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The Risk-Benefit Ratio of Anticonvulsant Drugs

  • Adverse Drug Experience Review
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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

  • Aarli JA. Drug-induced IgA deficiency in epileptic patients. Archives of Neurology 33: 296–299, 1976

    Article  PubMed  CAS  Google Scholar 

  • 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, 1983

    Google Scholar 

  • Aarskog D. Association between maternal intake of diazepam and oral clefts. Lancet 2: 921, 1975

    Article  PubMed  CAS  Google Scholar 

  • Agarwal BN, Cabebe FG, Hoffman BI. Diphenylhydantoin induced acute renal failure. Nephron 18: 249–251, 1977

    Article  PubMed  CAS  Google Scholar 

  • Albengres E, Tillement JP. Phenytoin in pregnancy: a review of the reported risks. Biological Research in Pregnancy 4: 71–74, 1983

    CAS  Google Scholar 

  • 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, 1984

    Article  PubMed  CAS  Google Scholar 

  • Angelopoulos AP, Goaz PW. Incidence of diphenylhydantoin gingival hyperplasia. Oral Surgery 34: 898–906, 1972

    Article  CAS  Google Scholar 

  • Annegers JF, Elveback LR, Hauser WA, Kurland LT. Do anti-convulsants have a teratogenic effect? Archives of Neurology 31: 364–373, 1974

    Article  PubMed  CAS  Google Scholar 

  • Beernink DH, MillerIII JJ. Anticonvulsant induced antinuclear antibodies and lupus like disease in children. Journal of Pediatrics 82: 113–117, 1973

    Article  PubMed  CAS  Google Scholar 

  • Beghi E, DiMasus R, Tognoni G. Drug treatment of epilepsy: outlines, criticism and perspectives. Drugs 31: 249–265, 1986

    Article  PubMed  CAS  Google Scholar 

  • Bjerkedal T. Czeizerl A, Goujard J, Kallen B, Mastroiacova P, et al. Valproic acid and spina bifida. Lancet 2: 1096, 1982

    Article  PubMed  CAS  Google Scholar 

  • Bodensteiner JB, Morris HH, Golden GS. Asterixis associated with sodium valproate. Neurology 31: 194–195, 1981

    Article  PubMed  CAS  Google Scholar 

  • 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, 1976

    Article  CAS  Google Scholar 

  • Coulter DL, Allen RJ. Hyperammonemia with valproic acid therapy. Journal of Pediatrics 99: 317–319, 1981

    Article  PubMed  CAS  Google Scholar 

  • Coulter DL, Allen RJ. Secondary hyperammonaemia: a possible mechanism for valproate encephalopathy. Lancet 1: 1310–1311, 1980

    Article  PubMed  CAS  Google Scholar 

  • Danks DM, Barry JE, Sheffield LJ. Digital hypoplasia and anti-convulsants during pregnancy. Journal of Pediatrics 85: 877, 1974

    Article  PubMed  CAS  Google Scholar 

  • Dent CE, Richens A, Rowe DJF, Stamp TCB. Osteomalacia with long-term anticonvulsant therapy. British Medical Journal 4: 69–72, 1970

    Article  PubMed  CAS  Google Scholar 

  • Donaldson GWK, Graham JG. Aplastic anaemia following the administration of Tegretol. British Journal of Clinical Practice 19: 699–702, 1965

    PubMed  CAS  Google Scholar 

  • Eadie MJ. Anticonvulsant drugs: an update. Drugs 27: 328–363, 1984

    Article  PubMed  CAS  Google Scholar 

  • Eadie MJ. Unwanted effects of anticonvulsant drugs. In Tyrer JH (Ed.) The treatment of epilepsy, pp. 129–160, MTP Press, Lancaster, 1980

    Google Scholar 

  • Eadie MJ, Tyrer JH. Anticonvulsant therapy: pharmacological basis and practice, 2nd ed., Churchill-Livingstone, Edinburgh, 1980

    Google Scholar 

  • Falconer MA, Davidson S. Coarse features in epilepsy as a consequence of anticonvulsant therapy. Drugs 7: 394–395, 1974

    Google Scholar 

  • Fichsel H, Knopfle G. Effects of anticonvulsant drugs on thyroid hormone in epileptic children. Epilepsia 19: 323–336, 1978

    Article  PubMed  CAS  Google Scholar 

  • Frey HH, Janz D (Eds). Antiepileptic drugs, Springer, Berlin, 1985

    Google Scholar 

  • Geraldini C, Faedda MT, Sideri G. Anticonvulsant therapy and its possible consequences on peripheral nervous system. Epilepsia 25: 502–505, 1984

    Article  PubMed  CAS  Google Scholar 

  • 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, 1982

    Article  PubMed  CAS  Google Scholar 

  • Goldberg EM, Sandbar SS. Hyperglycemic, non-ketotic coma following administration of Dilantin (diphenylhydantoin). Diabetes 18: 101–106, 1969

    PubMed  CAS  Google Scholar 

  • Gram L, Bentsen KD. Hepatic toxicity of antiepileptic drugs: a review. Acta Neurologica Scandinavica 68 (Suppl. 97): 81–90, 1983

    Article  Google Scholar 

  • Hegarty JE, Dundee JW. Sequelae after intravenous injection of three benzodiazepines — diazepam, lorazepam and flunitrazepam. British Medical Journal 2: 1384–1385, 1977

    Article  PubMed  CAS  Google Scholar 

  • Hunter J, Maxwell JD, Stewart DA, Parsons V, Williams R. Altered calcium metabolism in epileptic children on anticonvulsants. British Medical Journal 4: 202–204, 1971

    Article  PubMed  CAS  Google Scholar 

  • Hyman NM, Dennis PD, Sinclair KGA. Tremor due to sodium valproate. Neurology 29: 1177–1180, 1979

    Article  PubMed  CAS  Google Scholar 

  • Inoue F. Clinical implications of anticonvulsant-induced folate deficiency. Clinical Pharmacy 1: 372–373, 1982

    PubMed  CAS  Google Scholar 

  • Janz D. The teratogenic risk of antiepileptic drugs. Epilepsia 16: 159–169, 1975

    Article  PubMed  CAS  Google Scholar 

  • 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, 1983

    Google Scholar 

  • Jeavons PM. Hepatotoxicity of antiepileptic drugs. In Oxley et al. (Eds). Chronic toxicity of antiepileptic drugs, pp. 1–45, Raven Press, New York, 1983

    Google Scholar 

  • Jeavons PM. Sodium valproate and neural tube defects. Lancet 2: 1282–1283, 1982

    Google Scholar 

  • 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, 1973

    Article  PubMed  CAS  Google Scholar 

  • Kattan KR. Thickening of the heel pad associated with long term dilantin therapy. American Journal of Roentgenology 124: 52–56, 1975

    CAS  Google Scholar 

  • Kuiper JJ. Lymphocytic thyroiditis possibly induced by diphenylhydantoin. Journal of the American Medical Association 210: 2370–2372, 1969

    Article  PubMed  CAS  Google Scholar 

  • Kurtzke JF. Leukopenia with diphenylhydantoin. Journal of Nervous and Mental Diseases 132: 339–343, 1961

    Article  CAS  Google Scholar 

  • Kutt H. Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia 25 (Suppl. 2): 118–131, 1984

    Article  Google Scholar 

  • Laiwah AACY, Rapeport WG, Thompson GG, MacPhee GJA, Philip MF, et al. Carbamazepine-induced non-hereditary acute porphyria. Lancet 1: 790–792, 1983

    Article  Google Scholar 

  • Lehmann DF. Primidone crystalluria following overdose: a report of a case and an analysis of the literature. Medical Toxicology 2: 383–387, 1987

    PubMed  CAS  Google Scholar 

  • Lindhout D, Schmidt D. In-utero exposure to valproate and neural tube defects. Lancet 1: 1392–1393, 1986

    Article  PubMed  CAS  Google Scholar 

  • Livingstone S. Comprehensive management of epilepsy in infancy, childhood and adolescence, Charles C Thomas, Springfield, 1972

    Google Scholar 

  • Loiseau P. Sodium valproate, platelet dysfunction and bleeding. Epilepsia 22: 141–146, 1981

    Article  PubMed  CAS  Google Scholar 

  • Lovelace RE, Horowitz SJ. Peripheral neuropathy in long-term diphenylhydantoin therapy. Archives of Neurology 18: 69–77, 1968

    Article  PubMed  CAS  Google Scholar 

  • Luhdorf K, Lund M. Phenytoin-induced hyperkinesia. Epilepsia 18: 409–415, 1977

    Article  PubMed  CAS  Google Scholar 

  • 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, 1972

    Article  PubMed  CAS  Google Scholar 

  • 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, 1982

    Article  PubMed  CAS  Google Scholar 

  • 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, 1976

    Article  Google Scholar 

  • 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, 1980

    Article  PubMed  CAS  Google Scholar 

  • Nau H, Loscher W. Valproic acid and metabolites: pharmacological and toxicological studies. Epilepsia 25 (Suppl. 1): 14–22, 1984

    Article  CAS  Google Scholar 

  • 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, 1983

    Google Scholar 

  • Oxley J, Janz D, Meinardi H. Chronic toxicity of antiepileptic drugs, Raven Press, New York, 1983

    Google Scholar 

  • Perucca E. Pharmacokinetic interactions with antiepileptic drugs. Clinical Pharmacokinetics 7: 57–84, 1982

    Article  PubMed  CAS  Google Scholar 

  • Powell-Jackson PR, Tredger JM, Williams R. Hepatotoxicity to sodium valproate: a review. Gut 25: 673–681, 1984

    Article  PubMed  CAS  Google Scholar 

  • Quijano T, del Ser ?, Pareja FB, Munoz-Garcia D, Sanchez AP. Psychological disturbances and folic acid in chronic epileptic outpatients. Epilepsia 24: 588–596, 1983

    Article  Google Scholar 

  • 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, 1961

    CAS  Google Scholar 

  • Rapp RP, Norton JA, Young B, Tibbs PA. Cutaneous reactions in head-injured patients receiving phenytoin for seizure prophylaxis. Neurosurgery 13: 272–275, 1983

    Article  PubMed  CAS  Google Scholar 

  • Rausing A, Trell E. Malignant lymphogranulomatosis and anticonvulsant therapy. Acta Medica Scandinavica 189: 131–136, 1971

    Article  PubMed  CAS  Google Scholar 

  • Richens A. Interactions with antiepileptic drugs. Drugs 13: 266–275, 1977

    Article  PubMed  CAS  Google Scholar 

  • 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, 1984

    Article  PubMed  CAS  Google Scholar 

  • Robert E, Guibaud P. Maternal valproic acid and congenital neural tube defects. Lancet 2: 937, 1982

    Article  PubMed  CAS  Google Scholar 

  • Rodin EA. The prognosis of patients with epilepsy, Charles C Thomas, Springfield, 1968

    Google Scholar 

  • Saltzstein SL, Ackermann LV. Lymphadenopathy induced by anticonvulsant drugs and mimicking clinically and pathologically malignant lymphoma. Cancer 12: 164–182, 1959

    Article  PubMed  CAS  Google Scholar 

  • 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, 1983

    Google Scholar 

  • 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, 1986

    Article  PubMed  CAS  Google Scholar 

  • Schmidt D, Kluge W. Fatal toxic epidermal necrolysis following re-exposure to phenytoin: a case report. Epilepsia 24: 440–443, 1983

    Article  PubMed  CAS  Google Scholar 

  • Serrano EE, Wilder BJ. Intramuscular administration of diphenylhydantoin: histologic follow-up study. Archives of Neurology 31: 276–278, 1974

    Article  PubMed  CAS  Google Scholar 

  • 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, 1982

    Article  CAS  Google Scholar 

  • Silverstein FS, Parrish MA, Johnston MV. Adverse behavioral reactions in children treated with carbamazepine (Tegretol). Journal of Pediatrics 101: 785–787, 1982

    Article  PubMed  CAS  Google Scholar 

  • Simpson JR. Collagen disease due to carbamazepine (Tegretol). British Medical Journal 2: 1434, 1966

    Article  PubMed  CAS  Google Scholar 

  • Singsen BH, Fishman L, Hanson V. Antinuclear antibodies and lupus-like syndromes in children receiving anticonvulsants. Pediatrics 57: 529–534, 1976

    PubMed  CAS  Google Scholar 

  • Smith NJ, Espir MLE, Baylis PH. Raised plasma arginine vasopressin concentration in carbamazepine-induced water intoxication. British Medical Journal 2: 804, 1977

    Article  PubMed  CAS  Google Scholar 

  • Solomon GE, Hilgartner MW, Kutt H. Coagulation defects caused by diphenylhydantoin. Neurology 22: 1165–1171, 1972

    Article  PubMed  CAS  Google Scholar 

  • Stalnikowicz R, Mosseri M, Shalev O. Phenytoin-induced arthritis. Neurology 32: 1317–1318, 1982

    Article  PubMed  CAS  Google Scholar 

  • Stilman N, Masdeu JC. Incidence of seizures with phenytoin toxicity. Neurology 35: 1769–1772, 1985

    Article  PubMed  CAS  Google Scholar 

  • Temkin O. The falling sickness, 2nd ed., Johns Hopkins Press, Baltimore, 1971

    Google Scholar 

  • Thompson PJ, Trimble MR. Anticonvulsant serum levels: relationship to impairments of cognitive functioning. Journal of Neurology, Neurosurgery and Psychiatry 46: 227–233, 1983

    Article  CAS  Google Scholar 

  • Trimble MR, Thompson PJ. Anticonvulsant drugs, cognitive function, and behaviour. Epilepsia 24 (Suppl. 1): 55–63, 1983

    Article  Google Scholar 

  • Troupin AS, Ojemann LM. Paradoxical intoxication: a complication of anticonvulsant intoxication. Epilepsia 16: 753–758, 1976

    Article  Google Scholar 

  • Troupin AS, Ojemann LM, Dodrill CB. Mephenytoin: a reappraisal. Epilepsia 17: 403–414, 1976

    Article  PubMed  CAS  Google Scholar 

  • 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, 1983

    Article  PubMed  CAS  Google Scholar 

  • Williams LHP, Reynolds RP, Emery JL. Pancreatitis during sodium valproate treatment. Archives of Disease in Childhood 58: 543–544, 1983

    Article  PubMed  CAS  Google Scholar 

  • Woodbury DM, Penry JK, Pippenger CE (Eds). Antiepileptic drugs, 2nd ed., Raven Press, New York, 1982

    Google Scholar 

  • Zafrani ES, Berthelot P. Sodium valproate in the induction of unusual hepatotoxicity. Hepatology 2: 648–649, 1982

    Article  PubMed  CAS  Google Scholar 

  • Zimmerman HJ, Ishak KG. Valproate-induced hepatic injury: analysis of 23 fatal cases. Hepatology 2: 591–597, 1982

    Article  PubMed  CAS  Google Scholar 

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    M. J. Eadie

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Eadie, M.J. The Risk-Benefit Ratio of Anticonvulsant Drugs. Med Toxicol Adverse Drug Exp 2, 324–337 (1987). https://doi.org/10.1007/BF03259952

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