Treatment of neonatal seizures
- Renee Shellhaas, MD, MS
Renee Shellhaas, MD, MS
- Clinical Associate Professor, Dept of Pediatrics
- University of Michigan Pediatric Neurology
- Section Editors
- Douglas R Nordli, Jr, MD
Douglas R Nordli, Jr, MD
- Section Editor — Pediatric Neurology
- Professor of Neurology and Pediatrics
- Northwestern University Feinberg School of Medicine
- Joseph A Garcia-Prats, MD
Joseph A Garcia-Prats, MD
- Section Editor — Neonatology
- Professor of Pediatrics
- Baylor College of Medicine
The occurrence of neonatal seizures may be the first, and perhaps the only, clinical sign of a central nervous system (CNS) disorder in the newborn infant. Seizures may indicate the presence of a potentially treatable etiology and should prompt an immediate evaluation to determine cause and to institute etiology-specific therapy. In addition, seizures themselves may require emergent therapy, since they can adversely affect the infant's homeostasis or they may contribute to further brain injury. Some types of neonatal seizures are associated with a relatively high incidence of early death and, in survivors, a high incidence of neurologic impairment, developmental delay, and postneonatal epilepsy.
Management of neonatal seizures involves accurate diagnosis of seizures, expedited evaluation and targeted treatment for their etiology, and medication to abolish the electrographic seizures. This topic will discuss the approach to treatment of neonatal seizures. The etiology, clinical features and diagnosis of neonatal seizures are discussed separately. (See "Etiology and prognosis of neonatal seizures" and "Neonatal epileptic syndromes" and "Clinical features, evaluation, and diagnosis of neonatal seizures".)
Both seizures and their subsequent therapy may be associated with changes in respiration, heart rate, and blood pressure. An adequate airway and access to the circulatory system must be insured early in the course of treatment.
Treatment directed at the cause of neonatal seizures is critical since it may prevent further brain injury. This is particularly true for seizures associated with some metabolic disturbances (eg, hypoglycemia, hypocalcemia, and hypomagnesemia) and with central nervous system (CNS) or systemic infections. Furthermore, neonatal seizures may not be effectively controlled with antiepileptic drugs (AEDs) unless their underlying cause is treated.
The most common etiologies of neonatal seizures are reviewed in the Table (table 1).
- Glass HC, Wusthoff CJ, Shellhaas RA, et al. Risk factors for EEG seizures in neonates treated with hypothermia: a multicenter cohort study. Neurology 2014; 82:1239.
- Nicolai J, van Kranen-Mastenbroek VH, Wevers RA, et al. Folinic acid-responsive seizures initially responsive to pyridoxine. Pediatr Neurol 2006; 34:164.
- Bok LA, Maurits NM, Willemsen MA, et al. The EEG response to pyridoxine-IV neither identifies nor excludes pyridoxine-dependent epilepsy. Epilepsia 2010; 51:2406.
- Segal EB, Grinspan ZM, Mandel AM, Gospe SM Jr. Biomarkers aiding diagnosis of atypical presentation of pyridoxine-dependent epilepsy. Pediatr Neurol 2011; 44:289.
- Stockler S, Plecko B, Gospe SM Jr, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 2011; 104:48.
- Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 2006; 12:307.
- Mills PB, Footitt EJ, Mills KA, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain 2010; 133:2148.
- Gallagher RC, Van Hove JL, Scharer G, et al. Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol 2009; 65:550.
- van Karnebeek CD, Hartmann H, Jaggumantri S, et al. Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials. Mol Genet Metab 2012; 107:335.
- Booth D, Evans DJ. Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev 2004; :CD004218.
- Slaughter LA, Patel AD, Slaughter JL. Pharmacological treatment of neonatal seizures: a systematic review. J Child Neurol 2013; 28:351.
- Bartha AI, Shen J, Katz KH, et al. Neonatal seizures: multicenter variability in current treatment practices. Pediatr Neurol 2007; 37:85.
- Glass HC, Kan J, Bonifacio SL, Ferriero DM. Neonatal seizures: treatment practices among term and preterm infants. Pediatr Neurol 2012; 46:111.
- Hellström-Westas L, Boylan G, Ågren J. Systematic review of neonatal seizure management strategies provides guidance on anti-epileptic treatment. Acta Paediatr 2015; 104:123.
- 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.
- Antiepileptic Drugs, 4th, Levy, RA, Mattson, RH, Meldrum, BS, Perucca, E (Eds), Raven Press, New York 1995.
- DeLorenzo, RJ. Phenytoin. Mechanisms of Action. In: Antiepileptic Drugs, 4th, Levy, RH, Mattson, RH, Meldrum, BS (Eds), Raven Press, New York 1995. p.271.
- Macdonald, RL. Benzodiazepines. In: Antiepileptic Drugs, 4th, Levy, RH, Mattson, RH, Meldrum, BS (Eds), Raven Press, New York 1995. p.695.
- Painter, MJ, Gaus, LM.. Phenobarbital: Clinical Use. In: Antiepileptic Drugs, 4th, Levy, H, Mattson, RH, Meldrum, BS (Eds), Raven Press, New York 1995. p.401.
- Shellhaas RA, Ng CM, Dillon CH, et al. Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia. Pediatr Crit Care Med 2013; 14:194.
- Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology 1987; 37:1837.
- Mizrahi, EM, Kellaway, P. The response of electroclinical neonatal seizures to antiepileptic drug therapy. Epilepsia 1992; 33:114.
- Shellhaas RA, Chang T, Tsuchida T, et al. The American Clinical Neurophysiology Society's Guideline on Continuous Electroencephalography Monitoring in Neonates. J Clin Neurophysiol 2011; 28:611.
- Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology 2004; 62:486.
- Glass HC, Wirrell E. Controversies in neonatal seizure management. J Child Neurol 2009; 24:591.
- Silverstein FS, Ferriero DM. Off-label use of antiepileptic drugs for the treatment of neonatal seizures. Pediatr Neurol 2008; 39:77.
- Kilicdag H, Daglıoglu K, Erdogan S, et al. The effect of levetiracetam on neuronal apoptosis in neonatal rat model of hypoxic ischemic brain injury. Early Hum Dev 2013; 89:355.
- Komur M, Okuyaz C, Celik Y, et al. Neuroprotective effect of levetiracetam on hypoxic ischemic brain injury in neonatal rats. Childs Nerv Syst 2014; 30:1001.
- Talos DM, Chang M, Kosaras B, et al. Antiepileptic effects of levetiracetam in a rodent neonatal seizure model. Pediatr Res 2013; 73:24.
- Khan O, Chang E, Cipriani C, et al. Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol 2011; 44:265.
- Abend NS, Gutierrez-Colina AM, Monk HM, et al. Levetiracetam for treatment of neonatal seizures. J Child Neurol 2011; 26:465.
- Sharpe CM, Capparelli EV, Mower A, et al. A seven-day study of the pharmacokinetics of intravenous levetiracetam in neonates: marked changes in pharmacokinetics occur during the first week of life. Pediatr Res 2012; 72:43.
- Merhar SL, Schibler KR, Sherwin CM, et al. Pharmacokinetics of levetiracetam in neonates with seizures. J Pediatr 2011; 159:152.
- Castro Conde JR, Hernández Borges AA, Doménech Martínez E, et al. Midazolam in neonatal seizures with no response to phenobarbital. Neurology 2005; 64:876.
- Painter MJ, Pippenger C, MacDonald H, Pitlick W. Phenobarbital and diphenylhydantoin levels in neonates with seizures. J Pediatr 1978; 92:315.
- Gal P, Toback J, Boer HR, et al. Efficacy of phenobarbital monotherapy in treatment of neonatal seizures -- relationship to blood levels. Neurology 1982; 32:1401.
- Donn SM, Grasela TH, Goldstein GW. Safety of a higher loading dose of phenobarbital in the term newborn. Pediatrics 1985; 75:1061.
- Bourgeois BF, Dodson WE. Phenytoin elimination in newborns. Neurology 1983; 33:173.
- Dodson WE. Antiepileptic drug utilization in pediatric patients. Epilepsia 1984; 25 Suppl 2:S132.
- Malingré MM, Van Rooij LG, Rademaker CM, et al. Development of an optimal lidocaine infusion strategy for neonatal seizures. Eur J Pediatr 2006; 165:598.
- van den Broek MP, Rademaker CM, van Straaten HL, et al. Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing. Arch Dis Child Fetal Neonatal Ed 2013; 98:F341.
- van Rooij LG, Toet MC, Rademaker KM, et al. Cardiac arrhythmias in neonates receiving lidocaine as anticonvulsive treatment. Eur J Pediatr 2004; 163:637.
- Guillet R, Kwon J. Seizure recurrence and developmental disabilities after neonatal seizures: outcomes are unrelated to use of phenobarbital prophylaxis. J Child Neurol 2007; 22:389.
- Boer HR, Gal P. Neonatal seizures: a survey of current practice. Clin Pediatr (Phila) 1982; 21:453.
- Fenichel, GM. Paroxysmal disorders. In: Clinical Pediatric Neurology, 3rd, WB Saunders (Ed), Philadelphia 1997. p.1.
- ETIOLOGIC THERAPY
- Neonatal encephalopathy
- CNS infection
- Metabolic disturbances
- - Hypoglycemia
- - Hypocalcemia
- - Hypomagnesemia
- Pyridoxine or PLP responsive seizures
- Biotinidase deficiency
- ANTIEPILEPTIC DRUG THERAPY
- Decision to institute drug therapy
- Drug selection
- - First-line therapy
- - Endpoint of acute therapy
- - Refractory seizures
- Dosing considerations in neonates
- - Phenobarbital
- - Phenytoin
- - Levetiractetam
- - Lidocaine
- - Midazolam
- Duration of therapy
- SUMMARY AND RECOMMENDATIONS