Oral maintenance antiepileptic drug (AED) therapy is to provide long-term protection against recurring seizures. It is indicated and necessary as soon as two successive seizures have occurred at less than a six to eight week interval, as well as when the animal has had cluster seizures (CG) or a status epilepticus (SE), even if it was the first time it had seizures. Emergency parenteral AED therapy must also be provided at the time CS or SE occurs.

The primary goal of AED therapy is to obtain an adequate seizure control (less than one single seizure every six to eight weeks) as soon as possible while minimizing side effects and risks of toxicity. This requires selecting an effective and safe AED and prescribing it at a dosage that will provide an optimal therapeutic serum concentration to combine the best effectiveness with the least secondary effects and risks of long-term toxicity. The AED serum concentration rather than its dosage in mg/kg/day is the determinant for treatment effectiveness and safety, and must therefore be closely monitored.

Only a few AED are suitable for maintenance oral therapy in dogs and cats. The treatment protocol must be established based on the AED pharmacokinetics in the patient species and on the seizure frequency. The more frequent the seizures, the more aggressive must be the treatment. Modification of a maintenance AED therapy protocol is necessary as soon as two seizures occur at less than a six to eight week interval, after the serum AED concentration has reached the near maximal levels a given dosage can provide (87% within three half-lives and 97% within five half-lives). Prompt and appropriate dosage adjustment and addition of another AED to the treatment regimen are critical for optimizing seizure control.

The following tables summarize the recommendations for maintenance oral AED therapy in dogs and cats.

TABLE 1: Maintenance oral AED therapy in DOGS

I.   First-line AED (AED1): potassium bromide (KBr)

A.   Contraindications: renal insufficiency (rather use phenobarbital as a AED1; if this is not possible, use KBr but decrease its dosage and monitor the bromide serum concentration ([Br]_s) more often.

B.   Pre-treatment precautions: evaluate renal function (BUN, creatinine, USG)

C.   Treatment protocols:

1.   Maintenance dosage: 40-50 mg/kg q24h
Indication: seizures do not occur more frequently than once every three to four weeks (if more frequent, administer a loading dose; see section I.C.3 in this table)
Goal: aim at an optimal [Br]_s of 15–20 mmol/L (1.5–2.0 mg/ml) at steady state (reached within five half-lives: 5 x 21 days = 3 months)
Follow-up:

a)   Measure [Br]_s for the 1st time at three weeks (50% of the maximal [Br]_s is reached within 1 half-life) and adjust the dosage accordingly (at that time, use the formula: new dosage = actual dosage ÷ 2 actual [Br]_s x optimal [Br]_s).

b)   Measure [Br]_s for the 2nd time at steady state (three months after treatment initiation or dosage modification) and adjust the dosage accordingly (at steady state, use the formula: new dosage = actual dosage ÷ actual [Br]_s x optimal [Br]_s).

c)   Evaluate renal function (BUN, creatinine, USG) and [Br]_s every six months (older dogs) to 12 months (young dogs).

2.   If seizures are not adequately controlled despite an optimal [Br]_s,

a)   Increase the KBr dosage to reach a [Br]_s of 25–30 mmol/L, provided side effects are not already excessive and the seizure frequency has significantly decreased with an optimal [Br]_s, or,

b)   If side effects are excessive or if the seizure frequency has not been significantly reduced with an optimal [Br]_s, add a second AED (phenobarbital, unless there is liver disease; see section II of this table).

3.   Loading dose: 450–600 mg/kg PO once (then continue with the maintenance daily dosage)
Indication: seizures occur more frequently than once every three to four weeks (including recent CS and SE)
Goal: obtain a low therapeutic [Br]_s of 10–15 mmol/L (1.0–1.5 mg/ml) within 24–48 after the loading dose has been administered
Protocols:

a)   If > 1 seizure/week: divide into three to four sub-doses to be administered with food every three to four hours

b)   If < 1 seizure/week: divide into five sub-doses to be administered once daily for five days (also add the maintenance daily dose of 40–50 mg/kg for a total of 130–150 mg/kg/day for five days)

4.   Follow-up:

a)   Measure [Br]_s for the 1st time two days after the loading dose has been administered, then measure it a 2nd time at three weeks. If the [Br]_s is sub-optimal at three weeks, increase the maintenance dosage accordingly (new dosage = actual dosage ÷ actual [Br]_s x optimal [Br]_s)

(1)   A mini-loading dose of 225–250 mg/kg can be given at any time to increase the [Br]_s by 5 mmol/L (0.5 mg/ml) within 24-48 hours when the [Br]_s is documented to be too low and/or when the seizure frequency is still excessive (> 1 seizure/1–2 weeks)

b)   Measure [Br]_s at steady state (reached after three months of treatment initiation or modification) and adjust the dosage accordingly (use formula)

c)   Long-term follow-up recommendations are the same as in section I.C.1. of this table

D.   Other considerations:

1.   Ensure a stable salt (chloride) intake (type and amount of food and treats) because chloride interferes with the renal elimination of Br: when chloride intake increases, [Br]_s decreases (may lead to loss of seizure control) and when chloride intake decreases, [Br]_s increases (may cause excessive side effects)

a)   If the diet must be changed, monitor [Br]_s one and three months later and adjust the KBr dosage accordingly (use formula).

(1)   Introducing or stopping a low chloride (e.g., h/d) or high chloride (e.g., s/d) diet may cause the most marked [Br]_s changes

2.   Side effects of KBr in dogs are the same as with phenobarbital. Initial sedation and ataxia are usually temporary and subside within a few weeks unless [Br]_s has become excessive. Polyuria-polydipsia and polyphagia leading to weight gain are persistent.

3.   Hind limb paresis (e.g., difficulty getting up, jumping, falling into stairs) may be the only signs of bromide overdosage ([Br]_s > 20 mmol/L) or intolerance ([Br]_s is > 15 mmol/L) in some dogs

II.   Second-line AED (AED2): phenobarbital

A.   Contraindications: liver disease

B.   Pre-treatment precautions: evaluate liver function (ALT, ALP, albumin) and hematology

C.   Treatment protocols:

1.   Maintenance dosage: 3–4 mg/kg q 12h
Indication: seizures do not occur more frequently than once every three weeks
Goal: obtain an optimal [PB]_s of 100–130 µmol/L (23–30 µg/ml) at steady state (reached within 5 half-lives = 2–3 weeks)
Follow-up:

a)   Measure [PB]_s for the first time at three weeks and adjust the dosage accordingly (use the formula: new daily dosage = actual dosage ÷ actual [PB]_s x optimal [PB]_s); measure [PB]_s three weeks after any dosage modification (and adjust dosage again, if necessary)

b)   Ideally re-measure [PB]_S at six weeks, then at three and six months after treatment initiation to detect liver enzyme induction which may significantly increase PB hepatic metabolism and decrease [PB]_s

c)   Also perform a CBC at three and/or six weeks (early detection of idiosyncratic blood cell disturbances; e.g. leukopenia, thrombocytopenia, hemolytic anemia)

d)   Long-term follow-up must include monitoring of the [PB]_s, liver function (ALT, ALP, albumin, cholesterol, BUN) and CBC every six (older dogs) to 12 (young dogs) months. If seizures are not adequately controlled (as soon as two successive seizures have occurred at less than a six to eight week interval) despite an optimal [PB]_s, add a 3rd AED

2.   Loading dose: 15–20 mg/kg slow IV, then continue with the maintenance oral dose q 12h
Indication: seizures occur at less than seven to ten day intervals (including recent CS and SE)
Goal: obtain an optimal [PB] immediately (and maximal antiepileptic effects within 30 minutes)
Follow-up:

a)   Measure [PB]_s for the first time on day one, then at two to three weeks; adjust maintenance dosage accordingly (use formula: new dosage = actual dosage ÷ actual [PB]_s x optima [PB]_s)

D.    Other recommendations:

1.   Do not use vacutainer tubes that contain a separator because its silicone absorbs phenobarbital (and benzodiazepines), which may lead to falsely low [PB]s results (and decision to increase the PB dosage excessively)

2.   Dosage must be increased in puppies, often by up to 50% (increased distribution volume, clearance and decreased half-live)

a)   [PB]s can also be monitored sooner (seven to ten days is necessary to reach steady state instead of two to three weeks in adults)

III.   Third-line AED (AED3): consult a veterinary neurologist

A.   Felbamate (not available in Canada) 15–65 mg/kg q8h

B.   Gabapentin 10–20 mg/kg q8h

C.   Gamma-vinyl-GABA: 25 mg/kg q12h

D.   Clorazepate 1–2 mg/kg q8–12h

E.   Clonazepam 0.1–0.5 mg/kg q8h

TABLE 2: Maintenance oral AED therapy in CATS

I.   First-line AED (AED1): phenobarbital

A.   Contraindications: same as for dogs (see table 1)

B.   Pre-treatment precautions: same as for dogs

C.   Treatment protocols: the same guidelines as for dogs apply with only a few species differences:

1.   Initial maintenance oral dosage is slightly lower in cats: 2.0–2.5 mg/kg q 12h

2.   PB elimination half-life is shorter in cats so that steady state is reached within 10–14 days

3.   There has not yet been any reported case of liver toxicity in cats but the same precautions as for dogs should be observed with regards to the optimal [PB]s not to exceed and medical follow-up

4.   There is no liver enzyme induction in cats (no elevation of ALP, no acceleration of the PB hepatic metabolism during the first months of therapy)

II.   Second-line AED: diazepam

A.   Contraindications: liver disease

B.   Pre-treatment precautions: evaluate liver function

C.   Treatment protocol:

1.   Maintenance oral dosage: 0.5–1.0 mg/kg q 12h

a)   Measure total serum benzodiazepines ([BZ]s at steady state (four to five days after treatment initiation) and adjust the dosage to reach a therapeutic level of 500-700 nmole/L (0.5–0.7 ng/ml) using the formula new dosage = actual dosage ÷ actual [BZ]s x desired [BZ]s

b)   Also evaluate liver function (for early detection of acute hepatic necrosis)

III.   Third-line AED: KBr

A.   Contraindications: feline asthma (actual or previous), renal insufficiency

B.   Pre-treatment precautions: same as for dogs

C.   Treatment protocols:

1.   Maintenance oral dosage: same recommendations as for dogs with the exception of:

a)   Initial dosage is 20–30 mg/kg q 24h

b)   Elimination half-life is shorter in cats (two weeks) so that the first [Br]s determination should be done at two weeks ([Br]s should be at 50% of its maximum at that time)

2.   Loading dose: same recommendations as for dogs except that the dosage should be 300–400 mg/kg and the [Br]s should be monitored at two days and two months

D.   Discontinue treatment if the cat develops coughing or dyspnea (KBr predisposes to “asthma” in cats?)