Pediatric Neurology 50 (2014) 343e346
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Dispersion Durations of P-Wave and QT Interval in Children Treated With a Ketogenic Diet _ ¸ güder MD c, Önder Doksöz MD a, *, Orkide Güzel MD b, Ünsal Yılmaz MD b, Rana Is d a en MD , Timur Mes¸e MD Kübra Çeleg a
Department of Pediatric Cardiology, Izmir Dr. Behcet Uz Children’s Hospital, Izmir, Turkey Department of Pediatric Neurology, Izmir Dr. Behcet Uz Children’s Hospital, Izmir, Turkey c Pediatric Intensive Care Unit, Izmir Dr. Behcet Uz Children’s Hospital, Izmir, Turkey d Department of Pediatrics, Izmir Dr. Behcet Uz Children’s Hospital, Izmir, Turkey b
abstract BACKGROUND: Limited data are available on the effects of a ketogenic diet on dispersion duration of P-wave and QT-interval measures in children. We searched for the changes in these measures with serial electrocardiograms in patients treated with a ketogenic diet. METHODS: Twenty-five drug-resistant patients with epilepsy treated with a ketogenic diet were enrolled in this study. Electrocardiography was performed in all patients before the beginning and at the sixth month after implementation of the ketogenic diet. Heart rate, maximum and minimum P-wave duration, P-wave dispersion, and maximum and minimum corrected QT interval and QT dispersion were manually measured from the 12-lead surface electrocardiogram. RESULTS: Minimum and maximum corrected QT and QT dispersion measurements showed nonsignificant increase at month 6 compared with baseline values. Other previously mentioned electrocardiogram parameters also showed no significant changes. CONCLUSIONS: A ketogenic diet of 6 months’ duration has no significant effect on electrocardiogram parameters in children. Further studies with larger samples and longer duration of follow-up are needed to clarify the effects of ketogenic diet on P-wave dispersion and corrected QT and QT dispersion. Keywords: ketogenic diet, corrected QT, QT dispersion, P-wave dispersion
Pediatr Neurol 2014; 50: 343-346 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Despite recent advances in the development of new antiepileptic drugs, approximately 20%-30% of all children with epilepsy remain resistant to medical therapy.1 The main reasons for treatment failures are lack of efficacy and intolerability caused by adverse effects.2 The ketogenic diet, a high-fat, adequate-protein and low-carbohydrate diet, offers hope to children with intractable epilepsy. It is not a benign therapy, however, associated with a number of side effects, including disturbances of metabolic, gastrointestinal, and renal functions. Adverse effects include anorexia, Article History: Received October 31, 2013; Accepted in final form December 3, 2013 * Communications should be addressed to: Önder Doksöz; Department of Pediatric Cardiology; Izmir Dr. Behcet Uz Children’s Hospital; 1374 St. No: 11 Alsancak/Izmir, Turkey. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.12.005
constipation, renal stones, and dyslipidemias.3-6 Cardiac complications, including prolongation of the QT interval and sudden cardiac death, also have been reported in patients treated with ketogenic diet.7,8 Previous studies reported a prolonged corrected QT interval in children with other disorders associated with ketosis in the absence of electrolyte imbalance such as type 1 diabetes mellitus, severe malnutrition, and anorexia nervosa.9-11 The association between ketotic conditions and prolonged corrected QT and/or sudden cardiac death raises the question of whether ketosis directly affects cardiac repolarization resulting in arrhythmia and/or sudden cardiac death in patients with diabetic ketoacidosis and in patients receiving ketogenic diet.9,12,13 QT dispersion is defined as the interlead variability in the duration of the QT interval in the 12-lead electrocardiogram (ECG).14 It is a widely used parameter that can be used to assess the homogeneity of cardiac repolarization and autonomic function. In addition,
344
Ö. Doksöz et al. / Pediatric Neurology 50 (2014) 343e346
on a 12-lead ECG, maximum P-wave and P-wave dispersion durations are used to determine whether the sinus impulse is distributed homogeneously. These two measures are also used to determine the intra- and interatrial conduction times. Several studies have shown that the P-wave duration was an important indicator of a variety of clinical conditions, such as paroxysmal atrial fibrillation.15,16 Prolonged QT dispersion and P-wave dispersion can predispose patients to serious cardiac arrhythmias such as torsades de pointes and atrial fibrillation, respectively. Limited data are available for the effects of ketogenic diet on QT dispersion and P-wave dispersion measures. Therefore, we aimed to search for the changes in the corrected QT interval, QT dispersion and P-wave dispersion with serial ECGs in patients treated with a ketogenic diet. Materials and Methods The local ethics committee approved the study protocol. A total of 25 drug-resistant patients with epilepsy who were treated with a ketogenic diet at the pediatric neurology clinic from September 2012 to September 2013 were enrolled in this prospective study. ECG was performed in all patients before the beginning of the ketogenic diet and after the sixth month of treatment. Patients older than 1 year of age with intractable epilepsy who received a ketogenic diet for at least sixth months were included in the study. Patients with electrolyte imbalance, carnitine or selenium deficiency, cardiomyopathy, congenital heart disease, a history of familial sudden cardiac death, hereditary malignant arrhythmia and long QT syndrome, systemic or metabolic diseases affecting cardiac functions, and patients receiving medications that may have effects on ECG readings were excluded from the study. Ketogenic diet
All children were started on a standardized 3:1 ketogenic diet with a nonfasting gradual initiation protocol. During the diet’s initiation, patients were closely monitored for any acute adverse effects for the first week, and blood glucose and ketones were measured twice daily. The recipes were planned in-house and calculated considering the families and the child’s preferences and cultural differences. Patients who had medically refractory epilepsy, who had more than 4 seizures per week despite the appropriate use of at least two antiepileptic drugs, and who continued treatment for at least 6 months were identified. Patients with severe systemic illnesses, those who were currently on corticosteroids or adrenocorticotropic hormone treatment, and those with evidence of persistent noncompliance with the ketogenic diet were excluded from the study. Compliance was assessed by direct questioning and by the measurement of serum ketone concentrations. ECG, P-wave dispersion, and QT dispersion analysis
Heart rate, maximum and minimum P-wave durations, P-wave dispersion, and maximum and minimum corrected QT durations and QT dispersion were manually measured from the 12-lead surface ECGs. Standard 12-lead ECG (Cardiofax GEM, Model 9022 K; Nihon Kohden Tokyo, Japan) was obtained simultaneously using a recorder set at 25 mm/s paper speed and calibration of 10 mV/mm in a comfortable supine position. All of the ECG recordings digitally evaluated after loading in JPG format on preview program (MacBook Pro, Version 6.0.1; Apple Inc., Cupertino, CA). After zooming, JPG-formatted ECG recordings pixels are converted according to milliseconds or millivolts on original ECG paper. Every little square corresponds 40 ms (i.e., 1 little square ¼ 1 mm ¼ 40 ms ¼ 17 pixels; Fig). All ECGs were evaluated and analyzed by a senior pediatric cardiologist and by a third-year pediatric cardiology resident. The measurements of the two investigators showed no discrepancies. Interobserver variance for measurements of maximum and minimum P-wave durations, minimum and maximum corrected QT durations and QT dispersion were 0.06%, 0.04%, 0.12%, 0.15%, and 0.07%, respectively.
FIGURE. Electrocardiographic measurements and conversion of pixels to millimeter are shown. A little square ¼ 1 mm ¼ 40 ms ¼ 17 pixel. A big square ¼ 5 mm. (The color version of this figure is available in the online edition.) The onset of the P-wave was defined as the junction between the isoelectric line and the beginning of the P-wave deflection, and the offset of the P-wave was defined as the junction between the end of the P-wave deflection and the isoelectric line. QT interval also was measured from the beginning of the QRS complex to the end of the T wave, which was defined as return to baseline in each ECG lead. When U waves were present, the QT interval was measured to the nadir of the curve between the T and U waves.17 The corrected QT duration was calculated using Bazett’s formula (corrected QT ¼ QT/ORR, maximum and minimum corrected QT intervals).18 Dispersion of the P-wave was calculated as the difference between the maximum and minimum P-wave durations (P-wave dispersion ¼ maximum P-wave duration - minimum P-wave duration).15,16 Dispersion of QT interval was calculated as the difference between the longest and shortest QT interval measured in each individual ECG lead (QT dispersion ¼ maximum QT duration - minimum QT duration).17 An appropriate ECG was determined by its ability to measure P-wave duration in at least 8 of the 12 ECG leads recorded simultaneously. Statistical analyses
Statistical analyses were performed using the SPSS package program version 15. The variables were investigated using graphical and analytical methods to determine whether they are normally distributed. Comparisons between related measurements were performed with Wilcoxon signed-rank test. Data are presented as mean SD. An overall P-value of less than 0.05 was considered to show a statistical significance.
Results
A total of 25 patients (14 male and 11 female) with median age of 51 months ranging from 13 to 158 months were included in the study. ECG measurements before the beginning of the ketogenic diet and after sixth month of treatment are presented in Table. Minimum and maximum corrected QT and QT dispersion measurements showed nonsignificant increases at sixth month compared with baseline values. Other previously mentioned ECG parameters showed no significant changes (Table). Discussion
The present study demonstrated that a ketogenic diet of 6 months’ duration has no significant effect on ECG parameters in children. Similarly, Sharma and Gulati19 did not find any changes in the mean corrected QT interval after 1 year in patients treated with ketogenic diet. However, Best et al.7 studied the QT interval in the ECGs of 21 children receiving a ketogenic diet and found a prolonged QT interval in 3 patients. They reported a significant correlation
Ö. Doksöz et al. / Pediatric Neurology 50 (2014) 343e346
patients treated with ketogenic diet, until our findings verified with further studies.
TABLE. Electrocardiographic measurements of the patients
Variables
Baseline
Mean heart rate, beats/min P max, ms P min, ms P-wave dispersion, ms QTc max, ms QTc min, ms QT dispersion, ms
112 96 47 48 438 381 43
25 14 11 9 26 20 16
345
Sixth Month 115 95 46 51 455 389 47
28 20 9 12 41 28 18
P Value 0.521 0.768 0.716 0.242 0.053 0.209 0.382
Abbreviation: QTc ¼ Corrected QT
between prolonged corrected QT interval and both low serum bicarbonate and high beta-hydroxybutyrate levels. In addition, three patients had evidence of cardiac chamber enlargement. In the present study, nonsignificantly increased corrected QT interval and QT dispersion measurements were detected in patients in the absence of biochemical abnormality, cardiomyopathy, or selenium deficiency. Previous studies demonstrated an association between the ketogenic diet and corrected QT interval. However, the effect of the ketogenic diet on P-wave dispersion and QT dispersion in children has not been studied before. The QT interval is an indirect measure of the duration of ventricular depolarization and repolarization.20 Prolonged corrected QT interval is associated with serious ventricular arrhythmias and is an independent risk factor for sudden cardiac death.21 On the other hand, QT dispersion has been suggested as a measure for the heterogeneity of ventricular recovery time, which is a powerful determinant of the susceptibility to ventricular tachycardia and/or fibrillation in clinical studies.22 Both prolonged corrected QT interval and corrected QT dispersion have been shown as risk factors for sudden cardiac death.22 Increased corrected QT dispersion and corrected QT maximum in epileptic children compared with healthy subjects have been reported previously.23 Moreover, significantly shorter corrected QT interval has been reported in epileptic patients when compared to controls.24 Because calculation of corrected QT dispersion is influenced by sinus arrhythmia, which is common in children, correction of QT dispersion for heart rate is not recommended in children.25 Therefore, we used only QT dispersion instead of corrected QT dispersion. We used Bazett’s formula for correction of QT interval, although several different formulas have been developed since it was first introduced.26-28 Indeed, Bazett’s formula is the most widely used formula and no formula has been shown to have a clear advantage over Bazett’s formula. The use of other four-correction formulas has been recommended when corrected QT interval is in pathologic range.29 Because corrected QT interval was in normal range in all patients in the present study, we did not use other formulas. The small sample size of patients treated with a ketogenic diet likely obscured our ability to show corrected QT and QT dispersion prolongation in this study. However, sudden cardiac deaths in the ketotic metabolic situations and ketotic diet programs have been reported even in the patients with normal serum selenium levels. Therefore, we cannot suggest that ECG is unnecessary in follow-up of
Study limitations
Small sample size and short follow-up period (6 months) are the major limitations of this study. Corrected QT interval and QT dispersion measurements may prolong with increasing age. Because of the short period (6 months), and absence of significant change between the two measurements, we did not take into account the effect of increasing on these measures. Although several studies have reported that epilepsy was associated with a prolonged corrected QT interval,23,30 another study has shown an association with a shortened corrected QT interval.24 Moreover, antiepileptic drug polytherapy was found associated with a significantly lower corrected QT interval compared with monotherapy.31 Thus, there is no established consensus for the effects of antiepileptic drugs on corrected QT interval. In our series, the median antiepileptic drug numbers was three before the initiation of ketogenic diet, and it was reduced to one at the sixth month of therapy. Similarly, seizures themselves may have an effect on ECG indices. Whereas all patients had more than four seizures a week before the initiation of the ketogenic diet, seizures resolved totally in more than half of patients, and reduced more than 50% in the remainder. Because of these possible confounding effects of antiepileptic drugs and seizures, we cannot suggest that our findings reflect the pure effect of ketogenic diet on ECG indices. Conclusion
A ketogenic diet of 6 months’ duration has no effect on P-wave dispersion and QT dispersion in children with intractable epilepsy. Further studies with larger samples are needed to clarify the effects of ketogenic diet on P-wave dispersion and corrected QT and QT dispersion. References 1. Sillanpaa M, Schmidt D. Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain. 2006;129:617-624. 2. Dudley RW, Penney SJ, Buckley DJ. First-drug treatment failures in children newly diagnosed with epilepsy. Pediatr Neurol. 2009;40: 71-77. 3. Vining EP. Clinical efficacy of the ketogenic diet. Epilepsy Res. 1999; 37:181-190. 4. Furth SL, Casey JC, Pyzik PL, et al. Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol. 2000;15:125-128. 5. Kwiterovich PO, Vining EP, Pyzik P, et al. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA. 2003;290:912-920. 6. Freeman JM, Kossoff EH, Hartman AL. The ketogenic diet: one decade later. Pediatrics. 2007;119:535-543. 7. Best TH, Franz DN, Gilbert DL, et al. Cardiac complications in pediatric patients on the ketogenic diet. Neurology. 2000;54:2328-2330. 8. Bergqvist AG, Chee CM, Lutchka L, et al. Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet. Epilepsia. 2003;44:618-620. 9. Youssef OI, Farid SM. QTc and QTd in children with type 1 diabetes mellitus during diabetic ketoacidosis. ISRN Pediatr. 2012;2012: 619107. 10. Ellis LB. Electrocardiographic abnormalities in severe malnutrition. Br Heart J. 1946;8:53-61. 11. Cooke RA, Chambers JB, Singh R, et al. QT interval in anorexia nervosa. Br Heart J. 1994;72:69-73.
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12. Bank IM, Shemie SD, Rosenblatt B, et al. Sudden cardiac death in association with the ketogenic diet. Pediatr Neurol. 2008;39:429-431. 13. Sirikonda NS, Patten WD, Phillips JR, Mullett CJ. Ketogenic diet: rapid onset of selenium deficiency-induced cardiac decompensation. Pediatr Cardiol. 2012;33:834-838. 14. Kautzner J, Malik M. QT interval dispersion and its clinical utility. Pacing Clin Electrophysiol. 1997;20:2625-2640. 15. Aytemir K, Ozer N, Atalar E, et al. P-wave dispersion on 12-lead electrocardiography in patients with paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 2000;23:1109-1112. 16. Dilaveris PE, Gialafos EJ, Sideris SK, et al. Simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation. Am Heart J. 1998;135:733-738. 17. Postema PG, De Jong JS, Van der Bilt IA, Wilde AA. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart Rhythm. 2008;5:1015-1018. 18. Bazett HC. An analysis of time relations of electrocardiograms. Heart. 1920;7:353-367. 19. Sharma S, Gulati S. The ketogenic diet and the QT interval. J Clin Neurosci. 2012;19:181-182. 20. Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN. The QT interval. Prog Cardiovas Dis. 2001;43(5 Suppl 1):1-45. 21. Karjalainen J, Reunanen A, Ristola P, Viitasalo M. QT interval as a cardiac risk factor in a middle aged population. Heart. 1997;77:543-548. 22. Elming H, Holm E, Jun L, et al. The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac
23.
24. 25.
26.
27. 28.
29.
30. 31.
mortality and morbidity in a population of Danish citizens. Eur Heart J. 1998;19:1391-1400. Dogan EA, Dogan U, Yildiz GU, et al. Evaluation of cardiac repolarization indices in well-controlled partial epilepsy: 12-Lead ECG findings. Epilepsy Res. 2010;90:157-163. Teh HS, Tan HJ, Loo CY, Raymond AA. Short QTc in epilepsy patients without cardiac symptoms. Med J Malaysia. 2007;6:104-108. Tutar HE, Ocal B, Imamoglu A, Atalay S. Dispersion of QT and QTc interval in healthy children, and effects of sinus arrhythmia on QT dispersion. Heart. 1998;80:77-79. Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken [The duration of systole in an electrocardiogram in normal humans and in patients with heart disease]. Acta Med Scand. 1920;53:469-486. Funck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limitations. Am J Cardiol. 1993;72:17-22. Sagie A, Larson MG, Goldberg RJ, Bengtson JR, Levy D. An improved method for adjusting the QT interval for heart rate (the Framingham Heart Study). Am J Cardiol. 1992;70:797-801. Luo S, Michler K, Johnston P, Macfarlane PW. A comparison of commonly used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. J Electrocardiol. 2004;37:81-90. Neufeld G, Lazar JM, Chari G, et al. Cardiac repo-larization indices in epilepsy patients. Cardiology. 2009;114:255-260. Krishnan V, Krishnamurthy KB. Interictal 12-lead electrocardiography in patients with epilepsy. Epilepsy Behav. 2013;29:240-246.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Dispersion Durations of P-Wave and QT Interval in Children Treated With a Ketogenic Diet _ ¸ güder MD c, Önder Doksöz MD a, *, Orkide Güzel MD b, Ünsal Yılmaz MD b, Rana Is d a en MD , Timur Mes¸e MD Kübra Çeleg a
Department of Pediatric Cardiology, Izmir Dr. Behcet Uz Children’s Hospital, Izmir, Turkey Department of Pediatric Neurology, Izmir Dr. Behcet Uz Children’s Hospital, Izmir, Turkey c Pediatric Intensive Care Unit, Izmir Dr. Behcet Uz Children’s Hospital, Izmir, Turkey d Department of Pediatrics, Izmir Dr. Behcet Uz Children’s Hospital, Izmir, Turkey b
abstract BACKGROUND: Limited data are available on the effects of a ketogenic diet on dispersion duration of P-wave and QT-interval measures in children. We searched for the changes in these measures with serial electrocardiograms in patients treated with a ketogenic diet. METHODS: Twenty-five drug-resistant patients with epilepsy treated with a ketogenic diet were enrolled in this study. Electrocardiography was performed in all patients before the beginning and at the sixth month after implementation of the ketogenic diet. Heart rate, maximum and minimum P-wave duration, P-wave dispersion, and maximum and minimum corrected QT interval and QT dispersion were manually measured from the 12-lead surface electrocardiogram. RESULTS: Minimum and maximum corrected QT and QT dispersion measurements showed nonsignificant increase at month 6 compared with baseline values. Other previously mentioned electrocardiogram parameters also showed no significant changes. CONCLUSIONS: A ketogenic diet of 6 months’ duration has no significant effect on electrocardiogram parameters in children. Further studies with larger samples and longer duration of follow-up are needed to clarify the effects of ketogenic diet on P-wave dispersion and corrected QT and QT dispersion. Keywords: ketogenic diet, corrected QT, QT dispersion, P-wave dispersion
Pediatr Neurol 2014; 50: 343-346 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Despite recent advances in the development of new antiepileptic drugs, approximately 20%-30% of all children with epilepsy remain resistant to medical therapy.1 The main reasons for treatment failures are lack of efficacy and intolerability caused by adverse effects.2 The ketogenic diet, a high-fat, adequate-protein and low-carbohydrate diet, offers hope to children with intractable epilepsy. It is not a benign therapy, however, associated with a number of side effects, including disturbances of metabolic, gastrointestinal, and renal functions. Adverse effects include anorexia, Article History: Received October 31, 2013; Accepted in final form December 3, 2013 * Communications should be addressed to: Önder Doksöz; Department of Pediatric Cardiology; Izmir Dr. Behcet Uz Children’s Hospital; 1374 St. No: 11 Alsancak/Izmir, Turkey. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2013.12.005
constipation, renal stones, and dyslipidemias.3-6 Cardiac complications, including prolongation of the QT interval and sudden cardiac death, also have been reported in patients treated with ketogenic diet.7,8 Previous studies reported a prolonged corrected QT interval in children with other disorders associated with ketosis in the absence of electrolyte imbalance such as type 1 diabetes mellitus, severe malnutrition, and anorexia nervosa.9-11 The association between ketotic conditions and prolonged corrected QT and/or sudden cardiac death raises the question of whether ketosis directly affects cardiac repolarization resulting in arrhythmia and/or sudden cardiac death in patients with diabetic ketoacidosis and in patients receiving ketogenic diet.9,12,13 QT dispersion is defined as the interlead variability in the duration of the QT interval in the 12-lead electrocardiogram (ECG).14 It is a widely used parameter that can be used to assess the homogeneity of cardiac repolarization and autonomic function. In addition,
344
Ö. Doksöz et al. / Pediatric Neurology 50 (2014) 343e346
on a 12-lead ECG, maximum P-wave and P-wave dispersion durations are used to determine whether the sinus impulse is distributed homogeneously. These two measures are also used to determine the intra- and interatrial conduction times. Several studies have shown that the P-wave duration was an important indicator of a variety of clinical conditions, such as paroxysmal atrial fibrillation.15,16 Prolonged QT dispersion and P-wave dispersion can predispose patients to serious cardiac arrhythmias such as torsades de pointes and atrial fibrillation, respectively. Limited data are available for the effects of ketogenic diet on QT dispersion and P-wave dispersion measures. Therefore, we aimed to search for the changes in the corrected QT interval, QT dispersion and P-wave dispersion with serial ECGs in patients treated with a ketogenic diet. Materials and Methods The local ethics committee approved the study protocol. A total of 25 drug-resistant patients with epilepsy who were treated with a ketogenic diet at the pediatric neurology clinic from September 2012 to September 2013 were enrolled in this prospective study. ECG was performed in all patients before the beginning of the ketogenic diet and after the sixth month of treatment. Patients older than 1 year of age with intractable epilepsy who received a ketogenic diet for at least sixth months were included in the study. Patients with electrolyte imbalance, carnitine or selenium deficiency, cardiomyopathy, congenital heart disease, a history of familial sudden cardiac death, hereditary malignant arrhythmia and long QT syndrome, systemic or metabolic diseases affecting cardiac functions, and patients receiving medications that may have effects on ECG readings were excluded from the study. Ketogenic diet
All children were started on a standardized 3:1 ketogenic diet with a nonfasting gradual initiation protocol. During the diet’s initiation, patients were closely monitored for any acute adverse effects for the first week, and blood glucose and ketones were measured twice daily. The recipes were planned in-house and calculated considering the families and the child’s preferences and cultural differences. Patients who had medically refractory epilepsy, who had more than 4 seizures per week despite the appropriate use of at least two antiepileptic drugs, and who continued treatment for at least 6 months were identified. Patients with severe systemic illnesses, those who were currently on corticosteroids or adrenocorticotropic hormone treatment, and those with evidence of persistent noncompliance with the ketogenic diet were excluded from the study. Compliance was assessed by direct questioning and by the measurement of serum ketone concentrations. ECG, P-wave dispersion, and QT dispersion analysis
Heart rate, maximum and minimum P-wave durations, P-wave dispersion, and maximum and minimum corrected QT durations and QT dispersion were manually measured from the 12-lead surface ECGs. Standard 12-lead ECG (Cardiofax GEM, Model 9022 K; Nihon Kohden Tokyo, Japan) was obtained simultaneously using a recorder set at 25 mm/s paper speed and calibration of 10 mV/mm in a comfortable supine position. All of the ECG recordings digitally evaluated after loading in JPG format on preview program (MacBook Pro, Version 6.0.1; Apple Inc., Cupertino, CA). After zooming, JPG-formatted ECG recordings pixels are converted according to milliseconds or millivolts on original ECG paper. Every little square corresponds 40 ms (i.e., 1 little square ¼ 1 mm ¼ 40 ms ¼ 17 pixels; Fig). All ECGs were evaluated and analyzed by a senior pediatric cardiologist and by a third-year pediatric cardiology resident. The measurements of the two investigators showed no discrepancies. Interobserver variance for measurements of maximum and minimum P-wave durations, minimum and maximum corrected QT durations and QT dispersion were 0.06%, 0.04%, 0.12%, 0.15%, and 0.07%, respectively.
FIGURE. Electrocardiographic measurements and conversion of pixels to millimeter are shown. A little square ¼ 1 mm ¼ 40 ms ¼ 17 pixel. A big square ¼ 5 mm. (The color version of this figure is available in the online edition.) The onset of the P-wave was defined as the junction between the isoelectric line and the beginning of the P-wave deflection, and the offset of the P-wave was defined as the junction between the end of the P-wave deflection and the isoelectric line. QT interval also was measured from the beginning of the QRS complex to the end of the T wave, which was defined as return to baseline in each ECG lead. When U waves were present, the QT interval was measured to the nadir of the curve between the T and U waves.17 The corrected QT duration was calculated using Bazett’s formula (corrected QT ¼ QT/ORR, maximum and minimum corrected QT intervals).18 Dispersion of the P-wave was calculated as the difference between the maximum and minimum P-wave durations (P-wave dispersion ¼ maximum P-wave duration - minimum P-wave duration).15,16 Dispersion of QT interval was calculated as the difference between the longest and shortest QT interval measured in each individual ECG lead (QT dispersion ¼ maximum QT duration - minimum QT duration).17 An appropriate ECG was determined by its ability to measure P-wave duration in at least 8 of the 12 ECG leads recorded simultaneously. Statistical analyses
Statistical analyses were performed using the SPSS package program version 15. The variables were investigated using graphical and analytical methods to determine whether they are normally distributed. Comparisons between related measurements were performed with Wilcoxon signed-rank test. Data are presented as mean SD. An overall P-value of less than 0.05 was considered to show a statistical significance.
Results
A total of 25 patients (14 male and 11 female) with median age of 51 months ranging from 13 to 158 months were included in the study. ECG measurements before the beginning of the ketogenic diet and after sixth month of treatment are presented in Table. Minimum and maximum corrected QT and QT dispersion measurements showed nonsignificant increases at sixth month compared with baseline values. Other previously mentioned ECG parameters showed no significant changes (Table). Discussion
The present study demonstrated that a ketogenic diet of 6 months’ duration has no significant effect on ECG parameters in children. Similarly, Sharma and Gulati19 did not find any changes in the mean corrected QT interval after 1 year in patients treated with ketogenic diet. However, Best et al.7 studied the QT interval in the ECGs of 21 children receiving a ketogenic diet and found a prolonged QT interval in 3 patients. They reported a significant correlation
Ö. Doksöz et al. / Pediatric Neurology 50 (2014) 343e346
patients treated with ketogenic diet, until our findings verified with further studies.
TABLE. Electrocardiographic measurements of the patients
Variables
Baseline
Mean heart rate, beats/min P max, ms P min, ms P-wave dispersion, ms QTc max, ms QTc min, ms QT dispersion, ms
112 96 47 48 438 381 43
25 14 11 9 26 20 16
345
Sixth Month 115 95 46 51 455 389 47
28 20 9 12 41 28 18
P Value 0.521 0.768 0.716 0.242 0.053 0.209 0.382
Abbreviation: QTc ¼ Corrected QT
between prolonged corrected QT interval and both low serum bicarbonate and high beta-hydroxybutyrate levels. In addition, three patients had evidence of cardiac chamber enlargement. In the present study, nonsignificantly increased corrected QT interval and QT dispersion measurements were detected in patients in the absence of biochemical abnormality, cardiomyopathy, or selenium deficiency. Previous studies demonstrated an association between the ketogenic diet and corrected QT interval. However, the effect of the ketogenic diet on P-wave dispersion and QT dispersion in children has not been studied before. The QT interval is an indirect measure of the duration of ventricular depolarization and repolarization.20 Prolonged corrected QT interval is associated with serious ventricular arrhythmias and is an independent risk factor for sudden cardiac death.21 On the other hand, QT dispersion has been suggested as a measure for the heterogeneity of ventricular recovery time, which is a powerful determinant of the susceptibility to ventricular tachycardia and/or fibrillation in clinical studies.22 Both prolonged corrected QT interval and corrected QT dispersion have been shown as risk factors for sudden cardiac death.22 Increased corrected QT dispersion and corrected QT maximum in epileptic children compared with healthy subjects have been reported previously.23 Moreover, significantly shorter corrected QT interval has been reported in epileptic patients when compared to controls.24 Because calculation of corrected QT dispersion is influenced by sinus arrhythmia, which is common in children, correction of QT dispersion for heart rate is not recommended in children.25 Therefore, we used only QT dispersion instead of corrected QT dispersion. We used Bazett’s formula for correction of QT interval, although several different formulas have been developed since it was first introduced.26-28 Indeed, Bazett’s formula is the most widely used formula and no formula has been shown to have a clear advantage over Bazett’s formula. The use of other four-correction formulas has been recommended when corrected QT interval is in pathologic range.29 Because corrected QT interval was in normal range in all patients in the present study, we did not use other formulas. The small sample size of patients treated with a ketogenic diet likely obscured our ability to show corrected QT and QT dispersion prolongation in this study. However, sudden cardiac deaths in the ketotic metabolic situations and ketotic diet programs have been reported even in the patients with normal serum selenium levels. Therefore, we cannot suggest that ECG is unnecessary in follow-up of
Study limitations
Small sample size and short follow-up period (6 months) are the major limitations of this study. Corrected QT interval and QT dispersion measurements may prolong with increasing age. Because of the short period (6 months), and absence of significant change between the two measurements, we did not take into account the effect of increasing on these measures. Although several studies have reported that epilepsy was associated with a prolonged corrected QT interval,23,30 another study has shown an association with a shortened corrected QT interval.24 Moreover, antiepileptic drug polytherapy was found associated with a significantly lower corrected QT interval compared with monotherapy.31 Thus, there is no established consensus for the effects of antiepileptic drugs on corrected QT interval. In our series, the median antiepileptic drug numbers was three before the initiation of ketogenic diet, and it was reduced to one at the sixth month of therapy. Similarly, seizures themselves may have an effect on ECG indices. Whereas all patients had more than four seizures a week before the initiation of the ketogenic diet, seizures resolved totally in more than half of patients, and reduced more than 50% in the remainder. Because of these possible confounding effects of antiepileptic drugs and seizures, we cannot suggest that our findings reflect the pure effect of ketogenic diet on ECG indices. Conclusion
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