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Dilantin Hypersensitivity Syndrome

Dilantin, like most anticonvulsant drugs, demonstrates a variety of metabolic activity and thus may produce many untoward effects, both chronic and acute. A "phenytoin syndrome" has been recognized since 1950. This hypersensitivity syndrome is typically characterized by fever, cutaneous eruption, lymphadenopathy, and hepatitis, but may be accompanied by a constellation of other clinical manifestations. Among the latter are interstitial nephritis, anemia, interstitial pulmonary infiltrates, thrombocytopenia, eosinophilia, myopathy, and diffuse intravascular coagulation.

This distinctive hypersensitivity reaction occurs mainly in black males and has been seen in patients from the pediatric age group up to as old as 66 years. General hypersensitivity reactions to phenytoin are mild and not rare. In fact the incidence of mild morbilliform rash secondary to phenytoin therapy may be as high as 10%. The rash may become desquamative and pruritic in two thirds of the patients and is sometimes mistaken for rubella. The white blood count may be normal or low early but usually gives way to a brisk leukocytosis with marked eosinophilia and relative lymphocytosis. Eosinophilia occurs in upwards of 70% of cases, reaching counts of 35%. Atypical lymphocytes, possibly a reflection of changes in the lymph nodes, has been reported in nearly 40-50% of patients reaching a count of 48-50%. Atypical lymphocytes in the clinical syndrome may be confused with infectious mononucleosis.

The most worrisome aspect of the phenytoin hypersensitivity syndrome is the hepatotoxicity that may accompany this syndrome. In phenytoin- induced hepatotoxicity the liver damage may be one which resolves promptly or may proceed to fatal hepatic necrosis in up to 40% of patients. This hepatic necrosis will continue even after removal of the offending drug. The hepatotoxicity is often first noticed as pain in the right upper quadrant, elevation in the transaminase and jaundice. There is nothing specific about the liver biopsy which points to phenytoin hepatitis, although with the clinical syndrome, this histologic picture of hepatitis, with or without cholestasis but with eosinophilia, is suggestive.

There may be fatty infiltration or cellular infiltration, or both, with variable amounts of mononuclear cells, segmented leukocytes and eosinophils in the portal and lobular areas; or focal (centrilobular) or diffuse parenchymal necrosis. There may be necrotizing vasculitis. There is often sinusoidal budding and congestion with inspissated bile plugs. Overall there appears to be mixed hepatocellular damage of cholestasis and necrosis. Occasionally the clinical symptoms may recur after apparent recovery.

The pathogenesis of phenytoin-induced hepatotoxicity remains unexplained. Genetic susceptibility has been postulated, but the eosinophilia, rash, lymphadenopathy, fever and exfoliative dermatitis suggests a hypersensitivity reaction. Ten months after recovery from phenytoin hepatotoxicity, blood lymphocytes of one patient recognized the drug as a previously encountered antigen. Circulating antibodies to the drug hapten have also been demonstrated. The lack of relation between dose and blood level excludes a direct toxic effect.

It is hard to evaluate the effectiveness of proposed treatments for dilantin-induced hepatotoxicity because the outcome is unpredictable and some patients spontaneously improve. In any case, immediate withdrawal of phenytoin is mandatory. Steroids have been used in over half the cases of phenytoin-induced hepatotoxicity reported in the literature. Although they were thought to suppress the hypersensitivity phenomenon, they may not be beneficial, and may even be detrimental, because gastrointestinal hemorrhage and perforation may complicate therapy. Exchange blood transfusions have been employed, although some doubt has been expressed about their safety and efficacy. Another noted undesirable effect of steroid use is the occurrence of "flare-ups" when the dose of steroids is tapered after the reaction has cleared. Nonetheless, the outcome depends upon the severity and extent of the liver damage and treatment is mainly supportive.

Phenytoin-induced hepatotoxicity imparts significant morbidity and mortality. Potentially fatal hepatic necrosis can develop at virtually any time with any dose. Clinicians must be alert to patients receiving phenytoin therapy who present with vague complaints and symptom complexes suggestive of measles, infectious mononucleosis or influenza, inasmuch as early detection, intervention and treatment are mandatory for a successful outcome.