Treatment plans for the routine and difficult-to-control epileptic (Proceedings)

Deciding on a treatment plan for an animal with seizures depends on a number of factors, including the suspected etiologic cause of the seizures, the frequency and severity of the observed seizures, and the financial constraints or intentions of the owner.

Address the underlying cause

If an underlying cause of the seizures is known or suspected, it should be appropriately addressed, if possible. Thus, animals with hypoglycemia or electrolyte abnormalities may require no therapy other than correction of these deficiencies (or excesses). Likewise, patients with hepatic encephalopathy, hypertriglyceridemia or various intoxications may not require long-term anticonvulsant therapy if the primary disease is appropriately addressed, although they may benefit from shorter-term treatment with these drugs. In some cases, damage to the brain may lead to acquired (probably symptomatic) epilepsy, requiring long-term treatment.

Animals with intracranial diseases also benefit from addressing the underlying condition, although these patients are more likely to require maintenance anticonvulsant therapy. Thus, placement of a ventriculoperitoneal shunt for hydrocephalus, anti-inflammatory and/or antimicrobial medications for meningoencephalitis, surgery or radiation therapy for brain tumors, and other specific therapies address the underlying disease process and may reduce or eliminate the need for anticonvulsant therapy.

Maintenance anticonvulsant therapy

Maintenance anticonvulsant therapy is used as an adjunct in symptomatic epilepsy and is the cornerstone of therapy for patients with idiopathic or probably symptomatic (acquired, cryptogenic) epilepsy. The first question to address is: When to start anticonvulsant therapy? There are no hard and fast rules on this issue, and each patient much be approached individually. However, some guidelines apply. In general, maintenance therapy should be considered if:

     • Seizures are more frequent than once every 6-8 weeks

     • Seizures are obviously increasing in frequency

     • Status epilepticus or cluster seizures occur

     • Seizures last longer than 5 minutes

     • Seizures are very severe or involve aggression towards the owner

The second question to address is: Which anticonvulsant should I choose? Historically in dogs, the two main initial options for therapy have been phenobarbital and (potassium) bromide. These medications are chosen because of their long history of use, apparent efficacy, ease of dosing, favorable pharmacokinetics and inexpensiveness. There is limited evidence to suggest that phenobarbital may be slightly more efficacious as a first line agent in the dog. Diazepam is not effective as a maintenance anticonvulsant in the dog due to a very short elimination half-life, and the development of tolerance within several weeks. Some of the newer anticonvulsant medications can be effective as initial therapy, and the author uses zonisamide and levetiracetam with some frequency as first-line agents in dogs. Zonisamide is particularly attractive in this setting due to its low incidence of side effects and its relatively long half-life, allowing twice daily administration.3 However, published reports of efficacy in this setting are lacking in veterinary patients. Use of these newer drugs has been limited in the past by their expense when compared with traditional anticonvulsants, although generic versions of most of these newer generation drugs are now available at reduced costs. In the cat, phenobarbital (preferred) and diazepam are the historical maintenance drugs of choice. Bromide is an effective anticonvulsant in the cat, but is associated with a very high incidence of inflammatory lung disease, and is not recommended. Diazepam should be used with extreme caution in cats, as it has been associated with idiosyncratic hepatic necrosis after oral administration. Levetiracetam may be a reasonable choice in the cat if phenobarbital is not an option, although the drug must be administered three times daily. There is limited information available on zonisamide in cats, although side effects seem to occur more frequently in this species.

Initial maintenance therapy for epileptic animals

     • Phenobarbital – 2.5-3 mg/kg q 12 hours (Dogs or cats)

     • Potassium bromide – 40-50 mg/kg/day q 24 hours or divided (q 12 hours) (Dogs)

     • Zonisamide – 3-5 mg/kg q 12 hours (Dogs)

     • Levetiracetam – 20 mg/kg q 8 hours (Dogs and Cats)

     • Diazepam – 0.2-1.0 mg/kg q 12 hours (Cats, use with caution)

Phenobarbital is available in generic tablets (15, 30, 60, 90, 100 mg) or suspension (3 and 4 mg/ml) formulations, as is diazepam (2, 5, 10 mg tabs; 1 and 5 mg/ml suspension). Zonisamide is available as 25, 50 and 100 mg capsules. Levetiracetam is available as 250, 500, 750 and 1000 mg tablets and a 100 mg/ml suspension. Bromide is typically compounded from the chemical grade salt, and complexed with potassium (KBr) or less frequently with sodium (NaBr). It should be noted that due to molecular weight differences between the cation, equal amounts of KBr and NaBr do not contain the same amounts of bromide, and therefore have different anticonvulsant potencies (250 mg KBr = 211 mg NaBr). KBr is available from a number of compounding pharmacies. Liquid formulations are preferred over capsules, as they facilitate dosage adjustments, and KBr is best administered with food to reduce gastrointestinal irritation. Dietary salt affects serum levels of bromide, and a constant salt level should be maintained in the diet.

Monitoring maintenance therapy

A complete blood count (CBC), serum biochemical evaluation and urinalysis should be performed before starting maintenance anticonvulsant therapy, both as part of the diagnostic evaluation (see previous talk) and as a baseline before starting therapy. In addition, the metabolism of these drugs varies between patients. Blood levels are essential to guide therapy for phenobarbital and bromide, and may be indicated for some of the newer drugs, depending on the response to therapy. Steady state of a drug after regular oral dosing depends on its half-life in the body, and varies between medications and species. Monitoring times and desired blood levels are shown below.

Table 1. Monitoring anticonvulsant therapy

These desired blood levels are a guide only, and must be interpreted in light of the resulting seizure frequency and clinical condition of the patient. When measuring therapeutic blood levels, as with any medications, a serum separator tube ("tiger top") should be avoided, as the separator device may bind the drug and artificially decrease the serum levels. After the establishment of acceptable therapeutic levels of the medication, it is generally recommended that blood levels along with a CBC, serum chemistry and urinalysis be monitored every 6-12 months or in the event of an acute change in seizure frequency or new onset of sedation, weakness or ataxia. Animals receiving phenobarbital may also benefit from pre-and post-prandial serum bile acid evaluation at these times to detect changes in hepatic function. Therapeutic monitoring is very important for phenobarbital and bromide, but has been utilized less frequently for the newer generation of drugs. As these newer medications are quite safe, they have generally been used to effect, and until recently, routine therapeutic monitoring for these drugs was not available.

Potential side effects of maintenance therapy

Side effects of phenobarbital include sedation, polyphagia, polyuria, polydipsia, weight gain, and in rare cases hepatic failure and blood dyscrasias. Although hepatic damage is a commonly cited concern with this medication, it is an unusual sequela, particularly if the serum levels are maintained below 35 µg/ml. It should be noted that increases in liver enzyme levels are expected with this medication due to enzyme induction, and this does not indicate hepatic failure. If this is a concern, serum bile acids should be evaluated. Side effects of bromide are similar for the most part, including sedation, polyphagia, polyuria, polydipsia, and weight gain but in rare cases also include pancreatitis. Vomiting related to the salt content can be minimized by administration with food. Diazepam may lead to sedation and polyphagia, and rare idiosyncratic reactions causing acute hepatic necrosis have been described in the cat.6 Zonisamide and levetiracetam may both cause sedation, while the former may also cause vomiting and diarrhea.

Dealing with the refractory epileptic

Monotherapy with one of the medications above controls an estimated 60-80% of epileptic dogs and the majority of cats. However, a number of animals will have their condition remain unchanged or worsen in the face of this therapy. In this situation, a number of additional steps may be considered:

     • Ensure owner is administering drug correctly

     • Ask about dietary changes, other medications or herbal preparations, and topical anti-parasite medications which may interfere with seizure control

     • Reconsider diagnosis, pursue additional diagnostic testing

     • Ensure optimal blood levels of maintenance drug

     • Increase dosing frequency (Phenobarbital - from q12 h to q 8 h) if seizures occur at times corresponding to "trough" blood levels (base on therapeutic monitoring)

     • Ensure female dogs have been spayed

     • Add a second anticonvulsant drug

Regarding these points, many animals require blood levels of phenobarbital above 25 µg/ml for seizure control, although levels exceeding 35 µg/ml should be avoided. Although unusual, some animals receiving phenobarbital metabolize the drug very rapidly, and may benefit from dosing every 8 hours. Having the owner maintain a seizure diary is useful to document these cases, as seizures may occur during the expected "trough" period of drug metabolism and peak and trough serum levels may be beneficial in guiding therapy. Serum levels of bromide above 3000 µg/ml are tolerated in some dogs, especially when used as a monotherapy.

Adding a second anticonvulsant drug

In the cat, diazepam may be added successfully to phenobarbital to control seizures (although as mentioned above, this drug should be used with extreme caution in this species). In the dog, a combination of phenobarbital and KBr (starting dose 20-30 mg/kg daily) is effective in controlling the majority of patients refractory to monotherapy with either drug alone. However, side effects are common with this protocol, and may be unacceptable to the owner. These include sedation, pelvic limb weakness and ataxia, polyphagia, polyuria and polydipsia. It should be noted that side effects may subside approximately 1-2 weeks after initiating the new drug, and so patience can pay off. Generally, a balance must be achieved between an acceptable seizure frequency and these side effects, although this may be impossible in some dogs. Generally, the best success is achieved by aiming for a serum bromide level between 2000-3000 mg/l and maintaining a lower phenobarbital level (e.g. 10-20 µg/ml).

If seizure control cannot be obtained with this combination of drugs, then other options exist. Many refractory dogs experience cluster seizures at varying time intervals, with relatively good control between cluster episodes. In this case, administration of rectal or nasal diazepam or other benzodiazepines (see next talk) may help to control the cluster events and avoid an emergency visit to the hospital. A third anticonvulsant medication may be added, and includes the following choices:

     • Zonisamide (Zonegran) – 6-10 mg/kg q 12 hours (dogs only [dose doubled when administered with phenobarbital])

     • Levetiracetam (Keppra) – 20 mg/kg q 8 hours

     • Felbamate (Felbatol) – 15-20 mg/kg q 8 hours (dogs only)

     • Gabapentin (Neurontin) – 10-30 mg/kg q 8 hours (dog) or q 8-12 hours (cat)

     • Pregabalin (Lyrica) – 2 mg/kg q 8-12 hours, increasing 1 mg/kg/dose each week to a total of 3-4 mg/kg (dogs only)

These drugs have a variety of mechanisms of action, which appear to be different from phenobarbital and bromide, and patients may receive additional benefit from a multimodal antiseizure effect. Another advantage of the newer drugs is their improved side effect profile, as side effects are essentially limited to sedation (which tends to be less severe than that seen with either phenobarbital or bromide) and gastrointestinal side effects (vomiting, diarrhea) for some drugs. Felbamate is an exception, as there is concern with hepatic dysfunction, particularly when used in combination with phenobarbital. Elimination half-lives are relatively short, and drug steady state levels are reached relatively quickly with administration of a regular oral dose. The main disadvantages of these newer drugs are their expense (although most are now available generically, and costs are decreasing) and requirement for administration every 8-12 hours.

Of these newer generation drugs, the author generally prefers to use zonisamide or levetiracetam. Assays to measure blood levels of these drugs are available at a few select laboratories, but these drugs are often administered to effect. In some cases, success with the addition of an anticonvulsant drug may allow the eventual withdrawal of the initial medication, although this must be accomplished gradually and with caution. The author frequently uses these newer anticonvulsant medications (particularly zonisamide and levetiracetam) as the second drug choice (typically instead of bromide). Other potential interventions to consider in select situations include acupuncture and the administration of a hypoallergenic diet.

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