See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/6362000

The efficacy and tolerability of Levetiracetam in pharmacoresistant epileptic

dogs

Article  in  The Veterinary Journal · July 2008

DOI: 10.1016/j.tvjl.2007.03.002 · Source: PubMed

CITATIONS READS

87 1,296

5 authors, including:

Holger Andreas Volk Alejandro Lujan-Feliu-Pascual

University of Veterinary Medicine Hannover Aúna Especialidades Veterinarias
236 PUBLICATIONS   3,067 CITATIONS    57 PUBLICATIONS   205 CITATIONS   

SEE PROFILE SEE PROFILE

Simon R Platt
University of Georgia
104 PUBLICATIONS   1,650 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

 Mielopatías en imagen avanzada centradas en mieloTC a través de un caso clínico View project

Influence of an MCT enriched diet on canine idiopathic epilepsy View project

All content following this page was uploaded by Alejandro Lujan-Feliu-Pascual on 17 January 2018.

The user has requested enhancement of the downloaded file.

 The
Veterinary Journal
The Veterinary Journal 176 (2008) 310–319
www.elsevier.com/locate/tvjl

The efficacy and tolerability of levetiracetam

in pharmacoresistant epileptic dogs
a,*
Holger A. Volk , Lara A. Matiasek b, Alejandro Luján Feliu-Pascual b,
Simon R. Platt c, Kate E. Chandler a
a
Department of Veterinary Clinical Sciences, Neurology, Royal Veterinary College, Hatfield AL9 7TA, UK
b
Centre for Small Animal Studies, Animal Health Trust, Neurology, Newmarket CD8 7UU, UK
c
Department of Small Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7390, USA

Accepted 8 March 2007

Abstract

Twenty-two dogs with idiopathic epilepsy which were pharmacoresistant to phenobarbitone and bromide were treated with levetirace-
tam as an add-on medication. Records of eight dogs were used retrospectively to determine a safe, efficient levetiracetam dosage. Four-
teen dogs were entered into a prospective, open label, non-comparative study. After 2 months of levetiracetam oral treatment (10 mg/kg
TID), 8/14 dogs responded significantly to the treatment and seizure frequency was reduced by P50%. In dogs that remained refractory,
the dosage was increased to 20 mg/kg TID for 2 months. One further dog responded to levetiracetam treatment.
Levetiracetam responders had a significant decrease in seizure frequency of 77% (7.9 ± 5.2 to 1.8 ± 1.7 seizures/month) and a decrease
in seizure days per month of 68% (3.8 ± 1.7 to 1.2 ± 1.1 seizure days/month). However, 6/9 responders experienced an increase in seizure
frequency and seizure days after 4–8 months continuing with the levetiracetam treatment at the last effective dosage. Levetiracetam was
well tolerated by all dogs and sedation was the only side-effect reported in just one of the 14 dogs.
Ó 2007 Elsevier Ltd. All rights reserved.

Keywords: Dog; Seizure; Levetiracetam; Antiepileptic drug; Refractory

Introduction polyphagia, ataxia, lethargy and hepatotoxicity) (Dewey,

2006).
Epilepsy is the most common chronic neurological dis- In human medicine there has been progress in develop-
order in both humans and dogs (Berendt, 2004; Chandler, ing better tolerated epilepsy treatment over recent decades
2006). Most epileptic dogs are treated successfully for life, (Beghi, 2004; Rogawski and Löscher, 2004; French et al.,
with the standard seizure suppressing drugs (‘‘antiepileptic 2004a,b). Conversely, in veterinary medicine there is still
drugs’’, AEDs) phenobarbitone (PB) and/or potassium a lack of data concerning new pharmacological treatment
bromide (KBr). However, in about 20–30% of treated dogs, options for epileptic patients, especially for pharmacoresis-
seizures are poorly responsive to treatment with a combi- tant patients. Many of the newer AEDs that show some
nation of PB and KBr (Schwartz-Porsche et al., 1985; effect and are well tolerated in humans (Beghi, 2004;
Podell and Fenner, 1993; Trepanier et al., 1998; Riek French et al., 2004a,b), are not efficacious in small animals
et al., 2002). Increasing the dosage of PB and KBr may due to inappropriate pharmacokinetics or life-threatening
improve seizure control but this is not always possible side-effects; these include vigabatrin, lamotrigine, tiagabine
due to side-effects and toxicity (e.g. polyuria/polydipsia, and oxcarbazepine (Podell, 1998; Löscher, 2003).
There are few alternative AEDs to use in canine phar-
*
Corresponding author. Tel.: +44 1707 666366; fax: +44 1707 649384. macoresistant patients. The human AEDs felbamate, gaba-
E-mail address: [email protected] (H.A. Volk). pentin and zonisamide have been successfully used as

1090-0233/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tvjl.2007.03.002
 H.A. Volk et al. / The Veterinary Journal 176 (2008) 310–319 311

additional drugs in some dogs with pharmacoresistant epi- specific for the laboratory of the Royal Veterinary College. Additional
lepsy (Podell, 1998; Dewey et al., 2004; Govendir et al., inclusion criteria were age of first seizure (<6 years) and no abnormal
magnetic resonance imaging findings.
2005; Von Klopmann et al., 2005; Dewey, 2006; Platt Epileptic dogs were considered eligible for LEV therapy if they met the
et al., 2007). The efficacy of felbamate has been presented criteria of pharmacoresistance. A dog was defined as pharmacoresistant if
in the form of a research abstract. Twelve of 16 dogs refrac- PB and KBr administration achieving therapeutic serum concentration
tory to PB and KBr treatment experienced a reduction in and steady state did not result in a seizure frequency reduction of P50%
seizure frequency after initiation of felbamate treatment (Trepanier et al., 1998; Regesta and Tanganelli, 1999). Dogs were included
if they were pharmacoresistant to the combination of PB and KBr. They
(Dayrell-Hart et al., 1996). Gabapentin and zonisamide were also accepted in the study if one of the drugs had caused life
have been shown to provide good short-term seizure con- threatening side-effects in the past which had resulted in the cessation of
trol (Dewey et al., 2004; Govendir et al., 2005; Platt the medication. The serum concentrations of PB and KBr were evaluated
et al., 2007), but their long-term efficacy is questionable prior to LEV administration. Only dogs which were in the upper part of
(Govendir et al., 2005; Von Klopmann et al., 2005). Thus, the therapeutic range were permitted to enter the study. The therapeutic
range for PB was 15–40 lg/mL (Cambridge Specialist Laboratory Ser-
new pharmacological treatment options with a high long- vices) and for KBr 0.5–1.9 mg/mL (Cambridge Specialist Laboratory
term efficacy and without risk of toxicity in dogs are Services).
urgently needed. A consistent patient history was collected using a questionnaire
Levetiracetam (LEV) is a structurally novel AED that designed according to guidelines provided by McColl et al. (2001) to avoid
has demonstrated a broad spectrum of antiepileptic activi- leading questions or bias and which had been previously tested on a
number of people with epileptic dogs (Holt et al., 2005). The data collected
ties both in experimental and human clinical studies. Previ- included: age of dog at first seizure, seizure type, frequency, severity,
ous experiments in chronic epilepsy models in rodents behaviour alterations, previous and current medications, side-effects seen.
suggested that LEV, in addition to its seizure-suppressing Seizures were classified according to the guidelines of the International
activity, may possess antiepileptogenic or disease-modify- League Against Epilepsy (ILAE; Wieser et al., 2001) modified for veteri-
ing activity (Löscher et al., 1998; Klitgaard and Pitkanen, nary patients as previously described by Berendt and Gram (1999) and
Licht et al. (2002). Cluster seizures were defined as an episode where more
2003; Yan et al., 2005). Epileptogenesis is generally defined than one seizure occurred within a 24-h period. Seizures were classified as
as the process that leads to the development of epilepsy. primary partial if there was consistent evidence of pre-ictal signs minutes
LEV seems to act by a unique mechanism, i.e. modulation prior to the ictal event or if initial clinical signs involved unilateral or
of synaptic release of neurotransmitters by binding to the asymmetric motor signs or only involved limited parts of the body. They
synaptic vesicle protein, SV2A (Lynch et al., 2004; Gillard were classified as simple partial seizures if there was no observed alteration
in consciousness and complex partial seizures if consciousness was altered
et al., 2006). Apart from its unique mechanism of action, in some way. Primary generalized seizures were classified if there were no
LEV is known to be well tolerated in humans on chronic pre-ictal signs (or aura) present and no particular part of the body was
treatment (Harden, 2001; Beghi, 2004; Grosso et al., involved first.
2005; Wilby et al., 2005; Yan et al., 2005). In veterinary The classification of primary generalised seizures that were used in this
medicine, only one abstract describes the tolerability and study were defined by the ILAE (tonic, clonic, tonic-clonic, myoclonic,
atonic and absence seizure types). Prodromal signs were defined when the
efficacy of LEV (Steinberg and Faissler, 2004). These seizure was preceded by a long period (lasting hours to days) of altered
authors showed a seizure frequency decrease of 54% when behaviour (such as attention seeking, irritability, or anxious behaviour)
LEV was added to PB and or KBr treatment but effects on without impairment of consciousness and without motor signs.
cluster seizures, seizure severity and long-term follow up Each owner was provided with a standard year diary to record the
was not described in the abstract. seizure frequency, severity, occurrences of cluster seizures, behaviour
alterations, side-effects (such as ataxia, sedation, aggression, tremor,
Here, we report a study designed to test the hypothesis weight gain, gastrointestinal disturbances) and any other significant events
that LEV is a highly efficacious and well tolerated AED recognised during LEV treatment.
in dogs with idiopathic epilepsy which are pharmacoresis- The study period was divided into pre-LEV and LEV administration
tant to PB and KBr. We studied the efficacy of different periods (Fig. 1). Each period consisted of two consecutive months to
dosages, effects on seizures and cluster seizures, seizure eliminate skewing of data based on cluster seizure episodes.
LEV (Keppra Solution, UCB Pharma) was given as an oral solution to
severity and discuss side-effects seen. The data have impli- ensure precise dosage administration. During the LEV-period, the dogs
cations for the clinical management of PB and/or KBr received 10 mg/kg of LEV three times daily (TID) per os for a 2 month
resistant dogs with epilepsy. period. If a dog had a seizure frequency reduction of <50% (LEV-non-
responder) and had no major side-effects, it then received 20 mg/kg TID
Materials and methods for a period of 2 consecutive months. Dogs with a seizure frequency
reduction of P50% in the LEV-period compared to the pre-LEV-period
The prospective part of the study was approved by the Royal Veteri- were classified as LEV-responders. The LEV selected doses of the study
nary College Care and Ethics committee. Participation was entirely vol- were based on the LEV dosage range used in the Steinberg and Faissler
untary and was only performed with signed owner consent. (2004) study and our own clinical experience (see below and Table 1). The
Only dogs which had an extensive work-up for idiopathic epilepsy were files of eight pharmacoresistant dogs presented in the past were reviewed
included in the study. The dogs had been diagnosed with idiopathic epi- for LEV dosage, efficacy (Table 1) and side-effects.
lepsy using the following inclusion criteria: normal interictal neurological At the end of the LEV-period (10 mg/kg TID [LEV1] or 20 mg/kg TID
examination, no significant abnormalities detected on haematology, bio- [LEV2]) the dogs’ status was examined (physical and neurological exam-
chemistry, dynamic bile acid testing, serology or quantitative polymerase ination, haematology, biochemistry, PB and KBr serum concentrations).
chain reaction (Toxoplasma gondii, Neospora caninum and canine dis- Additionally the seizure frequency, seizure type, intensity and associated
temper virus) and on cisterna magna cerebrospinal fluid examination. The side-effects were assessed by the aforementioned questionnaire. After the
reference values used for haematology and biochemistry in this study were sixth month and at the time of writing, the dogs receiving LEV were
312 H.A. Volk et al. / The Veterinary Journal 176 (2008) 310–319

Study design
2 months 2 months 2 months 5-6 months longterm

6m on
Pre-LEV LEV 1 LEV 2 LEV
Spontaneous recurrent
seizures treated with
phenobarbitone and\or
potassium bromide
no 50% reduction
of seizure frequency
if still refractory

No LEV LEV 10 mg/kg LEV 20 mg/kg LEV 10 or 20 mg/kg LEV 10 or 20 mg/kg

SEIZURE-MONITORING

Fig. 1. Schematic illustration of the protocol of the prospective study.

Table 1
Patient information and frequency of seizures or seizure days per month pre- and during LEV-treatment (retrospective study)
Case Breed Age (yr) Sex LEVdosea Seizures/month Seizure days/month
Pre-LEV LEV Pre-LEV LEV
1 Italian Spinone 4 ME 12.5 10.0 0 4.0 0
2 Border Collie 7 MN 20.0 25.0 0 8.0 0
3 Crossbreed 4 FN 23.3 5.0 0 3.0 0
4 Dalmatian 7 ME 24.0 5.0 0 1.0 0
5 Crossbreed 8 MN 30.0 1.0 0 0.5 0
6 Boxer 3 FE 10.0 6.0 6.0 2.0 2.0
7 Golden Retriever 5 FN 32.8 10.0 10.0 2.5 2.5
8 Crossbreed 5 MN 21.0 15.5 15.5 10.0 10.0
21.7 ± 7.8 9.7 ± 7.6 3.9 ± 6.0* 3.9 ± 3.4 1.8 ± 3.5*
LEV = levetiracetam; ME = male entire; MN = male neutered; FE = female entire; FN = female neutered.
a
P < 0.05 vs. Pre-LEV period.
*
LEV dose (mg/kg three times daily).

assessed for seizure frequency, seizure type, intensity and associated side- marrow suppression. LEV had been added to the treatment
effects of the previous 2 month period by telephone questionnaire. protocol TID (21.7 ± 7.8 mg/kg; range 10–32.8 mg/kg).
The responsible clinician chose the dosage according to
Statistical analysis its clinical efficacy (first two months), side-effects and the
owners’ concerns and financial constraints. The monthly
The D’Agostino and Pearson omnibus test was used to determine if the
data were normally distributed. All data were normally distributed. seizure frequency and the seizure days were significantly
Within group comparisons were performed by repeated measures reduced by 60% and by 53%, respectively.
ANOVA, followed by the paired t test. The paired t test was used to Five out of eight cases were classified as LEV-respond-
calculate significant differences between seizure frequency and seizure days ers having a 100% reduction in both seizure frequency
pre or during LEV treatment. The significance of differences in the seizure
and seizure days. The owners of the three LEV-non-
frequency or seizure days was calculated by the t test. Significant differ-
ences in the incidence of cluster seizures between LEV-responders and responders reported that the seizure frequency did not
LEV-non-responders were calculated by the Chi square test. All tests were change, but the seizure severity and post-ictal period
used two-sided; a P < 0.05 was considered significant. improved. Two of the initial LEV-responders (cases No.
1 and No. 5) had an increase in their seizure frequency 3
Results months following the start of LEV treatment. At this point
gabapentin was added to the former medication of PB,
Retrospective study KBr and LEV which did not improve the seizure control.
Dog No. 5 did not tolerate gabapentin and developed gen-
Eight pharmacoresistant patients from our case log were eralised paraesthesia. Thus, gabapentin was discontinued
reviewed (Table 1). All dogs were pharmacoresistant to PB and topiramate was added which did not improve the sei-
and KBr and had cluster seizures, apart from Case No. 1 in zure control P50% compared to its pre-LEV seizure fre-
which PB was formerly stopped due to evidence of bone quency. Two dogs (No. 5 and No. 7) receiving the
 H.A. Volk et al. / The Veterinary Journal 176 (2008) 310–319 313

highest doses of LEV (30 mg/kg or 32.8 mg/kg TID) were seizure frequency decreased significantly by 51%
reported to be sedated and due to the severity of sedation (8.21 ± 4.8 to 4.0 ± 3.0 seizures/month) and the seizure
in dog No. 7 the LEV dose was reduced. days frequency by 41% (4.9 ± 3.6 to 2.9 ± 2.8 seizure
Based on these data and the data of Steinberg and Faiss- days/month). Three of the eight LEV-responders had no
ler (2004) regarding effective LEV dosages and possible seizures in the first study period. Cases No. 11, No. 15
associated side effects, we chose to use a lower (10 mg/kg and No. 16 had a decrease in seizure severity. These dogs
TID) and a higher dosage (20 mg/kg TID) for the prospec- all had complex partial seizures with secondary generalisa-
tive study. tion in the pre-LEV period.
In the LEV drug period, cases No. 11, No. 15 and No.
Prospective study 16 demonstrated substantially less generalised seizure activ-
ity. Indeed, 66%, 60% and 100% of their complex partial
Fourteen dogs were included in this study. All dogs were seizures respectively, did not secondarily generalise,
pharmacoresistant to PB and KBr. In one dog, potassium whereas all of their partial seizures had generalised in the
bromide was stopped 6 months prior to the study due to pre-LEV period. One dog (case No. 17) had severe post-
the development of severe pancreatitis. Information con- ictal periods lasting up to 1 h in the pre-LEV period. On
cerning all patients: breed, sex, weight at study entry, age LEV the post-ictal period was only 5–15 min and the owner
at first seizure, age at study entry, seizure type, length of no longer had to restrain the dog. Case No. 15 had a 55%
time previously treated with PB and KBr and the serum reduction in seizure frequency, however the frequency of
concentration of PB and KBr at study entry is provided seizure days was only decreased by 45%. The dog’s LEV
in Table 2. Information regarding the frequency of seizures dosage was increased to 20 mg/kg TID which resulted in
and seizure days per month prior and during LEV treat- a response in both categories. The monthly seizure fre-
ment is presented in Table 3. quency was now reduced by 81% and the frequency of sei-
zure days by 73%. Case No. 17 became a LEV-responder at
Outcome after first or second dose of LEV the higher dosage and had a reduction of seizure frequency
and seizure days of 75%.
After the first two months 8/14 dogs responded signifi- Treatment with the higher LEV dosage was initiated
cantly to the lower LEV dosage with a 73% (8.4 ± 5.3 to which decreased the seizure frequency to a similar level
2.3 ± 2.2 seizures/month) decrease in seizure frequency than with the initial LEV dose. LEV-responders at both
and a 67% (3.9 ± 1.7 to 1.3 ± 1.2 seizure days/month) the lower and higher dosage had significant decreases in
decrease in seizure days per month. The overall monthly the frequency of seizures by 77% (7.9 ± 5.2 to 1.8 ± 1.7 sei-

Table 2
Patient information prior to entering the study, seizure type, time on PB and KBr treatment prior study and the corresponding serum concentration
Case Breed Sex Weight Age of 1st Age at Seizure Time on PB Time on KBr PB serum KBr serum
(kg) seizure study typea prior LEV prior LEV conc. prior conc. prior
LEV LEV
(lg/mL) (mg/mL)
9 German Shepherd FN 35.0 1 yr 6 mo 2 yr 7 mo CP 1 yr 6 mo 8 mo 29.0 1.3
10 Crossbreed FE 25.0 2 yr 6 mo 7 yr 0 mo SP 2 yr 9 mo 3 yr 0 mo 37.0 2.3
11 Crossbred FN 26.0 1 yr 6 mo 3 yr 10 mo CP 2 yr 4 mo 2 yr 2 mob 34.0
12 Lurcher MN 34.0 4 yr 0 mo 5 yr 8 mo TC 1 yr 3 mo 4 moc 43.0 1.7
13 German Pointer ME 33.0 1 yr 8 mo 3 yr 6 mo CP 1 yr 8 mo 1 yr 5 mo 32.5 1.7
14 Lurcher FN 20.5 1 yr 0 mo 1 yr 10 mo CP 10 mo 5 mo 29.7 1.6
15 Weimaraner FE 28.4 3 yr 0 mo 5 yr 0 mo CP 1 yr 8 mo 4 mo 35.0 1.2
16 German Shepherd FN 45.0 4 yr 2 mo 6 yr 10 mo CP 4 yr 2 mo 4 yr 0 mo 42.0 1.1
17 German Pointer ME 33.5 1 yr 6 mo 6 yr 0 mo TC 3 yr 6 mo 7 mo 38.0 1.5
18 Labrador Retriever MN 35.5 10 mo 2 yr 10 mo CP 1 yr 9 mo 9 mo 34.0 2.0
19 Labrador Retriever FN 24.6 2 yr 3 mo 2 yr 9 mo CP 2 yr 4 mo 3 moc 21.0 2.4
20 Beagle ME 21.8 2 yr 0 mo 7 yr 0 mo CP 5 yr 0 mo 3 yr 11 mo 37.0 1.7
21 Crossbreed ME 6.5 1 yr 6 mo 5 yr 0 mo CP 3 yr 3 mo 2 yr 3 mo 40.0 1.6
22 Border Collie ME 29.8 11 mo 2 yr 0 mo TC 1 yr 1 mo 5 mo 45.0 1.8
28.5 ± 2.4 2 yr ± 3 mo 4 yr 5 mo ± 6 mo 2 yr 4 mo ± 4 mo 1 yr 5 mo ± 5 mo 35.5 ± 6.3 1.7 ± 0.4
(LEV = levetiracetam; PB = phenobarbitone; KBr = potassium bromide; ME = male entire; MN = male neutered; FE = female entire; FN = female
neutered).
a
All seizures are primary (tonic-clonic = TC) or secondary (complex partial = CP; simple partial = SP) generalised seizures.
b
KBr was stopped 6 mo prior study, because the dog developed pancreatitis. The dog was refractory to KBr and had at that time point a serum
concentration of 1.9 mg/mL.
c
KBr treatment was initiated by a KBr loading protocol of 600 mg/kg distributed equally over 3 days in addition to the KBr maintenance dose.
314 H.A. Volk et al. / The Veterinary Journal 176 (2008) 310–319

Table 3
Frequency of seizures or seizure days pre- and during LEV-treatment
Case Cluster seizures Number of seizures/month Number of seizure days/month
a b
Pre-LEV LEV 1 LEV 2 6m on LEV Pre-LEV LEV 1a LEV 2b 6m on LEV
LEV-responder (LEV 1)
9 No 3.0 0.0 3.0 0.0
10 No 3.0 0.0 0.0 3.0 0.0 0.0
11 Yes 13.5 1.5 2.0 6.5 1.0 2.0
12 Yes 4.0 0.0 3.5 1.0 0.0 2.0
13 Yes 6.0 3.0 1.0 4.0 2.0 1.0
14 Yes 8.5 4.0 4.0 3.5 2.0 4.0
15 Yes 13.0 5.5 2.5c 4.5c 5.5 3.0 1.5 2.5
16 Yes 16.5 4.0 4.5c 5.5c 5.0 2.0 3 3.5
LEV-responder (LEV 2)
17 No 4.0 2.5 1.0 1.0 2.5 4.0 1.0 1.0
LEV-nonresponder
18 No 16.0 9.0 8.5 16.0 9.0 8.5
19 No 5.0 6.0 9.0 12.0 5.0 6.0 9.0 12.0
20 Yes 9.5 8.0 7.0 9.0 7.5 7.0 6.0 6.0
21 Yes 4.0 4.0 5.0 4.0 4.0 5.0
22 Yes 9.0 8.0 6.0 12.0 2.0 2.0 1.5 3.5
a
LEV 1 (10 mg/kg TID).
b
LEV 2 (20 mg/kg TID).
c
See details in the text.

zures/month) and seizure days per month of 68% (3.8 ± 1.7 again. At the time of writing, 6 months later the dog had
to 1.2 ± 1.1 seizure days/month). The overall monthly sei- around 14–16 seizures per month.
zure frequency and frequency of seizure days were reduced
significantly by 55% (8.21 ± 4.8 to 3.7 ± 3.1 seizures/ Long-term follow up
month) and 43% (4.9 ± 3.6 to 2.8 ± 3.0 seizure days/
month), respectively. At the time of writing only three dogs remained as LEV-
responders. In cases No. 10 and No. 13 the follow up time
Six month follow up was 6 months. Cases No. 12, No. 15, No. 16 and No. 17
had an increase in seizure frequency in the seventh or
Six months after starting the last effective dosage of eighth month and were subsequently euthanased. The own-
LEV, 11 dogs were continued on LEV. Only these 11 dogs ers were reluctant to increase the LEV dosage due to finan-
were included in the comparison of pre-LEV and LEV per- cial constraints or concerns about the dog’s quality of life.
iod. The seizure frequency per month was significantly Case No. 14 remained controlled in the eighth month. The
decreased by 40% (8.4 ± 4.5 to 5.0 ± 4.3 seizures/month). dog had no cluster seizures and a frequency of four seizures
The frequency of seizure days did not differ significantly per month.
between the Pre- and LEV-period (4.1 ± 2.0 and Case No. 11 had an increase in seizure frequency after
3.4 ± 3.3 seizure days/month). LEV was stopped in case the first 6 months. The seizures were controlled for a fur-
No. 9 after the second month, because the dog became ther 4 months with 20 mg/kg LEV TID, before the seizure
severely sedated. Case No. 12 had an increase in seizure fre- frequency increased again. By the seventeenth month on
quency and in number of seizure days and was reclassified LEV the dog was maintained on PB and the cluster seizures
as a LEV-non-responder. Thus, six LEV-responders are controlled by a short period of LEV at 20 mg/kg TID.
remained 6 months post initiation of treatment. Their After each cluster the dog’s LEV dosage is tapered off over
monthly frequency of seizures and seizure days were signif- a 3 day period.
icantly decreased by 75% (9.2 ± 5.2 and 2.3 ± 2.0 seizures/ Only two of the LEV-non-responders were alive at the
month) and 53% (4.3 ± 1.4 and 2.0 ± 1.4 seizure days/ submission of the manuscript, cases No. 18 and No. 21
month), respectively. (see above). Cases No. 19 and No. 22 were both euthan-
The LEV-non-responder case No. 18 had a 47% ased in the seventh month of the study. Case No. 20
decrease in frequency of seizures and seizure days when received topiramate 2.5 mg/kg TID which did not decrease
he was treated with LEV. Gabapentin 10 mg/kg TID was the seizure frequency in addition to PB, KBr and LEV. The
added and LEV was tapered off. This resulted in an dog had a second magnetic resonance scan and cisternal
increase of seizures to 14 seizures per month. The dog cerebrospinal fluid analysis, which were unremarkable.
was also severely sedated and gabapentin was tapered off The dog was euthanased three months later. At this time
 H.A. Volk et al. / The Veterinary Journal 176 (2008) 310–319 315

point the dog had multiple generalised seizures around 3–4 active again. Three of these dogs were LEV-non-
days a week. responders.

Discussion
Differences in seizure frequency and pattern
The results of this study demonstrate that LEV is an ini-
Prior to the LEV treatment the seizure frequency per
tially effective treatment in about two-thirds of dogs with
month or seizure days was not statistically different
PB and KBr resistant epilepsy. However, most of these
between LEV-non-responders (8.7 ± 4.7 or 6.9 ± 5.5) and
dogs experienced an increase in seizure frequency and sei-
LEV-responders (7.9 ± 5.2 or 3.8 ± 1.7). Dogs with cluster
zure days after 4–8 months. Three out of 14 dogs were still
seizures were no more likely to respond to LEV.
responding to LEV treatment at the time of the manu-
script. Two dogs were still controlled after 6 months, and
Blood evaluation and side-effects one after 8 months. LEV was well tolerated by all of the
dogs; sedation was the only side-effect reported in 3/22
In 12 dogs the weight was also evaluated during the dogs.
LEV period at the time of re-examination. In these dogs Around 60% of human patients with intractable epilepsy
the weight was not different prior or during LEV treatment, suffer from partial seizures, mainly of the complex type
30.6 ± 6.9 kg or 30.3 ± 6.1 kg. (Reynolds et al., 1983; Regesta and Tanganelli, 1999). To
The PB and KBr serum concentration were evaluated the authors’ knowledge no similar investigation has been
before and after the first two months of the study in eight performed in dogs. Interestingly, in our study, 79% of the
and seven dogs respectively. There was no significant differ- dogs’ seizures were classified as complex partial. It is gener-
ence between the two time points in PB (32.5 ± 5.8 lg/mL ally believed that partial seizures are more challenging to
and 32.8 ± 4.6 lg/mL) and KBr serum concentrations treat in both humans and dogs. Apart from the seizure type
(1.8 ± 0.4 mg/mL and 1.7 ± 0.3 mg/mL). as a predictor for refractoriness a high seizure frequency
Complete blood counts and serum biochemical profiles has been suggested to be correlated with intractable epi-
were performed in 12 dogs before and after the first 2 lepsy in human medicine (Regesta and Tanganelli, 1999).
months of LEV treatment. There were no haematological All of the dogs in this study had three or more seizures a
abnormalities noted pre or during LEV treatment. The bio- month. The mean frequency of seizures or seizure days
chemistry variables were not different pre- or during LEV per month was 8.2 or 4.9, respectively, prior to LEV treat-
treatment and were all within normal limits apart from ala- ment. Nine of the 14 n dogs had episodes of cluster sei-
nine aminotransferase (ALT) and alkaline phosphatase zures. We found no difference between the LEV-
(ALP) activity. Two dogs (cases No. 11 and No. 22) had responders and LEV-non-responders in terms of frequency
marked elevation in ALT and/or ALP activity already of seizures or of seizure days.
before LEV treatment. In case No. 11 the ALT activity LEV is a novel AED available in Europe and USA and
was pre-LEV 124 U/L (Reference range: 13–88 U/L) and unique in its pharmacological properties. It differs from
during LEV treatment 115 U/L, the ALP activity was currently available AEDs in that its inhibitory effects are
1303 U/L (Reference range: 19–285 U/L) and 1125 U/L not observed in models of acute seizure such as the maxi-
respectively. The ALT activity of the second dog, case mal electroshock seizure and pentylenetetrazole tests.
No. 22, was pre-LEV 224 U/L and during 118 U/L, the LEV is however effective in controlling seizures in certain
ALP activity was 817 U/L and 788 U/L. Both dogs had chronic animal models such as the kindling and genetic
normal dynamic bile acids testing. Four dogs had elevated models (Löscher and Honack, 1993; Gower et al., 1995;
ALP activity prior to LEV treatment and five dogs during Klitgaard et al., 1998; Klitgaard, 2001; Glien et al., 2002;
LEV treatment. Sasa et al., 2005). Additionally, unlike other AEDs, the
Prior to LEV administration a baseline for AED side- main mechanism for the antiepileptic action of LEV does
effects was evaluated. The side-effects reported in all dogs not involve Na+ channels and/or GABA or glutamate
treated with KBr and PB were polyphagia, weight gain, receptors (Sills et al., 1997; Zona et al., 2001; Tong and
polyuria, polydipsia and moderate ataxia. Two dogs were Patsalos, 2001; Rigo et al., 2002; Margineanu and Klitg-
reported to vomit occasionally after KBr administration. aard, 2003). However, some of the antiepileptic effects
One dog suffered from pancreatitis prior to the trial. Four include allosteric modulation of GABA/glycine receptors
dogs developed aggression towards other dogs during their (Rigo et al., 2002), inhibition of neuronal hypersynchrony
epilepsy and one of them developed aggression towards (Margineanu and Klitgaard, 2000) and inhibition of the N-
strangers. type Ca2+ channel (Niespodziany et al., 2001; Lukyanetz
During LEV treatment, the owners reported no change et al., 2002).
in the variables polyphagia, weight gain, polyuria, polydip- Recently, the synaptic vesicle protein SV2A has been
sia, ataxia and aggression. One dog was heavily sedated found to bind with LEV specifically (Fuks et al., 2003; Gil-
during the first 2 months. On the other hand, eight dog lard et al., 2003; Lynch et al., 2004; Gillard et al., 2006).
owners documented their dogs being more lively and inter- Although the physiological role of SV2A is not fully under-
316 H.A. Volk et al. / The Veterinary Journal 176 (2008) 310–319

stood, it may play an important role in the process of endo- Menachem et al., 2003). In rodent epilepsy models, toler-
cytosis, exocytosis, and recycling of neurotransmitters since ance also occurred after prolonged treatment with LEV
SV2A knockout mice show severe convulsions leading to (Löscher and Schmidt, 2006). In veterinary medicine, it
death (Crowder et al., 1999). While it is unknown whether has recently been reported that the ‘‘honeymoon effect’’
LEV inhibits or facilitates SV2A function, binding of LEV might also be present in zonisamide-responders (Von Klop-
to SV2A may be involved in the antiepileptic effects. There mann et al., 2005).
is a strong correlation between binding affinity of LEV Pharmacokinetic tolerance has been associated with
derivatives to SV2A and their ability to protect against sei- multiple factors provoked by drug administration. These
zures in an audiogenic mouse model of epilepsy (Lynch include induction of drug-metabolizing enzymes and
et al., 2004). increase of multidrug transporters in the liver and kidney
In human medicine LEV has been shown to have a high (Löscher and Schmidt, 2006). The expression of P-glyco-
efficacy as a monotherapy for epilepsy (Alsaadi et al., 2005; protein at the BBB seems not to be induced by PB or phe-
Brodie et al., 2007) and as an add-on medication for phar- nytoin (Seegers et al., 2002). To the authors’ knowledge no
macoresistant epileptic patients (Beghi, 2004; French et al., such investigation identifies pharmacokinetic tolerance
2004b). In veterinary medicine, only one abstract describes resulting from LEV administration. However, pharmaco-
the efficacy of LEV in dogs with pharmacoresistant epi- dynamic tolerance is not an uncommon clinical occurrence.
lepsy (Steinberg and Faissler, 2004) where an overall reduc- Seizures can return in human patients following several
tion of seizure frequency of 54% was demonstrated when months of seizure freedom without change of the treatment
LEV was added to PB and/or KBr treatment. The number plan (Löscher and Schmidt, 2006). Factors other than tol-
of dogs that responded significantly or had P50% reduc- erance have to be considered for the return of poor seizure
tion in their seizure frequency was not documented in the control. These include progression of the epilepsy, poor
research abstract. Also the time of LEV treatment was owner compliance, natural fluctuations of seizure fre-
not indicated. quency and acquired drug resistance mediated by mecha-
In the initial periods (LEV 1 and 2) of our prospective nisms other than tolerance (Löscher and Schmidt, 2006).
study, 36% of dogs were classified as LEV-non-responders. In one dog we used a previously described strategy to
Two of these dogs also received a further AED, topiramate overcome tolerance (Löscher and Schmidt, 2006) where
or gabapentin, which did not improve their response to the dog developed tolerance to LEV and the medication
treatment. In recent studies using zonisamide and gabapen- was ceased. Following this, only the dog’s cluster seizures
tin as an add on treatment for pharmacoresistant dogs with were intermittently treated successfully with short courses
epilepsy, the percentages of non-responders in their 3-and of LEV, which was stopped at the end of each cluster.
4-month study period were slightly higher at 42% and The owner reported good control of the cluster seizure epi-
55–59%, respectively, (Platt et al., 2007; Dewey et al., sodes with this strategy. This might be an interesting and
2004; Govendir et al., 2005), when our definition for phar- cost-effective strategy for the treatment of dogs with cluster
macoresistant epilepsy was applied. Despite the use of dif- seizures. Further studies are warranted to determine its
ferent AEDs with different mechanisms of action, it seems clinical potential.
that a similar percentage of dogs do not respond to phar- The pharmacokinetic profile of LEV has been regarded
macotherapy regardless of the particular drug used. as ‘‘ideal’’ for an AED, with good bioavailability, rapid
Nine of 14 dogs were classified as LEV-responders after achievement of steady-state concentrations, linear and
the initial study period. Interestingly, 6/9 LEV-responders time-invariant kinetics, minimal protein binding and mini-
experienced an increase in their seizure frequency and sei- mal metabolism (Patsalos, 2000). Orally administered LEV
zure days after 4–8 months. The remaining dogs had a fol- has approximately 100% bioavailability in dogs (Dewey,
low up of either 6 (n = 2) or 8 months (n=1). In two initial 2006). The major metabolic pathway of LEV is not depen-
LEV-responders we increased the LEV dose, which dent on the hepatic cytochrome P450 system, and LEV
resulted in a similar response to the lower dose. One possi- does not inhibit or induce hepatic enzymes to produce clin-
ble explanation is that the dogs developed tolerance to the ically relevant interactions in dogs or humans (Patsalos,
LEV treatment. Tolerance can be defined as the reduction 2000; Isoherranen et al., 2001; Benedetti et al., 2004). This
in response to the drug after repeated administration is especially interesting in dogs with hepatic dysfunction
(Löscher and Schmidt, 2006). (Dewey, 2006) for example due to a PB induced hepatopa-
In human medicine, a recent study has shown that LEV thy. In one study in dogs 50% of an administered LEV dose
had a high efficacy in the first weeks of treatment which was eliminated unchanged in urine (Isoherranen et al.,
was followed by a lower but more stable efficacy in the fol- 2001).
lowing weeks (French et al., 2005). This phenomenon, also In humans, LEV has a plasma half life of 7 ± 1 h, is
called the ‘‘honeymoon effect’’, has been documented for given twice daily and reaches steady state after 48 h (Patsa-
many AEDs such as carbamazepine, phenytoin, lamotri- los, 2000). In dogs, LEV has a plasma half life of
gine and gabapentin (Boggs et al., 2000). In a further 3.6 ± 0.8 h (Isoherranen et al., 2001) and administration
human study, 102/519 LEV-responders became LEV- has been recommended to be TID (Steinberg and Faissler,
non-responders after the first 3 months of treatment (Ben 2004; Dewey, 2006). Interestingly, it has been shown in rats
 H.A. Volk et al. / The Veterinary Journal 176 (2008) 310–319 317

that the half life of LEV in cerebrospinal fluid was signifi- of the children treated were reported to become ‘‘better
cantly longer and approximately twice that of the plasma behaved’’ and demonstrated increased levels of concentra-
half life (Doheny et al., 1999). Furthermore, it is believed tion (Grosso et al., 2005).
that the pharmacodynamic effect outlives the known
plasma half life (Cramer et al., 1999; Hovinga, 2001). Conclusion
In human medicine, therapeutic drug monitoring is not
widely practiced for LEV. This is because there is no clear LEV was effective in reducing seizure frequency initially
association between serum drug concentration and efficacy in the majority of dogs with PB and KBr resistant epilepsy.
of LEV and in any case it has an extremely high margin of However, most of the dogs experienced an increase in their
safety (Hovinga, 2001; Krakow et al., 2001; Johannessen seizure frequency and frequency of seizure days after 4–8
et al., 2003). There is no generally accepted serum target months. LEV was well tolerated in most dogs and the only
range for LEV in humans and the dose of an AED used side-effect reported was sedation. However, further studies
in humans tends to be limited by the side-effects. Johannes- would be necessary before to confirm the absence of behav-
sen et al. (2003) proposed a therapeutic serum concentra- ioural problems during LEV treatment. The drug is expen-
tion range of 5–45 lg/mL. We have measured serum sive for large breed dogs, which limited a further
concentrations in the past, but could not find a clinical incremental increase in those dogs which possibly devel-
association between the dosage given, the serum concentra- oped tolerance. Based on the results of this study, further
tion and the efficacy of LEV. Based on the human medicine investigation is warranted on the long-term efficacy of
guidelines and our clinical experience we did not measure LEV as an add-on medication for dogs with refractory epi-
LEV serum concentrations in this prospective study. lepsy. Furthermore, intermittent pulsed treatment of clus-
In the present study we found that LEV had a high tol- ter seizures could be efficacious and cost effective but this
erability. It did not change the severity of side effects exhib- hypothesis needs to be tested.
ited by all dogs on KBr and PB prior to LEV
administration. Furthermore, LEV treatment caused no Acknowledgements
significant changes in weight nor affected laboratory results
for hepatic, renal and haematological criteria. The only We thank Dr. Rodolfo Cappello, Dr. Giunio Bruto
side effect reported in our prospective study was sedation Cherubini, Emma Davies and Dr. Annette Wessmann for
in one dog. Long-term toxicity data for LEV in dogs shows their support during the study. We also thank Professor
that the drug is extremely safe (Dewey, 2006). In one study, Potschka for critical reading of the manuscript. Thanks
oral LEV was given in doses up to 1200 mg/kg/day for 1 also to the referring veterinarians. The first 2-4 months of
year, which caused salivation and vomiting in some dogs. the prospective study were supported by UCB Pharma
A stiff and unsteady gait was described in 1/8 dogs receiv- (Braine l’Alleud, Belgium).
ing 300 mg/kg/day. Treatment-related mortalities and his-
topathological changes were not reported (Dewey, 2006). References
As reported above, LEV also has a wide margin of
safety in humans that distinguishes it from other currently Alsaadi, T.M., Shatzel, A., Marquez, A.V., Jorgensen, J., Farias, S., 2005.
available AEDs (Briggs and French, 2004). Side-effects Clinical experience of levetiracetam monotherapy for adults with
usually occur in people within the first month after epilepsy: 1-year follow-up study. Seizure-European Journal of Epilepsy
treatment initiation, are not dose-dependent, are mainly 14, 139–142.
Beghi, E., 2004. Efficacy and tolerability of the new antiepileptic drugs:
mild-to-moderate, commonly resolve without stopping comparison of two recent guidelines. Lancet Neurology 3, 618–621.
the medication, and are transient when the medication is Ben Menachem, E., Edrich, P., Van Vleymen, B., Sander, J.W.A.,
stopped (Harden, 2001; Briggs and French, 2004). LEV Schmidt, B., 2003. Evidence for sustained efficacy of levetiracetam as
can cause side-effects such as sedation, nervousness, diar- add-on epilepsy therapy. Epilepsy Research 53, 57–64.
Benedetti, M.S., Coupez, R., Whomsley, R., Nicolas, J.M., Collart, P.,
rhoea, ataxia, tremor, and behavioural problems in a small
Baltes, E., 2004. Comparative pharmacokinetics and metabolism of
percentage of treated humans (Harden, 2001; Briggs and levetiracetam, a new anti-epileptic agent, in mouse, rat, rabbit and dog.
French, 2004; French et al., 2004a). Behavioural problems Xenobiotica 34, 281–300.
such as aggression are described primarily in children and Berendt, M., 2004. Epilepsy. In: Vite, C.H. (Ed.), Braund’s Clinical
adults with a prior psychiatric history (Harden, 2001; Neurology in Small Animals: Localization, Diagnosis and Treatment,
Briggs and French, 2004). The aggressive behaviour of International Veterinary Information Service, Ithaca, NY, USA
(www.ivis.org), July 2004. http://www.ivis.org/advances/Vite/ber-
the four dogs in our study was not exacerbated during endt/chapter_frm.asp?LA=1. (accessed 10 October 2006).
LEV treatment. However, further studies are necessary Berendt, M., Gram, L., 1999. Epilepsy and seizure classification in 63
before the possibility of this side-effect can be excluded. dogs: a reappraisal of veterinary epilepsy terminology. Journal of
Interestingly, eight dog owners documented that their Veterinary Internal Medicine 13, 14–20.
Boggs, J.G., Nowack, W.J., Drinkard, C.R., 2000. Analysis of the
dogs became more lively and interactive on LEV treatment.
‘‘honeymoon effect’’ in adult epilepsy patients. Epilepsia 41, 222.
Three of these dogs were LEV-non-responders. Similar Briggs, D.E., French, J.A., 2004. Levetiracetam safety profiles and
observations have been described in children with refrac- tolerability in epilepsy patients. Expert Opinion on Drug Safety 3,
tory epilepsy treated with LEV. In one study, 17 per cent 415–424.
318 H.A. Volk et al. / The Veterinary Journal 176 (2008) 310–319

Brodie, M.G., Perucca, E., Ryvlin, P., Ben-Menachem, E., Meencke, H.J., Govendir, M., Perkins, M., Malik, R., 2005. Improving seizure control in
2007. Levetiracetam Monotherapy Study Group. Comparison of dogs with refractory epilepsy using gabapentin as an adjunctive agent.
levetiracetam and controlled-release carbamazepine in newly diag- Australian Veterinary Journal 83, 602–608.
nosed epilepsy. Neurology 68, 402–408. Gower, A.J., Hirsch, E., Boehrer, A., Noyer, M., Marescaux, C., 1995.
Chandler, K., 2006. Canine epilepsy: what can we learn from human Effects of levetiracetam, a novel antiepileptic drug, on convulsant
seizure disorders? The Veterinary Journal 172, 207–217. activity in two genetic rat models of epilepsy. Epilepsy Research 22,
Cramer, J.A., Fisher, R., Ben Menachem, E., French, J., Mattson, R.H., 207–213.
1999. New antiepileptic drugs: comparison of key clinical trials. Grosso, S., Franzoni, E., Coppola, G., Iannetti, P., Verrotti, A., Cordelli,
Epilepsia 40, 590–600. D.M., Marchiani, V., Pascotto, A., Spalice, A., Acampora, B., Morgese,
Crowder, K.M., Gunther, J.M., Jones, T.A., Hale, B.D., Zhang, H.Z., G., Balestri, P., 2005. Efficacy and safety of levetiracetam: an add-on
Peterson, M.R., Scheller, R.H., Chavkin, C., Bajjalieh, S.M., 1999. trial in children with refractory epilepsy. Seizure 14, 248–253.
Abnormal neurotransmission in mice lacking synaptic vesicle protein Harden, C., 2001. Safety profile of levetiracetam. Epilepsia 42, 36–39.
2A (SV2A). Proceedings of the National Academy of Sciences of the Holt, G., Volk, H.A., Chandler, K., 2005. The use of a questionnaire to
United States of America 96, 15268–15273. compare clinical characteristics and type of seizure occurring in 3 dog
Dayrell-Hart, B., Tiches, D., Vite, C., Steinberg, S., 1996. Efficacy and breeds with idiopathic epilepsy. In: Proceedings of 18th Annual
safety of felbamate as an anticonvulsant in dogs with refractory European College of Veterinary Neurologist Symposium, Munich,
seizures. Journal of Veterinary Internal Medicine 10, 174. Germany.
Dewey, C.W., 2006. Anticonvulsant therapy in dogs and cats. The Hovinga, C.A., 2001. Levetiracetam: a novel antiepileptic drug. Pharma-
Veterinary Clinics of North America. Small Animal Practice 36, 1107– cotherapy 21, 1375–1388.
1127. Isoherranen, N., Yagen, B., Soback, S., Roeder, M., Schurig, V., Bialer, M.,
Dewey, C.W., Guiliano, R., Boothe, D.M., Berg, J.M., Kortz, G.D., 2001. Pharmacokinetics of levetiracetam and its enantiomer (R)-alpha-
Joseph, R.J., Budsberg, S.C., 2004. Zonisamide therapy for refractory ethyl-2-oxo-pyrrolidine acetamide in dogs. Epilepsia 42, 825–830.
idiopathic epilepsy in dogs. Journal of the American Animal Hospital Johannessen, S.I., Battino, D., Berry, D.J., Bialer, M., Kramer, G.,
Association 40, 285–291. Tomson, T., Patsalos, P.N., 2003. Therapeutic drug monitoring of the
Doheny, H.C., Ratnaraj, N., Whittington, M.A., Jefferys, J.G., Patsalos, newer antiepileptic drugs. Therapeutic Drug Monitoring 25, 347–363.
P.N., 1999. Blood and cerebrospinal fluid pharmacokinetics of the Klitgaard, H., 2001. Levetiracetam: the preclinical profile of a new class of
novel anticonvulsant levetiracetam (ucb L059) in the rat. Epilepsy antiepileptic drugs? Epilepsia 42, 13–18.
Research 34, 161–168. Klitgaard, H., Matagne, A., Gobert, J., Wulfert, E., 1998. Evidence for a
French, J., di Nicola, S., Arrigo, C., 2005. Fast and sustained efficacy of unique profile of levetiracetam in rodent models of seizures and
levetiracetam during titration and the first 3 months of treatment in epilepsy. European Journal of Pharmacology 353, 191–206.
refractory epilepsy. Epilepsia 46, 1304–1307. Klitgaard, H., Pitkanen, A., 2003. Antiepileptogenesis, neuroprotection,
French, J.A., Kanner, A.M., Bautista, J., Abou-Khalil, B., Browne, T., and disease modification in the treatment of epilepsy: focus on
Harden, C.L., Theodore, W.H., Bazil, C., Stern, J., Schachter, S.C., levetiracetam. Epileptic Disorders 5 (Supp. 1), S9–S16.
Bergen, D., Hirtz, D., Montouris, G.D., Nespeca, M., Gidal, B., Krakow, K., Walker, M., Otoul, C., Sander, J.W.A.S., 2001. Long-term
Marks Jr., W.J., Turk, W.R., Fischer, J.H., Bourgeois, B., Wilner, A., continuation of levetiracetam in patients with refractory epilepsy.
Faught Jr., R.E., Sachdeo, R.C., Beydoun, A., Glauser, T.A., 2004a. Neurology 56, 1772–1774.
Efficacy and tolerability of the new antiepileptic drugs I: treatment of Licht, B.G., Licht, M.H., Harper, K.M., Lin, S., Curtin, J.J., Hyson, L.L.,
new onset epilepsy: report of the Therapeutics and Technology Willard, K., 2002. Clinical presentations of naturally occurring canine
Assessment Subcommittee and Quality Standards Subcommittee of seizures: similarities to human seizures. Epilepsy and Behavior 3, 460–
the American Academy of Neurology and the American Epilepsy 470.
Society. Neurology 62, 1252–1260. Löscher, W., 2003. Pharmakologische Grundlagen zur Behandlung der
French, J.A., Kanner, A.M., Bautista, J., Abou-Khalil, B., Browne, Epilepsie bei Hund und Katze. Der Praktische Tierarzt 8, 574–586.
T., Harden, C.L., Theodore, W.H., Bazil, C., Stern, J., Schachter, Löscher, W., Honack, D., 1993. Profile of ucb L059, a novel anticonvul-
S.C., Bergen, D., Hirtz, D., Montouris, G.D., Nespeca, M., Gidal, sant drug, in models of partial and generalized epilepsy in mice and
B., Marks Jr., W.J., Turk, W.R., Fischer, J.H., Bourgeois, B., rats. European Journal of Pharmacology 232, 147–158.
Wilner, A., Faught Jr., R.E., Sachdeo, R.C., Beydoun, A., Löscher, W., Honack, D., Rundfeldt, C., 1998. Antiepileptogenic effects of
Glauser, T.A., 2004b. Efficacy and tolerability of the new the novel anticonvulsant levetiracetam (ucb L059) in the kindling
antiepileptic drugs II: treatment of refractory epilepsy: report of model of temporal lobe epilepsy. Journal of Pharmacology and
the Therapeutics and Technology Assessment Subcommittee and Experimental Therapeutics 284, 474–479.
Quality Standards Subcommittee of the American Academy of Löscher, W., Schmidt, D., 2006. Experimental and clinical evidence for
Neurology and the American Epilepsy Society. Neurology 62, loss of effect (tolerance) during prolonged treatment with antiepileptic
1261–1273. drugs. Epilepsia 47, 1253–1284.
Fuks, B., Gillard, M., Michel, P., Lynch, B., Vertongen, P., Leprince, P., Lukyanetz, E.A., Shkryl, V.M., Kostyuk, P.G., 2002. Selective blockade
Klitgaard, H., Chatelain, P., 2003. Localization and photoaffinity of N-type calcium channels by levetiracetam. Epilepsia 43, 9–18.
labelling of the levetiracetam binding site in rat brain and certain cell Lynch, B.A., Lambeng, N., Nocka, K., Kensel-Hammes, P., Bajjalieh,
lines. European Journal of Pharmacology 478, 11–19. S.M., Matagne, A., Fuks, B., 2004. The synaptic vesicle protein SV2A
Gillard, M., Chatelain, P., Fuks, B., 2006. Binding characteristics of is the binding site for the antiepileptic drug levetiracetam. Proceedings
levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain of the National Academy of Sciences of the United States of America
and in CHO cells expressing the human recombinant protein. 101, 9861–9866.
European Journal of Pharmacology 536, 102–108. Margineanu, D.G., Klitgaard, H., 2000. Inhibition of neuronal hypersyn-
Gillard, M., Fuks, B., Michel, P., Vertongen, P., Massingham, R., chrony in vitro differentiates levetiracetam from classical antiepileptic
Chatelain, P., 2003. Binding characteristics of [3H]ucb 30889 to drugs. Pharmacological Research 42, 281–285.
levetiracetam binding sites in rat brain. European Journal of Pharma- Margineanu, D.G., Klitgaard, H., 2003. Levetiracetam has no significant
cology 478, 1–9. gamma-aminobutyric acid-related effect on paired-pulse interaction in
Glien, M., Brandt, C., Potschka, H., Löscher, W., 2002. Effects of the the dentate gyrus of rats. European Journal of Pharmacology 466,
novel antiepileptic drug levetiracetam on spontaneous recurrent 255–261.
seizures in the rat pilocarpine model of temporal lobe epilepsy. McColl, E., Jacoby, A., Thomas, L., Soutter, J., Bamford, C., Steen, N.,
Epilepsia 43, 350–357. Thomas, R., Harvey, E., Garratt, A., Bond, J., 2001. Design and use of
 H.A. Volk et al. / The Veterinary Journal 176 (2008) 310–319 319

questionnaires: a review of best practice applicable to surveys of health glycoprotein in various rat brain regions. European Journal of
service staff and patients. Health Technology Assessment 5, 1–256. Pharmacology 451, 149–155.
Niespodziany, I., Klitgaard, H., Margineanu, D.G., 2001. Levetiracetam Sills, G.J., Leach, J.P., Fraser, C.M., Forrest, G., Patsalos, P.N., Brodie,
inhibits the high-voltage-activated Ca(2+) current in pyramidal M.J., 1997. Neurochemical studies with the novel anticonvulsant
neurones of rat hippocampal slices. Neuroscience Letters 306, 5–8. levetiracetam in mouse brain. European Journal of Pharmacology 325,
Patsalos, P.N., 2000. Pharmacokinetic profile of levetiracetam: toward 35–40.
ideal characteristics. Pharmacology and Therapeutics 85, 77–85. Steinberg, M., Faissler, D., 2004. Levetiracetam therapy for longterm
Platt, S.R., Abrams, V., Garosi, L.S., Abramson, C.J., Penderis, J., De idiopathic epileptic dogs. In: Proceedings of the 22nd Annual
Stefani, A., Wieczorek, L., 2007. Gabapentin Therapy for Refractory American College of Veterinary Internal Medicine Forum.
Idiopathic Epilepsy in Dogs. The Veterinary Record 159, 881–884. Tong, X., Patsalos, P.N., 2001. A microdialysis study of the novel
Podell, M., 1998. Antiepileptic drug therapy. Clinical Techniques in Small antiepileptic drug levetiracetam: extracellular pharmacokinetics and
Animal Practice 13, 185–192. effect on taurine in rat brain. British Journal of Pharmacology 133,
Podell, M., Fenner, W.R., 1993. Bromide therapy in refractory canine 867–874.
idiopathic epilepsy. Journal of Veterinary Internal Medicine 7, 318– Trepanier, L.A., Van Schoick, A., Schwark, W.S., Carrillo, J., 1998.
327. Therapeutic serum drug concentrations in epileptic dogs treated with
Regesta, G., Tanganelli, P., 1999. Clinical aspects and biological bases of potassium bromide alone or in combination with other anticonvul-
drug-resistant epilepsies. Epilepsy Research 34, 109–122. sants: 122 cases (1992–1996). Journal of the American Veterinary
Reynolds, E.H., Elwes, R.D.C., Shorvon, S.D., 1983. Why Does Epilepsy Medical Association 213, 1449–1453.
Become Intractable - Prevention of Chronic Epilepsy. Lancet 2, 952– Von Klopmann, T., Simon, D., Tipold, A., 2005. Zonisamide add-on
954. therapy for canine refractory epilepsy: Benefit or ‘‘Honey -Moon
Riek, S., Löscher, W., Rundfeldt, C., Tipold, A., 2002. Wirkung Effect’’. In: Proceedings of 18th Annual European College of Veter-
verschiedener antiepileptischer Substanzen beim Hund. Tierärztliche inary Neurologist Symposium, Munich, Germany.
Praxis 3, 91–92. Wieser, H.G., Blume, W.T., Fish, D., Goldensohn, E., Hufnagel, A.,
Rigo, J.M., Hans, G., Nguyen, L., Rocher, V., Belachew, S., Malgrange, King, D., Sperling, M.R., Luders, H., Pedley, T.A., 2001. ILAE
B., Leprince, P., Moonen, G., Selak, I., Matagne, A., Klitgaard, H., Commission Report. Proposal for a new classification of outcome with
2002. The anti-epileptic drug levetiracetam reverses the inhibition by respect to epileptic seizures following epilepsy surgery. Epilepsia 42,
negative allosteric modulators of neuronal. British Journal of Phar- 282–286.
macology 136, 659–672. Wilby, J., Kainth, A., Hawkins, N., Epstein, D., McIntosh, H., McDaid,
Rogawski, M.A., Löscher, W., 2004. The neurobiology of antiepileptic C., Mason, A., Golder, S., O’Meara, S., Sculpher, M., Drummond,
drugs. Nature reviews. Neuroscience 5, 553–564. M., Forbes, C., 2005. Clinical effectiveness, tolerability and cost-
Sasa, M., Yan, H.D., Ishihara, K., Nagayama, T., Serikawa, T., 2005. Is effectiveness of newer drugs for epilepsy in adults: a systematic review
levetiracetam distinct from conventional antiepileptic drugs in anti- and economic evaluation. Health Technology Assessment 9, 1–4.
epileptogenic properties in spontaneous epileptic rats? Epilepsia 46, Yan, H.D., Ji-qun, C., Ishihara, K., Nagayama, T., Serikawa, T., Sasa,
94–95. M., 2005. Separation of antiepileptogenic and antiseizure effects of
Schwartz-Porsche, D., Löscher, W., Frey, H.H., 1985. Therapeutic efficacy levetiracetam in the spontaneously epileptic rat (SER). Epilepsia 46,
of phenobarbital and primidone in canine epilepsy: a comparison. 1170–1177.
Journal of Veterinary Pharmacology and Therapeutics 8, 113–119. Zona, C., Niespodziany, I., Marchetti, C., Klitgaard, H., Bernardi, G.,
Seegers, U., Potschka, H., Löscher, W., 2002. Lack of effects of prolonged Margineanu, D.G., 2001. Levetiracetam does not modulate neuronal
treatment with phenobarbital or phenytoin on the expression of P- voltage-gated Na+ and T-type Ca2+ currents. Seizure 10, 279–286.

View publication stats