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The ketogenic diet and the QT interval
Journal of Clinical Neuroscience 19 (2012) 181–182
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Short Communication
The ketogenic diet and the QT interval Suvasini Sharma, Sheffali Gulati ⇑ Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Shri Aurobindo Marg Street, New Delhi 110029, India
a r t i c l e
i n f o
Article history: Received 6 January 2011 Accepted 1 May 2011
Keywords: Cardiac complications Arrhythmias Electrocardiograms Epilepsy
a b s t r a c t Cardiac complications have been rarely reported associated with the ketogenic diet. Prolonged QT interval in the electrocardiogram and torsades de pointes arrhythmias have been described in a few cases. The effect of the ketogenic diet on QT interval has not been systematically evaluated. We obtained serial electrocardiograms in our patients on the ketogenic diet to look for changes in the mean QT interval. Twenty seven children aged 6 months to 5 years with refractory epilepsy were enrolled. Classic ketogenic diet was introduced using a non-fasting gradual initiation protocol. All patients were supplemented with oral calcium and selenium. Electrocardiograms were obtained at baseline and after 1, 3, 6, and 12 months on the ketogenic diet. There was no statistically significant change in the corrected QT interval over time. There were no ST segment changes or dysrhythmias in any of the electrocardiograms. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
were enrolled. Children with known or suspected inborn errors of metabolism, systemic illness, or surgically remediable causes of epilepsy were excluded. The demographic and clinical profile of this cohort has been described in an earlier study.4 The ketogenic diet was introduced using a non-fasting gradual initiation protocol, starting with a full calorie, ketogenic ratio of 1:1. This was built up over a period of 4 days to 3:1 in children younger than 18 months, and 4:1 in children older than 18 months. Diets were based on Indian recipes and prepared with common locally available foods. Electrocardiograms were obtained at baseline and after 1, 3, 6, and 12 months on the diet. The corrected QT interval (QTc) was calculated using the Bazett’s formula:5
The ketogenic diet is a medically supervised high fat, low carbohydrate diet which has been demonstrated to be an effective therapy for refractory epilepsy. The diet is however associated with adverse effects which need to be monitored. Known adverse effects include anorexia, constipation, renal stones and dyslipidemias. Cardiac complications, including prolongation of the QT interval have been reported.1,2 The effect of the ketogenic diet on the QT interval has not been systematically evaluated. In the recently published recommendations of the International Ketogenic Diet Study group on the optimal management of children receiving the ketogenic diet, electrocardiograms have not been recommended either at baseline or follow-up, unless there is a history of pre-existing heart disease.3 As QT interval prolongation can predispose to serious cardiac arrhythmias such as torsades de pointes, there is a need for more data on QT interval in patients on the ketogenic diet. Hence we planned to study serial electrocardiograms in patients started on the ketogenic diet at our center to look for changes in the QT interval.
Normal QTc was defined as 6 0.44 sec. Total serum calcium levels were also obtained at baseline and follow up. All patients were supplemented with oral calcium and selenium. A generalized estimating equation model was fitted to assess the change in the mean QTc and serum calcium levels over time.
2. Methods
3. Results
This prospective study was conducted in a tertiary care hospital between September 2006 and April 2008. Children aged 6 months to 5 years who had daily seizures (or at least seven seizures/week) despite the appropriate use of at least three anti-epileptic drugs
Twenty seven children were enrolled. The ages ranged from 9 months to 5 years (median 2.5 years). None of the patients had a pre-existing cardiac disease or family history of long QT syndrome or sudden unexplained deaths. No patient was on any other medication which could potentially increase the QT interval. Fifteen patients remained on the diet at 6 months, and 10 patients remained on it at 1 year (Table 1). At one year, five children
⇑ Corresponding author. Tel.: +91 011 26593209; fax: +91 011 26588641. E-mail address: [email protected] (S. Gulati). 0967-5868/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2011.05.012
pffiffiffiffiffiffi QTc ¼ QT interval= RR interval
182
S. Sharma, S. Gulati / Journal of Clinical Neuroscience 19 (2012) 181–182
Table 1 The corrected QT interval (QTc) and serum calcium levels on the ketogenic diet.
QTc (seconds), Mean [SD] Serum calcium (mg/dl), Mean [SD]
Baseline (n = 27)
1 month (n = 27)
2 months (n = 26)
3 months (n = 24)
6 months (n = 15)
12 months (n = 10)
p value
0.37 [0.03] 8.96 [.75]
0.37 [0.02] 9.28 [.26]
0.38 [0.02] 9.22 [.44]
0.37 [0.04] 9.03 [.59]
0.37 [0.02] 9.33 [.34]
0.36 [0.02] 9.22 [.30]
0.697 0.632
(18.5%) were seizure free, and overall 10 children (37%) had achieved a greater than 50% reduction in seizures. There was no statistically significant change in the mean QTc or serum calcium level over time. No patient developed a prolonged QT interval during the study period. There were no ST segment changes or dysrhythmias in any of the patients. 4. Discussion We did not find any changes in the mean QTc over time in our cohort. Best et al. studied the QT interval in the electrocardiograms of 21 children on the ketogenic diet.1 In their study, prolonged QT interval was documented in three children. Pre-diet electrocardiograms were available on two of these patients and indicated development of prolonged QTc after diet initiation. Two of the patients with prolonged QTc also had left atrial and left ventricular enlargement. The diet was discontinued in one patient with normalization of QTc and resolution of dilated cardiomyopathy. Normal calcium and selenium levels were documented in these patients. The mechanism of QT prolongation with the ketogenic diet is not well understood. The ketogenic diet functions by mimicking a starvation state, although still maintaining adequate protein and high fat intake. Severe malnutrition can cause bradycardia, diminished QRS voltage, and prolonged QT interval.6 Other starvation states such as anorexia nervosa have been associated with QT prolongation and sudden death.7 A significant limitation of the study is the small number of patients who stayed on the diet for 1 year. Hence the study is underpowered to detect a possible rare complication. However, this is the first study in which serial electrocardiograms have been prospectively and systematically evaluated in children on the ketogenic diet. More data from larger patient cohorts is needed to
formulate recommendations regarding electrocardiographic monitoring in patients on the ketogenic diet. 5. Details of contributions The study was conceptualized by SS and SG. SS collected the data and wrote the first draft of the manuscript, which was revised critically and approved by SG. 6. Ethical approval Ethical approval was obtained from the All India Institute of Medical Sciences Ethics Committee, Reference Number B-08/ 4.12.2006 (dated 22nd December 2006). References 1. Best TH, Franz DN, Gilbert DL, et al. Cardiac complications in pediatric patients on the ketogenic diet. Neurology 2000;54:2328–30. 2. Bergqvist AG, Chee CM, Lutchka L, et al. Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet. Epilepsia 2003;44:618–20. 3. Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group. Epilepsia 2009;50:304–17. 4. Sharma S, Gulati S, Kalra V, et al. Seizure control and biochemical profile on the ketogenic diet in young children with refractory epilepsy: Indian experience. Seizure 2009;18:446–9. 5. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353–70. 6. Ellis LB. Electrocardiographic abnormalities in severe malnutrition. Br Heart J 1946;8:53–61. 7. Cooke RA, Chambers JB, Singh R, et al. QT interval in anorexia nervosa. Br Heart J 1994;72:69–73.
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Short Communication
The ketogenic diet and the QT interval Suvasini Sharma, Sheffali Gulati ⇑ Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Shri Aurobindo Marg Street, New Delhi 110029, India
a r t i c l e
i n f o
Article history: Received 6 January 2011 Accepted 1 May 2011
Keywords: Cardiac complications Arrhythmias Electrocardiograms Epilepsy
a b s t r a c t Cardiac complications have been rarely reported associated with the ketogenic diet. Prolonged QT interval in the electrocardiogram and torsades de pointes arrhythmias have been described in a few cases. The effect of the ketogenic diet on QT interval has not been systematically evaluated. We obtained serial electrocardiograms in our patients on the ketogenic diet to look for changes in the mean QT interval. Twenty seven children aged 6 months to 5 years with refractory epilepsy were enrolled. Classic ketogenic diet was introduced using a non-fasting gradual initiation protocol. All patients were supplemented with oral calcium and selenium. Electrocardiograms were obtained at baseline and after 1, 3, 6, and 12 months on the ketogenic diet. There was no statistically significant change in the corrected QT interval over time. There were no ST segment changes or dysrhythmias in any of the electrocardiograms. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
were enrolled. Children with known or suspected inborn errors of metabolism, systemic illness, or surgically remediable causes of epilepsy were excluded. The demographic and clinical profile of this cohort has been described in an earlier study.4 The ketogenic diet was introduced using a non-fasting gradual initiation protocol, starting with a full calorie, ketogenic ratio of 1:1. This was built up over a period of 4 days to 3:1 in children younger than 18 months, and 4:1 in children older than 18 months. Diets were based on Indian recipes and prepared with common locally available foods. Electrocardiograms were obtained at baseline and after 1, 3, 6, and 12 months on the diet. The corrected QT interval (QTc) was calculated using the Bazett’s formula:5
The ketogenic diet is a medically supervised high fat, low carbohydrate diet which has been demonstrated to be an effective therapy for refractory epilepsy. The diet is however associated with adverse effects which need to be monitored. Known adverse effects include anorexia, constipation, renal stones and dyslipidemias. Cardiac complications, including prolongation of the QT interval have been reported.1,2 The effect of the ketogenic diet on the QT interval has not been systematically evaluated. In the recently published recommendations of the International Ketogenic Diet Study group on the optimal management of children receiving the ketogenic diet, electrocardiograms have not been recommended either at baseline or follow-up, unless there is a history of pre-existing heart disease.3 As QT interval prolongation can predispose to serious cardiac arrhythmias such as torsades de pointes, there is a need for more data on QT interval in patients on the ketogenic diet. Hence we planned to study serial electrocardiograms in patients started on the ketogenic diet at our center to look for changes in the QT interval.
Normal QTc was defined as 6 0.44 sec. Total serum calcium levels were also obtained at baseline and follow up. All patients were supplemented with oral calcium and selenium. A generalized estimating equation model was fitted to assess the change in the mean QTc and serum calcium levels over time.
2. Methods
3. Results
This prospective study was conducted in a tertiary care hospital between September 2006 and April 2008. Children aged 6 months to 5 years who had daily seizures (or at least seven seizures/week) despite the appropriate use of at least three anti-epileptic drugs
Twenty seven children were enrolled. The ages ranged from 9 months to 5 years (median 2.5 years). None of the patients had a pre-existing cardiac disease or family history of long QT syndrome or sudden unexplained deaths. No patient was on any other medication which could potentially increase the QT interval. Fifteen patients remained on the diet at 6 months, and 10 patients remained on it at 1 year (Table 1). At one year, five children
⇑ Corresponding author. Tel.: +91 011 26593209; fax: +91 011 26588641. E-mail address: [email protected] (S. Gulati). 0967-5868/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2011.05.012
pffiffiffiffiffiffi QTc ¼ QT interval= RR interval
182
S. Sharma, S. Gulati / Journal of Clinical Neuroscience 19 (2012) 181–182
Table 1 The corrected QT interval (QTc) and serum calcium levels on the ketogenic diet.
QTc (seconds), Mean [SD] Serum calcium (mg/dl), Mean [SD]
Baseline (n = 27)
1 month (n = 27)
2 months (n = 26)
3 months (n = 24)
6 months (n = 15)
12 months (n = 10)
p value
0.37 [0.03] 8.96 [.75]
0.37 [0.02] 9.28 [.26]
0.38 [0.02] 9.22 [.44]
0.37 [0.04] 9.03 [.59]
0.37 [0.02] 9.33 [.34]
0.36 [0.02] 9.22 [.30]
0.697 0.632
(18.5%) were seizure free, and overall 10 children (37%) had achieved a greater than 50% reduction in seizures. There was no statistically significant change in the mean QTc or serum calcium level over time. No patient developed a prolonged QT interval during the study period. There were no ST segment changes or dysrhythmias in any of the patients. 4. Discussion We did not find any changes in the mean QTc over time in our cohort. Best et al. studied the QT interval in the electrocardiograms of 21 children on the ketogenic diet.1 In their study, prolonged QT interval was documented in three children. Pre-diet electrocardiograms were available on two of these patients and indicated development of prolonged QTc after diet initiation. Two of the patients with prolonged QTc also had left atrial and left ventricular enlargement. The diet was discontinued in one patient with normalization of QTc and resolution of dilated cardiomyopathy. Normal calcium and selenium levels were documented in these patients. The mechanism of QT prolongation with the ketogenic diet is not well understood. The ketogenic diet functions by mimicking a starvation state, although still maintaining adequate protein and high fat intake. Severe malnutrition can cause bradycardia, diminished QRS voltage, and prolonged QT interval.6 Other starvation states such as anorexia nervosa have been associated with QT prolongation and sudden death.7 A significant limitation of the study is the small number of patients who stayed on the diet for 1 year. Hence the study is underpowered to detect a possible rare complication. However, this is the first study in which serial electrocardiograms have been prospectively and systematically evaluated in children on the ketogenic diet. More data from larger patient cohorts is needed to
formulate recommendations regarding electrocardiographic monitoring in patients on the ketogenic diet. 5. Details of contributions The study was conceptualized by SS and SG. SS collected the data and wrote the first draft of the manuscript, which was revised critically and approved by SG. 6. Ethical approval Ethical approval was obtained from the All India Institute of Medical Sciences Ethics Committee, Reference Number B-08/ 4.12.2006 (dated 22nd December 2006). References 1. Best TH, Franz DN, Gilbert DL, et al. Cardiac complications in pediatric patients on the ketogenic diet. Neurology 2000;54:2328–30. 2. Bergqvist AG, Chee CM, Lutchka L, et al. Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet. Epilepsia 2003;44:618–20. 3. Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group. Epilepsia 2009;50:304–17. 4. Sharma S, Gulati S, Kalra V, et al. Seizure control and biochemical profile on the ketogenic diet in young children with refractory epilepsy: Indian experience. Seizure 2009;18:446–9. 5. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353–70. 6. Ellis LB. Electrocardiographic abnormalities in severe malnutrition. Br Heart J 1946;8:53–61. 7. Cooke RA, Chambers JB, Singh R, et al. QT interval in anorexia nervosa. Br Heart J 1994;72:69–73.