- Email: [email protected]
Off-Label Use of Antiepileptic Drugs for the Treatment of Neonatal Seizures
Original Articles
Off-Label Use of Antiepileptic Drugs for the Treatment of Neonatal Seizures Faye S. Silverstein, MD* and Donna M. Ferriero, MD† Medically refractory neonatal seizures represent a major therapeutic challenge in neonatal intensive care units. Conventional antiepileptic drugs demonstrate limited efficacy. Previous studies documented a high frequency of off-label drug therapy in neonates. We sought to determine if pediatric neurologists are recommending treatment of neonatal seizures with newer agents, despite a lack of information about their safety or efficacy in this population. Surveys were distributed at the 2007 Annual Meeting of the Child Neurology Society. Responses from 55 pediatric neurologists were analyzed. Seventy-three percent (40/55) recommended treatment of neonatal seizures with one or both of levetiracetam and topiramate; 47% (26/55) recommended levetiracetam; and 55% (30/55) recommended topiramate. Despite an absence of data on neonatal pharmacokinetics of either drug, neurologists made different dosing recommendations for these two drugs (P ⴝ 0.003, chi-square test). Respondents considered both agents to be efficacious in the majority of cases; adverse effects were recognized more frequently with topiramate. These results highlight the urgent need for rigorous clinical trials to understand the risks and benefits of new drug therapies for neonatal seizures. © 2008 by Elsevier Inc. All rights reserved.
nytoin was effective in less than 50% of cases [1], almost a decade later, these drugs remain the most common treatment for neonatal seizures [2]. A recent survey of 5 American neonatal intensive care units showed that anticonvulsant therapy is initiated in over 94% of neonates with seizures, and that phenobarbital is the drug of first choice for 82% [3]. There is a paucity of data regarding the pharmacokinetics of many drugs and interactions among medications in neonates, and “off-label” drug use is very common in this age group [4,5]. Although neonatologists frequently initiate treatment for neonatal seizures, they often consult pediatric neurologists if seizures recur after the administration of a loading dose of phenobarbital. Over the past decade, several newer antiepileptic drugs have gained wide acceptance in pediatric neurology practice. Anecdotal reports suggest that some of these antiepileptic drugs are being used to treat neonatal seizures. To gain an understanding of this rapidly evolving practice, we surveyed pediatric neurologists about their recommendations for the treatment of neonatal seizures with newer antiepileptic drugs. We hypothesized that 2 drugs, levetiracetam and topiramate, would be recommended more frequently than other newer antiepileptic drugs, and we focused on these agents.
Silverstein FS, Ferriero DM. Off-label use of antiepileptic drugs for the treatment of neonatal seizures. Pediatr Neurol 2008;39:77-79.
Methods and Results
Introduction The treatment of neonatal seizures is often unsatisfactory. Despite evidence from a rigorously conducted clinical trial that the administration of phenobarbital or phe-
At the 2007 Annual Meeting of the Child Neurology Society, surveys were distributed at a poster presentation that discussed the treatment of neonatal seizures [6], and at a meeting of the Neonatal Neurology Interest Group. Fifty-five completed surveys were collected. All respondents were pediatric neurologists, and all but one indicated that they consulted in neonatal intensive care units. Forty respondents were in academic practice, 12 were in hospital-based or private practice, and 3 were in training. Thirty-nine practiced in the United States, 11 in Canada, and 5 in other countries.
From the *Departments of Pediatrics and Neurology, University of Michigan, Ann Arbor, Michigan; and †Departments of Neurology and Pediatrics, University of California at San Francisco, San Francisco, California.
Communications should be addressed to: Dr. Silverstein; Departments of Pediatrics and Neurology; University of Michigan; 8301 MSRB III; 1150 W. Medical Center Drive; Ann Arbor, MI 48109-5646. E-mail: [email protected] Received January 4, 2008; accepted April 16, 2008.
© 2008 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2008.04.008 ● 0887-8994/08/$—see front matter
Silverstein and Ferriero: Off-Label Treatment of Neonatal Seizures 77
Because the primary role of most pediatric neurologists in neonatal intensive care units is that of consultant, the questions were phrased in terms of “recommendations for treatment.” Over 70% (40/55) recommended the treatment of neonatal seizures with one or both of levetiracetam and topiramate; only one respondent indicated that such treatment was not implemented. Sixteen (29%) advised treatment with both drugs; 14 (25%) recommended topiramate, but not levetiracetam; and 10 (18%) recommended levetiracetam, but not topiramate. Seventeen respondents (33%) indicated that they had recommended treatment with other novel agents (discussed below). A parenteral formulation of levetiracetam has been available in the United States since January 2007, and an oral liquid formulation is available. Topiramate is available only as tablets (that can be crushed and suspended in water) or as capsules that release sprinkles. Both the parenteral and oral formulations of levetiracetam were recommended for neonates (by 18/26 and 22/26, respectively). We did not obtain information about the circumstances in which each formulation was selected. For topiramate, respondents indicated that they had recommended the oral administration of crushed tablets or sprinkles. We analyzed the experiences reported with levetiracetam and topiramate (Table 1). Levetiracetam was never a first-line treatment, and topiramate was recommended first only once. Both drugs were typically recommended as second, third, or subsequent agents, and there was no difference in the rank-order in which the drugs were used. In contrast, there were marked differences in recommended doses. Neurologists recommended much higher doses of levetiracetam than of topiramate (P ⫽ 0.0003, chi-square test comparing the frequency of 4 dose categories). In over half the cases in which either drug was used, treatment was considered beneficial, and continued treatment was advised. No side effects were reported in levetiracetam-treated neonates. Adverse effects were recognized more frequently in topiramate-treated
Table 1.
infants (P ⫽ 0.002, Fisher’s exact test). The 9 cited side effects included metabolic acidosis (4 cases) with transient hyperammonemia in one, and irritability or feeding problems (5 cases). Several respondents commented that adverse neurologic effects were difficult to discern in encephalopathic neonates. No specific diagnosis prompted the utilization of either drug. Seventeen respondents indicated that they had recommended another “novel” antiepileptic drug for the treatment of neonatal seizures. The most frequently cited agents were valproic acid in 4 cases, and lidocaine, zonisamide, and oxcarbamazepine each in 3 cases. In 5 cases, neonatologists initiated treatment with a novel agent, with levetiracetam in 3 cases, topiramate once, and lidocaine and paraldehyde once.
Discussion Published guidelines for levetiracetam and topiramate in one of the most commonly used pharmacy references, the Micromedex Healthcare Series-Drugdex, reveal that no information is available for levetiracetam regarding its use as an intravenous formulation for children less than 16 years old, and for the oral formulation, no information is available about safety or efficacy for children below age 4 years. For topiramate, the entry states, “Efficacy in seizures not established in children under 2 years.” Despite the paucity of pharmacokinetic or efficacy data, the results indicate that these antiepileptic agents are among the drugs being prescribed off-label in neonatal intensive care units. They are typically prescribed for the treatment of neonates
Experiences with levetiracetam and topiramate for treatment of neonatal seizures
Recommended treatment Timing (in relation to other antiepileptic drugs) (%)† First Second Third or subsequent No answer Dose recommended (%)‡ 10 mg/kg 20 mg/kg 30 mg/kg Other doses Treatment considered beneficial (%)† Yes No Uncertain Recommended continuing treatment (%)† Yes No No answer Side effects attributed to treatment (%) ¶ Yes None Uncertain
Levetiracetam
Topiramate
47% (26/55)*
55% (30/55)
0% 54% (14/26) 50% (13/26) 0%
2% (1/30) 33% (10/30) 53% (16/30) 10% (3/30)
32% (8/25) 40% (10/25) 20% (5/25) 8% (2/25, higher doses)
60% (18/30) 10% (3/30) 0% 30% (9/30, lower doses)
58% (14½§/25) 14% (3½§/25) 31% (7/25)
70% (21/30) 10% (3/30) 20% (6/30)
58% (14½§/25) 17% (4½§/25) 28% (7/25)
60% (18/30) 23% (7/30) 17% (5/30)
0% 92% (24/25) 8% (2/25)
30% (9/30) 63% (19/30) 7% (2/30)
* Recommendation was not implemented in one case. † P ⫽ 0.003 (chi-square test), comparing distribution of dosing recommendations. There was one missing value for each drug. ‡ P ⫽ NS (chi-square test), comparing timing of recommended therapy, perceived benefit of treatment, or recommendations to continue treatment between the two drugs. § One respondent gave both answers, reflecting divergent responses to treatment in 2 cases. ¶ P ⫽ 0.002 (Fisher’s exact test), comparing frequency of recognized side effects.
78
PEDIATRIC NEUROLOGY
Vol. 39 No. 2
with seizures refractory to phenobarbital, a group of critically ill infants who are at high risk for poor neurologic outcomes. Moreover, based on significant differences in doses recommended for the two agents, clinicians are evidently extrapolating from their experiences in treating older children or adults to guide their practice. These findings highlight the urgent need for rigorous clinical trials to determine the safest and most effective treatment(s) for neonatal seizures. Many practical challenges must be addressed to implement clinical trials of new antiepileptic drugs in neonates. A recent survey of neurologists and neonatologists suggested that it would be impossible to conduct a placebocontrolled trial with a new anticonvulsant drug in the current medical environment. Add-on trials would be feasible and welcome only if the capability to recognize electrographic seizures existed for study participants [6]. In the context of a clinical trial, most survey participants agreed that the cessation of electrographic (rather than clinically detected) seizures would be the appropriate endpoint. It is particularly difficult to assess the adverse effects of prescribed drugs on central nervous system development and integrity, and to distinguish adverse effects attributable to treatment from those attributable to an underlying neurologic disorder. A major issue in the design of future clinical trials involves the delineation of a relatively homogeneous study population. There is substantial support for a focus on term infants with hypoxic-ischemic encephalopathy [6]. It is in this population that seizures are most frequently refractory to initial anticonvulsant therapy [7,8]. Moreover, the seizures themselves may have deleterious effects on brain integrity in this setting [9]; this is the most serious concern. Although suggested by animal models that seizures exacerbate neonatal hypoxic-ischemic injury [10], it is uncertain whether the same holds true for human newborns. Rigorous long-term follow-up is also essential to identify deleterious and beneficial treatment effects. Experimental data, obtained in neonatal rodents, suggest that levetiracetam and topiramate may be safer than the conventionally used antiepileptic drugs (phenobarbital, phenytoin, and benzodiazepines) in neonates [11,12]. Although data regarding the potential safety of these agents are encouraging, there are no data about their effects on brain development. Refractory neonatal seizures remain a significant clinical problem. There will certainly be opportunities to perform therapeutic trials of new agents. The systematic clinical evaluation of safety and pharmacokinetics in the
appropriate study populations must precede any analysis of efficacy, and this is particularly challenging in neonates. It will also be essential to assess antiepileptic drug interactions with other therapies (e.g., induced hypothermia) in critically ill infants. If encephalopathic neonates are treated with hypothermia, it will be essential to evaluate the impact of therapeutic cooling on the pharmacokinetics of antiepileptic drugs. Thus, future studies must take into account gestational age, seizure etiology, and other concurrent treatments. Finally, the data presented here should not be interpreted as an endorsement for wider implementation of the treatments described. Rather, these data highlight the urgent need for rigorous study of new antiepileptic drugs in neonates and infants. The authors acknowledge funding from the Child Neurology Foundation, the cooperation of individuals who completed the survey, the assistance of Hannah Glass, MD (University of California at San Francisco) in data collection, and the assistance of John Barks, MD (University of Michigan) in statistics calculations.
References [1] Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485-9. [2] Sankar R, Painter MJ. Neonatal seizures: After all these years we still love what doesn’t work. Neurology 2005;64:776-7. [3] Bartha A, Shen J, Katz KH, et al. Neonatal seizures: Multicenter variability in current treatment practices. Pediatr Neurol 2007;37:85-90. [4] Barr J, Brenner-Zada G, Heiman E, et al. Unlicensed and off-label medication use in a neonatal intensive care unit: A prospective study. Am J Perinatol 2002;19:67-72. [5] Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Reported medication use in the neonatal intensive care unit: Data from a large national data set. Pediatrics 2006;117:1979-87. [6] Silverstein FS, Ferriero DM. Challenges in improving the treatment of neonatal seizures. Ann Neurol 2007;62(Suppl.):S139. [7] Silverstein FS, Jensen FE. Neurological progress: Neonatal seizures. Ann Neurol 2007;62:112-20. [8] Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117:1270-80. [9] Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002;58: 542-8. [10] Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res 2001;50:445-54. [11] Glier C, Dzietko M, Bittigau P, Jarosz B, Korobowicz E, Ikonomidou C. Therapeutic doses of topiramate are not toxic to the developing rat brain. Exp Neurol 2004;187:403-9. [12] Manthey D, Asimiadou S, Stefovska V, et al. Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain. Exp Neurol 2005;193:497-503.
Silverstein and Ferriero: Off-Label Treatment of Neonatal Seizures 79
Off-Label Use of Antiepileptic Drugs for the Treatment of Neonatal Seizures Faye S. Silverstein, MD* and Donna M. Ferriero, MD† Medically refractory neonatal seizures represent a major therapeutic challenge in neonatal intensive care units. Conventional antiepileptic drugs demonstrate limited efficacy. Previous studies documented a high frequency of off-label drug therapy in neonates. We sought to determine if pediatric neurologists are recommending treatment of neonatal seizures with newer agents, despite a lack of information about their safety or efficacy in this population. Surveys were distributed at the 2007 Annual Meeting of the Child Neurology Society. Responses from 55 pediatric neurologists were analyzed. Seventy-three percent (40/55) recommended treatment of neonatal seizures with one or both of levetiracetam and topiramate; 47% (26/55) recommended levetiracetam; and 55% (30/55) recommended topiramate. Despite an absence of data on neonatal pharmacokinetics of either drug, neurologists made different dosing recommendations for these two drugs (P ⴝ 0.003, chi-square test). Respondents considered both agents to be efficacious in the majority of cases; adverse effects were recognized more frequently with topiramate. These results highlight the urgent need for rigorous clinical trials to understand the risks and benefits of new drug therapies for neonatal seizures. © 2008 by Elsevier Inc. All rights reserved.
nytoin was effective in less than 50% of cases [1], almost a decade later, these drugs remain the most common treatment for neonatal seizures [2]. A recent survey of 5 American neonatal intensive care units showed that anticonvulsant therapy is initiated in over 94% of neonates with seizures, and that phenobarbital is the drug of first choice for 82% [3]. There is a paucity of data regarding the pharmacokinetics of many drugs and interactions among medications in neonates, and “off-label” drug use is very common in this age group [4,5]. Although neonatologists frequently initiate treatment for neonatal seizures, they often consult pediatric neurologists if seizures recur after the administration of a loading dose of phenobarbital. Over the past decade, several newer antiepileptic drugs have gained wide acceptance in pediatric neurology practice. Anecdotal reports suggest that some of these antiepileptic drugs are being used to treat neonatal seizures. To gain an understanding of this rapidly evolving practice, we surveyed pediatric neurologists about their recommendations for the treatment of neonatal seizures with newer antiepileptic drugs. We hypothesized that 2 drugs, levetiracetam and topiramate, would be recommended more frequently than other newer antiepileptic drugs, and we focused on these agents.
Silverstein FS, Ferriero DM. Off-label use of antiepileptic drugs for the treatment of neonatal seizures. Pediatr Neurol 2008;39:77-79.
Methods and Results
Introduction The treatment of neonatal seizures is often unsatisfactory. Despite evidence from a rigorously conducted clinical trial that the administration of phenobarbital or phe-
At the 2007 Annual Meeting of the Child Neurology Society, surveys were distributed at a poster presentation that discussed the treatment of neonatal seizures [6], and at a meeting of the Neonatal Neurology Interest Group. Fifty-five completed surveys were collected. All respondents were pediatric neurologists, and all but one indicated that they consulted in neonatal intensive care units. Forty respondents were in academic practice, 12 were in hospital-based or private practice, and 3 were in training. Thirty-nine practiced in the United States, 11 in Canada, and 5 in other countries.
From the *Departments of Pediatrics and Neurology, University of Michigan, Ann Arbor, Michigan; and †Departments of Neurology and Pediatrics, University of California at San Francisco, San Francisco, California.
Communications should be addressed to: Dr. Silverstein; Departments of Pediatrics and Neurology; University of Michigan; 8301 MSRB III; 1150 W. Medical Center Drive; Ann Arbor, MI 48109-5646. E-mail: [email protected] Received January 4, 2008; accepted April 16, 2008.
© 2008 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2008.04.008 ● 0887-8994/08/$—see front matter
Silverstein and Ferriero: Off-Label Treatment of Neonatal Seizures 77
Because the primary role of most pediatric neurologists in neonatal intensive care units is that of consultant, the questions were phrased in terms of “recommendations for treatment.” Over 70% (40/55) recommended the treatment of neonatal seizures with one or both of levetiracetam and topiramate; only one respondent indicated that such treatment was not implemented. Sixteen (29%) advised treatment with both drugs; 14 (25%) recommended topiramate, but not levetiracetam; and 10 (18%) recommended levetiracetam, but not topiramate. Seventeen respondents (33%) indicated that they had recommended treatment with other novel agents (discussed below). A parenteral formulation of levetiracetam has been available in the United States since January 2007, and an oral liquid formulation is available. Topiramate is available only as tablets (that can be crushed and suspended in water) or as capsules that release sprinkles. Both the parenteral and oral formulations of levetiracetam were recommended for neonates (by 18/26 and 22/26, respectively). We did not obtain information about the circumstances in which each formulation was selected. For topiramate, respondents indicated that they had recommended the oral administration of crushed tablets or sprinkles. We analyzed the experiences reported with levetiracetam and topiramate (Table 1). Levetiracetam was never a first-line treatment, and topiramate was recommended first only once. Both drugs were typically recommended as second, third, or subsequent agents, and there was no difference in the rank-order in which the drugs were used. In contrast, there were marked differences in recommended doses. Neurologists recommended much higher doses of levetiracetam than of topiramate (P ⫽ 0.0003, chi-square test comparing the frequency of 4 dose categories). In over half the cases in which either drug was used, treatment was considered beneficial, and continued treatment was advised. No side effects were reported in levetiracetam-treated neonates. Adverse effects were recognized more frequently in topiramate-treated
Table 1.
infants (P ⫽ 0.002, Fisher’s exact test). The 9 cited side effects included metabolic acidosis (4 cases) with transient hyperammonemia in one, and irritability or feeding problems (5 cases). Several respondents commented that adverse neurologic effects were difficult to discern in encephalopathic neonates. No specific diagnosis prompted the utilization of either drug. Seventeen respondents indicated that they had recommended another “novel” antiepileptic drug for the treatment of neonatal seizures. The most frequently cited agents were valproic acid in 4 cases, and lidocaine, zonisamide, and oxcarbamazepine each in 3 cases. In 5 cases, neonatologists initiated treatment with a novel agent, with levetiracetam in 3 cases, topiramate once, and lidocaine and paraldehyde once.
Discussion Published guidelines for levetiracetam and topiramate in one of the most commonly used pharmacy references, the Micromedex Healthcare Series-Drugdex, reveal that no information is available for levetiracetam regarding its use as an intravenous formulation for children less than 16 years old, and for the oral formulation, no information is available about safety or efficacy for children below age 4 years. For topiramate, the entry states, “Efficacy in seizures not established in children under 2 years.” Despite the paucity of pharmacokinetic or efficacy data, the results indicate that these antiepileptic agents are among the drugs being prescribed off-label in neonatal intensive care units. They are typically prescribed for the treatment of neonates
Experiences with levetiracetam and topiramate for treatment of neonatal seizures
Recommended treatment Timing (in relation to other antiepileptic drugs) (%)† First Second Third or subsequent No answer Dose recommended (%)‡ 10 mg/kg 20 mg/kg 30 mg/kg Other doses Treatment considered beneficial (%)† Yes No Uncertain Recommended continuing treatment (%)† Yes No No answer Side effects attributed to treatment (%) ¶ Yes None Uncertain
Levetiracetam
Topiramate
47% (26/55)*
55% (30/55)
0% 54% (14/26) 50% (13/26) 0%
2% (1/30) 33% (10/30) 53% (16/30) 10% (3/30)
32% (8/25) 40% (10/25) 20% (5/25) 8% (2/25, higher doses)
60% (18/30) 10% (3/30) 0% 30% (9/30, lower doses)
58% (14½§/25) 14% (3½§/25) 31% (7/25)
70% (21/30) 10% (3/30) 20% (6/30)
58% (14½§/25) 17% (4½§/25) 28% (7/25)
60% (18/30) 23% (7/30) 17% (5/30)
0% 92% (24/25) 8% (2/25)
30% (9/30) 63% (19/30) 7% (2/30)
* Recommendation was not implemented in one case. † P ⫽ 0.003 (chi-square test), comparing distribution of dosing recommendations. There was one missing value for each drug. ‡ P ⫽ NS (chi-square test), comparing timing of recommended therapy, perceived benefit of treatment, or recommendations to continue treatment between the two drugs. § One respondent gave both answers, reflecting divergent responses to treatment in 2 cases. ¶ P ⫽ 0.002 (Fisher’s exact test), comparing frequency of recognized side effects.
78
PEDIATRIC NEUROLOGY
Vol. 39 No. 2
with seizures refractory to phenobarbital, a group of critically ill infants who are at high risk for poor neurologic outcomes. Moreover, based on significant differences in doses recommended for the two agents, clinicians are evidently extrapolating from their experiences in treating older children or adults to guide their practice. These findings highlight the urgent need for rigorous clinical trials to determine the safest and most effective treatment(s) for neonatal seizures. Many practical challenges must be addressed to implement clinical trials of new antiepileptic drugs in neonates. A recent survey of neurologists and neonatologists suggested that it would be impossible to conduct a placebocontrolled trial with a new anticonvulsant drug in the current medical environment. Add-on trials would be feasible and welcome only if the capability to recognize electrographic seizures existed for study participants [6]. In the context of a clinical trial, most survey participants agreed that the cessation of electrographic (rather than clinically detected) seizures would be the appropriate endpoint. It is particularly difficult to assess the adverse effects of prescribed drugs on central nervous system development and integrity, and to distinguish adverse effects attributable to treatment from those attributable to an underlying neurologic disorder. A major issue in the design of future clinical trials involves the delineation of a relatively homogeneous study population. There is substantial support for a focus on term infants with hypoxic-ischemic encephalopathy [6]. It is in this population that seizures are most frequently refractory to initial anticonvulsant therapy [7,8]. Moreover, the seizures themselves may have deleterious effects on brain integrity in this setting [9]; this is the most serious concern. Although suggested by animal models that seizures exacerbate neonatal hypoxic-ischemic injury [10], it is uncertain whether the same holds true for human newborns. Rigorous long-term follow-up is also essential to identify deleterious and beneficial treatment effects. Experimental data, obtained in neonatal rodents, suggest that levetiracetam and topiramate may be safer than the conventionally used antiepileptic drugs (phenobarbital, phenytoin, and benzodiazepines) in neonates [11,12]. Although data regarding the potential safety of these agents are encouraging, there are no data about their effects on brain development. Refractory neonatal seizures remain a significant clinical problem. There will certainly be opportunities to perform therapeutic trials of new agents. The systematic clinical evaluation of safety and pharmacokinetics in the
appropriate study populations must precede any analysis of efficacy, and this is particularly challenging in neonates. It will also be essential to assess antiepileptic drug interactions with other therapies (e.g., induced hypothermia) in critically ill infants. If encephalopathic neonates are treated with hypothermia, it will be essential to evaluate the impact of therapeutic cooling on the pharmacokinetics of antiepileptic drugs. Thus, future studies must take into account gestational age, seizure etiology, and other concurrent treatments. Finally, the data presented here should not be interpreted as an endorsement for wider implementation of the treatments described. Rather, these data highlight the urgent need for rigorous study of new antiepileptic drugs in neonates and infants. The authors acknowledge funding from the Child Neurology Foundation, the cooperation of individuals who completed the survey, the assistance of Hannah Glass, MD (University of California at San Francisco) in data collection, and the assistance of John Barks, MD (University of Michigan) in statistics calculations.
References [1] Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485-9. [2] Sankar R, Painter MJ. Neonatal seizures: After all these years we still love what doesn’t work. Neurology 2005;64:776-7. [3] Bartha A, Shen J, Katz KH, et al. Neonatal seizures: Multicenter variability in current treatment practices. Pediatr Neurol 2007;37:85-90. [4] Barr J, Brenner-Zada G, Heiman E, et al. Unlicensed and off-label medication use in a neonatal intensive care unit: A prospective study. Am J Perinatol 2002;19:67-72. [5] Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Reported medication use in the neonatal intensive care unit: Data from a large national data set. Pediatrics 2006;117:1979-87. [6] Silverstein FS, Ferriero DM. Challenges in improving the treatment of neonatal seizures. Ann Neurol 2007;62(Suppl.):S139. [7] Silverstein FS, Jensen FE. Neurological progress: Neonatal seizures. Ann Neurol 2007;62:112-20. [8] Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117:1270-80. [9] Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002;58: 542-8. [10] Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res 2001;50:445-54. [11] Glier C, Dzietko M, Bittigau P, Jarosz B, Korobowicz E, Ikonomidou C. Therapeutic doses of topiramate are not toxic to the developing rat brain. Exp Neurol 2004;187:403-9. [12] Manthey D, Asimiadou S, Stefovska V, et al. Sulthiame but not levetiracetam exerts neurotoxic effect in the developing rat brain. Exp Neurol 2005;193:497-503.
Silverstein and Ferriero: Off-Label Treatment of Neonatal Seizures 79