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]