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Stevens-Johnson Syndrome triggered by a

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 Annals of Burns and Fire Disasters - vol. XXVII - n. 3 - September 2014

STEVENS-JOHNSON SYNDROME TRIGGERED BY A

COMBINATION OF CLOBAZAM, LAMOTRIGINE AND VALPROIC
ACID IN A 7-YEAR-OLD CHILD

Yapici A.K.,1* Fidanci M.K.,2 Kilic S.,3 Balamtekin N.,4 Mutluay Arslan M.,5 Yavuz S.T.,6
Kalman S.7

Gulhane Military Medical Academy Ankara, Turkey

Department of Plastic Reconstructive Surgery and Burn Center
1

Department of Pediatric Cardiology

2

Department of Pediatrics
3

Department of Pediatric Gastroenterology and Nutrition

4

5
Department of Pediatric Neurology
Department of Pediatric Allergy and Immunology
6

Department of Pediatric Nephrology

7

SUMMArY. Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are diseases within the spectrum of severe
cutaneous adverse reactions affecting skin and mucous membranes. Antiepileptic drugs (AEDs) are used in combination, leading
to potential pharmacokinetic or pharmacodynamic interactions, causing more adverse effects than might occur when the AED is
taken as monotherapy. Here, we report a rare case of SJS triggered by a combination of clobazam, lamotrigine and valproic acid
in a 7-year-old boy. Because of inadequate seizure control, lorazepam was replaced with clobazam. Four weeks after the addition
of clobazam, the patient developed SJS with a generalized rash, fever, with liver and kidney involvement, and eosinophilia one
week after the initiation of treatment. All antiepileptic drugs were discontinued, and intravenous methylprednisolone, prophylactic
systemic antibiotics, intravenous fluid supplement, antipyretic, special wound care, and supportive medical care for SJS were ad-
ministered. He was discharged in a stable condition on the 18th day. Our case suggests that a drug-drug interaction between val-
proate, lamotrigine and clobazam contributed to the development of SJS. When the clobazam was added to valproic acid and lam-
otrigine co-medication, the lamotrigine dose should have been decreased.

Keywords: Stevens-Johnson Syndrome, toxic epidermal necrolysis, valproic acid, lamotrigine, clobazam

Introduction ti-infective sulfonamides are strongly associated with

Stevens-Johnson Syndrome (SJS) and Toxic Epider-
mal Necrolysis (TEN) are rare, potentially life-threatening
and severe epidermolytic adverse drug reactions. They are
initially described as separate entities, but today consid-
ered variants of the same pathologic process and differing
only for severity.1 Cutaneous erythema with blister for-
mation to a various extent and hemorrhagic erosions of
mucous membranes are characteristic of SJS and TEN.
Frequently, fever, stinging eyes, and pain upon swallow-
ing are the first symptoms of the disease, which may per-
sist or even increase once the mucocutaneous lesions ap-
pear.2 Lamotrigine, carbamazepine and phenobarbital, an-
SJS/TEN in children. Valproic acid, acetaminophen, and
nonsteroidal anti-inflammatory drugs as a group also in-
crease the risk of SJS/TEN.3 Combined usage of antiepilep-
tic drugs (AED) may cause potential pharmacokinetic or
pharmacodynamic interactions which may result in more
adverse effects than might occur when the AED is taken
as monotherapy.4 Here, we report a rare case of SJS trig-
gered by a combination of clobazam, lamotrigine and val-
proic acid in a child, and review the related literature.
case report
A 7-year-old boy, who had been a known epileptic for

* Corresponding author: Abdul Kerim Yapici, Department of Plastic and Reconstructive Surgery and Burn Center, Gulhane Military Medical Academy Ankara,
Turkey. Tel.: +903123045411; fax: +903123045404; e-mail: dryapici@hotmail.com

121
Annals of Burns and Fire Disasters - vol. XXVII - n. 3 - September 2014
A
B for epidermal surfaces were applied daily.
Fig. 1a - Hemorrhagic crust on lips, purpuric lesions on the trunk
and upper extremities of the patient. b - Blistering and epidermal
sloughing on the back.
the last 6 years, was admitted with a three-day history of
oral mucous ulceration, followed by a maculo-papular and
bullous rash on his face, neck, trunk, and limbs, which
was associated with fever. He was diagnosed with cere-
bral palsy at 2 and half months old. His first seizure oc-
curred when he was 1 year old, and his anticonvulsant
therapy was started with phenobarbital. When he was 2
years old, he began to receive valproic acid (350mg bd)
and lamotrigine (50mg bd). The patient had been under
the treatment of valproic acid (350mg bd), lamotrigine
(50mg bd) and lorazepam (1mg/day) for the last 2 years.
122
Because of inadequate seizure control, clobazam (10mg/bd)
was used in place of lorazepam in his treatment regime.
Four weeks after the addition of clobazam, a fever reach-
ing 39.5oC occurred, for which he received paracetamol
and ibuprofen. Two days later, an erythematous and bul-
lous rash started on his face and neck, which rapidly spread
to his trunk, arms and legs. Three days later he was ad-
mitted to our burn center.
On physical examination, he was found to have fever
(38.5-39oC) and his general status was poor. Dermatolog-
ic examination revealed: oral mucosal ulcerations, hemor-
rhagic crust on lips and nose, bilateral hyperemic con-
junctivae, erythematous papules and bullae located main-
ly on the face, neck, trunk, and genitalia, and sparsely on
the upper and lower extremities. There were confluent bul-
lae formation and epidermal loss located especially on his
face, neck, back and genitalia that accounted for approxi-
mately 10% of the total body surface area (Fig. 1).
Laboratory examinations, including complete blood
count, liver and renal function tests, electrolytes, urine
analysis, and erythrocyte sedimentation rate, were all eval-
uated. CRP levels were measured higher (48.5mg/L) and
serum albumin levels were measured lower (2.48g/dl) than
normal limits. The patient had hypochromic microcytic
anemia and monocytosis.
The child was diagnosed with SJS based on clinical
findings and physical examinations without the need for skin
biopsy. All antiepileptic drugs were discontinued, and in-
travenous methylprednisolone at 2mg/kg/day, prophylactic
systemic antibiotics (Vancomycine 60mg/kg/day and Cef-
triaxone 75mg/kg/day), and antipyretic were administered.
Intravenous fluid supplement was administered to meet the
daily maintenance (1500cc/m2) and loss calculated by weight.
In addition, he was administered an enteral nutrition solu-
tions of 40-50 kcal/kg/day. Tetanus prophylaxis was per-
formed. Topical rifamycine (Rifocin 250mg/3ml amp, Sanofi
Aventis) and sterilized vaseline embedded gause dressing
On the fourth day following the discontinuation of
the antiepileptic drugs, he had a generalized seizure last-
ing one minute and the seizures repeated. Valproic acid
(20mg/kg/day) and phenytoin (5mg/kg/day) were started
to control the seizures. He continued to have spiking fever
(38.5oC). Urine, wound and blood cultures were negative,
and chest radiograph showed no sign of infection. The Flu-
conazole (6mg/kg/day) was added to his treatment and then
his fever decreased two days later.
On the seventh day of parenteral corticosteroid ad-
ministration, the patients lesions progressively resolved
and his skin showed re-epithelization (Fig. 2). The dose
of parenteral corticosteroid was reduced gradually and dis-
continued on the 14th day. All his laboratory findings re-
turned to normal limits. He was discharged in a stable con-
dition on the 18th day.

A
B physiology of SJS/TEN remains unknown but it is gen-
Fig. 2a,b - Progressively resolved the patients lesions and re-ep-
ithelization of the skin.
Discussion
Stevens-Johnson Syndrome (SJS) and toxic epidermal
necrolysis (TEN) are diseases within the spectrum of se-
vere cutaneous adverse reactions affecting skin and mu-
cous membranes.2 Both are rare, with SJS and TEN af-
fecting approximately 1 or 2/1,000,000 annually, and are
considered medical emergencies as they are potentially
fatal.5
Initial symptoms of both TEN and SJS can be fever,
stinging eyes, 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 por-
tions of the arms as well as the legs are relatively spared,
but the palms and soles can be an early site of involve-
ment. Erythema and erosions of the buccal, ocular, and
Annals of Burns and Fire Disasters - vol. XXVII - n. 3 - September 2014
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 oc-
cur. The skin lesions are usually tender, and mucosal ero-
sions are very painful.6,9 In accordance with the literature,
our case had oral mucosa ulcerations, hemorrhagic crust
on lips and nose, bilateral hyperemic conjunctivas, ery-
thematous papules and bullae located mainly on the face,
neck, trunk, and genitalia, and sparsely on the upper and
lower extremities. Our case was a 7-year-old boy with cere-
bral palsy, which might cause a delay in early diagnosis
as the patient was not able to tell his initial symptoms,
such as stinging eyes and pain upon swallowing.
The total body surface area (TBSA) of the detachment
is the main distinguishing factor between SJS, SJS-TEN
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 epi-
dermal detachment of 30% TBSA or more.7 Epidermal loss
in our case accounted for approximately 10% TBSA, so
our diagnosis was SJS.
Drug exposure and non-drug risk factors are the caus-
es of SJS/TEN. Allopurinol, anti-infective sulfonamides,
carbamazepine, lamotrigine, nevirapine, oxicam-NSAIDs,
phenobarbital, and phenytoin are highly suspected drugs
for development of SJS/TEN. Aminopenicillins, tetracy-
clines, quinolones, cephalosporins, macrolides, diclofenac
and related NSAIDs, corticosteroids, acetaminophen,
pyrazolones, and acetylsalicylic acid are other suspect-
ed drugs. HIV and other infections, recent cancer, re-
cent radiotherapy, and collagen vascular diseases are sus-
pected non-drug confounding risk factors.6 The patho-
erally assumed to be an autoimmune phenomenon trig-
gered by drug intake, viral syndrome or autoimmune dis-
ease. Moreover, SJS/TEN is associated with an impaired
capacity to detoxify reactive intermediate drug metabo-
lites.8,9
When seizures are poorly controlled, anti-epileptic
drugs (AED) are used in combination, leading to potential
pharmacokinetic or pharmacodynamic interactions that
cause more adverse effects than might occur when the AED
is taken as monotherapy.4 The case presented here was un-
der the treatment of valproic acid, lamotrigine and lo-
razepam for the last 2 years. There were no adverse ef-
fects and skin lesions while using these three antiepilep-
tic drugs during this period. However, due to ongoing
seizures, lorazepam was changed to clobazam, and SJS de-
veloped four weeks later. As a result, we think that the
triggering factor of SJS in our case was clobazam.
It is known that clearances of most conventional
antiepileptics are not affected by co-therapy with clobazam.
However, clearances of valproic acid and primidone are
significantly reduced by clobazam. When clobazam is
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Annals of Burns and Fire Disasters - vol. XXVII - n. 3 - September 2014

added to a therapy regimen that includes valproic acid, the
patient should be closely monitored for possible adverse
drug reactions caused by elevated valproic acid serum con-
centrations, and monitoring of valproate serum levels
should be considered.10
Furthermore, co-administration with valproic acid has
been shown to significantly increase the plasma concen-
trations of lamotrigine and the risk of a potentially seri-
ous and life-threatening rash induced by lamotrigine, in-
cluding SJS/TEN.11,12 The clobazam has no significant phar-
macokinetic interaction with lamotrigine.12 In a major ret-
rospective study of 1,890 outpatients with epilepsy, re-
searchers assessed the rates of rash associated with 15
AEDs. The highest rash rates occurred with phenytoin
(5.9%), lamotrigine (4.8%) and carbamazepine (3.7%). The
lowest rash rates occurred with felbamate, primidone, top-
iramate (all <1%), levetiracetam (0.6%), gabapentin (0.3%),
and valproate (0.7%).13
It has been suggested in the literature that rapid ele-
vation of lamotrigine levels may increase the occurrence
of lamotrigine-related skin lesions and rash.14 As valproic
acid decreases lamotrigine clearance by 60%, the combined
usage of these drugs may easily result in increased lam-
otrigine levels.12 Based on this information, we think that
the clobazam elevated valproic acid serum concentration.
These elevated valproic acid levels led to an increase in
the plasma concentration of lamotrigine. So, in our case,
the reason for SJS development was thought to be related
to a secondary increase of plasma levels of lamotrigine.
However, we were not able to confirm this by plasma lam-
otrigine measurement.
SJS/TEN usually occurs within the first 2 months of
treatment, with a sharp decrease of incidence thereafter.15
In various studies, this period was reported to be between
1 and 8 weeks.1,16 In our case, the skin rash was seen 4
weeks after the addition of clobazam to the treatment. How-
ever, clobazam is a relatively safe AED in terms of anti-
convulsant hypersensitivity syndrome. SJS/TEN due to
clobazam usage is infrequent. We identified one published
report of a case in which TEN was caused by clobazam.17
In this case, TEN was reported to occur at photo-exposed
areas in a patient who was receiving clobazam, which was
different from our case. Thus, we think that clobazam may
not be the primary reason albeit the triggering factor of
the SJS.
Another case of SJS triggered by the combination of
clobazam, lamotrigine and valproic acid treatment has been
reported in the literature.18 In this case, lamotrigine thera-
py had been withdrawn, and treatment with valproic acid
and clobazam had been continued. The skin lesions of the
patient subsided after discontinuation of lamotrigine, which
shows that the reason for SJS was lamotrigine. In our cas-
es, lamotrigine, valproic acid and clobazam were all with-
drawn. Valproic acid and fenitoin were started two days
later due to recurrence of seizures. Re-epithelialization was
nearly completed 8 days after usage of parenteral corti-
costeroids.
The treatment of SJS/TEN is similar to the treatment
of major burns and it is reported that early transfer to a
burn center is important for the outcome. In addition to
supportive treatment and wound care, treatment with im-
munosuppressive drugs was expected to be useful in
SJS/TEN because of the immunologic background of the
disease. Corticosteroids inhibit inflammatory and immune
response and have been the first-line drug for the treat-
ment of SJS/TEN for 30 years.3 In our case, parenteral
corticosteroid was administered and the skin lesions sub-
sided. Although intravenous immunoglobulin (IVIG) is al-
so used for treatment of SJS/TEN, the largest trial in-
cluding 281 patients showed no benefit from using IVIG,
so we did not use this during the treatment of our pa-
tient.19
conclusion
In conclusion, we reported a case in which a drug-
drug interaction between valproate, lamotrigine and
clobazam contributed to the development of SJS. It should
be kept in mind that when clobazam is added to valproic
acid and lamotrigine co-medication, the serum level of lam-
otrigine can be increased. Plasma lamotrigine levels should
be followed up; in case of an elevation, the dosage of lam-
otrigine may be titrated. Physicians should be alert and in-
form the patient and his/her family of the possible devel-
opment of SJS/TEN when clobazam treatment is combined
with valproic acid and lamotrigine.

rSUM. La syndrome de Stevens-Johnson (SJS) et la ncrolyse pidermique toxique sont des maladies dans le spectre de rac-
tions cutanes graves affectant la peau et les muqueuses. Les mdicaments antipileptiques sont utiliss en combinaison, et ceci
peut provoquer des effets indsirables. Ici, nous rapportons un cas rare de SJS dclench par une combinaison de clobazam, la la-
motrigine et lacide valproque chez un garon de 7 ans. En raison de l insuffisante matrise des crises, le lorazpam a t utili-
s avec le clobazam. Quatre semaines aprs lajout de clobazam, le patient a dvelopp SJS avec une ruption cutane gnrali-
se, de la fivre. Il y avait la participation de la foie et les reins, et une osinophilie, une semaine aprs le dbut du traitement.
Tous les mdicaments antipileptiques ont t abandonnes, et la mthylprednisolone intraveineuse, des antibiotiques systmiques
prophylactiques, supplment de liquide par voie intraveineuse, antipyrtique, les soins des plaies spcial, et de soutien pour les
soins mdicaux ont t administrs. Il a t libr dans un tat stable la 18me journe. Notre cas suggre quune interaction mdi-

124

camenteuse entre le valproate, la lamotrigine et clobazam ait contribu au dveloppement de SJS. Lorsque le clobazam a t ajou-
t lacide valproque et la lamotrigine, la dose de lamotrigine aurait d tre diminu.
Mots-cls: syndrome de Stevens-Johnson, ncrolyse pidermique toxique, lacide valproque, la lamotrigine, clobazam
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This paper was accepted on 25 January 2014.
125