Pharmacological Reports Copyright © 2013 2013, 65, 399409 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Single centre 20 year survey of antiepileptic drug-induced hypersensitivity reactions
Barbara B³aszczyk1,2, Monika Szpringer3, Stanis³aw J. Czuczwar4,5, W³adys³aw Lasoñ6,7
1Faculty of Health Sciences, High School of Economics and Law, Jagielloñska 109 A, PL 25-734 Kielce, Poland
2Private Neurological Practice, Ró¿ana 8, PL 25-729 Kielce, Poland
3Faculty of Health Sciences, Jan Kochanowski University, IX Wieków Kielc 19, PL 25-517 Kielce, Poland
4Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland
5Department of Physiopathology, Institute of Rural Health, Jaczewskiego 2, PL 20-950 Lublin, Poland
6Department of Experimental Neuroendocrinology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland
7Department of Drug Management, Institute of Public Health, Jagiellonian University Medical College, Grzegórzecka 20, PL 31-351 Kraków, Poland
Correspondence: Barbara B³aszczyk, e-mail: [email protected]
Abstract: Background: Epilepsy is a chronic neurological disease which affects about 1% of the human population. There are 50 million pa- tients in the world suffering from this disease and 2 million new cases per year are observed. The necessary treatment with antiepi- leptic drugs (AEDs) increases the risk of adverse reactions. In case of 15% of people receiving AEDs, cutaneous reactions, like maculopapular or erythematous pruritic rash, may appear within four weeks of initiating therapy with AEDs. Methods: This study involved 300 epileptic patients in the period between September 1989 and September 2009. A cutaneous adverse reaction was defined as a diffuse rash, which had no other obvious reason than a drug effect, and resulted in contacting a physician. Results: Among 300 epileptic patients of Neurological Practice in Kielce (132 males and 168 females), a skin reaction to at least one AED was found in 30 patients. As much as 95% of the reactions occurred during therapies with carbamazepine, phenytoin, lamotrig- ine or oxcarbazepine. One of the patients developed Stevens-Johnson syndrome. Conclusion: Some hypersensitivity problems of epileptic patients were obviously related to antiepileptic treatment. Among AEDs, gabapentin, topiramate, levetiracetam, vigabatrin, and phenobarbital were not associated with skin lesions, although the number of patients in the case of the latter was small.
Key words: epilepsy, antiepileptic drugs, hypersensitivity syndrome, skin lesions
Abbreviations: AED(s) – antiepileptic drug(s), CBZ – carba- DRESS – drug reaction with eosinophilia and systemic symp- mazepine, DIHS – drug-induced hypersensitivity syndrome, toms, HSS – hypersensitivity syndrome, LTG – lamotrigine,
Pharmacological Reports, 2013, 65, 399409 399 OXC – oxcarbazepine, PB – phenobarbital, PHT – phenytoin, ered if treatment was immediately discontinued [4, 6, SJS – Stevens-Johnson syndrome, TEN – toxic epidermal ne- 113]. On the basis of the manifestations and time crolysis, VPA – valproate course of appearance of symptoms, the clinical profile of ‘‘nirvanol sickness” was regarded as similar to se- rum sickness and therefore likely to have an immune basis. Although much has been learned about the phe- Introduction nomenon of drug hypersensitivity over the last 65 years, a fundamental understanding of the basic According to the recent classification, drug-induced mechanisms remains elusive [125]. It is known, for skin injury comprises Stevens-Johnson syndrome/ example, that a large number of drugs, including sev- toxic epidermal necrolysis (SJS/TEN), acute general- eral AEDs, are linked to the disorder of internal or- ized exanthematous pustulosis and hypersensitivity gans, which affects a significant proportion of pa- syndrome (HSS), which is also recognized as drug re- tients, and that hypersensitivity is fatal in rare in- action with eosinophilia and systemic symptoms stances. There is also evidence to suggest that (DRESS) or drug-induced hypersensitivity syndrome pharmacogenetic variation in drug biotransformation (DIHS) [88, 89, 111]. According to Shiohara et al. may play a role in inducing these undesired effects [111], DIHS, in spite of worldwide distribution, is fre- [37, 112, 127]. It should be stressed, however, that the quently underdiagnosed due to its particular clinical mechanism of HSS is thought to involve deficiency or features, as delayed onset or unexplained cross- abnormality of the epoxide hydroxylase enzyme that reactivity to many drugs of different chemical struc- detoxifies the metabolites of aromatic amine anticon- tures. It is also of interest that up to 15% of acute liver vulsants, associated reactivation of herpes-type vi- failures may result from the drug intake leading to the ruses, and ethnic predisposition with certain human drug-induced liver injury [1, 4, 5]. leukocyte antigen subtypes. The toxic intermediates The necessary treatment with AEDs bears the risk in the metabolism of anticonvulsant drugs can accu- of adverse reaction. About 70% of patients receiving mulate and directly cause cell death, or, as prohap- antiepileptic drugs (AEDs) have a good control of tens, bind to T cells evoking immune response [15, epilepsy, but in some instances hypersensitivity to 65, 115]. AED interaction with immune system ap- AEDs is observed [15, 16, 87, 88, 103]. AEDs have pears to be complex and has been only partially un- been recognized as being among the most common raveled [11, 30, 102, 122]. Although a majority of medications associated with severe cutaneous adverse classical AEDs show immunosuppressive effects, reactions, with relative risks reported to be 15, 11, 13, they can also enhance immunoactivity. Preclinical and less than 5% for phenobarbital (PB), carba- studies have revealed that PHT and CBZ attenuated mazepine (CBZ), phenytoin (PHT), and oxcar- both humoral and cellular response, and an involve- bazepine (OXC), respectively [4, 13, 76, 90, 91, 108, ment of CD8+ cells in these effects was postulated. 112, 129]. Other investigators reported that valproate (VPA) and Fortunately, many cutaneous reactions to AEDs are PB attenuated humoral response and lymphocyte T not severe. They are most commonly exanthematous cytotoxicity in mice, respectively. Interestingly, with- or morbilliform and fade within a few days without drawal of CBZ and PHT increased autoimmune re- consequences [37–41]. Hypersensitivity to the ad- sponse in experimental encephalomyelitis in mice. ministration of AEDs was firstly reported in 1934 by Regarding newer AEDs, it has been found that felba- Silber and Epstein [113]. Described as “nirvanol sick- mate, stiripentol, loreclezole and tiagabine suppress ness”, this disorder was labeled after the original Ger- mitogen-stimulated proliferative activity of mouse man name for the “nerve sedative” PHT. The hyper- splenocytes in vitro, whereas CBZ and VPA stimu- sensitivity to PHT administration was recognized lated T-cell-mediated immunity [9]. Clinical data while the medicine was used for the treatment of a va- have shown that PHT, CBZ, and VPA, suppressed im- riety of clinical disorders, including psychoses, en- munoactivity, decreased protein synthesis in lympho- cephalitis, chorea, and epilepsy. The original descrip- cytes, lowered CD4+/CD8+ ratio, and altered IgA, tion detailed the appearance of rash, fever, leuko- IgG and IgM serum concentrations. In vitro, CBZ in- penia, and eosinophilia in a group of children with hibited IL-2, IL-4 but enhanced IL-10 synthesis, chorea, and noted that the children uniformly recov- whereas VPA decreased TNFa and IL-6 production.
400 Pharmacological Reports, 2013, 65, 399409 Antiepileptic drug-induced hypersensitivity Barbara B³aszczyk et al.
Measurement of cytokine levels in patients with epi- [7, 17, 18, 44, 71, 77, 78, 81, 99, 105, 107]. After the lepsy has revealed that CBZ and PHT elevated IL-2 occurrence of HSS associated with PHT, CBZ or PB, and IL-1 blood concentration, respectively. On the it is important to reassess the necessity of administer- other hand, VPA increased IL-1, IL-6 and IL-5 blood ing an AED [94, 95, 119, 120]. If seizure control is levels. The postulated mechanism of the hypersensi- needed, then alternative drug therapy should be cho- tivity to LTG, CBZ, PHB and PHT comprises activa- sen. It must be remembered that older aromatic AEDs tion of drug specific CD4+ and CD8+, elevation in exhibit high degree of cross-reactivity and that PRM IL-4 and IL-5 level, receptor T polymorphism or in- is partly metabolized to PB. It remains unclear teraction of an AED with lymphocyte T receptors whether LTG might be a safe alternative for these [10]. patients, because LTG can also induce HSS [12, 19, Therefore, HSS requires close scrutiny and de- 21, 52, 55, 73, 74, 118, 120]. Because VPA is dissimi- serves wider recognition among clinicians. It is neces- lar in its structure to the aromatic AEDs and has been sary to learn more about hypersensitivity, which is well-tolerated by patients with HSS, it is usually particularly important for pediatric neurologists and considered as a safe alternative for these patients. epileptologists [3, 13, 39, 56, 100, 102, 109]. HSS is However, at least one case report of HSS, probably associated with an erythematous morbilliform erup- related to VPA therapy, has been published. SJS and tion, which can develop into an exfoliative dermatitis TEN (Lyell syndrome) are severe albeit rare adverse [2]. These entities share some common features, such drug reactions to several AED such as PHT, CBZ, PB, as fever and hepatitis, but other features differ, such as LTG and VPA [8, 36, 79, 81, 85–87, 96–98, 106, 112, degree of mucosal involvement, which is less remark- 117, 123]. able in HSS than in SJS/TEN [35, 46–49, 58, 62, 68, 80, 82, 84, 101]. The time course for development of eruptions is also different, being delayed in AHS. Prognosis is also variable, with mortality rates rang- Materials and Methods ing from 4% in SJS to 10% in case of HSS and to 30% in case of TEN [45, 50, 100, 104]. Although the rash The observational, retrospective, single centre investi- in HSS may initially appear benign, the syndrome gation study was carried out in Private Neurological complex has been defined as including not only the Practice in Kielce from September 1989 to September rash and fever but also systemic toxicity. In addition 2009. to the skin, multiple organs can be involved, includ- The inclusion criteria were: ing, apart from the liver, kidneys, and lungs. Lympha- • Age: 18–90 years denopathy and blood dyscrasias are common [24, 42, • Diagnosis: Well characterized epilepsy or epilep- 57, 59–61, 69]. HSS is an adverse drug reaction asso- tic syndrome (International League Against Epilepsy, ciated with the aromatic AEDs, PHT, CBZ, PB, zo- 1989) nisamide, and primidone (PRM) [51, 53, 54, 65, 66, • Concomitant antiepileptic drugs (AEDs) 92]. It is usually defined by the triad of fever, skin The following exclusion criteria were applied: rash, and symptomatic or asymptomatic internal or- • History or presence of pseudo-seizures gan involvement [14, 116, 117]. Correct diagnosis of • Rapidly progressing brain disorder or tumor HSS may be difficult because of the wide variety of • Serious uncontrolled disease possible clinical and laboratory abnormalities and A cutaneous adverse reaction was defined as a dif- manifestations [63, 92, 93, 114, 126] and because the fuse rash, which had no other obvious reason than syndrome may mimic infectious, neoplastic, or colla- a drug effect, and resulted in contacting a physician. gen vascular disorders [70]. In a recent record linkage Dates of onset and termination of any AED treatment study, the risk for developing HSS within 60 days of were recorded and the reasons for termination were the first or second prescription of PHT or CBZ for assessed. Date of occurrence of rash and its clinical new users was estimated to be 2.3–4.5 per 10,000 and description, when available, were documented. Tele- 14.1 per 10,000, respectively [67, 91]. Whether the phone interviews were performed if written documen- incidence of lamotrigine (LTG)-induced HSS is com- tation was considered insufficient. Age, gender, epi- parable to that of older aromatic AEDs is not known lepsy syndromes were also recorded. Some analyses
Pharmacological Reports, 2013, 65, 399409 401 were done separately for each gender because logistic patients (54%), 75 (25%) had partial epilepsy with regression analyses (not included here) showed a pos- secondary generalization, and 33 (11%) displayed sibility of interactions between gender and several generalized tonic-clonic seizures. In 30 patients un- other variables. All the skin lesions were evaluated by classified seizures were diagnosed (10%). A skin a dermatologist. reaction to at least one AED was found in 30 patients The patient data were secured on a personal com- (10%). Clinical and demographic characteristics of puter (protected by a password) and coded. patients are shown in Table 1. The local Ethical Commission of Regional Cham- The treatment with AEDs was discontinued in all ber of Physicians approved this study (licence no.: patients with skin lesions, except two (receiving CBZ 18/2009). and OXC in the form of monotherapy) in whom the dosages were reduced and this was sufficient for the skin reactions to disappear. As much as 95% of the re- actions occurred during therapies with CBZ, PHT, Results LTG, and OXC. The severe skin lesions, SJS and ery- thema nodosum were associated with monotherapy of CBZ and OXC, respectively. The frequency of skin A total of 300 patients were included in the study, of lesions associated with administration of AEDs is which 132 (44%) were males and 168 (56%) were fe- shown in Table 2. Some related features (fever or males. Partial epilepsy was diagnosed in case of 162 multiorgan affection) were also included. Most pa- tients had common morbilliform rashes; in nine in- stances febrile reactions were reported, two had mul- tiorgan affection, including elevated liver enzymes. Tab. 1. Clinical and demographic characteristics of patients ex- posed to antiepileptic drugs (AEDs) However, internal organ affection and eosinophilia were not routinely searched for. Most rashes (86%) occurred less than three months after commencement Characteristics Epileptic Patients with patients skin reactions of medication. The median time from the exposure to the development of symptoms was two weeks (inter- Number 300 30 quartile range 2–5.25 weeks). Treatment and co- Gender ( Females/Males) 168/132 21/9 medications are listed in Table 3 for the AEDs with Age (years) span 18–79 18–77 the highest frequencies of skin eruptions. mean 61.7 62.5 Among the 30 patients experiencing rashes or other skin lesions to a given AED, nine were males and 21 Observation period (years) 1–10 1–10 were females. Women were overall more than twice mean 3.5 4.0 likely to develop a skin reaction as were men. Etiology: The risk of AED-related skin lesions increased • cryptogenic 53 8 with age. The average age of patients experiencing • 147 symptomatic 13 CBZ and PHT-dependent events was higher (34 and • 100 idiopathic 9 27 years, respectively) than that of non-affected pa- Seizure type: tients (24 and 18 years, respectively). When subdivid- • complex partial 162 21 ing the population into two age groups (18–49 years • complex partial with 75 5 and over 50 years), both PHT and CBZ tended to dis- secondary generalization play higher incidences of skin reactions in both age • generalized tonic-clonic 33 4 groups. As for individuals above 50 years of age, seizures there were no gender differences in overall skin lesion • unclassified 30 0 rates, but between the age of 18 and 50 this difference AEDs therapy: was quite distinct, 5% of males vs. 22% of females. • monotherapy 207 17 Skin lesions from more than one AED occurred in • polytherapy 93 13 case of six patients (in 2% of all patients and in 20% of those with skin reactions). Four patients experi- Etiology of epilepsy was assessed according to Shorvon [112] enced skin reactions from more than two AEDs.
402 Pharmacological Reports, 2013, 65, 399409 Antiepileptic drug-induced hypersensitivity Barbara B³aszczyk et al.
Tab. 2. Clinical characteristics and associated features of antiepileptic drug(AED)-evoked skin reactions, as reported in medical records
Skin reaction Number of features AEDs AEDs Time to skin Females (F)/Males (M) monotherapy polytherapy reaction (weeks)
Maculopapulous 5 (3/2) 3 (CBZ, LTG) 2 2–12
“Rash” 30 (21/7) 16 (CBZ, PHT, LTG, OXC) 14 2–4
Urticaria 2 (1/1) 0 2 2–3
Erythema nodosum 1 (1/0) 1 (OXC) 0 7
Stevens–Johnson 1 (0/1) 1 (CBZ) 0 6 syndrome
Associated features
9 (7/2) 3 ( CBZ, LTG) 6 NA Fever multiorgan affection 2 (1/1) 2 (OXC, CBZ) 0
There were 39 skin reactions observed (F/M - 26/11); 7 patients had two different skin reactions and 2 patients three skin lesions. CBZ car- bamazepine, LTG lamotrigine, PHT phenytoin, OXC oxcarbazepine, NA not applicable
Tab. 3. Frequency of skin reactions in patients exposed to antiepileptic drugs (AEDs)
AEDs Monotherapy CBZ PHT LTG OXC VPA Other AEDs
CBZ no reaction (110) 70 NA 12 10 0 18 0
CBZ skin lesion (20) 8 NA 3 4 0 4 1
PHT no reaction (27) 10 7 NA 5 0 5 0
PHT skin lesion (13) 3 4 NA 3 2 1 0
LTG no reaction (40) 15 10 5 NA 6 4 0
LTG skin lesion (13) 4 3 2 NA 1 2 1
OXC no reaction (22) 7 0 5 6 NA 4 0
OXC skin lesion (4) 2 0 1 0 NA 1 0
VPA no reaction (70) 38 10 8 7 7 NA 0
VPA skin lesion (1) 0 0 1 0 0 NA 0
Total exposures: 269/51 157/17 34/7 37/7 35/7 16/3 39/8 2/2
A total of 300 patients were on monotherapy (207 patients) or polytherapy (93 patients). Some patients are not shown in this table these are ones without skin lesions, receiving monotherapy (50 patients) or polytherapy (27 patients) with AEDs not listed in the table gabapentin (20), levetiracetam (3), phenobarbital (2), topiramate (47), vigabatrin (5). Total exposures to AEDs of patients listed in the table are shown as total number of patients/number of patients with skin lesions. The total number of exposures to AEDs was 320 and the total number of exposures to AEDs in patients with skin lesions was 51. Among patients reporting skin reactions, 17 were on monotherapy and 13 on polytherapy (7 on bi- therapy, 4 receiving three AEDS, 2 on four AEDs). AEDs listed in the left column were given as first ones in patients on polytherapy. That is why combinations of for example CBZ + LTG or LTG + CBZ differ in the number of patients. CBZ carbamazepine, PHT phenytoin, LTG lamo- trigine, OXC oxcarbazepine, VPA valproate, NA not applicable
Pharmacological Reports, 2013, 65, 399409 403 The statistic analysis of the correlation between pa- nance during puberty is reported for asthma, atopic tient age, gender, etiology of epilepsy, seizures type, conditions, and hay fever [31, 32, 83, 109]. medication and skin reactions was performed. In all the tests, the correlation between gender and skin lesions Age was considered, but it was statistically insignificant. In general, it has been assumed that elderly patients experience skin reactions from drug therapy at higher rates [121]. Accordingly, the total amount of CBZ, PHT, and OXC-rashes tended to increase with age, Discussion a finding that may seem to correlate with falling tes- tosterone levels in case of elderly men. Decreasing liver volume, blood flow, and metabolism, as well as As in previous studies, AEDs with aromatic ring other biological factors may contribute to this effect structures had the highest incidences of cutaneous ad- [41]. In a randomized, controlled multi-center trial, verse reactions [56, 75, 76, 98]. The risk was most the rash rate for CBZ was surprisingly high, 25%, pronounced for CBZ. The somewhat higher frequency causing withdrawal for 19% of patients with new on- of OXC related skin reactions in the present study set epilepsy above 65 years [17]. Women displayed (8%), compared to the findings derived from con- a significantly higher frequency of CBZ- and PHT- trolled clinical studies (3%) [30, 56, 106, 110] may be rash during fertile age. However, we found no signifi- due to the fact that OXC often had been tried in pa- cant association between LTG-rash and age, but a ten- tients with a previous CBZ-dependent rash [20, dency toward higher rash frequency in case of young 22–28]. We found several factors to be associated patients. Some previous studies [52, 71], but not all with the development of skin reactions. In general, [128], have reported an increased risk in children, par- older age and female gender appeared to increase the ticularly for severe skin reactions [44]. In the above- risk of these events. mentioned multi-center trial of elderly patients, the rash occurred in 9% of patients from the LTG group, Gender causing withdrawal in as little as 3% of cases [17].
It is already recognized that drug-induced skin reac- Co-medication tions are in general more frequent in case of women [30, 43, 83, 121, 124]. However, in the present study, VPA co-medication is an established risk factor for the tendency was 7% vs. 3%, which did not reach the LTG rash due to its inhibiting effect on uridine di- level of statistical significance (Fisher’s exact prob- phosphate glucuronyltransferase, but it was not identi- ability test). This tendency has previously been re- fied as a risk factor in our study, probably due to care- ported for LTG [29, 128], but to our knowledge it has ful LTG dosing in accordance with current guidelines not been demonstrated for other AEDs. A rash is an [31, 32, 34, 120]. immunologically mediated process, which is influ- To our knowledge, no earlier study had reported enced by steroid hormones. Female and male sex hor- VPA co-medication as a risk factor for PHT-induced mones influence T-cell populations, the production of rash (Tab. 3). VPA increases the unbound concentra- specific antibodies and proinflammatory mediators tion of PHT by displacing PHT from protein-binding [31, 43]. In general, female sex steroids enhance im- sites and may cause accumulation of reactive PHT mune responses in both physiological and pathologi- metabolites through its enzyme-inhibiting effect [4, cal states, whereas androgens dampen inflammatory 28, 33, 72]. However, the number of patients on PHT responses even more effectively than endogenous glu- who received VPA pretreatment was low (Tab. 3). cocorticoids [30, 83, 122]. In our study, there were no gender differences in Reliability of the study skin lesion rates with regard to patients above the age of 50, whereas the risk for females in their reproduc- The best estimates of rash rates are obtained from pro- tive period increased when compared to males in the spective clinical trials, which permit careful follow up same age group. A similar shift to female predomi- and detailed descriptions of the development of all
404 Pharmacological Reports, 2013, 65, 399409 Antiepileptic drug-induced hypersensitivity Barbara B³aszczyk et al.
emerging adverse events. Although our study has ret- also bears a risk of skin injury, adds further evidence rospective character and the number of patients in for avoiding this particular add-on therapy in epileptic some of the subgroups was rather small, it allows patients. comparisons among currently used drugs. Other dif- fuse skin symptoms, due to infections or other immu- nological reactions [64], may have occurred in case of Acknowledgment: some patients. We consider the problem of over- The authors express their thanks to Dr. Gra¿yna S³aweta, a dermatologist, who evaluated the skin lesions in epileptic patients diagnosing as insignificant, since rashes were very receiving AEDs. rare with known low-risk drugs. The reliability of the findings is supported by similar rash frequencies in randomized controlled trials and other surveys, even for the older drugs [55]. References:
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