Download Epilepsy and Anti-epileptic Therapy Veterinarians generally

Epilepsy and Anti-epileptic Therapy
Veterinarians generally diagnose idiopathic epilepsy (IE) based primarily upon signalment and
history. Since there is no diagnostic test for IE, the arrival at a diagnosis is done by excluding other
disorders that may have caused the seizures. The minimum database for any animal presenting for
evaluation of seizures should consist of: CBC, serum chemistry profile, urinalysis, pre- and postprandial serum bile acid levels to exclude potential metabolic causes of seizures. Most dogs with
IE will begin their seizure histories between 1 and 5 years of age. Be aware that you will encounter
dogs with IE that are younger (juvenile epilepsy) and older (late-onset) epilepsy, so the 6months
to 6 years should only be used as a guideline. Excluding pre-ictal and post-ictal behavior, dogs
with IE are normal between seizures. A subset of these dogs appear to have behavioral disorders.
These dogs are typically described by their owners as being anxious or fearful, but this perceived
behavioral abnormality is constant rather than episodic.
Phenobarbital and potassium bromide have long been the therapy of choice for epilepsy in dogs.
Both drugs are active at the GABA receptor reducing seizure frequency via hyperpolarization of
neurons. They are both extremely effective drugs.
Phenobarbital is the most frequently used antiepileptic and is well suited for seizure control in
dogs and cats. Initial oral dosing is 2-3mg/kg twice a day. The half-life in dogs is about 2 days
and time to steady state is 10-14 days. Therapeutic serum concentrations are typically between
15-30µg/ml, with a recommended maximum of 35µg/ml because of an increased risk of
hepatotoxicity at higher concentrations. Phenobarbital induces hepatic enzyme activity, which
can result in increased blood levels of these enzymes and increased metabolism of many drugs,
including itself. Common side effects of phenobarbital include polyuria and polydipsia,
polyphagia, hepatotoxicity, bone marrow dyscrasias and sedation.
Potassium bromide is not metabolized and is excreted unchanged by the kidneys. It’s
mechanism of action is related to the hyperpolarization of chloride channels. Daily maintenance
dose is 40-50mg/kg as monotherapy or 30mg/kg in combination with other anti-epileptic drugs.
The half-life in dogs is typically 25 days and time to steady state levels is 3-4 months. Typically,
a loading dose is given to accelerate the time to steady state. Standard loading is achieved with
100-120mg/kg/day for 5 days, or for an extremely quick load, 400-600mg/kg can be given
divided over one day. Once-daily administration is effective, although the dose may be divided
to reduce gastric irritation and given with small amount of wet food or bread. Common side
effects include polyuria, polydipsea and polyphagia, and hind limb weakness and sedative.
Potassium bromide has been associated with pancreatitis in dogs and pneumonitis in cats. Dogs
and cats should be evaluated every12 months with a physical and neurological examination,
serum phenobarbital or bromide levels, and minimum database.
There has long been a need for additional antiepileptic drugs that are effective, safe and practical
in terms of dosing frequency.
Zonisamide represents a viable first choice or add-on therapy for dogs with primary epilepsy.
Zonisamide blocks excitatory sodium and calcium channels and influences neurotransmitter
synthesis and degradation. Canine studies have shown that 5mg/kg twice a day is an appropriate
starting dose. For animals on phenobarbital a starting dose of 7-10mg/kg twice a day may be
needed. Reference blood levels have been taken from the human literature and are 10-40ug/ml. I
typically measure blood levels when seizures are poorly controlled and the dose is at the higher
end of the dosing range (>10mg/kg BID). Zonisamide is metabolized by the liver and has a
reasonably long half-life of 15 hours. Side effects in dogs include ataxia, lethargy and vomiting.
There have been three case reports of an idiosyncratic hepatotoxicity that resolved with
discontinuation of the drug.
Levetiracetam is another viable first choice or add-on therapy. Levetiracetam alters seizure
activity by binding to the synaptic protein, SV2A and inhibiting excitatory neurotransmitter
release. It is primarily excreted renally with little to no hepatic metabolism, making it an ideal
choice for any animal with compromise of hepatic function. The half-life in dogs is about 3
hours and dosing typically starts at 20mg/kg three times a day. Plasma reference ranges are 5 –
45ug/ml, although it is believed a minimum level of 10ug/ml is required for seizure control in
dogs. Higher doses may be necessary for dogs on phenobarbital. The only side effect typically
reported is sedation. Levetiracetam is also available in an intravenous form making it a
functional complement to phenobarbital and benzodiazepines in managing patients with status
epilepticus or cluster seizures. In patients with cluster seizures I may administer pulse therapy
with an initial dose of 50mg/kg followed by subsequent doses of 25mg/kg every 6-8 hours over
the next 48 to 72 hours. Levetiracetam has also been used in cats with similar half-life and
dosing. Side effects noted in cats included lethargy and inappetance.
Gabapentin has been used as an effective treatment of pain in dogs and cats, but can also be
used as an antiepileptic drug. Gabapentin was initially synthesized to mimic the chemical
structure of the neurotransmitter gamma-aminobutyric acid (GABA), but is believed to act on
different brain receptors. Its anticonvulsant activity may involve interaction with voltage-gated
calcium channels. It is primarily renally excreted. Typical dosing in dogs is 10 to 20 mg/kg
every eight hours. The half-life in dogs is approximately 3 hours. Sedation appears to be the
most commonly reported side effect. Gabapentin has been used in cats and can be useful and
safe. Cats are more likely to become sedate so I suggest starting at a dose of 8-10mg/kg twice a
day.
Antiepileptic therapy should be considered when single seizures occur more frequently than once
every 4 weeks or when seizures occur in clusters, animals have severe post-ictal signs or an
animal with an increasing seizure frequency should be started on therapy, patients present in
status epilepticus should be started on maintenance therapy once seizures are controlled.
What are the important tips when combining drugs to control seizures? Please explain the rationale
of each combination as well as describe what the best combination is if considering current
available drugs for both humans and animals.
In general, drugs should be chosen that have different mechanisms of action and do not have
similar adverse side effects. There is no “best” combination overall-treatment needs to be tailored
to the individual.
What is the time point to start blood monitoring of the drugs after administering the drugs? How
often should you monitor plasma drug levels?
The time point at which blood monitoring should begin is any point after which five elimination
half-lives of the drug in question have transpired. Whether or not drugs should automatically be
monitored on a regular basis if seizure control is good and side effects are minimal is a matter of
clinician opinion and preference. Markers should include drug levels below and above therapeutic
range, but these numbers should not always be considered as absolute.
How do you determine the loading dose of a drug?
The loading dose for a particular drug is derived from the formula below:
Loading dose (DL)=Vdss x Css
The dosing interval is primarily based on expected side effects of loading a particular drug.
Typically loading I give one to two double doses of Zonisamide (20mg/kg), Levetiracetam (4060mg/kg) and or Phenobarbital (12-24mg/kg over 12-24 hours) as loading doses.
What should veterinarians explain to pet owners about epilepsy?
It is important to let owners know the following: 1) most patients will not become seizure-free, but
it is still our goal to achieve this within the confines of minimizing drug side effects 2) drug
therapy is currently a process of trial and error and it may take a while to get the right protocol for
a particular patient 3) most dogs with IE seizure at rest, so playing and exercising are fine 4)
though the genetics are not well worked out, IE is considered to be inherited. Dogs suspected to
have IE should not be bred and 5) the refractory rate for IE in dogs is up to 30%. This means that
poor response to therapy may well mean that another therapy should be attempted, rather than
immediately looking for another cause with MRI.
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Review Article. Topics in Companion Animal Medicine. 2013; 28:34-41.
Moore, SA. A Clinical and Diagnostic Approach to the Patient with Seizures. Topical Review.
Topics in Companion Animal Medicine. 2013; 28:46-50.
Podell, M. Antiepileptic Drug Therapy and monitoring. Review Article. Topics in Companion
Animal Medicine. 2013; 28:59-66.
Munana, KR. Management of Refractory Epilepsy. Review Article. Topics in Companion
Animal Medicine. 2013; 28:67-71.