What can we do for patients with refractory epilepsy?

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We all have seen those patients. The ones that you really want to help, but their seizures remain poorly controlled despite using everything at your disposal. (And what is a “well-controlled seizure,” anyway?) These situations can leave owners feeling frustrated or discouraged and veterinarians feeling helpless.

This article will provide some tips that may be useful in managing these difficult cases, along with some information that may even help the more routine seizure patients.

Note: Diagnosis, loading-dose protocols for initial case induction, and emergency treatment protocols are beyond the scope of this discussion.

Commonly used medications

Let’s start at the beginning. The most commonly used antiepileptic drugs (AEDs) are phenobarbital, potassium bromide (KBr), levetiracetam (Keppra), zonisamide, and pregabalin (Lyrica). More recently available in some areas is cannabidiol (CBD) oil. Many of these (excluding KBr) are safe for use in both cats and dogs. The Table provides dose ranges, elimination half-life, and time to reach steady-state therapeutic serum concentrations.

A number of additional AEDs are commonly used in human medicine, but their use and efficacy in dogs is low due to their short elimination half-life and need for frequent dosing (eg, every 3 to 4 hours in some cases) (see Box). These medications will not be included in this discussion; however, it is important to note that lamotrigine (Lamictal) breaks down into a cardiotoxic metabolite in dogs and should not be given.

Box. AEDs With Short Elimination Half-life in Dogs Not Practical for Use in Canine Epilepsy

• Phenytoin (Dilantin)
• Carbamazepine
• Valproic acid
• Ethosuximide
• Vigabatrin
• Oxcarbazepine
• Tiagabine
• Topiramate

AEDs, antiepileptic drugs.

Selecting a first-line medication

A consensus statement from the American College of Veterinary Internal Medicine published in 2016 presented the available evidence-based support for the use of various AEDs.¹ This consensus statement is often referred to by neurologists when selecting AEDs; however, significant variability is associated with individual case management in a clinical setting, particularly when selecting additional AEDs for multimodal therapy. Even so, phenobarbital, KBr, levetiracetam, and zonisamide remain the most commonly selected first-line drugs.

Generally, it is best to select an AED for which the time to steady state is shorter than the seizure frequency. Alternatively, there are options for loading dosages to reach therapeutic concentrations earlier than the listed time to steady state. Dosing frequency should also be taken into consideration (eg, an owner who works 12-hour days is not likely to be able to give regular-release levetiracetam). Contraindications also need consideration. These are sometimes firm (eg, KBr is contraindicated in cats), but others are more flexible (eg, a patient with renal insufficiency can still receive levetiracetam, but the dose should be reduced to account for decreased renal clearance and may require that serum drug concentrations be monitored). Anecdotally, levetiracetam appears less efficacious than phenobarbital at recommended dosages; however, it still has a role in seizure management due to its safety profile. In toxicity studies in which dosages were well above published dosages, adverse effects were negligible. Note that zonisamide is in the sulfa family and should be avoided in patients with sulfa sensitivities.

There are no set protocols for selecting one medication over another or in what order; however, taking these factors into account will contribute to the rationale you would use on any individual case selection.

Adding more or multiple AEDs

Thankfully, the majority of patients with epilepsy are likely to respond favorably to a single agent or combination of 2 agents at therapeutic serum concentrations and to achieve control such that they have only have a few seizures a year. There are, as we have all seen, exceptions to this, and some patients with difficult-to-control patients will require multiple AEDs.

Generally speaking, it is wise to attempt to control seizures on one AED until the dose is maximally titrated before adding a second AED. Likewise, each new AED should be added when titration of the prior AED is maximal or earlier if adverse effects are noted. For those medications with therapeutic ranges established in veterinary medicine (predominantly phenobarbital and KBr), dosages should be titrated based on serum concentrations using the following formula. For AEDs with veterinary therapeutic ranges not established and simply extrapolated from human medicine (eg, zonisamide, levetiracetam, pregabalin), the dosage ranges are generally used as the determination of maximal limits.

When increasing dosages of phenobarbital or KBr in a dog, the following formula should be used to determine the increase: current dose (total mg/day)× (target concentration¸current concentration)=new dose (total mg/day)

As an example, the therapeutic range for phenobarbital for most laboratories is approximately 15 to 40 mcg/mL. If you started a dog on a dose of 60 mg every 12 hours and the patient’s measured therapeutic level is 15 mcg/mL, but they are still having frequent seizures, then you would likely want to increase the dosage. So let’s say you wanted to aim for a moderate increase to reach a goal (target) concentration of 20 mcg/mL. You would divide 20 by 15, for a factor of 1.33. You would then multiply the current daily dose (60 mg every 12 hours or 120 mg per day) by 1.33 for the new recommended dosage of 160 mg per day (divided for twice daily, this would be 80 mg every 12 hours).

You may need to round up or down slightly depending on what pill sizes are available. For example, in this dog, you may wish to use either 75 mg (1.25 tablets) or 90 mg (1.5 tablets) of a 60 mg tablet. Whether to round up or down depends on how close you are to the ceiling of the therapeutic or dose range. The closer to the ceiling you are, the better it is to round down versus up.

Of note, this formula also works for decreasing dosages due to adverse effects or if you have surpassed the safety ceiling of a medication because then the ratio of target concentration to current concentration is less than 1, resulting in a decrease in dosage.

Generally for refractory cases, we will maximize the dosage of the current AED and then add in another AED. We don’t normally substitute or remove medications for these refractory cases because there can be a synergy of mechanisms among therapy combinations. There is no limit to the number of AEDs you can administer at once; however, you will be limited by accumulation of sedative effects or ataxia/paresis in the patient likely due to the combination of medications and not due to a single individual medication—so reducing any of the AEDs is reasonable, depending on their relative dosages.

Ultimately, drug serum concentrations are helpful to not only evaluate whether a patient is receiving a therapeutic dose of an AED and whether they may be at risk of toxicity, but also in determining appropriate dose adjustments. For this reason, drug serum concentrations should be measured after initiation of therapy and again after dose adjustments are made. Testing should be timed such that steady state has been achieved (see Table).

Choosing which AED to add next

It is reasonable to combine mechanisms of action in strategic ways. For example, phenobarbital binds to the γ-aminobutyric acid type A (or GABAA) channel and promotes opening to allow chloride influx, which hyperpolarizes the cell and inhibits the action potential. KBr dissociates, and thebromide ion is recognized and treated similar to chloride ions—so bromide floods the cell further with negative charge. Together, this results in one drug (phenobarbital) enhancing channel opening and the other drug (KBr) flooding the system with even more negative charge. That is an example of synergy in which the combination of medications may be very effective.

In other situations, it may be beneficial to combine AEDs that primarily promote inhibition (eg, phenobarbital, KBr), with those that primarily depress excitation (eg, zonisamide) so that complementary mechanisms may collectively work together to suppress seizures.

Much like selecting an initial AED, there are no rules or specific recommendations as to which order to use AEDs.

Is CBD oil the cure we’ve all been waiting for?

Studies on the dose and efficacy of CBD oil in dogs and cats are limited. Those studies that are available do suggest a benefit and reduction in seizure frequency, albeit not the magical outcome that the popular media may have led us to expect. Pharmacokinetic studies in dogs found that dosages of 2.5 mg/kg to 10 mg/kg of several formulations and routes of administration were tolerated with no significant adverse effects to systemic health.² Efficacy studies using 2.5 mg/kg orally every 12 hours did show a significant reduction in seizure frequency in a recent canine study; however, the actual number of responders was similar in both control and CBD groups.² Further studies are ongoing to better understand the potential benefit of CBD oil in veterinary epilepsy patients.

Amount of control to expect in patients with refractory epilepsy

There are varying schools of thought as to the goals of managing a veterinary patient with refractory epilepsy. Due to the potential risk of kindling (seizures beget more seizures over time), attempting to achieve control so that a patient may only have 2 to 3 seizures per year is a worthwhile pursuit initially. Whereas a typical patient with epilepsy may achieve such satisfactory seizure control easily and have only a few isolated seizures a year, the patient with refractory epilepsy may routinely have clusters of 20 to 30 seizures in one day and may have seizures every week or two. Thus, the goals for these refractory patients need to be adjusted to at least minimize the occurrence and severity of cluster events and reduce the frequency as much as possible.

Cluster events can be minimized by using pulse therapies given upon recovery from a seizure and continued for 2 to 3 days, in addition to their maintenance multimodal medication protocols. For example, a patient may be prescribed an additional dose of regular-release levetiracetam (30-40 mg/kg orally every 8 hours for 3 days) to commence upon recovery from a seizure. This dose would be given in addition to their maintenance protocols and can be done even if their maintenance protocols include levetiracetam. The pulse dosage is discontinued after 2 to 3 days. Should the cluster of seizures continue despite the use of pulse therapies, then an increase in maintenance therapy may also be warranted. The goal of this pulse therapy is to reduce the severity of the cluster in terms of frequency, duration, or both. As such, the time to steady state must be relatively short so that effective serum concentrations are achieved quickly. Common “cluster buster” medications used in pulse protocols include:

• Dogs or cats: levetiracetam (regular release, 30-40 mg/kg orally every 8 hours for 2-3 days)
• Dogs: clorazepate (Tranxene) (1-2 mg/kg orally evert 8 hours for 2-3 days)

In addition, midazolam or diazepam may be administered intranasally at 0.2 to 0.5 mg/kg once or twice to stop an active seizure (or rectally at 1-2 mg/kg), followed by the pulse protocol of levetiracetam or clorazepate upon recovery. Because their half-life is very short, midazolam and diazepam are not effective at preventing future seizures in pulse-therapy protocols for cluster events and should only be used with the intent to stop an ongoing, active seizure. Daily administration limits apply to benzodiazepines.

Another goal of seizure control for patients with refractory epilepsy is to reduce cluster events and the severity and frequency of isolated seizures. In the case of these patients, however, this goal may be difficult to achieve. An example of a good outcome for a refractory patient may be to reduce seizure events from a frequency of 1 to 2 weeks to every 6 to 8 weeks, with severe cluster events limited to once or twice a year, although this is not always attained and may require up to 4 to 5 concurrent AEDs.

Although it is worth striving for better control, refractory patients may sometimes reach dose-limiting adverse effects (often sedation and ataxia), which limits our ability to treat to the point of effect.

References

1. Podell M, Volk HA, Berendt M, et al. 2015 ACVIM Small Animal Consensus Statement on Seizure Management in Dogs. J Vet Intern Med. 2016;30(2):477-490. doi:10.1111/jvim.13841
2. McGrath S, Bartner LR, Rao S, Packer RA, Gustafson DL. Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. J Am Vet Med Assoc. 2019;254(11):1301-1308. doi:10.2460/javma.254.11.1301

Dr Packer is board certified in neurology by the American College of Veterinary Internal Medicine and is an associate veterinarian at BluePearl Specialty and Emergency Pet Hospital in Lafayette, Colorado. She is also the founder and owner of the Pre-Veterinary Mentoring Group, LLC, where she provides mentorship for pre-veterinary students during their path to veterinary school. Plus, she is the founder and owner of The Pocket Neurologist, LLC, a vet-to-vet teleconsulting service.