Pediatric Neurology 50 (2014) 101e103
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
The Ketogenic Diet for the Treatment of Pediatric Status Epilepticus Sunila E. O’Connor MD a, *, Candy Richardson RD, LDN, CNSC b, Willam H. Trescher MD c, Debra L. Byler MD c, Joan D. Sather MPH, RD, LDN c, Elizabeth H. Michael RN, MS, CRNP c, Kelly B. Urbanik RD, CSP, LDN d, Jennifer L. Richards MSN, ARNP d, Ronald Davis MD d, Mary L. Zupanc MD e, Beth Zupec-Kania RND f a
Department of Pediatrics, Section of Epilepsy, Lurie Children’s Hospital, Chicago, Illinois The Children’s Health Center, Duke University Hospital, Durham, North Carolina c Pennsylvania State Hershey Children’s Hospital, Hershey, Pennsylvania d Arnold Palmer Hospital for Children, Orlando, Florida e Children’s Hospital of Orange County, Orange, California f Ketogenic Therapies LLC, Elm Grove, Wisconsin b
abstract BACKGROUND: Refractory status epilepticus carries a high risk of morbidity and mortality for children. Traditional treatment of status epilepticus consists of multiple anticonvulsant drugs and, if needed, induction of a medical coma. The ketogenic diet has been used for intractable epilepsy for many years. The purpose of this article is to report a case series of five patients with refractory status epilepticus successfully managed with the ketogenic diet. METHODS: A summary of pediatric patients with refractory status epilepticus treated with diet was performed. CONCLUSIONS: Ketogenic diet therapy should be considered as a treatment option in pediatric patients with refractory status epilepticus. Keywords: ketogenic diet, status epilepticus, pediatric, epilepsy, treatment, refractory
Pediatr Neurol 2014; 50: 101-103 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Although the anticonvulsant effects of the ketogenic diet are not fully understood, it has been used since the 1920s as treatment for various types of epilepsies.1 Typically, the high-fat, low-carbohydrate diet is used in children with medication-resistant epilepsy. More recently, the diet has been shown to be particularly effective in patients with infantile spasms, severe myoclonic epilepsy, and tuberous sclerosis complex.2-4 Status epilepticus is defined as “an acute epileptic condition characterized by continuous seizures for at least 30 minutes, or by 30 minutes of intermittent seizures without full recovery of consciousness between the Article History: Received June 28, 2013; Accepted in final form July 30, 2013 * Communications should be addressed to: Dr. O’Connor; Associate Professor; Department of Pediatrics; Section of Epilepsy; Lurie Children’s Hospital; 225 E. Chicago Avenue; Box 29; Chicago, IL. 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.2013.07.020
seizures.”5 The treatment of status epilepticus usually consists of multiple, successive antiepileptic drugs (AED). Patients refractory to initial management may require temporary coma induction with barbiturates or anesthetics to obtain seizure control. A newer application that has shown promise in critical care is using the ketogenic diet for treating status epilepticus.6-9 The purpose of this article is to report a case series of five patients with refractory status epilepticus successfully managed with the ketogenic diet. Case 1
A previously healthy 9-year-old boy was admitted to the hospital with a 3-day history of clinical seizures. Electroencephalography (EEG) confirmed continuous electrographic seizures arising from both temporal lobes with generalization. Complete evaluation with serum chemistries, brain imaging and lumbar puncture did not reveal an etiology for status epilepticus. Despite pharmacologic intervention with eight AEDs, a pentobarbital drip, and
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intravenous immunoglobulin, the EEG continued to exhibit focal status epilepticus. The ketogenic diet was initiated via continuous nasoduodenal feeds. Five days after achieving the goal diet, the patient became ketotic and electrographic seizures abated. During this period, his glucose ranged from 42 to 60 mg/dL with a beta hydroxybutyrate level of 3.4 to 4.3 mmol/L. The patient has been continued on a 4:1 ketogenic diet plus multiple anticonvulsants since discharge. He continues to improve with regard to motor and cognitive function with follow-up of 12 months.
or pentobarbital coma induction. Initiation of a 4:1 ketogenic diet via nasogastric tube commenced on hospital day seven. The EEG improved within 36 hours, coinciding with a beta hydroxybutyrate level of 3.8 mmol/L. Serum glucose ranged from 65 to 74 mg/dL. Clinically, the patient became responsive within 48 hours of diet initiation. She has been maintained on the ketogenic diet and one antiepileptic drug without recurrence of status epilepticus for 18 months. Case 5
Case 2
An otherwise healthy 10-month-old boy presented with status epilepticus, specifically epilepsia partialis continua, resistant to seven AEDs, midazolam drip, and a pentobarbital coma. Approximately 15 days after the onset of status epilepticus and after pentobarbital discontinuation, a 4:1 ketogenic diet was initiated via a nasogastric tube. Five days later, with a urine ketone level of 15 mg/dL, serum glucose readings of 62-87 mg/dL, and beta hydroxybutyrate levels of 2.9-5.1 mmol/L, no further clinical seizures were noted. An EEG performed 10 days after diet initiation demonstrated a marked improvement compared with the previous studies. He underwent percutaneous gastrostomy tube placement and 4:1 ketogenic enteral feeds were given. After discharge, he was diagnosed with a mutation in polymerase gamma 1 gene and Alpers-Huttenlocher syndrome.10 The patient died soon after of disease-associated liver failure. Case 3
A previously healthy 5-year-old boy presented to another institution with a 6-day history of fever, coryza, and seizures. Continuous EEG monitoring demonstrated multiple independent areas of epileptiform activity. Seizure frequency worsened despite aggressive treatment with seven AEDs and induction of a barbiturate coma. Results of an extensive search for infectious, inflammatory, metabolic, and autoimmune etiologies were negative. The 4:1 ketogenic diet was implemented on hospital day 22. Eight days later, clinical and electrographic seizures were remarkably improved, coinciding with the appearance of urinary ketones. Concomitant mean beta hydroxybutyrate level was 4.1 mmol/L. Serum glucose ranged from 62 to 84 mg/dL. The patient was discharged home on the ketogenic diet, multiple AEDs, and monthly intravenous immunoglobulin. At the 15-month follow-up, the patient has infrequent seizures and remains on the diet and three AEDs. He has regained ambulation but cognitive and language impairment persist. Case 4
A 10-year-old girl with a history of symptomatic generalized epilepsy (characterized by atypical absence and generalized tonic-clonic seizures) presented with a 3 day history of mental status changes. Evaluation was negative for infectious diseases. Long-term video EEG monitoring confirmed nonconvulsive status epilepticus with nearly continuous generalized spike and slow wave discharges. She failed to respond to four intravenous AEDs
A 9-year-old girl with progressive myoclonic epilepsy due to a mitochondrial defect presented with lethargy and an increase in seizure frequency. She was found to be infected with influenza A. She developed multiorgan system failure and showed clinical and electrographic signs of status epilepticus. Five intravenous antiepileptic agents did not significantly alter the continuous EEG findings. Propofol was not given secondary to her mitochondrial disease. Pentobarbital was not administered because of multiorgan system failure associated with the patient’s severe influenza A infection. The 4:1 ketogenic diet was started via nasogastric tube on hospital day four. Electrographic and clinical seizures abated 48 hours later, corresponding to a beta hydroxybutyrate level of 3.2 mmol/L. Serum glucose titers ranged from 61 to 68 mg/dL. Followup 12 months later revealed the patient was clinically at baseline, successfully maintained on the ketogenic diet and one AED. No further episodes of status epilepticus occurred. Discussion
Standard treatments for seizure control resulting from status epilepticus include intravenous antiepileptic medications and coma-inducing agents such as midazolam, pentobarbital, or propofol. Unfortunately, a significant subset of these patients does not respond to conventional therapies. We present a case series of five patients with refractory status epilepticus successfully managed with the ketogenic diet. Previously, the ketogenic diet was most commonly used for symptomatic generalized epilepsies. In our cohort, the diet was used successfully in individuals with various EEG patterns, including both generalized and focal seizures. The 4:1 ketogenic diet via an enteral feeding tube was started in all patients a mean of 12.8 days after the onset of refractory status epilepticus. Multiple AEDs were used unsuccessfully in each patient. A medically induced coma was used without significant reduction in seizure frequency in four of five children before the start of the diet. The ketogenic diet resulted in the resolution of status epilepticus in all children within 4.6 days (range: 2-8 days), similar to findings from other published reports.6,7 A previously published series by Nabbout et al. reported the successful use of the ketogenic diet to treat status epilepticus caused by fever-induced refractory epileptic encephalopathy in eight of nine patients.7 In our report, the five status epilepticus patients had a variety of etiologies that led to their conditions, including an acute influenza A infection, underlying mitochondrial epilepsy,
S.E. O’Connor et al. / Pediatric Neurology 50 (2014) 101e103 TABLE. Key steps when administering ketogenic diet for status epilepticus
Pre-diet Evaluate for disorders of fatty acid metabolism Consult the pharmacy department to convert medications to carbohydrate-free form (if possible) Consult the nutrition department to determine appropriate 4:1 ketogenic formula
103
In our case series, no patient complications from the diet were reported. Close monitoring of patient weight and serum titers (lactate, glucose, and beta hydroxybutyrate) was helpful when adjusting ketogenic therapy and maximizing ketosis. Table summarizes key points to consider when administering ketogenic diet for status epilepticus.
Initiation
Establish monitoring guidelines including: Every-4-hour serum glucose Daily ketones: urine ketones or serum beta hydroxybutyrate Daily electrolytes (low carbon dioxide level indicates acidosis) Initiate formula at a continuous rate via enteral feeding tube at 50% of goal; increase to goal as tolerated Carnitine supplements may be needed if receiving valproate or if triglycerides are elevated Monitor/treat acidosis
Follow-up Seizure control should occur within 2 weeks of diet initiation Taper off ketogenic diet if no improvement or if adverse effect cannot be rectified Continue ketogenic diet based on seizure control and tolerability. Ideal duration is not known.
Alpers-Huttenlocher syndrome, and/or fever-induced refractory epileptic encephalopathy. Previously, the diet was thought to be contraindicated in patients with underlying metabolic abnormalities.11 Kang et al., and now this case series, have given evidence that the diet may be a safe and beneficial treatment options for such patients with refractory status epilepticus.12 The mechanism of action of seizure control via the ketogenic diet is not fully understood but may be related to anti-inflammatory effects.13 Enteral nutrition was chosen for all patients over parenteral for the following reasons. (1) The 4:1 ketogenic diet includes 90% of calories from lipid, which exceeds the pediatric parenteral nutrition limit (4 g/kg). (2) Many AEDs are metabolized in the liver. A high-lipid infusion in the face of hepatically metabolized drugs may result in cholestasis or hepatic toxicity. One patient received a gastrostomy tube and four had naso-jejunal feeding tubes placed to administer the diet. The administration of formula for all five patients was provided at a continuous rate during diet initiation to optimize tolerance and to minimize the potential for gastric reflux. After extubation, the diets were advanced to bolus feedings and two of the five children were able to return to oral diets. All surviving patients have continued on the ketogenic diet on discharge. The optimal duration of the diet in such patients is not yet known. Challenges may occur when attempting to achieve ketosis in critically ill patients. Carbohydrate load from concomitant medications can be significant. One child in the case series unknowingly received 11 additional grams of carbohydrate in the intravenous phenobarbital solution. As a result, ketosis did not occur until the total carbohydrate intake was reduced. Additionally, propofol infusion in combination with the ketogenic diet administration may be contraindicated based on a published case resulting in death.14
Conclusions
Our experience suggests that the ketogenic diet can be useful in managing refractory status epilepticus in children. Collaboration and daily communication among the nutritionist, neurology service, and the intensive care team is essential to provide accurate therapy and to prevent errors that could result in loss of ketosis and seizure control. In the future, earlier utilization of the diet in the treatment plan may prove beneficial for similar patients. Larger, multiinstitutional studies are needed to provide more robust evidence.
References 1. Kossoff EH, Zupec-Kania BA, Rho JM. Ketogenic diets: an update for child neurologists. J Child Neurol. 2009;24:979-988. 2. Kossoff EH, Pyzik PL, McGrogan JR, Vining EP, Freeman JM. Efficacy of the ketogenic diet for infantile spasms. Pediatrics. 2002;109: 780-783. 3. Caraballo RH, Cersosimo RO, Sakr D, Cresta A, Escobal N, Fejerman N. Ketogenic diet in patients with Dravet syndrome. Epilepsia. 2005;46: 1539-1544. 4. Kossoff EH, Thiele EA, Pfeifer HH, McGrogan JR, Freeman JM. Tuberous sclerosis complex and the ketogenic diet. Epilepsia. 2005;46:1684-1686. 5. Wasterlain CG, Chen JW. Definition and classification of status epilepticus. In: Wasterlain CG, Treiman DM, eds. Status Epilepticus. Cambridge, MA: MIT Press; 2006. 6. Bodenant M, Moreau C, Sejourne C, et al. Interest of the ketogenic diet in a refractory status epilepticus in adults. Rev Neurol (Paris). 2008;164:194-199. 7. Nabbout R, Mazzuca M, Hubert P, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia. 2010;51:2033-2037. 8. Wusthoff CJ, Kranick SM, Morley JF, Bergqvist AGC. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus. Epilepsia. 2010;51:1083-1085. 9. Nam SH, Lee BL, Lee CG, Yu HJ, Joo EY, Lee M. The role of ketogenic diet in the treatment of refractory status epilepticus. Epilepsia. 2011; 52:181-184. 10. Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Huttenlocher syndrome. Pediatr Neurol. 2013;48:167-178. 11. Nordli DR Jr, De Vivo DC. The ketogenic diet. In: Elaine Wyllie, ed. The Treatment of Epilepsy. 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001. 12. Kang HC, Lee YM, Kim HD, Lee JS, Slama A. Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Epilepsia. 2007;48:82-88. 13. Jeong EA, Jeon BT, Shin HJ, et al. Ketogenic diet-induced peroxisome proliferator-activated receptor-g activation decreases neuroinflammation in the mouse hippocampus after kainic acid-induced seizures. Exp Neurol. 2011;232:195-202. 14. Baumeister FA, Oberhoffer R, Liebhaber GM, et al. Fatal propofol infusion syndrome in association with ketogenic diet. Neuropediatrics. 2004;35:250-252.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Clinical Observations
The Ketogenic Diet for the Treatment of Pediatric Status Epilepticus Sunila E. O’Connor MD a, *, Candy Richardson RD, LDN, CNSC b, Willam H. Trescher MD c, Debra L. Byler MD c, Joan D. Sather MPH, RD, LDN c, Elizabeth H. Michael RN, MS, CRNP c, Kelly B. Urbanik RD, CSP, LDN d, Jennifer L. Richards MSN, ARNP d, Ronald Davis MD d, Mary L. Zupanc MD e, Beth Zupec-Kania RND f a
Department of Pediatrics, Section of Epilepsy, Lurie Children’s Hospital, Chicago, Illinois The Children’s Health Center, Duke University Hospital, Durham, North Carolina c Pennsylvania State Hershey Children’s Hospital, Hershey, Pennsylvania d Arnold Palmer Hospital for Children, Orlando, Florida e Children’s Hospital of Orange County, Orange, California f Ketogenic Therapies LLC, Elm Grove, Wisconsin b
abstract BACKGROUND: Refractory status epilepticus carries a high risk of morbidity and mortality for children. Traditional treatment of status epilepticus consists of multiple anticonvulsant drugs and, if needed, induction of a medical coma. The ketogenic diet has been used for intractable epilepsy for many years. The purpose of this article is to report a case series of five patients with refractory status epilepticus successfully managed with the ketogenic diet. METHODS: A summary of pediatric patients with refractory status epilepticus treated with diet was performed. CONCLUSIONS: Ketogenic diet therapy should be considered as a treatment option in pediatric patients with refractory status epilepticus. Keywords: ketogenic diet, status epilepticus, pediatric, epilepsy, treatment, refractory
Pediatr Neurol 2014; 50: 101-103 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Although the anticonvulsant effects of the ketogenic diet are not fully understood, it has been used since the 1920s as treatment for various types of epilepsies.1 Typically, the high-fat, low-carbohydrate diet is used in children with medication-resistant epilepsy. More recently, the diet has been shown to be particularly effective in patients with infantile spasms, severe myoclonic epilepsy, and tuberous sclerosis complex.2-4 Status epilepticus is defined as “an acute epileptic condition characterized by continuous seizures for at least 30 minutes, or by 30 minutes of intermittent seizures without full recovery of consciousness between the Article History: Received June 28, 2013; Accepted in final form July 30, 2013 * Communications should be addressed to: Dr. O’Connor; Associate Professor; Department of Pediatrics; Section of Epilepsy; Lurie Children’s Hospital; 225 E. Chicago Avenue; Box 29; Chicago, IL. 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.2013.07.020
seizures.”5 The treatment of status epilepticus usually consists of multiple, successive antiepileptic drugs (AED). Patients refractory to initial management may require temporary coma induction with barbiturates or anesthetics to obtain seizure control. A newer application that has shown promise in critical care is using the ketogenic diet for treating status epilepticus.6-9 The purpose of this article is to report a case series of five patients with refractory status epilepticus successfully managed with the ketogenic diet. Case 1
A previously healthy 9-year-old boy was admitted to the hospital with a 3-day history of clinical seizures. Electroencephalography (EEG) confirmed continuous electrographic seizures arising from both temporal lobes with generalization. Complete evaluation with serum chemistries, brain imaging and lumbar puncture did not reveal an etiology for status epilepticus. Despite pharmacologic intervention with eight AEDs, a pentobarbital drip, and
102
S.E. O’Connor et al. / Pediatric Neurology 50 (2014) 101e103
intravenous immunoglobulin, the EEG continued to exhibit focal status epilepticus. The ketogenic diet was initiated via continuous nasoduodenal feeds. Five days after achieving the goal diet, the patient became ketotic and electrographic seizures abated. During this period, his glucose ranged from 42 to 60 mg/dL with a beta hydroxybutyrate level of 3.4 to 4.3 mmol/L. The patient has been continued on a 4:1 ketogenic diet plus multiple anticonvulsants since discharge. He continues to improve with regard to motor and cognitive function with follow-up of 12 months.
or pentobarbital coma induction. Initiation of a 4:1 ketogenic diet via nasogastric tube commenced on hospital day seven. The EEG improved within 36 hours, coinciding with a beta hydroxybutyrate level of 3.8 mmol/L. Serum glucose ranged from 65 to 74 mg/dL. Clinically, the patient became responsive within 48 hours of diet initiation. She has been maintained on the ketogenic diet and one antiepileptic drug without recurrence of status epilepticus for 18 months. Case 5
Case 2
An otherwise healthy 10-month-old boy presented with status epilepticus, specifically epilepsia partialis continua, resistant to seven AEDs, midazolam drip, and a pentobarbital coma. Approximately 15 days after the onset of status epilepticus and after pentobarbital discontinuation, a 4:1 ketogenic diet was initiated via a nasogastric tube. Five days later, with a urine ketone level of 15 mg/dL, serum glucose readings of 62-87 mg/dL, and beta hydroxybutyrate levels of 2.9-5.1 mmol/L, no further clinical seizures were noted. An EEG performed 10 days after diet initiation demonstrated a marked improvement compared with the previous studies. He underwent percutaneous gastrostomy tube placement and 4:1 ketogenic enteral feeds were given. After discharge, he was diagnosed with a mutation in polymerase gamma 1 gene and Alpers-Huttenlocher syndrome.10 The patient died soon after of disease-associated liver failure. Case 3
A previously healthy 5-year-old boy presented to another institution with a 6-day history of fever, coryza, and seizures. Continuous EEG monitoring demonstrated multiple independent areas of epileptiform activity. Seizure frequency worsened despite aggressive treatment with seven AEDs and induction of a barbiturate coma. Results of an extensive search for infectious, inflammatory, metabolic, and autoimmune etiologies were negative. The 4:1 ketogenic diet was implemented on hospital day 22. Eight days later, clinical and electrographic seizures were remarkably improved, coinciding with the appearance of urinary ketones. Concomitant mean beta hydroxybutyrate level was 4.1 mmol/L. Serum glucose ranged from 62 to 84 mg/dL. The patient was discharged home on the ketogenic diet, multiple AEDs, and monthly intravenous immunoglobulin. At the 15-month follow-up, the patient has infrequent seizures and remains on the diet and three AEDs. He has regained ambulation but cognitive and language impairment persist. Case 4
A 10-year-old girl with a history of symptomatic generalized epilepsy (characterized by atypical absence and generalized tonic-clonic seizures) presented with a 3 day history of mental status changes. Evaluation was negative for infectious diseases. Long-term video EEG monitoring confirmed nonconvulsive status epilepticus with nearly continuous generalized spike and slow wave discharges. She failed to respond to four intravenous AEDs
A 9-year-old girl with progressive myoclonic epilepsy due to a mitochondrial defect presented with lethargy and an increase in seizure frequency. She was found to be infected with influenza A. She developed multiorgan system failure and showed clinical and electrographic signs of status epilepticus. Five intravenous antiepileptic agents did not significantly alter the continuous EEG findings. Propofol was not given secondary to her mitochondrial disease. Pentobarbital was not administered because of multiorgan system failure associated with the patient’s severe influenza A infection. The 4:1 ketogenic diet was started via nasogastric tube on hospital day four. Electrographic and clinical seizures abated 48 hours later, corresponding to a beta hydroxybutyrate level of 3.2 mmol/L. Serum glucose titers ranged from 61 to 68 mg/dL. Followup 12 months later revealed the patient was clinically at baseline, successfully maintained on the ketogenic diet and one AED. No further episodes of status epilepticus occurred. Discussion
Standard treatments for seizure control resulting from status epilepticus include intravenous antiepileptic medications and coma-inducing agents such as midazolam, pentobarbital, or propofol. Unfortunately, a significant subset of these patients does not respond to conventional therapies. We present a case series of five patients with refractory status epilepticus successfully managed with the ketogenic diet. Previously, the ketogenic diet was most commonly used for symptomatic generalized epilepsies. In our cohort, the diet was used successfully in individuals with various EEG patterns, including both generalized and focal seizures. The 4:1 ketogenic diet via an enteral feeding tube was started in all patients a mean of 12.8 days after the onset of refractory status epilepticus. Multiple AEDs were used unsuccessfully in each patient. A medically induced coma was used without significant reduction in seizure frequency in four of five children before the start of the diet. The ketogenic diet resulted in the resolution of status epilepticus in all children within 4.6 days (range: 2-8 days), similar to findings from other published reports.6,7 A previously published series by Nabbout et al. reported the successful use of the ketogenic diet to treat status epilepticus caused by fever-induced refractory epileptic encephalopathy in eight of nine patients.7 In our report, the five status epilepticus patients had a variety of etiologies that led to their conditions, including an acute influenza A infection, underlying mitochondrial epilepsy,
S.E. O’Connor et al. / Pediatric Neurology 50 (2014) 101e103 TABLE. Key steps when administering ketogenic diet for status epilepticus
Pre-diet Evaluate for disorders of fatty acid metabolism Consult the pharmacy department to convert medications to carbohydrate-free form (if possible) Consult the nutrition department to determine appropriate 4:1 ketogenic formula
103
In our case series, no patient complications from the diet were reported. Close monitoring of patient weight and serum titers (lactate, glucose, and beta hydroxybutyrate) was helpful when adjusting ketogenic therapy and maximizing ketosis. Table summarizes key points to consider when administering ketogenic diet for status epilepticus.
Initiation
Establish monitoring guidelines including: Every-4-hour serum glucose Daily ketones: urine ketones or serum beta hydroxybutyrate Daily electrolytes (low carbon dioxide level indicates acidosis) Initiate formula at a continuous rate via enteral feeding tube at 50% of goal; increase to goal as tolerated Carnitine supplements may be needed if receiving valproate or if triglycerides are elevated Monitor/treat acidosis
Follow-up Seizure control should occur within 2 weeks of diet initiation Taper off ketogenic diet if no improvement or if adverse effect cannot be rectified Continue ketogenic diet based on seizure control and tolerability. Ideal duration is not known.
Alpers-Huttenlocher syndrome, and/or fever-induced refractory epileptic encephalopathy. Previously, the diet was thought to be contraindicated in patients with underlying metabolic abnormalities.11 Kang et al., and now this case series, have given evidence that the diet may be a safe and beneficial treatment options for such patients with refractory status epilepticus.12 The mechanism of action of seizure control via the ketogenic diet is not fully understood but may be related to anti-inflammatory effects.13 Enteral nutrition was chosen for all patients over parenteral for the following reasons. (1) The 4:1 ketogenic diet includes 90% of calories from lipid, which exceeds the pediatric parenteral nutrition limit (4 g/kg). (2) Many AEDs are metabolized in the liver. A high-lipid infusion in the face of hepatically metabolized drugs may result in cholestasis or hepatic toxicity. One patient received a gastrostomy tube and four had naso-jejunal feeding tubes placed to administer the diet. The administration of formula for all five patients was provided at a continuous rate during diet initiation to optimize tolerance and to minimize the potential for gastric reflux. After extubation, the diets were advanced to bolus feedings and two of the five children were able to return to oral diets. All surviving patients have continued on the ketogenic diet on discharge. The optimal duration of the diet in such patients is not yet known. Challenges may occur when attempting to achieve ketosis in critically ill patients. Carbohydrate load from concomitant medications can be significant. One child in the case series unknowingly received 11 additional grams of carbohydrate in the intravenous phenobarbital solution. As a result, ketosis did not occur until the total carbohydrate intake was reduced. Additionally, propofol infusion in combination with the ketogenic diet administration may be contraindicated based on a published case resulting in death.14
Conclusions
Our experience suggests that the ketogenic diet can be useful in managing refractory status epilepticus in children. Collaboration and daily communication among the nutritionist, neurology service, and the intensive care team is essential to provide accurate therapy and to prevent errors that could result in loss of ketosis and seizure control. In the future, earlier utilization of the diet in the treatment plan may prove beneficial for similar patients. Larger, multiinstitutional studies are needed to provide more robust evidence.
References 1. Kossoff EH, Zupec-Kania BA, Rho JM. Ketogenic diets: an update for child neurologists. J Child Neurol. 2009;24:979-988. 2. Kossoff EH, Pyzik PL, McGrogan JR, Vining EP, Freeman JM. Efficacy of the ketogenic diet for infantile spasms. Pediatrics. 2002;109: 780-783. 3. Caraballo RH, Cersosimo RO, Sakr D, Cresta A, Escobal N, Fejerman N. Ketogenic diet in patients with Dravet syndrome. Epilepsia. 2005;46: 1539-1544. 4. Kossoff EH, Thiele EA, Pfeifer HH, McGrogan JR, Freeman JM. Tuberous sclerosis complex and the ketogenic diet. Epilepsia. 2005;46:1684-1686. 5. Wasterlain CG, Chen JW. Definition and classification of status epilepticus. In: Wasterlain CG, Treiman DM, eds. Status Epilepticus. Cambridge, MA: MIT Press; 2006. 6. Bodenant M, Moreau C, Sejourne C, et al. Interest of the ketogenic diet in a refractory status epilepticus in adults. Rev Neurol (Paris). 2008;164:194-199. 7. Nabbout R, Mazzuca M, Hubert P, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia. 2010;51:2033-2037. 8. Wusthoff CJ, Kranick SM, Morley JF, Bergqvist AGC. The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus. Epilepsia. 2010;51:1083-1085. 9. Nam SH, Lee BL, Lee CG, Yu HJ, Joo EY, Lee M. The role of ketogenic diet in the treatment of refractory status epilepticus. Epilepsia. 2011; 52:181-184. 10. Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Huttenlocher syndrome. Pediatr Neurol. 2013;48:167-178. 11. Nordli DR Jr, De Vivo DC. The ketogenic diet. In: Elaine Wyllie, ed. The Treatment of Epilepsy. 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001. 12. Kang HC, Lee YM, Kim HD, Lee JS, Slama A. Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Epilepsia. 2007;48:82-88. 13. Jeong EA, Jeon BT, Shin HJ, et al. Ketogenic diet-induced peroxisome proliferator-activated receptor-g activation decreases neuroinflammation in the mouse hippocampus after kainic acid-induced seizures. Exp Neurol. 2011;232:195-202. 14. Baumeister FA, Oberhoffer R, Liebhaber GM, et al. Fatal propofol infusion syndrome in association with ketogenic diet. Neuropediatrics. 2004;35:250-252.
