Side Effects of Ketogenic Therapy
Early side effects
During initiation of ketogenic therapy there is a risk of hypoglycaemia, acidosis, dehydration and high levels of ketones (1). Children on carbonic anhydrase inhibitor medications (for example, topiramate or zonisamide) may have increased risk of excess ketosis and metabolic acidosis on commencing ketogenic therapy (2).
Nutrition and growth
Children with drug resistant epilepsy are at risk of insufficient vitamin D status prior to starting ketogenic therapy (3) and although levels can be normalised with vitamin D supplementation, a decline in both whole body and spine bone mineral content while on the ketogenic diet has been reported (4) despite reduction in anticonvulsant medication. Selenium deficiency can occur in children on the ketogenic diet (5) with risk of impaired myocardial function (6). Low plasma magnesium has also been reported (1) and may be a particular problem in children on the classical diet despite micronutrient supplementation (7). Vitamin C deficiency was found in one child on the ketogenic diet (8) but plasma levels of fat soluble vitamins A and E can often be raised as a consequence of a high fat intake (7). A fall in carnitine status of children and young adults during the first few months of the ketogenic diet has been seen with some cases requiring supplementation (9), although levels tended to normalise with time on diet therapy.
There is evidence of impaired growth in children on the ketogenic diet (10, 11, 12); younger children may be more at risk (13). Despite the higher protein allowance of the medium chain triglyceride (MCT) diet, no differences were seen in the growth of children on this diet compared to the lower-protein classical diet (14). Long-term follow up of children treated with the ketogenic diet in the past suggests that although growth does improve after diet treatment is discontinued, height gain can still be below expected (15).
Individual requirements for vitamin, mineral and trace element supplementation must be monitored by a dietitian. A child’s growth should be regularly assessed while on ketogenic therapy taking into account that children with neurological disability will often have growth measurements that fall well below the expected for age.
Elevated blood cholesterol and triglyceride levels have been reported in children on the ketogenic diet with significant increases in atherogenic apoB-containing lipoproteins (16). Raised blood lipids may trend back to normal with time on treatment (17) and dietary modifications can also help to achieve healthy levels (18). The full assessment of cardiovascular risk requires investigation of any physiological changes in the function of the arteries. Results suggest that while arterial stiffness may increase initially on the ketogenic diet (19), the changes in arterial function observed within the first year of treatment are not significant after 24 months and appear to be reversible (20).
The reported incidence of kidney stones in children on the ketogenic diet is higher than that of the general paediatric population. Uric acid, calcium oxalate, calcium phosphate or mixed composition stones have been reported in up to 7% of children on the diet (21, 22, 23). Risk may be higher with long-term treatment (12) and concurrent use of carbonic anhydrase inhibitors such as topiramate or zonisamide (24).
Gastro-intestinal problems are common side effects of ketogenic therapy however can usually be alleviated with dietary manipulation. Vomiting, nausea, diarrhoea, and abdominal discomfort have been reported in studies of the MCT (25, 26) and classical ketogenic diets (1). There is a risk that children with pre-existing gastro oesophageal reflux will have symptoms exacerbated by a high fat regime. Constipation is the most common reported complication of ketogenic therapy; despite dietary changes to help lessen the problem many individuals do need additional treatment with medication.
Other side effects
Other rare side effects that have been reported with ketogenic therapy are increased infection risk, bruising, raised uric acid in the blood, bone fractures, pancreatitis, lipid-aspiration pneumonia, and cardiac abnormalities (1, 6, 27, 28, 29). Ketogenic diet-induced toxicity of the anticonvulsant medication sodium valproate has been reported (30) however these treatments can be used together without problem in most cases (31).
The literature on side effects of ketogenic therapies has mainly studied traditional ketogenic diets. The limited reports of complications arising from use of the modified Atkins diet (MAD) or low glycaemic index treatment suggest fewer and less serious adverse events when these more liberal modified diets are used (32, 33, 34, 35), although a prospective review of 6 MAD studies found 13% of 92 children and adults discontinued the diet due to intolerance or side effects (36).
- Kang, H.C., Chung, D.E., Kim, D.W. and Kim, H.D. (2004) Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia 45, 1116–1123.
- Takeoka M, Riviello JJ Jr, Pfeifer H, Thiele EA (2002) Concomitant treatment with topiramate and ketogenic diet in pediatric epilepsy. Epilepsia 43(9):1072-5.
- Bergqvist, A.G., Schall, J.I. and Stallings, V.A. (2007) Vitamin D status in children with intractable epilepsy, and impact of the ketogenic diet. Epilepsia 48, 66–71.
- Bergqvist, A.G., Schall, J.I., Stallings, V.A. and Zemel, B.S. (2008) Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am J Clin Nutr 88, 1678–1684.
- Bergqvist, A.G., Chee, C.M., Lutcha, L., Rychik, J. and Stallings, V.A. (2003) Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet. Epilepsia 44, 618–620.
- Bank, I.M., Shemie, S.D., Rosenblatt, B., Bernard, C. and Mackie, A.S. (2008) Sudden cardiac death in association with the ketogenic diet. Pediatr Neurol 39, 429–431.
- Christodoulides, S.S., Neal, E.G., Fitzsimmons, G. et al. (2012) The effect of the classical and medium chain triglyceride ketogenic diet on vitamin and mineral levels. J Hum Nutr Diet 25, 16–26.
- Willmott, N.S. and Bryan, R.A. (2008) Case report: scurvy in an epileptic child on a ketogenic diet with oral complications. Eur Arch Paediatr Dent 9, 148–152.
- Berry-Kravis, E., Booth, G., Sanchez, A.C. and Woodbury-Kolb, J. (2001) Carnitine levels and the ketogenic diet. Epilepsia 42, 1445–1451
- Liu, Y.M., Williams, S., Basualdo-Hamond, C., Stephens, D. and Curtis, R. (2003) A prospective study: growth and nutritional status of children treated with the ketogenic diet. J Am Diet Assoc 103, 107–112.
- Peterson, S.J., Tangey, C.C., Pimentel-Zablah, E.M., Hjelmgren, B., Booth, G. and Berry-Kravis, E. (2005) Changes in growth and seizure reduction in children on the ketogenic diet as a treatment for intractable epilepsy. J Am Diet Assoc 105, 725–726.
- Groesbeck, D.K., Bluml, R.M. and Kossoff, E.H. (2006) Long-term use of the ketogenic diet in the treatment of epilepsy. Dev Med Child Neurol 48, 978–981.
- Vining, E.P.G., Pyzik, P., McGrogan, J. et al. (2002) Growth of children on the ketogenic diet. Dev Med Child Neurol 44, 796–802.
- Neal, E.G., Chaffe, H.M., Edwards, N., Lawson, M., Schwartz, R. and Cross, J.H. (2008) Growth of children on classical and MCT ketogenic diets. Pediatrics 122, e334–e340.
- Patel, A., Pyzik, P.L., Turner, Z., Rubenstein, J.E and Kossoff, E.H. (2010) Long-term outcomes of children treated with the ketogenic diet in the past. Epilepsia 51, 1277–1282.
- Kwiterovich, P., Vining, E.P.G., Pyzik, P., Skolasky, M.A. and Freeman, J.M. (2003) Effect of a high fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA 290, 912–919.
- Nizamuddin, J., Turner, Z., Rubenstein, J.E., Pyzik, P.L. and Kossoff, E.H. (2008) Management and risk factors for dyslipidemia with the ketogenic diet. J Child Neurol 23, 758–761.
- Liu YM, Lowe H, Zak MM, Kobayashi J, Chan VW, Donner EJ (2013) Can children with hyperlipidemia receive ketogenic diet for medication-resistant epilepsy? J Child Neurol 28(4):479-83.
- Coppola G, Natale F, Torino A, et al. (2014) The impact of the ketogenic diet on arterial morphology and endothelial function in children and young adults with epilepsy: A case-control study. Seizure 23(4):260-5.
- Kapetanakis M, Liuba P, Odermarsky M, Lundgren J, Hallböök T. Effects of ketogenic diet on vascular function. (2014) Eur J Paediatr Neurol. 8(4):489-94
- Hertzberg, G.Z., Fivush, B.A., Kinsman, S.L. and Gearhart, J.P. (1990) Urolithiasis associated with the ketogenic diet. J Pediatr 117, 743–745.
- Furth, S.L., Casey, J.C., Pyzik, P.L. et al. (2000) Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol 15, 125–128.
- Kielb, S., Koo, H., Bloom, D.A. and Faerber, G.J. (2000) Nephrolithiasis associated with the ketogenic diet. J Urol 164, 464–466.
- Paul, E., Conant, K.D., Dunne, I.E. et al. (2010) Urolithiasis on the ketogenic diet with concurrent topiramate or zonisamide therapy. Epilepsy Res 90, 151–156.
- Sills, M.A., Forsythe, W.I., Haidukewych, D., MacDonald, A. and Robinson, M. (1986) The medium chain triglyceride diet and intractable epilepsy. Arch Dis Child 61, 1168–1172.
- Schwartz, R.H., Eaton, J., Bower, B.D. and Aynsley-Green, A. (1989) Ketogenic diets in the treatment of epilepsy: short term clinical effects. Dev Med Child Neurol 31, 145–151.
- Berry-Kravis, E., Booth, G., Taylor, A. and Berman, W. (2001) Bruising and the ketogenic diet: evidence for diet-induced changes in platelet function. Ann Neurol 49, 98–103.
- Best, T.H., Franz, D.N., Gilbert, D.L., Nelson, D.P. and Epstein, M.R. (2000) Cardiac complications in pediatric patients on the ketogenic diet. Neurology 54, 2328–2330.
- Stewart, W.A., Gordon, K. and Camfield, P. (2001) Acute pancreatitis causing death in a child on the ketogenic diet. J Child Neurol 16, 633–635.
- Ballaban-Gil, K., Callahan, C., O’Dell, C., Pappo, M., Moshe, S. and Shinnar, S. (1998) Complications of the ketogenic diet. Epilepsia 39, 744–748.
- Lyczkowski, D.A., Pfeifer, H.H., Ghosh, S. and Thiele, E.A. (2005) Safety and tolerability of the ketogenic diet in pediatric epilepsy: effects of valproate combination therapy. Epilepsia 46, 1533–1538.
- Kim YM, Vaidya VV, Khusainov T, Kim HD, Kim SH, Lee EJ, Lee YM, Lee JS, Kang HC (2012) Various indications for a modified Atkins diet in intractable childhood epilepsy. Brain Dev.34(7):570-5.
- Muzykewicz DA, Lyczkowski DA, Memon N, Conant KD, Pfeifer HH, Thiele EA (2009) Efficacy, safety, and tolerability of the low glycemic index treatment in pediatric epilepsy. Epilepsia, 50, 1118-26.
- Miranda MJ, Mortensen M, Povlsen JH, Nielsen H, Beniczky S (2011) Danish study of a modified Atkins diet for medically intractable epilepsy in children: can we achieve the same results as with the classical ketogenic diet? Seizure. 20(2):151-5.
- Coppola G, D’Aniello A, Messana T, Di Pasquale F, della Corte R, Pascotto A, Verrotti A (2011) Low glycemic index diet in children and young adults with refractory epilepsy: first Italian experience. Seizure 20(7):526-8.
- Auvin S (2012) Should we routinely use modified Atkins diet instead of regular ketogenic diet to treat children with epilepsy? Seizure. 21(4):237-40.