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Saturday, August 15, 2009

Although the ketogenic and modified Atkins diets can be very helpful in the treatment of epilepsy, similar to any medically approved therapy, there are real side effects. Fortunately, these side effects tend to be reversible and treatable without the need for discontinuing the diet (unlike a rash with an anticonvulsant, for example). In the 2009 ketogenic diet expert consensus guideline, in fact, side effects were described in detail but none were believed specifically to warrant automatically stopping the diet.

However, most ketogenic diet researchers today want to PREVENT side effects before they actually occur, rather than just treat them afterwards. Many of the studies of side effects of the diet prior to the past decade just reported the likelihood of these side effects occurring. Dr. Christina Bergqvist’s landmark study from 2005 published in Epilepsia showed that starting the ketogenic diet without a fasting period led to less hypoglycemia and acidosis, helped lead the way in this line of research. A study from our group published just last month looking at the use of Polycitra K supplements to prevent kidney stones adds to this growing field.

What are these major side effects of the diet that are being actively studied?

Kidney stones

In 2000, a report from our group found that 6% of children on the ketogenic diet had kidney stones, and they seemed to be more common in those children who had elevated urine calcium levels. This study theorized in its discussion section that treating those with elevated urine calcium with oral potassium citrates (e.g. Polycitra K™) would reduce the risk of stones. For 6 years our ketogenic diet center at Hopkins did just that – and it mostly worked. However, several children still developed kidney stones, sometimes due to missed lab results, parents refusing to give it, or stones occurring before the first lab results were ever done. Since January 2006, we have been giving all children starting the ketogenic diet Polycitra K™ at a dose of 2 meq/kg/day automatically. The risk of kidney stones is now less than 1%, justifying its use for all children on the ketogenic diet. This research was published last month in Pediatrics.

Cytra-k Crystals

Constipation

MiralaxFirm bowel movements and some degree of constipation are nearly universal on the diet, likely as a combined result of decreased fiber (vegetables) and fluids and the high fat nature of the foods. Although not life-threatening, it is certainly uncomfortable for children. We have found that by using fiber supplements, most often polyethylene glycol (Miralax™), which is also over-the-counter, this problem is rarely significant. Nowadays, when a child is started on the ketogenic diet at our institution, and the parents mention constipation at the first visit, we’ll start Miralax™ immediately. In addition, extra fluids, MCT oil, and salt seem to help as well. In some rare occasions, we will also recommend enemas.

High cholesterol

Over time on the diet, approximately 60% of children will have a high cholesterol (>200 mg/dl). We do not know the long-term effects of high cholesterol although we suspect children are doing well as adults and suffer no long-term ramifications. Studies are underway to prove this guess. However, in situations where the total cholesterol is over 300mg/dl, most ketogenic diet teams will react, typically by either reducing the ketogenic ratio (e.g. to 3:1 or 2:1), adding MCT oil, supplementing with carnitine, or substituting polyunsaturated for saturated fats. In a study from 2008, Nizamuddin et al. looked at the success of these interventions, and found that although 60% had at least a 20% decrease in cholesterol by making these changes, 41% (which was not significantly lower statistically) also showed improvement just by watching and repeating the fasting lipid profile a few months later! One very significant finding was that those children who were on formula-only ketogenic diets had lower cholesterol values than those receiving solid foods. This was discussed in last month’s KetoNews.

Growth

Does the ketogenic diet stunt growth? Studies from the US and Sweden suggest that although children do grow on the ketogenic diet, they grow less well than other children, typically consistently at the 5th percentile. Our data shows that this is more commonly a problem in those on the ketogenic diet over 6 years and in infants. The most common intervention is to lower the ketogenic ratio, therefore increasing the relative amount of protein in the diet. However, research this year from the group at Astrid Lindgren Children’s Hospital in Sweden suggests that may not be enough, and high levels of serum ketosis may be the culprit behind decreased growth. In that way, diets like the low glycemic index treatment in which serum ketosis is low or even non-existent, may be better options for children either at risk for or already having growth disturbance.

Bone fractures

It is known that anticonvulsants can lead to bone mineral density problems long-term, what about the diet? Dr. Bergqvist’s group from Philadelphia would suggest the diet by itself can also impact bone density. In their study published this December of 15 patients over 5 years of age, whole body and spine bone mineral density decreased while on the diet. This was most pronounced in young children who were not walking and were underweight to start. Information from our institution also confirms this as a problem; 20% of children on the diet continually for >6 years had a history of bone fractures. Is this due to the diet or perhaps the diet used in combination with anticonvulsants? Is this just a problem of children who are not walking? Is calcium and Vitamin D enough or should medications that grow bone (e.g. pamidronate) be used? These questions remain to be answered.

Gastroesophageal reflux

One of the more recent side effects to become discussed and studied, gastroesophageal reflux, has been also highlighted as a problem worth solving. The ketogenic diet team from Korea first reported in 2004 that as high as 39% of children on the diet had gastrointestinal disturbance such as vomiting. They followed this up in 2008 with an interesting study in which they did endoscopies before starting the diet in 35 children. They found that those children who had erosive findings before starting the diet had a much higher risk of later problems (85% vs. 33%). Although they did not recommend endoscopy as a routine screening method, they did find that using medications such as antiacids were helpful and all but one case were able to stick with the diet. Today, this is certainly a problem for our ketogenic diet patients and we often recommend lansoprazole, ranitidine, slow feedings (for those with gastrostomy tubes), and occasionally pediatric gastroenterology consultations for those with significant reflux at baseline.

References

Bergqvist AG, Schall JI, Stallings VA, Zemel BS. Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am J Clin Nutr. 2008;88(6):1678-1684.

Bergqvist AG, Schall JI, Gallagher PR, Cnaan A, Stallings VA. Epilepsia 2005 46(11):1810-1819.

Groesbeck DK, Bluml RM, Kossoff EH. Long-term use of the ketogenic diet in the treatment of epilepsy. Dev Med Child Neurol. 2006;48(12):978-981.

Jung da E, Chung JY, Kang HC, Kim HD. Improving tolerability of the ketogenic diet in patients with abnormal endoscopic findings. Brain Dev 2008;30(6):416-419.

Kang HC, Chung DE, Kim DW, Kim HD. Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia 2004;45(9):1116-1123.

McNally MA, Pyzik PL, Rubenstein JE, Hamdy RF, Kossoff EH. Empiric Use of Potassium Citrate Reduces Kidney-Stone Incidence With the Ketogenic Diet. Pediatrics. 2009 Jul 13. [Epub ahead of print]

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(7):758-761.

Sampath A, Kossoff EH, Furth SL, Pyzik PL, Vining EP. Kidney stones and the ketogenic diet: risk factors and prevention. J Child Neurol. 2007;22(4):375-378.

Spulber G, Spulber S, Hagenäs L, Amark P, Dahlin M. Growth dependence on insulin-like growth factor-1 during the ketogenic diet. Epilepsia 2009;50(2):297-303.

Authored by: Eric Kossoff, MD on 8/2009
Reviewed by: Robert Fisher MD PhD on 7/2009
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