Top 10 Ketogenic Diet Articles for 2008

For our annual Top 10 list of the "best" articles of the past year related to the ketogenic diet, I decided to get a "second opinion"! I asked Dr. Christina Bergqvist from the Children’s Hospital of Philadelphia to weigh in on her personal top 10. Dr. Bergqvist is an Assistant Professor of Pediatrics and Neurology and an expert on the ketogenic diet. She has published 10 peer-reviewed articles about the ketogenic diet and is well-known especially for her prospective, randomized trial that showed that a fasting approach is not necessary for seizure control.

- Eric Kossoff MD

These articles and summaries are presented at a technical level, but it may be interesting to some readers to scan over the conclusions, and see the research being done on the diet.

Happy New Year to all our friends of the ketogenic diet (KD) and dietary treatment for epilepsy! 2008 was an exciting year. There have been many firsts this year. Our first consensus article was written, there was a first international KD conference in Phoenix, and the first case controlled study of the KD was completed by the British. The KD should no longer be considered an "alternative treatment" instead considered a mainstay treatment for refractory epilepsy. There has been progress when it comes to understanding of the mechanism(s) involved with the KD and its use may expand into other diseases. Over 80 articles have been published. Below are the top ten "must read articles" in no particular order.

1. "The Ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial", by Neal et al. Much of the critique regarding the use of the KD has been related to the lack of class I evidence (randomized, double blinded, placebo controlled trials), which is considered the gold standard for drug testing in epilepsy. In this study, the British group used a prospective case- controlled approach. Although no one was blinded, the subjects were randomized to start the diet immediately (treatment group) or delaying treatment 3 months with no change in other interventions (control group). At 3 months of KD therapy there was a significant difference in the treated group seizure frequency compared to the control group (62% reduction vs 137 % increase in seizures). In addition, 38% of the KD treated subjects had a > 50% reduction in seizures, versus 6% in the control group; 7% of the KD group had a >90% reduction vs 0% in the control group. This study adds to the evidence of the KD efficacy and is the first prospective case controlled study of its kind. See June 2008 Keto News.
2. "Growth of children on classical and medium-chain triglyceride ketogenic diets", by Neal et al. There are concerns about long-term side effects of the KD. This includes growth status, specifically deceleration in linear growth (height Z scores). The British group followed the responders from their case controlled KD study over 12 months. Their goals were to describe changes in height, weight, and body mass index Z- score comparing the traditional KD with the MCT oil KD (which allows for more protein). Of the 75 children enrolled, 40 completed the 12 month visit. Both weight and height Z scores declined over time, calories were not different in the two groups and most importantly, the type of diet did not affect the growth outcomes.
3. "Case controlled evaluation of the ketogenic diet vs. ACTH for infantile spasms" by Kossoff et al. This analysis from the Johns Hopkins group looked at their retrospective data of infants and children with new onset infantile spasms who had used the KD (n=13) as their first treatment and compared them to the children who had used ACTH (n=20). They found that 62% of the KD treated group was spasm free by 1 month compared to 90% of the ACTH treated group. EEG normalization in the KD treated group lagged behind but eventually normalized in all who became spasm free. See November 2008 Keto News.
4. "Long-term outcome of the ketogenic diet for childhood with intractable epilepsy due to focal malformation of cortical development", by Jung et al. In this study the Korean group did a retrospective analysis of patients with focal cortical dysplasia(s) who had epilepsy surgery (n=22) or were treated and seizure free with the KD at 3 mo (n=21). In the KD treated group 16/21 remained on the KD without relapse of seizures 2 years later and 10/21 remained seizure free after cessation of the KD. In the epilepsy surgery group 13/22 remained seizure free at similar intervals. This data is interesting as it is directly opposite to other retrospective data (Stainman et al 2007) and suggests that the KD could be offered to children with focal cortical dysplasias possibly with similar treatment effects. To settle this issue a large prospective trial will be necessary.
5. "Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group". This is the first consensus article written by a group of international ketogenic diet experts. It reviews our current practices and scientific background (when known) for our current management of the ketogenic diet. Although written with health professionals in mind we recommended it for any one interested in the ketogenic diet. At this time, this consensus statement is "online early" at Epilepsia. When it is published formally, it will be discussed here at Keto News.
6. "Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet" by Bergqvist et al. This article is written our group at the Children’s Hospital of Philadelphia/ University of Pennsylvania KD group. This is the first longitudinal study of bone health in children on the ketogenic diet. 25 children were followed for 15 months on the KD. Bone mineral content status dropped dramatically and the children’s growth was affected. This occurred even though the children used many fewer medications (36% were treated with the KD alone), their vitamin D status improved and the calcium status was considered adequate. The cause for the BMC loss is unclear. This article suggests that our current supplementation practices are not adequate and that screening for bone health in children with refractory epilepsy on medication and on the KD is needed.
7. "Influence of ketogenic diet on 24 hour EEG electroencephalogram in children with epilepsy" by Remahl et al. This article by one of the Swedish KD groups looks for correlations in in EEG changes associated with the ketogenic diet. In a prospective study design, they used the ambulatory 24 hour EEG before and after 3 months KD treatment. 15/23 children had improved background and decreased interictal activity but these changes did not predict KD response status.
8. "Management of risk factors for dyslipidemias with the ketogenic diet" Nizamuddin et al. Hyperlipidemias have long been recognized as a common side-effect of the KD. In this prospective study, 137 children treated with the KD had their lipid panel evaluated at baseline and follow up (q 3-6 months). Hyperlipidemias occurred in 25% at baseline increasing to 60% on the KD. Interventions decreased the hypercholesterolemia by 20%, however, children who received no intervention improved over time also. Solid food (more saturated fat) was related to the hypercholesterolemia while children who received formula had more normal lipid values.
9. "Polyunsaturated Fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: A putative mechanisms of antiseizure action" by Xu et al. There are likely multiple mechanisms of the KD. This is an interesting article by the Swedish KD group who has done cerebral spinal fluid studies in their children. In this study they used the CSF samples of children on the KD an showed that it was the increased concentration of PUFA that induced the openings of the voltage gated K channels, not ketone bodies.
10. "Ketogenic Diet prevents cardiac arrest-induced cerebral ischemic neurodegeneration" by Tai et al. In this study rats fed the KD and control rats were exposed to cardiac arrest and the brains were then examined. They found extensive neuronal degeneration in the control rats while the KD fed rats had no evidence of neurodegeneration. This article is interesting as it may lead to expansion of the use of the KD to "post arrest care".

REFERENCES

1. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. The Ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial. Lancet Neurology.2008, 7(6):500-6 Jun
2. Neal EG, Chaffe H, Schwartz RHm Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. Growth of children in classical and medium-chain triglyceride ketogenic diet. Pediatrics, 2008, 122;e334-40
3. Kossoff EK, Hedderick E, Turner Z, Freeman JM. A case-control evaluation of the ketogenic diet versus ACTH for new onset infantile spasms. Epilepsia, 2008,49(9)1504-09.
4. Jung DE, Kang HC, Kim HD. Long-term outcome of the ketogenic diet for childhood intractable epilepsy due to focal malformation of cortical development. Pediatrics, 2008:122:330-3.
5. Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Bergqvist ACG, Blackford R, Buchhalter JR, Caraballo RH, Cross JH, Dahlin MG, Donner EJ, Jehle RS, Klepper J, Kim HD, Liu YMC, Nation J, Nordli, DR Jr, Pfeifer HH, Rho JM, Stafstrom CE, Thiele EA, Turner Z, Veggiotti P, Vining EPG, Wheless JW, Wirrell EC, The Charlie Foundation, and the Practice Committee of the Child Neurology Society. Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group. Epilepsia, Epub 24 Sept 2008; doi: 10.1111/j.1528-1167.2008.01765.x.
6. Bergqvist AGC, Schall JI, Stallings VA, Zemel BS. Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. American Journal of Clinical Nutrition, 2008, 88;1678-84.
7. Remahl S, Dahlin M, Åmark P. Influence of ketogenic diet on 24 hour EEG electroencephalogram in children with epilepsy. Pediatric Neurology, 2008,38;38-43.
8. Nizamuddin J, Turner Z, Rubenstein JE, Pyzik PL, Kossoff EH. Management and risk factors for dyslipidemia with the ketogenic diet. J Child Neurol, 2008, 23;758-61
9. Xu XP, Erichsen D, Börjesson SI, Dahlin M, Åmark P, Elinder F. Polyunsaturated Fatty acids and cerebraospinal fluid from children on the ketogenic diet open a voltage-gated K channel: A putative mechanisms of antiseizure action. 2008, 80;57-66.
10. Tai KK,Nguyen N, Pham L, Truong DD. Ketogenic Diet prevents cardiac arrest-induced cerebral inschemic neurodegeneration. J Neural Transm, 2008, 115:1011-1017