Medical Toxicology and Adverse Drug Experience

, Volume 2, Issue 5, pp 324–337 | Cite as

The Risk-Benefit Ratio of Anticonvulsant Drugs

  • M. J. Eadie
Adverse Drug Experience Review

Summary

The concepts underlying the notion of a risk-benefit ratio for anticonvulsant therapy have determined the development of the drug treatment of epilepsy over many years. The risk element in the ratio arises from the various possible physical and psychological adverse effects of anticonvulsant therapy; the benefit is derived from the capacity of therapy to prevent seizures and thus reduce the disadvantages which result from having epilepsy.

The physical adverse effects of anticonvulsant therapy may involve many tissues and organs. The drugs tend to depress cerebral, cerebellar and brain stem function, and may slow peripheral nerve conduction. Prolonged intake may cause hypocalcaemia and osteoporosis, folate depletion, various haematological and immunological abnormalities, and overgrowth of subcutaneous and gingival tissues. Idiopathic reactions may involve the skin, lymph nodes, liver, pancreas, kidney and thyroid, and cause electrolyte disturbances, while maternal anticonvulsant intake during pregnancy may be associated with an increased incidence of fetal malformations. Local reactions may occur at drug administration sites, and anticonvulsants may interact pharmacokinetically and pharmacodynamically with co-administered drugs. The taking of anticonvulsants sometimes has undesirable psychological effects on both the patient and his or her family.

Epilepsy itself often results in adverse psychological consequences which emanate from the uncertainty and insecurity that is imposed by the unpredictable occurrence of seizures, from the limitations epilepsy sets on the patient’s lifestyle and employment prospects, and from unfavourable community attitudes towards the disorder. Contemporary anticonvulsant therapy is not fully effective in all patients, but to the extent that it can control seizures it may help alleviate these emotional burdens that are a result of epilepsy.

The consensus of present day medical opinion is that, in the great majority of clinical situations, the benefits of anticonvulsant therapy outweigh the disadvantages. However, to provide optimal management for individual patients, the risk-benefit ratio of therapy must be repeatedly assessed at all stages of a patient’s treatment, and therapeutic decisions taken in the light of the ratio as it applies to the individual.

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References

  1. Aarli JA. Drug-induced IgA deficiency in epileptic patients. Archives of Neurology 33: 296–299, 1976PubMedCrossRefGoogle Scholar
  2. Aarli JA, Gilhus NE. Antiepileptic drugs and resistance to infections. In Oxley et al. (Eds) Chronic toxicity of antiepileptic drugs, pp. 261–267, Raven Press, New York, 1983Google Scholar
  3. Aarskog D. Association between maternal intake of diazepam and oral clefts. Lancet 2: 921, 1975PubMedCrossRefGoogle Scholar
  4. Agarwal BN, Cabebe FG, Hoffman BI. Diphenylhydantoin induced acute renal failure. Nephron 18: 249–251, 1977PubMedCrossRefGoogle Scholar
  5. Albengres E, Tillement JP. Phenytoin in pregnancy: a review of the reported risks. Biological Research in Pregnancy 4: 71–74, 1983Google Scholar
  6. Andrewes DG, Tomlinson L, Elwes RDC, Reynolds EH. The influence of carbamazepine and phenytoin on memory and other aspects of cognitive function in new referrals with epilepsy. Acta Neurologica Scandinavica 99 (Suppl.): 23–30, 1984PubMedCrossRefGoogle Scholar
  7. Angelopoulos AP, Goaz PW. Incidence of diphenylhydantoin gingival hyperplasia. Oral Surgery 34: 898–906, 1972CrossRefGoogle Scholar
  8. Annegers JF, Elveback LR, Hauser WA, Kurland LT. Do anti-convulsants have a teratogenic effect? Archives of Neurology 31: 364–373, 1974PubMedCrossRefGoogle Scholar
  9. Beernink DH, MillerIII JJ. Anticonvulsant induced antinuclear antibodies and lupus like disease in children. Journal of Pediatrics 82: 113–117, 1973PubMedCrossRefGoogle Scholar
  10. Beghi E, DiMasus R, Tognoni G. Drug treatment of epilepsy: outlines, criticism and perspectives. Drugs 31: 249–265, 1986PubMedCrossRefGoogle Scholar
  11. Bjerkedal T. Czeizerl A, Goujard J, Kallen B, Mastroiacova P, et al. Valproic acid and spina bifida. Lancet 2: 1096, 1982PubMedCrossRefGoogle Scholar
  12. Bodensteiner JB, Morris HH, Golden GS. Asterixis associated with sodium valproate. Neurology 31: 194–195, 1981PubMedCrossRefGoogle Scholar
  13. Chadwick D, Reynolds EH, Marsden CD. Anticonvulsant-induced dyskinesias: a comparison with dyskinesias induced by neuroleptics. Journal of Neurology, Neurosurgery and Psychiatry 39: 1210–1218, 1976CrossRefGoogle Scholar
  14. Coulter DL, Allen RJ. Hyperammonemia with valproic acid therapy. Journal of Pediatrics 99: 317–319, 1981PubMedCrossRefGoogle Scholar
  15. Coulter DL, Allen RJ. Secondary hyperammonaemia: a possible mechanism for valproate encephalopathy. Lancet 1: 1310–1311, 1980PubMedCrossRefGoogle Scholar
  16. Danks DM, Barry JE, Sheffield LJ. Digital hypoplasia and anti-convulsants during pregnancy. Journal of Pediatrics 85: 877, 1974PubMedCrossRefGoogle Scholar
  17. Dent CE, Richens A, Rowe DJF, Stamp TCB. Osteomalacia with long-term anticonvulsant therapy. British Medical Journal 4: 69–72, 1970PubMedCrossRefGoogle Scholar
  18. Donaldson GWK, Graham JG. Aplastic anaemia following the administration of Tegretol. British Journal of Clinical Practice 19: 699–702, 1965PubMedGoogle Scholar
  19. Eadie MJ. Anticonvulsant drugs: an update. Drugs 27: 328–363, 1984PubMedCrossRefGoogle Scholar
  20. Eadie MJ. Unwanted effects of anticonvulsant drugs. In Tyrer JH (Ed.) The treatment of epilepsy, pp. 129–160, MTP Press, Lancaster, 1980Google Scholar
  21. Eadie MJ, Tyrer JH. Anticonvulsant therapy: pharmacological basis and practice, 2nd ed., Churchill-Livingstone, Edinburgh, 1980Google Scholar
  22. Falconer MA, Davidson S. Coarse features in epilepsy as a consequence of anticonvulsant therapy. Drugs 7: 394–395, 1974Google Scholar
  23. Fichsel H, Knopfle G. Effects of anticonvulsant drugs on thyroid hormone in epileptic children. Epilepsia 19: 323–336, 1978PubMedCrossRefGoogle Scholar
  24. Frey HH, Janz D (Eds). Antiepileptic drugs, Springer, Berlin, 1985Google Scholar
  25. Geraldini C, Faedda MT, Sideri G. Anticonvulsant therapy and its possible consequences on peripheral nervous system. Epilepsia 25: 502–505, 1984PubMedCrossRefGoogle Scholar
  26. Gilhus NE, Strandjord RE, Aarli JA. Respiratory disease in patients with epilepsy on single-drug therapy with carbamazepine or phenobarbital. European Neurology 21: 284–288, 1982PubMedCrossRefGoogle Scholar
  27. Goldberg EM, Sandbar SS. Hyperglycemic, non-ketotic coma following administration of Dilantin (diphenylhydantoin). Diabetes 18: 101–106, 1969PubMedGoogle Scholar
  28. Gram L, Bentsen KD. Hepatic toxicity of antiepileptic drugs: a review. Acta Neurologica Scandinavica 68 (Suppl. 97): 81–90, 1983CrossRefGoogle Scholar
  29. Hegarty JE, Dundee JW. Sequelae after intravenous injection of three benzodiazepines — diazepam, lorazepam and flunitrazepam. British Medical Journal 2: 1384–1385, 1977PubMedCrossRefGoogle Scholar
  30. Hunter J, Maxwell JD, Stewart DA, Parsons V, Williams R. Altered calcium metabolism in epileptic children on anticonvulsants. British Medical Journal 4: 202–204, 1971PubMedCrossRefGoogle Scholar
  31. Hyman NM, Dennis PD, Sinclair KGA. Tremor due to sodium valproate. Neurology 29: 1177–1180, 1979PubMedCrossRefGoogle Scholar
  32. Inoue F. Clinical implications of anticonvulsant-induced folate deficiency. Clinical Pharmacy 1: 372–373, 1982PubMedGoogle Scholar
  33. Janz D. The teratogenic risk of antiepileptic drugs. Epilepsia 16: 159–169, 1975PubMedCrossRefGoogle Scholar
  34. Janz D, Piltz U. Frozen shoulder induced by primidone. In Oxley et al. (Eds) Chronic toxicity of antiepileptic drugs, pp. 155–159, Raven Press, New York, 1983Google Scholar
  35. Jeavons PM. Hepatotoxicity of antiepileptic drugs. In Oxley et al. (Eds). Chronic toxicity of antiepileptic drugs, pp. 1–45, Raven Press, New York, 1983Google Scholar
  36. Jeavons PM. Sodium valproate and neural tube defects. Lancet 2: 1282–1283, 1982Google Scholar
  37. Kapur RN, Girgis S, Little TM, Masotti RE. Diphenylhydantoin-induced gingival hyperplasia: its relationship to dose and serum level. Developmental Medicine and Child Neurology 15: 483–487, 1973PubMedCrossRefGoogle Scholar
  38. Kattan KR. Thickening of the heel pad associated with long term dilantin therapy. American Journal of Roentgenology 124: 52–56, 1975Google Scholar
  39. Kuiper JJ. Lymphocytic thyroiditis possibly induced by diphenylhydantoin. Journal of the American Medical Association 210: 2370–2372, 1969PubMedCrossRefGoogle Scholar
  40. Kurtzke JF. Leukopenia with diphenylhydantoin. Journal of Nervous and Mental Diseases 132: 339–343, 1961CrossRefGoogle Scholar
  41. Kutt H. Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 25 (Suppl. 2): 118–131, 1984CrossRefGoogle Scholar
  42. Laiwah AACY, Rapeport WG, Thompson GG, MacPhee GJA, Philip MF, et al. Carbamazepine-induced non-hereditary acute porphyria. Lancet 1: 790–792, 1983CrossRefGoogle Scholar
  43. Lehmann DF. Primidone crystalluria following overdose: a report of a case and an analysis of the literature. Medical Toxicology 2: 383–387, 1987PubMedGoogle Scholar
  44. Lindhout D, Schmidt D. In-utero exposure to valproate and neural tube defects. Lancet 1: 1392–1393, 1986PubMedCrossRefGoogle Scholar
  45. Livingstone S. Comprehensive management of epilepsy in infancy, childhood and adolescence, Charles C Thomas, Springfield, 1972Google Scholar
  46. Loiseau P. Sodium valproate, platelet dysfunction and bleeding. Epilepsia 22: 141–146, 1981PubMedCrossRefGoogle Scholar
  47. Lovelace RE, Horowitz SJ. Peripheral neuropathy in long-term diphenylhydantoin therapy. Archives of Neurology 18: 69–77, 1968PubMedCrossRefGoogle Scholar
  48. Luhdorf K, Lund M. Phenytoin-induced hyperkinesia. Epilepsia 18: 409–415, 1977PubMedCrossRefGoogle Scholar
  49. Malherbe G, Burrill KC, Levin SR, Karam JH, Forsham PH. Effect of diphenylhydantoin in insulin secretion in man. New England Journal of Medicine 286: 339–342, 1972PubMedCrossRefGoogle Scholar
  50. Marescaux C, Warter JM, Micheletti G, Rumbach L, Coquillat G, et al. Stuporous episodes during treatment with sodium valproate: report of seven cases. Epilepsia 23: 297–305, 1982PubMedCrossRefGoogle Scholar
  51. Mosenkilde L, Meisen F. Anticonvulsant osteomalacia determined by quantitative analysis of bone changes: population study and possible risk factors. Acta Medica Scandinavica 199: 349–355, 1976CrossRefGoogle Scholar
  52. Nakane Y, Okuma T, Takahashi R, Sato Y, et al. Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan. Epilepsia 21: 663–680, 1980PubMedCrossRefGoogle Scholar
  53. Nau H, Loscher W. Valproic acid and metabolites: pharmacological and toxicological studies. Epilepsia 25 (Suppl. 1): 14–22, 1984CrossRefGoogle Scholar
  54. Offermann G. Chronic antiepileptic drug treatment and disorders of mineral metabolism. In Oxley et al. (Eds) Chronic toxicity of antiepileptic drugs, pp. 175–184, Raven Press, New York, 1983Google Scholar
  55. Oxley J, Janz D, Meinardi H. Chronic toxicity of antiepileptic drugs, Raven Press, New York, 1983Google Scholar
  56. Perucca E. Pharmacokinetic interactions with antiepileptic drugs. Clinical Pharmacokinetics 7: 57–84, 1982PubMedCrossRefGoogle Scholar
  57. Powell-Jackson PR, Tredger JM, Williams R. Hepatotoxicity to sodium valproate: a review. Gut 25: 673–681, 1984PubMedCrossRefGoogle Scholar
  58. Quijano T, del Ser ?, Pareja FB, Munoz-Garcia D, Sanchez AP. Psychological disturbances and folic acid in chronic epileptic outpatients. Epilepsia 24: 588–596, 1983CrossRefGoogle Scholar
  59. Rallison ML, Carlisle JW, Lee RE, Vernier RL, Good RA. Lupus erythematosus and Stevens-Johnson syndrome. American Journal of Diseases of Childhood 101: 725–738, 1961Google Scholar
  60. Rapp RP, Norton JA, Young B, Tibbs PA. Cutaneous reactions in head-injured patients receiving phenytoin for seizure prophylaxis. Neurosurgery 13: 272–275, 1983PubMedCrossRefGoogle Scholar
  61. Rausing A, Trell E. Malignant lymphogranulomatosis and anticonvulsant therapy. Acta Medica Scandinavica 189: 131–136, 1971PubMedCrossRefGoogle Scholar
  62. Richens A. Interactions with antiepileptic drugs. Drugs 13: 266–275, 1977PubMedCrossRefGoogle Scholar
  63. Riva R, Albani F, Ambrosetto G, Contin M, Cortelli P, et al. Diurnal fluctuations in free and total steady-state plasma levels of carbamazepine and correlation with intermittent side effects. Epilepsia 25: 476–481, 1984PubMedCrossRefGoogle Scholar
  64. Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 2: 937, 1982PubMedCrossRefGoogle Scholar
  65. Rodin EA. The prognosis of patients with epilepsy, Charles C Thomas, Springfield, 1968Google Scholar
  66. Saltzstein SL, Ackermann LV. Lymphadenopathy induced by anticonvulsant drugs and mimicking clinically and pathologically malignant lymphoma. Cancer 12: 164–182, 1959PubMedCrossRefGoogle Scholar
  67. Schmidt D. Connective tissue disorders induced by antiepileptic drugs. In Oxley et al. (Eds) Chronic toxicity of antiepileptic drugs, pp. 115–124, Raven Press, New York, 1983Google Scholar
  68. Schmidt D, Einicke I, Hanel F. The influence of seizure type on the efficacy of plasma concentrations of phenytoin, phenobarbital and carbamazepine. Archives of Neurology 43: 263–265, 1986PubMedCrossRefGoogle Scholar
  69. Schmidt D, Kluge W. Fatal toxic epidermal necrolysis following re-exposure to phenytoin: a case report. Epilepsia 24: 440–443, 1983PubMedCrossRefGoogle Scholar
  70. Serrano EE, Wilder BJ. Intramuscular administration of diphenylhydantoin: histologic follow-up study. Archives of Neurology 31: 276–278, 1974PubMedCrossRefGoogle Scholar
  71. Shorvon SD, Reynolds EH. Anticonvulsant peripheral neuropathy: a clinical and electrophysiological study of patients on single drug treatment with phenytoin, carbamazepine or barbiturates. Journal of Neurology, Neurosurgery and Psychiatry 45: 620–626, 1982CrossRefGoogle Scholar
  72. Silverstein FS, Parrish MA, Johnston MV. Adverse behavioral reactions in children treated with carbamazepine (Tegretol). Journal of Pediatrics 101: 785–787, 1982PubMedCrossRefGoogle Scholar
  73. Simpson JR. Collagen disease due to carbamazepine (Tegretol). British Medical Journal 2: 1434, 1966PubMedCrossRefGoogle Scholar
  74. Singsen BH, Fishman L, Hanson V. Antinuclear antibodies and lupus-like syndromes in children receiving anticonvulsants. Pediatrics 57: 529–534, 1976PubMedGoogle Scholar
  75. Smith NJ, Espir MLE, Baylis PH. Raised plasma arginine vasopressin concentration in carbamazepine-induced water intoxication. British Medical Journal 2: 804, 1977PubMedCrossRefGoogle Scholar
  76. Solomon GE, Hilgartner MW, Kutt H. Coagulation defects caused by diphenylhydantoin. Neurology 22: 1165–1171, 1972PubMedCrossRefGoogle Scholar
  77. Stalnikowicz R, Mosseri M, Shalev O. Phenytoin-induced arthritis. Neurology 32: 1317–1318, 1982PubMedCrossRefGoogle Scholar
  78. Stilman N, Masdeu JC. Incidence of seizures with phenytoin toxicity. Neurology 35: 1769–1772, 1985PubMedCrossRefGoogle Scholar
  79. Temkin O. The falling sickness, 2nd ed., Johns Hopkins Press, Baltimore, 1971Google Scholar
  80. Thompson PJ, Trimble MR. Anticonvulsant serum levels: relationship to impairments of cognitive functioning. Journal of Neurology, Neurosurgery and Psychiatry 46: 227–233, 1983CrossRefGoogle Scholar
  81. Trimble MR, Thompson PJ. Anticonvulsant drugs, cognitive function, and behaviour. Epilepsia 24 (Suppl. 1): 55–63, 1983CrossRefGoogle Scholar
  82. Troupin AS, Ojemann LM. Paradoxical intoxication: a complication of anticonvulsant intoxication. Epilepsia 16: 753–758, 1976CrossRefGoogle Scholar
  83. Troupin AS, Ojemann LM, Dodrill CB. Mephenytoin: a reappraisal. Epilepsia 17: 403–414, 1976PubMedCrossRefGoogle Scholar
  84. Warter JM, Brandt C, Marescaux C, Rumbach L, Micheletti G, et al. The renal origin of sodium valproate-induced hyper-ammonemia in fasting humans. Neurology 33: 1136–1140, 1983PubMedCrossRefGoogle Scholar
  85. Williams LHP, Reynolds RP, Emery JL. Pancreatitis during sodium valproate treatment. Archives of Disease in Childhood 58: 543–544, 1983PubMedCrossRefGoogle Scholar
  86. Woodbury DM, Penry JK, Pippenger CE (Eds). Antiepileptic drugs, 2nd ed., Raven Press, New York, 1982Google Scholar
  87. Zafrani ES, Berthelot P. Sodium valproate in the induction of unusual hepatotoxicity. Hepatology 2: 648–649, 1982PubMedCrossRefGoogle Scholar
  88. Zimmerman HJ, Ishak KG. Valproate-induced hepatic injury: analysis of 23 fatal cases. Hepatology 2: 591–597, 1982PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Limited 1987

Authors and Affiliations

  • M. J. Eadie
    • 1
  1. 1.University of QueenslandBrisbaneAustralia

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