Hypersensitivity to Lamotrigine and Nonaromatic Anticonvulsant Drugs: A Review

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2874 Current Pharmaceutical Design, 2008, 14, 2874-2882

Francesco Gaeta1,2

, Cristiana Alonzi1, Rocco Luigi Valluzzi

1, Marinella Viola

1, Maurizio Elia

Antonino Romano1,3,*

1Department of Internal Medicine and Geriatrics, UCSC-Allergy Unit, Complesso Integrato Columbus, Rome, Italy;

2IRCCS Clinica Pineta Grande, Castelvolturno, Italy and

3IRCCS Oasi Maria S.S., Troina, Italy

Abstract: Lamotrigine and nonaromatic antiepileptic drugs (valproate, gabapentin, and topiramate) are associated with

hypersensitivity reactions, mainly cutaneous eruptions. The underlying mechanisms of these manifestations are not yet

completely understood. A cell-mediated pathogenic mechanism has been demonstrated in some cases on the basis of posi-

tive patch tests and/or lymphocyte transformation tests. Moreover, an in vitro lymphocyte toxicity assay, which exposes

the patient's lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in patients with hy-

persensitivity reactions to lamotrigine. Subjects with a history of mild hypersensitivity reactions and negative allergologic

tests can be challenged with the suspected drugs. Challenge tests can also be useful to identify safe alternatives.

Our study reports hypersensitivity reactions to lamotrigine and to nonaromatic antiepileptic drugs, especially those as-

sessed by allergologic tests.

Key Words: Lamotrigine, valproate, gabapentin, topiramate, aromatic anticonvulsant, nonaromatic anticonvulsant, hypersensi-tivity, cutaneous adverse reactions.

INTRODUCTION

Lamotrigine (LTG), a relatively new aromatic antiepilep-tic drug (AED), and nonaromatic AEDs [valproate (VPA), gabapentin (GBP), and topiramate (TPM)] (Fig. 1) are asso-ciated with hypersensitivity reactions, mainly cutaneous, which can be classified as maculopapular exanthems, and bullous and pustular eruptions on the basis of their clinical, cellular and molecular pathophysiology [1]. They usually occur more than 1 hour after the last drug administration (i.e., they are non-immediate reactions) and are self-limiting and benign [2]. However, some severe life-threatening reac-tions (SCARs – severe cutaneous adverse reactions) have been reported: in some cases they are the cutaneous expres-sion of syndromes such as Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), characterized by high fever, malaise, erythema, skin blistering, crusting, and ul-ceration of mucous membranes [3, 4], or the hypersensitivity syndrome (HS), in which fever, lymphadenopaty and sys-temic symptoms typically coincide with or precede cutane-ous eruption [5]. Systemic HS manifestations can include hepatitis, nephritis, and colitis, the liver being the internal organ most frequently involved [6]. The severity of internal organ involvement may vary greatly, ranging from mild self-limiting symptoms to death [5]. Since HS is often associated with eosinophilia, it is also termed drug rash (or reaction) with eosinophilia and systemic symptoms (DRESS) [7]. Al-though the incidence of HS associated with anticonvulsant therapy (AHS) is low, a correct and early diagnosis is impor-

*Address correspondence to this author at the Unità di Allergologia, Com-

plesso Integrato Columbus, Via G. Moscati, 31, 00168 Rome, Italy; Tel.

+39 06 3503782; Fax +39 06 3503235;

E-mail: antoninoromano@h-columbus.it

tant to limit the sequelae due to the progression of this syn-drome.

The underlying mechanisms of the above mentioned manifestations are not yet completely understood. A toxic pathogenic mechanism related to reactive metabolites, as well as an immunological T-cell mediated mechanism, or a combination of both has been hypothesized [8, 9]. The role of viral infections (naïve or reactivated) has also been in-volved in the pathogenesis of AHS; specifically, reactivation of HHV-6 has been observed in some patients 2 to 3 weeks after the onset of the eruption [10]. Such infections seem to be associated with more severe and prolonged episodes [5, 11-13]. The mechanism of viral reactivation is not clear, but it is likely related to either the stimulation of the immune system by the toxic reactive intermediaries of anticonvulsant drug metabolism or a transient immune dysfunction such as hypogammaglobulinemia and/or decreased B-cell count, induced by AEDs in susceptible patients [14].

With regard to the diagnosis, cell-mediated reactions can be evaluated with both patch tests and lymphocyte transfor-mation tests (LTTs). In patch testing, the allergen is usually applied on the back of the patient for 2 days and the result is read 1 to 3 days after removal [15]. The LTT measures the drug-related T-cell response [16, 17]. In LTT studies, dem-onstration of drug-specific proliferation of peripheral blood mononuclear cells from anticonvulsant sensitive patients, but not from subjects who tolerate them, is indicative of the in-volvement of the immune system in the development of the clinical symptoms [16, 18-20]. As cytotoxic reactions to AEDs are not detected by either LTTs or patch tests, subjects with serious adverse reactions and negative tests should be evaluated by the lymphocyte toxicity assay (LTA). In this

Hypersensitivity to Lamotrigine and Nonaromatic Anticonvulsant Drugs Current Pharmaceutical Design, 2008, Vol. 14, No. 27 2875

test, the patient’s lymphocytes are incubated with AEDs and a mouse hepatic microsomal drug metabolizing system, which generates reactive aromatic epoxide intermediates called arene oxides [21]. The LTA assesses AED-associated toxicity by trypan blue dye exclusion and may detect the individual lymphocyte susceptibility to these toxic metabo-lites. In effect, aromatic AEDs are primarily metabolized by cytochrome P450 to reactive arene oxides, which are then detoxified by an enzyme, epoxide hydrolase [9, 21]. It has been postulated that individuals with a deficient activity of epoxide hydrolase develop AHS due to accumulation of arene oxides. These arene oxides are toxic and responsible for the manifestations of AHS, including early lymphocyte death [9, 21].

Subjects who have suffered mild reactions, such as macu-lopapular rashes, and have negative allergy testing, can be challenged with the culprit drugs. Challenge tests can also be used to identify safe alternatives [22]. However this proce-dure is contraindicated in case of SCARs [22].

Our study reports the hypersensitivity reactions to LTG and to nonaromatic AEDs, especially those assessed by al-lergologic tests.

Actually, the use of such tests varies according to the drugs involved. Therefore the latter will be discussed one by one.

LAMOTRIGINE

LTG is an aromatic AED used to treat epilepsy and bipo-lar disorder, and there is evidence that it is effective in the

treatment of absence and primary generalized tonic-clonic seizures, neuropathic pain, and depression. The exact way LTG works is unknown: it seems to inhibit voltage-dependent sodium channels and, at higher concentrations, calcium channels, resulting in a stabilization of neuronal membranes.

Rash is a common side effect of LTG therapy (5-10%) [23-26]; it can be severe, and thus require discontinuation in 3-4% of adults [27, 28]. Rash has been associated with hos-pitalization in 0.1-0.3% of adults and 1% of children [23, 25]. In a recent retrospective study, Alvestad et al. [29] found no significant association between LTG-rash and age, even if children are more susceptible to develop a rash than adults. According to Hirsch et al. [28], a history of AED-related rash is the strongest predictor of rash to LTG (14% versus 5% in patients without history). They retrospectively analyzed 988 patients on therapy with LTG: 56 had experi-enced rash attributed to LTG, one patient had experienced SJS, no one had required hospitalization or experienced TEN [28]. These results are consistent with those from another retrospective study on 1,037 patients (14.4% with a history of AED rash versus 4.8% without such history) [30]. In a recent retrospective study by Alvestad et al. [31], the clinical cross-reactivity among LTG and other aromatic AEDs was evaluated in patients with histories of skin reactions. LTG appeared to be involved in cross-reactions less often than carbamazepine (CBZ), oxcarbazepine, and phenytoin (PHT).

Rash seems to occur more often in patients treated with both LTG and VPA, because the former prolongs the half-life of LTG [32]. Fitton et al. [33] suggested that the inci-

Fig. (1). Chemical structures of lamotrigine and nonaromatic anticonvulsant drugs (valproate, gabapentin, topiramate).

2876 Current Pharmaceutical Design, 2008, Vol. 14, No. 27 Gaeta et al.

dence of rash, SJS, and TEN can be reduced by starting ther-apy with a slow dosage titration schedule and a low-dose-escalation. In 1993, when LTG was marketed in Germany with recommended doses exceeding the current recommen-dation, 5 confirmed cases of SJS and TEN occurred within few months [4]. Although in earlier studies LTG was associ-ated with a relatively high risk of SJS and TEN, particularly in children who had an incidence of 1% [4, 34], the current risk of SJS and TEN during the first two months of therapy is assessed between 0.01 and 0.1% of new users [2, 4]. How-ever, these observations were not confirmed by a multina-tional case-control study conducted in Europe between 1997 and 2001 [35]. In this study, LTG was associated with a high risk of SJS and TEN, even if the recommendations for dose escalation were followed, suggesting that a slow titration neither reduced the risk nor influenced the severity of cuta-neous reactions; the risk was restricted to the first 8 weeks of drug intake.

The reason why the skin is so frequently involved in hy-persensitivity reactions to LTG is not known. The admini-stration of LTG may result in the production of reactive me-tabolites able to activate the immune system and cause tissue damage. This process would depend on the high concentra-tion of drug (or its metabolite) in the skin [36]. A previous study by Maggs et al. [37] conducted in a rat model showed that more than 10% of LTG is found in the skin 4 hours after a single i.v. injection. In this study, it was not possible to evaluate the oxidative metabolism of the drug. It has been hypothesized that oxidation may represent a minor metabolic pathway also in humans and be associated with skin rash. The importance of this pathway may increase when glucu-ronidation is inhibited by concurrent VPA treatment [38]. However extensive studies have failed to identify reactive metabolites that would be a likely candidate for mediating LTG-induced skin rash, thus indicating that skin reactions may be due to the parent drug [39].

Naisbitt et al. [40] demonstrated that T-cells involved in LTG-hypersensitivity reactions are mainly Th1 CD4+ (T-cell clones generate only occasional CD8+ cells), expressing the

T-cell receptor with V 5.1 chain. The LTT was per-formed in 4 hypersensitive patients: lymphocytes from 3 of them proliferated when stimulated with LTG. T-cell clones were generated from one patient to further elucidate the na-ture of the T-cell involvement. Cells were characterized in terms of their phenotype, functionality, and mechanisms of antigen presentation and cytotoxicity. Drug-specific T-cell clones expressed the skin-homing receptor cutaneous lym-phocyte antigen. LTG-stimulated T cells were cytotoxic and secreted perforin, IFN- , IL-5, and macrophage inflamma-tory proteins 1 , and 1 , RANTES, as well as I-309. LTG was presented on HLA-DR and HLA-DQ by antigen-presenting cells in the absence of drug metabolism and proc-essing. The T-cell receptor of certain clones could accom-modate analogs of LTG, but no cross-reactivity was seen with other AEDs. These data demonstrated that T cells are involved in the pathogenesis of some LTG-hypersensitivity reactions. The identification of drug-specific cells that ex-press cutaneous lymphocyte antigen and type-1 cytokines after T-cell receptor activation is consistent with the clinical symptoms. Moreover, identification of large numbers of V 5.1(+) T cells suggests that polymorphisms within T-cell

receptor genes might act as determinants of susceptibility [40]. Since no apparent drug metabolism, covalent-binding, or antigen processing has been demonstrated, LTG could act as other drugs (e.g., cotrimoxazole, lidocaine and celecoxib) by directly stimulating T cells, (pharmacological interaction, the p-i concept), as postulated by Pichler [41] to explain the mechanisms involved in hypersensitivity reactions to chemi-cally inert drugs.

Ethnicity and genetic factors may play an important role in the development of SCAR. Recently, a weak association has been found between patients of European ancestry with LTG-related SJS and TEN and the allele HLA-B*38 [0.13 versus 0.022, P cor < 0.02, OR = 6.8 (2.6-18)] [42].

Some authors [43-45] reintroduced LTG in patients with histories of mild cutaneous reactions, starting with very low doses and increasing them slowly in a few weeks. In many studies, such procedure has been called “rechallenge”. Tav-ernor et al. [43] evaluated 8 patients, 5 of whom with onset of symptoms from 10 to 20 days after therapy was started; they all were able to reintroduce LTG in daily therapy. Besag et al. [44] rechallenged 7 patients with a very low dose esca-lation: they started with a daily dose of 0.1 mg-LTG to reach the final dose of 12.5 mg/daily in 12 weeks. They also hy-pothesized that the success of such approach could be related to a “desensitizing” mechanism [44]. P-Codrea Tigaran et al. [45] failed to reintroduce LTG in 3 of 19 outpatients; the remaining 16 patients tolerated it during a 4-year follow-up. In all these studies, LTG was successfully reintroduced de-spite a concomitant treatment with VPA (50% in Tavernor’s study, 43% in Besag’s, and 84% in P-Codrea Tigaran’s) [43-45].

In Table 1 are displayed some cases of SCARs associated with LTG-treatment [18, 46-75].

Two fatal episodes of TEN were reported in 1995 and 1998 [46, 57]; in the latter, VPA was a concomitant drug.

Clinical manifestations of AHS are similar to those of other AEDs, apart from a higher incidence of severe skin rashes (TEN and SJS) and a lower frequency of eosinophilia and lymphadenopathy [2]. A fatal case of AHS during LTG-therapy has been reported by Makin et al. [48]; a 22-year-old woman, on therapy with an association of VPA and CBZ started LTG therapy with 50 mg and reached the dose of 200 mg/daily in 3 weeks. Two days after reaching the highest dose, she presented fever, maculopapular rash, and hepatic failure. Schlienger et al. [6] described 26 cases of LTG-related AHS, 9 of which had been previously published. Fe-ver was present in all the patients, and eosinophilia in 19%. The most common skin reaction was maculopapular rash (77%); 2 patients presented SJS (7.7%), and 3 TEN (11.5%). The liver was the organ most commonly involved (65%), followed by the kidney and the musculoskeletal apparatus. In 46% of the cases a multiorgan involvement was documented. In an interesting case report by Fervenza et al. [62], manifes-tations of LTG-related AHS were associated with systemic granulomatous reactions (nephritis, colitis, and ileitis). The first pediatric case of AHS associated with LTG was re-ported by Parri et al. [72]. In a 4-year-old girl, symptoms started 6 weeks after the beginning of LTG therapy and re-mitted within 36 hours after its discontinuation.

Table 1. Characteristics of Published Cases with SCARs Induced by LTG

Author (Ref.) Age/Sex Concomitant Drugs Time

Interval* Dose

Clinical

Manifestations

Biopsy/

Autopsy

Test LTT

Sterker [46] 56/M Carbamazepine 23 200 mg TEN Np Np Np

Duval [47] 40/M Valproate, Clonazepam 21 25 mg SJS Y Np Np

Makin [48] 22/F† Valproate, Carbamazepine 23 200 mg AHS Y Np Np

Campistol [49] 18/F Valproate, Clonazepam 30 100 mg SJS Y Np Np

Dooley [50]

Clozabam

Phenitoyn, Nitrazepam

Valproate

Clozabam

300 mg

150 mg

100 mg

250 mg

150 mg

Sullivan [51] 27/F Valproate 23 25 mg TEN Np Np Np

Sachs [52] 30/M Valproate 35 50 mg TEN Np Np Pos

Wadelius [53]

Valproate

Valproate, Levothyroxine

Chaffin [54] 74/M Carbamazepine 19 100 mg TEN Y Np Np

Chattergoon [55] 3/M

Valproate, Clozabam

Valproate

12,5 mg

Iannetti [56] 2/F

Valproate, Nitrazepam

Valproate

0,5 mg/kg/die

Page [57] 54/M† Valproate, Allopurinol, Captopril 28 50 mg TEN Y Np Np

Bocquet [58] 9/M

Valproate, Hydrocortisone

Valproate, Amoxicillin

200 mg

150 mg

Brown [59] 6/M - 11 - AHS Np Np Np

Gücüyener [60] 8/M - 25 5 mg/kg/die AHS Np Np Np

Sarris [61] 27/F Phenobarbital 11 - AHS Np Np Np

Fervenza [62] 17/F - 28 - AHS Y Np Np

Schaub [63] 36/M Valproate 30 200 mg AHS Np Neg Pos

Galindo [64]

Phenobarbital

Phenobarbital, Felbamate

Carbamazepine

Overstreet [65] 35/F† Topiramate, Olanzepine, Trazodone,Tylenol,

Chloral hydrate 39 300 mg AHS Y Np Np

Sladden [66] 26/F

Valproate

200 mg

Rahman [67] 50/F Valproate, Lithium, Clonidine, Trazodone,

Bupropion, Clonazepam 15 50 mg AHS Np Np Np

Mansouri [68] 25/F Carbamazepine 49 - TEN Np Np Np

(Table 1) contd….

Author (Ref.) Age/Sex Concomitant Drugs Time

Interval* Dose

Clinical

Manifestations

Biopsy/

Autopsy

Test LTT

Karande [69] 1/M Valproate 84 - AHS Np Np Np

Chang [70] 32/F Valproate, Trazodone 14 25 mg TEN Y Np Np

Chang [71] 48/F Valproate, Venlaflaxine 8 100 mg AHS Np Np Np

Parri [72] 4/F Carvedilol, Furosemide 73 40 mg AHS Np Np Np

Kocak [73] 23/F Carbamazepine, Valproate - - SJS Np Np Np

Melandri [74] 33/M - 30 - TEN Np Np Np

Sahin [75] 23/M - 12 50 mg TEN Np Np Np

Np, Not performed; Y, Yes; Pos, Positive; Neg, Negative.

*Time interval (days) between start of therapy and onset of symptoms; †Fatal reaction.

In a total of 12 patients from 4 different studies (Table 1), an allergological evaluation (skin tests and/or LTTs and/or provocation tests) was performed [18, 60, 63, 64]. Gücüyener et al. [60] carried out a placebo-controlled oral challenge in a 8-year-old boy with a history of generalized urticarial rash, high fever, and bilateral lymphadenopathies induced by LTG treatment. He reacted on the second day of provocation (cumulative dose of 75 mg) with urticaria-angioedema. The onset of symptoms after 3 weeks of treat-ment, and their early recurrence during the challenge proved that his manifestations were LTG-induced. Sachs [18] re-ported the first case of positive LTT in a patient with SJS, demonstrating an underlying T-cell-mediated mechanism. Schaub and Bircher [63] presented the case of a patient with AHS who displayed a positive response to the LTT, and a negative one to patch testing with the suspected drug. They explained these results with the inability of LTG to pass the skin barrier. However, positive responses to LTG patch tests have been reported [64] in 1 out of 3 patients with AHS. Nevertheless, patch testing with LTG seems to have a very low sensitivity: in a study by Lammintausta and Kortekan-gas-Savolainen [77], none of 5 cases with cutaneous erup-tions during LTG-therapy had a positive patch test to LTG.

With regards to a toxic pathogenic mechanism of LTG-related AHS, Karande et al. [69] evaluated a 2-year-old boy with the LTA. They demonstrated an increased cell death following exposure not only to LTG, but also to 3 other first-line AEDs (CBZ, phenobarbital, and PHT).

VALPROATE

VPA and its derivative sodium salts (sodium valproate and valproate semisodium) are used as AEDs and mood-stabilizing drug, primarily in the treatment of epilepsy and bipolar disorder. The exact mechanism of action of VPA is unknown. The most widely accepted theory is that VPA ex-erts its effects by increasing the concentration of -aminobutyric acid (GABA) in the brain.

Cutaneous adverse reactions to VPA are rare [78-80]. Tennis and Stern [80] showed no serious rashes in 1,504 VPA new users. The risk of hospitalization for SJS and TEN

is also low in new users [4], and VPA by itself does not seem to be a major risk factor for SJS and TEN [35].

Earlier studies showed a greater risk of rash when VPA was combined with LTG; as previously mentioned, such higher risk seems to be linked to the inhibition of LTG clear-ance by VPA [81-84]. The retrospective analysis of Hirsh et al. [28] showed that comedication with VPA was an univari-ate predictor of rash with LTG. This effect was not con-firmed as significant by multivariate analysis, whereas a his-tory of other AED rashes turned out to be a stronger risk factor. Rash can be associated with a relatively rapid dosage escalation. A slow titration rate can be helpful, especially in children or in patients with a prior drug-related rash [30, 85].

With regard to the pathogenic mechanism of such cuta-neous reactions, Osawa et al. [86] reported positive re-sponses to patch tests in 4 out of 5 patients.

Only 3 AHS cases during VPA-treatment have been de-scribed [87-89]. All the patients presented a high leukocyte count and a high level of transaminases, while 2 of them also presented lymphocytosis with eosinophilia. In all of them, a cell-mediated pathogenic mechanism was demonstrated on the basis of positive responses to patch tests. Conilleau et al. [87] described a generalized eruption following patch testing in a patient, but such reaction was less severe than the previ-ous one.

Cogrel et al. [90] reported the case of a VPA-induced cutaneous pseudolymphoma, appearing as erythematous papulae, confirmed by skin biopsy. The lesions regressed after discontinuing VPA, and occurred again after admini-stration of CBZ, with the same clinical and pathological fea-tures and even the same T-cell clone involved. They hy-pothesized a cross-reactivity between a nonaromatic (VPA) and an aromatic (CBZ) AED. However, such cross-reactivity has not been confirmed in other studies.

A single case of fatal AHS induced by VPA has been reported by Huang et al. [91]. It regarded a 2-year-old girl, who developed fever, rash, and multiorgan involvement after 17 days of VPA therapy. She presented concomitant cy-tomegalovirus and adenovirus infections, which could have

played a pathogenetic role, as reported in similar cases of AED-associated HS [11].

GABAPENTIN

GBP is a new AED for the treatment of partial seizures, which is thought to work differently from other AEDs. GBP is not protein-bound or metabolized in humans, but is elimi-nated by renal excretion. It does not induce liver enzymes responsible for drug metabolism.

In an epidemiologic study by Wilton and Shakir [92] about the use of GBP, rash was the most common skin ad-verse event reported (55 patients, 1.8% of the cohort), but it required drug discontinuation in only 12 patients (0.4%), 6 of whom within the first month. No SCARs were reported.

GBP was also dispensed to 136 children younger than 12 years. The most frequently reported events during treatment were eczema (6 patients) and rash (6 patients). In 2 children, rash was assessed as being possibly related to GBP and the drug was discontinued. Similar results are shown in a recent study performed by Arif et al. [30]. They retrospectively examined the incidence of rash and identified some risk and protective factors for rash associated with all AEDs. Of 378 patients treated with GBP, only 0.3% presented a rash neces-sitating treatment discontinuation. Limiting the analysis to new users, the rate of rash was 0.6%, while it rose to 1.3% in patients with histories of rash associated with a different AED. The authors concluded that GBP, as well as VPA, is unlikely to cause rash.

There are only few studies, single case reports, in which GBP is associated with severe adverse reactions.

DeToledo et al. [93] reported a skin eruption associated with GBP in a patient with a history of repeated SJS induced by different AEDs (PHT and CBZ). The authors concluded that, even if there is no evidence of cross-reactivity, patients with histories of severe drug-induced reactions may experi-ence such reactions to GBP as well. Ragucci and Cohen [94] described a GBP-induced AHS (confusion, fever, general-ized macular rash, and splenomegaly) in a 72-year-old man, which occurred 9 days after GBP introduction. Poon and Sahin [95, 96] presented two cases of cutaneous leukocyto-clastic vasculitis associated with GPB confirmed by biopsy, Oskay [97] a case of AHS with maculopapular rash in a 52-year-old woman, and Fletcher [98] the case of a young one with self-limiting high fever, leucopenia and bilateral cervi-cal lymphadenopathy without rash, for which any infective cause was excluded. In all these cases, GPB discontinuation led to complete remission and allergologic tests were not carried out.

TOPIRAMATE

TPM is used to treat epilepsy in both children and adults. It acts by blocking sodium channels, enhancing GABA-induced influx of chloride, and inhibiting glutamate recep-tors. It is also a weak carbonic-anhydrase inhibitor.

According to different trials (both open prospective and double-blind placebo-controlled) regarding the effectiveness and tolerability of TPM in adults and children [99-102], TPM was not associated with a high rate of SCAR. In the retrospective study by Arif et al. [30], the rate of rash to

TPM was low (<1% of subjects treated). There were no re-ported cases of SCAR.

Ochoa [103] described 5 patients with epilepsy who had experienced pruritus after TPM was added to their anticon-vulsant treatment. The reaction resolved after TPM discon-tinuation or a dose reduction. Four out of 5 patients had pre-vious histories of AED hypersensitivity.

A cell-mediated hypersensitivity has been diagnosed on the basis of positive patch testing in a 55-year-old woman with seizure, who had experienced neck erythema, nausea, and vomiting after a 2-month treatment with TPM. When her symptoms remitted, she started a new therapy with a non-structurally-related AED, CBZ, but the symptoms reoc-curred. Patch tests with both TPM and CBZ were positive. Considering that these 2 AEDs have different chemical structures, the authors hypothesized a concomitant hypersen-sitivity rather than a cross-reactivity [104].

CONCLUSIONS

LTG is associated with rashes, most of which are benign. However several cases of SCAR connected with LTG ther-apy have been reported [18, 46-76]. There is evidence that, after excluding systemic involvement, LTG may be readmin-istered in patients who have had a rash.

Nonaromatic AEDs (VPA, tiagabine, GBP, TPM, and levetiracetam) have a low risk of serious immune-mediated reactions and their use should be recommended in patients with a history of serious reactions to other AEDs. If an alter-native drug has to be administered during the acute phase, VPA should be avoided, because its hepatic metabolism may delay the detoxification of residual reactive metabolites of the previous responsible AED and increase the risk of hepa-titis.

Patch tests and LTTs are useful tools in the diagnosis of cell-mediated reactions. However, further studies in large samples are necessary in order to fully establish their sensi-tivity and specificity in evaluating subjects with hypersensi-tivity reactions to LTG and nonaromatic AEDs. The LTA is helpful to diagnose cytotoxic reactions. All these tests can also be used in patients with histories of AED reactions, in order to find safe alternatives. However, their negative pre-dictive value is unknown. Challenge tests with the suspected drug could be performed in selected cases of not life-threatening reactions.

There is no evidence of cross-reactivity among nonaro-matic AEDs. However further studies are needed in large samples of subjects with hypersensitivity reactions to these drugs.

The risk and nature of the possible reactions vary among the different AEDs. Even if life-threatening reactions are rare, early recognition is extremely important, because full recovery is possible and depends on the immediate with-drawal of the culprit drug.

ABBREVIATIONS

AHS = Anticonvulsant hypersensitivity syndrome

AED = Antiepileptic drug

CBZ = Carbamazepine

DRESS = Drug rash with eosinophilia and systemic symptoms

GABA = -Aminobutyric acid

GBP = Gabapentin

HS = Hypersensitivity syndrome

LTA = Lymphocyte toxicity assay

LTG = Lamotrigine

LTT = Lymphocyte transformation test

PHT = Phenytoin

SCAR = Severe cutaneous adverse reaction

SJS = Stevens-Johnson syndrome

TEN = Toxic epidermal necrolysis

TPM = Topiramate

VPA = Valproate

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Hypersensitivity to Lamotrigine and Nonaromatic Anticonvulsant Drugs: A Review

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