Comparison of caregivers’ assessments of clinical outcome in dogs with idiopathic epilepsy administered levetiracetam, zonisamide, or phenobarbital monotherapy

Bryanna R. Gristina Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Rennie J. Waldron Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Julie A. Nettifee Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Karen R. Muñana Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC

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Abstract

OBJECTIVE

To investigate caregivers’ assessments of outcome in dogs with idiopathic epilepsy (IE) administered levetiracetam (LEV), zonisamide (ZNS), or phenobarbital (PB) monotherapy.

ANIMALS

100 dogs with IE administered LEV (n = 34), ZNS (31), or PB (35) monotherapy between January 1, 2003, and February 6, 2019, and survey responses from their caregivers.

PROCEDURES

Information on duration of therapy, adverse effects (AEs), and outcome was obtained from medical record review and caregiver questionnaire.

RESULTS

A significant improvement in mean quality of life score was reported during monotherapy (7.7; SD, 2.14) compared to before treatment (6.25; SD, 2.63; P < .0001), with no difference identified between monotherapy groups. Compared to ZNS monotherapy, dogs prescribed PB monotherapy had a significantly younger median age at seizure onset (2.6 vs 4.3 years; P = .024). A significant relationship was identified between the occurrence of reported AEs and monotherapy group, with a higher prevalence in the PB group (77% [27/35]) and a lower prevalence in the ZNS group (39% [12/31]; P = .0066). Treatment failure rates for PB, LEV, and ZNS monotherapy were 51%, 35%, and 45%, respectively, with failure attributed most commonly to inadequate seizure control. No significant difference was identified between groups with respect to rate of or time to failure.

CLINICAL RELEVANCE

Most caregivers reported a favorable outcome with administration of LEV, ZNS, or PB monotherapy to dogs with IE. Phenobarbital is associated with the highest prevalence of AEs but no difference in quality of life score. Prospective controlled studies are needed to further compare the efficacy and safety of these monotherapies in dogs with IE.

Abstract

OBJECTIVE

To investigate caregivers’ assessments of outcome in dogs with idiopathic epilepsy (IE) administered levetiracetam (LEV), zonisamide (ZNS), or phenobarbital (PB) monotherapy.

ANIMALS

100 dogs with IE administered LEV (n = 34), ZNS (31), or PB (35) monotherapy between January 1, 2003, and February 6, 2019, and survey responses from their caregivers.

PROCEDURES

Information on duration of therapy, adverse effects (AEs), and outcome was obtained from medical record review and caregiver questionnaire.

RESULTS

A significant improvement in mean quality of life score was reported during monotherapy (7.7; SD, 2.14) compared to before treatment (6.25; SD, 2.63; P < .0001), with no difference identified between monotherapy groups. Compared to ZNS monotherapy, dogs prescribed PB monotherapy had a significantly younger median age at seizure onset (2.6 vs 4.3 years; P = .024). A significant relationship was identified between the occurrence of reported AEs and monotherapy group, with a higher prevalence in the PB group (77% [27/35]) and a lower prevalence in the ZNS group (39% [12/31]; P = .0066). Treatment failure rates for PB, LEV, and ZNS monotherapy were 51%, 35%, and 45%, respectively, with failure attributed most commonly to inadequate seizure control. No significant difference was identified between groups with respect to rate of or time to failure.

CLINICAL RELEVANCE

Most caregivers reported a favorable outcome with administration of LEV, ZNS, or PB monotherapy to dogs with IE. Phenobarbital is associated with the highest prevalence of AEs but no difference in quality of life score. Prospective controlled studies are needed to further compare the efficacy and safety of these monotherapies in dogs with IE.

Introduction

Epilepsy is the most common chronic neurologic condition in dogs, with an estimated prevalence of 0.62% to 0.82% in the general dog population.13 The majority of dogs with epilepsy are diagnosed with idiopathic epilepsy (IE), a disorder characterized by recurrent seizures for which there is no underlying cause aside from a known or presumed genetic predisposition. The standard of care for IE is therapy with antiseizure drugs (ASDs). Currently, there are over 30 ASDs approved in the US for use in humans with epilepsy,4 but only a handful of these drugs are routinely prescribed for dogs, primarily due to species differences in pharmacokinetics and metabolism. Furthermore, there is limited evidence-based data regarding the safety and efficacy of these ASDs in dogs with IE, constraining the establishment of general treatment recommendations.5,6

Historically, phenobarbital (PB) has been the most widely used ASD in veterinary practice. It has an established efficacy as first-line therapy711 and is easy to administer and monitor, widely available, and affordable. However, PB has a relatively narrow therapeutic index, such that adverse effects (AEs) are common.12 Levetiracetam (LEV) and zonisamide (ZNS) are 2 newer-generation ASDs that are being utilized with increasing frequency as first-line therapy in dogs with epilepsy due to their favorable safety profiles. Despite their widespread use, there is limited published information on either LEV or ZNS as monotherapy in dogs. The aim of this study was to retrospectively investigate and compare outcomes in dogs with IE treated with PB monotherapy compared to either LEV or ZNS monotherapy on the basis of caregivers’ perceptions of seizure control, presence of AEs, and quality of life (QoL).

Materials and Methods

Medical records of cases admitted to NC State Veterinary Hospital between January 1, 2003, and February 6, 2019, were retrospectively searched to identify dogs with a diagnosis of IE that were dispensed PB, LEV, or ZNS from the hospital pharmacy. To be included in the study, dogs must have been diagnosed with IE on the basis of the following criteria: (1) presence of 2 or more seizures at least 24 hours apart, (2) onset of seizure activity between 6 months and 5 years of age, (3) normal interictal neurologic examination, and (4) unremarkable hemogram and serum biochemical profile to suggest reactive seizures were unlikely. Dogs with an onset of seizures at < 6 months or > 5 years of age were included if brain imaging—either MRI or CT—was performed and a cause for seizures was not identified. Results of CSF analysis, if performed, had to be within normal limits for study participation. In addition, all dogs must have been administered oral PB, LEV, or ZNS as maintenance monotherapy for a minimum duration of 21 days. This time span was selected to ensure that drugs achieved steady-state concentrations and dogs had time to acclimate to the drug prior to any assessment of outcome. Dogs were excluded from the study if medical records were incomplete, concurrent medical issues were present, or adequate follow-up information could not be obtained. The study aimed to evaluate a similar number of dogs in each monotherapy group, which was to be determined by the outcome of the medical record review for the least frequently prescribed ASD at our institution during the study period. If an excess of eligible cases was identified on the medical records search for a specific monotherapy compared to the least-prescribed drug, the medical records were randomly reviewed for inclusion in the study until a similar number was achieved in all 3 groups. Dogs were included in the LEV group if they were administered either the immediate-release or extended-release formulation of the drug; however, records were initially reviewed to include all identified dogs on the immediate-release formulation, as this ASD was utilized throughout the study period, and then the LEV group was completed by randomly selecting dogs being administered the extended-release formulation, as its use increased toward the end of the study.

Information retrieved from the medical records included age, breed, sex, neuter status, diagnostics performed, monotherapy drug prescribed and initial dosage, whether the monotherapy was the initial treatment for IE or the dog had been trialed on another ASD in the past, date of monotherapy initiation, and whether monotherapy had been discontinued and the date of and reason for discontinuation. For dogs that were trialed on another ASD in the past and transitioned to the monotherapy being evaluated, the date of initiation of monotherapy as recorded for the study was determined after the initial drug had been discontinued for a minimum period of time to allow for the drug to be completely eliminated from the body (ie, 5 half-lives). Caregivers of eligible dogs were contacted by email or phone and asked to complete an online survey to provide information on their assessment of monotherapy (Supplementary Appendix). The survey comprised a series of closed-ended questions created with online survey software (Qualtrics XM; Qualtrics International Inc) that addressed seizure frequency, presence of AEs, outcome, and QoL. To assess seizure frequency both before and after the initiation of monotherapy, caregivers were asked to select a category that most appropriately represented their dogs’ average seizure days per month from the following: < 1 day, 1 to 2 days, 3 to 5 days, 6 to 8 days, > 8 days, or unknown. The category “no seizures” was also included as a response for the question on seizure frequency after the initiation of monotherapy. Caregivers were asked to indicate whether seizure frequency and severity had increased, decreased, or remained unchanged with monotherapy and, for dogs that experienced cluster seizures (defined as 2 or more seizures within a 24-hour period), choose a category to indicate the number of seizures in each cluster episode prior to and after treatment. Survey questions addressed whether caregivers had observed any ASD-related AEs, and if so, they were asked to select the observed AEs from a provided list or describe the AEs in an open-ended box. Additional questions addressed the outcome of treatment, including whether the dog was still on monotherapy and whether the dog was alive or deceased. Finally, caregivers were asked to rate their dog’s QoL before the initiation of monotherapy and while on monotherapy using a scale of 1 to 10, with a higher score designating a better QoL.

Statistical analysis

Dogs were grouped according to the monotherapy administered (PB, LEV, and ZNS), and differences between the groups were analyzed using the Kruskal-Wallis test for numeric data and χ2 test for categorical data. In a separate analysis, the Wilcoxon rank sum test was used to compare the PB group to the LEV and ZNS groups. To analyze changes in seizure frequency and number of seizures per cluster, categories were treated as ordinal variables and differences were calculated as the number of categories of change. Kaplan-Meier curves were plotted for time to treatment discontinuation and the Cox proportional hazards model used to assess for differences between treatment groups, with data censored from dogs that were still on monotherapy at the time of survey completion or death. A significance value of P < .05 was established for all comparisons. Statistical analyses were performed with available software (R version 4.2.1; The R Project for Statistical Computing).

Results

The medical record search identified 1,742 dogs with a diagnosis of IE that were prescribed PB, LEV, or ZNS, of which a total of 260 dogs were screened and determined to meet the inclusion criteria. Dogs were excluded if they failed to meet the criteria for a diagnosis of IE as established for the study or had concurrent systemic disease, if review of the medical record determined that dogs were not on monotherapy (were being administered > 1 ASD), or if the medical record was incomplete. Zonisamide was the least frequently prescribed monotherapy, with 77 dogs determined to be eligible for the study. Caregivers of these dogs were contacted, of which 31 (40%) completed the survey. Caregivers of 90 dogs treated with PB monotherapy and 88 dogs treated with LEV monotherapy that were determined to be eligible for the study were contacted, with surveys completed for 35 (39%) and 34 (39%) dogs, respectively. The overall response rate for the survey was 38% (100/260), with the study population consisting of a total of 100 dogs; 34 dogs were administered LEV monotherapy (22 dogs on the immediate-release and 12 dogs on the extended-release formulations), 31 dogs were administered ZNS monotherapy, and 35 dogs were administered PB monotherapy. Dogs were reported as Labrador Retriever (n = 18), mixed breed (9), Beagle (7), German Shepherd Dog (4), Shetland Sheepdog (4), Border Collie (3), Golden Retriever (3), Siberian Husky (3), Australian Shepherd (2), Cavalier King Charles Spaniel (2), Chihuahua (2), English Bulldog (2), Golden Retriever and Poodle cross (2), Great Dane (2), Miniature Schnauzer (2), Rottweiler (2), Standard Poodle (2), and 1 each of the following: Afghan Hound, Airedale Terrier, Basset Hound, Boston Terrier, Boxer, Boykin Spaniel, Cane Corso, Chow Chow, Dalmatian, Doberman Pinscher, Dogue de Bordeaux, English Springer Spaniel, Fox Terrier, French Bulldog, German Shorthaired Pointer, Great Pyrenees, Greater Swiss Mountain Dog, Greyhound, Havanese, Maltese, Mastiff, Miniature Dachshund, Pembroke Welsh Corgi, Plott Hound, Pomeranian, Rhodesian Ridgeback, Shih Tzu, Soft-Coated Wheaten Terrier, Standard Schnauzer, Toy Poodle, and Yorkshire Terrier. The study population comprised 57% males (46 neutered and 11 intact) and 43% females (38 spayed and 5 intact). The mean body weight of dogs in the study was 24.9 kg (SD, 15.1 kg). Fifty-two of the 100 dogs (52%) had advanced imaging performed (MRI in 50 dogs and CT in 2 dogs), including 13 dogs on PB monotherapy, 21 dogs on LEV monotherapy, and 18 dogs on ZNS monotherapy. Forty-nine of the 52 (94%) dogs that underwent advanced imaging also had CSF analysis performed. Results of imaging and CSF analysis were unremarkable in all instances, as per inclusion criteria. No difference was identified between monotherapy groups with respect to the parameters of sex, body weight, and whether advanced imaging was performed (Table 1).

Table 1

Key demographic characteristics and seizure history for 100 dogs with idiopathic epilepsy evaluated between January 1, 2003, and February 6, 2019, that were administered levetiracetam (LEV; n = 34), zonisamide (ZNS; 31), or phenobarbital (PB; 35) monotherapy as reported in medical records and owner-completed questionnaire.

Variables LEV group ZNS group PB group P value
Sex .65
 Female 16 (47%) 13 (42%) 14 (40%)
 Male 18 (53%) 18 (58%) 21 (60%)
Body weight (kg)a 23.38 (15.3) 24.99 (17.8) 26.34 (12.2) .48
Age at seizure onset (y)b 3.5 (0.2, 13) 4.3 (0.9, 13.7) 2.6 (0.6, 6.5) .024c
Seizure frequency (d/mo) prior to initiation of therapy .79
 < 1 6 (18%) 8 (26%) 6 (17%)
 1–2 6 (18%) 10 (32%) 11 (31%)
 3–5 7 (21%) 5 (16%) 9 (26%)
 6–8 2 (6%) 2 (7%) 3 (9%)
 > 8 8 (22%) 5 (16%) 4 (11%)
 Unknown 5 (15%) 1 (3%) 2 (6%)
Cluster seizures prior to initiation of therapy .42
 Present 25 (74%) 18 (58%) 23 (66%)
 Absent 9 (26%) 13 (42%) 12 (34%)
Initial prescribed ASD?
 Yes 28 (82%) 26 (84%) 34 (97%) .12
 No 6 (18%) 5 (16%) 1 (3%)

Data are presented as number and percentage unless otherwise indicated.

ASD = Antiseizure drug.

aData presented as mean (SD). bData presented as median (range). cResults differed significantly between the PB and ZNS groups only.

The median age at onset of seizures for the entire study population was 3 years (range, 0.2 to 13.7 years). The median age at seizure onset for the PB group (2.6 years; range, 0.6 to 6.5 years) was significantly younger than that for the ZNS group (4.3 years; range, 0.9 to 13.7 years; P = .024), but did not differ from the LEV group (3.5 years; range, 0.2 to 13 years; Table 1). None of the dogs in the PB group had an onset of seizures outside the age range established by the International Veterinary Epilepsy Task Force for a diagnosis of IE (6 months to 6 years),13 while 4 of 34 (12%) dogs in the LEV group and 11 of 31 (35%) dogs in the ZNS group had an onset of seizures at > 6 years of age.

The monotherapy evaluated in the study was the initial prescribed ASD in 88% (88/100) of dogs, including 34 of 35 (97%) dogs on PB, 28 of 34 (82%) dogs on LEV and 26 of 31 (84%) dogs on ZNS. The remaining 12 dogs were transitioned to the monotherapy evaluated in the study after treatment failure with another ASD, due to either intolerable AEs (11/12 [92%]) or inadequate seizure control (1/12 [8%]). The dog with inadequate seizure control was transitioned to a second drug within a month of initiation of therapy, and the first drug was weaned completely to maintain the dog on monotherapy with the second ASD. No significant difference was identified between groups with respect to whether monotherapy was initiated as the first ASD or after failure with another ASD (Table 1). The initial mean daily dosage for PB, LEV, and ZNS were 4.9 mg/kg (SD, 1.7 mg/kg), 53.8 mg/kg (SD, 18.7 mg/kg), and 12.4 mg/kg (SD, 6.4 mg/kg), respectively.

For the study population as a whole, the monthly seizure frequency before initiation of monotherapy was categorized as < 1 day in 20 dogs (20%), 1 to 2 days in 27 dogs (27%), 3 to 5 days in 21 dogs (21%), 6 to 8 days in 7 dogs (7%), > 8 days in 17 dogs (17%), and unknown in 8 dogs (8%). For analysis, seizure frequency data reported as unknown were excluded. No difference was identified between groups with respect to the monthly seizure frequency prior to initiating monotherapy (Table 1).

An improvement in seizure frequency after initiation of monotherapy was reported in 76% (76/100) of dogs, with 24% (24/100) noted to be seizure free. Among dogs in the PB group, 86% (30/35) were reported to have an improvement in seizure frequency with monotherapy, compared to 76% (26/34) in the LEV group and 65% (20/31) in the ZNS group. The seizure freedom rate for the PB, LEV, and ZNS groups was 23% (8/35), 21% (7/34), and 29% (9/31), respectively. The remaining 24% (24/100) of study dogs had either no change or a worsening in seizure frequency. No significant difference was identified between groups with respect to the change in seizure frequency with the administration of monotherapy.

Sixty-six percent (66/100) of dogs in the study were reported to have a history of cluster seizures, including 23 of 35 (66%) dogs in the PB group, 25 of 34 (74%) dogs in the LEV group, and 18 of 31 (58%) dogs in the ZNS group. Caregivers were asked to choose a category that best described the average number of seizures in each cluster episode both before and after initiation of monotherapy. After removing dogs for which the number of seizures in each cluster episode was reported as unknown, 38 of 60 (63%) dogs were noted to have a decrease in the number of seizures in each cluster episode after the initiation of monotherapy. This included 80% (16/20) of dogs in the PB group, 61% (14/23) of dogs in the LEV group, and 47% (8/17) dogs in the ZNS group. Dogs in the PB group were significantly more likely to have a decrease in the number of seizures in each cluster episode after the initiation of monotherapy when compared to dogs in the ZNS group (P = .04).

Among dogs that continued to have seizures after initiation of monotherapy, 42% (31/74) of caregivers of dogs that continued to have seizures reported a subjective improvement in seizure severity after the initiation of monotherapy, with 2 owners not providing a response to the question. This included 8 of 26 (31%) dogs administered PB, 15 of 26 (58%) dogs administered LEV, and 8 of 22 (36%) dogs administered ZNS. The remaining 58% (43/74) had no change or a worsening of seizure severity after the initiation of monotherapy. No difference was identified between groups with respect to a change in seizure severity with monotherapy.

Drug-associated AEs that persisted beyond the initial period of drug acclimatization were reported in 59% (59/100) of study dogs. One or more AEs was reported in 77% (27/35) of dogs in the PB group, compared to 59% (20/34) of dogs in the LEV group and 39% (12/31) of dogs in the ZNS group (Table 2). A significant relationship was identified between the occurrence of AEs and monotherapy group, with dogs on ZNS monotherapy having a lower reported rate of AEs and dogs on PB having a higher reported rate of AEs (P = .0066). The mean number of reported AEs per dog for the PB, LEV, and ZNS monotherapy groups was 2.74 (SD, 1.3), 1.71 (SD, 0.78), and 1.75 (SD, 0.97), respectively, with dogs on PB monotherapy having a significantly greater number of AEs compared to the LEV and ZNS groups (P = .0076).

Table 2

Numbers and percentages of the 100 dogs described in Table 1 with owner-reported long-term adverse effects grouped on the basis of monotherapy received: LEV (n = 34), ZNS (31), or PB (35).

Adverse effect LEV group ZNS group PB group
Any adverse effect 20 (59%) 12 (39%) 27 (77%)
Sedation 13 (38%) 9 (29%) 13 (37%)
Ataxia 7 (21%) 5 (16%) 13 (37%)
Polyphagia 1 (3%) 0 19 (54%)
Polydipsia 1 (3%) 0 16 (46%)
Polyuria 0 0 10 (29%)
Hyporexia 4 (12%) 2 (7%) 0
Diarrhea 3 (9%) 1 (3%) 0
Vomiting 1 (3%) 1 (3%) 0
Behavioral changes 3 (9%) 1 (3%) 1 (3%)
Rhinorrhea 1 (3%) 0 0
Thrombocytopenia 0 1 (3%) 0
Hepatotoxicity 0 0 1 (3%)
Circling 0 0 1 (3%)

For the population of study dogs, a significant improvement in mean QoL score was reported after initiation of monotherapy (7.7; SD, 2.14) compared to prior to therapy (6.25; SD, 2.63; P < .0001), with 54% (54/100) of caregivers reporting an improvement in their dog’s QoL while on monotherapy. Similarly, the mean QoL score significantly increased while on treatment for all monotherapy groups; QoL scores before and after treatment were 6.8 (SD, 2.6) and 7.7 (SD, 2.5) for PB monotherapy (P = .0280), 5.8 (SD, 3.0) and 7.8 (SD, 1.8) for LEV monotherapy (P = .0022), and 6.1 (SD, 2.1) and 7.7 (SD, 2.1) for ZNS monotherapy (P = .0015). No difference was identified between change in QoL and monotherapy group.

Fifty-one percent (51/100) of the study dogs were maintained on monotherapy at the time of survey completion or death, with a median duration of therapy of 804 days (range, 112 to 4,207 days). In the remaining 49 dogs, monotherapy was withdrawn due to treatment failure in 45 dogs, which was attributed to either inadequate seizure control in 39 (80%) dogs or the presence of intolerable AEs in 6 (12%) dogs, and remission of seizures in 4 dogs (8%; Table 3). In all instances, therapy was tapered over time rather than abruptly withdrawn. Treatment withdrawal rates for the PB, LEV, and ZNS monotherapy groups were 57% (20/35 dogs), 38% (13/34 dogs) and 52% (16/31 dogs), respectively, with no significant difference identified between groups. The median duration of therapy for dogs in which monotherapy was withdrawn for the PB, LEV, and ZNS groups was 197, 115, and 237 days, respectively. Kaplan-Meier analysis identified no significant difference in the time to treatment withdrawal between groups (Figure 1).

Table 3

Numbers and percentages of the dogs described in Table 1 for which LEV, ZNS, or PB monotherapy was discontinued (treatment withdrawn) and the reason for drug withdrawal.

Outcome LEV group ZNS group PB group
Monotherapy withdrawn 13 (38%) 16 (52%) 20 (57%)
Reason for drug withdrawal
  Inadequate seizure control 11 (32%) 11 (35%) 17 (48%)
  Intolerable adverse effects 2 (6%) 3 (10%) 1 (3%)
  Seizure remission 0 2 (7%) 2 (6%)
Figure 1
Figure 1

Kaplan-Meier curves for the time from initiation to withdrawal of treatment for 100 dogs with idiopathic epilepsy administered either levetiracetam (LEV), zonisamide (ZNS), or phenobarbital (PB) monotherapy between January 1, 2003, and February 6, 2019. Tick marks denote censored dogs; each step represents the withdrawal of treatment for ≥ 1 dog. No significant difference was identified between monotherapy groups.

Citation: Journal of the American Veterinary Medical Association 261, 7; 10.2460/javma.22.10.0469

Discussion

LEV and ZNS are commonly prescribed in veterinary practice. A recent descriptive survey of ASD use in veterinary specialty practice identified LEV as the initial drug of choice among 16% of 128 veterinary neurologists for new-onset seizures in dogs with presumed IE, with ZNS considered the initial drug of choice in 15%. Similarly, among 172 emergency and critical care specialists, 25.5% considered LEV their first-line drug of choice, followed by ZNS in 9%.14 Despite widespread acceptance, there are limited data supporting the use of LEV or ZNS when prescribed as monotherapy in dogs with IE. The aim of this study was to retrospectively compare LEV and ZNS to PB when administered as monotherapy to dogs with IE to gain additional information on caregivers’ perceptions and explore any differences in caregiver-reported outcome among treatments. Overall, caregivers reported a favorable outcome with all ASDs. Approximately three-quarters of study dogs were reported to have an improvement in seizure frequency with monotherapy, with one-quarter of dogs reported to be seizure free. In addition, a significant improvement in QoL after the initiation of monotherapy was reported by caregivers for dogs across all treatment groups. Similarly, drug withdrawal rates were similar among groups, ranging from 38% to 57%. However, the PB monotherapy group was associated with a higher overall incidence of AEs and a greater number of AEs per dog compared to both the ZNS and LEV groups.

The demographics of the study population were similar to those reported for dogs with IE. There were slightly more males than females in our study, and most of the dogs were large breeds, with a mean weight > 20 kg. Several previous studies13,15 have demonstrated that male dogs are at increased odds for IE compared to females. In addition, greater body weight has been reported as a risk factor for epilepsy, with dogs weighing > 40 kg described as being at higher risk for seizures compared to dogs weighing < 10 kg.3 The Labrador Retriever breed accounted for 18% (18/100) of dogs in the study. This was likely attributed to both the popularity of the breed as well as a known familial predisposition for IE in Labrador Retrievers.16 The lifetime prevalence of epilepsy in a large group of Danish Labrador Retrievers was reported to be 3.1%,17 which is considerably higher than the reported prevalence in the general canine population of up to 0.82%.13

There are only isolated reports describing the use of LEV or ZNS as monotherapy for dogs with IE. There is a single published study11 evaluating LEV monotherapy compared to PB in dogs with newly diagnosed IE. In this prospective, single-blinded, parallel group study with follow-up for 1 year, no difference in seizure frequency compared to baseline was demonstrated for 6 dogs administered LEV at an initial oral dose of 10 to 20 mg/kg every 8 hours, and none of the dogs achieved a ≥ 50% reduction in seizure frequency. In comparison, a significant decrease in seizure frequency from baseline was noted in the 6 dogs administered PB at an initial oral dose of 2 mg/kg every 12 hours, with 5 of the 6 dogs experiencing a ≥ 50% reduction in seizure frequency. The use of ZNS as monotherapy is described in a single noncomparative, open-label study18 involving 10 dogs with IE, in which ZNS was administered orally at a dosage of 5 to 15 mg/kg every 12 hours to achieve a serum ZNS concentration of 10 to 40 μg/mL, and dogs were followed up for 1 year. Of those 10 dogs, 6 (60%) were reported to respond favorably to treatment with a ≥ 50% reduction in seizure frequency compared to a retrospective baseline. In contrast, the efficacy of PB as monotherapy in dogs with IE has been demonstrated in several prospective, comparative studies. PB has been shown to have superior efficacy to potassium bromide and LEV,7,11 superior or comparable efficacy to imepitoin,10,19 and comparable efficacy to primidone.9 Furthermore, seizure freedom has been reported in 40% to 85% of dogs with IE after the administration of PB monotherapy.7,9,10

The design of the current study did not allow for an assessment of the comparative efficacy among LEV, ZNS, or PB monotherapy in dogs with IE on the basis of the uncontrolled and retrospective nature of the data obtained, dependence on caregiver recall, and no requirement for seizure documentation. However, the study did provide some general information on caregivers’ assessment of the success of therapy on the basis of whether they perceived seizure frequency as improving, worsening, or remaining unchanged and whether seizure freedom was attained. Overall, the majority of caregivers reported a favorable outcome with all of the monotherapies evaluated; 86% (30/35) of dogs in the PB monotherapy group were reported to have an improvement in seizure control, compared to 76% (26/34) and 65% (20/31) in the LEV and ZNS groups, respectively. Furthermore, the rate of seizure freedom was similar among the 3 monotherapy groups, ranging from 21% to 29%. These findings may be reflective in part on the monotherapy being the initial treatment in the vast majority of study dogs. A study evaluating the response to ASD therapy in dogs with IE presenting to an academic referral hospital with a minimum follow-up period of 300 days reported that 14% of dogs achieved seizure freedom with initial monotherapy.20

Dogs on PB monotherapy were reported to have a greater improvement in cluster seizures when compared to ZNS based on the number of seizures in each cluster episode. However, no difference was noted between groups with respect to whether cluster seizures resolved with monotherapy. Monotherapy with PB has been shown to be superior to imepitoin for the prevention of cluster seizures in dogs with IE.19 Similarly, in a study11 comparing LEV and PB as monotherapy in dogs with newly diagnosed IE, 2 of 6 dogs administered LEV were noted to have cluster seizures after the initiation of treatment and an additional 2 dogs had a history of cluster seizures that were not controlled with the administration of LEV. In comparison, of the 6 dogs in the PB monotherapy group, 1 dog was reported to develop cluster seizures after the initiation of PB monotherapy, 1 dog had persistence of cluster seizures that were present prior to initiation of treatment, and 2 dogs had resolution of cluster seizures with PB monotherapy.11 Randomized controlled trials are needed to determine whether PB is more efficacious in controlling cluster seizures in dogs compared to other ASDs.

Adverse effects are an important consideration in the success of an epilepsy management plan. A survey of caregivers of dogs with IE that were being administered PB, potassium bromide, or both found that drug-related AEs ranked third with respect to caregiver-perceived importance in assessing the success of seizure management, behind QoL and seizure frequency.21 Additional studies22,23 have also demonstrated the negative impact that drug-related AEs have on caregiver-related QoL score for dogs with IE. Long-term AEs were reported to occur in over half of the dogs in the current study, with a significant difference identified between the rate of occurrence of AEs for dogs on monotherapy, with PB having the highest rate (77% [27/35]) and ZNS the lowest (39% [12/31]). The most commonly reported AEs across all treatment groups were sedation (35% [35/100]) and ataxia (25% [25/100]), which is in agreement with previous reports.12 Polyphagia, polydipsia, and polyuria are commonly reported AEs in dogs administered PB7,10,11 and were described in approximately one-third to half of dogs on PB monotherapy. The most frequently reported AEs in both the LEV and ZNS monotherapy groups after sedation and ataxia were gastrointestinal related and included hyporexia, vomiting, and diarrhea.

The number of AEs reported per dog was significantly greater with PB monotherapy compared to ZNS or LEV. A previous systematic review of ASD-related AEs in dogs concluded that although there is evidence to support the safety of PB, the drug may be less safe than LEV.12 Interestingly, although the rate of AEs and the number of AEs per dog were greater in the PB group, the drug withdrawal rate did not differ between monotherapy groups. Furthermore, QoL score was reported to significantly increase after initiation of monotherapy in all study dogs, with no difference noted between monotherapy groups. These findings suggest that although AEs are more commonly encountered with PB monotherapy, they may not result in drug withdrawal or adversely impact QoL to a large degree.

The mean age at seizure onset was significantly lower for dogs in the PB monotherapy group compared to the ZNS group. Although this study focused on dogs with IE, a diagnosis of which is based in part on age at onset of seizures of 6 months to 6 years,13 dogs > 5 years of age were included if they underwent advanced imaging with unremarkable results. All of the dogs in the PB monotherapy group were ≤ 6 years of age at seizure onset, while 29% (9/31) of dogs in the ZNS monotherapy group were > 6 years of age at the onset of seizures. The younger age of seizure onset in dogs administered PB monotherapy might reflect a tendency for clinicians to prescribe newer-generation ASDs to more aged dogs based on concerns regarding AEs. Further study is warranted on the prescribing patterns of veterinarians for ASDs in dogs based on patient characteristics such as age.

Approximately half of the dogs were maintained on monotherapy at the time of survey completion or death, and monotherapy was withdrawn in the remaining half. The most common cause for monotherapy withdrawal across all treatment groups was treatment failure due to unacceptable seizure frequency, accounting for 80% of the reported drug discontinuations among study dogs. Seizure frequency has been shown to be an important determinant of the success of an epilepsy management plan. A study evaluating risk factors for survival in 78 dogs with IE determined that 52% of dogs were euthanized due to epilepsy, with a strong significant effect of cluster seizures and status epilepticus on survival time.24 Similarly, a prospective longitudinal study25 of 63 dogs with epilepsy with follow-up until death, euthanasia, or a maximum of 12 years identified euthanasia due to unacceptable seizure control as the most common cause of death among dogs. A survey of caregivers of epileptic dogs in Italy identified a significant negative correlation between the success of seizure management and the frequency of seizures,26 and a separate survey of caregivers of dogs with epilepsy residing primarily in the US found that caregiver-reported QoL scores for dogs were significantly lower with cluster versus isolated seizures and a higher average monthly seizure frequency.22 It is likely that caregivers consider several factors in assessing the success of an epilepsy management plan, with seizure frequency and presence of AEs both playing a role. Caregivers may be more likely to discontinue therapy sooner when there is unacceptable seizure control along with the presence of AEs, although the frequency of seizures may be cited as the primary cause for treatment withdrawal. Conversely, caregivers may be more tolerant of AEs if they perceive an improvement in seizure control.

Of the 100 dogs in the present study, 4 (4%; 2 dogs in each of the PB and ZNS monotherapy groups) were reported to have discontinued therapy due to remission of seizures. In all cases, the monotherapy was slowly tapered over time, with no recurrence of seizures. This incidence is similar to previous reports that have described spontaneous remission of seizures in approximately 5% of dogs with IE, based on a minimum duration of seizure freedom of 1 to 3 years.25,27,28 However, a minimum duration of seizure freedom was not established in the current study because of the nature of the retrospective and survey-based data. Consequently, it was not possible to confirm the presence or duration of the spontaneous remission reported.

This study had several limitations, primarily due to the retrospective nature of the data collection. These included variability in the time between monotherapy and follow-up that predisposed the data to recall bias and the subjective nature of much of the information collected from caregivers. The variability in time to follow-up confounded the QoL assessments, as there were likely many changes during the time period that could have influenced a caregiver’s assessment of their dog’s QoL. In addition, the survey utilized for this study had not been validated. Furthermore, the relatively small sample size in each monotherapy group along with the inherent heterogeneity of IE may have resulted in insufficient power to detect a difference in some of the variables described. We chose to include dogs in the LEV group that were on either the immediate-release or extended-release formulation, and this could have added additional variability to the analyses. When the study was initiated, the immediate-release formulation of LEV was used most commonly. However, over the time span of this study, the extended-release formulation gained in popularity, due to the greater ease of administration with dosing every 12 hours and the availability of a generic formulation that decreased the cost. Pharmacokinetic studies2931 of both healthy and epileptic dogs have demonstrated the suitability of both formulations of LEV for the treatment of seizure in dogs. Nonetheless, it is possible that the 2 formulations of LEV may be associated with differing outcomes, and the small number of dogs administered each formulation in this study precluded a meaningful analysis of this. Finally, the study population was from a referral institution, which may not have been representative of dogs seen in primary care practice. Nonetheless, the study provided some insight into caregiver-reported outcomes in dogs with IE treated with PB, LEV, or ZNS monotherapy. For many of the variables assessed in the survey, no difference between the monotherapy groups was identified, suggesting that all 3 drugs may be reasonable options for monotherapy on the basis of caregivers’ perspectives. However, the study was not designed to provide an objective evaluation of the drugs’ effectiveness, and a randomized controlled clinical trial is needed to more accurately assess the comparative safety and efficacy of LEV, ZNS, and PB when used as monotherapy in dogs with IE.

Supplementary Materials

Supplementary materials are posted online at the journal website: avmajournals.avma.org

Acknowledgments

Funding for this study was provided by Emma’s Fund of the North Carolina Veterinary Medical Foundation. The funding source did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript.

The authors declare that there were no conflicts of interest.

Preliminary results of this study were presented in abstract form at the 33rd Annual Forum of the American College of Veterinary Internal Medicine, Indianapolis, Indiana, June 2015.

The authors wish to thank James Robertson for his assistance with the statistical analyses.

References

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    • Search Google Scholar
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    Heske L, Nødtvedt A, Jäderlund KH, Berendt M, Egenvall A. A cohort study of epilepsy among 665,000 insured dogs: incidence, mortality and survival after diagnosis. Vet J. 2014;202(3):471-476. doi:10.1016/j.tvjl.2014.09.023

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    Erlen A, Potschka H, Volk HA, Sauter-Louis C, O’Neill DG. Seizure occurrence in dogs under primary veterinary care in the UK: prevalence and risk factors. J Vet Intern Med. 2018;32(5):1665-1676. doi:10.1111/jvim.15290

    • Search Google Scholar
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    Vossler DG, Weingarten M, Gidal BE; American Epilepsy Society Treatments Committee. Summary of antiepileptic drugs available in the United States of America. Epilepsy Curr. 2018;18(4 suppl 1):1-26. doi:10.5698/1535-7597.18.4s1.1

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    • Search Google Scholar
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    Charalambous M, Brodbelt D, Volk HA. Treatment in canine epilepsy-a systematic review. BMC Vet Res. 2014;10(1):257. doi:10.1186/s12917-014-0257-9

    • Search Google Scholar
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    Boothe DM, Dewey C, Carpenter DM. Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. J Am Vet Med Assoc. 2012;240(9):1073-1083. doi:10.2460/javma.240.9.1073

    • Search Google Scholar
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    Farnbach GC. Serum concentrations and efficacy of phenytoin, phenobarbital, and primidone in canine epilepsy. J Am Vet Med Assoc. 1984;184(9):1117-1120.

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    Schwartz-Porsche D, Löscher W, Frey HH. Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison. J Vet Pharmacol Ther. 1985;8(2):113-119. doi:10.1111/j.1365-2885.1985.tb00934.x

    • Search Google Scholar
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  • 10.

    Tipold A, Keefe TJ, Löscher W, Rundfeldt C, de Vries F. Clinical efficacy and safety of imepitoin in comparison with phenobarbital for the control of idiopathic epilepsy in dogs. J Vet Pharmacol Ther. 2015;38(2):160-168. doi:10.1111/jvp.12151

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    • Export Citation
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    Fredsø N, Sabers A, Toft N, Møller A, Berendt M. A single-blinded phenobarbital-controlled trial of levetiracetam as mono-therapy in dogs with newly diagnosed epilepsy. Vet J. 2016;208:44-49. doi:10.1016/j.tvjl.2015.10.018

    • Search Google Scholar
    • Export Citation
  • 12.

    Charalambous M, Shivapour SK, Brodbelt DC, Volk HA. Antiepileptic drugs’ tolerability and safety-a systematic review and meta-analysis of adverse effects in dogs. BMC Vet Res. 2016;12(1):79. doi:10.1186/s12917-016-0703-y

    • Search Google Scholar
    • Export Citation
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    De Risio L, Bhatti S, Muñana K, et al. International veterinary epilepsy task force consensus proposal: diagnostic approach to epilepsy in dogs. BMC Vet Res. 2015;11(1):148. doi:10.1186/s12917-015-0462-1

    • Search Google Scholar
    • Export Citation
  • 14.

    Meland T, Carrera-Justiz S, Buckley GJ. Antiepileptic drug use patterns in suspect epileptic dogs among neurology and emergency specialists. J Am Anim Hosp Assoc. 2019;55(3):138-143. doi:10.5326/JAAHA-MS-6795

    • Search Google Scholar
    • Export Citation
  • 15.

    Van Meervenne SA, Volk HA, Matiasek K, Van Ham LM. The influence of sex hormones on seizures in dogs and humans. Vet J. 2014;201(1):15-20. doi:10.1016/j.tvjl.2014.05.008

    • Search Google Scholar
    • Export Citation
  • 16.

    Jaggy A, Faissler D, Gaillard C, Srenk P, Graber H. Genetic aspects of idiopathic epilepsy in Labrador Retrievers. J Small Anim Pract. 1998;39(6):275-280. doi:10.1111/j.1748-5827.1998.tb03650.x

    • Search Google Scholar
    • Export Citation
  • 17.

    Berendt M, Gredal H, Pedersen LG, Alban L, Alving J. A cross-sectional study of epilepsy in Danish Labrador Retrievers: prevalence and selected risk factors. J Vet Intern Med. 2002;16(3):262-268. doi:10.1892/0891-6640(2002)016<0262:acsoei>2.3.co;2

    • Search Google Scholar
    • Export Citation
  • 18.

    Chung JY, Hwang CY, Chae JS, et al. Zonisamide monotherapy for idiopathic epilepsy in dogs. N Z Vet J. 2012;60(6):357-359. doi:10.1080/00480169.2012.680855

    • Search Google Scholar
    • Export Citation
  • 19.

    Stabile F, van Dijk J, Barnett CR, De Risio L. Epileptic seizure frequency and semiology in dogs with idiopathic epilepsy after initiation of imepitoin or phenobarbital monotherapy. Vet J. 2019;249:53-57. doi:10.1016/j.tvjl.2019.05.007

    • Search Google Scholar
    • Export Citation
  • 20.

    Packer RMA, Shihab NK, Torres BBJ, Volk HA. Responses to successive anti-epileptic drugs in canine idiopathic epilepsy. Vet Rec. 2015;176(8):203. doi:10.1136/vr.102934

    • Search Google Scholar
    • Export Citation
  • 21.

    Chang Y, Mellor DJ, Anderson TJ. Idiopathic epilepsy in dogs: owners’ perspectives on management with phenobarbitone and/or potassium bromide. J Small Anim Pract. 2006;47(10):574-581. doi:10.1111/j.1748-5827.2006.00203.x

    • Search Google Scholar
    • Export Citation
  • 22.

    Nettifee JA, Munana KR, Griffith EH. Evaluation of the impacts of epilepsy in dogs on their caregivers. J Am Anim Hosp Assoc. 2017;53(3):143-149. doi:10.5326/JAAHA-MS-6537

    • Search Google Scholar
    • Export Citation
  • 23.

    Wessmann A, Volk HA, Packer RMA, Ortega M, Anderson TJ. Quality-of-life aspects in idiopathic epilepsy in dogs. Vet Rec. 2016;179(9):229. doi:10.1136/vr.103355

    • Search Google Scholar
    • Export Citation
  • 24.

    Fredsø N, Koch BC, Toft N, Berendt M. Risk factors for survival in a university hospital population of dogs with epilepsy. J Vet Intern Med. 2014;28(6):1782-1788. doi:10.1111/jvim.12443

    • Search Google Scholar
    • Export Citation
  • 25.

    Berendt M, Gredal H, Ersbøll AK, Alving J. Premature death, risk factors, and life patterns in dogs with epilepsy. J Vet Intern Med. 2007;21(4):754-759. doi:10.1892/0891-6640(2007)21[754:pdrfal]2.0.co;2

    • Search Google Scholar
    • Export Citation
  • 26.

    Masucci M, Di Stefano V, Donato G, Mangano C, De Majo M. How owners of epileptic dogs living in Italy evaluate their quality of life and that of their pet: a survey study. Vet Sci. 2021;8(8):140. doi:10.3390/vetsci8080140

    • Search Google Scholar
    • Export Citation
  • 27.

    Fredsø N, Toft N, Sabers A, Berendt M. A prospective observational longitudinal study of new-onset seizures and newly diagnosed epilepsy in dogs. BMC Vet Res. 2017;13(1):54. doi:10.1186/s12917-017-0966-y

    • Search Google Scholar
    • Export Citation
  • 28.

    Hülsmeyer V, Zimmermann R, Brauer C, Sauter-Louis C, Fischer A. Epilepsy in Border Collies: clinical manifestation, outcome, and mode of inheritance. J Vet Intern Med. 2010;24(1):171-178. doi:10.1111/j.1939-1676.2009.0438.x

    • Search Google Scholar
    • Export Citation
  • 29.

    Moore SA, Muñana KR, Papich MG, Nettifee-Osborne J. Levetiracetam pharmacokinetics in healthy dogs following oral administration of single and multiple doses. Am J Vet Res. 2010;71(3):337-341. doi:10.2460/ajvr.71.3.337

    • Search Google Scholar
    • Export Citation
  • 30.

    Boozer LB, Platt SR, Haley AC, et al. Pharmacokinetic evaluation of immediate- and extended-release formulations of levetiracetam in dogs. Am J Vet Res. 2015;76(8):719-723. doi:10.2460/ajvr.76.8.719

    • Search Google Scholar
    • Export Citation
  • 31.

    Muñana KR, Otamendi AJ, Nettifee JA, Papich MG. Population pharmacokinetics of extended-release levetiracetam in epileptic dogs when administered alone, with phenobarbital or zonisamide. J Vet Intern Med. 2018;32(5):1677-1683. doi:10.1111/jvim.15298

    • Search Google Scholar
    • Export Citation

Supplementary Materials

  • Figure 1

    Kaplan-Meier curves for the time from initiation to withdrawal of treatment for 100 dogs with idiopathic epilepsy administered either levetiracetam (LEV), zonisamide (ZNS), or phenobarbital (PB) monotherapy between January 1, 2003, and February 6, 2019. Tick marks denote censored dogs; each step represents the withdrawal of treatment for ≥ 1 dog. No significant difference was identified between monotherapy groups.

  • 1.

    Kearsley-Fleet L, O’Neill DG, Volk HA, Church DB, Brodbelt DC. Prevalence and risk factors for canine epilepsy of unknown origin in the UK. Vet Rec. 2013;172(13):338. doi:10.1136/vr.101133

    • Search Google Scholar
    • Export Citation
  • 2.

    Heske L, Nødtvedt A, Jäderlund KH, Berendt M, Egenvall A. A cohort study of epilepsy among 665,000 insured dogs: incidence, mortality and survival after diagnosis. Vet J. 2014;202(3):471-476. doi:10.1016/j.tvjl.2014.09.023

    • Search Google Scholar
    • Export Citation
  • 3.

    Erlen A, Potschka H, Volk HA, Sauter-Louis C, O’Neill DG. Seizure occurrence in dogs under primary veterinary care in the UK: prevalence and risk factors. J Vet Intern Med. 2018;32(5):1665-1676. doi:10.1111/jvim.15290

    • Search Google Scholar
    • Export Citation
  • 4.

    Vossler DG, Weingarten M, Gidal BE; American Epilepsy Society Treatments Committee. Summary of antiepileptic drugs available in the United States of America. Epilepsy Curr. 2018;18(4 suppl 1):1-26. doi:10.5698/1535-7597.18.4s1.1

    • Search Google Scholar
    • Export Citation
  • 5.

    Podell M, Volk HA, Berendt M, et al. 2015 ACVIM Small Animal consensus statement on seizure management in dogs. J Vet Intern Med. 2016;30(2):477-490. doi:10.1111/jvim.13841

    • Search Google Scholar
    • Export Citation
  • 6.

    Charalambous M, Brodbelt D, Volk HA. Treatment in canine epilepsy-a systematic review. BMC Vet Res. 2014;10(1):257. doi:10.1186/s12917-014-0257-9

    • Search Google Scholar
    • Export Citation
  • 7.

    Boothe DM, Dewey C, Carpenter DM. Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. J Am Vet Med Assoc. 2012;240(9):1073-1083. doi:10.2460/javma.240.9.1073

    • Search Google Scholar
    • Export Citation
  • 8.

    Farnbach GC. Serum concentrations and efficacy of phenytoin, phenobarbital, and primidone in canine epilepsy. J Am Vet Med Assoc. 1984;184(9):1117-1120.

    • Search Google Scholar
    • Export Citation
  • 9.

    Schwartz-Porsche D, Löscher W, Frey HH. Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison. J Vet Pharmacol Ther. 1985;8(2):113-119. doi:10.1111/j.1365-2885.1985.tb00934.x

    • Search Google Scholar
    • Export Citation
  • 10.

    Tipold A, Keefe TJ, Löscher W, Rundfeldt C, de Vries F. Clinical efficacy and safety of imepitoin in comparison with phenobarbital for the control of idiopathic epilepsy in dogs. J Vet Pharmacol Ther. 2015;38(2):160-168. doi:10.1111/jvp.12151

    • Search Google Scholar
    • Export Citation
  • 11.

    Fredsø N, Sabers A, Toft N, Møller A, Berendt M. A single-blinded phenobarbital-controlled trial of levetiracetam as mono-therapy in dogs with newly diagnosed epilepsy. Vet J. 2016;208:44-49. doi:10.1016/j.tvjl.2015.10.018

    • Search Google Scholar
    • Export Citation
  • 12.

    Charalambous M, Shivapour SK, Brodbelt DC, Volk HA. Antiepileptic drugs’ tolerability and safety-a systematic review and meta-analysis of adverse effects in dogs. BMC Vet Res. 2016;12(1):79. doi:10.1186/s12917-016-0703-y

    • Search Google Scholar
    • Export Citation
  • 13.

    De Risio L, Bhatti S, Muñana K, et al. International veterinary epilepsy task force consensus proposal: diagnostic approach to epilepsy in dogs. BMC Vet Res. 2015;11(1):148. doi:10.1186/s12917-015-0462-1

    • Search Google Scholar
    • Export Citation
  • 14.

    Meland T, Carrera-Justiz S, Buckley GJ. Antiepileptic drug use patterns in suspect epileptic dogs among neurology and emergency specialists. J Am Anim Hosp Assoc. 2019;55(3):138-143. doi:10.5326/JAAHA-MS-6795

    • Search Google Scholar
    • Export Citation
  • 15.

    Van Meervenne SA, Volk HA, Matiasek K, Van Ham LM. The influence of sex hormones on seizures in dogs and humans. Vet J. 2014;201(1):15-20. doi:10.1016/j.tvjl.2014.05.008

    • Search Google Scholar
    • Export Citation
  • 16.

    Jaggy A, Faissler D, Gaillard C, Srenk P, Graber H. Genetic aspects of idiopathic epilepsy in Labrador Retrievers. J Small Anim Pract. 1998;39(6):275-280. doi:10.1111/j.1748-5827.1998.tb03650.x

    • Search Google Scholar
    • Export Citation
  • 17.

    Berendt M, Gredal H, Pedersen LG, Alban L, Alving J. A cross-sectional study of epilepsy in Danish Labrador Retrievers: prevalence and selected risk factors. J Vet Intern Med. 2002;16(3):262-268. doi:10.1892/0891-6640(2002)016<0262:acsoei>2.3.co;2

    • Search Google Scholar
    • Export Citation
  • 18.

    Chung JY, Hwang CY, Chae JS, et al. Zonisamide monotherapy for idiopathic epilepsy in dogs. N Z Vet J. 2012;60(6):357-359. doi:10.1080/00480169.2012.680855

    • Search Google Scholar
    • Export Citation
  • 19.

    Stabile F, van Dijk J, Barnett CR, De Risio L. Epileptic seizure frequency and semiology in dogs with idiopathic epilepsy after initiation of imepitoin or phenobarbital monotherapy. Vet J. 2019;249:53-57. doi:10.1016/j.tvjl.2019.05.007

    • Search Google Scholar
    • Export Citation
  • 20.

    Packer RMA, Shihab NK, Torres BBJ, Volk HA. Responses to successive anti-epileptic drugs in canine idiopathic epilepsy. Vet Rec. 2015;176(8):203. doi:10.1136/vr.102934

    • Search Google Scholar
    • Export Citation
  • 21.

    Chang Y, Mellor DJ, Anderson TJ. Idiopathic epilepsy in dogs: owners’ perspectives on management with phenobarbitone and/or potassium bromide. J Small Anim Pract. 2006;47(10):574-581. doi:10.1111/j.1748-5827.2006.00203.x

    • Search Google Scholar
    • Export Citation
  • 22.

    Nettifee JA, Munana KR, Griffith EH. Evaluation of the impacts of epilepsy in dogs on their caregivers. J Am Anim Hosp Assoc. 2017;53(3):143-149. doi:10.5326/JAAHA-MS-6537

    • Search Google Scholar
    • Export Citation
  • 23.

    Wessmann A, Volk HA, Packer RMA, Ortega M, Anderson TJ. Quality-of-life aspects in idiopathic epilepsy in dogs. Vet Rec. 2016;179(9):229. doi:10.1136/vr.103355

    • Search Google Scholar
    • Export Citation
  • 24.

    Fredsø N, Koch BC, Toft N, Berendt M. Risk factors for survival in a university hospital population of dogs with epilepsy. J Vet Intern Med. 2014;28(6):1782-1788. doi:10.1111/jvim.12443

    • Search Google Scholar
    • Export Citation
  • 25.

    Berendt M, Gredal H, Ersbøll AK, Alving J. Premature death, risk factors, and life patterns in dogs with epilepsy. J Vet Intern Med. 2007;21(4):754-759. doi:10.1892/0891-6640(2007)21[754:pdrfal]2.0.co;2

    • Search Google Scholar
    • Export Citation
  • 26.

    Masucci M, Di Stefano V, Donato G, Mangano C, De Majo M. How owners of epileptic dogs living in Italy evaluate their quality of life and that of their pet: a survey study. Vet Sci. 2021;8(8):140. doi:10.3390/vetsci8080140

    • Search Google Scholar
    • Export Citation
  • 27.

    Fredsø N, Toft N, Sabers A, Berendt M. A prospective observational longitudinal study of new-onset seizures and newly diagnosed epilepsy in dogs. BMC Vet Res. 2017;13(1):54. doi:10.1186/s12917-017-0966-y

    • Search Google Scholar
    • Export Citation
  • 28.

    Hülsmeyer V, Zimmermann R, Brauer C, Sauter-Louis C, Fischer A. Epilepsy in Border Collies: clinical manifestation, outcome, and mode of inheritance. J Vet Intern Med. 2010;24(1):171-178. doi:10.1111/j.1939-1676.2009.0438.x

    • Search Google Scholar
    • Export Citation
  • 29.

    Moore SA, Muñana KR, Papich MG, Nettifee-Osborne J. Levetiracetam pharmacokinetics in healthy dogs following oral administration of single and multiple doses. Am J Vet Res. 2010;71(3):337-341. doi:10.2460/ajvr.71.3.337

    • Search Google Scholar
    • Export Citation
  • 30.

    Boozer LB, Platt SR, Haley AC, et al. Pharmacokinetic evaluation of immediate- and extended-release formulations of levetiracetam in dogs. Am J Vet Res. 2015;76(8):719-723. doi:10.2460/ajvr.76.8.719

    • Search Google Scholar
    • Export Citation
  • 31.

    Muñana KR, Otamendi AJ, Nettifee JA, Papich MG. Population pharmacokinetics of extended-release levetiracetam in epileptic dogs when administered alone, with phenobarbital or zonisamide. J Vet Intern Med. 2018;32(5):1677-1683. doi:10.1111/jvim.15298

    • Search Google Scholar
    • Export Citation

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