The Epileptic Patient - Suggestions for Their Successful Management

VCS Milford
For the purposes of this article we will assume that we are managing a patient diagnosed as an idiopathic (or primary) epileptic. Although the information within this article may be applied to patients who have other diagnoses, such as intracranial malformations (anomalies), encephalitis or intracranial neoplasia, these patients are often more complex with additional therapies indicated that will not be discussed within this document.

Epilepsy is a disorder characterized by at least two seizures. There are many different seizure classification systems. In general two categories of seizures can be considered.
  • Primary generalized seizures due to a symmetrical dysfunction of the brain causing, for example, the classic tonic-clonic seizures or absence seizures.
  • Partial seizures that are due to a focal dysfunction of the brain, sometimes with normal consciousness, that may have focal motor, autonomic or sensory signs associated with the event. The term idiopathic epileptic describes a patient suffering from generalized seizures with no demonstrable cause.

Approximately 2 to 3 % of the veterinary canine population and 0.5% of the feline population is affected by epilepsy. Among this population can be some of the most challenging and frustrating long-term management cases for both the practitioner and the client. The swift and appropriate introduction of appropriate therapies, along with adequate dosing and monitoring, can make a significant difference in the response of the epileptic patient.

Inadequate suppression of the seizure focus can lead to kindling (a progressive intensification of seizure activity) or the development of a mirror focus. When these phenomena develop, the patient’s seizure disorder can become more severe. For example, the seizures may increase in frequency, they may begin to cluster (greater than one seizure within a 24-hour period), the patient may develop status epilepticus (a period of continuous seizure activity of at least 30 minutes duration), the recovery phase of the seizure (post-ictal period) may become exaggerated, or the patient may be more refractory to conventional seizure management once it is applied.

It is also important to recognize that there are epileptics that do not require anticonvulsant therapy. A patient that cluster seizures or that has a seizure frequency of every two to three months should be placed on anticonvulsant therapy. It is helpful to establish the seizure frequency prior to initiating therapies. This allows us to readily assess the magnitude of the patient’s response to the anticonvulsant. However, if a patient presents with severe clusters I often do not wait to establish the seizure frequency since a repeat episode may be devastating.

The goal of anticonvulsant therapy is to diminish the frequency and the severity of the seizure activity while the patient, and the owner, experience as few side effects from the medication as possible. Unfortunately, veterinary patients seldom achieve seizure eradication. However, some individuals may experience a diminution in their seizure frequency without any significant change in anticonvulsant levels or their condition may resolve completely.

If a patient remains seizure free for six months to one year, I recommend withdrawal of the anticonvulsant in hopes that the medication is no longer required. Anticonvulsant withdrawal should be done gradually. Rapid withdrawal of anticonvulsants, such as phenobarbital, can actually precipitate seizures. Remember that the gradual reduction of serum anticonvulsant levels also allows more rapid re-introduction of a drug at higher levels should the patient develop seizures.

Once we have established the need for anticonvulsant therapy, the next challenge is to choose the appropriate medication for the individual. To be considered when making this choice are factors such as the elimination half-life, access to serologic monitoring of the drug, the patient’s other metabolic issues (ie. hepatic dysfunction), cost, and the ease of administration and dosing. The following is a discussion of the medications that I have found the most useful in my practice.
  • Phenobarbital: One of the most frequently utilized anticonvulsants for both dogs and cats. An inexpensive and readily available barbiturate that acts by increasing the duration of the openings of chloride channels associated with the GABA-A receptor (GABA is the main inhibitory neurotransmitter to the brain).
    • Phenobarbital undergoes hepatic metabolism. Pre-therapy bile acids (pre and post prandial) testing allows us the benefit of a reference value should hepatic function be compromised in the future and establishes normal function prior to treatment. Phenobarbital has an elimination half-life of approximately 24 hours. This means the frequency of dosing is every 12 hours (BID); there are very few individuals that require a TID regimen.
    • Initial suggested dose is 2.5 mg/kg BID with adjustments made based on blood levels of the drug and the therapeutic response (see below). Blood levels should initially be checked after two weeks of therapy and, if the patient has had no change in the dosage regimen or seizure frequency has not escalated, every 6 months thereafter. Interestingly, recent reports find that we no longer have to concern our selves with trough or peak levels for phenobarbital. Timing of blood sampling has no effect on clinical assessments. Phenobarbital dosages are adjusted based on the patient’s response and blood levels.
    • Side effects of phenobarbital therapy include hepatic enzyme induction (increased SAP and ALT), polyphagia, polydipsia, polyuria, splenic enlargement, neutropenia and thrombocytopenia, decreased serum T4, free T4 and increased clearance of dexamethasone.
  • Bromide (sodium or potassium): Since the 1990’s bromide has become a popular anticonvulsant used either as a single agent or in combination with other anticonvulsants.
    • Bromide’s mechanism of action is poorly understood. It is thought to prolong inhibitory postsynaptic currents in the cerebral cortex and therefore inhibit propagation of excitatory impulses. Bromide is excreted through the kidneys and the rate of elimination is increased proportionally to the amount of dietary salt. A change in the patient’s diet should be followed by bromide levels checked at one month and three months after the diet change.
    • Although patients receiving Bromide may demonstrate many of the side effects reported with phenobarbital administration, clinically I have not appreciated these side effects as often as I do with patients on phenobarbital. Particularly as a single agent, Bromide is very attractive since it is effective and the rate of reported side effects is less than with other anticonvulsant medications.
    • The elimination half-life of Bromide is 24 days. Because of its long half-life, bromide need only be administered once daily. Dividing the daily dose into a twice-daily schedule is acceptable if the patient has problems with gastrointestinal upset when given the full daily dose.
    • Bromide therapy, at a maintenance dose, is best considered if the patient’s seizures are relatively infrequent, every 4-8 weeks, or bromide is being added to an anticonvulsant regimen with a relatively stable patient, then a dose on 30mg/kg daily may be administered.
    • Remember that it will take 3 months for this patient to achieve a steady state drug level. If the patient is seizuring more frequently, suffering from cluster seizures, or status epilepticus, loading doses should be considered. If the patient is loaded on bromide, their serum levels will rise quickly, sedation and ataxia may become evident quickly.
    • The initial dose is 120mg/kg/day, divided BID-QID for 5 days. Then decrease to the dose of 30mg/kg daily. Check levels in 10days and again in 4 weeks to make sure the patient’s bromide level is being maintained. Side effects of bromide include ataxia, sedation, polydypsia, polyphagia, hyperactivity, skin rash and intestinal upset (easily remedied in many cases by giving the medication with food or dividing the dose).
    • When bromide is given with phenobarbital, pelvic limb weakness is a common observation. Bromide has been utilized in cats, but there have been recent reports of severe respiratory consequences (bronchial asthma). At this time it appears the side effects make its use in feline patients prohibitive.
  • Benzodiazepines: The benzodiazepines act by modulating the chloride channels associated with the GABA-A receptor and making it more difficult for the neuron to develop an action potential. Although there are a number of different benzodiazepines that may be considered for their anticonvulsive effects, I will limit the discussion to the following:
  • Diazepam: Diazepam is best used for the treatment of active seizures intravenously because rapid tolerance develops when it is administered orally. A dose of 0.5 mg/kg IV bolus is recommended and may be repeated once, but after that the patient is refractory to the drug’s anticonvulsant effect. Doses are available for rectal administration, however I find this route ineffective. Cats suffer from weight gain as well as sedation and an irreversible hepatotoxicosis has been documented in association with chronic oral diazepam therapy.
  • Clorazepate: Clorazepate has been proven helpful in the long-term management of partial and generalized seizure disorders. I use clorazepate most often in combination with phenobarbital and/or bromide. I have also used it successfully to manage anxiety related to thunderstorms.
    •  The half-life of clorazepate is less than 12 hours. Recommended dose is 1-2 mg/kg BID-TID. Due to the short half-life, missing a dose could precipitate seizures. Recommended peak blood level is 300-500ng/ml and can be run through some commercial laboratories (peak and trough levels are recommended). Sedation is the greatest side effect noted in dogs.
  • Felbamate: Felbamate is a relatively new anticonvulsant and still quite costly. The mechanism of action is unknown. It is excreted through the kidneys and can induce liver enzymes. The drugs half-life of elemination is 5-6 hours and the recommended starting dose in 15mg/kg divided BID-TID. The drugs dose may be increased in 15mg/kg/day increments every 2 weeks, not to exceed 300mg/kg. Felbamate is commonly an addition to an anticonvulsant regimen. Phenobarbital doses can be decreased once improved seizure control has been established. At this time, I am not aware of any commercially available veterinary serologic assay.
    • Side effects include sedation, nausea, tremor, limb rigidity, salivation, restlessness and vomiting. Hepatic dysfunction and blood dyscrasias are reported in people. This medication, like clorazepate, is more costly than phenobarbital and bromide.
  • Alternative Therapies: Vagal stimulation, hypoallergenic diets, acupuncture and gold bead implantation are all alternative therapies for epilepsy that have had some beneficial effect for certain patients. Their merits and application are beyond the scope of this article. However, my experience has been that acupuncture, gold bead implantation and dietary trials do no harm and may offer benefits to some patients.

In general, single drug therapy is chosen when a patient is initially placed on anticonvulsants. Polypharmacy is chosen when seizures are not well controlled on maximum levels of a single agent, the side effects of the single agent are too severe, or when the patient’s seizure episodes, even if infrequent, are life threatening (status, clusters).

The drugs are chosen based on the patient’s signs and the drug that best meets the patient’s needs. Typically, phenobarbital is a first choice followed by additions of bromide, clorazepate or felbamate. However, bromide is proving to be a very effective single agent.

Remember that the interpretation of blood levels must be made when considering the patients clinical response. Some individuals respond favorably to low serum drug levels, others may need to be in the high or slightly above the therapeutic range to achieve the appropriate response. High levels of a drug may be appropriate, but be aware of the side effects and monitor the patient carefully. Regardless of the dose, it is all a matter of balancing the patient, the side effects and the drug.

Drug levels must be monitored at an appropriate frequency. The steady state serum level should be documented for each dose adjustment. For example, a patient on phenobarbital should have the serum phenobarbital level evaluated 14 days after the medication was started. Then, if the patient is not responding, the dose is adjusted and another level checked in 14 days. If the patient responds favorably, then the blood level is checked every 6 months.

Applying this same rule to the use of bromide, or any other drug that lends itself to serologic monitoring, will allow accurate adjustments in the dosing regimen. Then the clinician will then have access to accurate blood levels for the patient should their seizure frequency increase and dosages can be changed accordingly.

Finally, communication is key. The owners should be encouraged to keep a log detailing the date, time and characteristics of each seizure. Recognition of changes in the pattern of seizure activity is integral in managing the epileptic.

Making the owners aware of when to seek veterinary care, should their pet seizure, is equally important. I typically recommend that, if a pet has two or more seizures in 24 hours time or if a seizure lasts five minutes and is not resolving, they should seek veterinary care. These parameters hopefully prevent having a patient progress to status epilepticus (20-30 minutes of continual seizure activity).

Swift intervention will help prevent brain injury, additional problems with seizure management, and protracted hospital stays. Owners should also be educated regarding the goals of anticonvulsant therapy, the side effects of the drugs and the importance of regular dosing.

Posted on July 14, 2014
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