practices were In contrast, the placebo effect has been largely disre- based on the placebo effect, wherein placebos were ad- garded in veterinary medicine, with only 2 publications ministered with the purpose of producing a desired identified that address the issue of a placebo effect in an- therapeutic response. More recently, the use of placebos imals.1,5 However, with the recent emphasis placed on has focused primarily on its role as a control in random- evidence based medicine in veterinary practice, it seems 3 ized-clinical trials that allows for an unbiased estimate of appropriate to consider the effect of placebos in veteri- the treatment effects of the agent being evaluated. nary patients, particularly the extent to which animals Results from numerous human trials have demon- may demonstrate an improvement in disease manifesta- strated that placebos can improve subjective and tions that could be because of nonspecific effects of a objective outcomes in patients with a wide range of therapeutic intervention. clinical conditions. A beneficial effect of placebo admin- The hypothesis tested in this study is that nonpharma- istration has been reported in 60–90% of all human cologic therapeutic effects play a role in response rates diseases,2 including musculoskeletal, respiratory, car- identified in canine epilepsy trials. The specific aim is to diac, dermatologic, gastrointestinal, and nervous system determine the magnitude of the placebo response in ran- disorders. Furthermore, a placebo response rate of ap- domized-controlled trials evaluating new treatment proximately 35% is commonly cited in the medical modalities for refractory canine epilepsy. literature,3 although higher rates have been reported and are most frequently seen in diseases with clinical Materials and Methods signs that wax and wane, fluctuate, or spontaneously re- mit.4 Because of the potential magnitude of this effect, Study Design Data was compiled from 3 clinical trials evaluating the safety and efficacy of novel treatments for refractory canine epilepsy in which a From the Department of Clinical Sciences, College of Veterinary placebo arm was a component of the study protocol. The studies Medicine (Munãna) and the Department of Statistics (Zhang), evaluated were performed by 2 of the authors (K.R.M., E.E.P.), en- North Carolina State University, Raleigh, NC and the Department abling easy access to the data necessary to undertake the present of Veterinary Clinical Science (Patterson), University of Minnesota, analysis. A database search was performed to identify any addi- St Paul, MN. Presented at the 26th Annual Forum of the American College of Veterinary Medicine, San Antonio, TX, June 2008. tional placebo-controlled canine epilepsy trials that might be Corresponding author: Karen R. Munãna, Department of Clinical included in the analysis, but none were found. Inclusion criteria Sciences, College of Veterinary Medicine, North Carolina State Uni- were similar for all 3 studies and consisted of (1) an onset of seizures versity, 4700 Hillsborough Street, Raleigh, NC 27606; e-mail: between 1 and 5 years of age; (2) a normal diagnostic evaluation, [email protected] including physical examination, neurological examination, CBC, Submitted April 17, 2009; Revised July 17, 2009; Accepted chemistry profile, urinalysis, and bile acid tolerance test; (3) treat- September 16, 2009 ment with either phenobarbital and/or potassium bromide at Copyright r 2009 by the American College of Veterinary Internal established therapeutic serum levels; (4) a seizure frequency of at Medicine least 4 seizures per month or a history of cluster seizures; and (5) a 1 10.1111/j.1939-1676.2009.0407.x year documented history of seizures. All dogs were classified as Charalambous et al. BMC Veterinary Research 2014, 10:257 Page 20 of 24 http://www.biomedcentral.com/1746-6148/10/257

for the efficacy of oral primidone, zonisamide, gabapentin, AED in human epilepsy, its tolerability issues lead to the 8/13/19 sodium valproate, pregabalin, felbamate and topiramate as investigation and use of other AEDs with almost the same adjunct AEDs, but there was insufficient level of evidence efficacy but more tolerable. Imepitoin was initially devel- to support their efficacy. oped as a new AED for humans, but development was Overall risk of bias ranged from low/moderate to high; ceased because of differences in pharmacokinetic values only four studies [11-14] categorized as low/moderate between smokers and non-smokers, although the toler- overall risk and the remaining as moderate/high or high. ability of this drug in humans was high [39]. Studies in group A which were considered to offer lower In canine epilepsy there are limitations in treatment of overall risk of bias were too few compared to those of IE due to the rapid elimination of the majority of the group B (study group A:group B proportion was 1:6). AEDs with only few, i.e. phenobarbital, primidone and Therefore, the results from the studies concerning the potassium bromide, having sufficient half-life [40,41]. The efficacy of each AED should be interpreted with caution. same drugs have been approved for treatment of canine In addition, only 17% and 10% of the 29 studies included epilepsy in Europe and/or USA, with phenobarbital to be well characterized groups and evaluated good numbers of one of the most effective and well-known AED. Recently, dogs, respectively. None of the bRCTs included well char- imepitoin was also approved for the treatment of canine acterized groups and only two of them evaluated a good epilepsy based on some RCTs [13,14]. Monotherapy with number of dogs. The same studies, though, were consid- imepitoin in dogs with newly diagnosed epilepsy showed ered to offer the highest quality of evidence among all the that it was moderately less effective but potentially studies and recommended the use of phenobarbital and more tolerated than phenobarbital or primidone. Also, imepitoin in particular as well as potassium bromide and in dogs with chronic epilepsyreceivingphenobarbital levetiracetam as AEDs. However, mainly due to the small and/or primidone, most dogs exhibited a reduction in Charalambousnumber ofet bRCTs al. BMC and Veterinary to a lesser Research extend2014, 10 due:257 to the inad- seizure frequency and severity after adjunctive therapy http://www.biomedcentral.com/1746-6148/10/257equate disease definitions and study group sizes, definitive with imepitoin [26,27]. In a laboratory study, imepitoin was suggestions concerning their efficacy are precluded. compared with phenobarbital in an acute canine seizure Based on the level of quality of evidence provided by model using pentylenetetrazole, resulting in a compar- studies for each AED as well as the assessment of their able anticonvulsant efficacy [42]. In the European pseudo- Side effects RESEARCHefficacy, a pyramid ARTICLE of hierarchy was proposed (Figure 1). placebo trial, high dose (30 mg/kg PO Open BID) ofAccess imepitoin Phenobarbital and imepitoin were found to be at the top was compared to low dose (1 mg/kg PO/BID) and results of the pyramid. In human epilepsy, many AEDs are used showed that seizure frequency was significantly reduced in for the management of seizures but phenobarbital remains the first– compared to the second group [13]. In the same Treatmentone of the most important; in meta-analyses canine of RCTs epilepsy found study, baselinea systematic seizure frequency was differentreview between Mariosthat only Charalambous minor differences1*, David occur Brodbelt on the2 groundsand Holger of efficacy A Volk1 the two groups; thus, the change in seizure frequency between phenobarbital and other established AEDs [38]. reduction between the groupswassignificant.InaUS Although phenobarbital may remain the most efficient field study, imepitoin was compared to primidone but Abstract Background: Various antiepileptic drugs (AEDs) are used for the management of canine idiopathic epilepsy (IE). Information on their clinical efficacy remains limited. A systematic review was designed to evaluate existing evidence for the effectiveness of AEDs for presumptive canine IE. Electronic searches of PubMed and CAB Direct were carried out without date or language restrictions. Conference proceedings were also searched. Peer-reviewed full-length studies describing objectively the efficacy of AEDs in dogs with IE were included. Studies were allocated in two groups, i.e. blinded randomized clinical trials (bRCTs), non-blinded randomized clinical trials (nbRCTs) and non-randomized clinical trials (NRCTs) (group A) and uncontrolled clinical trials (UCTs) and case series (group B). Individual studies were evaluated based on the quality of evidence (study design, study group sizes, subject enrolment quality and overall risk of bias) andtheoutcomemeasuresreported(inparticulartheproportionofdogs with ≥50% reduction in seizure frequency). Results: Twenty-six studies, including two conference proceedings, reporting clinical outcomes of AEDs used for management of IE were identified. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. Only four bRCTs were identified in group A and were considered to offer higher quality of evidence among the studies. A good level of evidence supported the efficacy of oral phenobarbital and imepitoin and fair level of evidence supported the efficacy of oral potassium bromide and levetiracetam. For the remaining AEDs, favorable results were reported regarding their efficacy, but there was insufficient evidence to support their use due to lack of bRCTs. Conclusions:Figure 1 PyramidOral of phenobarbital hierarchy describing and theimepitoin recommendation in particular, of AEDs as well based as on potassium the assessment bromide of their and efficacy levetiracetam and quality are of likelyevidence. to be effective for the treatment of IE. However, variations in baseline characteristics of the dogs involved, significant differences between study designs and several potential sources of bias preclude definitive recommendations. There is a need for greater numbers of adequately sized bRCTs evaluating the efficacy of AEDs for IE. Keywords: Systematic review, Epilepsy, Antiepileptic drugs, Treatment, Canine

Background background and in veterinary medicine the terms idio- Epilepsy is the most common chronic neurological dis- pathic or primary are generally used for any epilepsy of order in dogs, with a formerly reported prevalence of be- unidentified etiology even if no genetic or familial causes tween 0.5% and 5% in non-referral populations [1,2]. In are suspected [5]. In this study the term idiopathic epilepsy a recent study, this prevalence was estimated to be 0.62% (IE) will be used for all the cases of unidentified etiology, in a large UK primary care population [3]. Epilepsy is not including cases with a suspected genetic background. one single disease process but can be elicited by mul- Various antiepileptic drugs (AEDs) are used for the tiple causes and, accordingly, can be classified as genetic management of IE in dogs. Clinical information on the (primary or idiopathic), structural and of unknown origin/ grounds of their efficacy remains limited, with most evi- etiology [4]. When chronic recurring seizures occur and dence derived from non-blinded non-randomized uncon- no underlying abnormality is detected, epilepsy is clas- trolled trials and case series [6]. In addition, many of these sified typically as primary or idiopathic epilepsy [1]. How- previous reports do not use an objective measurement of ever, idiopathic epilepsy could imply a potential genetic efficacy, e.g. a% reduction in seizure frequency in a proportion of dogs of a study population after a specific period of * Correspondence: [email protected] treatment; instead they are based on subjective observa- 1Department of Clinical Science and Services, Royal Veterinary College, tions, e.g. ‘improvement in seizure control’ or ‘change Hawkshead Lane, Hatfield, Herts AL9 7TA, UK in seizure frequency’. Full list of author information is available at the end of the article

© 2014 Charalambous et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, The Veterinary Journal 208 (2016) 44–49 distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. ACVIM Panel Grade of Recommendations (Level of Contents lists available at ScienceDirect Evidence) for AED Monotherapy The Veterinary Journal

journal homepage: www.elsevier.com/locate/tvjl

A single-blinded phenobarbital-controlled trial of levetiracetam as A (HIGH) B (MODERATE) C (LOW) D (NO) mono-therapy in dogs with newly diagnosed epilepsy N. Fredsø a,*, A. Sabers b, N. Toft c, A. Møller d, M. Berendt a • Bromide (I) • Levetiracetam • Primidone (II) a Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlaegevej 16, 1870 • Phenobarbital Frederiksberg C, Denmark b The Epilepsy Clinic, Department of Neurology, University State Hospital (Rigshospitalet), Blegdamsvej 9, 2100 Copenhagen Ø, Denmark (I) (IV) c NationalIn the Veterinary levetiracetam Institute, Section for Epidemiology,treated Technical dogs University ofthere Denmark, Bülowsvejwas 27,no 1870 significant Frederiksberg C, Denmark difference in the d Centre of Functional Integrative Neuroscience, Aarhus University/Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus, Denmark • Imepitoin (I) • Zonisamide monthly number of seizures before and after treatment, whereas in the (III) ARTICLEphenobarbital INFO treated dogsABSTRACT there were significantly (P = 0.013) fewer seizures after

Articletreatment. history: Five phenobarbitalTreatment treated of canine epilepsy dogs is problematic. were Fewclassified antiepileptic drugsas true have proven responders efficacy in dogs and Accepted 5 October 2015 undesirable adverse effects and pharmacoresistance are not uncommon. Consequently, the need for in- (≥50% reduction in seizures/month)vestigation of alternative whereas treatment options none is ongoing. of the The objective levetiracetam of this study was to investigatetreated the Keywords: efficacy and tolerability of levetiracetam as mono-therapy in dogs with idiopathic epilepsy. The study Antiepilepticdogs fulfilled drug this criterion.used a prospective single-blinded parallel group design. Twelve client-owned dogs were included and Canine were randomised to treatment with levetiracetam (30 mg/kg/day or 60 mg/kg/day divided into three daily Monotherapy dosages) or phenobarbital (4 mg/kg/day divided twice daily). Control visits were at days 30, 60 and then Seizure every 3 months for up to 1 year. Two or more seizures within 3 months led to an increase in drug dosage (levetiracetam: 10 mg/kg/day, phenobarbital: 1 mg/kg/day). Five of six levetiracetam treated dogs and one of six phenobarbital treated dogs withdrew from the study within 2–5 months due to insufficient seizure control. In the levetiracetam treated dogs there was no significant difference in the monthly number of seizures before and after treatment, whereas in the phenobarbital treated dogs there were significantly (P = 0.013) fewer seizures after treatment. Five phenobarbital treated dogs were classified as true responders (≥50% reduction in seizures/month) whereas none of the levetiracetam treated dogs fulfilled this criterion. Adverse effects were reported in both groups but were more frequent in the phenobarbital group. In this study levetiracetam was well tolerated but was not effective at the given doses as monotherapy in dogs with idiopathic epilepsy. © 2015 Elsevier Ltd. All rights reserved.

Introduction pancreatitis have also been associated with these drugs (Dayrell-Hart et al., 1991; Jacobs et al., 1998; Gaskill and Cribb, 2000; Müller et al., The management of epilepsy in dogs is complicated by the fact 2000; March et al., 2004; Gaskill et al., 2005). Imepitoin was reg- that only a few drugs are available and effective. Undesirable adverse istered for use in dogs in 2013 (Europe) and has so far shown a more effects (AE) are not uncommon and failure to control seizures ap- beneficial profile regarding AE (Tipold et al., 2015). propriately may lead to euthanasia (Berendt et al., 2007; Fredsø et al., Levetiracetam, a pyrrolidone derivative, was introduced as an 2014). Potassium bromide and phenobarbital were introduced to antiepileptic drug for humans in 1999 (Brodie et al., 2007). The drug human medicine in 1857 and 1912, respectively, (Locock, 1857a and is believed to act as a modulator of synaptic vesicle exocytosis by b; Hauptmann, 1912), and have traditionally dominated the man- binding to the synaptic vesicle protein 2A (SV2A) (Lynch et al., 2004). agement of canine epilepsy. Both drugs are reasonably effective The pharmacokinetic properties of levetiracetam have been inves- (Boothe et al., 2012) and their long elimination half-lives facilitate tigated in healthy dogs (Dewey et al., 2008; Patterson et al., 2008; a 12–24 h dosing regimen. However, undesirable AE, such as poly- Moore et al., 2010a, 2010b; Peters et al., 2014). Levetiracetam has phagia, polydipsia, polyuria, sedation and ataxia, are common been investigated as adjunctive treatment for refractory idio- (Boothe et al., 2012). Although rare, more serious AE including su- pathic epilepsy in companion dogs (Steinberg and Faissler, 2004; perficial necrolytic dermatitis, pancytopenia, hepatotoxicity and acute Volk et al., 2008; Muñana et al., 2012). Dogs with refractory idiopathic epilepsy have shown a favourable response to levetiracetam as an add-on antiepileptic drug, with a significant reduction in *Correspondingauthor.Tel.:+45 35 33 09 14. seizure frequency compared to baseline in two open-label studies, E-mail address: [email protected] (N. Fredsø). (Steinberg and Faissler, 2004; Volk et al., 2008), whereas no effect

http://dx.doi.org/10.1016/j.tvjl.2015.10.018 IVETF - Consensus proposal - Choice AED 1090-0233/© 2015 Elsevier Ltd. All rights reserved. Bhatti et al. BMC Veterinary Research (2015) 11:176 DOI 10.1186/s12917-015-0464-z

CORRESPONDENCE Open Access • In an otherwise healthy dog International Veterinary Epilepsy Task Force consensus proposal: medical treatment of • Start with PB canine epilepsy in Europe When would you check Phenobarbitone Sofie F.M. Bhatti1*, Luisa De Risio2, Karen Muñana3, Jacques Penderis4, Veronika M. Stein5, Andrea Tipold5, Mette Berendt6, Robyn G. Farquhar7, Andrea Fischer8, Sam Long9, Wolfgang Löscher10, Paul J.J. Mandigers11, • Recurrent single generalized epileptic seizures (IE) Kaspar Matiasek12, Akos Pakozdy13, Edward E. Patterson14, Simon Platt15, Michael Podell16, Heidrun Potschka17, Clare Rusbridge18,19 and Holger A. Volk20 serum levels for the first time? • Clusters seizures and/or status epilepticus (IE) Abstract In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. • Other epilepsy types Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for 1. 2 days dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition 2. 12 days • Start with Imepitoin to treating the underlying cause, if possible. Keywords: Dog, Epileptic seizure, Epilepsy, Treatment

Background drugs in Europe, and 3) reflects the authors’ experience. 3. 30 days • Recurrent single generalized epileptic seizures (IE) In Europe, the number of antiepileptic drugs (AEDs) li- With this paper it is aimed to provide a consensus for the censed for dogs has grown considerably over the last management of canine idiopathic epilepsy. Furthermore, years. Nevertheless, the same questions remain, which for the management of structural epilepsy AEDs are in- include, 1) when to start treatment, 2) which drug is best evitable in addition to treating the underlying cause, if 4. 90 days used initially, 3) which adjunctive AED can be advised if possible. treatment with the initial drug is unsatisfactory, and 4) At present, there is no doubt that the administration when treatment changes should be considered. In this of AEDs is the mainstay of therapy. In fact, the term • consensus proposal, an overview is given on the aim of AED is rather inappropriate as the mode of action of KBr AED treatment, when to start long-term treatment in most AEDs is to suppress epileptic seizures, not epilep- canine epilepsy and which veterinary AEDs are currently togenesis or the pathophysiological mechanisms of epi- in use for dogs. The consensus proposal for drug treatment lepsy. Perhaps, in the future, the term anti-seizure drugs • protocols, 1) is based on current published evidence-based might be more applicable in veterinary neurology, a term Add-on literature [17], 2) considers the current legal framework of that is increasingly used in human epilepsy. Additionally, the cascade regulation for the prescription of veterinary it is known that epileptic seizure frequency appears to International Veterinary Epilepsy Task Force – increase over time in a subpopulation of dogs with un- * Correspondence: [email protected] treated idiopathic epilepsy, reflecting the need of AED 1Department of Small Animal Medicine and Clinical Biology, Faculty of treatment in these patients [63]. Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke 9820, In our consensus proposal on classification and termin- Consensus Proposals Belgium Full list of author information is available at the end of the article ology we have defined idiopathic epilepsy as a disease in

© 2015 Bhatti et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Phenobarbitone (dog)– First line treatment

• Phenobarbitone (PB) When would you check Phenobarbitone • Dose ~2.5 mg/kg BID serum levels for the first time? • Peak serum concentration 4-8 hours (oral) • Half-life 24-40 hrs • Time to steady state 10-14 days 1. 2 days • Therapeutic range 15.0 – 35 µg/ml • Potential side effects Sedation, PU/PD, polyphagia, hepatotoxicity 2. 12 days • Metabolism liver 3. 30 days • Drug interaction Can alter serum levels of liver metabolised drugs • Obtain plasma level 14, 45, 90, 180, 360 d, then q 6m 4. 90 days • Loading dosage if indicated • 12 to 24 mg/kg total dose within 24 hours (equal dose q 30 min to 4 hrs to effect, i.e. no seizures)

SPC Epiphen®; Phenoleptil®

The peak and trough debate Phenobarbital – Side effects

• Rare but severe (idiosyncratic reactions): • Behavioural alterations • Immune-mediated neutropaenia, thrombocytopaenia, anaemia • Superficial, necrlolytic dermatitis • Idiosynchratic hepatotoxic reactions (rapid elevation of ALT and abnormal bile acids)

Action: stop drug immediately – load with another AED

• Withdrawal seizures (drug dependence) • How to stop?

Monteiro et al., 2009, Vet Record

Phenobarbital

Comparison of phenobarbital with bromide SMALL ANIMALS as a ﬁrst-choice antiepileptic drug for treatment of epilepsy in dogs

Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP; Curtis Dewey, DVM, MS, DACVS, DACVIM; David Mark Carpenter, PhD

Objective—To compare efficacy and safety of treatment with phenobarbital or bromide as the first-choice antiepileptic drug (AED) in dogs. Design—Double-blinded, randomized, parallel, clinical trial. Animals—46 AED-naïve dogs with naturally occurring epilepsy. Procedures—Study inclusion was based on age, history, findings on physical and neuro- logic examinations, and clinicopathologic test results. For either phenobarbital treatment (21 dogs) or bromide treatment (25), a 7-day loading dose period was initiated along with a maintenance dose, which was adjusted on the basis of monthly monitoring. Efficacy and safety outcomes were compared between times (baseline and study end [generally 6 months]) and between drugs. Results—Phenobarbital treatment resulted in eradication of seizures (17/20 [85%]) significantly more often than did bromide (12/23 [52%]); phenobarbital treatment also resulted in a greater percentage decrease in seizure duration (88 ± 34%), compared with bromide (49 ± 75%). Seizure activity worsened in 3 bromide-treated dogs only. In dogs with seizure eradication, mean ± SD serum phenobarbital concentration was 25 ± 6 µg/mL (phenobarbital dosage, 4.1 ± 1.1 mg/kg [1.9 ± 0.5 mg/lb], PO, q 12 h) and mean serum bromide concentration was 1.8 ± 0.6 mg/mL (bromide dosage, 31 ± 11 mg/kg [14 ± 5 mg/lb], PO, q 12 h). Ataxia, lethargy, and polydipsia were greater at 1 month for phenobarbital-treated dogs; vomiting was greater for bromide-treated dogs at 1 month and study end. Conclusions and Clinical Relevance—Both phenobarbital and bromide were reasonable first-choice AEDs for dogs, but phenobarbital was more effective and better tolerated during the first 6 months of treatment. (J Am Vet Med Assoc 2012;240:1073–1083)

ince the early 1990s, bromide (most commonly ad- ABBREVIATIONS Sministered as a potassium salt) has been used as an AED for the long-term management of epilepsy in AED Antiepileptic drug dogs.1–4 Increasingly, it is considered as an alternative CI Confidence interval to phenobarbital as the first-choice sole AED used for long-term control of epilepsy in dogs.5–8 Successful use of Each drug has its disadvantages. Both are associated with both phenobarbital and bromide is facilitated by a long polyuria, polydipsia, and polyphagia and the sequelae as- elimination half-life, which minimizes fluctuation in sociated with general sedation (eg, lethargy and ataxia), drug concentrations during a 12-hour dosing interval.7–11 adverse effects to which an animal may develop toler- Therapeutic drug monitoring is widely available and is ance.1,2,5–7,17 In addition, each has unique characteristics supported by canine (rather than human) therapeutic that complicate successful treatment. Long-term pheno- ranges as follows: serum phenobarbital concentrations of barbital treatment has been associated with hepatotox- 15 to 45 µg/mL7,12–14 and serum bromide concentrations icity, although a cause-and-effect relationship has not of 1 to 3 mg/mL (when used as a sole treatment).7,12–17 been proven.18–20 Phenobarbital also has been associated with unpredictable, idiosyncratic adverse drug reactions, From the Department of Anatomy, Physiology and Pharmacology, including pancytopenia,21,22 and drug interactions that College of Veterinary Medicine (Boothe) and the Department of reflect induction of selected hepatic drug-metabolizing Mathematics and Statistics, College of Sciences and Mathematics enzymes that target xenobiotics23–30 as well as endoge- (Carpenter), Auburn University, Auburn, AL 36849; and the De- 31,32 partment of Clinical Sciences, College of Veterinary Medicine, Cor- nous compounds. Induction of its own metabolism nell University, Ithaca, NY 14850 (Dewey). might result in a decrease in plasma drug concentrations This study was implemented at Texas A&M University’s Texas Vet- and therapeutic failure. In contrast, although renal ex- erinary Medical Center but included the participation of referral cretion of bromide limits hepatotoxicity or induction practitioners throughout the United States. of hepatic enzymes, its elimination half-life in dogs is Supported by the Canine Health Foundation and the American Ken- so long that several months of treatment must occur nel Club. Presented as a poster at the 20th American College of Veterinary In- with each change in dosage before steady-state con- 33,34 ternal Medicine Annual Forum, Dallas, May 2002. centrations (and thus maximum effect) are reached. Address correspondence to Dr. Boothe ([email protected]). Although this delay can be overcome by administration

JAVMA, Vol 240, No. 9, May 1, 2012 Scientiﬁc Reports 1073

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Bhatti et al. BMC Veterinary Research (2015) 11:176 Page 5 of 16

Bhatti et al. BMC Veterinary Research (2015) 11:176 Page 5 of 16 Bhatti et al. BMC Veterinary Research (2015) 11:176 Page 7 of 16 IVETF - Phenobarbitone IVETF - Imepitoin

Fig. 1 PB treatment flow diagram for decision making during seizure management in an otherwise healthy dog. The authors advise to start with PB (and add KBr if inadequate seizure control after optimal use of PB (Fig. 3)): in dogs with idiopathic epilepsy experiencing recurrent single generalised epileptic seizures; in dogs with idiopathic epilepsy experiencing cluster seizures or status epilepticus; in dogs with other epilepsy types. *Criteria for (in)adequate seizure control with regard to efficacy and tolerability (see Consensus proposal: Outcome of therapeutic interventions in canine and feline epilepsy [94]). 1. Treatment efficacious: a: Achievement of complete treatment success (i.e. seizure freedom or extension of the interseizure interval to three times the longest pretreatment interseizure interval and for a minimum of three months (ideally > 1 year); b: Achievement of partial treatment success (i.e. a reduction in seizure frequency including information on seizure incidence (usually at least 50 % or more reduction defines a drug responder), a reduction in seizure severity, or a reduction in frequency of seizure clusters and/or status epilepticus). 2. Treatment not tolerated i.e. appearance of severe adverse effects necessitating discontinuation of the AED to the individual patient based on seizure control, adverse and should be avoided [22, 75]. In case of inadequate seiz- effects and serum concentration monitoring. ure control, serum PB concentrations must be used to Because of considerable variability in the pharmaco- guide increases in drug dose. Dose adjustments can be cal- kinetics of PB among individuals, the serum concentra- culated according to the following formula (Formula A): tion should be measured 14 days after starting therapy Fig. 1 PB treatment flow diagram for decision making during seizure management in an otherwise healthy dog. The authors advise to start with (baseline concentration for future adjustments) or after New PB total daily dosage in mg PB (and add KBr if inadequate seizure control after optimal use of PB (Fig. 3)): in dogs with idiopathic epilepsy experiencing recurrent single a change in dose. To evaluate the effect of metabolic desired serum PB concentration=actual serum PB concentration generalised epileptic seizures; in dogs¼ ðÞ with idiopathic epilepsy experiencing cluster seizures or status epilepticus; in dogs with other epilepsy tolerance, a second PB serum concentration can be types. *Criteria for (in)adequate seizureactual control PB total with daily regarddosage in to mg efficacy and tolerability (see Consensus proposal: Outcome of therapeutic measured 6 weeks after initiation of therapy. Recom- Â interventions in canine and feline epilepsy [94]). 1. Treatment efficacious: a: Achievement ofBhatti completeet al. BMC treatment Veterinary Research success (2015) 11:176 (i.e. seizure freedom or Page 3 of 16 Fig. 2 Imepitoin treatment flow diagram for decision making during seizure management in anBhatti otherwiseet al. BMC healthy Veterinary dog. Research The authors (2015) 11:176 advise to Page 3 of 16 mendations on optimal timing of blood collection for extension of the interseizure intervalA dog to with three adequate times the seizure longest control, pretreatment but serum interseizure drug interval and for a minimum of three months (ideally > 1 start with imepitoin in dogs with idiopathic epilepsy experiencing recurrent single generalised epileptic seizures. *Criteria for (in)adequate seizure serum PB concentration monitoring in dogs vary among year); b: Achievement of partialconcentrations treatment success below (i.e. the a reduction reported in therapeutic seizure frequency range, including information on seizure incidence (usually at least control with regard to efficacy and tolerability (see Consensus proposal: Outcome of therapeutic interventions in canine and feline epilepsy [94]). studies [23]. Generally, serum concentrations50 % or more reduction can be definesdoes a notdrug require responder), alteration a reduction of the in seizure drug severity, dose, as or this a reduction in frequency of seizure clusters and/or status 1. Treatment efficacious: a: Achievement of complete treatment success (i.e. seizure freedom or extension of the interseizure interval to three checked at any time in the dosing cycle as the change serum concentration may be sufficient for that individ- Until recently, primary treatment options for dogs Br as a monotherapy, providing better seizure control times the longest pretreatment interseizure interval and for a minimum of three months (ideally >Until 1 year), recently, b: Achievement primary oftreatment partial treatment options for dogs Br as a monotherapy, providing better seizure control epilepticus). 2. Treatment not tolerated i.e. appearance of severe adverse effects necessitatingwith discontinuation epilepsy have focused of the mainly AED on phenobarbital (PB) and showing fewer side effects. success (i.e. a reduction in seizure frequency including information on seizure incidence (usually atwith least epilepsy 50 %have or more focused reduction mainly defines on phenobarbital a drug (PB) and showing fewer side effects. in PB concentrations through a daily dosing interval is ual. Generally, the desired serum AED concentration for and potassium bromide (KBr) due to their long standing and potassium bromide (KBr) due to their long standing responder), a reduction in seizure severity, or a reduction in frequency of seizure clusters and/or status epilepticus). 2. Treatment not tolerated i.e. not therapeutically relevant once steady-state has been individual patients should be the lowest possible concen- history, widespread availability, and low cost. While both Pharmacokinetics # history, widespread availability, and low cost. While both Pharmacokinetics appearance of severe adverse effects necessitating discontinuation of the AED. Currently there are no data available on which AED should be achieved [62, 70]. However, in dogs receiving a dose of tration associated with >50 % reduction in seizure fre- AEDs are still widely used in veterinary practice, several PB is rapidly (within 2h) absorbed after oral administra- AEDs are still widely used in veterinary practice, several PB is rapidly (within 2h) absorbed after oral administra- to the individual patient based on seizure control, adverse and should benewer avoided AEDs approved [22, 75]. for use In in case people of are inadequate also being tion seiz- in dogs, with a reported bioavailability of approxi- added to imepitoin in case of inadequate seizure control. At this moment, the authors recommendnewer the AEDs use of approved PB as adjunct for use AED in peoplein dogs are also being tion in dogs, with a reported bioavailability of approxi- 5 mg/kg BID or higher, trough concentrations were sig- quency or seizure-freedom and absence of intolerable used for the management of canine idiopathic epilepsy mately 90 % [2, 87]. Peak serum concentrations are receiving the maximum dose of imepitoin and experiencing poor seizure control used for the management of canine idiopathic epilepsy mately 90 % [2, 87]. Peak serum concentrations are nificantly lower than non-trougheffects concentrations and serum and concentrationadverse effects monitoring. [23]. ure control,mainly serum as add-on PB treatment.concentrations Moreover, since must early 2013,be usedachieved to approximately 4−8h after oral administration in mainly as add-on treatment. Moreover, since early 2013, achieved approximately 4−8h after oral administration in serum PB concentration monitoringBecause at the of same considerable time In animalsvariability with in cluster the seizures, pharmaco- status epilepticusguide increases or imepitoin in drug has been dose. introduced Dose in adjustments most European coun- can bedogs cal- [2, 97]. The initial elimination half-life in normal imepitoin has been introduced in most European coun- dogs [2, 97]. The initial elimination half-life in normal tries for the management of recurrent single generalized dogs has been reported to range from 37−73h after mul-cardiac, gastrointestinal or other disease. No idiosyncratic concentrations amongtries for the individuals management and of recurrent sampling single generalized times. dogs has been reported to range from 37−73h after mul- post-drug dosing was recommended, in order to allow kinetics of PB among individuals,high seizure thefrequency, serum PB concentra- can be administeredculated at according a epileptic to seizures the followingin dogs with idiopathic formula epilepsy. (Formula A):tiple oral dosing [96]. Plasma protein binding is approxi-reactions have been demonstrated so far. The routinely However, no correlationepileptic seizures between in dogs plasma with idiopathic imepitoin epilepsy. con- tiple oral dosing [96]. Plasma protein binding is approxi- accurate comparison of results intion these should dogs [70]. be Another measuredloading 14 days dose of after 15−20 starting mg/kg therapy IV, IM or PO divided in Several AEDs of the older generation approved for mately 45 % in dogs [36]. PB crosses the placenta andmeasured liver enzymes’ activity do not appear to be in- centration and seizureSeveral frequency AEDs of the reduction older generation was identified approved for mately 45 % in dogs [36]. PB crosses the placenta and study recommended performing serum PB concentration multiple doses of 3−5 mg/kg over 24−48h to obtain a humans have been shown to be unsuitable for use in can be teratogenic. humans have been shown to be unsuitable for use in can be teratogenic. (baseline concentration for future adjustments) or after New PB totaldogs daily asdosage most have in mg an elimination half-life that is too PB is metabolized primarily by hepatic microsomal en-duced by imepitoin [96]. Compared with the traditional [64] therefore anddogs because as most of have its an wide elimination therapeutic half-life that index, is too PB is metabolized primarily by hepatic microsomal en- monitoring on a trough sample as a significant difference therapeutic brain concentration quickly and then sustain short to allow convenient dosing by owners, these in- zymes and approximately 25 % is excreted unchanged inbenzodiazepines, such as diazepam, which acts as full ago- serum imepitoin monitoringshort to allow is convenient not needed. dosing by owners, these in- zymes and approximately 25 % is excreted unchanged in between peak and trough PB concentrationa change was in identified dose. Toit evaluate [10]. Serum the PB effect concentrations of metabolic can be measured 1desired−3 clude serum phenytoin, PB concentration carbamazepine,=actual valproic serum acid, and PB concentrationetho- the urine. There is individual variability in PB absorption, clude phenytoin, carbamazepine, valproic acid, and etho- the urine. There is individual variability in PB absorption, ¼ ðÞnists at the benzodiazepine site of the GABAA receptor, The authors recommend a complete blood cell count in individual dogs [10]. The therapeutictolerance, range a of second PB in PBdays serum after loading. concentration Some authors can load be as soon as possibleactual PBsuximide total daily [119]. dosage Some are in mg even toxic in dogs such as excretion and elimination half-life [2, 87, 97]. In dogs, PB suximide [119]. Some are even toxic in dogs such as excretion and elimination half-life [2, 87, 97]. In dogs, PB lamotrigine (the metabolite is cardiotoxic) [26, 136] and is a potent inducer of cytochrome P450 enzyme activity inpartial agonists such as imepitoin show less sedative ad- and biochemicallamotrigine profile before (the metabolite starting is cardiotoxic) imepitoin [26, treat- 136] and is a potent inducer of cytochrome P450 enzyme activity in serum is 15 mg/l to 40 mg/l in dogs. However, it is the au- Â measured 6 weeks after(over initiation 40 to 60 min) of therapy. and start withRecom- a loading dose of 10 vigabatrin (associated with neurotoxicity and haemolytic the liver [48], and this significantly increases hepatic pro-verse effects and are not associated with tolerance and ment and periodicallyvigabatrin every (associated 6 months with neurotoxicity during treatment. and haemolytic the liver [48], and this significantly increases hepatic pro- thors’ opinion that in the majoritymendations of dogs a serum on optimal PB totiming 12 mg/kg of IVblood followed collection by two further for bolusesA of dog 4 towith 6 anemia) adequate [113, 131, seizure 138]. control, but serumduction drug of reactive oxygen species, thus increasing the riskdependence during long-term administration in animal If the dog is in remissionanemia) [113, or 131, has 138]. no seizures, a periodical duction of reactive oxygen species, thus increasing the risk concentration between 25−30 mg/l is required for optimal mg/kg 20 min apart. Since the 1990s, new AEDs with improved tolerability, of hepatic injury [107]. Therefore PB is contraindicated in Since the 1990s, new AEDs with improved tolerability, of hepatic injury [107]. Therefore PB is contraindicated in serum PB concentration monitoring in dogs vary among concentrationsfewer below side effects the and reduced reported drug interaction therapeutic potential range,dogs with hepatic dysfunction. The induction of cyto-models [122]. Also in epileptic dogs, tolerance did not control every 12fewer months side effects is advised. and reduced drug interaction potential dogs with hepatic dysfunction. The induction of cyto- seizure control. Serum concentrations of more than 35 Complete blood cell count, biochemical profile (includ- studies [23]. Generally, serum concentrations can be does not requirehave been alteration approved for the of management the drug of epilepsy dose, in aschrome this P450 activity in the liver can lead to autoinductiondevelop and no withdrawal signs were observed after have been approved for the management of epilepsy in chrome P450 activity in the liver can lead to autoinduction mg/l are associated with an increased risk of hepatotoxicity ing cholesterol and triglycerides), and bile acid stimulation humans. Many of these novel drugs appear to be rela- or accelerated clearance of itself over time, also known astreatment discontinuation [64]. humans. Many of these novel drugs appear to be rela- or accelerated clearance of itself over time, also known as checked at any time in the dosing cycle as the change serum concentrationtively safe in dogs, may these be include sufficient levetiracetam, forthat zonisa- individ-metabolic tolerance, as well as endogenous compounds Bromide tively safe in dogs, these include levetiracetam, zonisa- metabolic tolerance, as well as endogenous compounds in PB concentrations through a daily dosing interval is ual. Generally,mide, the felbamate, desired topiramate, serum gabapentin, AED and concentration pregabalin. (such for as thyroid hormones) [40, 48]. As a result, with Efficacy mide, felbamate, topiramate, gabapentin, and pregabalin. (such as thyroid hormones) [40, 48]. As a result, with Pharmacokinetic studies on lacosamide [68] and rufina- chronic PB administration in dogs, its total body clearanceDose and monitoring (Fig. 2) Br is usually administeredPharmacokinetic as studies the potassium on lacosamide salt [68] and (KBr). rufina- chronic PB administration in dogs, its total body clearance not therapeutically relevant once steady-state has been individual patientsmide [137] should support the be potential the lowest use of these possible drugs in concen-increases and elimination half-life decreases progressivelyThe oral dose range of imepitoin is 10−30 mg/kg BID. mide [137] support the potential use of these drugs in increases and elimination half-life decreases progressively dogs, but they have not been evaluated in the clinical which stabilizes between 30 45 days after starting therapy The sodium saltdogs, form but (NaBr) they have contains not been more evaluated Br per in the gram clinical which stabilizes between 30 45 days after starting therapy − When Thedoes recommended safe oral startingsailing dose of imepitoinbecomes is 10−20 a titanic experience? − achieved [62, 70]. However, in dogs receiving a dose of tration associatedsetting. Although with these >50 newer % reduction drugs have gained in consid- seizure[97]. fre- This can result in reduction of PB serum concen- of compound, therefore,setting. Although the these dose newer should drugs have be gained approxi- consid- [97]. This can result in reduction of PB serum concen- 5 mg/kg BID or higher, trough concentrations were sig- quency or seizure-freedomerable popularity in the management and absence of canine of epilepsy, intolerabletrations and therapeutic failure and therefore, monitor-mg/kg BID. If seizure control is not satisfactory after at erable popularity in the management of canine epilepsy, trations and therapeutic failure and therefore, monitor- scientific data on their safety and efficacy are very lim- ing of serum PB concentrations is very important forleast 1 week of treatment at this dose and the medica- mately 15 % lessscientific than that data on calculated their safety forand efficacyKBr [124]. are very In lim- ing of serum PB concentrations is very important for nificantly lower than non-trough concentrations and adverse effectsited [23]. and cost is often prohibitive. dose modulation over time. tion is well tolerated, the dose can be increased up to a most EU countries,ited and KBr cost is often approved prohibitive. only for add-on dose modulation over time. One month later the dog had 4 seizures. A parenteral form of PB is available for intramuscular treatment in dogs with epilepsy drug-resistant to first- A parenteral form of PB is available for intramuscular serum PB concentration monitoring at the same time In animalsPhenobarbital with cluster seizures, status epilepticus(IM) or intravenous (IV) administration. Different PBmaximum of 30 mg/kg BID. Reference range of plasma Phenobarbital (IM) or intravenous (IV) administration. Different PB post-drug dosing was recommended, in order to allow high seizureEfficacy frequency, PB can be administeredformulations at a are available in different countries, it shouldor serum imepitoin concentrations is unknown and line AED therapy.Efficacy PB and KBr have a synergistic effect formulations are available in different countries, it should What do you want to do now?PB has the longest history of chronic use of all AEDs in be emphasized, however, that IM formulations cannot be and add-on treatmentPB has the with longest KBr history in of epileptic chronic use dogs of all AEDs im- in be emphasized, however, that IM formulations cannot be accurate comparison of results in these dogs [70]. Another loading dose of 15−20 mg/kg IV, IM or PO divided in there are no therapeutic monitoring recommendations veterinary medicine. After decades of use, it has been used IV and vice versa. Parenteral administration of PBfor is imepitoin from the manufacturer. Pharmacokinetic proves seizure controlveterinary in medicine. dogs that After are decades poorly of use,controlled it has been used IV and vice versa. Parenteral administration of PB is study recommended performing serum PB concentration multiple dosesapproved of 3in− 20095 mg/kg for the prevention over 24 of seizures−48h caused to obtainuseful for a administering maintenance therapy in hospital- approved in 2009 for the prevention of seizures caused useful for administering maintenance therapy in hospital- by generalized epilepsy in dogs. PB has a favourable ized patients that are unable to take oral medication. Thestudies in dogs suggest variability in plasma imepitoin with PB alone [46,by 93,generalized 126]. epilepsyA recent in dogs. study PB showed has a favourable that ized patients that are unable to take oral medication. The monitoring on a trough1. sampleCheck as a significant serum differencelevelstherapeutic(PB)? brainpharmacokinetic concentration profile and is quickly relatively safe and [2, 87, then 97]. sustainpharmacokinetics of IM PB have not been explored in pharmacokinetic profile and is relatively safe [2, 87, 97]. pharmacokinetics of IM PB have not been explored in between peak and trough PB concentration was identified it [10]. SerumPB seems PB toconcentrations be effective in decreasing can seizure be measuredfrequency dogs, 1− however,3 studies in humans have shown a similar PB seems to be effective in decreasing seizure frequency dogs, however, studies in humans have shown a similar in approximately 60−93 % of dogs with idiopathic epi- absorption after IM administration compared to oral ad- in approximately 60−93 % of dogs with idiopathic epi- absorption after IM administration compared to oral ad- in individual dogs [10].2. TheAdd therapeutic potassium range of PBbromide in days afteror loading.lepsyanother when Some plasma authorsconcentrations load are maintained as soon within as possibleministration [135]. The elimination half-life in dogs after a lepsy when plasma concentrations are maintained within ministration [135]. The elimination half-life in dogs after a the therapeutic range of 25−35 mg/l [10, 31, 74, 105]. single IV dose is approximately 93h [87]. the therapeutic range of 25−35 mg/l [10, 31, 74, 105]. single IV dose is approximately 93h [87]. serum is 15 mg/l to 40 mg/l inantiepileptic dogs. However, it isdrug the au- ? (over 40 to 60According min) to and Charalambous start with et al. (2014) a loading [17], there dose is of 10 According to Charalambous et al. (2014) [17], there is thors’ opinion that in the majority of dogs a serum PB to 12 mg/kgoverall IV followed good evidence by for two recommending further the boluses use of PB of 4Pharmacokinetic to 6 interactions overall good evidence for recommending the use of PB Pharmacokinetic interactions 3. Refer to a neurologist? as a monotherapy AED in dogs with idiopathic epilepsy. In dogs, chronic PB administration can affect the dispos- as a monotherapy AED in dogs with idiopathic epilepsy. In dogs, chronic PB administration can affect the dispos- concentration between 25−30 mg/l is required for optimal mg/kg 20 minMoreover, apart. the superior efficacy of PB was demonstrated ition of other co-administered medications which are me- Moreover, the superior efficacy of PB was demonstrated ition of other co-administered medications which are me- seizure control. Serum concentrations of more than 35 Complete bloodin a randomized cell count, clinical trial biochemical comparing PB to profile bromide (includ-tabolized by cytochrome P450 subfamilies and/or bound in a randomized clinical trial comparing PB to bromide tabolized by cytochrome P450 subfamilies and/or bound 4. Repeat the neurological exam(Br) as first-line? AED in dogs, in which 85 % of dogs ad- to plasma proteins [48]. PB can alter the pharmacokinetics (Br) as first-line AED in dogs, in which 85 % of dogs ad- to plasma proteins [48]. PB can alter the pharmacokinetics mg/l are associated with an increased risk of hepatotoxicity ing cholesterolministered and triglycerides), PB became seizure-free and for bile 6 months acidcom- stimulationand as a consequence may decrease the therapeutic ef- ministered PB became seizure-free for 6 months com- and as a consequence may decrease the therapeutic ef- 5. Ask for a video of the seizurespared with? 52 % of dogs administered Br [10]. This fect of other AEDs (levetiracetam, zonisamide, and ben- pared with 52 % of dogs administered Br [10]. This fect of other AEDs (levetiracetam, zonisamide, and ben- study demonstrated a higher efficacy of PB compared to zodiazepines) as well as corticosteroids, cyclosporine, study demonstrated a higher efficacy of PB compared to zodiazepines) as well as corticosteroids, cyclosporine,

Packer et al. BMC Veterinary Research (2015) 11:25 DOI 10.1186/s12917-015-0340-x

When should a second AED be started? RESEARCH ARTICLE Open Access Assessment into the usage of levetiracetam in a • Strict criteria for decision-making strategy canine epilepsy clinic • ACVIM Panel Recommendations: Rowena MA Packer, George Nye†, Sian Elizabeth Porter† and Holger A Volk* on starting a second AED is lacking in • Documentation of appropriate drug and A All dogs C Maintenance E Pulse veterinary medicine 25Abstract* * 25 * * 25 * maximal level of first AED for a minimum of 3 Background: Retrospective studies can complement information derived from double-blinded randomized trials. 20 20 20 h h h t t There are multiple retrospective studies reportingt good efficacy and tolerability of the anti-epileptic drug levetiracetam n n n o • months o o

Risk factors associated with poorer seizure m m m

/ / /

(LEV) in human patients with epilepsy; however, reports of LEV's tolerability and efficacy in dogs with epilepsy remain

y 15

y 15 y 15 c c c n n n e e e u

u limited. The purpose of this retrospective studyu was to describe the use of LEV in a canine epilepsy clinic and determine q q q e

• e e r

> 50% increase in seizure frequency over 3 r r f

control include male dogs and prior cluster f f

e 10 e 10the long-term efficacy and tolerability of LEVe in10 veterinary clinical practice. The electronic database of a UK based r r r u u u z z z i i i e e referral hospital was searched for LEV usage ine dogs with seizures. Information and data necessary for the evaluation S seizure activity months S S 5were obtained from a combination of electronic and5 written hospital records, the referring veterinary surgeons5 ’ records • and telephone interviews with dog owners. Only dogs that were reportedly diagnosed with idiopathic epilepsy were • (Packer et al. 2014) New onset of status epilepticus 0included in the study. 0 0 LEV LEV LEV Results: Fifty-twoPrior LEV dogs were included in this retrospective study.Prior LEV Two treatment protocols were recognised; 29 dogsPrior LEV • New onset of cluster seizures Prior treatment Prior treatment Prior treatment • Factors to consider were treated continuously with LEV and 23 dogs received interval or pulse treatment for cluster seizures. LEV treatment • Presence of drug-toxicity B resulted in 69% of dogs having a 50% or greaterD reduction of seizure frequency whilst 15% of allF the dogs were 25completely free from seizures. Seizure frequency reduced25 significantly in the whole population. No dog25 was reported • Selection of an AED with a different to experience life-threatening* side effects. Mild side effects were* experienced by 46% of dogs and a significantly higher number of these dogs were in the pulse treatment group. The most common side-effects reported were sedation and 20 20 20 mechanism of action ataxia. h h h t t t n n n o Conclusions: LEV appears to be effective ando well tolerated for reduction of seizures. o m 15 m 15 m 15

/ / /

• Minimizing drug-drug interactions, avoiding s s s y y y a a a d

Keywords: Dog, Safety, Seizure, Tolerability, Treatmentd d

e e e r r r u 10 u 10 u 10

additive toxicity z z z i i i e e e S S S Background drugs (AED) have been developed in the last two de- • Determination of risk-benefit of Double-blinded,5 randomized controlled clinical trials5 to cades in human medicine, which have5 similar efficacy establish efficacy and safety of novel AEDs are of pivotal but are safer and better tolerated than older AEDs [3-5]. polypharmacy versus quality of life 0 importance, but are not without limitations due to0 their One such drug is levetiracetam (LEV),0 for which there LEV. LEV LEV

often strict dosingPrior LEV. and entry requirements, reducing are multiplePrior LEV clinical observational studies reportingPrior LEV theirPrior treatment. applicability to the wider population, e.g. geriatricPrior treatment good efficacy and tolerability in humanPrior treatment patients with patients or those with multiple co-occurring conditions. epilepsy [1,6-8]. In studies of epilepsy treatment in humans post-marketing Some of the new AEDs in humans, such as gabapentin, studies assessing the clinical use of a drug deemed an pregabalin, zonisamide and levetiracetam have been important tool, with the most valuable data on efficacy trialled in dogs with poorly controlled seizures with and safety thought to be obtained from prospective and variable success [9-15]. LEV, a structurally novel AED, retrospective studies that are monocentric, and gather is one of the more promising AEDs for canine epilepsy. information on long-term anti-epileptic drug therapy in LEV seems to act by a unique mechanism; modulation a single centre only [1,2]. Multiple new anti-epileptic of synaptic release of neurotransmitters by binding to the synaptic vesicle protein 2A (SV2A) [16,17]. In addition to * Correspondence: [email protected] its seizure-suppressing activity, previous experiments in † Equal contributors chronic epilepsy models in rodents suggested that LEV Department of Clinical Science and Services, Royal Veterinary College, Hatfield AL97TA, UK

© 2015 Packer et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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ACVIM Panel Grade of Recommendations Potassium bromide – (Level of Evidence) for Add-On AED Therapy add on/first line (not in cats)

• Potassium bromide (KBr) • Dose 30-40 mg/kg SID • Half-life 15-20 days A (HIGH) B (MODERATE) C (LOW) D (NO) • Time to steady state 100-200 days • Therapeutic range 0.7 – 1.9 mg/ml/2.3 mg/ml • Levetiracetam • Imepitoin (III) • Primidone (II) • Side effects sedation, weakness, PU, PD, GI irritation, (IB) (pancreatitis) • Bromide (II) • Excretion renal • Obtain plasma level 4 wks, 8-12 wks, then q 6m • Zonisamide (III) • Loading dosage if indicated • Phenobarbital • 600 mg/kg (equal doses over 6 days )+ maintenance dose (IV)

Bhatti et al. BMC Veterinary Research (2015) 11:176 Page 9 of 16 IVETF – Add-on Potassium Bromide Potassium bromide

• Potassium bromide – dose adjustment • Full oral dose in mg/kg/day = (Desired conc / Actual conc) X current dose

• Dietary effect • High chloride diet lower serum concentration

• Bromide toxicity (rare) • Severe ataxia, sedation, somnolence; skin reactions • E.g. dogs with renal insufficiency (reduced elimination) Action: i.v. saline to enhance renal excretion

Fig. 3 KBr adjunct treatment flow diagram for decision making during seizure management in an otherwiseBhatti healthyet al. dog.BMC Veterinary *Criteria Researchfor (in)adequate (2015) 11:176 Page 3 of 16 seizure control with regard to efficacy and tolerability (see Consensus proposal: Outcome of therapeutic interventions in canine and feline epilepsy [94]). 1. Treatment efficacious: a: Achievement of complete treatment success (i.e. seizure freedom or extension of the interseizure interval to three times the longest pretreatment interseizure interval and for a minimum of three months (ideally > 1 year), b: Achievement of partial treatment success (i.e. a reduction in seizure frequency including information on seizure incidence (usually at least 50 % or moreUntil reduction recently, defines primary a drug responder), treatmenta options for dogs Br as a monotherapy, providing better seizure control reduction in seizure severity, or a reduction in frequency of seizure clusters and/or status epilepticus). 2. Treatmentwith epilepsy not tolerated have focused i.e. appearan mainlyce ofon phenobarbital (PB) and showing fewer side effects. severe adverse effects necessitating discontinuation of the AED and potassium bromide (KBr) due to their long standing history, widespread availability, and low cost. While both Pharmacokinetics AEDs are still widely used in veterinary practice, several PB is rapidly (within 2h) absorbed after oral administra- KBr is used as adjunct AED to PB may be more prone to discussed in the followingnewer section AEDs approved are approved for use forin people treat- are also being tion in dogs, with a reported bioavailability of approxi- used for the management of canine idiopathic epilepsy mately 90 % [2, 87]. Peak serum concentrations are adverse effects. In these cases, a PB dose decrease of 25 % ment of dogs with epilepsy,mainly as thus, add-on according treatment. to Moreover, EU drug since early 2013, achieved approximately 4−8h after oral administration in may be needed. Serum KBr levels should be monitored 1 laws, these drugs canimepitoin only be has used been as introduced adjunctive in most treat- European coun- dogs [2, 97]. The initial elimination half-life in normal month after loading. ment if monotherapytries orpolytherapy for the management with ofthe recurrent approved single generalized dogs has been reported to range from 37−73h after mul- Dose increases can be calculated according to the fol- treatments have failed.epileptic Furthermore, seizures in except dogs with for idiopathic levetirac- epilepsy. tiple oral dosing [96]. Plasma protein binding is approxi- lowing formula etam, none of the AEDsSeveral discussed AEDs inof the older following generation sec- approved for mately 45 % in dogs [36]. PB crosses the placenta and humans have been shown to be unsuitable for use in can be teratogenic. Formula B: tion have been evaluateddogs in as randomized most have an controlled elimination trialshalf-life that is too PB is metabolized primarily by hepatic microsomal en- For concomitant PB and KBr treatment, the new main- in epileptic dogs, so thatshort the to evidence allow convenient for their dosing efficacy by owners, is these in- zymes and approximately 25 % is excreted unchanged in tenance dose can be calculated as follows: very limited [17]. clude phenytoin, carbamazepine, valproic acid, and etho- the urine. There is individual variability in PB absorption, suximide [119]. Some are even toxic in dogs such as excretion and elimination half-life [2, 87, 97]. In dogs, PB 2000 mg=l ‐ actual serum KBr steady‐state concentration 0:02 lamotrigine (the metabolite is cardiotoxic) [26, 136] and is a potent inducer of cytochrome P450 enzyme activity in ðÞÂLevetiracetam vigabatrin (associated with neurotoxicity and haemolytic the liver [48], and this significantly increases hepatic pro- mg=kg=day added to existing dose ¼ So far, three studies evaluatedanemia) [113, the 131, efficacy 138]. of levetirace- duction of reactive oxygen species, thus increasing the risk tam as an adjunct to otherSince the AEDs 1990s, [79, new 114, AEDs 127]. with improved In all tolerability, of hepatic injury [107]. Therefore PB is contraindicated in Formula C: these studies, the majorityfewer side of the effects dogs and were reduced treated drug interaction suc- potential dogs with hepatic dysfunction. The induction of cyto- In case of monotherapy KBr, the new maintenance have been approved for the management of epilepsy in chrome P450 activity in the liver can lead to autoinduction cessfully by oral levetiracetam as adjunct AED. The use dose can be calculated as follows: humans. Many of these novel drugs appear to be rela- or accelerated clearance of itself over time, also known as of oral levetiracetamtively was safe evaluated in dogs, these in an include open-label levetiracetam, zonisa- metabolic tolerance, as well as endogenous compounds 2500 mg=l − actual serum KBr steady−state concentration study and a responsemide, rate offelbamate, 57 % was topiramate, reported gabapentin, in dogs and pregabalin. (such as thyroid hormones) [40, 48]. As a result, with ðÞPharmacokinetic studies on lacosamide [68] and rufina- chronic PB administration in dogs, its total body clearance 0:02 mg=kg=day added to existing dose with drug resistant epilepsy [127]. In a recent random- Â ¼ ized placebo-controlledmide study [137] by support Muñana the potential et al.use (2012) of these drugs in increases and elimination half-life decreases progressively dogs, but they have not been evaluated in the clinical which stabilizes between 30−45 days after starting therapy Only PB and imepitoin are approved as first-line treat- [79], the use of levetiracetamsetting. Although was evaluated these newer in drugs dogs have with gained consid- [97]. This can result in reduction of PB serum concen- Other AEDs ment of canine epilepsy in the EU. In most EU coun- drug resistant epilepsy.erable A significant popularity in decrease the management in seizure of canine epilepsy, trations and therapeutic failure and therefore, monitor- tries, KBr is only approved as add-on treatment in dogs frequency was reportedscientific compared data on with their baseline, safety and however, efficacy are very lim- ing of serum PB concentrations is very important for resistant to first-line treatments. None of the drugs no difference was detectedited and cost in seizure is often prohibitive. frequency when dose modulation over time. A parenteral form of PB is available for intramuscular Phenobarbital (IM) or intravenous (IV) administration. Different PB •Felbamate Efficacy formulations are available in different countries, it should PB has the longest history of chronic use of all AEDs in be emphasized, however, that IM formulations cannot be •1 clinical study (N= 6) (III) veterinary medicine. After decades of use, it has been used IV and vice versa. Parenteral administration of PB is approved in 2009 for the prevention of seizures caused useful for administering maintenance therapy in hospital- •6/6 with > 50% reduction for 6 months (CP seizures) by generalized epilepsy in dogs. PB has a favourable ized patients that are unable to take oral medication.Insufficient The Data •Gabapentin pharmacokinetic profile and is relatively safe [2, 87, 97]. pharmacokinetics of IM PB have not been explored in PB seems to be effective in decreasing seizure frequency dogs, however, studies in humans have shown a similar •2 clinical studies N=25 (III) in approximately 60−93 % of dogs with idiopathic epi- absorption after IM administration compared to oralfor ad- Treatment lepsy when plasma concentrations are maintained within ministration [135]. The elimination half-life in dogs after a •11/25 with > 50% reduction for 3 or 4 months the therapeutic range of 25−35 mg/l [10, 31, 74, 105]. single IV dose is approximately 93h [87]. According to Charalambous et al. (2014) [17], there is Recommendations •Pregabalin overall good evidence for recommending the use of PB Pharmacokinetic interactions as a monotherapy AED in dogs with idiopathic epilepsy. In dogs, chronic PB administration can affect the dispos- •1 clinical study (n =9) (III) Moreover, the superior efficacy of PB was demonstrated ition of other co-administered medications which are me- •7/9 with > 50% reduction for 3 months in a randomized clinical trial comparing PB to bromide tabolized by cytochrome P450 subfamilies and/or bound (Br) as first-line AED in dogs, in which 85 % of dogs ad- to plasma proteins [48]. PB can alter the pharmacokinetics •Topiramate ministered PB became seizure-free for 6 months com- and as a consequence may decrease the therapeutic ef- pared with 52 % of dogs administered Br [10]. This fect of other AEDs (levetiracetam, zonisamide, and ben- •1 clinical study (n =10) (III) study demonstrated a higher efficacy of PB compared to zodiazepines) as well as corticosteroids, cyclosporine, •5/10 dogs with > 50% reduction for 6-15 months •Lacosamide •No clinical studies •Rufinamide •No clinical studies

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S. Shorvon / Epilepsy & Behavior 32 (2014) 1–8 3

Table 1 temporal lobe epilepsy (1956; see Shorvon [8]). Advances in clinical The seventeen categories of brain lesions causing symptomatic epilepsy listed by Dandy [7]. chemistry and the understanding of metabolic disease in the prewar Congenital malformation and maldevelopment, either general or focal and postwar years also identified some of the inherited metabolic Tumors causes of epilepsy, a paradigm being the identification of phenylketon- Abscesses uria (PKU) by Ivar Asbjørn Følling in 1934 (see Christ [9]). Tubercles Gummata Aneurysms 1.2.2. The multifactorial nature of causation of epilepsy Syphilis with or without demonstrable gummata or vascular occlusions The most important writer on the causes of epilepsy in this period Areas of cerebral degeneration and calcification was WG Lennox. Although Lennox was primarily interested in idiopath- Depressed fractures ic epilepsy, his greatest contribution, in my view, to the theory of causa- Hamartomata Foreign bodies tion was to rediscover and update the nineteenth century concept of the Injuries from trauma at birth or subsequently (focal or general) multifactorial nature of etiology [10]. He recognized that there was, in Connective tissue formation after trauma most cases, a combination of genetic acquired and precipitating causes. Atrophy of the brain after trauma His famous analogies of the ‘river’ and ‘reservoir’ are shown in Fig. 1. 8 S. ShorvonThrombosis / Epilepsy and embolism & Behavior 32 (2014) 1–8 Despite this fact, he tended to divide epilepsy into genetic, acquired, Cerebral arteriosclerosis Sequelae of obscure inflammatory processes including encephalitis and sympathetic categories (in the latter category, following Reynolds), factors [20]. The term acute provoked seizure can be used for the latter Acknowledgment based on what he considered their predominant cause. His acquired category of seizures, as has been anyway in use for over 100 years. OneHealth This paper is based on the Distinguished Epileptologist Lecture given at the 6th Cleveland International Epilepsy Symposium in May 2013. 8. Points to consider in future work The invitation to give the lecture was from Dr. Samden Lhatoo, and I gratefully acknowledge his support and assistance. The ideas for this It can be seen from the above that the concept of ‘symptomatic’ ep- lecture and paper are partly reproduced from the author's contributions ilepsy is complex. In future work, the following points might be to the book, The Causes of Epilepsy [12], and other papers [11,21]. considered:

Disclosure 1. In considering cause in epilepsy, it would be better to refer to ‘causal factors’ and to use risk factor methodologies (odd ratios; i.e., suscep- I confirm that I have no conflict of interest to declare in relation to tibilities) to provide a firm statistical basis of the strength of the this paper. I confirm that I have read the Journal's position on issues in- ‘causal factor’. This might obviate the need to divide into categories Evidence volved in ethical publication and affirm that this report is consistent (idiopathic/symptomatic, etc.). However, for the time being, al- with these guidelines. though artificial, such categorization is necessary clinically to bring order (see, for instance, Hughlings Jackson's distinction between the botanist's and the gardener's type of classification). References

2. A greater focus on the proximate causes (molecular causal factors) [1] Sieveking E. Epilepsy and epileptiform seizures: their causes, pathology and treat- than the remote causes (downstream pathologies) might lead to a ment. London: John Churchill; 1858. more rational classification than our current rather empirical schemes. [2] Spratling W. Epilepsy and its treatment. London, Philadelphia, New York: WB Saunders & Co; 1904. This would be the sort of paradigm shift which would justify the adop- [3] Reynolds JR. Epilepsy: its symptoms, treatment and relation to other chronic convul- tion of new classification schemes. sive diseases. London: Churchill; 1861. Owner’s 3. A binary division of causes into idiopathic/symptomatic epilepsies [4] Taylor J. Selected writings of John Hughlings Jackson, vol. 1. London: Hodder and fails to recognize the importance of ‘provoking’ factors (the ‘exciting’ Stoughton; 1930 162–72. Clinical understanding [5] Gowers W. A manual of diseases of the nervous system. London: Churchill; 1888. factors of the nineteenth century). These factors are often as impor- [6] Gowers W. Epilepsy and other chronic convulsive disorders. London: Churchill; Expertise and value tant a cause as any symptomatic or idiopathic causal factor. Although 1881. most epilepsies have contributions from genetic, symptomatic, [7] Dandy WE. The practice of surgery. The brain. In: Lewis D, editor. The practice of system surgery, vol. XII. Connecticut: Prior WF; 1932. and provoking causes, to have a separate category of ‘provoked’ [8] Shorvon SD. An episode in the history of temporal lobe epilepsy: the quadrennial epilepsy at least emphasizes the importance of the latter category. meeting of the ILAE in 1953. Epilepsia 2006;47:1288–91. 4. It is now possible to list the remote causal factors in symptomatic ep- [9] Christ SE. Asbjørn Følling and the discovery of phenylketonuria. J Hist Neurosci 2003;12:44–54. ilepsy. It is likely that all or almost all of the structural and monogenic Fig. 1. a. The multifactorial concept[10] ofLennox epilepsy — WG,the analogy Lennox of the M. river Epilepsy of causal and factors related from Lennox disorders. and Lennox Boston:[10]. “ LittleThe genetic Brown; watershed 1960. is represented as three generations: par- metabolic disorders have been recognized. However, itents, is grandparents, also likely and great grandparents[11] Wilson [e.g.,SAK. at A, a Neurology.paternal grandmother London: has epilepsy].Edward A Arnold; confluence 1940. of transmitted traits follows into (and through) the patient …. In addition to these branching streams, there is an[12] independentShorvon stream SD, which Andermann rises in a lake F,Guerrini (the uterus). R, The editors. outlet is The the causesbirth canal of and epilepsy: below that common are contributing and streams: infections [e.g., at B, a viral that when there are new investigatory modalities, especially in rela- fl encephalitis], brain trauma from diverseuncommon sources, brain causes tumor, and inadults circulatory and disorders. children. This side Cambridge: stream enters Cambridge the main stream University at the patient Press; level and combines with the genetic in u- tion to molecular mechanisms, new ‘causes’ will be recognized.ences which had travelled through three generations to make him have epilepsy. There is then a third stream which enters below the confluence of the two main streams. This represents transient conditions which may precipitate2011. certain seizures in a person already having epilepsy or “all set” to be. This evoking circumstance may be physiologic (say at C, hypoglycemia) or 5. Idiopathic epilepsy is not simply ‘genetic’. There are inemotionalfluences (say from at D, a broken wedding[13] Shorvon engagement) SD.”. The b. The etiologic epileptic threshold classification— the analogy of epilepsy. of the reservoir Epilepsia from Lennox 2011;52(6):1052 and Lennox. “Causes–7. may be represented as the sources of a fl reservoir. At the bottom is the[14] alreadyJohnson present volume MR, ofShorvon water, which SD. represents Heredity the in person's epilepsy: predisposition, neurodevelopment, a fundamental cause. comorbidity, However, the reservoir is supplied also by streams neurodevelopment (the in uence of the dimension of time) and fl which represent the contributory conditions,and the such neurological as lesions of the trait. brain Epilepsy acquired since Behav conception, 2011;22(3):421 certain disorders–7. of bodily function, and emotional disturbances. Periodic over ow fl of the bank represents a seizure”. chance and epistatic and epigenetic in uences. These mechanisms [15] Aird RB, Gordon NS. Some excitatory and inhibitory factors involved in the epileptic require further investigation. state. Brain Dev 1993;15:299–304. 6. The term acute symptomatic seizure in its current form should be [16] Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Re- either abandoned or redefined. It should not include both the early vised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia seizures in acute brain insults (head injury, stroke, etc.)andseizures 2010;51:676–85. due to reversible provoking factors (fever, metabolic disturbance, [17] Shorvon SD. New terminologies: the downsides. Epilepsia 2013;54(6):1134. drugs, toxins, etc.). If it is retained, a more consistent approach to [18] Annegers JF, Hauser WA, Lee J, Rocca WA. Incidence of acute symptomatic seizures fi in Rochester Minnesota, 1935–1984. Epilepsia 1995;36:327–33. de ning criteria is needed. [19] Hauser W, Beghi E, Carpi A, Fosgren L, Hesdorffer D, Malmgren K, et al. Recommen- 7. In relation to etiology, the new ILAE classification scheme has not fully dations for a definition of acute symptomatic seizure. Epilepsia 2010;51:671–5. accounted for many of the complexities in defining cause. The [20] Shorvon S, Guerrini R. Acute symptomatic seizures—should we retain the term? Epilepsia 2010;51(4):722–3. renaming of idiopathic as genetic, symptomatic as structural/metabolic, [21] Shorvon SD. The causes of epilepsy: changing concepts of etiology of epilepsy over and cryptogenic as unknown should be reconsidered. the past 150 years. Epilepsia 2011;52(6):1033–44.

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Compliance

• Overall median compliance is 56.4% • 33% -> compliance rate of >80% • 21.3% -> 100% compliance • During a non-compliant prescription cycle, a patient will miss a median of 6 days of treatment.

Response Median compliance P- Compliance factors percentage (range) Value One medication 50% (0-100) (n=70) 0.031 Number of medications Two medications 75% (0-100) (n=24) One or less tablets 64.8% (0-100) (n=14) Number of tablets per day 0.61 1.5 or more tablets 56.4% (0-100) (n=80) Insured (n=15) 70% (0-100) Insurance 0.98 13.08.19 47 Not Insured (n=79) 55.6% (0-100)

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What next in canine epilepsy research?

A randomised trial of a medium-chain TAG diet as treatment for dogs with idiopathic epilepsy

Tsz Hong Law1,2, Emma S. S. Davies1, Yuanlong Pan3, Brian Zanghi3, Elizabeth Want2 and Holger A. Volk1* 1Department of Clinical Science and Services, Royal Veterinary College, Hatﬁeld AL9 7TA, UK 2Section of Computational and Systems Medicine, Imperial College, London SW7 2AZ, UK 3Nestlé Purina Research, St Louis, MO 63164, USA

(Submitted 20 April 2015 – Final revision received 16 July 2015 – Accepted 21 July 2015)

Abstract Despite appropriate antiepileptic drug treatment, approximately one-third of humans and dogs with epilepsy continue experiencing seizures, emphasising the importance for new treatment strategies to improve the quality of life of people or dogs with epilepsy. A 6-month prospective, randomised, double-blinded, placebo-controlled cross-over dietary trial was designed to compare a ketogenic medium-chain TAG diet (MCTD) with a standardised placebo diet in chronically antiepileptic drug-treated dogs with idiopathic epilepsy. Dogs were fed either MCTD or placebo diet for 3 months followed by a subsequent respective switch of diet for a further 3 months. Seizure frequency, clinical and laboratory data were collected and evaluated for twenty-one dogs completing the study. Seizure frequency was significantly lower when dogs were fed the MCTD (2·31/month, 0–9·89/month) in comparison with the placebo diet (2·67/month, 0·33–22·92/month, P = 0·020); three dogs achieved seizure freedom, seven additional dogs had ≥50 % reduction in seizure frequency, five had an overall <50 % reduction in seizures (38·87 %, 35·68–43·27 %) and six showed no response. Seizure day frequency were also significantly lower when dogs were fed the MCTD (1·63/month, 0–7·58/month) in comparison with the placebo diet (1·69/month, 0·33–13·82/month, P = 0·022). Consumption of the MCTD also resulted in significant elevation of blood β-hydroxybutyrate concentrations in comparison with placebo diet (0·041 (SD 0·004) v. 0·031 (SD 0·016) mmol/l, P = 0·028). There were no significant changes in serum concentrations of glucose (P = 0·903), phenobarbital (P = 0·422), potassium bromide (P = 0·404) and weight (P = 0·300) between diet groups. In conclusion, the data show antiepileptic properties associated with ketogenic diets and provide evidence for the efficacy of the MCTD used in this study as a therapeutic option for epilepsy treatment.

Key words: Epilepsy: Ketogenic diets: Medium-chain TAG: Seizures

Epilepsy is a common chronic neurological disorder in humans treatment, approximately one-third of dogs and humans with and dogs, with an estimated prevalence in dogs of 1–2%(1) in idiopathic epilepsy continue to experience seizures that are a referral hospital population and 0·6%(2) in first-opinion difficult to control(9–11). Furthermore, AED-related side-effects practice. Higher prevalences up to 18 %(3) have been reported such as ataxia, polyphagia, polyuria, polydipsia and incontinence in breed-specific studies with up to 33 % seen in certain in dogs as well as behavioural, sedative, cognitive or psychiatric families(4). Epilepsy is characterised by recurrent epileptic adverse reactions in humans also contribute to reduction in seizures caused by abnormal, excessive, synchronous neuronal QoL(12,13). This emphasises the importance of new treatment firing patterns(5). Epilepsy has been associated with increased strategies to improve the welfare of people with epilepsy. risk of premature and unexpected death, injuries, cognitive A myriad of anecdotal reports and some published literature deterioration, neurobehavioural dysfunction and reduced have suggested the importance of dietary manipulation in quality of life (QoL)(6–8). Despite ongoing research in under- seizure management(14). In particular, the ketogenic diet (KD) standing the pathophysiological manifestation of seizures and has been proposed as an alternative treatment strategy for epilepsy, the cellular mechanisms remain elusive. As a result, canine epilepsy(15). The ‘classic’ KD consisting of high fat, approaches towards antiepileptic therapy are usually directed low protein and low carbohydrate, typically with ratios of up to towards the control of seizures, most commonly chronic 4:1 fats to proteins and carbohydrates, was first introduced administration of antiepileptic drugs (AED), rather than prevention in the 1920s for use in patients with childhood epilepsy(16). of epileptogenesis or comorbidities. Despite appropriate AED Wilder initially suggested the use of the KD in order to mimic

Abbreviations: AED, antiepileptic drug; BHB, β-hydroxybutyrate; KBr, potassium bromide; KD, ketogenic diet; MCT, medium-chain TAG; MCTD, medium-chain TAG diet; MCTKD, medium-chain TAG ketogenic diet; PB, phenobarbital. * Corresponding author: H. A. Volk, fax +44 170 764 9384, email: [email protected]

Summary and Conclusion

MCTD improves seizure control • Most dogs showed a reduction in seizure frequency in 30 days when fed as an adjunct to veterinary therapyPage 27 of 36 British Journal of Nutrition Investigating the short-term effects of medium- • Over the course of 90 days: ! chain triglycerides (MCT) supplement on canine epilepsy in drug-non responders

2.0 Dr Dr Benjamin-A. Berk MSc MRCVS1 For Review Only Resident ECVCN 1.5 RMA Packer1, TH Law1, A Wessmann2, A Bathen-Nöthen3, TS Jokinen-Pääkkönen4 • No effect on antiepileptic drug serum levels A Knebel5, A Tipold5, Holger A. Volk1 • MCTD significantly increases BHB serum levels 1.0 1 Royal Veterinary College, Department of Clinical Science and Services (CSS), Hatfield, United Kingdom 2 BHB BHB levels (mg/dL) Pride Veterinary Centre, Riverside Road, Pride Park, Derby, UK 0.5 3 Tierarztpraxis , Dr. A. Bathen-Nöthen ,Hatzfeldstraße, Cologne, Germany 4 Faculty of Veterinary Medicine, Dep. of Equine and Small Animal Medicine, Helsinki, Finland 5 Klinik für Kleintiere, Stiftung Tierärztliche Hochschule Hannover, Bünteweg, Hanover, Germany 0.0 PLACEBO MCTD

Cambridge University Press

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