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Published: July 1998

Anticonvulsant Hypersensitivity Syndrome

Prescriber Update 16: 28–31
July 1998

Dr Sonya Havill, Dermatology Registrar and Dr Marius Rademaker, Dermatologist, Health Waikato, Hamilton

Anticonvulsant Hypersensitivity Syndrome occurs in some patients taking anticonvulsant medication. It is characterised by fever, rash, hepatitis and other multiorgan abnormalities. The mechanism is unknown. Patients who have experienced this syndrome should not receive anticonvulsants in the phenytoin category, carbamazepine, phenobarbitone and lamotrigine.

Anticonvulsant Hypersensitivity Syndrome (AHS) is a drug-induced, multiorgan syndrome which is potentially fatal. The syndrome has been reported with anticonvulsants such as carbamazepine, phenytoin, phenobarbitone and lamotrigine. Other medicines, such as sulphonamides, sulphones, allopurinol and NSAIAs (e.g. piroxicam), have also caused a multiorgan hypersensitivity syndrome.1-3 It is a clinical diagnosis. The interval between first drug exposure and symptoms is usually 2-4 weeks but has been reported in individuals receiving anticonvulsants for 3 months.1 The syndrome is more severe in previously sensitised individuals.4 The incidence of AHS is not known because of the variability in presentation, lack of strict diagnostic criteria and underreporting of cases.1 However, it is considered rare. Whilst up to 1 in 5 patients on phenytoin may develop cutaneous eruptions, only a small proportion will progress to AHS.

Fever, rash and hepatitis are common features

Each clinical feature may be of variable onset, leading to confusion and delay in diagnosis.5 Fever is the most common feature, seen in 90-100% of cases.6,7 High and spiking fevers are characteristic although an intermittently elevated temperature may persist for weeks after the offending drug is discontinued.7 The fever may precede or be concurrent with the cutaneous eruption.6

A rash is present in 90% of cases.7 This is usually a macular erythema that becomes confluent and may generalise into erythroderma. The face, trunk and upper limbs are the first to be involved followed by the lower limbs. The rash may spare the face. Desquamation occurs with resolution. Periorbital and facial oedema may be severe and occurs in 25% of cases. Blistering may be seen over oedematous areas.7

A variety of other cutaneous reactions, not related to AHS, may be seen with anticonvulsants. These include urticaria, purpura, erythema multiforme, and exfoliative dermatitis.8 Toxic epidermal necrolysis, whilst uncommon, usually occurs in patients who are re-exposed or continue to receive anticonvulsants after hypersensitivity has developed.9

Hepatitis, seen in 50% of cases of AHS, is usually mild but can be severe.7,10 The mortality rate is between 18 and 40% if hepatitis is present. Liver function tests may be grossly elevated and continue to rise after the drug has been discontinued.7 Return of liver function tests to normal may take up to a year. Tender lymphadenopathy occurs in 70% of cases and may be either local or generalised. Splenomegaly may be seen.7

Fifty per cent of patients with AHS have haematological abnormalities. Leucocytosis with atypical lymphocytes and eosinophilia are most commonly seen.3 Coagulopathy may occur.7,11

Possibly allergy-mediated

The mechanism of AHS is unknown. There is no relation to dose or serum levels. There are some features to suggest that it is a form of allergic hypersensitivity.1 The phenytoin class of drugs is metabolised by cytochrome P-450 to intermediate metabolites, arene oxides. Arene oxides can contribute to an immunological response or even cause cell death.12,13 They are usually detoxified by epoxide hydroxylase but there is evidence that the individuals who develop AHS are unable to detoxify arene oxides. Family members may have a similar inability to detoxify arene oxides which could account for the reported familial cases.12,14

Clinical diagnosis

The high rate of cross reactivity between the phenytoin group of drugs is of concern to those treating seizure disorders as it limits treatment choices.12,15 If the diagnosis of AHS is in doubt and seizure control with one of these medications is required, patch testing may be helpful.4,16 It is recommended that negative patch tests should be repeated several months after an episode of AHS, as delayed results have been reported.16 In vitro lymphocyte transformation tests have also been used to diagnose AHS.12 However, they are not generally available in clinical practice. Both tests are reliable only after the signs of AHS have subsided.4

Discontinue medicine and provide general supportive measures

Treatment of AHS is largely symptomatic. The offending medicine should be immediately discontinued.7 Topical steroids and antihistamines are helpful in controlling symptoms associated with the rash. Systemic corticosteroids are often used, although there have been no trials to assess the efficacy of this treatment. It appears that they may benefit the cutaneous but not the systemic manifestations of the syndrome.1 Supportive care and monitoring of haematological and biochemical values is important. Relapse of the condition is often seen.1

Patients who have experienced AHS should avoid arene oxide anticonvulsants (carbamazepine, phenytoin and phenobarbitone) in the future. All cases of AHS should be reported to the Centre for Adverse Reactions Monitoring.

Conclusion

Anticonvulsant Hypersensitivity Syndrome should be considered in any patient treated with phenytoin, carbamazepine or phenobarbitone who presents with fever, rash or lymphadenopathy. The medication should be immediately discontinued pending investigation. Although the syndrome is rare, recognition is essential to avoid considerable morbidity and possible fatal outcome.

Correspondence to Dr Marius Rademaker, Director of Dermatology, Health Waikato, Hamilton. phone 07 839 8944, fax 07 839 8787, e-mail rademakm@hwl.co.nz

References
  1. Silverman AK, Fairley J, Wong RC. Cutaneous and immunologic reactions to phenytoin. J Am Acad Dermatol 1988;18:721-41.
  2. Prussick R, Shear NH. Dapsone hypersensitivity syndrome. J Am Acad Dermatol 1996;35:346-9.
  3. Ray-Chaudhuri K, Pye IF, Boggild M. Hypersensitivity to carbamazepine presenting with a leukemoid reaction, eosinophilia, erythroderma and renal failure. Neurology 1989;39:436-8.
  4. De Vriese ASP, Philippe J, Van Renterghem DM, De Cuyper CA, et al. Carbamazepine Hypersensitivity Syndrome: report of 4 cases and review of the literature. Medicine 1995;74:144-52.
  5. Haruda H. Phenytoin hypersensitivity: 38 cases. Neurology 1979;29:1480-5.
  6. Chang DKM, Shear NH. Cutaneous reactions to anticonvulsants. Semin Neurol 1992;12:329-37.
  7. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Int Med 1995;155:2285-93.
  8. Champion RH, Burton JL, Ebling FGJ. Textbook of Dermatology. Fifth edition. London: Blackwell Science Publications, 1992:2986-7.
  9. Schmidt D, Kluge W. Fatal toxic epidermal necrolysis following reexposure to phenytoin: a case report. Epilepsia 1983;24:440-3.
  10. Smythe MA, Umstead GS. Phenytoin hepatotoxicity: a review of the literature. Ann Pharmacother 1989;23:13-18.
  11. Handfield-Jones SE, Jenkins RE, Whittaker SJ, Besse CP, McGibbon DH. The anticonvulsant hypersensitivity syndrome. British J Dermatol 1993;129:175-7.
  12. Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome: in vitro assessment of risk. J Clin Invest 1988;82:1826-32.
  13. Spielberg SP, Gordon GB, Blake DA, Goldstein DA, Herlong HF. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 1981;305:722-7.
  14. Gennis MA, Vemuri R, Burns EA, Hill JV, Miller MA, Spielberg SP. Familial occurrence of hypersensitivity to phenytoin. Am J Med 1991;91:631-4.
  15. Spielberg SP, Gordon GB, Blake DA, Mellits ED, Bross DS. Anticonvulsant toxicity in vitro: possible role of arene oxides. J Pharmacol Exp Ther 1981;217:386-9.
  16. Howerzijl J, De Gast GC, Nater JP, Esselink MT, Niewig HO. Lymphocyte-stimulation tests and patch tests in carbamazepine hypersensitivity. Clin Exp Immunol 1977;29:272-7.

 

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