Benign Neonatal Convulsions Medication
- Author: Nitin C Patel, MD, MPH, FAAN; Chief Editor: Amy Kao, MD more...
No specific antiepileptic medication is preferred for the treatment of benign neonatal convulsions. In general, most epileptologists agree that status epilepticus should be treated when it occurs. Most neonates are best treated at this time with phenobarbital because of long experience with the drug, convenient monitoring, and adequate intravenous (IV) and (PO) absorption in the neonate or levetiracetam for its low adverse effect profile and ease of use with either parenteral (IV) or liquid (PO) formulations. However, treatment has not been shown unequivocally to have an effect, except possibly to decrease the duration or severity of the seizures. By definition, the seizures resolve in days (benign idiopathic neonatal convulsions [BINCs]) to weeks (benign familial neonatal convulsions [BFNCs]).
Limit the choice of antiepileptic drug to those with no serious potential adverse effects. Most notably, avoid valproate in this age group if benign convulsions are suspected, because neonates are at the highest risk for liver failure due to valproate. Avoid phenytoin because of cardiac adverse effects, the high possibility of extravasation in neonates, and problems with reliable absorption if administered PO. A trial off the antiepileptic drug(s) should begin soon after the seizures stop and the electroencephalogram (EEG) is normal.
An important factor to remember when treating neonates is that pharmacokinetics and pharmacodynamics are very different than in infants. Do not use infant loading dosages, as they may lead quickly to toxic levels that resolve slowly.
Neonatal pharmacology is complex. Maturation of general liver and renal function is in a period of transition from the fetal to infant state. Stresses or lack of stress on the systems in utero greatly affect the function and maturation of both systems.
Normal glomerular filtration rate (GFR) in the neonate varies in individuals from 1 to 4 mL/min and can increase rapidly as maturation of the renal cortex progresses. Adult values for GFR are not reached before the infant is aged 2.5-5 months.
Blood flow within the hepatic portal system changes at birth with closing of the ductus venosus. Maturation of the glucuronidation pathway is often slowed. Neonates whose mothers have been exposed to drugs (both prescribed and otherwise) may have active cytochrome P-450 enzymes, and unexposed neonates have initial low activities that usually increase rapidly with the introduction of drugs such as phenobarbital.
Anticonvulsants prevent seizure recurrence and terminate clinical and electrical seizure activity.
Phenobarbital is the drug of choice for treatment of neonatal seizures. Use care in the dosing of this agent, as toxicity can occur quickly and resolve slowly. Also note doses that are initially adequate may need to be increased quickly as cytochrome P-450 becomes more active.
Fosphenytoin may initially be used to control status epilepticus in patients with benign neonatal convulsions; however, this agent is unsuitable for long-term therapy.
Topiramate is a sulfamate-substituted monosaccharide with a broad spectrum of antiepileptic activity that may have state-dependent sodium channel blocking action. This agent potentiates the inhibitory activity of the neurotransmitter gamma-aminobutyric acid (GABA) and may block glutamate activity.
The exact mechanism of action is unknown. Stereoselective binding of levetiracetam is confined to synaptic plasma membranes in the central nervous system with no binding occurring in peripheral tissue. Levetiracetam inhibits burst firing without affecting normal neuronal excitability, which suggests it may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.
Alternative intravenous medications used in treating benign neonatal convulsions include benzodiazepines. The disadvantages of benzodiazepines are that they are overdosed easily in the neonate and can be very sedating.
Lorazepam is a benzodiazepine with a short onset of effects and relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, it may depress all levels of the CNS, including limbic and reticular formation.
Diazepam is a benzodiazepine that is an extremely lipid-soluble agent and enters brain very quickly in first pass and often will stop seizures in 1-2 min. It modulates the postsynaptic effects of GABA-A transmission, resulting in an increase in presynaptic inhibition. It appears to act on part of the limbic system, the thalamus, and hypothalamus, to induce a calming effect.
Quattlebaum TG. Benign familial convulsions in the neonatal period and early infancy. J Pediatr. 1979 Aug. 95(2):257-9. [Medline].
Mizrahi EM. Seizure disorders in children. Curr Opin Pediatr. 1994 Dec. 6(6):642-6. [Medline].
Plouin P. Benign idiopathic neonatal convulsions (familial and non-familial): open questions about these syndromes. In: Wolf P, ed. Epileptic Seizures and Syndromes. London: John Libbey & Co; 1994. 193-201.
Pettit RE, Fenichel GM. Benign familial neonatal seizures. Arch Neurol. 1980 Jan. 37(1):47-8. [Medline].
Plouin P. [Value of video electroencephalography in neonatology] [French]. Arch Pediatr. 2000 May. 7 suppl 2:332s-333s. [Medline].
Tang B, Li H, Xia K, et al. A novel mutation in KCNQ2 gene causes benign familial neonatal convulsions in a Chinese family. J Neurol Sci. 2004 Jun 15. 221(1-2):31-4. [Medline].
Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998 Jan. 18(1):25-9. [Medline].
Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science. 1998 Jan 16. 279(5349):403-6. [Medline].
Hirose S, Zenri F, Akiyoshi H, et al. A novel mutation of KCNQ3 (c.925T-->C) in a Japanese family with benign familial neonatal convulsions. Ann Neurol. 2000 Jun. 47(6):822-6. [Medline].
Schroeder BC, Kubisch C, Stein V, et al. Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature. 1998 Dec 17. 396(6712):687-90. [Medline].
Schwake M, Pusch M, Kharkovets T, et al. Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy. J Biol Chem. 2000 May 5. 275(18):13343-8. [Medline].
Leppert M, Anderson VE, Quattlebaum T, et al. Benign familial neonatal convulsions linked to genetic markers on chromosome 20. Nature. 1989 Feb 16. 337(6208):647-8. [Medline].
Leppert M. Novel K+ channel genes in benign familial neonatal convulsions. Epilepsia. 2000 Aug. 41(8):1066-7. [Medline].
Lewis TB, Shevell MI, Andermann E, et al. Evidence of a third locus for benign familial convulsions. J Child Neurol. 1996 May. 11(3):211-4. [Medline].
Bellini G, Miceli F, Soldovieri MV, et al. Benign Familial Neonatal Seizures. NCBI. Available at http://www.ncbi.nlm.nih.gov/books/NBK32534/. Accessed: November 15, 2011.
Singh NA, Westenskow P, Charlier C, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain. 2003 Dec. 126:2726-37. [Medline].
Kananura C, Biervert C, Hechenberger M, et al. The new voltage gated potassium channel KCNQ5 and neonatal convulsions. Neuroreport. 2000 Jun 26. 11(9):2063-7. [Medline].
Beck C, Moulard B, Steinlein O, et al. A nonsense mutation in the alpha4 subunit of the nicotinic acetylcholine receptor (CHRNA4) cosegregates with 20q-linked benign neonatal familial convulsions (EBNI). Neurobiol Dis. 1994 Nov. 1(1-2):95-9. [Medline].
Steinlein O, Sander T, Stoodt J, et al. Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit alpha4 with common idiopathic generalized epilepsies. Am J Med Genet. 1997 Jul 25. 74(4):445-9. [Medline].
Lerche H, Biervert C, Alekov AK, et al. A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol. 1999 Sep. 46(3):305-12. [Medline].
Zhu G, Okada M, Murakami T, et al. Dysfunction of M-channel enhances propagation of neuronal excitability in rat hippocampus monitored by multielectrode dish and microdialysis systems. Neurosci Lett. 2000 Nov 10. 294(1):53-7. [Medline].
Burgess DL. Neonatal epilepsy syndromes and GEFS+: mechanistic considerations. Epilepsia. 2005. 46 suppl 10:51-8. [Medline].
Lehmann-Horn F, Jurkat-Rott K. Voltage-gated ion channels and hereditary disease. Physiol Rev. 1999 Oct. 79(4):1317-72. [Medline].
Mulley JC, Scheffer IE, Petrou S, et al. Channelopathies as a genetic cause of epilepsy. Curr Opin Neurol. 2003 Apr. 16(2):171-6. [Medline].
Zara F, Specchio N, Striano P, et al. Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia. 2013 Mar. 54 (3):425-36. [Medline].
Webb R, Bobele G. Benign' familial neonatal convulsions. J Child Neurol. 1990 Oct. 5(4):295-8. [Medline].
Tharp BR. Neonatal seizures and syndromes. Epilepsia. 2002. 43 suppl 3:2-10. [Medline].
DeLorenzo RJ. The challenging genetics of epilepsy. Epilepsy Res Suppl. 1991. 4:3-17. [Medline].
Hirose S, Mitsudome A, Okada M, et al. Genetics of idiopathic epilepsies. Epilepsia. 2005. 46 suppl 1:38-43. [Medline].
Ben-Ari Y, Khazipov R, Leinekugel X, et al. GABAA, NMDA and AMPA receptors: a developmentally regulated 'menage a trois'. Trends Neurosci. 1997 Nov. 20(11):523-9. [Medline].
Dzhala VI, Talos DM, Sdrulla DA, et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005 Nov. 11(11):1205-13. [Medline].
Leinekugel X, Medina I, Khalilov I, et al. Ca2+ oscillations mediated by the synergistic excitatory actions of GABA(A) and NMDA receptors in the neonatal hippocampus. Neuron. 1997 Feb. 18(2):243-55. [Medline].
Rivera C, Voipio J, Payne JA, et al. The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999 Jan 21. 397(6716):251-5. [Medline].
Ben-Ari Y. Excitatory actions of gaba during development: the nature of the nurture. Nat Rev Neurosci. 2002 Sep. 3(9):728-39. [Medline].
Fransen E. Neurons Associated With Epilepsy Rescued By Optimal Modulation Of Ion Channels. Biophysical J. Oct 2011.
Miles DK, Holmes GL. Benign neonatal seizures. J Clin Neurophysiol. 1990 Jul. 7(3):369-79. [Medline].
Lewis TB, Leach RJ, Ward K, et al. Genetic heterogeneity in benign familial neonatal convulsions: identification of a new locus on chromosome 8q. Am J Hum Genet. 1993 Sep. 53(3):670-5. [Medline].
Treiman LJ. Genetics of epilepsy: an overview. Epilepsia. 1993. 34 suppl 3:S1-11. [Medline].
Turnbull J, Lohi H, Kearney JA, et al. Sacred disease secrets revealed: the genetics of human epilepsy. Hum Mol Genet. 2005 Sep 1. 14(17):2491-500. [Medline].
Elmslie F, Gardiner M. Genetics of the epilepsies. Curr Opin Neurol. 1995 Apr. 8(2):126-9. [Medline].
Gardiner M. Genetics of idiopathic generalized epilepsies. Epilepsia. 2005. 46 Suppl 9:15-20. [Medline].
Tharp BR. Neonatal seizures and syndromes. Epilepsia. 2002. 43 Suppl 3:2-10. [Medline].
Jallon P, Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia. 2005. 46 suppl 9:10-4. [Medline].
Concordance of clinical forms of epilepsy in families with several affected members. Italian League Against Epilepsy Genetic Collaborative Group. Epilepsia. 1993 Sep-Oct. 34(5):819-26. [Medline].
North KN, Storey GN, Henderson-Smart DJ. Fifth day fits in the newborn. Aust Paediatr J. 1989 Oct. 25(5):284-7. [Medline].
Mizrahi EM, Clancy RR. Neonatal seizures: early-onset seizure syndromes and their consequences for development. Ment Retard Dev Disabil Res Rev. 2000. 6(4):229-41. [Medline].
Camfield PR, Dooley J, Gordon K, et al. Benign familial neonatal convulsions are epileptic. J Child Neurol. 1991 Oct. 6(4):340-2. [Medline].
Tibbles JA. Dominant benign neonatal seizures. Dev Med Child Neurol. 1980 Oct. 22(5):664-7. [Medline].
Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger J. Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol. 2011 Jan. 15(1):1-7. [Medline].
Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology. 2006 Jun 13. 66(11):1654-60. [Medline].
Glass HC, Wirrell E. Controversies in neonatal seizure management. J Child Neurol. 2009 May. 24(5):591-9. [Medline].