By Peter Morrison, MD

Although the ketogenic diet is increasingly being used as a “first-line” treatment for certain types of epilepsy, it is more commonly used in children with difficult to control seizures. Because of this, the diet is often initiated in patients who are already on one or more medications. In addition, some patients are also treated with other nonpharmacologic therapies, such as the vagus nerve stimulator (VNS). Despite this, relatively little is known about how drugs and the VNS work in combination with the diet. Do certain combinations work well or poorly together? Some research has addressed this question in terms of side effects, and more information is becoming available about efficacy.

Ketogenic diet and medication combinations

The ketogenic diet is commonly used in conjunction with one of more anticonvulsant medication, and more is being learned about the risks and benefits of these combinations. To begin with, the ketogenic diet does not seem to change the blood (plasma) levels of common anticonvulsant medications in any significant way. Investigators have measured plasma levels both before and after diet initiation and found no significant differences. (Dahlin et al., 2007). It seems that you don’t need to decrease or increase any medications when starting the diet to keep blood levels the same.

Regarding tolerability, valproic acid, topiramate and zonisamide have garnered the most concern, as the side effects of the ketogenic diet and these medications overlap. Traditionally, there has been a perception that valproic acid and the ketogenic diet should not be used together because of the increased risk of side effects such as liver toxicity and pancreatitis. Recent clinical evidence, however, suggests that the use of valproic acid in patients on the ketogenic diet is safe and well tolerated. (Lyczkowski et al., 2005)

Concerns regarding combination therapy with topiramate or zonisamide have been largely based on side effects similar to those seen with the ketogenic diet; namely the risk of kidney stones and the development of metabolic acidosis. Despite these concerns, studies show that these medications can be used safely with the ketogenic diet, without an increased risk of stones and only minimal increased risk of symptomatic acidosis (Kossoff et al 2002; Takeoka et al 2002).

Some specialists advocate the routine use of PolyCitraK™ when on the diet, to decrease the acidity of urine and help prevent stones. (Sampath et al., 2007).

Which medications work well with the diet

Aside from side effects, another important question is: “Do any medications work particularly well with the diet?” With our current state of knowledge, the answer to this question is unclear, although some new information is emerging. To date, no single anticonvulsant drug has been shown to be more effective in combination with the ketogenic diet, nor has any particular medication been shown to be less effective in those patients on the diet. There are some reports of patients who respond very well to particular combinations, for example the diet plus valproic acid. (Lyczkowski et al., 2005)

Our group at Johns Hopkins presented a poster at the 2007 American Epilepsy Society meeting looking at this question. Interestingly, those patients taking phenobarbital were less likely to respond to the diet than those patients on other medications over the first few months. There was also a suggestion that zonisamide may work well in conjunction with the diet, although this remains unclear. Hopefully, further research will help elucidate the interaction between the diet and anticonvulsant medications.

Ketogenic diet and vagus nerve stimulation

The vagus nerve stimulator is also used in patients with difficult to control seizures. A multicenter study published in 2007 looked at the combined use of the ketogenic diet and vagus nerve stimulation. The concept of “rational polytherapy” stimulated this investigation. Simply put, this theory is that therapies that work in different ways are more likely to work well in combination than therapies that work similarly. Thirty children from several epilepsy centers were followed, and more than two thirds reported additional benefits when the ketogenic diet and vagus nerve stimulator were combined. The combination was also well tolerated, with no increase in side effects. (Kossoff et al., 2007)

In summary, clinicians and patients have a variety of tools to help stop seizures, such as medications, therapeutic diets, VNS and even surgery. In patients with difficult to control epilepsy, these modalities often need to be used in conjunction. Our knowledge of how these therapies specifically work together is limited, but we are learning increasingly more about how to combine differing strategies to achieve optimum outcomes for patients living with epilepsy.

Topic Editor’s Note:

In this month’s issue of Ketogenic News, Dr. Peter Morrison, a second year pediatric epilepsy fellow at Johns Hopkins Hospital, addresses one of the most common questions parents ask when they start the diet: “Can we (or should we) start to get rid of some of the seizure medications?” There is a lot of misinformation about what anticonvulsants are good (or bad) in combination with the diet. Since nearly all children on the diet remain on at least one medication, this is not a trivial issue. Eric Kossoff, MD, editor

References

• Sampath A, Kossoff EH, Furth SL, Pyzik PL, Vining EPG. Kidney stones and the ketogenic diet: risk factors and prevention. J Child Neurol 2007;22:375-378.
• Kossoff EH, Pyzik PL, Furth SL, Hladky HD, Freeman JM, Vining EPG. Kidney stones, carbonic anhydrase inhibitors, and the ketogenic diet. Epilepsia 2002;43:1168-1171.
• Kossoff EH, Pyzik PL, Rubenstein JE, Bergqvist AGC, Buchhalter JR, Donner EJ, Nordli DR, Wheless JW. Combined ketogenic diet and vagus nerve stimulation: rational polytherapy? Epilepsia 2007;48:77-81.
• Takeoka M, Riviello JJ Jr, Pfeifer H, Thiele EA. Concomitant treatment with topiramate and ketogenic diet in pediatric epilepsy. Epilepsia 2002;43:1072-1075.
• Lyczkowski DA, Pfeifer HH, Ghosh S, Thiele EA. Safety and tolerability of the ketogenic diet in pediatric epilepsy: effects of valproate combination therapy. Epilepsia 2005;46:1533-1538.

Submitted on March 30, 2009

Edited by Steven C. Schachter, MD