Packer et al. 8MC Veterinary Research (2015) 11:25
`DOI 10.1186/s12917-015-0340-x
`
`RESEARCH ARTICLE
`
`(3-;
`Veterinary Research
`
`Open Access
`
`Assessment into the usage of levetiracetam in a
`canine epilepsy clinic
`
`Rowena MA Packer, George Nyet, Sian Elizabeth Porters 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 remain
`limited. The purpose of this retrospective study was to describe the use of LEV in a canine epilepsy clinic and determine
`the long-term efficacy and tolerability of LEV in veterinary clinical practice. The electronic database of a UK based
`referral hospital was searched for LEV usage in dogs with seizures. Information and data necessary for the evaluation
`were obtained from a combination of electronic and written hospital records, the referring veterinary surgeons' records
`and telephone interviews with dog owners. Only dogs that were reportedly diagnosed with idiopathic epilepsy were
`included in the study.
`Results: Fifty-two dogs were included in this retrospective study. Two treatment protocols were recognised; 29 dogs
`were treated continuously with LEV and 23 dogs received interval or pulse treatment for cluster seizures. LEV treatment
`resulted in 69% of dogs having a 50% or greater reduction of seizure frequency whilst 15% of all the dogs were
`completely free from seizures. Seizure frequency reduced significantly in the whole population. No dog was reported
`to experience life-threatening side effects. Mild side effects were experienced by 46% of dogs and a significantly higher
`number of these dogs were in the pulse treatment group. The most common side-effects reported were sedation and
`ataxia.
`Conclusions: LEV appears to be effective and well tolerated for reduction of seizures.
`
`Keywords: Dog, Safety, Seizure, Tolerability, Treatment
`
`Background
`Double-blinded, randomized controlled clinical trials to
`establish efficacy and safety of novel AEDs are of pivotal
`importance, but are not without limitations due to their
`often strict dosing and entry requirements, reducing
`their applicability to the wider population, e.g. geriatric
`patients or those with multiple co-occurring conditions.
`In studies of epilepsy treatment in humans post-marketing
`studies assessing the clinical use of a drug deemed an
`important tool, with the most valuable data on efficacy
`and safety thought to be obtained from prospective and
`retrospective studies that are monocentric, and gather
`information on long-term anti-epileptic drug therapy in
`a single centre only [1,2]. Multiple new anti-epileptic
`
`Correspondence: hvolk@rvc.ac.uk
`'Equal contributors
`Department of Clinical Science and Services, Royal Veterinary College,
`Hatfield AL97TA, UK
`
`drugs (AED) have been developed in the last two de-
`cades in human medicine, which have similar efficacy
`but are safer and better tolerated than older AEDs [3-5].
`One such drug is levetiracetam (LEV), for which there
`are multiple clinical observational studies reporting
`good efficacy and tolerability in human patients with
`epilepsy [1,6-8].
`Some of the new AEDs in humans, such as gabapentin,
`pregabalin, zonisamide and levetiracetam have been
`trialled in dogs with poorly controlled seizures with
`variable 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; modulation
`of synaptic release of neurotransmitters by binding to the
`synaptic vesicle protein 2A (SV2A) [16,17]. In addition to
`its seizure-suppressing activity, previous experiments in
`chronic epilepsy models in rodents suggested that LEV
`
`C.) BioMed Central
`
`0 2015 Packer et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
`Commons Attribution License (http://creativecommoniorg/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 fhttp://creativecommons.org/publicdomainizero/1.0/1 applies to the data made available in t
`unless otherwise stated.
`
`ARGENTUM Exhibit 1055
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`Fit57-6;]
`
`Page 00001
`
`(cid:9)
`

`
`Packer et al. 8MC Veterinary Research (2015)11:25
`
`Page 2 of 8
`
`might also possess anti-epileptogenic or disease-modifying
`activity [18-21].
`Despite its potential, reports of LEVs tolerability and
`efficacy in epileptic dogs remain limited. Two recent
`clinical studies of acute seizures showed that LEV had
`good seizure suppressing activity in the dog. Dogs re-
`ceiving LEV 24 h prior to undergoing surgical attenuation
`of extrahepatic congenital shunts had a significantly de-
`creased risk of postoperative seizures [22]. In another
`study entailing dogs with cluster seizures or status epilep-
`ticus, LEV was superior compared to a placebo group in
`controlling seizure activity [23]. However, our current
`knowledge of LEV's efficacy in chronic canine epilepsy is
`limited to three studies using LEV in dogs with epilepsy
`refractory to Phenobarbitone (PB) and/or Potassium
`bromide (KBr) [12,14,24]. Two of these studies showed a
`good tolerability of the drug, but its efficacy was not as
`promising long-term as initially anticipated [12,14]. How-
`ever, it is known from epidemiological studies in human
`medicine that only very few patients will respond to a
`third AED, if they have not responded adequately to two
`standard AEDs [25]. Despite the aforementioned evidence
`of LEV's efficacy and tolerability for acute seizures
`and chronic epilepsy further studies are needed to evalu-
`ate LEV's long-term efficacy and tolerability in canine
`epilepsy.
`The aim of this retrospective study was to:
`
`(i) Describe the way LEV is used to treat epilepsy in a
`canine epilepsy clinic in a small animal referral hospital.
`(ii)Evaluate the long-term efficacy and tolerability of
`LEV in these dogs.
`
`Methods
`The study was approved by the Animal Care and Ethics
`committee of the Royal Veterinary College (RVC 2012/
`P129). The hospital's electronic records were searched
`for the terms 'levetiracetam','dog' and 'epilepsy' or 'seizure'
`between February 2006 and February 2012. Information
`and data necessary for the evaluation were obtained from
`a combination of electronic and written hospital records,
`the referring veterinary surgeons records and telephone
`interview with the dog's owner. Only dogs which were re-
`ported in the records to be diagnosed with idiopathic epi-
`lepsy (no remarkable findings on interictal neurological
`examination, haematology, biochemistry, brain magnetic
`resonance imaging and cerebrospinal fluid examination)
`and were administered LEV for .3 months were included
`in the study.
`Seizures were classified according to the former guide-
`lines of the International League Against Epilepsy, modi-
`fied for veterinary patients [26,27]. Cluster seizures were
`defined as an episode where more than one seizure oc-
`curred within a 24 h period. Status epilepticus was
`
`defined as seizure activity lasting longer than 5 min
`without gaining consciousness. A consistent history was
`collected with the help of a questionnaire [14]. The data
`collected included: signalment, age of dog at the time of
`the first seizure, age at death (if appropriate), age at
`diagnosis, age at start of treatment, age at follow up,
`weight recorded in the hospital, total number of seizures
`prior to any treatment with an antiepileptic drug (AED),
`seizure frequency (mean seizure frequency per month; in
`the case of cluster seizures each seizure was counted as
`one event) and seizure days frequency (number of days
`per month at which the dog had at least one seizure in a
`24 hours period) prior to administration of an AED,
`prior to LEV (Keppra, UCB Pharma) and during LEV
`treatment, seizure severity and intensity, alterations of
`behaviour, previous and current medications, side-effects
`seen with LEV and in particular whether there was an
`increase in the following variables during LEV treatment;
`sedation, polyphagia, decreased appetite, polydipsia, poly-
`uria, gastrointestinal signs, ataxia, restlessness, aggression
`and skin reactions.
`
`Statistical analysis
`Data is presented as median with range and interquartile
`ranges (IQR). Differences between variables of the two
`treatment protocols were tested with a Fisher's exact test
`for categorical variables and the Mann—Whitney U-test
`for continuous variables. Within groups, comparisons
`were performed by McNemar test for categorical data
`and the Friedman test, followed by the Dunn multiple
`comparison test for continuous data. Univariate analyses
`for non-parametric data were used to investigate associa-
`tions between AED-use prior to LEV and other clinical
`variables on treatment success (either a >50% reduction in
`seizure frequency or seizure freedom) using Chi-squared
`and Mann—Whitney U test for categorical and continuous
`variables, respectively. All tests were used two-sided with
`P < 0.05 being considered statistically significant.
`
`Results
`The search of the RVC's electronic database revealed
`128 dogs with epilepsy for which LEV was either recom-
`mended or prescribed. Sixty-four dogs fulfilled the in-
`clusion criteria of which six owners did not give consent
`to participate in the study and from a further six dogs
`follow-up data could not be gathered, leaving a study
`population of 52 dogs in total.
`
`(i) How was levetiracetam used to treat epilepsy in a
`canine epilepsy clinic?
`
`Study population
`Breeds represented in the study were Golden retriever
`(n = 7), Border collie (n = 5), crossbreed (n = 6), German
`
`Page 00002
`
`(cid:9)
`

`
`Packer et at. BMC Veterinary Research (2015)11:25
`
`Page 3 of 8
`
`shepherd (n = 4), Labrador retriever (n = 3), Staffordshire
`bull terrier (n = 3), Yorkshire terrier (n = 2), Weimeraner
`(n = 2), German shorthaired pointer (n = 2), Doberman
`pinscher (n = 2), Cocker spaniel (n = 2), Boxer (n = 2),
`Bichon Frise (n = 2), Hungarian Viszla, Beagle, Airedale
`terrier, Jack Russell terrier, Rottweiler, English springer
`spaniel, Welsh springer spaniel, Cavalier King Charles
`spaniel, Curly coated retriever and Irish setter (n =1
`each).
`
`Levetiracetam protocols
`Two LEV treatment protocols were recognised, 'mainten-
`ance' and 'pulse'. There was a trend for clinicians to use
`pulse therapy more frequently in the more recent years.
`Twenty-nine dogs were included in the maintenance
`group and were treated continuously with LEV. Twenty-
`three dogs received a pulse treatment protocol for cluster
`seizures (general protocol: an initial dose of —60 mg/kg
`after a seizure occurred or pre-ictal signs were recognised
`by the owner, followed by —20 mg/kg every 8 h until sei-
`zures did not occur for 48 h).
`LEV was prescribed for all dogs to improve seizure
`control apart from one case for which it was prescribed
`to shorten the post-ictal phase and in five cases it was
`used as a result of side-effects attributable to KBr and/or
`PB use (pancreatitis, marked behaviour change, severe
`ataxia).
`The LEV dose for the maintenance group was
`19.5 mg/kg three times daily (9-26.8; IQR 17-22.9 mg/kg),
`for the pulse treatment group the initial dose was approxi-
`mately three times the 8 hourly maintenance dose of
`22.2 mg/kg (10.6-31.3; IQR 19.9-23.8 mg/kg).
`
`Differences between levetiracetam maintenance and
`pulse treatment groups
`All the dogs in the pulse treatment group experienced
`cluster seizures and cluster seizures were reported in
`83% (95% CI 67.7-98.4%) of the dogs in the maintenance
`treatment group (P = 0.04). Twenty-four per cent (95%
`CI 6.6-41.5%) of dogs in the maintenance and 22% (95%
`CI 3.4-40.6%) in the pulse treatment group had a status
`epilepticus prior to LEV treatment (P > 0.05).
`There was no significant difference between the main-
`tenance and the pulse groups for the following variables;
`weight at start of LEV, age at first seizure, age at follow
`up, length of epilepsy, total number of seizures prior to
`treatment, time on PB and KBr prior to LEV treatment
`and age at start of LEV treatment (Table 1).
`Ninety per cent of dogs received treatment with an AED
`prior to LEV (Table 1), with 89.6% of the maintenance
`group and 91.3% of the pulse group. In addition to main-
`tenance treatment, 29% of dog owners were provided with
`rectal diazepam tubes to be used for prolonged seizure
`activity.
`
`(ii)Long-term efficacy and tolerability of LEV in
`epileptic dogs
`
`Results in seizure frequency and pattern
`LEV treatment resulted in 69% (95% CI 56.4-81.6%) of
`dogs having a 50% or greater reduction of seizure fre-
`quency with 15% (95% CI 5.3-24.7%) of dogs being free
`from seizures with a follow up time of 1.2 (0.3-6.4 years)
`and of 1.4 years (0.3-6.4 years) respectively. There was
`no significant difference in the number of responders
`between the maintenance and the pulse treatment
`group (a5096 seizure frequency reduction, 66% (95% CI
`46.6-85.4%) vs. 74% (95% CI 54.3-93.7%); free of seizures,
`7% (95% CI 0-17.4%) vs. 26% (95% CI 6.3-45.7); P> 0.05).
`Forty-two per cent (95% CI 28.6-55.4%) of dogs had
`a a50% reduction of seizure days frequency with a
`follow up time of 1.3 years (0.3-6.4 years). There was
`also no significant difference between the two groups
`in respect of the number of dogs that had a reduction
`of seizure days frequency (a50% seizure days frequency
`reduction, 44% (95% CI 23.7-64.3%) vs. 52% (95% CI
`29.5-74.5%); free of seizures, 7% (95% 0-17.4%) vs. 26%
`(95% CI 6.3-45.7%); P > 0.05).
`The seizure frequency (whole population, maintenance
`group) and the seizure days frequency (maintenance
`group) increased prior to LEV treatment compared to
`before any treatment (Figure 1). LEV reduced the seiz-
`ure frequency significantly in all groups, but the reduc-
`tion in seizure days frequency was only significant when
`analysing the data for the whole population.
`The percentage of dogs having cluster seizures in-
`creased prior to LEV treatment from 50% (95% CI
`36.4-63.6%) to 90% (95% CI 81.9-98.2%) (P = 0.02), which
`was also significant in the pulse treatment group (from
`39% (95% CI 17.1-60.9%) to 100%; P = 0.02) but not in the
`maintenance treatment group (from 59% (95% CI 38.9-
`79.1%) to 83% (95% CI 67.7-98.4%); P> 0.05). The number
`of dogs experiencing cluster seizures decreased on LEV
`treatment from 90% (95% CI 81.9-98.2%) to 27% (95% CI
`14.9-39.1%) (P = 0.0001). The dog owners reported that
`their dog's seizure severity (maintenance treatment group,
`45% (95% CI 24.7-65.3%); pulse treatment group, 43%
`(95% CI 20.7-65.3%)) and duration (maintenance treat-
`ment group, 7% (95% CI 0-17.4%); pulse treatment group,
`30% (95% CI 9.4-50.6%) improved during LEV treatment.
`
`Additional AEDs
`Five dogs in the LEV maintenance group did not re-
`spond adequately to LEV and zonisamide (n = 3) or
`gabapentin (n = 2) was added after 168 days (55-616;
`1QR 101-539 days). One dog did not respond to LEV in
`the pulse treatment group and topiramate was added
`after 92 days.
`
`Page 00003
`
`(cid:9)
`

`
`Packer et al. BMC Veterinary Research (2015) 11:25
`
`Page 4 of 8
`
`Table 1 Signalment of dogs included and relevant history
`Variable
`Maintenance (n = 29)
`Sex
`
`Male
`
`Male neutered
`
`Female
`
`Female neutered
`
`8 (27.4%)
`
`9 (31%)
`
`n/a
`
`12 (41.4%)
`
`Pulse (n = 23)
`
`Total (n = 52)
`
`5 (22%)
`
`10 (43.3%)
`
`1 (4.3%)
`
`7 (30.4%)
`
`13 (25%)
`
`19 (36.5%)
`
`1 (2%)
`
`19 (365%)
`
`Weight at start of LEV (kg)
`
`Age at first seizure (years)
`
`28.3 (7.5-77.9; IQR 23.3-33.6)
`
`22.8 (3.4-55; IQR 18.6-442)
`
`26.3 (3.4-77.9; IQR 19.2-362)
`
`1.9 (0.2-7.2; IQR 1.4-4)
`
`2.6 (0.8-7.6; IQR 1.5-4.8)
`
`2.6 (0.2-7.6; IQR 1.5-4.1)
`
`Age at follow up/death (years)
`
`6 (1-12; IQR 4.8-8)a
`
`Length of epilepsy (years)
`
`3 (0.1-8.6; IQR 1.5-5.5)
`
`Total number of seizures prior AED
`
`2 (0.3-60; IQR 1-3.5)
`
`Total number of seizures prior LEV
`
`53 (0.7-60; IQR 2.5-12)
`
`Total number of seizures on LEV
`
`2 (0-40; IQR 0.8-5.7)
`
`Total number of seizure days prior AED
`
`1 (0.3-7; IQR 1-2.5)
`
`Total number of seizure days prior LEV
`
`2 (0.7-12; IQR 1.2-4)
`
`Total number of seizures days on LEV
`
`2 (0-12; IQR 0.6-3)
`
`Treatment prior LEV
`
`No AED
`
`1 AED
`
`2 AED
`
`3 (10%)
`
`8 (28%)
`
`18 (62%)
`
`3 AED
`Time on PB prior LEV (days)
`
`n/a
`336 (2-1724; IQR 101-713)`
`
`6 (2-12; IQR 4.1-7.9)°
`2.3 (0.3-6.9;1Q11 1.6-3.2)
`
`3 (0.4-20; IQR 2-5)
`
`4 (0.7-15; IQR 2-9)
`
`1 (0-12; IQR 0-4)
`
`2 (0.3-6; IQR 1.3-3)
`1.5 (0.5-5.3; IQR 1-2)
`
`1 (0-4.7; IQR 0-2)
`
`2 (996)
`
`3 (13%)
`
`17 (74%)
`
`1 (4%)
`
`6.1 (1-12; IQR 4.6-8)
`
`3 (0.1-8.6; IQR 1.5-4.9)
`
`2.5 (0.3-60; IQR 1.1-5)
`
`4.8 (0.7-40; IQR 2-9.8)
`
`1.3 (0-40; IQR 0.5-4.8)
`1.6 (0.3-7; IQR 1-3)
`
`2 (0.5-10; IQR 1-3)
`
`1 (0-10; IQR 0.4-2.8)
`
`5 (10%)
`
`11 (21%)
`
`35 (67%)
`
`1 (2%)
`
`386 (3-2023; IQR 218-1044) °
`
`343(2-2023;10R 120-782)
`
`Time on KBr prior LEV (days)
`
`1047 (190-2443; IQR 713-1594)e
`
`1073 (330-2999; IQR 660-2449)f
`
`1101 (190-2999; IQR 689-1978)
`
`Age at start of LEV (years)
`
`3.8 (1-8.2; IQR 2.4-6)
`
`4.8 (1.5-10.7; IQR 2.6-7.7)
`
`4.2 (1-10.7; IQR 2.5-6.6)
`
`1.1 (0.3-75; IQR 0.6-2.3)
`1.4 (0.3-7.5; IQR 0.8-3.6)
`0.8 (0.3-3.4; IQR 0.5-2)
`Length of LEV treatment (years)
`'Death at follow up (n =13); °Death at follow up (n = 8); Not treated with P8 when on LEV(`n =3 or Gln = 3); Not treated with KBr when on LEV ('n =11 or fn =4);
`IQR Interquartile range; LEV, levetiracetam; AED, Antiepileptic drugs; PB, phenobarbitone; Kbr, potassium bromide; n/a = not applicable.
`
`Side effects
`Life-threatening side effects during the follow-up
`period was not reported in any of the LEV treated
`dogs. Forty-six per cent (95% CI 32.5-59.6%) of the
`dogs in the study experienced side effect during LEV
`treatment. More dogs in the LEV pulse treatment
`group were reported to have side effects than in the
`maintenance treatment group (65% (95% CI 43.6-86.5%)
`vs. 34% (95% CI 14.6-53.4%), P = 0.03). The following side
`effects were reported to be increased after initiation of
`LEV treatment; LEV maintenance treatment group: ataxia
`(n = 5; 17%; 95% CI 1.7-32.4%), polyphagia (n = 3; 10%;
`95% CI 0-22.3%), sedation (n = 3; 10%; 95% CI 0-22.3%),
`polydipsia (n = 1; 3%; 95% CI 0-10%), vomiting (n = 1; 3%;
`95% CI 0-10%) and diarrhoea (n = 1; 3%; 95% CI 0-10%);
`LEV pulse treatment group: Ataxia (n = 10; 43%; 95% CI
`20.7-65.3%), sedation (n = 9; 39%; 95% Cl 17.1-60.9%),
`polyphagia (n = 3; 13%; 95% CI 0-28.1%), polydipsia (n = 2;
`9%; 95% CI 0-21.9%), aggression (n = 1; 4%; 95% CI 0-
`12.8%) and restlessness (n = 1; 4%; 95% CI 0-12.8%).
`
`Mortality
`Mortality was not significantly different between the
`maintenance (52% (95% CI 31.6-72.4%)) and the pulse
`treatment groups (35% (95% CI 15.5-54.5%)) in the pro-
`portion of dogs having been euthanized at follow-up.
`Seventy-four per cent (95% CI 53.7-94.3%) of these dogs
`were euthanized because the owners perceived the seiz-
`ure control not to be sufficient.
`
`Influence of prior AED treatment
`No associations were found between AED-use prior to
`LEV and treatment success (either a >50% reduction in
`seizure frequency or seizure freedom), including length
`of previous epilepsy treatment, time on PB or KBr
`prior to LEV. There was no difference in seizure fre-
`quency or seizure days frequency, or presence of clus-
`ter seizures between dogs that achieved a >50% seizure
`frequency reduction or remission, indicating that phar-
`macoresponse to LEV is not dependent on seizure
`type.
`
`Page 00004
`
`(cid:9)
`

`
`Packer et al. BMC Veterinary Research (2015)11:25
`
`Page 5 of 8
`
`A
`
`All dogs
`
`Maintenance
`
`C
`
`I
`I
`
`B
`
`I
`
`Pulse
`
`E
`
`I
`I
`I
`
`F
`
`Figure 1 Seizure frequency and seizure days frequency of all dogs (A, B) and the two treatment groups, maintenance (C, D) and pulse
`treatment (E, F) group. The seizure frequency and seizure days frequency are displayed prior to any treatment, prior to levetiracetam treatment
`(Prior LEV), and while receiving levetiracetam (LEV). Central lines of the box represent the median, lower and upper limits of the box represent
`the 25th and 75th percentiles and whiskers represent the 10th and 90th percentiles. Mean values are denotated as +. (Friedman test, post-hoc
`Dunn's multiple comparison test; *P <
`
`Discussion
`The results of this retrospective study provide further evi-
`dence that LEV is a well tolerated, seizure-suppressing
`drug in dogs with epilepsy when used as a maintenance or
`pulse therapy. Spontaneous and drug-induced epilepsy re-
`mission rates in human medicine are around 63% [25],
`which is markedly higher than most reported in veterinary
`medicine which range between 14 and 24% [28-31]. Sixty-
`nine per cent of the dogs had a 50% or greater reduction
`in seizure frequency including 15% of dogs having no fur-
`ther seizures in the LEV treatment period. Our results are
`similar to the findings from clinical studies assessing the
`overall usage of LEV in human neurology practice
`where the percentage of seizure-free patients ranges
`from 11-32% [1,6,7]. Using LEV as a monotherapy the
`seizure-free population was 49% in a recent clinical
`retrospective study in human medicine [8], which is
`comparable to the 56% of seizure free patients seen in a
`randomized controlled trial comparing LEV monotherapy
`
`to carbamazepine [32]. However, it needs to be considered
`that in our study, one of the eight seizure-free dogs on
`LEV had a follow up of less than 6 months and five dogs
`of less than 1 year. It is possible that the number of
`seizure-free dogs might decline should the follow-up
`period be extended.
`Ninety per cent of the dogs had cluster seizures prior
`to LEV treatment. In a recent epidemiological study, 38%
`of dogs with epilepsy had cluster seizures [33], however in
`referral populations the number of dogs presenting with
`cluster seizures is usually higher. In a separate study 64%
`of the epileptic dogs presented at a UK referral hospital
`had cluster seizures [28]. It is generally accepted that clus-
`ter seizures are more challenging to control and therefore
`referral to a specialist hospital could be more likely. The
`cluster seizure population in this retrospective study is
`higher than previously reported and it can be assumed
`that the clinicians in this study used LEV mainly for dogs
`presenting with cluster seizures. Interestingly, a recent
`
`Page 00005
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Packer et al. BMC Veterinary Research (2015)11:25
`
`Page 6 of 8
`
`
`
`study documented that LEV was superior over placebo
`in controlling cluster seizures and prolonged seizure
`activity [23]. Forty-four per cent of dogs in this study
`were treated with a pulse treatment protocol for cluster
`seizures. The initial dose of 60 mg/kg was also used suc-
`cessfully in the study from Hardy et al. [26].
`The introduction of the pulse treatment protocol was
`developed after our former study showed that some dogs
`develop a tolerance to LEV when used chronically [14].
`In human medicine, a recent study has shown that LEV
`had a high efficacy in the first weeks of treatment which
`was followed by a lower but more stable efficacy in the
`following weeks [34]. This phenomenon, the 'honeymoon
`effect', has been documented for zonisamide and LEV in
`dogs with epilepsy [14,15]. Prolonged treatment with LEV
`has also been shown to induce tolerance in rodent epi-
`lepsy models [35]. Pharmacokinetic tolerance is associated
`with multiple factors provoked by drug administration.
`These indude induction of drug-metabolizing enzymes
`and increase of multidrug transporters in the liver and
`kidney. Concurrent PB administration to LEV can increase
`the clearance of LEV significantly in dogs [36]. Further-
`more, pharmacodynamic tolerance is not an uncommon
`clinical occurrence. Despite no change in drug treatment,
`seizures can reoccur in human patients following several
`months of seizure freedom. Factors other than tolerance
`have to be considered for the return of poor seizure
`control, such as progression of epilepsy, poor owner
`compliance, placebo effect of using a novel AED, natural
`fluctuations of seizure frequency, regression to the
`mean and acquired drug resistance mediated by mecha-
`nisms other than tolerance [35,37]. In our former study
`[14] we used a previously described strategy to over-
`come tolerance [35]. During the former study one dog
`developed tolerance to LEV and the medication was
`ceased. Following this, only the dog's cluster seizures
`were intermittently treated successfully with the afore-
`mentioned LEV pulse treatment protocol. The current
`study supports this clinical approach, as the pulse treatment
`protocol was as effective in controlling duster seizures.
`Pulse treatment was associated with more side effects
`post LEV administration than seen in the maintenance
`group. This could be secondary to the threefold initial
`LEV dose (60 mg/kg). Another explanation could be that
`the owners were not able to discriminate between the
`side effects caused by LEV and the changes seen as a
`result of seizures. However, overall the drug was well tol-
`erated. No serious life-threatening side effects were re-
`ported. The most common side effects associated with
`LEV in this study were sedation and ataxia which were
`around three times more common in the pulse treat-
`ment group compared to the maintenance treatment
`group. This is similar to previous clinical and toxicity
`studies [12,14,23,38]. Long-term toxicity studies revealed
`
`that LEV in dogs is extremely safe [38]. Oral LEV can be
`given in doses up to 1200 mg/kg/day for one year with
`minor side effects. Some dogs developed gastrointestinal
`signs. One dog in the current study also had an episode
`of vomiting and diarrhoea, which the owner associated
`with the LEV administration. In human medicine, LEV
`also has been recognised to have a wide margin of safety
`[39]. Side effects that commonly occur in people within
`their first month of maintenance LEV treatment are
`usually not dose-dependent, mainly mild-to-moderate,
`frequently resolve without cessation of the medication
`and are transient when the medication is stopped
`[39,40]. The side effects reported in humans with LEV
`are similar to those seen in the dog such as sedation,
`restlessness, gastrointestinal irritations, ataxia, and neuro-
`behavioural problems in a small percentage [5,39,40].
`Neuro-behavioural problems, such as aggression occur
`mainly in children with a former psychiatric history
`[39,40]. In a small proportion of dogs in this study the
`owner reported an increase in restlessness and aggres-
`sion. This could be associated with LEV, but it can also
`be secondary to the epilepsy. It was formerly reported
`that epilepsy can cause abnormal behaviour and that
`pharmacoresistant dogs are more likely to show signs
`of aggression [41].
`In a former study, eight dog owners documented that
`their dogs became more lively and interactive on LEV
`treatment [14]. In the current study this effect on the
`dogs' behaviour was not seen. However, a recent study
`has demonstrated that the owners perceived an im-
`proved quality of life when treated with LEV compared
`to placebo [12].
`A main predictor for drug-resistance is a high seizure
`frequency prior to treatment [25,30,42,43]. In the current
`study the dogs had a significant increase in seizure fre-
`quency from three to five seizures per month prior to
`LEV treatment. As aforementioned most dogs also had
`cluster seizures. Despite the high seizure frequency and
`cluster seizures, 67% of dogs had a decrease in seizure fre-
`quency by 50% or more. This is a higher success rate than
`the results of a recent study, which failed to show a signifi-
`cant change in seizure frequency comparing LEV to a pla-
`cebo group [12]. The trial was designed as a cross over
`study, however, as many dogs dropped out of the study
`the authors could not perform a cross-over comparison
`and only compared the initial placebo to the LEV group.
`Interestingly, LEV showed a significant decrease to the
`baseline seizure frequency, which the placebo group did
`not. Another former study showed a good initial response,
`which decreased over time [14]. In the current study, the
`population was not restricted to dogs with drug-resistant
`epilepsy to two or more AEDs. The more heterogeneous
`population in this study could explain the higher long-
`term success rate.
`
`Page 00006
`
`(cid:9)
`

`
`Packer et at BMC Veterinary Research (2015) 11:25
`
`Page 7 of 8
`
`Conclusions (cid:9)
`There is no doubt that double-blinded, randomized con-
`trolled clinical trials are of pivotal importance to establish
`efficacy and safety of novel AEDs, however, in recent years
`studies assessing the use of AEDs in practice are increas-
`ingly accepted to provide additional useful data in human
`medicine. The clinical study population is heterogeneous
`and as the groups are not as standardized as in a prospect-
`ive blinded trial, which is a significant limitation when
`drug efficacy is evaluated. However, it is interesting that
`despite studying a heterogeneous population, potentially
`useful data was gathered which showed that LEV has a
`good tolerability and is potentially efficacious in treating
`epilepsy in the dog. Based on the current study LEV pulse
`treatment protocol should be considered as an alternative
`for LEV maintenance therapy. Future studies are needed
`to confirm this finding.
`
`Abbreviations
`LEV: Levetiracetam; AED. Antiepileptic drug; PB: Phenobarbitone; KBr: Potassium
`bromide; IQR: interquartile range; 95% CI: 95% Confidence interval.
`
`Competing interests
`Desitin financially supported the study by financially supporting clinical
`investigation staff to collect data. However, the commercial sponsor has not
`been involved in case recruitment, data handling, data analysis and data
`storage. The commercial sponsor could not prevent the manuscript from
`being submitted for publication.
`
`Authors' contributions
`SEP, GN, HAV conceived the study and participated in its design and
`coordination. RMAP and HAV wrote the final version of the manuscript. SEP
`and GN collected data. HAV performed statistical analysis verified by RMAP
`and both interpreted the data obtained. All authors have read and approved
`the final manuscript. (cid:9)
`
`Acknowledgements
`The study was funded by Desitin Arzneimittel GmbH. The authors are
`grateful to participating owners and pets and would like to acknowledge
`Ms. Nadia Shihab and Cohn Driver for reviewing the manuscript prior to
`submission. The authors also would like to thank the research office for
`assessing the manuscript according to the Royal Veterinary College's code of
`good research practice (Authorisation Number - VCS_00436).
`
`Received: 11 September 2014 Accepted: 22 January 2015
`Published online: 07 February 2015
`
`4.
`
`References
`1. Betts T, Yarrow H, Greenhill L, Barrett M. Clinical experience of marketed
`Levetiracetam in an epilepsy clinic-a one year follow up study. Seizure.
`2003;12(3):136-40.
`2. Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy response to
`sequential treatment schedules. Eur J Neurol. 2006;13(3)277-82.
`3. Beghi E. Efficacy and tolerability of the new antiepileptic drugs: comparison
`of two recent guidelines. Lancet Neurol. 2004;3(10)618-21.
`French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL,
`et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment
`of refractory epilepsy: report of the Therapeutics and Technology
`Assessment Subcommittee and Quality Standards Subcommittee of the (cid:9)
`American Academy of Neurology and the American Epilepsy Society.
`Neurology. 2004;62(8):1261-73. (cid:9)
`5. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL,
`et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new
`onset epilepsy. report of the Therapeutics and Technology Assessment Sub- (cid:9)
`committee and Quality Standards Subcommittee of the American Academy of
`Neurology and the American Epilepsy Society. Neurology. 203462(8)1252-60.
`
`6.
`
`7.
`
`8.
`
`9
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`Kuba FL Novotna I, Brazdil M, Kocvarova 1, Tyrlikova I, Mastik I, et al.
`L