Treating seizures: The old and the new (Proceedings)

Principles and philosophy of therapy

The primary goal is to treat the underlying disorder. Even if an underlying disorder exists, antiepileptic drugs (AED) may be needed for adjunctive therapy (ie. brain tumor, encephalitis). If the primary treatment does not achieve seizure control, or the animal has primary epilepsy, chronic anticonvulsant therapy is warranted. In some disorders, such as reactive seizures (i.e. portosystemic shunt), AED therapy may be contraindicated.

It is difficult to know when to initiate AED therapy. Most clinicians agree that seizures occurring more often than every 4-6 weeks may benefit from chronic AED therapy. It is not warranted to treat with anticonvulsants after 1 mild to moderate generalized seizure. Severe seizures, cluster seizures or status epilepticus do warrant early therapy. It is best to start chronic therapy early in the course of the disease, but starting after the first seizure makes it difficult to know if therapy is truly needed.

Basics and goals of using anticonvulsant drugs

The ability to control seizures will depend upon the serum concentration of the anticonvulsant drug. Serum concentration will depend on the half-life of the drug. The dosage interval should not exceed the half-life of the drug. It will require approximately 5 half-lives to achieve steady state concentrations. Fluctuations in the serum concentration will still occur following steady state. The peak (highest) concentration will usually occur a few hours after oral dosing. The trough (lowest) level will occur just prior to the next dose. Therapeutic control often depends on the trough concentration. This is the serum concentration that should be measured. (For example, if an animal is normally dosed at 8:00 a.m., then blood should be obtained between 7:00-8:00 a.m. and the anticonvulsant should be administered on time.). This is probably most important early in phenobarbital therapy as once the animal has been chronically treated, peaks and trough concentrations will be very similar. Most therapies will require dosing q8-12 hours. Dosing at fixed times will decrease the chance for fluctuations of drug concentrations outside of the therapeutic range and may decrease the sedative properties associated with most anticonvulsant drugs.

With few exceptions, phenobarbital will always be the most efficacious and least costly medication. It is the only anticonvulsant with proven efficacy in dogs. However, Bromide is becoming a more commonly used single agent. There is no proven efficacy to initial multiple drug therapy. Monotherapy is always warranted initially.

The owner must play an integral role in the management of seizures in their pet. The client should be educated about use of the medications, side effects, monitoring, and expectations of the therapy. The owner should be encouraged to keep a journal describing the frequency, duration, and severity of the seizures. Additionally, they should record any suspected precipitating conditions. The client should be aware that anticonvulsant therapy is rarely curative. A seizure-free status without adverse effects of the anticonvulsant therapy is the ultimate goal. This is not always attainable. Control may be considered a 50% decrease in the frequency, duration, and severity of seizures. The owner needs to know that the therapy may be lifelong, and in some instances, costly. The client should not attempt to "help" the dog during a seizure, unless the animal's life is threatened (i.e. potential to fall off a porch). The client needs to know that most seizures are relatively short in duration and the animal will not "swallow its tongue". The client should contact the veterinarian if there is an increase in frequency, severity, or duration of seizures. The animal should be taken to the veterinarian if cluster seizures (several seizures over a short duration) or status epilepticus occurs.

Animals are frequently left for long periods of the day and a seizure may not be seen. However, there is often evidence of seizure activity, such as urination, defecation, salivation, and disrupted environment. Knowing when the animal is most likely to seizure may help in dosing the medication. For example, if a dosage can not be divided equally, and the animal is more likely to seizure in the early morning hours, giving the larger portion of the dose at night is warranted.

Maintenance antiepileptic therapies (AED)

Unlike human neurologists, veterinarians have a limited range of effective AEDs from which to choose. Many of the drugs used in people cannot be prescribed to small animals either due to inappropriate pharmacokinetics (too rapid of an elimination) or potential hepatotoxicity. Monotherapy is indicated initially to reduce lack of compliance, drug-drug interactions, and adverse effects. Several limitations exist in the selection AEDs in veterinary medicine: 1. toxicity, 2. tolerance, 3. inappropriate pharmacokinetics, and 4. expense.

Antiepileptic drugs can be classified into 3 broad mechanisms of action: 1. reduction of excitatory neurotransmission, 2. enhancement of inhibitory processes via facilitated action of GABA (the most important inhibitory neurotransmitter) or its receptor, and 3. modulation of membrane cation conductance. Drugs that increase inhibitory neurotransmission will hyperpolarize post-synaptic neuronal membranes and raise the seizure threshold. This prevents spread of epileptic activity in the brain. Drugs that act at the GABA-receptor will increase chloride permeability and cause membrane hyperpolarization. Bromide is thought to produce synergistic inhibition with drugs that open the chloride channel via the GABA-receptor, such as phenobarbital.

It is important to choose the appropriate AED. This based on the pharmacokinetic properties, efficacy, and adverse effects of the drug. The acceptable AED is one that can be dosed 2-3 times daily, has documentable efficacy, and is well-tolerated by the animal.

First-line anti-epileptic medications

Phenobarbital (PB)

Postassium bromide (KBr)

Add-on ant-ieptleptic medications

Felbamate (Felbatol®); generic not available

Levetiracetam (Keppra®); generic available in Canada

Gabapentin (Neurontin®); generic available

Zonisamide (Zonagren®); generic not available

Clorazepate (Tranxene®); generic available

Antiepileptic drug monitoring and adjustment

Monitoring both AED levels and routine blood values are an important part of intelligent seizure therapy. There are many reasons it should be done.

Benefits of AED monitoring

• achieve baseline values (CBC, serum chemistry) in newly treated cases

• titration to effective dosages

• monitor trends in hepatic and other blood values to detect significant changes that warn of toxicity

• optimize therapy when multiple AEDs are used

• detect drug-drug interactions or changes in renal/hepatic function that may change drug availability

• detect poor owner patient compliance

• establish steady-state values

o serum concentration is a statistical estimate of minimum efficacy (lower limit) and maximal safety (upper limit)

o many variables come into play in treatment (i.e. age, disease, medications, metabolic differences

In general, the trough AED level is usually used to identify the minimum efficacy and the peak level when toxicity is a concern. With chronic phenobarbital therapy, the trough and peak levels are often not statistically different and this may be less of a concern. Monitoring should be done on a routine basis of twice yearly. Monitoring should be done at the initiation of therapy until the animal is well-controlled or as needed to monitor for early toxicity (see individual AED for timing). Monitoring should be done whenever there is a trend toward increasing seizure frequency, duration, and severity.

The measured serum concentration can be used to adjust the dosage of phenobarbital to a desired level. For instance, if the measured blood level is 18 •g/ml and the animal is still poorly controlled, a serum concentration of 25 •g/ml may be desired. Below is a formula that usually closely predicts the drug dosage change by a proportion. This formula can also be used to lower phenobarbital dosage. This formula does not work well for bromide adjustments.

new dosage/day = old dosage x desired concentration

.....................................................measured concentration

Therefore, if the same dog above was administered 30 mg/day, his new dose would be new dose = 30 mg x 25 = 42 mg/day.

Therapeutic failure

Therapeutic failure may have one or multiple causes. Therapeutic failure is usually due to owner noncompliance or mistakes made by the veterinarian. Client education is one of the most important factors related to therapeutic failure. Owners must realize that the medication will probably be a lifetime commitment, they may need to travel to emergency clinics at unpredictable times, and must follow-up with evaluation and diagnostic monitoring, and watch pets for adverse effects of the drugs. The balance between quality-of-life and therapeutic success is the key issue for the owner to continue treatment. Despite financial and emotional commitment, a significant proportion of animals may be refractory to medication (up to 40%). There are a few other mistakes that are made by veterinarians that influence therapeutic success. Physiologic factors can also play a role with seizure control.

Refractory seizures

There is no single definition of medically refractory epilepsy, nor is there a consensus on how long or vigorously an animal must be treated before they are considered refractory to treatment. Ideally, if an animal continues to seizure unacceptably with appropriate medication regimens they may be called a refractory epileptic. This may occur in up to 40% of the cases. Often an animal is labeled refractory after improper usage of medications. Medications are often changed too quickly or unnecessarily discontinued for fear of adverse effects.

If an animal is refractory, consulting a specialist often helps to adjust medications and find new ways of dealing with the case. Evaluation of all AEDs used, the highest dosages, combinations, serum levels, dosing schedule, drug-drug interactions, side effects, length of time used may shed light on whether the animal is truly refractory or not. Another problem is animals whose dosage is routinely raised after a seizure. This is inappropriate therapy as anticonvulsants are not a cure but a treatment. Dogs may still seizure occasionally even with well-controlled. Dosage change should be considered when there is a trend toward increase in seizure frequency, duration, and severity. Before a dosage is raised, a serum AED concentration should be measured to establish current levels and help guide dosage adjustment.