What are the evidence-based options for managing refractory epilepsy in dogs unresponsive to phenobarbital and bromide?

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For dogs with idiopathic epilepsy refractory to both phenobarbital and potassium bromide, the evidence-based add-on options are imepitoin, levetiracetam, zonisamide, and cannabidiol (CBD), with emerging data for telmisartan. Imepitoin add-on to phenobarbital achieves a ≥50% reduction in monthly seizure frequency in 36–42% of dogs, at a mean effective dose of approximately 15 mg/kg PO q12h when titrated from a starting dose of 5 mg/kg PO q12h.6 The lower starting dose of 5 mg/kg PO q12h is better tolerated than starting at 10 mg/kg PO q12h.6 Importantly, neither imepitoin nor phenobarbital add-on treatment suppresses cluster seizure activity, making persistent cluster seizures a strong predictor of ongoing drug resistance.6 The full dose range is 10–30 mg/kg PO q12h.3 Levetiracetam (immediate-release: 20–60 mg/kg PO q8h; extended-release: 30 mg/kg PO q12h) carries fair evidence as an adjunct antiseizure medication (ASM) in dogs, supported by at least one blinded randomized controlled trial.311 It is a first-choice add-on for dogs not responding to bromides.3 Zonisamide (5–10 mg/kg PO q12h) is increasingly used as a first-choice ASM in dogs, with steady state achieved within approximately 1 week.3 Favorable efficacy results have been reported as an adjunct, though the overall level of evidence remains insufficient for definitive recommendations.11 The combination of phenobarbital (2–5 mg/kg PO q12h) and KBr (15–30 mg/kg PO q24h) is noted as often effective for dogs unresponsive to either drug alone, though this applies to dogs failing monotherapy rather than those who have already failed both.3 Adverse effects including ataxia, lethargy, polyuria, and polydipsia are exacerbated with combination use.3 Cannabidiol (CBD) has demonstrated adjunct benefit in drug-resistant canine idiopathic epilepsy, though the veterinary literature characterizes the supporting evidence as limited.13 Refractory epilepsy affects approximately 25–30% of epileptic dogs despite phenobarbital,