IDIOPATHIC EPILEPSY AND SECONDLINE MEDICATIONS: CATS AND DOGS

However, 20 per cent to 30 per cent of dogs have poorly controlled epileptic seizures, despite adequate target serum levels of ’first line” anti-epileptic medications, such as phenobarbital and KBr²,³.

In this article we will describe “second-line” anti-epileptic medications, such as gabapentin, pregabalin, levetiracetam and zonisamide, which veterinary surgeons can use in combination with phenobarbital and/or KBr in epileptic patients with poorly controlled epileptic seizures.

In addition, some of these “second-line” anti-epileptic medications can be used when phenobarbital or KBr dosage needs to be reduced or discontinued due to intolerable side effects.

Gabapentin

Gabapentin is a structural analogue of gamma-amino-butyric acid (GABA), but does not interact with GABA receptors, nor does it inhibit GABA uptake, nor is it metabolised into GABA or a GABA agonist.

To date, there has been no consensus on the mechanism of action of gabapentin. Data suggest that gabapentin binds to the α2δ accessory subunit of voltage-gated calcium channel complexes on the neuronal cellular membrane, and inhibits intracellular calcium influx, with a subsequent reduction in the release of excitatory neurotransmitters (such as glutamate, norepinephrine or substance P) into the synaptic cleft⁴–⁷.

Gabapentin has a high oral bioavailability in dogs (80 per cent administered at a dose of 50mg/kg)⁸ and its absorption in the small intestine is not influenced by dietary factors⁹. In dogs, 30 per cent to 40 per cent of the administered oral dose of gabapentin undergoes hepatic metabolism to N-methyl-gabapentin and is excreted by the kidneys⁸,⁹.

Despite the reported hepatic metabolism in dogs, there is no evidence of any appreciable induction of hepatic microsomal enzymes⁸,⁹.

Peak serum levels are reached two hours after oral administration in dogs10. Gabapentin has a very short elimination half-life in dogs and cats after oral and intravenous administration (three to four hours). Therefore, it needs to be administered (at least) every eight hours⁶,⁹.

Because of its short half-life, some authors suggest gabapentin should be administered every six hours to maintain adequate serum concentrations over 24 hours⁵,¹¹. However, regular administration every six hours is not practical for most pet owners¹¹.

Proposed target serum levels have been evaluated in dogs and reported to range between 4mg/L to 16mg/L¹². However, serum gabapentin level monitoring is rarely pursued in the clinical setting due to gabapentin high therapeutic index and the high dose required to cause any sign of toxicity¹³. The recommended oral dosage of gabapentin is: 10mg/kg to 20mg/kg bodyweight every six to eight hours in dogs⁴,⁵,¹¹ and 5mg/kg to 10mg/kg every eight to 12 hours in cats⁶,¹¹.

The role of gabapentin as adjunctive treatment to phenobarbital and/or KBr for canine idiopathic (primary) epilepsy has been investigated in two clinical studies⁴,⁵. The study by Platt et al included 11 epileptic dogs (refractory to phenobarbital and KBr) treated with gabapentin at 10mg/kg every eight hours. The frequency of seizures was estimated from the owners’ seizure diaries during the three months before and after treatment with gabapentin began. Six out of 11 dogs had a reduction in the number of seizures per week equal or greater than 50 per cent – however, there was no significant change in seizure duration. Side effects (ataxia and sedation) occurred in five out of the 11 dogs, but were not severe enough to warrant treatment discontinuation during the study⁵.

The study by Govendir et al⁴ included 17 epileptic dogs (considered refractory to phenobarbital and/or KBr) treated with gabapentin at 35mg/kg/d to 50mg/kg/d (divided twice or three times daily) for four months. There was no significant improvement in overall seizure frequency during the four-month study period. This may be due to the fact gabapentin was administered every 12 hours in the majority of dogs included in this study. Side effects included:

• sedation in three dogs;

• pelvic limb ataxia in six dogs;

• polyuria-polydipsia in one dog; and

• polyphagia in one dog.

However, as polyuriapolydipsia and polyphagia are reported side effects of phenobarbital and/or KBr, it is difficult to establish to which anti-epileptic medication these side effects may be related to⁴.

To the author’s knowledge, no clinical studies on the safety and efficacy of chronic gabapentin administration to cats exist.

Pregabalin

Pregabalin is the “next generation” of gabapentin.

Pregabalin has an increased affinity for the α2δ accessory subunit of voltage-gated calcium channel complexes (compared to gabapentin)¹⁴,¹⁵. Pregabalin is suspected to be a more potent anti-convulsant and antinociceptive agent than gabapentin, on the basis of experimental studies in rodents and clinical trials in humans. More than 90 per cent of pregabalin is excreted unchanged in the urine¹⁵. The only pharmacokinetics study in dogs (administered a single dose of pregabalin orally at 4mg/kg) has shown 80 per cent oral bioavailability, peak concentration at 1.5 hours after oral administration and an elimination half-life of seven hours¹⁵. The recommended oral dose of pregabalin in dogs is 3mg/kg to 4mg/kg every eight to 12 hours¹⁴.

The role of pregabalin as adjunctive treatment to phenobarbital and/or KBr for canine idiopathic (primary) epilepsy has been investigated in one clinical study that included 11 dogs¹⁴. Pregabalin was administered at 3mg/kg to 4mg/kg orally, every eight hours for three months. The number of generalised seizures in the three months before and after initiating pregabalin treatment was recorded.

Seven of the 11 dogs had mean and median seizure reductions of 64 per cent and 58 per cent, respectively. Side effects attributed to pregabalin treatment were reported in 10 dogs and included ataxia and sedation. To minimise side effects, pregabalin can be started at 2mg/kg orally every eight to 12 hours, and be increased by 1.0mg/kg each week until the target dose of 3mg/kg to 4mg/kg is reached¹⁴. No information is available on using pregabalin in cats¹⁶.

Gabapentin and pregabalin have been reported as effective medications for treating neuropathic pain, chronic pain, cancerous pain or surgical pain in human and veterinary literature¹⁷–²⁰.

Levetiracetam

Levetiracetam is a pyrrolidinebased anti-epileptic medication. Its mechanism of action has been postulated to involve inhibition of excitatory neurotransmitter release by binding to the synaptic vesicle protein SV2A²¹–²³.

Levetiracetam seems to have a unique ability to suppress seizure activity without affecting normal neuronal excitability²¹,²². Neuroprotective properties leading to decreased seizures-induced brain damage²⁴, have also been reported²⁵, ²⁶.

Levetiracetam is rapidly absorbed following oral administration and its oral bioavailability has been reported as 100 per cent in recent pharmacokinetics studies performed on healthy dogs and cats²⁷–²⁹. Peak serum concentration is achieved in approximately 40 minutes in dogs and two hours in cats after oral administration28,30,31. Levetiracetam has an elimination half-life of about three to four hours in dogs and three hours in cats – therefore, it needs to be administered (at least) every eight hours²¹,²⁷,³⁰.

About 70 per cent to 90 per cent of the medication is excreted unchanged in the urine, and it is reported to have no or minimal hepatic metabolism²¹,²⁷,³⁰. For this reason, it can be used in patients with liver disease²⁷,³⁰.

Target serum levels (therapeutic range) for levetiracetam have not been definitively established in humans, dogs or cats. Recent pharmacokinetics studies in healthy dogs administered levetiracetam intravenously, intramuscularly, subcutaneously or orally, and in healthy cats receiving levetiracetam orally or intravenously, have suggested that levetiracetam target serum levels may be similar to those proposed to be effective in people (5µg/ml to 45µg/ ml)²⁷,²⁹,³¹,³². Levetiracetam serum levels are not commonly measured in veterinary patients due to the limited knowledge on target serum levels, the high safety of this medication and the high dose required to cause toxicity¹⁶,³³.

Toxicity trials on healthy dogs reported no side effects when levetiracetam was administered intravenously as a single dose up to 210mg/kg²⁸.

A one-year toxicological study performed in healthy dogs receiving levetiracetam orally at 1,200mg/kg daily revealed vomiting, salivation and ataxia as the only side effects, with no treatment related mortality¹¹. The recommended dosage of levetiracetam is 20mg/kg every eight hours in dogs and cats³³.

Side effects at the recommended dosage are generally uncommon and include mild sedation and ataxia in dogs and cats, and decreased appetite and transient hypersalivation in cats administered levetiracetam oral solution²⁹,³⁰,³³.

Intravenous bolus administration (over two to five minutes) of a single loading dose of levetiracetam at 60mg/kg resulted in the rapid achievement of proposed target serum levels for at least eight hours and no obvious side effects in healthy dogs. Intravenous levetiracetam can be used in treating cluster seizures or status epilepticus. This initial loading intravenous dosage can be followed by the maintenance oral dosage²⁸,³⁴.

A recent clinical research abstract from the American College of Veterinary Internal Medicine (ACVIM) in 2011 investigated the pharmacokinetics of an extended-release formulation of levetiracetam administered orally in five healthy dogs. It revealed a fivefold increment in bioavailability of the extended-release formulation of levetiracetam compared to the immediate-release levetiracetam formulation.

Moreover, levetiracetam plasma concentration eight hours after oral administration were higher than 10µg/ ml, suggesting the extended release formulation may be administered less frequently than the formulation available on the market. No adverse effects were observed in any of the dogs in this study³⁵.

Only one study has evaluated the clinical efficacy of levetiracetam in dogs considered refractory to phenobarbital and/ or KBr³³. This study included 22 epileptic dogs (considered refractory to phenobarbital and/or KBr) treated with levetiracetam at 10mg/kg to 20mg/ kg every eight hours for four months. There was significant improvement in overall seizure frequency during the fourmonth study period. After four to eight months of treatment, two-thirds (six of nine dogs) of the dogs that initially responded to levetiracetam treatment suffered an increment in seizure frequency to pre-treatment level. To avoid tolerance to levetiracetam, intermittent short treatment with this medication only during cluster seizures has been suggested as a cost-effective treatment strategy³³,³⁶.

In their review on treatment of feline seizures, Bailey et al¹⁶ reported treating two cats (suspected idiopathic-primaryepileptic) with levetiracetam monotherapy with successful results. The same authors reported successful results in treating structural epilepsy in two cats with intracranial meningioma, in which seizure activity was not controlled with phenobarbital administration only (^{Figure 1})¹⁶. Unfortunately, studies on the clinical efficacy of levetiracetam in cats are not available.

Zonisamide

Zonisamide is a sulfonamidebased anticonvulsant medication. The mechanisms of action include enhancement of the effect of GABA, modulation of dopaminergic metabolism in the central nervous system, blockage of T-type calcium channels and voltage-gated sodium channels, and inhibition of carbonic anhydrase activity, hence increase of seizures threshold³⁷,³⁸.

Zonisamide is primarily metabolised in the liver by the microsomal enzymes cytocrome P450 and glucuronyltransferase, and it is excreted mainly in the urine and partially in the faeces³⁷,³⁹,⁴⁰. Its elimination half-life in dogs is about 15 hours with steady-state serum levels occurring three to four days after initiating treatment. Zonisamide elimination half-life is shortened in dogs already treated with phenobarbital due to hepatic enzyme induction of phenobarbital⁴¹. For this reason, reported zonisamide dosages for dogs are:

• 10mg/kg orally twice daily when used in combination with phenobarbital; and

• 5mg/kg orally twice daily when used as monotherapy⁴¹–⁴⁴.

The elimination half-life in cats is about 33 hours and, therefore, zonisamide can be administered at 5mg/kg to 10mg/kg every 24 hours, although more pharmacokinetic studies are needed to investigate this further⁴⁰. The longer elimination half-life in cats compared to dogs is probably due to the feline deficiency of glucuronyltransferase⁴⁰.

Reported target zonisamide serum levels are between 10 and 40µg/ml in dogs, whereas target range interval has not yet been established in cats ³⁷,⁴⁵.

In a toxicity study on healthy dogs administered zonisamide at 75mg/kg daily for 52 weeks, the only consistent laboratory abnormalities were a mild decrease in plasma albumin and elevation in liver enzyme activities, and particularly of alkaline phosphatase (ALP)⁴⁵.

However, no significant differences in liver enzymes level pre and post-zonisamide treatment were noticed in the only two veterinary published studies on the clinical efficacy of zonisamide in idiopathic (primary) epileptic dogs (^{Figure 2}) treated with phenobarbital or a combination of phenobarbital and potassium bromide⁴²,⁴⁴.

A study investigating the role of zonisamide as adjunctive treatment to phenobarbital and/or KBr for canine idiopathic (primary) epilepsy reported a reduction of seizure frequency in eight out of 11 dogs during the first eight months of treatment⁴⁴. Long-term follow-up after 17 months revealed a loss of efficacy in three of the eight dogs that had a satisfactory initial response to zonisamide treatment⁴⁴. The authors suggested possible explanations for this phenomenon were either the induction of tolerance to the medication or increased severity of the epileptic process⁴⁴. In this study, the authors also reported zonisamide was used as monotherapy in one dog, which achieved 100 per cent reduction of seizure frequency at 17 months follow-up⁴⁴.

Another study on investigating the role of zonisamide as adjunctive treatment to phenobarbital and/or KBr for canine idiopathic (primary) epilepsy reported that seven out of 12 dogs had a reduction in seizure frequency of at least 50 per cent, with a median followup of nine months⁴². Six of these 12 dogs experienced side effects, including:

• ataxia in three dogs treated orally with 6mg/kg to 11mg/kg every 12 hours⁴²;

• transient lethargy in one dog treated with 11mg/kg every 12 hours⁴²; and

• vomiting in one dog treated with 9.5mg/kg every 12 hours⁴².

Idiosyncratic hepatopathy has recently been described in two dogs (with probable symptomatic or cryptogenic epilepsy) treated with zonisamide monotherapy⁴⁶,⁴⁷.

One of the reported dogs developed inappetence and vomiting 10 days after the beginning of the treatment with zonisamide (at 7.7mg/kg orally every 12 hours) and died of acute hepathic necrosis on the 11th day of treatment.

The diagnosis of acute hepatic necrosis was reached based on serum biochemistry results (increased activity of alanine aminotransferase, aspartate transaminase, ALP, gamma-glutamyl transpeptidase and hyperbilirubinaemia), coagulation panel abnormalities (increase in prothrombin time and activated partial thromboplastin time) and postmortem examination⁴⁶.

The second reported dog, treated with zonisamide monotherapy at 8.3mg/kg orally every 12 hours, developed inappetence, vomiting and icterus 21 days after beginning treatment.

Serum biochemistry abnormalities similar to the above case were noticed, but coagulation panel was unremarkable. The patient survived and achieved complete recovery after adequate supportive care and discontinuation of the zonisamide treatment, along with initiating KBr treatment⁴⁷.

Renal tubular acidosis has been reported in one dog receiving zonisamide at 7.9mg/ kg to 8.4mg/kg orally every 12 hours, after 18 months of treatment. Serum zonisamide level was 39ìg/ml (target range 10µg/ml to 40µg/ml). The dog was hyperchloraemic, urinary pH was 6.5 and arterial blood gas analysis indicated a primary respiratory alkalosis. Following this report, monitoring of serum electrolytes and acid-base status was recommended in dogs treated with zonisamide⁴⁸.

There are no publications on the clinical efficacy of zonisamide in epileptic cats. A pharmacokinetics and toxicity study on the use of zonisamide in healthy cats administered 20mg/kg daily for nine weeks revealed that anorexia, sedation, somnolence, ataxia, vomiting and diarrhoea were the most common side effects⁴⁰.

In a recent review on diagnosing and treating feline idiopathic epilepsy, Bailey et al¹⁶ reported treating two cats with zonisamide as monotherapy. One of the cats developed severe anorexia and the treatment was, therefore, withdrawn, the other cat experienced a significant reduction in seizure frequency¹⁶.

Summary

At present, the use of pregabalin, levetiracetam and zonisamide might be prohibitively expensive for some owners, especially when treating largebreed dogs (Figure 3).

References

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