hypersensitivity syndrome is an idiosyncratic , serious drug reaction that consists of a rash , fever , involvement of multiple visceral organs , and hematological abnormalities such as eosinophilia .
to better individualize drug hypersensitivity reaction and to distinguish the hypersensitivity reaction from drug - induced pseudolymphoma , bocquet et al .
have recently introduced the term drug rash with eosinophilia and systemic symptoms ( dress ) syndrome ( 1 ) .
anticonvulsants are the principal drugs responsible for this malady . among them , arene oxide producing aromatic anticonvulsants such as phenytoin and carbamazepine are the particular drugs most frequently implicated for dress syndrome or the anticonvulsant hypersensitivity syndrome ( ahs ) ( 2 - 10 ) .
cross - reactivity among the aromatic anticonvulsants frequently occurs when a previous history of dress syndrome exists ( 10 - 12 ) .
many studies have described cross sensitivity as a worsening of the initial features of dress syndrome when switching from a sensitive anticonvulsant to a cross - reactive anticonvulsant ( 8,13 - 15 ) .
however limited data have described the development of dress syndrome after switching medication from a previously well - tolerated anticonvulsant to another ( 5 - 7 ) .
we present here a case of dress syndrome in which hypersensitivity reaction to a previously well - tolerated phenytoin was induced by hypersensitivity to carbamazepine , and we show that the patch test may be a useful method for detecting possible cross - reactive drugs in such situations .
a 40-yr - old man suffering from epilepsia presented with a generalized skin rash , facial edema , sore throat and high - grade fever of 3-day duration .
he had been taken phenytoin and sodium valproate for 4 yr without having any adverse reaction .
because of several attacks of seizure while taking these anticonvulsants , the medications were switched to carbamazepine and sodium valproate 16 weeks before the onset of skin rash and fever . at admission
his temperature was 38.9 , blood pressure 90/50 mmhg , pulse 140 beats / min , and respiratory rate 17 breaths / min . on physical examination , generalized ,
diffuse , maculopapular , erythematous , pruritic rash was noted over the face , trunk and extremities with marked facial edema ( fig .
1 ) . he had moderately enlarged tonsils , injected oropharynx , and bilateral cervical lymphadenopathy .
the laboratory studies showed a leukocytosis of 16.110/l with an eosinophilia of 2.710/l ( table 1 ) .
the creactive protein was high at 11.3 mg / dl ( normal < 0.3 mg / dl ) , and the erythrocyte sedimentation rate was 2 mm in the first hour .
iu / l ) , alanine aminotransferase 122 iu / l ( normal 10 - 72
iu / l ) , alkaline phosphatase 232 iu / l ( normal 30 - 140
serology for antinuclear factor , ra factor , hbs ag , anti - hiv antibodies , anti - mycoplasma antibodies , igm anti - eb virus antibodies , anti - hantan virus antibodies , anti - leptospiral antibodies , anti - rickettsial antibodies , p - anca and c - anca antibodies was all negative .
skin biopsy showed moderate perivascular and interstitial infiltration of lymphocytes , eosinophils with exocytosis , basal cell vacuolization and marked upper dermal edema .
the diagnosis of dress syndrome due to carbamazepine was proposed on the basis of his clinical and biological findings .
carbamazepine was discontinued , phenytoin was restarted at the dose of 300 mg / day , and he was also treated with prednisolone ( 40 mg / day ) . however , during the next 7 days his skin rashes and facial edema progressively worsened , and mucosal lesions developed with the persistence of fever ( fig .
rapid progression of the leukocytosis with an eosinophilia was also noted ( table 1 ) . on the seventh day of hospitalization ,
phenytoin was stopped while continuing prednisolone based on a presumed diagnosis of hypersensitivity reaction to phenytoin .
there was marked improvement in his general condition over the next several days with subsidence of the fever .
following the resolution of his skin eruption and laboratory abnormalities , the prednisolone was tapered over the next 3 weeks . after obtaining informed consent , patch test
several anticonvulsants including carbamazepine and phenytoin were tested at concentrations of 1% and 10% in petrolatum with / without 1% and 10% in water . using finn chambers on scanopor tape , 2-day closed patch testing was performed on the backs of the patient .
the reactions were scored at 30 min after removal and 4 days after application , according to the international contact dermatitis research group recommendations ( 16,17 ) .
carbamazepine and phenytoin patch tests were positive at day 2 and day 4 , however , phenobarbital , sodium valproate , topiramate , gabapentin , and vigabatrin showed no significant response on the patch tests ( fig .
, he was completely asymptomatic and was tolerating sodium valproate ( 1,200 mg / day ) and topiramate ( 250 mg / day ) .
dress syndrome can manifest 1 - 8 weeks after starting the anticonvulsant therapy with a mean of 3 weeks ( 11 - 13,18 ) . in previously sensitized individuals
the patient had no known exposure to other medications that have been implicated in development of the dress syndrome .
various factors may have contributed to this long induction period ; interindividual variations , individual susceptibility , and induction of the carbamazepine metabolism via the hepatic cytochrome p-450 system by the previously administered phenytoin , which might have reduced the tendency to develop dress syndrome .
cross sensitivity among the aromatic anticonvulsants occurs at a rate as high as 80% ( 11,12 )
. however , development of dress syndrome to one anticonvulsant after switching medication , and the subsequent development of hypersensitivity to a previously well - tolerated anticonvulsant upon second exposure rarely occurs ( 5 - 7 ) . for most of these cases
, there was no objective evidence about secondary induction of hypersensitivity to a previously tolerated drug , and only a presumptive diagnosis was made based on the clinical manifestations ( 5,7 ) .
some patients with dress syndrome may have flare - up of symptoms 3 to 4 weeks after the initiation of the reaction despite the discontinuation of the offending drug .
in addition , once the offending drug is discontinued , those organs initially involved may show progressive changes or organs that were previously uninvolved may manifest involvement ( 11 ) .
therefore , we can not exclude the possibility that the worsening of the clinical features was not due to cross - reactivity but due to the natural course of the dress syndrome in some reports ( 5,7 ) .
klassen and sadler ( 6 ) only showed induction of hypersensitivity to the previously tolerated phenytoin by carbamazepine with the reintroduction of phenytoin to the patient . the initial lack of adverse reaction to phenytoin , followed by immediate adverse response on later rechallenge several months after development of hypersensitivity to carbamazepine indirectly suggest induction of hypersensitivity to phenytoin in that report . besides the clinical features , we showed induction of hypersensitivity to phenytoin with the results of the patch tests .
the diagnosis of dress syndrome is made based on the history of drug exposure and clinical examination .
the differential diagnosis includes other cutaneous drug reactions , acute infections , neoplastic , and other immunologic disorders .
withdrawal of the suspicious drug and subsequent improvement of clinical manifestations makes the diagnosis more reliable .
when anticonvulsant therapy is invaluable , however , additional diagnostic methods can be sought to select safe drugs for seizure control .
although no gold standard exists , in vitro lymphocyte toxicity assay or lymphocyte transformation tests ( ltt ) , and in vivo patch tests may be helpful in such situations .
many studies have showed the usefulness of ltt and patch testing for the diagnosis of hypersensitivity to anticonvulsants ( 11,12,17 - 23 ) .
but false negative reaction of ltt was also noted in patients with simultaneous positive patch test ( 20 ) .
as patch testing is less cumbersome and seems more reliable , it is more frequently used in the case of diagnostic uncertainty ( 17,19 - 24 ) . positive rate of patch tests to carbamazepine were relatively high from 70% to 100% ( 20 - 24 ) . however ,
positive patch test results in phenytoin - induced ahs were much lower ( 30 - 60% ) than in carbamazepine - induced ahs ( 25,26 ) .
moreover , it is not yet known accurately how many patients who are on anticonvulsants have a positive patch test .
thus the diagnostic accuracy of patch test in dress syndrome is currently unknown . in general ,
positive predictive value of patch test is relatively good , but negative results of patch test can not exclude the possibility of hypersensitivity . if patch testing is to be performed , 1% and 10% carbamazepine or phenytoin in petrolatum , in water or in alcohol is recommended ( 11,19 ) .
it is also recommended that at least 2 months should elapse from the time of the skin eruption to the testing date since either false positive reactions due to increased reactivity or false negative reactions due to a refractory state may exist .
we performed patch tests 3 months after the total resolution of symptoms with several anticonvulsants at 1% and 10% concentrations , and both carbamazepine and phenytoin showed positive results . although we did not perform an oral rechallenge testing with phenytoin , the imputability of these two drugs was possible because of the clinical features and the in vivo patch test results .
aromatic anticonvulsants are metabolized by the cytochrome p-450 enzyme to a common arene oxide metabolite that is normally detoxified by enzyme systems such as epoxide hydrolase .
genetically determined abnormalities in enzyme systems leading to inability to detoxify toxic metabolites may be involved in the pathogenesis of ahs ( 11,12,25 ) .
reactive toxic metabolites irreversibly modify cellular proteins , and then initiate or serve as targets for an immune attack on modified proteins in target organs ( 27,28 ) . thus both pharmacogenetic and immunologic mechanism may play an important role in anticonvulsant - induced dress syndrome , and this immune response can explain the late induction of hypersensitivity to the previously tolerated phenytoin after sensitization to carbamazepine .
recent studies have strongly suggested that viral infections , especially reac - tivation of human herpesvirus 6 , contribute to the pathogen - esis of drug hypersensitivity to anticonvulsants ( 4,9,10 ) . however further study will be required to establish the relationship between human herpesvirus 6 infection and drug hypersensitivity . in conclusion , we present a case of carbamazepine - induced dress syndrome that also showed induction of hypersensitivity to the previously well - tolerated phenytoin .
our case suggests that physician should be aware that hypersensitivity to previously tolerated anticonvulsants can be induced by hypersensitivity to another anticonvulsant , and patch test may be a worthwhile method for detecting other possible cross - reactive drugs in such situations .
 drug rash with eosinophilia and systemic symptoms ( dress ) syndrome associated with anticonvulsant drugs is a rare but potentially life - threatening disease that occurs in response to arene oxide producing anticonvulsant such as phenytoin and carbamazepine . 
 there have been many reports of cross reactivity among the anticonvulsants upon first exposure to the offending drugs . 
 however , there has been few data describing the development of dress syndrome after switching medication from previously well - tolerated phenytoin to carbamazepine , and the induction of hypersensitivity to phenytoin by dress to carbamazepine . 
 we experienced a case of a 40-yr - old man who had uncontrolled seizure that led to the change of medication from the long - term used phenytoin to carbamazepine . 
 he developed dress syndrome after changing the drugs . 
 we stopped carbamazepine and restored phenytoin for seizure control , but his clinical manifestations progressively worsened and he recovered only when both drugs were discontinued . 
 patch tests with several anticonvulsants showed positive reactions to both carbamazepine and phenytoin . 
 our case suggests that hypersensitivity to a previously tolerated anticonvulsant can be induced by dress to another anticonvulsant , and that the patch test may be a useful method for detecting cross - reactive drugs in anticonvulsant - associated dress syndrome . 
INTRODUCTION
CASE REPORT
DISCUSSION