How should we interpret negative studies on dietary therapy?

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Epilepsy News From:

Sunday, March 3, 2019

Research is a tricky unpredictable business.

As doctor-scientists involved in research, we hypothesize (make a prediction or propose a theory), then design a study to carefully prove our opinion, enroll subjects into the trial, and lastly make it happen. There can be problems along the way, but eventually the study ends and, along with statisticians, we analyze the results.

  • What happens when the results are negative, or DIS-prove our hypothesis?
  • How should parents and people with epilepsy interpret these often-confusing findings?
  • Does it mean the treatment (in this case, the ketogenic diet) doesn’t work?
  • What do we tell friends and family who see these negative results, sometimes on the internet?

Back in 2010, I published results from a small pilot trial of the modified Atkins diet for chronic daily headaches in teenagers. In this study, the diet unfortunately did not help. I strongly believe that negative results are important, guide the field (sometimes in new, different directions or towards better studies), and help doctors provide good honest advice to their patients.

In the past few months, there have been three published trials of the ketogenic and modified Atkins diet that can be classified based on results as negative. In addition, a ketogenic supplement was found by its developing pharmaceutical company to not be effective in a clinical trial.

Studies with Negative Results

For this edition of Keto News, I thought I’d focus on this issue and provide some general guidance for those reading these studies or being asked about it by friends and family.

  • Implementation of ketogenic diet in children with drug-resistant epilepsy in a medium resources setting: Egyptian experience.” Dr. Gerges and the team from Cairo published results from a prospective study of 28 patients treated from 12/12-3/14 with a non-fasting, no-admission ketogenic diet. Unfortunately, the drop-out rate was very high, with only 3 patients remaining on the diet by 6 months. Using an intent-to-treat analysis (which assumes children who stopped the diet had no seizure reduction), only 3 of 28 (11%) were responders (greater than 50% seizure reduction), which is much lower than the typical 50% ketogenic diet responder rate by 6 months.
  • Efficacy of the ketogenic diet in Chinese children with Dravet syndrome: A focus on neuropsychological development.” Dr. Liu and the team from Xiangya Hospital in Changsha China performed a study of 26 children with Dravet syndrome (DS) on the ketogenic diet (compared to 40 with Dravet not on the ketogenic diet). Although it helped reduce seizures, in both groups the developmental quotient scores worsened over time, and there was no difference between those on the diet and those not. The authors concluded, “The ketogenic diet may not promote neuropsychological development of DS patients obviously as previously reported.”
  • Effect of modified Atkins diet in adults with drug-resistant focal epilepsy: A randomized clinical trial.” Dr. Kverneland and the team from Oslo University Hospital reported their findings of adults with focal epilepsy treated with the modified Atkins diet (24 adults) compared to a control group on a regular diet (32 adults). They did not find a significant difference in improvement between groups: 3 diet patients vs. 2 controls only had greater than 50% reduction in seizures. Moderate benefit was seen only when looking at those with greater than 25% seizure reduction and using an intent-to-treat analysis. Many possible reasons for the negative results were discussed including possible antiseizure drug level reductions by the diet, a short trial time (12 weeks), focal epilepsy (perhaps not as responsive to diet as generalized), and relatively small numbers of patients.
  • Just recently Ultragenyx announced the failure of their drug (UX007, also called triheptanoin) in a phase 3 trial of 44 children and adults with Glut1 deficiency syndrome. It did not help the movement disorder events compared to placebo. As a result of this trial, this company is no longer investigating it for Glut1 deficiency syndrome (but they still are for fatty acid oxidation defects).

What do these results mean?

So how should parents, people with epilepsy, neurologists, dietitians, and anyone interested in the ketogenic diet interpret these “negative” findings?

  • As I mentioned earlier, these findings are still very important! Negative results can reshape research and guide clinical practice. It is imperative that researchers publish these results, even when disappointing. Journals are being asked to strongly consider publication of these findings, even though they are perhaps not “newsworthy.” Pharmaceutical companies also are encouraged to publish these results.
  • Be careful about what you see on the internet and in the press. Catchy headlines about “failure” may not fully give the entire story and rarely mention some positive results. Read the entire study. (Or ask your keto team to!)
  • Remember, one negative study does not invalidate an entire body of literature on a subject. There is no need to be defensive: no treatment, the ketogenic diet included, is the answer for everyone and works in every clinical trial. Most of these negative studies will say that, and near the end of the paper state “worthy of additional study.”
  • Additionally, realize for every trial there are often several reasons that could explain why it didn’t show benefit. These are also mentioned typically in the discussion sections of published research. Situations such as small numbers of people in the study, particularly in highly refractory epilepsies being studied, participants stopping the trial early due to lack of success, etc., may lead to a poor result. They can be corrected for another trial.


Kossoff EH, Huffman J, Turner Z, Gladstein J. Use of the modified Atkins diet for adolescents with chronic daily headache. Cephalalgia 2010;30:1014-1016.

Liu F, Peng J, Zhu C, Xiao H, He F, Yin F, Chen C. Efficacy of the ketogenic diet in Chinese children with Dravet syndrome: A focus on neuropsychological development. Epilepsy Behav 2019;92:98-102.

Gerges M, Selim L, Girgis M, El Ghannam A, Abdelghaffar H, El-Avadi A. Implementation of ketogenic diet in children with drug-resistant epilepsy in a medium resources setting: Egyptian experience. Epilepsy Behav Case Rep 2018;11:35-38.

Kverneland M, Molteberg E, Iversen PO, Vejerod MB, Tauboll E, Selmer KK, Nakken KO. Effect of modified Atkins diet in adults with drug-resistant focal epilepsy: A randomized clinical trial. Epilepsia 2018;59:1567-1576.

Authored by: Eric Kossoff MD on 3/2019

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