Ketogenic Diet, Zonisamide Ease Seizures

A reduction in seizures can be accomplished with a ketogenic diet.

Based on Abstracts presented at the 23rd annual ACVIM Forum in Baltimore (2005).

Speculation exists that diet may have an effect on seizure activity. A prominent role has been played by so-called ketogenic diets. These diets are low in carbohydrates, moderate in protein and high in fat. This diet results in the production of ketones and mild to moderate acidosis.

The diet is generally used in patients with seizures that are refractory to other medications, often in children. In children with either glucose transporter deficiency (GLUT-1) or pyruvate dehydrogenase deficiency, this diet is the primary form of therapy.

The exact reason this diet has a beneficial effect is uncertain (Sinha SR. The ketogenic diet. The neurologist 11;161-170:2005). The acidosis or ketones may play a direct role.

Alternatively, changes in polyunsaturated fatty acid profiles may be the cause of the benefit. This diet may also induce changes in the energy metabolism of the neuron.

Regardless of the reason the diet works, it seems to have significant benefits in approximately two-thirds of patients using the diet. The diet can cause significant problems, however, especially GI tract upset, hyperlipidemia, renal calculi, stunted growth and pancreatitis.

Ketogenic Diet Trial in Dogs

Researchers from the universities of Tennessee, Minnesota and North Carolina State and the Hill's Pet Nutrition Center investigated whether a ketogenic diet might be an option in seizuring pets (Patterson, EE, Munana KR, et al. Results of a ketogenic food trial for dogs with idiopathic epilepsy. JVIM 19:421:2005). The study was prospective, double masked and placebo controlled.

Initially the dogs were fed a control diet with 16 percent crude fat, 25 percent crude protein and 54 percent NFE (carbohydrates) for three to six months while seizure frequency was established.

All dogs in the study were on phenobarbital and/or potassium bromide and had at least three seizures in the three months before the study began.  

Dogs that had five or more seizures during the monitoring phase were randomized to receive either the same diet or a ketogenic diet (57 percent fat, 5.8 percent NFE, 28 percent protein). Although 31 dogs entered the trial, only 17 were randomized and of these 17 only 12 completed the trial.

The ketogenic diet resulted in a significant rise in ketones. Two dogs in each group had a 50 percent or greater reduction in their seizure activity. Three of nine dogs fed the ketogenic diet developed pancreatitis, whereas two of 31 dogs fed the control diet did so; this was not statistically significantly different.

Owners were highly satisfied with both diets.

Statistical analysis showed that at least 22 dogs had to be in each group for the study to have enough power to detect a difference between the diets.

Dietary Consistency

Though this study does not support or refute use of the diet, a ketogenic diet can be considered in those patients that fail to respond adequately to 'typical' anticonvulsant medications.

Since some dogs achieved better control on a normal diet, it may also indicate that dietary consistency may help in controlling epileptic seizures.

One explanation for this is that with a steady diet the amount of chloride fed is consistent. It is known that chloride intake influences bromide excretion. If chloride in the diet increases, more bromide is excreted.

Zonisamide and Dogs

Two studies presented at ACVIM looked at the pharmacokinetics of the anticonvulsant zonisamide. This medication was used in the treatment of 12 dogs with refractory epilepsy (Dewey CW, Guiliano R, et al. Zonisamide therapy for refractory idiopathic epilepsy in dogs. JAAHA 40;285-291:2004).

The study showed that approximately 60 percent of dogs responded favorably with a mean reduction in seizures of 81 percent. Five dogs, however, had an increase in seizure activity. Mild side effects were seen in six dogs. The mean dose used was 8.9 mg/kg twice daily.

The studies presented at ACVIM looked in more detail at the pharmacokinetics of this medication, which is important for effective use. One study was from researchers associated with Auburn and the Long Island Veterinary Specialists group; the other was from Japanese investigators.

The study from Auburn used the medication in healthy dogs (Boothe DM, Perkins J, et al. Clinical pharmacokinetics and safety of the anticonvulsant zonisamide in healthy dogs following single and multiple dosing, JVIM 19;421:2005).

Steady state was reached in seven days. The dogs were given 10 mg/kg twice daily. This dose resulted in what would be considered therapeutic drug concentrations in humans.

The Japanese researchers used zonisamide in healthy dogs as well (Saito M, Orito K, et al. Pharmacokinetics of zonisamide administered alone and in combination with pheobarbital in dogs. JVIM 19;421-422:2005).

After initial therapy with zonisamide alone, the dogs were concurrently given phenobarbital and zonisamide. It was suspected that phenobarbital might change the drug's metabolism. The dogs were given 5 mg/kg of zonisamide.

Adding phenobarbital considerably shortened the duration of effect of the drug and reduced blood concentrations.

A minimum of 6 mg/kg twice daily is needed to keep drug concentrations above the lower end of the therapeutic range.

The studies on zonisamide published to date show that this medication is an acceptable add-on drug for dogs with seizures that are poorly controlled with standard medications. So far, side effects have been mild.

A dose of between 6 mg/kg and 10 mg/kg twice daily should achieve adequate blood concentrations, but therapeutic monitoring is clearly indicated with this medication.

Anthony Carr, DVM, Dipl. ACVIM, is an associate professor at the Western College of Veterinary Medicine in Saskatoon, Saskatchewan, Canada.

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