7 antiepileptic therapy in dogs - fundamentals and...

8/13/19

1

Antiepileptic Therapy in Dogs - Fundamentalsand Cases

Department of Small Animal Diseases

Prof. Holger A. Volk DipECVN, PhD, PGCAP, FHEA, MRCVSHead of Department, Tierärztliche Hochschule HannoverRCVS & EBVS® European Specialist in Veterinary NeurologyPast-President of the European College of Veterinary NeurologyTreasurer of the European Board of Veterinary SpecialisationHonorary Senior Lecturer -UCL Institute of NeurologyHonorary Professor of Veterinary Neurology and Neurosurgery -Royal Veterinary College

Disclosures

è FINANCIAL DISCLOSURE: • Grant/Research Support – Purina, Boehringer Ingelheim, BBSRC,

Wellcome Trust, AKC Canine Health Foundation• Consulting and Speaker Engagement – Purina, Boehringer Ingelheim.

è UNLABELED/ UNAPPROVED USES DISCLOSURE: • 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 check local authorities before use.

How does success look like?Outcome in individual patients: impact on seizures

Therapeutic success

Outcome in individual patients: impact on seizures

Evaluate short-term & long-term success.

Term drug-resistant combined with drug information.

(e.g. PHB resistant)

Thank you Marios Charalambous

8/13/19

2

IVET

F –

ww

w.iv

etf.

org

International Veterinary Epilepsy Task Force

Berendt M; Bhatti SFM; De Risio L; Farquhar RG; Fernández-Flores F; Fischer A, Hasegawa D; Hülsmeyer VI; Jokinen-Pääkkönen T; Jovanovik E; Löscher W, 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; PumarolaMB; Rosati M; Rusbridge C; Saito M; Stein VM; Tipold A; Volk H; Wagner E.

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 processing of brains from epileptic dogs and cats (Chaired by Profs. Kaspar Matiasek and Martí Pumarola Batlle).

ACVIM consensus statement - Panel Members

Scenario

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.

Which drug would you use?

1. Phenobarbitone2. Imepitoin3. Potassium bromide4. Levetiracetam5. Gabapentin6. Zonisamide

http://www.ivetf.org/

8/13/19

3

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.

Which drug would you use first line?


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 cluster seizures. The dog is normal between the episodes, idiopathic epilepsy is suspected. You wonder what the best treatment would be.

Which drug would you use first line?


How high is the placebo effect if you are a surgeon or a medic?

Placebo Effect in Canine Epi lepsy Trials

K.R. Munana, D. Zhang, and E.E. Patterson

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.

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

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% (P5 .0018), 29%

(P 5 .17), and 46% (P5 .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.

The placebo effect is a well recognized, but poorly un-derstood phenomenon that involves a nonspecific

psychological or physiological therapeutic effect of amedical intervention that lacks specific activity for thecondition being treated.1 Early medical practices werebased on the placebo effect, wherein placebos were ad-ministered with the purpose of producing a desiredtherapeutic response. More recently, the use of placeboshas focused primarily on its role as a control in random-ized-clinical trials that allows for an unbiased estimate ofthe treatment effects of the agent being evaluated.Results from numerous human trials have demon-

strated that placebos can improve subjective andobjective outcomes in patients with a wide range ofclinical conditions. A beneficial effect of placebo admin-istration has been reported in 60–90% of all humandiseases,2 including musculoskeletal, respiratory, car-diac, dermatologic, gastrointestinal, and nervous systemdisorders. Furthermore, a placebo response rate of ap-proximately 35% is commonly cited in the medicalliterature,3 although higher rates have been reportedand are most frequently seen in diseases with clinicalsigns that wax and wane, fluctuate, or spontaneously re-mit.4 Because of the potential magnitude of this effect,

placebo-controlled studies are considered necessary togauge the true efficacy of a novel intervention, and arethe basis for drug evaluation and approval in humanmedicine.

In contrast, the placebo effect has been largely disre-garded in veterinary medicine, with only 2 publicationsidentified that address the issue of a placebo effect in an-imals.1,5 However, with the recent emphasis placed onevidence based medicine in veterinary practice, it seemsappropriate to consider the effect of placebos in veteri-nary patients, particularly the extent to which animalsmay demonstrate an improvement in disease manifesta-tions that could be because of nonspecific effects of atherapeutic intervention.

The hypothesis tested in this study is that nonpharma-cologic therapeutic effects play a role in response ratesidentified in canine epilepsy trials. The specific aim is todetermine the magnitude of the placebo response in ran-domized-controlled trials evaluating new treatmentmodalities for refractory canine epilepsy.

Materials and Methods

Study Design

Data was compiled from 3 clinical trials evaluating the safety and

efficacy of novel treatments for refractory canine epilepsy in which a

placebo arm was a component of the study protocol. The studies

evaluated were performed by 2 of the authors (K.R.M., E.E.P.), en-

abling easy access to the data necessary to undertake the present

analysis. A database search was performed to identify any addi-

tional placebo-controlled canine epilepsy trials that might be

included in the analysis, but none were found. Inclusion criteria

were similar for all 3 studies and consisted of (1) an onset of seizures

between 1 and 5 years of age; (2) a normal diagnostic evaluation,

including physical examination, neurological examination, CBC,

chemistry profile, urinalysis, and bile acid tolerance test; (3) treat-

ment with either phenobarbital and/or potassium bromide at

established therapeutic serum levels; (4) a seizure frequency of at

least 4 seizures per month or a history of cluster seizures; and (5) a 1

year documented history of seizures. All dogs were classified as

From the Department of Clinical Sciences, College of VeterinaryMedicine (Munana) and the Department of Statistics (Zhang),North Carolina State University, Raleigh, NC and the Departmentof Veterinary Clinical Science (Patterson), University of Minnesota,St Paul, MN. Presented at the 26th Annual Forum of the AmericanCollege of Veterinary Medicine, San Antonio, TX, June 2008.

Corresponding author: Karen R. Munana, Department of ClinicalSciences, College of Veterinary Medicine, North Carolina State Uni-versity, 4700 Hillsborough Street, Raleigh, NC 27606; e-mail:[email protected]

Submitted April 17, 2009; Revised July 17, 2009; AcceptedSeptember 16, 2009

Copyright r 2009 by the American College of Veterinary InternalMedicine

10.1111/j.1939-1676.2009.0407.x

J Vet Intern Med 2010;24:166–170

8/13/19

4

RESEARCH ARTICLE Open Access

Treatment in canine epilepsy – a systematic reviewMarios Charalambous1*, David Brodbelt2 and Holger A Volk1

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 existingevidence for the effectiveness of AEDs for presumptive canine IE. Electronic searches of PubMed and CAB Directwere carried out without date or language restrictions. Conference proceedings were also searched. Peer-reviewedfull-length studies describing objectively the efficacy of AEDs in dogs with IE were included. Studies were allocatedin two groups, i.e. blinded randomized clinical trials (bRCTs), non-blinded randomized clinical trials (nbRCTs) andnon-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 enrolmentquality and overall risk of bias) and the outcome measures reported (in particular the proportion of dogswith ≥50% reduction in seizure frequency).

Results: Twenty-six studies, including two conference proceedings, reporting clinical outcomes of AEDs used formanagement of IE were identified. Heterogeneity of study designs and outcome measures made meta-analysisinappropriate. Only four bRCTs were identified in group A and were considered to offer higher quality of evidenceamong the studies. A good level of evidence supported the efficacy of oral phenobarbital and imepitoin and fair level ofevidence supported the efficacy of oral potassium bromide and levetiracetam. For the remaining AEDs, favorable resultswere reported regarding their efficacy, but there was insufficient evidence to support their use due to lack of bRCTs.

Conclusions: Oral phenobarbital and imepitoin in particular, as well as potassium bromide and levetiracetam are likelyto be effective for the treatment of IE. However, variations in baseline characteristics of the dogs involved, significantdifferences between study designs and several potential sources of bias preclude definitive recommendations. There is aneed for greater numbers of adequately sized bRCTs evaluating the efficacy of AEDs for IE.

Keywords: Systematic review, Epilepsy, Antiepileptic drugs, Treatment, Canine

BackgroundEpilepsy is the most common chronic neurological dis-order in dogs, with a formerly reported prevalence of be-tween 0.5% and 5% in non-referral populations [1,2]. Ina recent study, this prevalence was estimated to be 0.62%in a large UK primary care population [3]. Epilepsy is notone single disease process but can be elicited by mul-tiple causes and, accordingly, can be classified as genetic(primary or idiopathic), structural and of unknown origin/etiology [4]. When chronic recurring seizures occur andno underlying abnormality is detected, epilepsy is clas-sified typically as primary or idiopathic epilepsy [1]. How-ever, idiopathic epilepsy could imply a potential genetic

background and in veterinary medicine the terms idio-pathic or primary are generally used for any epilepsy ofunidentified etiology even if no genetic or familial causesare suspected [5]. In this study the term idiopathic epilepsy(IE) will be used for all the cases of unidentified etiology,including cases with a suspected genetic background.Various antiepileptic drugs (AEDs) are used for the

management of IE in dogs. Clinical information on thegrounds of their efficacy remains limited, with most evi-dence derived from non-blinded non-randomized uncon-trolled trials and case series [6]. In addition, many of theseprevious reports do not use an objective measurement ofefficacy, e.g. a% reduction in seizure frequency in a propor-tion of dogs of a study population after a specific period oftreatment; instead they are based on subjective observa-tions, e.g. ‘improvement in seizure control’ or ‘changein seizure frequency’.

* Correspondence: [email protected] of Clinical Science and Services, Royal Veterinary College,Hawkshead Lane, Hatfield, Herts AL9 7TA, UKFull 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 theCreative 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 PublicDomain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in thisarticle, unless otherwise stated.

Charalambous et al. BMC Veterinary Research 2014, 10:257http://www.biomedcentral.com/1746-6148/10/257

for the efficacy of oral primidone, zonisamide, gabapentin,sodium valproate, pregabalin, felbamate and topiramate asadjunct AEDs, but there was insufficient level of evidenceto support their efficacy.Overall risk of bias ranged from low/moderate to high;

only four studies [11-14] categorized as low/moderateoverall risk and the remaining as moderate/high or high.Studies in group A which were considered to offer loweroverall risk of bias were too few compared to those ofgroup B (study group A:group B proportion was 1:6).Therefore, the results from the studies concerning theefficacy of each AED should be interpreted with caution.In addition, only 17% and 10% of the 29 studies includedwell characterized groups and evaluated good numbers ofdogs, respectively. None of the bRCTs included well char-acterized groups and only two of them evaluated a goodnumber of dogs. The same studies, though, were consid-ered to offer the highest quality of evidence among all thestudies and recommended the use of phenobarbital andimepitoin in particular as well as potassium bromide andlevetiracetam as AEDs. However, mainly due to the smallnumber of bRCTs and to a lesser extend due to the inad-equate disease definitions and study group sizes, definitivesuggestions concerning their efficacy are precluded.Based on the level of quality of evidence provided by

studies for each AED as well as the assessment of theirefficacy, a pyramid of hierarchy was proposed (Figure 1).Phenobarbital and imepitoin were found to be at the topof the pyramid. In human epilepsy, many AEDs are usedfor the management of seizures but phenobarbital remainsone of the most important; meta-analyses of RCTs foundthat only minor differences occur on the grounds of efficacybetween phenobarbital and other established AEDs [38].Although phenobarbital may remain the most efficient

AED in human epilepsy, its tolerability issues lead to theinvestigation and use of other AEDs with almost the sameefficacy but more tolerable. Imepitoin was initially devel-oped as a new AED for humans, but development wasceased because of differences in pharmacokinetic valuesbetween smokers and non-smokers, although the toler-ability of this drug in humans was high [39].In canine epilepsy there are limitations in treatment of

IE due to the rapid elimination of the majority of theAEDs with only few, i.e. phenobarbital, primidone andpotassium bromide, having sufficient half-life [40,41]. Thesame drugs have been approved for treatment of canineepilepsy in Europe and/or USA, with phenobarbital to beone of the most effective and well-known AED. Recently,imepitoin was also approved for the treatment of canineepilepsy based on some RCTs [13,14]. Monotherapy withimepitoin in dogs with newly diagnosed epilepsy showedthat it was moderately less effective but potentiallymore tolerated than phenobarbital or primidone. Also,in dogs with chronic epilepsy receiving phenobarbitaland/or primidone, most dogs exhibited a reduction inseizure frequency and severity after adjunctive therapywith imepitoin [26,27]. In a laboratory study, imepitoin wascompared with phenobarbital in an acute canine seizuremodel using pentylenetetrazole, resulting in a compar-able anticonvulsant efficacy [42]. In the European pseudo-placebo trial, high dose (30 mg/kg PO BID) of imepitoinwas compared to low dose (1 mg/kg PO/BID) and resultsshowed that seizure frequency was significantly reduced inthe first compared to the second group [13]. In the samestudy, baseline seizure frequency was different betweenthe two groups; thus, the change in seizure frequencyreduction between the groups was significant. In a USfield study, imepitoin was compared to primidone but

Figure 1 Pyramid of hierarchy describing the recommendation of AEDs based on the assessment of their efficacy and quality of evidence.

Charalambous et al. BMC Veterinary Research 2014, 10:257 Page 20 of 24http://www.biomedcentral.com/1746-6148/10/257

Side effects

ACVIM Panel Grade of Recommendations (Level of Evidence) for AED Monotherapy

A (HIGH)

• Phenobarbital (I)

• Imepitoin (I)

B (MODERATE)

• Bromide (I)

C (LOW)

• Levetiracetam (IV)

• Zonisamide (III)

D (NO)

• Primidone (II)

A single-blinded phenobarbital-controlled trial of levetiracetam asmono-therapy in dogs with newly diagnosed epilepsyN. Fredsø a,*, A. Sabers b, N. Toft c, A. Møller d, M. Berendt a

a Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Dyrlaegevej 16, 1870Frederiksberg C, Denmarkb The Epilepsy Clinic, Department of Neurology, University State Hospital (Rigshospitalet), Blegdamsvej 9, 2100 Copenhagen Ø, Denmarkc National Veterinary Institute, Section for Epidemiology, Technical University of Denmark, Bülowsvej 27, 1870 Frederiksberg C, Denmarkd Centre of Functional Integrative Neuroscience, Aarhus University/Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus, Denmark

A R T I C L E I N F O

Article history:Accepted 5 October 2015

Keywords:Antiepileptic drugCanineMonotherapySeizure

A B S T R A C T

Treatment of canine epilepsy is problematic. Few antiepileptic drugs have proven efficacy in dogs andundesirable adverse effects and pharmacoresistance are not uncommon. Consequently, the need for in-vestigation of alternative treatment options is ongoing. The objective of this study was to investigate theefficacy and tolerability of levetiracetam as mono-therapy in dogs with idiopathic epilepsy. The studyused a prospective single-blinded parallel group design. Twelve client-owned dogs were included andwere randomised to treatment with levetiracetam (30mg/kg/day or 60mg/kg/day divided into three dailydosages) or phenobarbital (4 mg/kg/day divided twice daily). Control visits were at days 30, 60 and thenevery 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 andone of six phenobarbital treated dogs withdrew from the study within 2–5 months due to insufficientseizure control.

In the levetiracetam treated dogs there was no significant difference in the monthly number of sei-zures 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 re-sponders (≥50% reduction in seizures/month) whereas none of the levetiracetam treated dogs fulfilledthis criterion. Adverse effects were reported in both groups but were more frequent in the phenobarbi-tal group. In this study levetiracetam was well tolerated but was not effective at the given doses as mono-therapy in dogs with idiopathic epilepsy.

© 2015 Elsevier Ltd. All rights reserved.

Introduction

The management of epilepsy in dogs is complicated by the factthat only a few drugs are available and effective. Undesirable adverseeffects (AE) are not uncommon and failure to control seizures ap-propriatelymay lead to euthanasia (Berendt et al., 2007; Fredsø et al.,2014). Potassium bromide and phenobarbital were introduced tohumanmedicine in 1857 and 1912, respectively, (Locock, 1857a andb; Hauptmann, 1912), and have traditionally dominated the man-agement of canine epilepsy. Both drugs are reasonably effective(Boothe et al., 2012) and their long elimination half-lives facilitatea 12–24 h dosing regimen. However, undesirable AE, such as poly-phagia, polydipsia, polyuria, sedation and ataxia, are common(Boothe et al., 2012). Although rare, more serious AE including su-perficial necrolytic dermatitis, pancytopenia, hepatotoxicity and acute

pancreatitis have also been associatedwith these drugs (Dayrell-Hartet al., 1991; Jacobs et al., 1998; Gaskill and Cribb, 2000; Müller et al.,2000; March et al., 2004; Gaskill et al., 2005). Imepitoin was reg-istered for use in dogs in 2013 (Europe) and has so far shown amorebeneficial profile regarding AE (Tipold et al., 2015).

Levetiracetam, a pyrrolidone derivative, was introduced as anantiepileptic drug for humans in 1999 (Brodie et al., 2007). The drugis believed to act as a modulator of synaptic vesicle exocytosis bybinding to the synaptic vesicle protein 2A (SV2A) (Lynch et al., 2004).The pharmacokinetic properties of levetiracetam have been inves-tigated in healthy dogs (Dewey et al., 2008; Patterson et al., 2008;Moore et al., 2010a, 2010b; Peters et al., 2014). Levetiracetam hasbeen investigated as adjunctive treatment for refractory idio-pathic epilepsy in companion dogs (Steinberg and Faissler, 2004;Volk et al., 2008; Muñana et al., 2012). Dogs with refractory idio-pathic epilepsy have shown a favourable response to levetiracetamas an add-on antiepileptic drug, with a significant reduction inseizure frequency compared to baseline in two open-label studies,(Steinberg and Faissler, 2004; Volk et al., 2008), whereas no effect

* Corresponding author. Tel.: +45 35 33 09 14.E-mail address: [email protected] (N. Fredsø).

http://dx.doi.org/10.1016/j.tvjl.2015.10.0181090-0233/© 2015 Elsevier Ltd. All rights reserved.

The Veterinary Journal 208 (2016) 44–49

Contents lists available at ScienceDirect

The Veterinary Journal

journal homepage: www.elsevier.com/ locate / tv j l

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.

International Veterinary Epilepsy Task Force –Consensus Proposals

• In an otherwise healthy dog• Start with PB

• Recurrent single generalized epileptic seizures (IE)• Clusters seizures and/or status epilepticus (IE)• Other epilepsy types

• Start with Imepitoin• Recurrent single generalized epileptic seizures (IE)

• KBr• Add-on

IVETF - Consensus proposal - Choice AEDCORRESPONDENCE Open Access

International Veterinary Epilepsy Task Forceconsensus proposal: medical treatment ofcanine epilepsy in EuropeSofie 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,Kaspar Matiasek12, Akos Pakozdy13, Edward E. Patterson14, Simon Platt15, Michael Podell16, Heidrun Potschka17,Clare Rusbridge18,19 and Holger A. Volk20

Abstract

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years.Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best usedinitially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) whentreatment changes should be considered. In this consensus proposal, an overview is given on the aim of AEDtreatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use fordogs. 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 ofcanine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in additionto treating the underlying cause, if possible.

Keywords: Dog, Epileptic seizure, Epilepsy, Treatment

BackgroundIn Europe, the number of antiepileptic drugs (AEDs) li-censed for dogs has grown considerably over the lastyears. Nevertheless, the same questions remain, whichinclude, 1) when to start treatment, 2) which drug is bestused initially, 3) which adjunctive AED can be advised iftreatment with the initial drug is unsatisfactory, and 4)when treatment changes should be considered. In thisconsensus proposal, an overview is given on the aim ofAED treatment, when to start long-term treatment incanine epilepsy and which veterinary AEDs are currentlyin use for dogs. The consensus proposal for drug treatmentprotocols, 1) is based on current published evidence-basedliterature [17], 2) considers the current legal framework ofthe 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 themanagement of canine idiopathic epilepsy. Furthermore,for the management of structural epilepsy AEDs are in-evitable in addition to treating the underlying cause, ifpossible.At present, there is no doubt that the administration

of AEDs is the mainstay of therapy. In fact, the termAED is rather inappropriate as the mode of action ofmost AEDs is to suppress epileptic seizures, not epilep-togenesis or the pathophysiological mechanisms of epi-lepsy. Perhaps, in the future, the term anti-seizure drugsmight be more applicable in veterinary neurology, a termthat is increasingly used in human epilepsy. Additionally,it is known that epileptic seizure frequency appears toincrease over time in a subpopulation of dogs with un-treated idiopathic epilepsy, reflecting the need of AEDtreatment in these patients [63].In our consensus proposal on classification and termin-

ology we have defined idiopathic epilepsy as a disease in

* Correspondence: [email protected] of Small Animal Medicine and Clinical Biology, Faculty ofVeterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke 9820,BelgiumFull list of author information is available at the end of the article

© 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.

Bhatti et al. BMC Veterinary Research (2015) 11:176 DOI 10.1186/s12917-015-0464-z

When would you check Phenobarbitoneserum levels for the first time?

1. 2 days2. 12 days3. 30 days4. 90 days

8/13/19

5

When would you check Phenobarbitoneserum levels for the first time?

1. 2 days2. 12 days3. 30 days4. 90 days

Phenobarbitone (dog)–First line treatment

• Phenobarbitone (PB)• Dose ~2.5 mg/kg BID• Peak serum concentration 4-8 hours (oral)• Half-life 24-40 hrs• Time to steady state 10-14 days• Therapeutic range 15.0 – 35 µg/ml• Potential side effects Sedation, PU/PD, polyphagia, hepatotoxicity• Metabolism liver• Drug interaction Can alter serum levels of liver metabolised drugs• Obtain plasma level 14, 45, 90, 180, 360 d, then q 6m

• 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

M o n teiro et a l., 2009, V et R eco rd

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?

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

SM

ALL A

NIM

ALS

Since the early 1990s, bromide (most commonly ad-ministered as a potassium salt) has been used as

an AED for the long-term management of epilepsy in dogs.1–4 Increasingly, it is considered as an alternative to phenobarbital as the first-choice sole AED used for long-term control of epilepsy in dogs.5–8 Successful use of both phenobarbital and bromide is facilitated by a long elimination half-life, which minimizes fluctuation in drug concentrations during a 12-hour dosing interval.7–11 Therapeutic drug monitoring is widely available and is supported by canine (rather than human) therapeutic ranges as follows: serum phenobarbital concentrations of 15 to 45 µg/mL7,12–14 and serum bromide concentrations of 1 to 3 mg/mL (when used as a sole treatment).7,12–17

Comparison of phenobarbital with bromide 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%]) signifi-cantly 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 (phenobar-bital dosage, 4.1 ± 1.1 mg/kg [1.9 ± 0.5 mg/lb], PO, q 12 h) and mean serum bromide con-centration 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)

Each drug has its disadvantages. Both are associated with polyuria, polydipsia, and polyphagia and the sequelae as-sociated with general sedation (eg, lethargy and ataxia), adverse effects to which an animal may develop toler-ance.1,2,5–7,17 In addition, each has unique characteristics that complicate successful treatment. Long-term pheno-barbital treatment has been associated with hepatotox-icity, although a cause-and-effect relationship has not been proven.18–20 Phenobarbital also has been associated with unpredictable, idiosyncratic adverse drug reactions, including pancytopenia,21,22 and drug interactions that reflect induction of selected hepatic drug-metabolizing enzymes that target xenobiotics23–30 as well as endoge-nous compounds.31,32 Induction of its own metabolism might result in a decrease in plasma drug concentrations and therapeutic failure. In contrast, although renal ex-cretion of bromide limits hepatotoxicity or induction of hepatic enzymes, its elimination half-life in dogs is so long that several months of treatment must occur with each change in dosage before steady-state con-centrations (and thus maximum effect) are reached.33,34 Although this delay can be overcome by administration

From the Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine (Boothe) and the Department of Mathematics and Statistics, College of Sciences and Mathematics (Carpenter), Auburn University, Auburn, AL 36849; and the De-partment of Clinical Sciences, College of Veterinary Medicine, Cor-nell University, Ithaca, NY 14850 (Dewey).

This study was implemented at Texas A&M University’s Texas Vet-erinary Medical Center but included the participation of referral practitioners throughout the United States.

Supported by the Canine Health Foundation and the American Ken-nel Club.

Presented as a poster at the 20th American College of Veterinary In-ternal Medicine Annual Forum, Dallas, May 2002.

Address correspondence to Dr. Boothe ([email protected]).

ABBREVIATIONS

AED Antiepileptic drugCI Confidence interval

Phenobarbital

8/13/19

6

to the individual patient based on seizure control, adverseeffects and serum concentration monitoring.Because of considerable variability in the pharmaco-

kinetics of PB among individuals, the serum concentra-tion should be measured 14 days after starting therapy(baseline concentration for future adjustments) or aftera change in dose. To evaluate the effect of metabolictolerance, a second PB serum concentration can bemeasured 6 weeks after initiation of therapy. Recom-mendations on optimal timing of blood collection forserum PB concentration monitoring in dogs vary amongstudies [23]. Generally, serum concentrations can bechecked at any time in the dosing cycle as the changein PB concentrations through a daily dosing interval isnot therapeutically relevant once steady-state has beenachieved [62, 70]. However, in dogs receiving a dose of5 mg/kg BID or higher, trough concentrations were sig-nificantly lower than non-trough concentrations andserum PB concentration monitoring at the same timepost-drug dosing was recommended, in order to allowaccurate comparison of results in these dogs [70]. Anotherstudy recommended performing serum PB concentrationmonitoring on a trough sample as a significant differencebetween peak and trough PB concentration was identifiedin individual dogs [10]. The therapeutic range of PB inserum is 15 mg/l to 40 mg/l in dogs. However, it is the au-thors’ opinion that in the majority of dogs a serum PBconcentration between 25−30 mg/l is required for optimalseizure control. Serum concentrations of more than 35mg/l are associated with an increased risk of hepatotoxicity

and should be avoided [22, 75]. In case of inadequate seiz-ure control, serum PB concentrations must be used toguide increases in drug dose. Dose adjustments can be cal-culated according to the following formula (Formula A):

New PB total daily dosage in mg

¼ desired serum PB concentration=actual serum PB concentrationð Þ

$ actual PB total daily dosage in mg

A dog with adequate seizure control, but serum drugconcentrations below the reported therapeutic range,does not require alteration of the drug dose, as thisserum concentration may be sufficient for that individ-ual. Generally, the desired serum AED concentration forindividual patients should be the lowest possible concen-tration associated with >50 % reduction in seizure fre-quency or seizure-freedom and absence of intolerableadverse effects [23].In animals with cluster seizures, status epilepticus or

high seizure frequency, PB can be administered at aloading dose of 15−20 mg/kg IV, IM or PO divided inmultiple doses of 3−5 mg/kg over 24−48h to obtain atherapeutic brain concentration quickly and then sustainit [10]. Serum PB concentrations can be measured 1−3days after loading. Some authors load as soon as possible(over 40 to 60 min) and start with a loading dose of 10to 12 mg/kg IV followed by two further boluses of 4 to 6mg/kg 20 min apart.Complete blood cell count, biochemical profile (includ-

ing cholesterol and triglycerides), and bile acid stimulation

Fig. 1 PB treatment flow diagram for decision making during seizure management in an otherwise healthy dog. The authors advise to start withPB (and add KBr if inadequate seizure control after optimal use of PB (Fig. 3)): in dogs with idiopathic epilepsy experiencing recurrent singlegeneralised epileptic seizures; in dogs with idiopathic epilepsy experiencing cluster seizures or status epilepticus; in dogs with other epilepsytypes. *Criteria for (in)adequate seizure control with regard to efficacy and tolerability (see Consensus proposal: Outcome of therapeuticinterventions in canine and feline epilepsy [94]). 1. Treatment efficacious: a: Achievement of complete treatment success (i.e. seizure freedom orextension of the interseizure interval to three times the longest pretreatment interseizure interval and for a minimum of three months (ideally > 1year); b: Achievement of partial treatment success (i.e. a reduction in seizure frequency including information on seizure incidence (usually at least50 % or more reduction defines a drug responder), a reduction in seizure severity, or a reduction in frequency of seizure clusters and/or statusepilepticus). 2. Treatment not tolerated i.e. appearance of severe adverse effects necessitating discontinuation of the AED

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

IVETF - Phenobarbitone

Until recently, primary treatment options for dogswith epilepsy have focused mainly on phenobarbital (PB)and potassium bromide (KBr) due to their long standinghistory, widespread availability, and low cost. While bothAEDs are still widely used in veterinary practice, severalnewer AEDs approved for use in people are also beingused for the management of canine idiopathic epilepsymainly as add-on treatment. Moreover, since early 2013,imepitoin has been introduced in most European coun-tries for the management of recurrent single generalizedepileptic seizures in dogs with idiopathic epilepsy.Several AEDs of the older generation approved for

humans have been shown to be unsuitable for use indogs as most have an elimination half-life that is tooshort to allow convenient dosing by owners, these in-clude phenytoin, carbamazepine, valproic acid, and etho-suximide [119]. Some are even toxic in dogs such aslamotrigine (the metabolite is cardiotoxic) [26, 136] andvigabatrin (associated with neurotoxicity and haemolyticanemia) [113, 131, 138].Since the 1990s, new AEDs with improved tolerability,

fewer side effects and reduced drug interaction potentialhave been approved for the management of epilepsy inhumans. Many of these novel drugs appear to be rela-tively safe in dogs, these include levetiracetam, zonisa-mide, felbamate, topiramate, gabapentin, and pregabalin.Pharmacokinetic studies on lacosamide [68] and rufina-mide [137] support the potential use of these drugs indogs, but they have not been evaluated in the clinicalsetting. Although these newer drugs have gained consid-erable popularity in the management of canine epilepsy,scientific data on their safety and efficacy are very lim-ited and cost is often prohibitive.

PhenobarbitalEfficacyPB has the longest history of chronic use of all AEDs inveterinary medicine. After decades of use, it has beenapproved in 2009 for the prevention of seizures causedby generalized epilepsy in dogs. PB has a favourablepharmacokinetic profile and is relatively safe [2, 87, 97].PB seems to be effective in decreasing seizure frequencyin approximately 60−93 % of dogs with idiopathic epi-lepsy when plasma concentrations are maintained withinthe therapeutic range of 25−35 mg/l [10, 31, 74, 105].According to Charalambous et al. (2014) [17], there isoverall good evidence for recommending the use of PBas a monotherapy AED in dogs with idiopathic epilepsy.Moreover, the superior efficacy of PB was demonstratedin a randomized clinical trial comparing PB to bromide(Br) as first-line AED in dogs, in which 85 % of dogs ad-ministered PB became seizure-free for 6 months com-pared with 52 % of dogs administered Br [10]. Thisstudy demonstrated a higher efficacy of PB compared to

Br as a monotherapy, providing better seizure controland showing fewer side effects.

PharmacokineticsPB is rapidly (within 2h) absorbed after oral administra-tion in dogs, with a reported bioavailability of approxi-mately 90 % [2, 87]. Peak serum concentrations areachieved approximately 4−8h after oral administration indogs [2, 97]. The initial elimination half-life in normaldogs has been reported to range from 37−73h after mul-tiple oral dosing [96]. Plasma protein binding is approxi-mately 45 % in dogs [36]. PB crosses the placenta andcan be teratogenic.PB is metabolized primarily by hepatic microsomal en-

zymes and approximately 25 % is excreted unchanged inthe urine. There is individual variability in PB absorption,excretion and elimination half-life [2, 87, 97]. In dogs, PBis a potent inducer of cytochrome P450 enzyme activity inthe liver [48], and this significantly increases hepatic pro-duction of reactive oxygen species, thus increasing the riskof hepatic injury [107]. Therefore PB is contraindicated indogs with hepatic dysfunction. The induction of cyto-chrome P450 activity in the liver can lead to autoinductionor accelerated clearance of itself over time, also known asmetabolic tolerance, as well as endogenous compounds(such as thyroid hormones) [40, 48]. As a result, withchronic PB administration in dogs, its total body clearanceincreases and elimination half-life decreases progressivelywhich stabilizes between 30−45 days after starting therapy[97]. This can result in reduction of PB serum concen-trations and therapeutic failure and therefore, monitor-ing of serum PB concentrations is very important fordose modulation over time.A parenteral form of PB is available for intramuscular

(IM) or intravenous (IV) administration. Different PBformulations are available in different countries, it shouldbe emphasized, however, that IM formulations cannot beused IV and vice versa. Parenteral administration of PB isuseful for administering maintenance therapy in hospital-ized patients that are unable to take oral medication. Thepharmacokinetics of IM PB have not been explored indogs, however, studies in humans have shown a similarabsorption after IM administration compared to oral ad-ministration [135]. The elimination half-life in dogs after asingle IV dose is approximately 93h [87].

Pharmacokinetic interactionsIn dogs, chronic PB administration can affect the dispos-ition of other co-administered medications which are me-tabolized by cytochrome P450 subfamilies and/or boundto plasma proteins [48]. PB can alter the pharmacokineticsand as a consequence may decrease the therapeutic ef-fect of other AEDs (levetiracetam, zonisamide, and ben-zodiazepines) as well as corticosteroids, cyclosporine,


to the individual patient based on seizure control, adverseeffects and serum concentration monitoring.Because of considerable variability in the pharmaco-

kinetics of PB among individuals, the serum concentra-tion should be measured 14 days after starting therapy(baseline concentration for future adjustments) or aftera change in dose. To evaluate the effect of metabolictolerance, a second PB serum concentration can bemeasured 6 weeks after initiation of therapy. Recom-mendations on optimal timing of blood collection forserum PB concentration monitoring in dogs vary amongstudies [23]. Generally, serum concentrations can bechecked at any time in the dosing cycle as the changein PB concentrations through a daily dosing interval isnot therapeutically relevant once steady-state has beenachieved [62, 70]. However, in dogs receiving a dose of5 mg/kg BID or higher, trough concentrations were sig-nificantly lower than non-trough concentrations andserum PB concentration monitoring at the same timepost-drug dosing was recommended, in order to allowaccurate comparison of results in these dogs [70]. Anotherstudy recommended performing serum PB concentrationmonitoring on a trough sample as a significant differencebetween peak and trough PB concentration was identifiedin individual dogs [10]. The therapeutic range of PB inserum is 15 mg/l to 40 mg/l in dogs. However, it is the au-thors’ opinion that in the majority of dogs a serum PBconcentration between 25−30 mg/l is required for optimalseizure control. Serum concentrations of more than 35mg/l are associated with an increased risk of hepatotoxicity

and should be avoided [22, 75]. In case of inadequate seiz-ure control, serum PB concentrations must be used toguide increases in drug dose. Dose adjustments can be cal-culated according to the following formula (Formula A):

New PB total daily dosage in mg

¼ desired serum PB concentration=actual serum PB concentrationð Þ

$ actual PB total daily dosage in mg

A dog with adequate seizure control, but serum drugconcentrations below the reported therapeutic range,does not require alteration of the drug dose, as thisserum concentration may be sufficient for that individ-ual. Generally, the desired serum AED concentration forindividual patients should be the lowest possible concen-tration associated with >50 % reduction in seizure fre-quency or seizure-freedom and absence of intolerableadverse effects [23].In animals with cluster seizures, status epilepticus or

high seizure frequency, PB can be administered at aloading dose of 15−20 mg/kg IV, IM or PO divided inmultiple doses of 3−5 mg/kg over 24−48h to obtain atherapeutic brain concentration quickly and then sustainit [10]. Serum PB concentrations can be measured 1−3days after loading. Some authors load as soon as possible(over 40 to 60 min) and start with a loading dose of 10to 12 mg/kg IV followed by two further boluses of 4 to 6mg/kg 20 min apart.Complete blood cell count, biochemical profile (includ-

ing cholesterol and triglycerides), and bile acid stimulation

Fig. 1 PB treatment flow diagram for decision making during seizure management in an otherwise healthy dog. The authors advise to start withPB (and add KBr if inadequate seizure control after optimal use of PB (Fig. 3)): in dogs with idiopathic epilepsy experiencing recurrent singlegeneralised epileptic seizures; in dogs with idiopathic epilepsy experiencing cluster seizures or status epilepticus; in dogs with other epilepsytypes. *Criteria for (in)adequate seizure control with regard to efficacy and tolerability (see Consensus proposal: Outcome of therapeuticinterventions in canine and feline epilepsy [94]). 1. Treatment efficacious: a: Achievement of complete treatment success (i.e. seizure freedom orextension of the interseizure interval to three times the longest pretreatment interseizure interval and for a minimum of three months (ideally > 1year); b: Achievement of partial treatment success (i.e. a reduction in seizure frequency including information on seizure incidence (usually at least50 % or more reduction defines a drug responder), a reduction in seizure severity, or a reduction in frequency of seizure clusters and/or statusepilepticus). 2. Treatment not tolerated i.e. appearance of severe adverse effects necessitating discontinuation of the AED


IVETF - Imepitoin

cardiac, gastrointestinal or other disease. No idiosyncraticreactions have been demonstrated so far. The routinelymeasured liver enzymes’ activity do not appear to be in-duced by imepitoin [96]. Compared with the traditionalbenzodiazepines, such as diazepam, which acts as full ago-nists at the benzodiazepine site of the GABAA receptor,partial agonists such as imepitoin show less sedative ad-verse effects and are not associated with tolerance anddependence during long-term administration in animalmodels [122]. Also in epileptic dogs, tolerance did notdevelop and no withdrawal signs were observed aftertreatment discontinuation [64].

Dose and monitoring (Fig. 2)The oral dose range of imepitoin is 10−30 mg/kg BID.The recommended oral starting dose of imepitoin is 10−20mg/kg BID. If seizure control is not satisfactory after atleast 1 week of treatment at this dose and the medica-tion is well tolerated, the dose can be increased up to amaximum of 30 mg/kg BID. Reference range of plasmaor serum imepitoin concentrations is unknown andthere are no therapeutic monitoring recommendationsfor imepitoin from the manufacturer. Pharmacokineticstudies in dogs suggest variability in plasma imepitoin

concentrations among individuals and sampling times.However, no correlation between plasma imepitoin con-centration and seizure frequency reduction was identified[64] therefore and because of its wide therapeutic index,serum imepitoin monitoring is not needed.The authors recommend a complete blood cell count

and biochemical profile before starting imepitoin treat-ment and periodically every 6 months during treatment.If the dog is in remission or has no seizures, a periodicalcontrol every 12 months is advised.

BromideEfficacyBr is usually administered as the potassium salt (KBr).The sodium salt form (NaBr) contains more Br per gramof compound, therefore, the dose should be approxi-mately 15 % less than that calculated for KBr [124]. Inmost EU countries, KBr is approved only for add-ontreatment in dogs with epilepsy drug-resistant to first-line AED therapy. PB and KBr have a synergistic effectand add-on treatment with KBr in epileptic dogs im-proves seizure control in dogs that are poorly controlledwith PB alone [46, 93, 126]. A recent study showed that

Fig. 2 Imepitoin treatment flow diagram for decision making during seizure management in an otherwise healthy dog. The authors advise tostart with imepitoin in dogs with idiopathic epilepsy experiencing recurrent single generalised epileptic seizures. *Criteria for (in)adequate seizurecontrol 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 threetimes the longest pretreatment interseizure interval and for a minimum of three months (ideally > 1 year), b: Achievement of partial treatmentsuccess (i.e. a reduction in seizure frequency including information on seizure incidence (usually at least 50 % or more reduction defines a drugresponder), 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. #Currently there are no data available on which AED should beadded to imepitoin in case of inadequate seizure control. At this moment, the authors recommend the use of PB as adjunct AED in dogsreceiving the maximum dose of imepitoin and experiencing poor seizure control












One month later the dog had 4 seizures. What do you want to do now?

1. Check serum levels (PB)?2. Add potassium bromide or another

antiepileptic drug?3. Refer to a neurologist?4. Repeat the neurological exam?5. Ask for a video of the seizures?

When does safe sailing becomes a titanic experience?

When should a second AED be started?• Strict criteria for decision-making strategy

on starting a second AED is lacking in veterinary medicine

• Risk factors associated with poorer seizure control include male dogs and prior cluster seizure activity

• (Packer et al. 2014)

• Factors to consider• Selection of an AED with a different

mechanism of action• Minimizing drug-drug interactions, avoiding

additive toxicity• Determination of risk-benefit of

polypharmacy versus quality of life

• ACVIM Panel Recommendations:• Documentation of appropriate drug and

maximal level of first AED for a minimum of 3 months

• > 50% increase in seizure frequency over 3 months

• New onset of status epilepticus• New onset of cluster seizures• Presence of drug-toxicity

Prior tr

eatment

Prior LEV

LEV0

5

10

15

20

25 **

Seizu

re fre

quen

cy / m

onth

Prior tr

eatment.

Prior LEV.

LEV.0

5

10

15

20

25 *

Seizu

re da

ys / m

onth

Prior tr

eatment

Prior LEV

LEV0

5

10

15

20

25 **

Seizu

re fre

quen

cy / m

onth

Prior tr

eatment

Prior LEV

LEV0

5

10

15

20

25 *

Seizu

re da

ys / m

onth

Prior tr

eatment

Prior LEV

LEV0

5

10

15

20

25 *

Seizu

re fre

quen

cy / m

onth

Prior tr

eatment

Prior LEV

LEV0

5

10

15

20

25

Seizu

re da

ys / m

onth

All dogs Maintenance PulseA

B

C E

FD

RESEARCH ARTICLE Open Access

Assessment into the usage of levetiracetam in acanine epilepsy clinicRowena MA Packer, George Nye†, Sian Elizabeth Porter† and Holger A Volk*

Abstract

Background: Retrospective studies can complement information derived from double-blinded randomized trials.There are multiple retrospective studies reporting good efficacy and tolerability of the anti-epileptic drug levetiracetam(LEV) in human patients with epilepsy; however, reports of LEV's tolerability and efficacy in dogs with epilepsy remainlimited. The purpose of this retrospective study was to describe the use of LEV in a canine epilepsy clinic and determinethe long-term efficacy and tolerability of LEV in veterinary clinical practice. The electronic database of a UK basedreferral hospital was searched for LEV usage in dogs with seizures. Information and data necessary for the evaluationwere obtained from a combination of electronic and written hospital records, the referring veterinary surgeons’ recordsand telephone interviews with dog owners. Only dogs that were reportedly diagnosed with idiopathic epilepsy wereincluded in the study.

Results: Fifty-two dogs were included in this retrospective study. Two treatment protocols were recognised; 29 dogswere treated continuously with LEV and 23 dogs received interval or pulse treatment for cluster seizures. LEV treatmentresulted in 69% of dogs having a 50% or greater reduction of seizure frequency whilst 15% of all the dogs werecompletely free from seizures. Seizure frequency reduced significantly in the whole population. No dog was reportedto experience life-threatening side effects. Mild side effects were experienced by 46% of dogs and a significantly highernumber of these dogs were in the pulse treatment group. The most common side-effects reported were sedation andataxia.

Conclusions: LEV appears to be effective and well tolerated for reduction of seizures.

Keywords: Dog, Safety, Seizure, Tolerability, Treatment

BackgroundDouble-blinded, randomized controlled clinical trials toestablish efficacy and safety of novel AEDs are of pivotalimportance, but are not without limitations due to theiroften strict dosing and entry requirements, reducingtheir applicability to the wider population, e.g. geriatricpatients or those with multiple co-occurring conditions.In studies of epilepsy treatment in humans post-marketingstudies assessing the clinical use of a drug deemed animportant tool, with the most valuable data on efficacyand safety thought to be obtained from prospective andretrospective studies that are monocentric, and gatherinformation on long-term anti-epileptic drug therapy ina single centre only [1,2]. Multiple new anti-epileptic

drugs (AED) have been developed in the last two de-cades in human medicine, which have similar efficacybut are safer and better tolerated than older AEDs [3-5].One such drug is levetiracetam (LEV), for which thereare multiple clinical observational studies reportinggood efficacy and tolerability in human patients withepilepsy [1,6-8].Some of the new AEDs in humans, such as gabapentin,

pregabalin, zonisamide and levetiracetam have beentrialled in dogs with poorly controlled seizures withvariable success [9-15]. LEV, a structurally novel AED,is one of the more promising AEDs for canine epilepsy.LEV seems to act by a unique mechanism; modulationof synaptic release of neurotransmitters by binding to thesynaptic vesicle protein 2A (SV2A) [16,17]. In addition toits seizure-suppressing activity, previous experiments inchronic epilepsy models in rodents suggested that LEV

* Correspondence: [email protected]†Equal contributorsDepartment 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 CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.

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

8/13/19

7

ACVIM Panel Grade of Recommendations (Level of Evidence) for Add-On AED Therapy

A (HIGH) B (MODERATE)

• Levetiracetam (IB)

• Bromide (II)• Zonisamide

(III)• Phenobarbital

(IV)

C (LOW)

• Imepitoin (III)

D (NO)

• Primidone (II)

Potassium bromide –add on/first line (not in cats)

• Potassium bromide (KBr)• Dose 30-40 mg/kg SID• Half-life 15-20 days• Time to steady state 100-200 days• Therapeutic range 0.7 – 1.9 mg/ml/2.3 mg/ml• Side effects sedation, weakness, PU, PD, GI irritation,

(pancreatitis)• Excretion renal• Obtain plasma level 4 wks, 8-12 wks, then q 6m

• Loading dosage if indicated• 600 mg/kg (equal doses over 6 days )+ maintenance dose

IVETF – Add-on Potassium Bromide

KBr is used as adjunct AED to PB may be more prone toadverse effects. In these cases, a PB dose decrease of 25 %may be needed. Serum KBr levels should be monitored 1month after loading.Dose increases can be calculated according to the fol-

lowing formulaFormula B:For concomitant PB and KBr treatment, the new main-

tenance dose can be calculated as follows:

2000 mg=l ‐ actual serum KBr steady‐state concentrationð Þ # 0:02

¼ mg=kg=day added to existing dose

Formula C:In case of monotherapy KBr, the new maintenance

dose can be calculated as follows:

2500 mg=l − actual serum KBr steady−state concentrationð Þ

# 0:02 ¼ mg=kg=day added to existing dose

Only PB and imepitoin are approved as first-line treat-ment of canine epilepsy in the EU. In most EU coun-tries, KBr is only approved as add-on treatment in dogsresistant to first-line treatments. None of the drugs

discussed in the following section are approved for treat-ment of dogs with epilepsy, thus, according to EU druglaws, these drugs can only be used as adjunctive treat-ment if monotherapy or polytherapy with the approvedtreatments have failed. Furthermore, except for levetirac-etam, none of the AEDs discussed in the following sec-tion have been evaluated in randomized controlled trialsin epileptic dogs, so that the evidence for their efficacy isvery limited [17].

LevetiracetamSo far, three studies evaluated the efficacy of levetirace-tam as an adjunct to other AEDs [79, 114, 127]. In allthese studies, the majority of the dogs were treated suc-cessfully by oral levetiracetam as adjunct AED. The useof oral levetiracetam was evaluated in an open-labelstudy and a response rate of 57 % was reported in dogswith drug resistant epilepsy [127]. In a recent random-ized placebo-controlled study by Muñana et al. (2012)[79], the use of levetiracetam was evaluated in dogs withdrug resistant epilepsy. A significant decrease in seizurefrequency was reported compared with baseline, however,no difference was detected in seizure frequency when

Fig. 3 KBr adjunct treatment flow diagram for decision making during seizure management in an otherwise healthy dog. *Criteria for (in)adequateseizure 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 threetimes 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), areduction in seizure severity, or a reduction in frequency of seizure clusters and/or status epilepticus). 2. Treatment not tolerated i.e. appearance ofsevere adverse effects necessitating discontinuation of the AED












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

Other AEDs

Insufficient Data

for Treatment

Recommendations

•Felbamate•1 clinical study (N= 6) (III)•6/6 with > 50% reduction for 6 months (CP seizures)

•Gabapentin•2 clinical studies N=25 (III)•11/25 with > 50% reduction for 3 or 4 months

•Pregabalin•1 clinical study (n =9) (III)•7/9 with > 50% reduction for 3 months

•Topiramate•1 clinical study (n =10) (III)•5/10 dogs with > 50% reduction for 6-15 months

•Lacosamide•No clinical studies

•Rufinamide•No clinical studies

8/13/19

8

temporal lobe epilepsy (1956; see Shorvon [8]). Advances in clinicalchemistry and the understanding of metabolic disease in the prewarand postwar years also identified some of the inherited metaboliccauses of epilepsy, a paradigm being the identification of phenylketon-uria (PKU) by Ivar Asbjørn Følling in 1934 (see Christ [9]).

1.2.2. The multifactorial nature of causation of epilepsyThe most important writer on the causes of epilepsy in this period

wasWGLennox. Although Lennoxwas primarily interested in idiopath-ic epilepsy, his greatest contribution, inmy view, to the theory of causa-tionwas to rediscover and update the nineteenth century concept of themultifactorial nature of etiology [10]. He recognized that there was, inmost cases, a combination of genetic acquired and precipitating causes.His famous analogies of the ‘river’ and ‘reservoir’ are shown in Fig. 1.

Despite this fact, he tended to divide epilepsy into genetic, acquired,and sympathetic categories (in the latter category, following Reynolds),based on what he considered their predominant cause. His acquired

Table 1The seventeen categories of brain lesions causing symptomatic epilepsy listed by Dandy [7].

Congenital malformation and maldevelopment, either general or focalTumorsAbscessesTuberclesGummataAneurysmsSyphilis with or without demonstrable gummata or vascular occlusionsAreas of cerebral degeneration and calcificationDepressed fracturesHamartomataForeign bodiesInjuries from trauma at birth or subsequently (focal or general)Connective tissue formation after traumaAtrophy of the brain after traumaThrombosis and embolismCerebral arteriosclerosisSequelae of obscure inflammatory processes including encephalitis

Fig. 1. a. Themultifactorial concept of epilepsy— the analogy of the river of causal factors from Lennox and Lennox [10]. “The genetic watershed is represented as three generations: par-ents, grandparents, andgreat grandparents [e.g., at A, a paternal grandmother has epilepsy]. A confluence of transmitted traits follows into (and through) thepatient…. In addition to thesebranching streams, there is an independent stream which rises in a lake (the uterus). The outlet is the birth canal and below that are contributing streams: infections [e.g., at B, a viralencephalitis], brain trauma from diverse sources, brain tumor, and circulatory disorders. This side stream enters the main stream at the patient level and combines with the genetic influ-ences which had travelled through three generations tomake him have epilepsy. There is then a third streamwhich enters below the confluence of the twomain streams. This representstransient conditionswhichmay precipitate certain seizures in a person already having epilepsy or “all set” to be. This evoking circumstancemay be physiologic (say at C, hypoglycemia) oremotional (say at D, a broken wedding engagement)”. b. The epileptic threshold— the analogy of the reservoir from Lennox and Lennox. “Causes may be represented as the sources of areservoir. At the bottom is the already present volume of water, which represents the person's predisposition, a fundamental cause. However, the reservoir is supplied also by streamswhich represent the contributory conditions, such as lesions of the brain acquired since conception, certain disorders of bodily function, and emotional disturbances. Periodic overflowof the bank represents a seizure”.

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

factors [20]. The term acute provoked seizure can be used for the lattercategory of seizures, as has been anyway in use for over 100 years.

8. Points to consider in future work

It can be seen from the above that the concept of ‘symptomatic’ ep-ilepsy is complex. In future work, the following points might beconsidered:

1. In considering cause in epilepsy, it would be better to refer to ‘causalfactors’ and to use risk factor methodologies (odd ratios; i.e., suscep-tibilities) to provide a firm statistical basis of the strength of the‘causal factor’. This might obviate the need to divide into categories(idiopathic/symptomatic, etc.). However, for the time being, al-though artificial, such categorization is necessary clinically to bringorder (see, for instance, Hughlings Jackson's distinction betweenthe botanist's and the gardener's type of classification).

2. A greater focus on the proximate causes (molecular causal factors)than the remote causes (downstream pathologies) might lead to amore rational classification than our current rather empirical schemes.Thiswould be the sort of paradigm shiftwhichwould justify the adop-tion of new classification schemes.

3. A binary division of causes into idiopathic/symptomatic epilepsiesfails to recognize the importance of ‘provoking’ factors (the ‘exciting’factors of the nineteenth century). These factors are often as impor-tant a cause as any symptomatic or idiopathic causal factor. Althoughmost epilepsies have contributions from genetic, symptomatic,and provoking causes, to have a separate category of ‘provoked’epilepsy at least emphasizes the importance of the latter category.

4. It is now possible to list the remote causal factors in symptomatic ep-ilepsy. It is likely that all or almost all of the structural andmonogenicmetabolic disorders have been recognized. However, it is also likelythat when there are new investigatory modalities, especially in rela-tion to molecular mechanisms, new ‘causes’ will be recognized.

5. Idiopathic epilepsy is not simply ‘genetic’. There are influences fromneurodevelopment (the influence of the dimension of time) andchance and epistatic and epigenetic influences. These mechanismsrequire further investigation.

6. The term acute symptomatic seizure in its current form should beeither abandoned or redefined. It should not include both the earlyseizures in acute brain insults (head injury, stroke, etc.) and seizuresdue to reversible provoking factors (fever, metabolic disturbance,drugs, toxins, etc.). If it is retained, a more consistent approach todefining criteria is needed.

7. In relation to etiology, the new ILAE classification scheme has not fullyaccounted for many of the complexities in defining cause. Therenamingof idiopathic as genetic, symptomatic as structural/metabolic,and cryptogenic as unknown should be reconsidered.

Acknowledgment

This paper is based on theDistinguished Epileptologist Lecture givenat the 6th Cleveland International Epilepsy Symposium in May 2013.The invitation to give the lecture was from Dr. Samden Lhatoo, and Igratefully acknowledge his support and assistance. The ideas for thislecture and paper are partly reproduced from the author's contributionsto the book, The Causes of Epilepsy [12], and other papers [11,21].

Disclosure

I confirm that I have no conflict of interest to declare in relation tothis paper. I confirm that I have read the Journal's position on issues in-volved in ethical publication and affirm that this report is consistentwith these guidelines.

References

[1] Sieveking E. Epilepsy and epileptiform seizures: their causes, pathology and treat-ment. London: John Churchill; 1858.

[2] Spratling W. Epilepsy and its treatment. London, Philadelphia, New York: WBSaunders & Co; 1904.

[3] Reynolds JR. Epilepsy: its symptoms, treatment and relation to other chronic convul-sive diseases. London: Churchill; 1861.

[4] Taylor J. Selected writings of John Hughlings Jackson, vol. 1. London: Hodder andStoughton; 1930 162–72.

[5] Gowers W. A manual of diseases of the nervous system. London: Churchill; 1888.[6] Gowers W. Epilepsy and other chronic convulsive disorders. London: Churchill;

1881.[7] Dandy WE. The practice of surgery. The brain. In: Lewis D, editor. The practice of

surgery, vol. XII. Connecticut: Prior WF; 1932.[8] Shorvon SD. An episode in the history of temporal lobe epilepsy: the quadrennial

meeting of the ILAE in 1953. Epilepsia 2006;47:1288–91.[9] Christ SE. Asbjørn Følling and the discovery of phenylketonuria. J Hist Neurosci

2003;12:44–54.[10] Lennox WG, Lennox M. Epilepsy and related disorders. Boston: Little Brown; 1960.[11] Wilson SAK. Neurology. London: Edward Arnold; 1940.[12] Shorvon SD, Andermann F, Guerrini R, editors. The causes of epilepsy: common and

uncommon causes in adults and children. Cambridge: Cambridge University Press;2011.

[13] Shorvon SD. The etiologic classification of epilepsy. Epilepsia 2011;52(6):1052–7.[14] Johnson MR, Shorvon SD. Heredity in epilepsy: neurodevelopment, comorbidity,

and the neurological trait. Epilepsy Behav 2011;22(3):421–7.[15] Aird RB, Gordon NS. Some excitatory and inhibitory factors involved in the epileptic

state. Brain Dev 1993;15:299–304.[16] Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Re-

vised terminology and concepts for organization of seizures and epilepsies: report ofthe ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia2010;51:676–85.

[17] Shorvon SD. New terminologies: the downsides. Epilepsia 2013;54(6):1134.[18] Annegers JF, Hauser WA, Lee J, Rocca WA. Incidence of acute symptomatic seizures

in Rochester Minnesota, 1935–1984. Epilepsia 1995;36:327–33.[19] Hauser W, Beghi E, Carpi A, Fosgren L, Hesdorffer D, Malmgren K, et al. Recommen-

dations for a definition of acute symptomatic seizure. Epilepsia 2010;51:671–5.[20] Shorvon S, Guerrini R. Acute symptomatic seizures—should we retain the term?

Epilepsia 2010;51(4):722–3.[21] Shorvon SD. The causes of epilepsy: changing concepts of etiology of epilepsy over

the past 150 years. Epilepsia 2011;52(6):1033–44.

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

Evidence

Owner’s understanding

and value system

Clinical Expertise

OneHealth

8/13/19 46

13.08.19 47

• 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.

Compliance

Compliance factors Response

Median compliance percentage (range)

P-Value

Number of medications

One medication (n=70) 50% (0-100) 0.031

Two medications (n=24) 75% (0-100)

Number of tablets per day

One or less tablets (n=14) 64.8% (0-100)

0.61 1.5 or more tablets

(n=80) 56.4% (0-100)

Insurance Insured (n=15) 70% (0-100)

0.98 Not Insured (n=79) 55.6% (0-100)

8/13/19

9

What next in canine epilepsy research?

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

Tsz Hong Law1,2, Emma S. S. Davies1, Yuanlong Pan3, Brian Zanghi3, Elizabeth Want2 andHolger A. Volk1*1Department of Clinical Science and Services, Royal Veterinary College, Hatfield AL9 7TA, UK2Section of Computational and Systems Medicine, Imperial College, London SW7 2AZ, UK3Nestlé Purina Research, St Louis, MO 63164, USA

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

AbstractDespite 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 MCTDor placebo diet for 3 months followed by a subsequent respective switch of diet for a further 3 months. Seizure frequency, clinical andlaboratory data were collected and evaluated for twenty-one dogs completing the study. Seizure frequency was significantly lower when dogswere 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 dogsachieved 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 alsoresulted 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 associatedwith 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 humansand dogs, with an estimated prevalence in dogs of 1–2 %(1) ina referral hospital population and 0·6 %(2) in first-opinionpractice. Higher prevalences up to 18 %(3) have been reportedin breed-specific studies with up to 33 % seen in certainfamilies(4). Epilepsy is characterised by recurrent epilepticseizures caused by abnormal, excessive, synchronous neuronalfiring patterns(5). Epilepsy has been associated with increasedrisk of premature and unexpected death, injuries, cognitivedeterioration, neurobehavioural dysfunction and reducedquality of life (QoL)(6–8). Despite ongoing research in under-standing the pathophysiological manifestation of seizures andepilepsy, the cellular mechanisms remain elusive. As a result,approaches towards antiepileptic therapy are usually directedtowards the control of seizures, most commonly chronicadministration of antiepileptic drugs (AED), rather than preventionof epileptogenesis or comorbidities. Despite appropriate AED

treatment, approximately one-third of dogs and humans withidiopathic epilepsy continue to experience seizures that aredifficult to control(9–11). Furthermore, AED-related side-effectssuch as ataxia, polyphagia, polyuria, polydipsia and incontinencein dogs as well as behavioural, sedative, cognitive or psychiatricadverse reactions in humans also contribute to reduction inQoL(12,13). This emphasises the importance of new treatmentstrategies to improve the welfare of people with epilepsy.

A myriad of anecdotal reports and some published literaturehave suggested the importance of dietary manipulation inseizure management(14). In particular, the ketogenic diet (KD)has been proposed as an alternative treatment strategy forcanine epilepsy(15). The ‘classic’ KD consisting of high fat,low protein and low carbohydrate, typically with ratios of up to4:1 fats to proteins and carbohydrates, was first introducedin the 1920s for use in patients with childhood epilepsy(16).Wilder initially suggested the use of the KD in order to mimic

* Corresponding author: H. A. Volk, fax +44 170 764 9384, email: [email protected]

Abbreviations: AED, antiepileptic drug; BHB, β-hydroxybutyrate; KBr, potassium bromide; KD, ketogenic diet; MCT, medium-chain TAG; MCTD, medium-chainTAG diet; MCTKD, medium-chain TAG ketogenic diet; PB, phenobarbital.

British Journal of Nutrition, page 1 of 10 doi:10.1017/S000711451500313X© The Authors 2015

Summary and ConclusionMCTD improves seizure control

• Most dogs showed a reduction in seizure frequency in 30 days when fed as an adjunct to veterinary therapy

• Over the course of 90 days:

• No effect on antiepileptic drug serum levels• MCTD significantly increases BHB serum levels

For Review Only

!

PLACEBO MCTD 0.0

0.5

1.0

1.5

2.0

BH

B le

vels

(mg/

dL)

Page 27 of 36

Cambridge University Press

British Journal of Nutrition Investigating the short-term effects of medium-chain triglycerides (MCT) supplement on canine epilepsy in drug-non responders

Dr Dr Benjamin-A. Berk MSc MRCVS1Resident ECVCN

RMA Packer1, TH Law1, A Wessmann2, A Bathen-Nöthen3, TS Jokinen-Pääkkönen4

A Knebel5, A Tipold5, Holger A. Volk1

1 Royal Veterinary College, Department of Clinical Science and Services (CSS), Hatfield, United Kingdom2 Pride Veterinary Centre, Riverside Road, Pride Park, Derby, UK3 Tierarztpraxis , Dr. A. Bathen-Nöthen ,Hatzfeldstraße, Cologne, Germany4 Faculty of Veterinary Medicine, Dep. of Equine and Small Animal Medicine, Helsinki, Finland5 Klinik für Kleintiere, Stiftung Tierärztliche Hochschule Hannover, Bünteweg, Hanover, Germany

8/13/19 53

7 antiepileptic therapy in dogs - fundamentals and...

Documents