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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
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
68
Table 1
Summary of Antiepileptic Drugs Used as Add-on Therapy in Dogs and Cats With Refractory Seizures
Dogs
Cats
Drug
Gabapentin
Sedation
Ataxia
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
69
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
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
70
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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