Skip to main content
Log in

A Comparative Review of the Adverse Effects of Anticonvulsants in Children with Epilepsy

  • Review Article
  • Drug Experience
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

Phenobarbital (phenobarbitone) and phenytoin are the most useful anticonvulsants in neonates because adverse effects are most readily reversed when these drugs are used.

Most anticonvulsants are very rarely associated with haematological adverse effects. Platelet function is particularly vulnerable to valproic acid (sodium valproate) therapy.

Barbiturates and phenytoin can precipitate metabolic bone disease. Although very infrequent, lymphadenopathy is most common with phenytoin, and lupuslike illnesses with ethosuximide. Valproic acid may precipitate underlying metabolic disorders. Nephrolithiasis can occur with topiramate.

Liver disease is most likely with felbamate or valproic acid, but can occur with other anticonvulsants. Valproic acid and ethosuximide are the main precipitants of gastrointestinal symptomatology; while valproic acid and vigabatrin are frequently associated with excessive bodyweight gain.

Rash is most likely to occur with barbiturates, but there is a high risk of this adverse effect if large doses of lamotrigine are given with valproic acid. Adverse cosmetic effects are most likely with phenytoin, but valproic acid may cause alopecia.

All anticonvulsants may cause unwanted neurological effects: when they occur, diplopia is usually precipitated by carbamazepine; tremor by valproic acid; and other motor disturbances are probably most common with phenytoin. Most anticonvulsants can cause drowsiness. Phenobarbital leads anticonvulsants as a cause of behavioural difficulties. Effects of anticonvulsants on cognitive function are difficult to assess, but subtle changes have been reported for all anticonvulsants in use up to the 1980s. Compared with other anticonvulsant drugs, phenytoin and felbamate are more often discontinued as a result of unwanted effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Shaw PN, Houston JB, Rowland M, et al. Antipyrine metabolite kinetics in healthy human volunteers during multiple dosing of phenytoin and carbamazepine. Br J Clin Pharmacol 1985; 20: 611–8

    Article  PubMed  CAS  Google Scholar 

  2. Perucca E, Richens A. General principles: biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic Drugs. 4th ed. New York: Raven Press, 1995: 31–50

    Google Scholar 

  3. Connell J, Oozeer R, De Vries L, et al. Clinical and EEG responses to anticonvulsants in neonatal seizures. Arch Dis Child 1989; 64: 459–64

    Article  PubMed  CAS  Google Scholar 

  4. Bruni J. Phenytoin: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven, 1995: 345–50

    Google Scholar 

  5. Cramer JA, Mattson RH. Phenobarbital: toxicity. In Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic Drugs. 4th ed. New York: Raven, 1995: 409–20

    Google Scholar 

  6. Schiff D, Chan G, Stern L. Fixed drug combinations and the displacement of bilirubin from albumin. Pediatrics 1971; 48: 139–41

    PubMed  CAS  Google Scholar 

  7. Deshmukh A, Wittert W, Schnitzler E, et al. Lorazepam in the treatment of refractory neonatal seizures. Am J Dis Child 1986; 140: 1042–4

    PubMed  CAS  Google Scholar 

  8. McDermott CA, Kowalczyk AL, Schnitzler ER, et al. Clinical and laboratory observations: pharmacokinetics of lorazepam in critical ill neonates with seizures. J Pediatr 1992; 120: 479–83

    Article  PubMed  CAS  Google Scholar 

  9. Sinal SH, Crowe JE. Cyanosis, coughing and hypotension following intravenous administration of paraldehyde. Pediatrics 1976; 57: 158–9

    Google Scholar 

  10. Dreifuss FE. Valproic acid: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven, 1995: 641–8

    Google Scholar 

  11. Leppik I. Felbamate. Epilepsia 1995; 36Suppl. 2: S66–72

    Article  PubMed  CAS  Google Scholar 

  12. Holmes G. Carbamazepine: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven, 1995: 567–79

    Google Scholar 

  13. Dreifuss FE. Ethosuximide: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven, 1995: 675–9

    Google Scholar 

  14. Leppik IE, Cloyd JC. Primidone: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven, 1995: 487–90

    Google Scholar 

  15. Abu-Arafeh IA, Wallace SJ. Unwanted effects of antiepileptic drugs. Dev Med Child Neurol 1988; 30: 117–21

    Article  PubMed  CAS  Google Scholar 

  16. Mattson RH. Efficacy and adverse effects of established and new antiepileptic drugs. Epilepsia 1995: 36Suppl. 2: S13–26

    Article  PubMed  CAS  Google Scholar 

  17. Okuno T, Ho M, Nakano S, et al. Carbamazepine therapy and long-term prognosis in epilepsy of childhood. Epilepsia 1989; 30: 57–61

    Article  PubMed  CAS  Google Scholar 

  18. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995; 333: 1118–27

    Article  PubMed  CAS  Google Scholar 

  19. Loiseau P. Sodium valproate, platelet dysfunction and bleeding. Epilepsia 1981; 22: 141–6

    Article  PubMed  CAS  Google Scholar 

  20. Gidal B, Spencer N, Maly M, et al. Valproate mediated disturbances of hemostasis [letter]. Neurology 1994; 30: 354

    Google Scholar 

  21. Allarakhia IN, Garofalo EA, Komarynski MA, et al. Valproic acid and thrombocytopenia in children: a case-controlled retrospective study. Pediatr Neurol 1996; 14: 303–7

    Article  PubMed  CAS  Google Scholar 

  22. Appleton R. The role of vigabatrin in the management of infantile epileptic syndromes. Neurology 1993; 43Suppl. 5: S21–3

    PubMed  CAS  Google Scholar 

  23. Brodie MJ. Lamotrigine. Lancet 1992; 339: 1397–400

    Article  PubMed  CAS  Google Scholar 

  24. Ramsay RE. Gabapentin: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic Drugs. 4th ed. New York: Raven, 1995: 857–60

    Google Scholar 

  25. Leppik IE. Tiagabine: the safety landscape. Epilepsia 1995; 36Suppl. 6: S10–3

    Article  PubMed  CAS  Google Scholar 

  26. Reife RA, Pledger GW. Safety of topiramate in clinical use. Adv AED Ther 1995; 1(1): 24–9

    Google Scholar 

  27. Tada H, Wallace SJ, Hughes IA. Height in epilepsy. Arch Dis Child 1986; 61: 1224–6

    Article  PubMed  CAS  Google Scholar 

  28. Dam M, Ostergaard LH. Other Antiepileptic drugs: oxcarbazepine. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic Drugs. 4th ed. New York: Raven, 1995: 987–95

    Google Scholar 

  29. Schlumberger E, Chavez F, Palacios L, et al. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia 1994; 35: 359–67

    Article  PubMed  CAS  Google Scholar 

  30. Dodson WE. Felbamate in the treatment of Lennox-Gastaut Syndrome: results of a 12-month open-label study following a randomized clinical trial. Epilepsia 1993; 34Suppl. 7: S18–24

    Article  PubMed  Google Scholar 

  31. Bebin EM, Dogis TF, Dreifuss FE. Felbamate: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs, 4th ed. New York: Raven, 1995: 823–7

    Google Scholar 

  32. Dreifuss FE. Other antiepileptic drugs: bromides. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven, 1995: 949–51

    Google Scholar 

  33. Pellock JM. Carbamazepine side effects in children and adults. Epilepsia 1987; 28Suppl. 3: S64–70

    Article  PubMed  Google Scholar 

  34. Jeng Y-M, Tien H-F, Su I-J. Phenytoin-induced pseudolymphoma: re-evaluation using modern molecular biology techniques. Epilepsia 1996; 37(1): 104–7

    Article  PubMed  CAS  Google Scholar 

  35. Schaub JEM, Williamson PJ, Barnes EW, et al. Multisystem adverse reaction to lamotrigine [letter]. Lancet 1994; 344: 481

    Article  PubMed  CAS  Google Scholar 

  36. Baillie TA, Sheffels PR. Valproic acid: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic Drugs. 4th ed. New York: Raven, 1995: 589–604

    Google Scholar 

  37. Melegh B, Pap M, Morava E, et al. Carnitine-dependent changes of metabolic fuel consumption during long-term treatment with valproic acid. J Pediatr 1994; 125: 317–21

    Article  PubMed  CAS  Google Scholar 

  38. Thurston JH, Hauhart RE. Reversal of the adverse chronic effects of the unsaturated derivative of valproic acid — 2-n-pro-pyl-4-pentenoic acid — on ketogenesis and liver coenzyme A metabolism by a single injection of pantothenate, carnitine, and acetyl-cysteine in developing mice. Pediatr Res 1993; 33: 72–6

    Article  PubMed  CAS  Google Scholar 

  39. Murakami K, Sugimoto T, Nishira N, et al. Abnormal metabolism of carnitine and valproate in a case of acute encephalopathy during chronic valproate therapy. Brain Dev 1992; 14: 178–81

    Article  PubMed  CAS  Google Scholar 

  40. Kuhara T, Inoue Y, Matsumoto M, et al. Markedly increased co-oxidation of valproate in fulminant hepatic failure. Epilepsia 1990; 31: 214–7

    Article  PubMed  CAS  Google Scholar 

  41. Konig St A, Siemes H, Blaker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994; 35: 1005–15

    Article  Google Scholar 

  42. Bryant AE, Dreifuss FE. Valproic acid hepatic fatalities III: U.S. experience since 1986. Neurology 1996; 46: 465–9

    Article  PubMed  Google Scholar 

  43. Moore MR. International review of drugs in acute porphyria [letter]. Int J Biochem 1980; 12: 1089

    Article  PubMed  CAS  Google Scholar 

  44. Tatum WO, Zacharian SB. Gabapentin treatment of seizures in acute intermittent porphyria. Neurology 1995; 45: 1216–7

    Article  PubMed  Google Scholar 

  45. McLean MJ. Gabapentin. Epilepsia 1995; 36Suppl. 2: S73–86

    Article  PubMed  CAS  Google Scholar 

  46. Dreifuss FE, Santilli N, Langer DH, et al. Valproic acid hepatic fatalities: a retrospective review. Neurology 1987; 37: 379–85

    Article  PubMed  CAS  Google Scholar 

  47. Scheffner D, Konig S, Rauterberg-Rutland I, et al. Fatal liver failure in 16 children with valproate therapy. Epilepsia 1988; 29: 530–42

    Article  PubMed  CAS  Google Scholar 

  48. Herranz JL, Armijo JA, Artego R. Clinical side effects of phenobarbitone primidone, phenytoin, carbamazepine and valproate during monotherapy in children. Epilepsia 1988; 29: 794–804

    Article  PubMed  CAS  Google Scholar 

  49. Dulac O, Chiron C, Luna D, et al. Vigabatrin in childhood epilepsy. J Child Neurol 1991; 6Suppl. 2: S30–7

    Google Scholar 

  50. Feucht M, Brantner-Inthaler S. γ-vinyl GABA (vigabatrin) in the therapy of Lennox-Gastaut syndrome: an open study. Epilepsia 1994; 35(5): 993–8

    Article  PubMed  CAS  Google Scholar 

  51. Alving J. Case of severe acute intoxication with oxcarbazepine combined with lamotrigine [abstract]. Epilepsia 1994; 35Suppl. 7: 72

    Google Scholar 

  52. Aman MG, Werry JS, Paxton JW, et al. Effects of phenytoin on cognitive motor performance in children as a function of drug concentration, seizure type, and time of medication. Epilepsia 1994; 35: 172–80

    Article  PubMed  CAS  Google Scholar 

  53. Aman MG, Werry JS, Paxton JW, et al. Effect of sodium valproate on psychomotor performance in children as a function of dose, fluctuations in concentration, and diagnosis. Epilepsia 1987; 28: 115–28

    Article  PubMed  CAS  Google Scholar 

  54. Steinhoff BJ, Kruse R. Bromide treatment of pharmaco-resistant epilepsy with generalised tonic-clonic seizures: a clinical study. Brain Dev 1992; 14: 144–9

    Article  PubMed  CAS  Google Scholar 

  55. Corbett JA, Trimble MR, Nichol RC. Behavioural and cognitive impairments in children with epilepsy: the long-term effects of anticonvulsant therapy. J Am Acad Child Psychiatry 1985; 24: 17–23

    Article  PubMed  CAS  Google Scholar 

  56. Vining EPG, Mellits ED, Dorsen MM, et al. Psychologic and behavioural effects of antiepileptic drugs in children: a double-blind comparative comparison between phenobarbital and valproic acid. Pediatrics 1987; 80: 165–74

    PubMed  CAS  Google Scholar 

  57. Ounsted C. The hyperkinetic syndrome in epileptic children. Lancet 1955; II: 303–11

    Article  Google Scholar 

  58. Wolf SM, Shinnar S, Hang H, et al. Gabapentin toxicity in children manifesting as behavioural changes. Epilepsia 1995; 36(12): 1203–5

    Article  PubMed  CAS  Google Scholar 

  59. Lee DO, Steingard RJ, Cesena M, et al. Behavioural side effects of gabapentin in children. Epilepsia 1996; 37(1): 87–90

    Article  PubMed  CAS  Google Scholar 

  60. Camfield CS, Chaplin S, Doyle AB, et al. Side effects of phenobarbital in toddlers; behavioural and cognitive aspects. J Pediatr 1979; 95: 361–5

    Article  PubMed  CAS  Google Scholar 

  61. Canovas Martinez A, Ordovas Baines JP, Escriva Asparisi A, et al. Vigabatrin — associated reversible acute psychosis in a child. Ann Pharmacother 1995; 29: 1115–7

    PubMed  CAS  Google Scholar 

  62. Aldridge Smith J, Wallace SJ. Febrile convulsions: intellectual progress in relation to anticonvulsant therapy and recurrence of fits. Arch Dis Child 1982; 57: 104–7

    Article  Google Scholar 

  63. Chen Y, Kang W, Chin-Min So W. Comparison of antiepileptic drugs on cognitive function in newly diagnosed epileptic children: a psychometric and neurophysiological study. Epilepsia 1996; 37(1): 81–6

    Article  PubMed  CAS  Google Scholar 

  64. American Academy of Pediatrics’ Committee on Drugs. Behavioural and cognitive effects of anticonvulsant therapy. Pediatrics 1985; 76: 644–7

    Google Scholar 

  65. Stores G, Williams PL, Styles E, et al. Psychological effects of sodium valproate and carbamazepine in epilepsy. Arch Dis Child 1992; 67: 1330–7

    Article  PubMed  CAS  Google Scholar 

  66. Aldenkamp AP, Alpherts WCJ, Blennow G, et al. Withdrawal of antiepileptic medication in children — effects on cognitive function: the multicentre Holmfrid study. Neurology 1993; 43: 41–50

    Article  PubMed  CAS  Google Scholar 

  67. Forsythe I, Butler R, Berg I, et al. Cognitive impairment in new cases of epilepsy randomly assigned to carbamazepine, phenytoin and sodium valproate. Dev Med Child Neurol 1991; 33: 524–35

    Article  PubMed  CAS  Google Scholar 

  68. Shields WD, Saslow E. Myoclonic, atonic and absence seizures following institution of carbamazepine therapy in children. Neurology 1983; 33: 1487–9

    Article  PubMed  CAS  Google Scholar 

  69. Snead OC, Hosey LC. Exacerbation of seizures in children by carbamazepine. N Engl J Med 1985; 313: 916–21

    Article  PubMed  Google Scholar 

  70. Marciani MG, Gigli GL, Maschio CE, et al. Vigabatrin-induced myoclonus in four cases of partial epilepsy [abstract]. Epilepsia 1995; 36Suppl. 3: 107

    Google Scholar 

  71. Lortie A, Chiron C, Mumford J, et al. The potential for increasing seizure frequency, relapse and appearance of new seizure types with vigabatrin. Neurology 1993; 43Suppl. 5: S24–7

    PubMed  CAS  Google Scholar 

  72. Ceuleman B, Boel M. Lamotrigine: add on therapy in children with refractory epilepsies [abstract]. Epilepsia 1995; 36Suppl. 3: 110

    Google Scholar 

  73. Roussounis SH, Rudolf N de M. Clonazepam in the treatment of children with intractable seizures. Dev Med Child Neurol 1977; 19: 326–34

    Article  PubMed  CAS  Google Scholar 

  74. Piatella L, Zamponi N, Cardinali C. Vigabatrin versus carbamazepine in newly diagnosed partial epilepsy in childhood [abstract]. Epilepsia 1995; 36Suppl. 3: S103

    Google Scholar 

  75. Herranz JL, Campos J, Casas C, et al. Spanish experience with efficacy and tolerability of vigabatrin in 197 children with refractory epilepsy [abstract]. Epilepsia 1995; 36Suppl. 3: S103

    Google Scholar 

  76. Besag FMC, Wallace SJ, Dulac O, et al. Lamotrigine in the treatment of epilepsy in childhood. Pediatr Pharmacol Ther 1995; 127: 991–7

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wallace, S.J. A Comparative Review of the Adverse Effects of Anticonvulsants in Children with Epilepsy. Drug-Safety 15, 378–393 (1996). https://doi.org/10.2165/00002018-199615060-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199615060-00003

Keywords

Navigation