Topics in Compan An Med 28 (2013) 6771

Review Article

Management of Refractory Epilepsy

Karen R Muana, DVM, MS, Diplomate ACVIM (Neurology)n
Keywords:
seizures
pharmacoresistance
antiepileptic drug
alternative therapy
vagal nerve stimulation
diet
Department of Clinical Sciences, College of
Veterinary Medicine, North Carolina State
University, Raleigh, NC, USA
n

Address reprint requests to Karen R.

Muana, DVM, MS, Diplomate ACVIM
(Neurology), Department of Clinical
Sciences, College of Veterinary Medicine,
North Carolina State University, Raleigh, NC,
USA.

The term refractory epilepsy is utilized in veterinary medicine to describe a condition in which an
animal with epilepsy fails to attain satisfactory seizure control or suffers intolerable side effects despite
appropriate therapy with conventional antiepileptic drugs. Refractory epilepsy is an important problem
in small animal practice as it occurs in approximately one-third of dogs with epilepsy. Consequently,
there is much interest in identifying ways to more effectively treat this population of animals. More than
a dozen new antiepileptic drugs have been approved for humans over the last 2 decades, and several of
these drugs, including gabapentin, zonisamide, levetiracetam, and pregabalin, have been evaluated for
the treatment of refractory seizures in veterinary patients. Nonmedical methods to treat poorly
controlled epilepsy are also being explored. The 2 alternative forms of therapy that have shown the
most promise in humans with epilepsy are electrical stimulation of the brain and dietary modication,
both of which have also been evaluated in dogs. This overview summarizes the available data on
pharmacologic as well as nonmedical treatment options for dogs and cats with refractory epilepsy.
Although many forms of therapy are currently being utilized in clinical practice, our knowledge of the
safety and efcacy of these treatments is limited. Additional randomized controlled trials are needed to
better evaluate these novel therapies for refractory epilepsy in dogs and cats.
& 2013 Elsevier Inc. All rights reserved.

E-mail: Karen_Munana@ncsu.edu

Introduction
The term drug-resistant epilepsy has been dened in human
medicine as a failure of adequate trials of two tolerated and
appropriately chosen and used antiepileptic drug schedules
(whether as monotherapies or in combination) to achieve sustained seizure freedom.1 Although a similar denition has not
been established in veterinary medicine, it is generally agreed that
an animal that continues to have frequent or severe seizures or
intolerable side effects despite appropriate antiepileptic drug
therapy is considered refractory to treatment.2
Most of the dogs with epilepsy are successfully treated with the
conventional antiepileptic drugs phenobarbital and potassium
bromide. However, it has been estimated that up to 30% of dogs
have refractory epilepsy and do not attain satisfactory seizure
control with conventional therapy.3 Moreover, phenobarbital and
potassium bromide have a relatively narrow therapeutic index,
such that less than half of all dogs are able to maintain a seizurefree status without experiencing adverse medication-related
effects.4 These side effects range from sedation, ataxia, and
vomiting to more serious complications such as bone marrow
suppression and hepatotoxicity.
Interestingly, the incidence of refractory epilepsy in the human
population is similar to that reported in dogs. In humans, 30%-40%
of those with epilepsy continue to have seizures even with
maximal medical therapy, and less than half of them are able to
maintain a seizure-free status without unacceptable side effects
from the medication.5 The relatively high prevalence of drugresistant epilepsy has stimulated extensive research in this area,
and considerable progress has been made in the pathogenesis and
treatment of medically resistant epilepsy in humans over the last
few decades. Novel antiepileptic drugs have been developed with
a focus on improved efcacy and tolerability, and alternative
nonmedical therapies have been explored. These discoveries have
provided medical practitioners with additional resources to use in
the treatment of patients with epilepsy and have resulted in an

improved quality of life for many people with epilepsy. Several of

these treatment modalities are being utilized in veterinary medicine for providing additional options in the management of
epilepsy in dogs and cats as well. This review discusses the
pharmacologic and nonmedical therapies that have been evaluated for use in dogs and cats with refractory epilepsy.

Novel Antiepileptic Drugs

Since 1993, more than a dozen new antiepileptic drugs have
been approved for the treatment of epilepsy in humans. These
drugs tend to offer improved tolerability, fewer side effects, and
less potential for drug interactions when compared with the
conventional antiepileptic drugs used in humans. Many of these
drugs have been evaluated on a preclinical basis in animals such
that data on the pharmacokinetics and toxicity in dogs are
available. Several of the drugs have been shown to be unsuitable
for use in veterinary patients because of the species differences in
pharmacokinetics that render the drug ineffective, as is the case
with oxcarbazepine. Furthermore, species differences in metabolism can result in the drug having an unfavorable safety prole.
This is the case with lamotrigine, in which a metabolite is
cardiotoxic in dogs,6 and vigabatrin, which has been associated
with hemolytic anemia and neurotoxicity in dogs.7 However,
many of the novel drugs that have demonstrated favorable
pharmacokinetic and safety data are now being utilized in
veterinary practice. Reports evaluating the use of gabapentin,
zonisamide, levetiracetam, and pregabalin for the treatment of
refractory epilepsy in dogs have been published, and the pharmacokinetics of topiramate, lacosamide, and runamide in dogs have
been described. The only clinical report on the use of novel drugs
in cats with refractory epilepsy evaluated levetiracetam as add-on
therapy. The pharmacokinetics of zonisamide in cats have been
explored, but to date there are no published reports on its use in
cats with epilepsy. Information on the clinical use of these new

1527-3369/$ - see front matter & 2013 Topics in Companion Animal Medicine. Published by Elsevier Inc.
http://dx.doi.org/10.1053/j.tcam.2013.06.007

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K.R. Muana / Topics in Companion An Med 28 (2013) 6771

drugs as add-on therapy for dogs and cats is summarized in

Table 1, and is discussed in more detail in the following section.
Although the newer drugs have gained considerable popularity
in the management of epilepsy in dogs and cats, scientic data on
their safety and efcacy are limited. In fact, most of the clinical
information available is derived from retrospective or prospective
open-label studies in which the results of treatment are not
compared with any control group. Consequently, the reported
efcacy is likely to be exaggerated. Many studies on epilepsy are
designed to evaluate for a positive response to therapy, which is
dened as a 50% reduction in seizures. Individuals who reach this
level of seizure control are classied as responders. However, an
analysis of 3 placebo-controlled canine epilepsy trials demonstrated that a large proportion of dogs respond positively to
treatment with placebo alone, with a 50% reduction in seizures
following placebo administration.8 This placebo response has been
attributed to the natural waxing and waning course of epilepsy
over time, the potential for improved patient care during participation in the trial, and investigator and participant (owner) bias.
The presence of a strong placebo effect suggests that results from
open-label studies, particularly those that involve a small number
of animals, should be interpreted with some caution.
Gabapentin
Gabapentin received FDA approval in 1994 for the treatment of
partial seizures in humans. Its precise mechanism of action is
unclear, but there is evidence to suggest that much of its
antiepileptic effect is because of its binding to a specic modulatory protein of voltage-gated calcium channels, which results in
decreased release of excitatory neurotransmitters.9 Gabapentin is
eliminated entirely by the kidneys in humans. In contrast, gabapentin undergoes partial hepatic metabolism in dogs before its
renal excretion, with an elimination half-life of approximately 3-4
hours.10,11
There are 2 prospective clinical reports on the use of gabapentin
as an add-on drug for refractory epilepsy in dogs. In the rst study,
6 of 11 dogs were described as having a positive response to
treatment (50% reduction in seizures) following the addition of
gabapentin (10 mg/kg given orally every 8 hours) to their treatment regimen.12 The second published study evaluated adjunctive
treatment with oral gabapentin at a dose of 35-50 mg/kg/day
divided every 8-12 hours in 17 dogs and found no signicant
decrease in seizure frequency for the study population as a whole,

although the authors described 3 dogs becoming seizure free

during the study.13 Side effects in both reports were considered
mild and included sedation and ataxia.
Zonisamide
Zonisamide was approved in the United States in 2000 as
adjunctive treatment for partial-onset seizures in humans,
although the drug has been available in Japan since 1984. The
exact mechanism of action for zonisamide is unknown; however,
the drug has several pharmacologic effects that might contribute
to its antiepileptic properties, including the blockage of calcium
channels, inhibition of voltage-gated sodium channels, enhancement of GABA release, and inhibition of glutamate release.14
Zonisamide has a favorable pharmacokinetic prole in dogs with
respect to its use as an add-on antiepileptic drug: it is well
absorbed after oral administration, has a long elimination halflife (approximately 17 hours) that allows for twice daily dosing,
and has relatively low protein binding such that drug interactions
are minimized. Most of the drug undergoes hepatic metabolism
via the cytochrome P450 system before excretion by the kidneys.15
Two open-label trials that involved 25 dogs have been published evaluating zonisamide as an add-on treatment for refractory epilepsy. These studies reported response rates of 58%-82%,
with a median reduction in seizure frequency of 70%-81%.16,17 The
recommended starting dose for zonisamide in dogs is 5-10 mg/kg
given orally twice daily. The high end of the dose range is needed
when used in combination with phenobarbital as it has been
shown to increase the clearance of zonisamide through induction
of the cytochrome P450 system.18 Adverse effects of zonisamide
that have been described in dogs include sedation, ataxia, and loss
of appetite.16 In addition, there are 2 recent reports of dogs
developing hepatotoxicity following zonisamide administration,
which is believed to be an idiosyncratic reaction to the drug.19,20
The hepatopathy resolved in one of the dogs with discontinuation
of the drug, but was fatal in the other. Renal tubular acidosis has
also been described in a dog associated with zonisamide administration.21 Both hepatotoxicity and renal tubular acidosis are
documented adverse effects of zonisamide in humans.
There is a single report describing the pharmacokinetics of
zonisamide in cats, with maximum concentrations achieved
approximately 4 hours after oral administration and an elimination half-life of approximately 33 hours.22 Half of the cats
developed adverse effects, including anorexia, diarrhea, vomiting,

Table 1
Summary of Antiepileptic Drugs Used as Add-on Therapy in Dogs and Cats With Refractory Seizures
Dogs

Cats

Drug

Recommended Oral Starting Dose

Reported Adverse Effects

Recommended Oral Starting Dose

Reported Adverse Effects

Gabapentin

10-20 mg/kg q 6-8 h

Sedation
Ataxia

5-10 mg/kg q 8-12 h

Sedation
Ataxia

Zonisamide

5-10 mg/kg q 12 h

Sedation
Ataxia
Loss of appetite

5 mg/kg q 12-24 h

Sedation
Ataxia
Anorexia
Vomiting
Diarrhea

Levetiracetam

20 mg/kg q 8 h

Sedation
Ataxia

20 mg/kg q 8 h

Sedation
Ataxia
Inappetence
Hypersalivation

Pregabalin

3-4 mg/kg q 8 h

Sedation
Ataxia

1-2 mg/kg q 12 h

Sedation
Ataxia

Runamide49

20 mg/kg q 12 h

None published

None published

None published

K.R. Muana / Topics in Companion An Med 28 (2013) 6771

69

lethargy, and ataxia following administration of a daily oral dose

of 20 mg/kg.22 There are only anecdotal reports on the clinical use
of zonisamide in cats, with oral doses of 5 mg/kg every 12-24
hours utilized most commonly.
Zonisamide has a wide therapeutic index, such that the drug is
typically utilized in human medicine without the routine measurement of serum drug concentrations. A similar practice has been
accepted in veterinary medicine. Furthermore, a therapeutic range
has not been established for veterinary medicine, although a
target range of 12.5-40 mg/mL has been advocated for dogs based
on extrapolation from human data. The author recommends that
zonisamide serum concentrations be measured in animals that do
not attain satisfactory seizure control despite administration of the
drug at the high end of the recommended range to help determine
whether a dosage increase is warranted.

partial seizures in 2004. Pregabalin is more potent than gabapentin owing to a greater afnity for the binding site at which this
class of drugs exerts its effect.9 The pharmacokinetics of pregabalin have been evaluated in dogs with a reported elimination halflife of approximately 7 hours.32
The recommended dose of pregabalin in dogs is 3-4 mg/kg,
given orally every 8 hours. The common side effects include
sedation and ataxia, and to minimize these, it has been recommended that treatment be initiated at a dose of 2 mg/kg and the
dose escalated by 1 mg/kg each week until the target dose is
achieved.33 The use of pregabalin in dogs with refractory epilepsy
has been reported in a single open-label study, in which 7 of 11
dogs evaluated were classied as responders.33 There are anecdotal reports of the use of pregabalin in cats, with a dose of 1-2 mg/kg
given orally every 12 hours described.

Levetiracetam

Newer-Generation Antiepileptic Drugs

Levetiracetam was approved for use in 1999 as a treatment for

partial-onset seizures in humans. Its mechanism of action involves
selective binding to a presynaptic protein (SVA2), whereby it
modulates the release of neurotransmitters.23 Levetiracetam possesses a favorable pharmacokinetic prole in dogs with respect to
its use as an add-on antiepileptic medication. It has rapid and
complete absorption after oral administration, no signicant
protein binding, lack of hepatic metabolism, and linear pharmacokinetics; however, the short elimination half-life of 3-6 hours in
dogs necessitates frequent administration.23-26 In addition, concurrent administration of phenobarbital has been shown to
increase the clearance of levetiracetam in dogs.27 This cannot be
attributed to phenobarbital's effect on liver metabolism, as levetiracetam does not undergo hepatic clearance. Rather, phenobarbital is believed to induce the oxidative metabolism of
levetiracetam in extrahepatic tissues.
An open-label study evaluating the use of levetiracetam at a
dose of 10-20 mg/kg given orally every 8 hours in 14 dogs with
refractory epilepsy reported a response rate of 57%.28 More
recently, the use of oral levetiracetam in refractory epilepsy has
been evaluated in a randomized controlled trial involving 34
dogs.29 In this study, levetiracetam administration at an oral dose
of 20 mg/kg every 8 hours resulted in a signicant decrease in
seizure frequency compared with baseline; however, no difference
in seizure frequency was identied when levetiracetam was
compared with placebo. Reported adverse effects in dogs include
sedation and ataxia.28,29
The only published clinical trial involving cats with refractory
epilepsy evaluated the use of levetiracetam in an open-label study
design. Of the 10 cats studied, 7 were reported to have a favorable
response to treatment.30 The recommended dosage in cats is
similar to dogs (20 mg/kg given orally every 8 hours). Adverse
effects that were described include sedation, inappetence, and
hypersalivation.
An extended-release formulation of levetiracetam is available,
and a pharmacokinetic study of this formulation in dogs supports
its administration according to a 12-hour dosing interval.31 Twice
daily as opposed to 3 times daily administration is more convenient
for most pet owners and is likely to improve compliance. However,
the efcacy of the extended-release formulation has not been
evaluated in the clinical setting. In addition, this product is only
appropriate for larger dogs, as the smallest tablet size is 500 mg and
extended-release tablets should not be split before administration.

Pharmacokinetics studies on topiramate, lacosamide, and runamide support the potential use of these drugs in dogs, but their
safety and efcacy has not been evaluated in the clinical setting.

Pregabalin
Pregabalin is a newer-generation drug in the same class as
gabapentin, and it was approved by the FDA for treatment of

Pharmacoresistance
Despite the recent introduction of numerous new drugs, the
overall incidence of refractory epilepsy has remained fairly constant in the human population. In a prospective epidemiological
study of humans with epilepsy, only 3% of the patients who failed
to respond to a rst antiepileptic drug became seizure free when
treatment was attempted with a combination of 2 or more
drugs.34 Furthermore, this drug resistance occurs despite the use
of medications with differing pharmacologic properties and
modes of action, suggesting that a nonspecic mechanism is
involved in limiting the effectiveness of antiepileptic drugs. There
is insufcient data in veterinary medicine to assess whether the
introduction of new drugs has changed the incidence of refractory
epilepsy in dogs and cats, but the author suspects that the
situation in veterinary patients is similar to that in humans.
Pharmacoresistance in epilepsy is currently an area of intense
research, with efforts directing at understanding the mechanism
by which drug resistance occurs. The 2 theories that have gained
the most support are the drug transporter hypothesis and the
target hypothesis. The drug transporter hypothesis postulates that
drug resistance is due to overexpression of multidrug transporters,
the proteins that restrict the entry of lipophilic molecules into
the brain.35 The most well-known multidrug transporter is the
p-glycoprotein pump, which is encoded by the ABCB-1 (MDR-1)
gene. Overexpression of multidrug transporters within a seizure
focus can result in ineffective concentrations of antiepileptic drugs
at target sites in the brain, despite the drug being administered at
appropriate dosages. The drug target hypothesis is based on the
premise that drug resistance occurs because of changes in drug
targets in epileptogenic brain tissue, either genetic in origin or
disease related, that make them less sensitive to antiepileptic
drugs.36 Considerable data have been generated in support of both
these hypotheses but neither is able to completely explain the
phenomenon of drug resistance in epilepsy. More recently, inherent disease severity has been proposed to play a role in pharmacoresistant epilepsy.37 This theory is based on the premise that
there are individual differences in inherent disease severity in
epilepsy that are reected in the frequency of seizures in the early
phase of disease and inuence the response to antiepileptic
medication. Recent research suggests that inherent disease
severity might play a role in canine epilepsy as breed-related
differences in seizure severity have been reported. Studies have

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K.R. Muana / Topics in Companion An Med 28 (2013) 6771

demonstrated that the Australian shepherd38 and Border Collie39

have a high prevalence of drug-resistant seizures, while the course
of disease in Collies appears to be more favorable.40

Alternative Therapies for Epilepsy

Owing to the relatively high prevalence of drug resistance,
nonmedical treatment options are considered earlier in the course
of therapy for many humans with epilepsy. Epilepsy surgery is a
viable option for approximately 50% of patients with medically
refractory seizures. For the remaining population of patients,
alternative therapies are often explored. Of these, vagal nerve
stimulation (VNS) and the ketogenic diet have proven to be the
most successful and are now well-recognized treatment options
for human epilepsy. Both these alternative forms of therapy have
been evaluated in dogs.
VNS
VNS was approved in 1997 as an adjunctive therapy in adults
with partial-onset seizures that are refractory to antiepileptic
medications. This form of treatment involves surgical implantation
of a pacemaker-like device that delivers repetitive stimulation to
the left cervical vagus nerve. Results from human clinical trials
suggest that approximately one-third of patients treated with VNS
experience a reduction in seizure frequency of at least 50%, onethird of patients experience a reduction in seizure frequency
between 30% and 50%, and one-third of patients have little or no
change in seizure frequency.41 The side effects are considered mild
and include change in voice, cough, and throat pain.41
The precise means by which VNS works is not established, and
it appears as if no single mechanism of action is responsible for
the antiepileptic effects. VNS is believed to exert its effect by
modulating synaptic transmission, but it is unclear as to the
precise regions of the brain that are involved. Anatomic regions
that have been hypothesized to play a role include the reticular
activating system, the central autonomic network, the limbic
system, and the diffuse noradrenergic projection system.42
The rst report of the use of VNS in naturally occurring seizures
in dogs was in 1999, when Speciale retrospectively described the
use of ocular compression as a means to increase vagal tone in
epileptic dogs.43 This indirect method of vagal stimulation
resulted in short-term success in terminating seizure activity in
2 of the 7 dogs that were treated. However, unlike the results
obtained with repetitive electrical stimulation, the seizures
recurred after ocular compression was terminated. VNS was
subsequently evaluated in a randomized controlled trial involving
10 dogs with refractory epilepsy.44 A decrease in seizure frequency
was seen in some of the treated dogs but not in others. No adverse
effects of stimulation were detected, and most owners were
satised with the treatment. It was concluded that VNS is
potentially safe and appears to be efcacious in some dogs.
However, similar to the case in humans, it cannot be predicted
whether a dog will respond to VNS. Furthermore, the expense of
the device as well as its limited availability for veterinary use has
made this an unrealistic option for most owners of epileptic dogs.
Ketogenic Diet
The ketogenic diet was rst introduced into medical practice in
the 1920s and was designed to mimic the biochemical changes of
fasting, which had long been recognized to inuence seizure
control. Few antiepileptic medications were available at this time,
and consequently many children with epilepsy were treated with
the ketogenic diet with favorable results. However, the restrictive

nature of the diet was seen as a major disadvantage and as

antiepileptic medications became more readily available over the
years, therapeutic use of the diet declined. In the 1990s, there was
renewed interest in the use of the ketogenic diet to treat children
with epilepsy, especially those patients who were refractory to
antiepileptic medication, and multiple prospective studies on its
efcacy have yielded positive results. The diet has comparable or
better efcacy to many of the antiepileptic medications, appears to
be well tolerated by children and their families, and has a relatively
low incidence of side effects. Several forms of ketogenic diets have
been developed over recent years in an effort to improve tolerability. The diets currently utilized as a treatment for epilepsy
include the classic ketogenic diet, the medium-chain triglyceride
diet, the modied Atkins diet, and the low glycemic index diet.
The means by which the ketogenic diet exerts an antiepileptic
effect is unknown. It was previously believed to be dependent on a
state of ketosis, but this has recently come into question. The
ketogenic diet appears to improve energy metabolism of neurons,
and this is believed to involve the mitochondria, but the precise
mechanism of action remains uncertain.45
A randomized study undertaken in epileptic dogs to determine
if a high-fat, low-carbohydrate diet had an effect on seizure
frequency when compared with control diet failed to identify a
difference in seizure frequency between the groups.46 However, a
small number of dogs were evaluated. In addition, the dogs in the
study did not achieve a level of ketosis that has been associated
with seizure control in humans. Accordingly, there is presently no
scientic evidence to suggest that a high-fat diet is benecial for
seizure control in epileptic dogs as it is in humans.
Other Dietary Therapies
A randomized controlled trial was conducted to evaluate the
effects of fatty acid supplementation in 15 dogs with epilepsy. They
were treated with triple-puried omega-3 fatty acids containing
400-mg eicosapentaenoic acid, 250-mg docasahexaenoic acid, and
22-mg vitamin E per 1.5 mL at a dose of 1.5 mL/10 kg given once daily
for 12 weeks. The study failed to identify a difference in seizure severity or frequency with fatty acid supplementation compared with
placebo.47 In addition, there is an abstract reporting on a retrospective
study evaluating the use of a hypoallergenic diet in dogs with poorly
controlled epilepsy, in which 7 of 8 dogs were reported to have
improved seizure control.48 Additional studies involving larger numbers of animals are warranted to explore the potential role of dietary
modication in the treatment of epilepsy in dogs.

Conclusion
Medically refractory seizures remain a serious problem for a
proportion of the canine epileptic population. Refractory epilepsy
occurs in cats as well, but is encountered less frequently than it is in
dogs. Fortunately, treatment options available for patients with
refractory seizures have increased in recent years. Several of the
new drugs that have been approved for use in humans with seizures
are gaining popularity for the treatment of veterinary patients, and
alternative, nonmedical therapies are being explored. However, very
little is known about the safety and efcacy of these therapies in dogs
and cats with epilepsy and randomized controlled trials are needed
to help guide our recommendations for antiepileptic treatment.
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