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* This is the Veterinary Version. *

Maintenance Anticonvulsant or Antiepileptic Therapy

By Linda Shell, DVM, DACVIM-Neurology, Professor, Small Animal Internal Medicine, Ross University School of Veterinary Medicine

The decision to start maintenance anticonvulsant or antiepileptic therapy should be based on the frequency and severity of the seizures, the age of onset, the likely cause(s) of the seizures, and the results of diagnostic testing. In general, a maintenance antiepileptic drug (AED) should be considered in animals that have had more than one or two seizures within a 6-mo period (assuming these seizures were not caused by repeated toxin exposure) or in animals that have had more than one seizure of unknown cause on any particular day. A maintenance AED should also be considered if the first seizure episode is protracted or severe, or during an episode of status epilepticus (as a followup to emergency treatment, see Antiepileptic Drugs Used to Stop Ongoing Seizure Activity).

Treatment should begin with a single drug at the minimal required level for effect. Owners should keep a calendar to document the frequency and pattern of seizures as a guide for treatment strategy. This calendar, in conjunction with serum AED levels, can be used as a guide for dosage and drug treatment changes. If seizure control is unsatisfactory, the drug level should be checked. If the level is not within the middle of the therapeutic range, the dose should be increased before adding or switching to a new drug. Doses may be doubled in early stages and increased by 25%–50% in later stages. Monotherapy is preferred, but if the drug level is well into the middle or high therapeutic range, it may be necessary to consider the addition of another AED. To discontinue any AED, except bromide, the dose of the drug should be tapered gradually over a few weeks to avoid precipitating a seizure. Tapering phenobarbital is crucial, because it is addictive and can result in withdrawal seizures if stopped abruptly.

Maintenance Antiepileptic Drugs (Anticonvulsants)

In dogs, phenobarbital and bromide are considered first-line maintenance AEDs, but levetiracetam and zonisamide are often used as well. In cats, phenobarbital is the usual first choice, but levetiracetam and zonisamide are becoming more acceptable; diazepam is an alternative choice. In ruminants, phenobarbital is the first choice; in horses, both bromide and phenobarbital have been used.

Phenobarbital:

Phenobarbital has a long record of safety, efficacy, low cost, and convenience in regard to monitoring serum concentrations. For longterm maintenance in cats and dogs, phenobarbital may be given at 2–4 mg/kg/day, PO, bid. In all species, it takes ~2 wk to approach a steady-state plasma concentration, because oral absorption is extremely variable and the half-life is long. Drug levels are monitored 2 wk after initiation of therapy, 2 wk after any dosage change, and usually every 6–12 mo once seizure control is achieved. Serum therapeutic concentrations are 15–45 mcg/mL. The dosage should be adjusted on the basis of serum level and the history of seizure control. Tolerance to phenobarbital therapy may develop in dogs treated continually for months to years and may result in decreased seizure control; however, an increase (25%) in the dose usually will result in improved seizure control.

Phenobarbital causes physical dependence, and thus abrupt withdrawal may cause "barbiturate withdrawal" seizures. Hepatotoxicity and liver failure in dogs have been associated with high serum concentrations (>35 mcg/mL), necessitating the serum level checks every 6–12 mo. Adverse effects such as sedation, polydipsia, polyuria, and polyphagia are common but may decrease within the first few weeks. Other, less common adverse effects are idiosyncratic hyperexcitability, dermatitis, anemia, neutropenia, thrombocytopenia, gingival hyperplasia, and osteomalacia. Phenobarbital has also been used to treat episodic dyscontrol syndrome (rage) in dogs when seizure activity is demonstrable via electroencephalogram recordings.

Oral phenobarbital has been used in ruminants at 11 mg/kg/day and in horses at 3–11 mg/kg/day. Serum concentrations should be checked periodically.

Bromide:

Bromide appears to stabilize neuronal cell membranes by interfering with chloride transport across cell membranes and by potentiating the effect of GABA via hyperpolarizing membranes. Bromide (potassium or sodium salt) can be used as a first-choice AED in dogs with epilepsy, as an adjunctive AED in dogs with refractory seizure disorders, or for dogs that have unacceptable adverse effects related to phenobarbital or other AEDs. In countries where bromide is not available as a pharmaceutical formulation (USA), an analytical grade may be obtained from a chemical supply company, although caution is recommended in handling and packaging. Bromide can be formulated into a solution of various concentrations (100 mg/mL, 200 mg/mL, 250 mg/mL are convenient ones) or into tablets or capsules.

The elimination half-life is extremely long (24 days) in dogs; therefore, it takes ~4 mo to achieve steady state kinetics. Bromide is renally eliminated and thus should not be used in dogs with renal dysfunction without careful monitoring. If azotemia is present, a different AED can be used, or the initial bromide dose can be reduced by half and serum concentrations monitored. Because it does not undergo hepatic metabolism, bromide is useful in dogs with liver disease.

As adjunct therapy with phenobarbital, potassium bromide can be administered at 20–40 mg/kg/day, PO, either as one dose or divided into two or more doses; the sodium bromide dosage is slightly lower at 17–30 mg/kg/day, PO. When bromide is used as the sole treatment for epilepsy in dogs, higher dosages (50–80 mg/kg/day) may be necessary. Dogs on a high salt diet may require dosages of 50–80 mg/kg/day to maintain adequate serum concentrations, because high chloride intake increases bromide loss in the urine and lowers serum bromide concentrations. Many laboratory assays cannot distinguish between serum bromide and chloride ions, so serum chloride values may be reported as falsely high.

Because a daily maintenance dose may take 4 mo to reach steady state serum concentration, there are situations (eg, severe seizures, seizures that occur on a monthly basis, the need to rapidly switch from phenobarbital to bromide because of phenobarbital toxicity) when a loading dose of bromide should be administered. An oral loading dosage of 400–600 mg/kg of bromide is divided into four doses and given with food over a 1- to 4-day period. Smaller doses, such as 50 mg/kg, bid for 4–6 days, may reduce adverse effects (eg, nausea and vomiting) caused by rapid increase in serum bromide concentrations. The regular maintenance dose can be started at the same time as the loading dose or immediately afterward. The loading dose regimen can be discontinued if the dog becomes too sedated, or smaller divided daily doses can be tried. A serum sample can be submitted within 2 wk after loading to determine whether a therapeutic level has been reached. (If cost is an issue, however, a sample is best checked in 4 mo when steady-state concentrations have been reached.) The therapeutic range for bromide is 1–2 mg/mL (10–20 mmol/L) with concurrent phenobarbital treatment, or 1–3 mg/mL (10–30 mmol/L) for bromide as a monotherapy. However, the dosing regimen needs to be tailored for each animal; the upper end of the therapeutic range is only limited by adverse effects of bromide.

Bromide is generally well tolerated by dogs, but potential adverse effects include bitter taste, gastric irritation, nausea (particularly with the potassium form), polyuria, polydipsia, polyphagia, sedation, ataxia, and pancreatitis. It should be administered with food; the amount and type of food given should be kept constant, because variable dietary salt content will affect the elimination of bromide via the kidneys. Bromide therapy must be titrated to the individual animal based on careful therapeutic drug monitoring and careful monitoring by the owner for early signs of toxicity. Reports of hindlimb weakness should be investigated as potential bromide toxicosis by measuring serum bromide concentration and discontinuing bromide for several days to see whether the weakness improves. Severe bromide toxicosis (bromism) is characterized by lethargy, disorientation, delirium, and ataxia progressing to quadriplegia and coma. Bromide toxicity can be seen at any concentration in an unusually sensitive dog, but it is rare when bromide is used alone and when serum concentrations are <1.5 mg/mL (15 mmol/L). When used in combination with phenobarbital, bromide toxicity can be seen at concentrations of 2–3 mg/mL (20–30 mmol/L). Severe signs of toxicity are easily treated by IV administration of 0.9% sodium chloride, which promotes renal excretion of the bromide ion.

Bromide is an effective maintenance AED in cats, but the incidence of adverse effects does not warrant its routine use unless there is no other choice. Approximately 25%–50% of cats administered bromide developed signs of bronchial disease characterized by a cough and marked pulmonary infiltrates seen on radiographs. In some cases, the asthmatic changes were fatal, but in most cases the signs resolved after discontinuation of bromide.

Bromide has been used in horses as a maintenance AED, but there are no published studies on its clinical efficacy. Pharmacokinetic studies have suggested that a loading dose of potassium bromide of 120 mg/kg/day over 5 days and maintenance dosages of ~90–100 mg/kg/day will likely result in effective serum bromide concentrations.

Primidone:

Primidone is a barbiturate that has three metabolites: phenobarbital, primidone, and phenylethylmalonamide. The phenobarbital metabolite is likely the major functional one, and there may not be an advantage to using primidone over phenobarbital. Nevertheless, one report indicated that dogs with seizures that are not well controlled with phenobarbital may respond better to primidone (eg, psychomotor seizures). The initial dosage (dogs only) is 5–15 mg/kg/day in three divided doses, increased over time to a maximum of 35 mg/kg/day. Effective serum levels are determined by the serum level of phenobarbital (15–45 mcg/mL). If primidone is switched to phenobarbital, one grain of phenobarbital can be substituted for 250 mg primidone.

Primidone may be more likely to cause hepatotoxicity than phenobarbital, and it has been associated with hepatic necrosis and lipidosis and bile canaliculi obstruction. ALT, serum alkaline phosphatase, and/or bile acids should be monitored. Other adverse effects and signs of overdosage are similar to those of phenobarbital.

Primidone is not recommended for use in cats because of toxicity concerns. However, preliminary studies suggest primidone at 40 mg/kg/day for 90 days may be acceptable in cats.

Diazepam:

Diazepam is not suitable for oral maintenance therapy in dogs, because it is absorbed poorly, has a short half-life of 2.5–3.2 hr, and tolerance to its anticonvulsant effects develops rapidly. However, cats not only have a longer half-life (15–20 hr) than dogs but also do not develop a tolerance to the anticonvulsant effects. Thus, diazepam can be used as a maintenance treatment in cats, with dosages ranging from 0.25–0.5 mg/kg, PO, bid-tid. Acute hepatic failure has been reported in cats given diazepam for behavioral problems; thus, a pretreatment chemistry profile should be evaluated before using diazepam, and cats should be watched closely during the first 2 wk of use.

Newer or Adjunctive Anticonvulsants

Levetiracetam:

This pyrrolidine-based anticonvulsant has an unknown mechanism of action. It has been used as an adjunct AED for dogs and cats and is occasionally used as monotherapy. In dogs, it has excellent oral bioavailability, does not appear to undergo hepatic metabolism, is primarily excreted unchanged in the urine, and has a half-life of ~4 hr. It appears very safe with no to few adverse effects (ataxia, sedation, vomiting) reported at the routine dosage ranges. Levetiracetam is initially administered at 20 mg/kg, PO, tid, in dogs; 10–20 mg/kg, PO, tid, in cats. If adverse effects occur, the dosage should be reduced to 20 mg/kg, bid, and increased to 20 mg/kg, tid, gradually. Studies suggest that 60% of dogs respond initially; however, after 4–8 mo, there is a loss of effect in ⅔ of previous responders because of development of tolerance. In dogs, the dosage can be increased every 2 wk in increments of 20 mg/kg if therapeutic benefit has not been noted. Adverse effects of salivation, restlessness, vomiting, and ataxia at dosages >400 mg/kg/day have been seen experimentally in dogs but resolved within 24 hr of discontinuing the drug. Therapeutic monitoring is generally not necessary when using this drug, and there does not appear to be a correlation between serum drug concentration and therapeutic efficacy. An IV formulation can be used in status epilepticus.

Zonisamide:

This sulfonamide-based anticonvulsant restricts the propagation and spread of seizures and suppresses epileptogenic focus activity. It has been used as first-line AED as well as an adjunct AED in dogs not adequately controlled by phenobarbital and bromide. Although some of it is metabolized by the P450 enzyme system, much is excreted unchanged in the urine. Dogs receiving concurrent drug therapy known to induce hepatic microsomal enzymes (ie, phenobarbital) require nearly twice the dosage of zonisamide to achieve and maintain serum concentrations than dogs receiving zonisamide alone. Thus, the dose of zonisamide in dogs receiving phenobarbital is 10 mg/kg, PO, bid. In dogs not on drugs that induce hepatic microsomal enzymes, the dosage is 5 mg/kg, PO, bid. The dosage in cats has varied from 5 mg/kg, PO, bid, to 5–10 mg/kg/day, PO. The recommended therapeutic range is 10–40 mg/mL; trough concentrations can be measured ~7–10 days after initiating treatment or altering the dosage. The adverse effects are usually mild, such as transient ataxia, loss of appetite, lethargy, and vomiting. Although the drug appears safe, owners should be warned that because of the sulfonamide base, potential adverse effects (eg, keratoconjunctivitis sicca, bone marrow dyscrasia, hepatopathy, vasculitis, and metabolic acidosis) could occur. A nonfatal hepatopathy in a dog was attributed to zonisamide.

Gabapentin:

This synthetic analogue of the inhibitory neurotransmitter γ-amino butyric acid (GABA) inhibits seizure activity via multiple mechanisms, including inhibition of neuronal sodium channels and potentiation of the release and action of GABA. It is well absorbed in dogs after oral administration and undergoes both hepatic and renal metabolism. In dogs, the initial dosage is 10–15 mg/kg, PO, tid. Higher dosages (30–60 mg/kg, PO, tid-qid) may be necessary but can produce sedation and ataxia. If excessive sedation occurs, a lower dose should be used initially and gradually increased. Therapeutic monitoring is not usually necessary with this drug. No drug interactions have been reported. Gabapentin has been used in cats at 5–10 mg/kg, bid-tid.

Felbamate:

Felbamate is a dicarbamate AED that exerts its anticonvulsant effects through multiple mechanisms, including potentiating GABA-mediated neuronal inhibition, inhibiting voltage-sensitive neuronal calcium and sodium channels, and blocking N-methyl-d-aspartate–mediated neuronal excitation. It is primarily (70%) renally excreted in dogs, with the remainder of the drug undergoing hepatic metabolism. The recommended initial dosage is 15 mg/kg, PO, tid, but the dose can be increased every 14–21 days in increments of 15 mg/kg if therapeutic benefit has not been noted. The principle advantage of felbamate is a lack of sedation, and adverse effects are reportedly rare. Potential adverse effects are hepatotoxicity, reversible myelosuppression, generalized tremors, and possibly keratoconjunctivitis sicca; regular monitoring for anemia and liver dysfunction in dogs is recommended. In people, felbamate has been associated with aplastic anemia and liver toxicity. There is no clinical information on use of felbamate in cats.

Valproic Acid:

Valproic acid (10–60 mg/kg, tid) has been used as an adjunct to phenobarbital and primidone in dogs with refractory seizures. It has also been used to treat aggressive behavior problems (see Psychotropic Agents). Common adverse effects include transient GI distress, alopecia, sedation, and vomiting. Hepatic failure is rare. Use of valproic acid in dogs is limited because of rapid metabolism.

Clonazepam:

Clonazepam, unlike diazepam, can be used in dogs for oral maintenance therapy, because anticonvulsant tolerance develops less rapidly, the saturability of its metabolism reduces the elimination rate at therapeutic concentrations, and because it is more highly absorbed orally (particularly in micronized formulations). For maintenance therapy in dogs, it may be used alone at 0.5 mg/kg, tid, but it is best used as an adjunct to phenobarbital at dosages of 0.1–0.5 mg/kg/day. Diarrhea sometimes develops with clonazepam, but this may be avoided by starting with once daily dosing and increasing the frequency to three times daily over a period of several days.

Carbamazepine:

Carbamazepine is not recommended for use in dogs because of a rapid induction of hepatic enzymes that eliminate the drug quickly. Although plasma concentrations declined rapidly in dogs on a 1-wk regimen of 30 mg/kg, tid, one case report described adequate seizure control despite undetectable drug concentrations in plasma, possibly due either to an active metabolite or to a highly sensitive drug reaction. Carbamazepine has been used to treat aggressive behavior problems in cats (see Psychotropic Agents).

Clorazepate Dipotassium:

Clorazepate dipotassium (0.5–1 g/kg, tid) has been proposed as an adjunct to phenobarbital treatment in dogs. Severe withdrawal symptoms, even lethal seizures, may appear after abrupt discontinuation of chronic clorazepate treatment, in spite of the relatively low tolerance liability of clorazepate. Administration of phenobarbital alters the deposition of clorazepate such that the amount of nordiazepam in circulation during each dose interval is significantly reduced. Adequate control of seizures in epileptic dogs, therefore, may require higher dosages of clorazepate when coadministered with phenobarbital. However, clorazepate may increase phenobarbital concentrations, resulting in adverse effects.

Phenytoin:

Phenytoin (diphenylhydantoin) is no longer recommended for maintenance use in dogs, cats, or foals because of undesirable pharmacokinetic properties. Its metabolism is too rapid in dogs, which reduces its effectiveness, and too slow in cats, which increases the risk of toxicity (salivation, vomiting, weight loss). In foals, phenytoin has erratic plasma concentrations. It may still be used in status epilepticus in dogs as a slow IV injection of 2–5 mg/kg.

Mephenytoin:

Mephenytoin, although related to phenytoin, has been effective in dogs (10 mg/kg, tid) because of a slower rate of elimination. It may be combined with phenobarbital or bromide. Adverse effects consist of sedation only, but periodic hematologic monitoring is advised, because blood dyscrasia and hepatotoxicity are reported in people.

Topiramate:

Topiramate is a newer AED that is well tolerated by people and increasingly used for neuropathic pain. In one report, it was listed as an adjunct AED for dogs, but its effectiveness is not yet known. Because the elimination half-life is short in dogs (2–4 hr), it is probably not an effective anticonvulsant, but a dosage of 5–10 mg/kg, bid, has been suggested. There have been no clinical studies to date, and only limited information is currently available.

* This is the Veterinary Version. *