Seizure Management in a Fractious Dog

History & Signalment

Bully, a 5-year-old neutered male Labrador retriever, was presented for increased frequency of recurrent generalized seizures. Idiopathic/primary epilepsy was diagnosed 2 years prior based on age at onset of seizures (1-6 years), normal physical and interictal neurologic examinations, and normal metabolic test results (ie, CBC, serum chemistry profile, bile acids, urinalysis).¹ The maximum recommended dose of levetiracetam extended-release tablets (60 mg/kg PO every 12 hours) was administered.

Bully was often difficult to handle during clinic visits, resulting in stress for Bully, his owner, and the veterinary team. Multiple team members were needed for restraint during physical examination, and his owner was previously asked to apply a muzzle and Elizabethan collar.

Physical Examination

Physical examination findings were largely unremarkable. Temperature, pulse, and respiratory rate were normal. Heart and lungs were normal on auscultation, and no enlarged lymph nodes or abdominal organs were appreciated. A limited neurologic examination revealed normal proprioception and withdrawal reflex in all limbs, normal palpebral and pupillary light reflexes, normal menace response, and normal muscle mass of the temporalis and masseter muscles. Gag reflex could not be safely evaluated.

Diagnostics

Repeat CBC, serum chemistry profile, and urinalysis were performed to rule out metabolic changes as the cause of increased seizure frequency. ALP was mildly elevated, but there were no significant changes in RBC count, WBC count, platelet count, electrolytes, or kidney or liver values. The increase in ALP was attributed to hypoxia during a recent generalized seizure. Serum levetiracetam level was not measured, as therapeutic levels have not been established in dogs due to the drug’s high safety margin.

Diagnosis

The diagnosis of idiopathic/primary epilepsy was retained because of the lack of significant changes on physical and neurologic examinations and blood work.

Treatment & Management

Levetiracetam was a good initial treatment choice due to low risk for adverse effects and lack of required drug monitoring, as Bully was often fractious at the clinic; however, an additional antiepileptic drug was warranted because seizures had increased in frequency and the levetiracetam dose was already at the recommended maximum. Phenobarbital, zonisamide, and potassium bromide were discussed with the owner, and zonisamide (5-10 mg/kg PO every 12 hours) was elected as an add-on anticonvulsant.

Outcome

Liver values were checked 1 week after zonisamide was initiated. No significant changes were detected, and treatment was continued. In a follow-up phone call 2 weeks after zonisamide was initiated (when steady-state concentrations had been reached), the owner reported there were no seizures in the previous 12 days.

Discussion

Treatment Timing & Drug Selection

Antiepileptic drug therapy may be recommended in patients with idiopathic epilepsy when ≥2 seizures occur in a 6-month period, status epilepticus or cluster seizures are present, postictal periods are prolonged or severe, and/or seizure frequency or severity increases.²

If initial treatment is not successful and seizure control is established with an additional antiepileptic drug, the initial medication can be slowly tapered after the pet owner is informed of the risk for recurrent seizures.

Concurrent health concerns and medications, as well as owner attributes (eg, how frequently medications can be administered, financial limitations, tolerance for adverse effects), should be considered when selecting an antiepileptic drug.² Certain drugs warrant monitoring of therapeutic drug level and other hematologic parameters.

Treatment Options

Phenobarbital

Phenobarbital (starting maintenance dose, 2.5-3 mg/kg PO every 12 hours) is a common primary medication that is commercially available as an oral elixir and tablets. Steady state is reached in 10 to 14 days, at which point serum levels (ideally, 15-35 micrograms/mL) should be tested. CBC, serum chemistry profile, and serum bile acids should be evaluated every 6 months to monitor for hepatotoxicosis and bone marrow suppression (more common with serum levels >35 micrograms/mL), and serum phenobarbital levels should be monitored every 6 to 12 months to ensure maintenance of an effective therapeutic level. Patients with serum levels <25 micrograms/mL that are well controlled do not require dose adjustment. A small subset of patients may benefit from administration every 8 hours due to the medication’s relatively short half-life. Adverse effects can include polyuria, polydipsia, and polyphagia, and drug interactions (eg, decreased effects of levetiracetam, zonisamide, benzodiazepines, corticosteroids, cyclosporine, and metronidazole; increased phenobarbital levels with concurrent administration of certain antibiotics, felbamate, topiramate, and antifungal medications) are possible.^2,3 Care is needed when administering phenobarbital in dogs with aggressive tendencies, as polyphagia can lead to food aggression.^2,3

Potassium Bromide

Potassium bromide (20-40 mg/kg PO every 24 hours) has a long half-life and is therefore a good choice when owners cannot administer medication frequently; however, the long half-life results in a time to steady state of 4 months if a loading dose (commonly, 450-600 mg/kg PO divided and given every 4-6 hours for 5 days targeting serum levels of 1,000-1,270 mg/L) is not used. Serum level (ideally, 1,000-3,000 mg/L) should be tested every 6 to 12 months or following a dose change. Potassium bromide is not metabolized by the liver. Renal excretion is dependent on concurrent chloride intake, so diets should not be changed in patients receiving this medication. Polyuria, polydipsia, and polyphagia may occur, and hypertriglyceridemia is common with concurrent phenobarbital and potassium bromide administration. Hypertriglyceridemia can be treated with a low-fat diet, exercise, and omega-3 fatty acid supplementation (120 mg/kg^0.75 PO every 24 hours). If vomiting occurs following potassium bromide administration due to direct gastric irritation (especially with compounded oral solutions), the dose should be divided and given every 12 hours with food. If ataxia or paresis develops, the dose should be decreased by 15%; however, breakthrough seizures have occurred in 26% of patients receiving a decreased dose.⁴ Potassium bromide has been associated with aggression; caution should thus be used when prescribing this drug in aggressive patients.^2,5

Levetiracetam

Levetiracetam is available as a regular/immediate-release oral elixir or tablets (starting maintenance dose, 20-30 mg/kg PO every 8 hours) and as extended-release 500- or 750-mg capsules (starting dose, 30 mg/kg PO every 12 hours) that cannot be crushed, split, or chewed. Higher starting doses should be used in patients already receiving phenobarbital. Levetiracetam has the fewest adverse effects of available seizure medications, with minimal liver metabolism and no polyuria, polydipsia, or polyphagia. In the author’s experience, regular/immediate-release formulations can be increased to 60 mg/kg every 6 hours, and extended-release formulations can be increased to 60 mg/kg every 8 hours. Serum levels are not routinely measured due to lack of veterinary-specific therapeutic drug ranges.^2,6

Zonisamide 

Zonisamide (5-10 mg/kg PO every 12 hours) is commercially available as 25-, 50-, and 100-mg capsules. Owners should be counseled that bioavailability can differ among manufacturers and should note which brand is dispensed from the pharmacy. Because zonisamide is a sulfonamide medication, adverse effects can include keratoconjunctivitis sicca, vomiting, lameness, hepatoxicosis, and renal tubular acidosis but, unlike other anticonvulsants, not polyuria, polydipsia, or polyphagia. Food intake may decrease during zonisamide treatment. The author recommends CBC, serum chemistry profile, and urinalysis prior to and 1 to 2 weeks after starting zonisamide to detect major liver changes before they become irreversible; subsequent monitoring should occur every 6 to 12 months. Serum levels are not routinely measured due to lack of veterinary-specific therapeutic drug ranges.^2,7

Medium-Chain Triglycerides

Medium-chain triglyceride supplementation (9% of metabolic energy requirements) can be achieved by feeding certain commercial diets. At appropriate concentrations, inhibitory neurotransmitters are increased and excitatory neurotransmitters decreased, thus aiding in seizure control. In addition, behavioral abnormalities may be reduced and cognitive function improved during supplementation.⁸

Cannabidiol

Cannabidiol (CBD) is a controversial and sometimes legally ambiguous treatment option. Owners can purchase CBD from many sources but should be directed to trusted veterinary sources that test the concentrations and purity of the product. One study found administration of 2 mg/kg PO every 12 hours of a commercially available product reduced seizure frequency in 43% of patients.⁹ Another study found a lack of improvement in seizure control following administration of 2.5 mg/kg PO every 12 hours but a 24.1% decrease in seizure days following administration of 4.5 mg/kg PO every 12 hours.¹⁰ Elevations in ALP are expected.

Considerations for Fractious Patients

Patients with idiopathic epilepsy may have increased risk for development of behavioral abnormalities (eg, anxiety, fear, aggression). Anticonvulsants may help with new aggressive behaviors, but anxiety, attachment disorders, and increased reactivity may persist and negatively affect the human–animal bond.¹¹ Potassium bromide has been associated with increased aggression and should thus be used as an add-on rather than a first-line medication. In addition, medications that can cause polyphagia (ie, phenobarbital, potassium bromide) may result in food aggression. Owners should be counseled on these possibilities.

In patients with a history of fractious behavior in the clinic, administration of antiepileptic medication that requires the fewest clinic visits and blood draws can reduce stress for the patient and owner. Levetiracetam is ideal in these patients due to the drug’s lack of liver metabolism (and therefore monitoring) and wide safety margin.

When in-clinic testing is needed, stress can be minimized with previsit medication (eg, gabapentin, 10-50 mg/kg PO the night before and 2 hours prior to a morning appointment ± clorazepate, 0.5-2 mg/kg PO 1-2 hours before an appointment). Trazodone (5 mg/kg PO 1-2 hours before an appointment) is an effective anxiolytic but should be administered with caution in patients receiving anticonvulsants, as both drug classes can act as CNS depressants.¹² Previsit medication may be sufficient to allow testing or may calm the patient enough to allow stress-free IM or IV sedation with dexmedetomidine (5-10 micrograms/kg) with or without butorphanol (0.2-0.4 mg/kg).¹³ 

Prognosis & Outcome

Dogs with idiopathic epilepsy typically have a normal lifespan and good quality of life when seizures are well controlled and adverse effects from medications are minimized. Patients perceived as having a poor quality of life by their owners are reported to have reduced lifespans. Owners may perceive aggression as a quality-of-life issue in patients with new or worsening aggression following onset of idiopathic epilepsy.¹⁴ Owners should be warned of the risk for status epilepticus, cluster seizures, and sudden death, which can occur in a small subset of patients, especially brachycephalic patients and those with cluster seizures. The goal of antiepileptic drug therapy is to minimize the frequency and severity of seizures and the postictal period without adverse effects.³