The Evidence Behind the Treatment of Canine Idiopathic Epilepsy

Oral phenobarbital and imepitoin in particular, followed by potassium bromide and levetiracetam are likely to be effective for the treatment of canine idiopathic epilepsy. There is strong evidence supporting the use of oral phenobarbital and imepitoin as ‘first line’ medications. However, there remains a lack of evidence for targeted treatment for the various individual epileptic phenotypes and quite limited evidence on direct comparisons of the efficacy between various anti-epileptic drugs.

Limitations: Retrospective case series but mainly good follow up time 1.1 years (median).

Sample size: 120 dogs, n=120
Intervention details: 2 treatment groups (including the control group)

Outcome Studied: Objective:
To support the antiepileptic activity and safety of imepitoin in dogs with idiopathic epilepsy.

Main Findings (relevant to PICO question):
 Administration of imepitoin twice daily at a dose of 30 mg/kg results in significant and persistent antiepileptic effects in patients with newly diagnosed epilepsy suffering from generalized tonic-clonic seizures compared to 'pseudoplacebo' control group (1 mg/kg BID) of the same drug. The safety profile of imepitoin was good, and mostly CNS related ARs were transient and predominantly observed in the first weeks of treatment.

Limitations:
 Short follow up time for first phase of study (12 weeks).
 Open-labelled phase was an additional 12 weeks.
 A few cases had Tier I confidence level for the diagnosis of idiopathic epilepsy.

Sample size:
 After exclusion: 152, n=152 Outcome Studied: Objective: Evaluation of the antiepileptic action of imepitoin and phenobarbital based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 The majority of the dogs were managed successfully with imepitoin.
 The same study confirmed non-inferiority of imepitoin to phenobarbital.

Limitations:
 Statistical analysis was conducted before unblinding only on the per-protocol population and not on the intent-to-treat population.
 Tier I confidence level for the diagnosis of idiopathic epilepsy.

Sample size: 1153 dogs, n= 1153
Intervention details: Studies were grouped based on the antiepileptic drugs they evaluated and their overall quality of evidence.Details of drug's doses, treatment period, pre-and post-treatment seizure frequency, 95% confidence interval of the successfully (≥50% reduction in seizure frequency) study population were provided.
Study design: Systematic Review.
Outcome Studied: Objective: Individual studies were evaluated based on the quality of evidence (study design, study group sizes, diagnostic procedures for enrolling dogs with idiopathic epilepsy and overall risk of bias) and the outcome measures reported (in particular the proportion of dogs with ≥50%reduction in seizure frequency).

Main Findings (relevant to PICO question):
 Overall risk of bias was moderate/high to high in 85% of the studies included.
 The diagnostic investigation procedures were poorly defined or unclear in 50% of the studies.
 Small population of dogs (<20) included in 77% of the studies.
 Oral phenobarbital and imepitoin in particular, as well as potassium bromide and levetiracetam are likely to be effective for the treatment of IE.

Limitations:
 The review was an in depth and objective assessment of the drugs' efficacy and studies' quality of evidence.Therefore, the limitations occurred in this review, derived from the studies included and evaluated in this review. Precisely: the overall low quality of evidence; the variations in baseline characteristics of the dogs involved; the significant differences between study designs, and several potential sources of bias that were identified preclude definitive recommendations.
 The main limitation of this review is that it did not have free full access to unpublished data (e.g.EMEA report).

Fredsø (2014)
Population: Dogs with idiopathic epilepsy (Tier I or insufficient level of confidence) and structural epilepsy.

Sample size: 102 dogs, n=102
Intervention details:  One hundred and two client owned dogs; 78 dogs with idiopathic epilepsy and 24 dogs with epilepsy associated with a known intracranial cause.
 A retrospective hospital based study with follow-up.Dogs diagnosed with epilepsy between 2002 and 2008 were enrolled in the study.
 Owners were interviewed by telephone using a structured questionnaire addressing epilepsy status, treatment, death/alive, and cause of death.
Study design: Retrospective case series.Questionnaire.

Outcome Studied:
Objective: To investigate risk factors for survival and duration of survival in a population of dogs with idiopathic epilepsy or epilepsy associated with a known intracranial cause.

Main Findings (relevant to PICO question):
In dogs where monotherapy was not sufficient, the need for treatment with two AED's is not linked to a poor prognosis.
 Insufficient or Tier I confidence level for diagnosing idiopathic epilepsy.

Sample size: 344 dogs, n=344
Intervention details: Data from dogs was retrospectively collected from electronic patient records.Clinical data was originally gained via standardised owner questionnaires for epilepsy patients at their first appointment, and longitudinal follow up data was gained via telephone interview with the dogs' owners.

Main Findings (relevant to PICO question):
The presence of cluster seizures and thus seizure density is a more influential risk factor on the likelihood of achieving remission in canine epilepsy than seizure frequency or the total number of seizures prior to treatment.

Limitations:
 Retrospective case series study.
 However, thorough statistics were used which were good in filtering out the non-significant.

Treatment group:
Drug: Topiramate as an adjunct to phenobarbital and/or potassium bromide and/or levetiracetam Dose: 5 mg/kg PO BID for 2 months, then 10 mg/kg PO BID for 2 months and then 10 mg/kg PO TID for 2 months; doses of other AEDs were not available but reported to be within normal reference values

Main Findings (relevant to PICO question):
 Favourable results for topiramate adjunctive therapy.
 Approximately half of the study population had ≥50% reduction in seizure frequency.
 Low study population.
 Precise doses of concurrent AEDs were not reported.Srivastava (2013) Population: Dogs with idiopathic epilepsy (insufficient level of confidence).

Treatment group:
Drug: potassium bromide as an adjunct to phenobarbital

Main Findings (relevant to PICO question):
Favourable results for potassium bromide adjunctive therapy in all dogs.

Limitations:
 Only abstract was retrieved.Low study population.
 Insufficient confidence level for the diagnosis of idiopathic epilepsy.Precise reduction in seizure frequency could not be detected only based on the abstract.

Main Findings (relevant to PICO question):
 Favourable results for phenobarbital and potassium bromide monotherapy.
 The majority of the study population had ≥50% reduction in seizure frequency in both groups.The percentage of successfully treated cases was higher in phenobarbital group.
 Phenobarbital treated dogs had less side effects than potassium bromide dogs.
Limitations: Tier I confidence level for diagnosing idiopathic epilepsy.
Sample size: 10 dogs, n=10 Outcome Studied: Objective: Evaluation of the antiepileptic action of zonisamide based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
Favourable results for zonisamide monotherapy.Approximately half of the study population had ≥50% reduction in seizure frequency.
 Low study population.
 Research support but unclear if it was financial.
Sample size: 70 dogs, n=70 Outcome Studied: Objective: To determine the concentration of phenobarbital in dogs with idiopathic epilepsy in Croatia.

Main Findings (relevant to PICO question):
 In the investigated population 25 patients (36%) had measured concentration of phenobarbital under the lower therapeutic limit with adequate control of seizures.
 Only in 16% phenobarbital was ineffective in eradication of seizures.
 Phenobarbital is reasonable first-choice antiepileptic drug for treatment of canine idiopathic epilepsy in Croatia.
 Retrospective case series (high risk of bias).
 Tier I confidence level for diagnosing idiopathic epilepsy.

Main Findings (relevant to PICO question):
Fatty acid supplementation did not reduce seizure frequency or severity in dogs with idiopathic epilepsy.

Limitations:
 Low study population.
Outcome Studied: Objective: Evaluation of the antiepileptic action of levetiracetam based mainly on the seizure frequency change during specific treatment period and compared to the placebo group.

Main Findings (relevant to PICO question):
 Favourable results for levetiracetam adjunctive therapy.
 The majority of the study population had ≥50% reduction in seizure frequency.
 The latter was reduced significantly compared to baseline but no difference was detected when compared to the placebo group (dogs in both the placebo and levetiracetam group were on maintenance therapy with phenobarbital and/or potassium bromide and/or gabapentin).

Limitations:
 Potential risk of comparing to retrospective baseline.the results.

 The study had financial support but unclear if it influenced
 Tier I confidence level for diagnosing idiopathic epilepsy.
Outcome Studied: Objective: Evaluation of the antiepileptic action of verapamil based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
Failure of the maximum tolerated dose to improve seizure control.
 Low study population.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.

Sample size: 62 dogs, n=62
Intervention details: 2 comparison treatment groups.Phenobarbital (n=30) and potassium bromide (n=32) were compared as monotherapies for 12 months.Details of doses are not given.

Outcome Studied:
Objective: To compare phenobarbital to potassium bromide monotherapy.

Main Findings (relevant to PICO question):
Phenobarbital was more effective and better tolerated than potassium bromide monotherapy.

Limitations:
 Conference paper.
 Non-blinded and non-randomised.Insufficient confidence level for diagnosing idiopathic epilepsy.

Treatment group:
Drug: pregabalin as an adjunct to phenobarbital and potassium bromide Dose: pregabalin: 2 mg/kg PO TID (dose was increased up to until 3-4 mg/kg PO TID); doses of other AEDs were not available but reported to be within normal reference values Treatment period: 3 months n= 9 Study design: Uncontrolled clinical trial.
Outcome Studied: Objective: Evaluation of the antiepileptic action of pregabalin based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Favourable results for pregabalin adjunctive therapy.
 The majority of the study population had ≥50% reduction in seizure frequency.

Limitations:
 Non-blinded, non-randomised and uncontrolled trial  Low study population.
 Short follow up -3 months study duration.
 Precise doses of concurrent AEDs were not reported.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.
Supplement the dog's diet with moderate amounts of fish oil (oral omega-3 polyunsaturated fatty acids, 2 g/day).Phenobarbital (2.5 mg/kg, twice a day orally) Study design: Case report.
Outcome Studied: Subjective: To evaluate the effectiveness of daily intake of a moderate amount of fish oil in a case of canine epilepsy.

Main Findings (relevant to PICO question):
 The frequency of the epileptic seizures markedly fell after 50 days of combination therapy with phenobarbital and omega-3 fatty acid.
 During the subsequent 18-month period, seizure frequency fell to one per 3 months, a reduction of about 85%.

Limitations:
 Case report (high risk of bias). Insufficient confidence level for diagnosing idiopathic epilepsy. Insufficient details on the type of fish oil used or specific concentrations.

Main Findings (relevant to PICO question):
 Favourable results for levetiracetam adjunctive therapy.
 The majority of the study population had ≥50% reduction in seizure frequency in both, clinical trial and case series part.
 The study had financial support but unclear if it influenced the results. Part of the study was retrospective. Precise doses of concurrent AEDs were not reported; but phenobarbital and potassium bromide serum levels were reported.

Treatment group:
Drug: gabapentin as an adjunct to phenobarbital

Main Findings (relevant to PICO question):
 Favourable results for gabapentin as adjunctive therapy.
 Significant reduction in frequency of epileptic attacks (67.29+or-9.03%) in the majority of the dogs (7 patients) (63.63%) allowing a progressive reduction in the PB doses to 5 mg/kg PO BID.
 Only abstract was retrieved.Low study population.
 Insufficient confidence level for diagnosing idiopathic epilepsy.

Main Findings (relevant to PICO question):
Seizure-free status was achieved during the treatment period, but 20% of the dogs had again seizures 15-25 days after Belladona stopped.Then, it was restarted for 2-3 months until seizures were ceased.
 Controversial results.
 Unclear/Insufficient confidence level for diagnosing idiopathic epilepsy.

Treatment group:
Drug: zonisamide as an adjunct to phenobarbital and/or potassium bromide Dose: zonisamide: mean 8.9 mg/kg, range 5-11 mg/kg PO BID; doses of other AEDs were not available but reported to be within normal reference values.period.

Main Findings (relevant to PICO question):
 Favourable results for zonisamide adjunctive therapy.
 The majority of the study population had ≥50% reduction in seizure frequency.
 Low study population.
 Precise doses of concurrent AEDs were not reported.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.

Platt (2006)
Population: Dogs with idiopathic epilepsy (Tier I level of confidence).

Treatment group:
Drug: gabapentin as an adjunct to phenobarbital and potassium bromide Dose: gabapentin: mean 10.9 mg/kg, 9.

Main Findings (relevant to PICO question):
 Favourable results for gabapentin adjunctive therapy.
 Approximately half of the study population had ≥50% reduction in seizure frequency.
 Low study population.
 Less than 6 months study duration.Precise doses of concurrent AEDs were not reported.
 Tier I confidence level for diagnosing idiopathic epilepsy.bromide adjunctive treatment based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Only less than the half of the study population had ≥50% reduction in seizure frequency with imepitoin monotherapy, imepitoin adjunctive therapy and potassium bromide adjunctive therapy.
 The majority of the study population had ≥50% reduction in seizure frequency with phenobarbital and primidone monotherapy.
 Part of the study was retrospective.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.

Sample size: 17 dogs, n=17
Intervention details: Outcome Studied: Objective: Evaluation of the antiepileptic action of gabapentin based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Favourable results for gabapentin adjunctive therapy.
 Approximately more than the half of the study population had ≥50% reduction in seizure frequency.
 A few cases were treated by the referring vets.
 The study had financial support.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.Outcome Studied: Objective: Evaluation of the ketogenic food effectiveness in the seizure control based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Only 33% of the study population had ≥50% reduction in seizure frequency. No difference between two groups.
 Doses/quantity of food or AEDs are not mentioned.
 Low study population.
 Needed 22 dogs per group based on power calculation; thus, insufficient power in this study.
 Insufficient confidence level for diagnosing idiopathic epilepsy.

Dewey (2004)
Population: Dogs with idiopathic epilepsy (Tier I-II level of confidence).

Sample size: 12 dogs, n=12
Intervention details: Outcome Studied: Objective: Evaluation of the antiepileptic action of zonisamide based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Favourable results for zonismide adjunctive therapy. Approximately half of the study population had ≥50% reduction in seizure frequency.
 Low study population.
 Short follow-up period.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.

Treatment group:
Drug: levetiracetam as an adjunct to phenobarbital and potassium bromide Dose: levetiracetam: range 7.1-23.8mg/kg PO TID; doses of other AEDs were not available but reported to be within normal reference values

Main Findings (relevant to PICO question):
 Favourable results for levetiracetam adjunctive therapy. All the dogs of the study population had ≥50% reduction in seizure frequency.Limitations:  Low study population.
 Insufficient confidence level for diagnosing idiopathic epilepsy.
 Non-blinded, non-randomised and uncontrolled trial.
 Conference abstract.

Treatment group:
Vagal nerve stimulation adjunctive to phenobarbital and/or potassium bromide and/or felbamate

Control Group:
No device Method: 13 weeks of treatment followed (after 4 weeks wash-out) by 13 weeks of control (inactive device)

Study design: Double blinded crossover controlled clinical trial
Outcome Studied: Objective: To investigate the antiepileptic efficacy of vagal nerve stimulation.

Main Findings (relevant to PICO question):
Mean decrease in seizure frequency between the 2 groups was 5.1% and not significant.

Limitations:
 Low study population.
 Assessment bias in favor of the device introduced by owners' assessment could be a possibility.

Main Findings (relevant to PICO question):
 Favourable results for felbamate adjunctive therapy. All the dogs of the study population had ≥50% reduction in seizure frequency.
 Low study population.
 Part of the study was retrospective.No clarification of statistical analysis.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.

Treatment group:
Drug: potassium bromide as an adjunct to phenobarbital or primidone Dose: Doses were not available but adjusted according to the therapeutic serum levels and clinical response Treatment period: mean 14.2 +/-4.7 months n=6 Study design: Retrospective case series study.
Outcome Studied: Objective: Evaluation of the antiepileptic action of potassium bromide as adjunctive therapy based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Favourable results for potassium bromide adjunctive therapy. The majority of the study population had ≥50% reduction in seizure frequency.

Limitations:
 Retrospective nature of study.
 Insufficient confidence level for diagnosing idiopathic epilepsy.

Main Findings (relevant to PICO question):
 Favourable results for phenobarbital monotherapy.
 The majority of the study population had ≥50% reduction in seizure frequency.

Limitations:
 Retrospective nature of study.
 Less than 6 months study duration.
 The study had financial support but unclear if it influenced the results.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.

Treatment group:
Drug: nimodipine as an adjunct to phenobarbital or primidone.Study design: Uncontrolled clinical trial.

Dose
Outcome Studied: Objective: Evaluation of the antiepileptic action of nimodipine as adjunctive therapy based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
Nimodipine was not successful in controlling seizures in dogs.
 Insufficient confidence level for diagnosing idiopathic epilepsy.

Podell (1993)
Population: Dogs with idiopathic epilepsy (Tier I-II level of confidence) Sample size: 37 dogs, n=37 Outcome Studied: Objective: Evaluation of the antiepileptic action of potassium bromide as adjunctive therapy based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Favourable results for potassium bromide adjunctive therapy.
 The majority of the study population had ≥50% reduction in seizure frequency.

Limitations:
 Retrospective case series.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.

Schwartz-Porsche (1991)
Population: Dogs with idiopathic epilepsy (Tier II level of confidence).Outcome Studied: Objective: Evaluation of the antiepileptic action of potassium bromide as adjunctive therapy based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Favourable results for potassium bromide adjunctive therapy. More than half of the study population had ≥50% reduction in seizure frequency.

Treatment group:
Drug: potassium bromide as an adjunct to phenobarbital Dose: potassium bromide: 22 PO SID (dose increases occurred); phenobarbital: median 3.3 mg/kg, mean 3.8 mg/kg PO BID (dose was reduced by a mean of 50% in 7/10 dogs during the PBr treatment) Treatment period: median 7, mean 7.8 months n=10 Study design: Uncontrolled clinical trial.
Outcome Studied: Objective: Evaluation of the antiepileptic action of potassium bromide as adjunctive therapy based mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Favourable results for potassium bromide adjunctive therapy. The majority of the study population had ≥50% reduction in seizure frequency.Limitations:  Non-blinded, non-randomised and uncontrolled trial.
 Low study population.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases.

Main Findings (relevant to PICO question):
 Favourable results for primidone and phenobarbital monotherapy  The majority of the study population had ≥50% reduction in seizure frequency in primidone group.
 Approximately half of the study population had ≥50% reduction in seizure frequency in phenobarbital group.
 A few cases were treated by the referring vets.
 The study had financial support but unclear if it influenced the results.Insufficient confidence level for diagnosing idiopathic epilepsy.Population: Dogs with idiopathic epilepsy (insufficient level of confidence).

Main Findings (relevant to PICO question):
 Favourable results for phenobarbital and primidonemonotherapy.
 The majority of the study population had ≥50% reduction in seizure frequency.
 The study had research support but unclear if it influenced the results.
 No clarification of statistical analysis.Insufficient confidence level for diagnosing idiopathic epilepsy.

Cunningham (1983)
Population: Dogs with idiopathic epilepsy (Tier II level of confidence).

Sample size: 15 dogs, n=15
Intervention details: Outcome Studied: Objective: Evaluation of the action of primidonebased mainly on the seizure frequency change during specific treatment period.

Main Findings (relevant to PICO question):
 Favourable results for primidone monotherapy. The majority of the study population had ≥50% reduction in seizure frequency.
 Non-blinded, non-randomised and uncontrolled trial.
 Low study population.

Main Findings (relevant to PICO question):
 Favourable results for primidone monotherapy.
 The majority of the study population had ≥50% reduction in seizure frequency.
 Less than 6 months study duration.
 No seizure-free dogs.
 Tier I confidence level for diagnosing idiopathic epilepsy for some cases * The level of confidence for diagnosing idiopathic epilepsy (Tier I-III) used in this knowledge summary was based on the international veterinary epilepsy task force (IVETF) consensus statement on the diagnosis of idiopathic epilepsy (De Risio, L. et al. 2015).Any paper that included dogs with idiopathic epilepsy for which diagnostic investigations were below this Tier level of evidence or unclear was considered to provide insufficient level of confidence for diagnosing idiopathic epilepsy.Tier I was listed in the limitations of the papers as this could indicate that a few dogs might have suffered from structured epilepsy and as a result have not responded adequately or at all to the treatment.

Appraisal, application and reflection
Various antiepileptic drugs (AEDs) are used for the management of canine idiopathic epilepsy.Precisely, a good level of evidence supported the efficacy of oral phenobarbital and imepitoin as monotherapy AEDs, fair and insufficient level of evidence supported the efficacy of potassium bromide as monotherapy and adjunct AED respectively and fair level of evidence supported the efficacy of levetiracetam as adjunct AED.
Levetiracetam can be also used effectively as pulse therapy against cluster seizures according to a recent report by Packer, Nye et al. (2015).For the remaining AEDs (i.e.zonisamide, primidone, gabapentin, pregabalin, sodium valproate, felbamate, topiramate) favorable results were reported regarding their efficacy, but there was insufficient evidence to support their use mainly due to lack of bRCTs.
Although individual assumptions for AEDs' efficacy could be made based on the studies' results and the level of evidence provided, direct comparisons of efficacy between AEDs were limited due to lack of controlled studies.Precisely, based on the controlled studies, direct AED comparisons include: Phenobarbital vs Primidone Schwartz-Porsche et al. (1985) reported that the difference between the efficacy of phenobarbital and primidone was not significant, but primidone caused signs of liver toxicity in 70% of the dogs in the group.

Primidone vs Imepitoin
In a US field study, as reported in the EMEA (2012) report, imepitoin failed to demonstrate higher efficacy compared to primidone.However, this study was considered only as supportive information because the control group therapy (primidone) is not approved in Europe.
Finally, Muñana et al. (2012) compared levetiracetam to placebo and found that seizure frequency was reduced significantly compared to baseline but no difference was detected when compared to the placebo group.Direct comparisons between other AEDs could not be performed based on the current published evidence.Generally, AED monotherapy or adjunctive therapy with multiple drugs can be chosen according to the clinically successful control of seizures (i.e. usually >50% or, ideally, 100% reduction in seizure frequency) and side effects.2012) compared fatty acid supplementation to placebo but no differences in median seizure frequency or severity were detected between the two groups.Scorza et al. (2009) reported that the administration of fish oil at 2 g/d to a 2 year old female Great Dane successfully decreased the frequency of epileptic seizures.However, details on the type of fish oil used or specific concentrations were not reported.In a recent blinded randomised placebo-controlled cross-over trial, Law et al. (2015) compared a ketogenic medium-chain TAG diet (MCTD) with a standardised placebo diet in chronically antiepileptic drug-treated dogs with idiopathic epilepsy and showed that ketogenic diets can have antiepileptic properties translated as reduction in seizure activities.Implications for the future: Generally, several potential sources of bias and limitations were identified in the studies.Many of the studies included dogs with poor or unclear diagnostic investigations for idiopathic epilepsy and small study population and, consequently, definite recommendations are precluded.Therefore, further bRCTs are needed mainly for the AEDs, such as zonisamide, for which there are no high quality studies

Treatment period: 6 -15 months n= 10
Study design: Uncontrolled clinical trial.Outcome Studied: Objective: Evaluation of the antiepileptic action of topiramate based mainly on the seizure frequency change during specific treatment period.
Dose: potassium bromide: 30 mg/kg PO SID; phenobarbital: 4.25 mg/kg PO BID Treatment period: 6 months n=6 Study design: Uncontrolled clinical trial.Outcome Studied: Objective: Evaluation of the antiepileptic action of potassium bromide based mainly on the seizure frequency change during specific treatment period.

Sample size: 15 dogs, n= 15 Intervention details: 1
Treatment group, 1 Control group:  Treatment group: Fatty acid  Placebo group: Olive oil Twelve weeks of treatment with fatty acid supplementation, followed by a 12-week placebo period of olive oil supplementation.Study design: Blinded, placebo-controlled, clinical trial.Outcome Studied: Objective: Evaluation of the effect of fatty acid supplementation based mainly on the seizure frequency change during specific treatment period.
Dose: gabapentin: mean 40 mg/kg PO BID; initial doses of other AEDs were not available based on the abstract only Treatment period: Unclear n=11 Study design: Uncontrolled clinical trial.Outcome Studied: Objective: Evaluation of the antiepileptic action of gabapentin based mainly on the seizure frequency change during specific treatment period.

p a g e | 18 total pages: 38
Uncontrolled clinical trial.Outcome Studied: Objective: Evaluation of the antiepileptic action of zonisamide based mainly on the seizure frequency change during specific treatment Veterinary Evidence ISSN:2396-9776 Vol1, Issue1 DOI:http://dx.doi.org/10.18849/ve.v1i1.9 next review date: 27 Nov 2017 3-13.6 mg/kg PO TID; doses of other AEDs were not available but reported to be within normal reference values Treatment period:3 months n=11 Study design: Uncontrolled clinical trial.Outcome Studied: Objective: Evaluation of the antiepileptic action of gabapentin based mainly on the seizure frequency change during specific treatment period.

Treatment period: median 38 ,
range 13.8-95.5months n=15 Study design: Uncontrolled clinical trial.Outcome Studied: Objective: Evaluation of the antiepileptic action of levetiracetam based mainly on the seizure frequency change during specific treatment period.

7 Treatment group 2 :
Phenobarbital Dose: median 180 mg/kg, mean 283 mg/kg, range 60-90 mg/kg PO SID Treatment period: unclear n= Drug: primidone Dose: median 50 mg/kg, mean 48 mg/kg, range 18-94 mg/kg PO SID Treatment period: unclear n= 12 Study design: Uncontrolled clinical trial.Outcome Studied: Objective: Evaluation of the antiepileptic action of primidone and phenobarbital monotherapy based mainly on the seizure frequency change during specific treatment period.

Treatment group 2 :
Phenobarbital Dose: mean 15 mg/kg, range 7.3-32 mg/kg PO SID Treatment period: unclear n= Drug: primidone Dose: range 17-107 mg/kg PO SID Treatment period: mean 14, range 6.0-35months n= 20 Study design: Open-labeled, randomized, controlled clinical trial.Outcome Studied: Objective: Evaluation of the antiepileptic action of primidone and phenobarbital monotherapy based mainly on the seizure frequency change during specific treatment period.

1 .
Schwartz-Porsche et al. (1982) Population: Dogs with idiopathic epilepsy (Tier II level of confidence).Sample size: 30 dogs, n=30 Intervention details: 1 Treatment group, no Control group.Treatment group: Drug: primidone Dose: 13-100 mg/kg PO SID Treatment period: approximately 6 months n=15 Study design: Uncontrolled clinical trial.Outcome Studied: Objective: Evaluation of the antiepileptic action of primidone based mainly on the seizure frequency change during specific treatment period.
Jambroszyk et al. (2011) investigated verapamil as an adjunct to phenobarbital but even the maximum tolerated dose failed to improve seizure control in dogs.O'Brien et al. (1997) investigated nimodipine as an adjunct to phenobarbital or primidone but the results of the study did not support its use.At this point it is worth mentioning that the international veterinary epilepsy task force (IVETF) recently published a consensus statement(Bhatti et al. 2015) for treatment suggestions based mainly on current published evidence as provided and analyzed in this knowledge summary and in the systematic review byCharalambous et al. (2014) and it was additionally supported and adjusted by expert's opinions.

p a g e | 10 total pages: 38 Study design: Blinded
, randomised, controlled clinical trial.

Intervention details: 1
Treatment group, no Control group.

p a g e | 11 total pages: 38 Intervention details: 1
investigation group, no Control group.

p a g e | 12 total pages: 38
Dogs with idiopathic epilepsy (Tier I-II level of confidence).
Dogs with idiopathic epilepsy (insufficient level of confidence).
1 Treatment group, no Control group.
Veterinary Evidence ISSN:2396-9776 Vol1, Issue1 DOI:http://dx.doi.org/10.18849/ve.v1i1.9 next review date: 27 Nov 2017 p a g e | 22 total pages: 38 1 Treatment group, no Control group.Objective: Evaluation of the antiepileptic action of felbamate adjunctive therapy based mainly on the seizure frequency change during specific treatment period.
1 Treatment group, no Control group.
Dogs with idiopathic epilepsy (Tier I-II level of confidence).
Charalambous et al. (2014)performed a systematic review and suggested that the evidence-base in therapy of canine epilepsy is still unsatisfactory for some AEDs.Only four blinded randomized clinical trials (bRCTs) were reported which were considered to offer the highest quality of evidence amongst all the studies evaluated.The most recent one was performed byRundfeldt et al. (2015)who compared imepitoin high (30 mg/kg BID) to low (1 mg/kg BID) doses and concluded that doses of 30 mg/kg BID are effective in managing seizures in dogs with idiopathic epilepsy.Apart from these bRCTs, the majority of the evidence derived from non-blinded, non-randomised, uncontrolled clinical trials and case series.The studies included in this summary and the systematic reviewCharalambous et al. (2014)suggested that oral phenobarbital and imepitoin in particular, as well as potassium bromide and levetiracetam are likely to be effective for the treatment of idiopathic epilepsy.
Charalambous et al. (2014) that monotherapy with imepitoin in dogs with newly diagnosed epilepsy was almost similarly effective and potentially more tolerated than phenobarbital.The same result was reported within other studies investigated in the systematic review byCharalambous et al. (2014).
vs Potassium bromide Bootheet al. (2012) and Gaskill and Kimber (2010) found that phenobarbital was more effective and better tolerated than potassium bromide monotherapy.Veterinary Evidence ISSN:2396-9776 Vol1, Issue1 DOI:http://dx.doi.org/10.18849/ve.v1i1.9 next review date: 27 Nov 2017 p a g e | 33 total pages: 38 Patterson et al. (2005)orted that in dogs where monotherapy was not sufficient, the need for treatment with two AEDs has not been linked to a reduced survival.Packer et al. (2015)demonstrated that 37.5% of dogs that received a third-line AED after treatment failure with two AEDs were responsive to this drug (achieving > 50% reduction in seizure frequency).The same study found that only dogs that responded to the first AED became seizure-free.Lastly,Packer et al. (2014)found that the presence of cluster seizures and thus seizure density is a more influential risk factor on the likelihood of achieving remission in canine epilepsy than seizure frequency or the total number of seizures prior to treatment.Alternative therapies have been also investigated for treating canine epilepsy (including diet trials, nerve stimulation, homeopathic agents), but the results were not very encouraging based on these.Munana et al.  (2002)tried vagal nerve stimulation but the mean decrease in seizure frequency was approximately 34.4%.Varshney (2007) administered belladona and cocculus, which appeared to prevent further seizures, but in a few dogs these restarted once the agents were stopped.Patterson et al. (2005)tried ketogenic food to control seizures but included only 6 dogs (considerably less than the number that was initially estimated by power calculations).The results from the last two studies were considered controversial.Matthews et al. (

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Bhatti et al. (2015)able efficacy.Lastly, further and stronger evidence is vital for imepitoin as a new licensed drug in Europe before definite recommendation on its efficacy and tolerability are drawn.Limitation of the summary:The main limitation of this summary is that we could not obtain full access to a few papers included in the summary of evidence.These included: Srivastava M. et al. (2013), Kis, I. et al. (2012), Musteata, M. et al. (2007), Patterson.E.et al. (2005), Steinberg, M. (2004), Cunningham, G. et al. (1983) PubMed and CAB Abstracts 1973 to 2015 combined search on OVID platform Search terms: (dog or dogs or puppy or puppies or canis or canine) AND (idiopath*) AND (epilep* or seizur* or convuls*) AND (treat* or manag* or guideline* or guidance or principle* or recommend*) Studies evaluating or reporting the treatment, management and diagnosis of canine idiopathic epilepsy *There was one non-systematic review, Packer et al. (2014) that was included because it made important conclusions and valuable up-to-date points for our summary.The same paper was not included in the table though but in the text.The same applies for the IVETF consensus statements byBhatti et al. (2015)and De Risio et al.(2015).