Discussion
In pediatric population, cutaneous reactions constitute 35% to 36% of adverse drug reactions. [4] Despite the high prevalence of cutaneous adverse drug reactions, they are mostly of benign character and cause mild clinical symptoms and subside spontaneously with discontinuation of the suspected drug. [5] However, 2% to 6.7% Cutaneous adverse drug reactions can be severe and potentially life-threatening clinical syndromes. [6; 7]
Drug reaction with eosinophilia and Systemic Symptoms (DRESS), Steven-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are among the severe cutaneous adverse drug reactions as in our two cases.
DRESS syndrome is a rare, potentially life-threatening delayed drug induced hypersensitivity reaction. Symptoms include skin eruptions and systemic symptoms of fever, malaise, and lymphadenopathy. Additional symptoms are related to visceral involvement such as altered liver function, nephritis, and pneumonitis. Hematologic abnormalities may include leukocytosis with eosinophilia, thrombocytopenia, and atypical lymphocytosis. [8; 9] The syndrome begins within 2 to 6 weeks after drug introduction as in our first case. Reactivation of herpesviruses has also been shown to play a role in the pathogenesis of DRESS syndrome, especially human herpesvirus-6 (HHV-6) but also cytomegalovirus, Epstein-Barr virus (EBV). [10]
SJS and TEN are diseases within the spectrum of severe cutaneous adverse reactions affecting skin and mucous membranes. [11] Initial symptoms of both TEN and SJS can be fever, stinging, and pain upon swallowing, any of which can precede cutaneous manifestations by 1 to 3 days. Skin lesions tend to first appear on the trunk, spreading to the neck, face, and proximal upper extremities. The distal portions of the arms as well as legs are relatively spared, but the palms and soles can be an early site of involvement. Erythema and erosions of the buccal, ocular, and genital mucosa are present in more than 90% of patients. The epithelium of the respiratory tract is involved in 25% of cases of TEN, and gastrointestinal lesions can also occur. The skin lesions are usually tender, and mucosal erosions are very painful. [12, 13] The total body surface area (TBSA) of the detachment is the main distinguishing factor between SJS, SJS-TEN overlap and TEN. SJS presents with epidermal detachment of less than 10% TBSA , whereas involvement of 10-30% TBSA is defined as an SJS/TEN overlap. TEN is defined as epidermal detachment of 30% TBSA or more. Epidermal loss in our second case accounted for approximately 10% TBSA, so our diagnosis was SJS. [11]
Antiepileptic drugs are implicated in the occurrence of severe cutaneous adverse reactions,
Several antiepileptic drugs are used in combination when seizures are poorly controlled. This fact leads to more potential pharmacokinetic and pharmacodynamic interactions in comparison with monotherapy. [14]
When LTG was started, the patients were also receiving VPA for several years for the first case and several months for the second, and no cutaneous adverse effects were recorded during this therapy.  However, VPA even at low concentrations is known to decrease LTG clearance leading to higher serum concentrations of LTG which in turn increases the risk of serious rash. [15, 16, 17]
VPA is mainly metabolized by the liver, and it is a known inhibitor of UDP-glucuronosyltransferases; [15] according to some investigations, [16]
there was a significant increase in LTG serum concentrations from 4.67±3.66 to 9.56±5.27µg/mL by concomitant administration of VPA, indicating a decrease in LTG clearance when VPA was added to therapy. In this case, the minor elimination pathway of LTG would play a more important role, and the formation of the arene oxide metabolite would be enhanced. As this epoxide appears to be detoxified mainly by enzymatic reactions, involving microsomal epoxide hydrolase (EPHX) and/or GSH-S-transferases and these enzymes are polymorphologically expressed in humans, [18] arene oxide toxicity is increased when EPHX or GSH S-transferases is either defective or inhibited or a depletion of intracellular glutathione levels is taking place. Inhibition of EPHX can occur when VPA is coadministred. [19, 20] High concentrations of VPA can deplete glutathione levels. [21] These two facts could lead to the frequent adverse effects. [22, 23]
Considering serious morbidity with mortality, early treatment is crucial for severe skin drug reactions. Thus, in all cases, the mean treatments are the withdrawal of the culprit drug and management of symptoms. [24] Specific treatment in children is controversial. For the treatment of SJS/TEN, systemic steroids, IVIG appeared to have better outcomes. [4] However in DRESS syndrome the main treatment is the administration of systemic steroid, other treatment modalities such us IVIG, plasmapheresis, cyclophosphamide, and cyclosporine have been also used. [24]