General Principles of Epilepsy Treatment

There is an ongoing debate about the optimal moment of initiating anticonvulsive therapy. The following recommendations may serve as a guideline for initiating anticonvulsive therapy:

 2 or more seizures within 6 months

 Status epilepticus or cluster (more than one seizure within 24 hours)

 Symptomatic epilepsy caused by a known structural brain lesion

 Seizures starting within 2 weeks following brain trauma

 Severe and prolonged postictal sign

It is recommended to start with a single agent therapy. Combination therapy should only be considered if the upper end of the dose range does not result in desired seizure control. Sudden switching between different should be avoided. Once treatment has been started, life-long therapy is required in most cases. However, even following the principles of anticonvulsive therapy, treatment will result in seizure freedom in about 30–40% of dogs only. Another 30–40% of dogs are so-called "none-responders," where seizure frequency does not decrease by at least 50%.

Phenobarbital (PB)

PB is currently still considered the medication of choice for initiating anticonvulsive therapy in dogs. It is initiated at a dose of 2.5 mg/kg body weight (BW) orally twice daily (BID). Serum blood levels should be checked 2 weeks after initiating therapy and the individual dose should be adjusted accordingly. The owner should be informed that the medication may take up to 2 weeks to achieve full effectiveness. The desired serum level is 20–30 µg/ml, with levels <15 µg/ml being not effective in many patients, whereas levels >35 µg/ml lead to an increased risk of hepatotoxicity. The levels should be interpreted in the light of the achieved seizure control reported by the owner. For instance, there might be dogs that do not exhibit seizures at all anymore with a serum level between 10–15 µg/ml and therefore do not require an increase of the PB dose.

If a PB dose has to be adjusted, the new dose can be calculated due to a linear dosage-serum-level relationship. Should the blood level be increased by 50%, the PB dose has to be increased by 50% as well. Once desired serum level and seizure control have been achieved, serum blood levels should be checked again 3 months later. During the first 3 months of therapy the hepatocellular cytochrome-P-450 enzyme system is activated, resulting in increased PB metabolism. Therefore, a serum level well within the range of 20–30 µg/ml after 2 weeks of therapy may drop to subtherapeutic levels 3 months later. Further serum level checks are recommended every 6 months.

Serum level checks should be used to control the liver function as well by measuring alanine aminotransferase, glucose and albumin. The liver enzyme alkaline phosphatase will be increased in most dogs on PB treatment due to enzyme induction and therefore, it is not suited for evaluating liver cell damage. If there is any suspicion of impaired liver function, a serum bile acid test should be performed. Please, be aware that thyroid tests interfere with PB treatment and therefore those test results should be interpreted cautiously in dogs receiving PB treatment.

Side effects of PB treatment include the following. Frequent side effects: polyphagia, polydipsia/polyuria (do not restrict access to water!), sedation (usually in the first 2–3 weeks after starting treatment only). Less frequent side effects: hepatotoxicity, anaemia, neutropenia, thrombocytopenia, ataxia, hyperexcitability (medication has to be discontinued), pancreatitis.

Hepatotoxicity can manifest as chronic liver cell damage or as acute fulminating hepatic failure (hepatocutaneous syndrome). In those cases, PB has to be substitutes by another medication.

Imepitoin (IP)

IP exhibits its action similar as phenobarbital on the GABAA receptor even though both drugs use different binding sides. IP connects to the benzodiazepine receptor whereas phenobarbital is using the barbiturate receptor. In contrast to PB, however, IP is a low affinity partial GABAA receptor agonist. This may explain why patients do not develop tolerance. Therefore, IP can be abruptly discontinued if indicated, without any risk of withdrawal seizures, even though mild behavioural changes and muscular signs may be observed.

Anticonvulsive efficacy of IP seems to be close to but slightly less than with PB. Side effects are much less common than in PB and are mainly restricted to polyphagia. In addition, but less frequently, the following: hyperactivity, polyuria, polydipsia, somnolence, salivation, vomiting, ataxia, diarrhoea, third eyelid protrusion, impaired vision as well as hypersensitivity to noise.

Therapy is initiated at a dose of 10 mg/kg BID and it can be increased up to 30 mg/kg BID if necessary. In the author's experience, most dogs require a dose higher than 10 mg/kg BID. Serum level checks are not recommended since plasma levels do not correspond with seizure frequency. Effectiveness is solely based on reduction of the seizure frequency which can be assessed within a few days since full effect is expected within 2 days after initiating treatment. Therefore, IP is a good choice for patients with high seizure frequencies where a significant reduction of seizures is desired within a few days.

Because of the characteristics of IP, clinicians and owners may consider switching from PB and/or KBr to IP. However, changing anticonvulsive therapy in well-controlled cases is strongly discouraged, since any change includes the risk of increasing seizure frequency. In cases where impaired liver function or unacceptable side effects require switching from PB to IP the following protocol has been recommended: both medications are given simultaneously for a transitional period of 3 months. The PB dose is reduced by 25% every month before it is completely withdrawn at the end of the 3-month period.

Potassium Bromide (KBr)

KBr is the oldest of the anticonvulsives discussed here. It can be used as monotherapy but it is more commonly applied as add-on medication in case PB alone cannot control seizure activity sufficiently. In those patients, adding KBr results in seizures freedom in about 25% of dogs.

KBr is not metabolised by the liver but it is excreted unchanged by the kidneys. It is therefore used in dogs with impaired liver function. KBr is usually started at a dose of 20 mg/kg BID even though the extremely long half-life of 3–4 weeks would allow once daily medication of 40 mg/kg BW. This long half-life is one of the major disadvantages of KBr: a delay of 3 to 4 months is required before steady-state serum levels can be measured and full efficacy can be expected. The desired blood level in KBr monotherapy is 2000–3000 µg/ml (if combined with PB 1000–2000 µg/ml might be sufficient). It is possible to estimate the final serum level by measuring the value one month after starting therapy, when 50% of the final serum level should be reached. If after one month, blood levels are below 1000 µg/ml (monotherapy) or below 500 µg/ml (combination PB), the KBr dose should be increased by 25%. Once steady-state has been achieved, further serum level checks should be performed every 6 months.

In selected cases with high-seizure frequency achieving effective serum levels much earlier can be desired. In those dogs, loading the patient with KBr can be done by applying 70 mg/kg BID for 5 days. This protocol should result in a serum level of at least 1,000 µg/ml at the end of the loading period. Such loading dosages may result in significant sedation of the patient.

It is important to keep the salt intake constant in patients on KBr, since increased chloride intake can reduce bromide levels. Owners should be instructed accordingly.

Side effects of KBr include: polyphagia, polydipsia/ polyuria, sedation, excitability, gastrointestinal disturbances (gastritis, obstipation, pancreatitis), dermal reactions.

In addition to the common side effects, signs of bromide intoxication, called bromism, can be seen in about 2% of dogs. The signs of bromism are: reduced mentation, generalised ataxia, para- or tetraparesis and hyporeflexia. Bromism can be treated by intravenous infusion of 0.9% sodium chloride using the competitive reabsorption mechanism in the kidneys to flush out KBr. Usually the signs of bromism are completely reversible once the serum level has been decreased. However, this therapy may result in an unpredictable decrease in the serum level potentially resulting in increased seizure activity. Therefore, treatment of bromism should be performed under direct control of the clinician.

KBr is not recommended for cats since it may cause severe eosinophilic pneumonitis.

Levetiracetam (LT)

LT is a human medication, which is thought to exhibit not only anticonvulsive but true antiepileptic properties as well, since it may prevent the so-called kindling-effect, whereby seizure activity may "set up" the brain for further seizures by changing neuronal circuits. LT is used as add-on medication at an oral dose of 10–20 mg/kg three times a day (TID). In addition, it has been proposed as temporary medication in dogs with a tendency to develop clusters of seizures. In these cases, LT can be given as a single dose of 40–60 mg/kg orally when a cluster starts, followed by 20 mg/kg every 8 hours until the patient has been seizure-free for 48 hours. After 2 days without seizures, LT can be discontinued.

LT has a short elimination half-life of 3-4 hours. Therefore, effectiveness can be assessed within a few days without any need for serum level checks. It can be used in dogs with known impaired liver function, as only a small percentage is metabolised by the liver. Side effects are rare but may include sedation and ataxia.

Gabapentin, Pregabalin

Both have been recommended as add-on therapy in dogs with seizures. They are excreted unchanged by the kidneys, without any hepatic metabolism. Therefore, it can be used in dogs with impaired liver function. Adding pregabalin to dogs not responding to phenobarbital or potassium bromide (or a combination of both) may reduce seizure frequency by about 50%.

Gabapentin is given at a dose of 10 mg/kg TID, whereas pregabalin is initiated at a dose of 2 mg/kg BID to TID. The dose of pregabalin can be increased to 4 mg/kg BID to TID if necessary. Due to a short half-life, efficacy can be assessed with a few days. Serum level checks are not indicated. Side effects of both medications are usually mild and may include sedation, dizziness and hyperexcitability.

Topiramate

Adding topiramate results in a response rate of 50% in dogs that did not respond to a combination of phenobarbital and potassium bromide. Therapy is initiated with an oral dose of 2 mg/kg BID, but it is increased to 5 mg/kg BID 2 weeks later. Temporary side effects such as sedation and ataxia might be seen in half of dogs treated with topiramate.

Rarely Used

Primidone: Primidone is converted by hepatic cytochrome-P-450 enzymes into phenobarbital and phenylethylmalonamide. It is thought that phenobarbital is the major active metabolite. Studies have shown that primidone is not more effective than phenobarbital alone but it appears to be more hepatotoxic than phenobarbital. Therefore, primidone is no longer recommended.

Zonisamide: Zonisamide has been used as add-on medication for non-responders, but is by far the most expensive medication currently used in dogs. It is unlikely to be used extensively in the future until a generic drug becomes available.

Clinicians should consider the "3Ds" (dose, drug, diagnosis) in dogs not responding to medication by a reduction of seizure frequency by at least 50%. The first step would be to check if an appropriate dose at the upper end of the dosing interval is used and measure serum level for those drugs, where such test is available. Second step: Add another drug if the first drug/drugs are used in highest tolerable dose. Third step: If seizure control cannot be improved by the first 2 steps, reconsider your diagnosis. Additional diagnostic tests may be initiated in order to identify an underlying pathology that may have to be treated separately. Treating the underlying pathology may improve response to anticonvulsive medication.