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Single Centre 20 Year Survey of Antiepileptic Drug-Induced

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Single Centre 20 Year Survey of Antiepileptic Drug-Induced Pharmacological Reports Copyright © 2013 2013, 65, 399409 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Singlecentre20yearsurveyofantiepileptic drug-inducedhypersensitivityreactions BarbaraB³aszczyk1,2,MonikaSzpringer3,Stanis³awJ.Czuczwar4,5, W³adys³awLasoñ6,7 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 maculopapularorerythematouspruriticrash,mayappearwithinfourweeksofinitiatingtherapywithAEDs. 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 aphysician. 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- ineoroxcarbazepine.OneofthepatientsdevelopedStevens-Johnsonsyndrome. 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 patientsinthecaseofthelatterwassmall. Keywords: epilepsy,antiepilepticdrugs,hypersensitivitysyndrome,skinlesions 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-inducedliverinjury[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
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