Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 64 No. 1 pp.

89ñ92, 2007 ISSN 0001-6837

Polish Pharmaceutical Society

PHARMACOLOGY

STEVENS-JOHNSON SYNDROME INDUCED BY CARBAMAZEPINE

RAFA£ CZAJKOWSKI1,2, VIOLETTA WEISS-ROSTKOWSKA1, ANNA WANKIEWICZ1,
TOMASZ DREWA2, WALDEMAR PLACEK1, MARTA BIEDKA3 and BARBARA ZEGARSKA4

Department of Dermatology, 2 Department of Tissue Engineering,

1

The Chair and Clinic of Oncology and Brachytherapy, 4 Department of Cosmetology

3

Nicolaus Copernicus University in ToruÒ, Ludwik Rydygier Medical College in Bydgoszcz,

Abstract: Stevens-Johnson syndrome (SJS) is a mucocutaneous disorder induced by an immune-

complexñmediated hypersensitivity reaction. Nearly half of cases are caused by a reaction to drugs or appear
during viral infections and malignancies. A very few cases are caused by a bacterial infection (Streptococcus)
or Mycoplasma pneumoniae. Graft versus host disease is another well-established cause, independent of drugs.
No specific etiology has been identified in up to half of cases. We report a 54-year-old man with SJS induced
by carbamazepine. Reported patient had prodromal symptoms like fever, headache and polyarthralgia, which
preceded mucocutaneous lesions by 3 days. Physical examination on admission, revealed asthenic male with a
temperature of 37.2OC and generalized dermatitis with positive Nikolsky sign, large erosions of the palms and
soles, onychomadesis, numerous oral and vermilion border of the lips erosions. The patient was administered
systemic steroidotherapy and carbamazepine dose was gradually decreased and finally replaced with valproic
acid and valproate sodium. During the hospitalization, temperature normalized and the skin lesions disappeared
after 3 weeks of treatment.

Keywords: Stevens-Johnson syndrome, carbamazepine, symptoms, management.

Stevens-Johnson syndrome (SJS) is a mucocu- A very few cases are caused by a bacterial infection
taneous disorder that was first described in 1922. It (Streptococcus) or Mycoplasma pneumoniae. Graft
occurs predominantly in Caucasian subjects, with a versus host disease is an another well-established
male to female ratio of 2:1. SJS appears in all age cause, independent of drugs. No specific etiology
groups but is more common in older people, proba- has been identified in up to half of cases (4).
bly because of tendency to use more drugs. Most
patients are in the second to fourth decade, howev- Case report
er, it has been reported in children as young as 3 A 54-year-old man with generalized dermatitis
months (1). The disorder is more likely to occur in and large erosions localized on the palms and soles
people with AIDS (2). SJS and toxic epidermal was admitted to our department in February 2006.
necrolysis (TEN) are two forms of the same life- He had a three-day history of fever (up to 38.2OC),
threatening skin disease induced by an immune- headache and polyarthralgia. The oral pain, dyspha-
complexñmediated hypersensitivity reaction. In gia and first skin manifestations appeared two days
SJS, a patient has blistering of mucous membranes, later. Skin lesions were described as an erythema-
typically in the mouth, eyes, and vagina and wide- edematous patches forming concentric figures and
spread small blisters that arise on erythematous or rings, localized symmetrically on the lower and
purpuric maculae. There is a similar blistering of upper limbs and trunk and large serous blisters
mucous membranes, but in addition the entire top placed on the palms and soles. Medical history was
layer of the skin (the epidermis) peels off in sheets only remarkable for arterial hypertension, diabetes
from large areas of the body in TEN patients (3). mellitus type 2 and alcohol induced epilepsy (diag-
Nearly half of cases are caused by a reaction to nosed in August 2005). Medications included gli-
drugs (sulfonamides, barbiturates, anticonvulsants, clazide (Diaprel MR-30 mg once daily) and carba-
salicylates, cytostatics, thiazide diuretics, cocaine) mazepine (Tegretol-200 mg twice daily) during the
or appear during viral infections and malignancies. last six and almost two months, respectively. Family

* Corresponding author: Czajkowski Rafal, MD, PhD, 5 Kurpinskiego Str., 85-096 Bydgoszcz, Poland, tel./fax. 0048 52 585 40 18,
e-mail: rafal.czajkowski@poczta.pf.pl

89
90 RAFA£ CZAJKOWSKI et al.

history was unremarkable. Physical examination SJS and TEN are considered as cytotoxic
during admission, revealed asthenic male with a immune reaction leading to destruction of ker-
temperature of 37.2OC and generalized dermatitis atinocytes presenting drug related antigens. Drug
with blisters roofs sliping, large erosions of the metabolites such as arene oxides derived from aro-
palms and soles (Fig. 1), onychomadesis (Fig. 2) matic anticonvulsive drugs bind to cell constituents
numerous oral and vermilion border of the lips ero- if they are not quickly detoxified by epoxide hydro-
sions (Fig. 3). Mucous membranes were dry with no lase. Such metabolites act as haptens and render ker-
ocular and genital lesions. atinocytes antigenic. A detoxification system defect
Skin biopsy was performed for H&E histolog- may be one of the possible causes of skin adverse
ical examination (Fig. 4). Laboratory test results drug reactions (9). Patients suffering from SJS usu-
were as follows: RBC 3.66 (nl. 4.00-5.50K/CU ally have prodromal symptoms and signs including
MM), HGB 11.4 (nl. 12.0-18.0 g/dL), HCT 34,9 (nl. fever, cough, sore throat, headache, vomiting, myal-
37.0-54.0%), erythrocyte sedimentation rate (ESR) gia, polyarthralgia, diarrhea and lethargy. These
11 mm/hour and 29 mm/2h, albumins 56.6 (nl. 58.8- symptoms occur about 1 to 14 days before mucocu-
69.6%), alpha1 globulins 8.1 (nl. 1.8-3.8%), beta taneous lesions appearance (3). The reported patient
globulins 8.1 (nl. 8.9-13.6%). had prodromal symptoms like fever, headache and
The patient was administered prednisone polyarthralgia, which preceded mucocutaneous
(Encorton - 40 mg once daily), omeprazole (Polpra- lesions by 3 days. About 90% of patients suffering
zol - 20 mg once daily), loratadine (Loratan - 10 mg from SJS or TEN have a mucosal lesions that usual-
once daily), dexamethasone and neomycin sulfate ly precede cutaneous symptoms. The buccal
(Dexapolcort N aerosol), 1% chloramphenicol mucosa, hard and soft palate and vermilion border of
(Detreomycin ointment) topically, and 2% the lips are the most often affected. Some cases also
natamycin (Pimafucin) mouthwash solution. The involve tracheal, bronchial and gastrointestinal
carbamazepine dose was gradually decreased and epithelium, but it was not observed in our patient
finally replaced with valproic acid and valproate (10). His mucosal and skin lesions appeared simul-
sodium (Depakine Chrono - 300 mg twice daily) taneously and were limited to buccal mucosa and
after neurologist referral. During the hospitalization, vermilion border of the lips. Conjunctival lesions
temperature normalized and the skin lesions disap- such as hyperemia, painful erosions, inflammation
peared after 3 weeks of treatment. are present in about 85% of SJS and TEN patients
(11). Some patients may complain of dysuria and
DISCUSSION AND CONCLUSION the anogenital region may be involved in pathologi-
cal process (12). Prompt withdrawal of drug that is
Adverse cutaneous reactions to drugs are fre- suspected to trigger SJS or TEN may decrease mor-
quent and affect 2-3% of all hospitalized patients. tality and the risk of new mucocutaneous lesions
SJS and TEN are severe life-threatening dermatoses appearance what was observed in our patient (he did
with mortality rate about 30%. Prompt recognition, not develop any conjunctival and anogenital lesions)
early diagnosis, withdrawal of triggering drug and (13).
correct management might improve the prognosis The differential diagnosis of SJS includes
(5). The most common drugs responsible for SJS are TEN, SJS/TEN overlap, autoimmunological blister
antiepileptics (carbamazepine, lamotrigine, pheno- diseases (pemphigus velgaris and bullous pem-
barbital, phenytoin, valproic acid). Carbamazepine phigoid) and Duhring disease. In SJS erosions or
causes SJS/TEN in a frequency of about 14 per blisters involve less than 10% of the body surface
100000 users. In some retrospective studies carba- covered with atypical target lesions and maculae
mazepine was the commonest anticonvulsant impli- (mainly on the trunk). The hemorrhagic-erosive
cated in SJS and TEN (6). Another study revealed lesions are present on at least one mucosal surface.
that carbamazepine, phenytoin and allopurinol were SJS/TEN overlap is characterized by widespread
most associated with the risk of SJS appearance in atypical target lesions and maculae. The erosions or
the oriental population (7). The risk of SJS and TEN blisters involve 10-30% of the body surface. In TEN
is much higher at the beginning of antiepileptic syndrome body surface is covered with erosions or
management and 90% of all cases occur in the first blisters in more than 30% and the widespread target
63 days of treatment (8). In this case, mucocuta- lesions and maculae are present. Pemphigus vulgaris
neous symptoms specific for SJS appeared two and bullous Pemphigoid maybe both present with
month after carbamazepine application what was oral blisters and erythematous skin lesions. The clin-
consistent with previous epidemiological studies. ical course and the histologic and immunofluores-
 Steven-Johnson syndrome inducted by carbamazepine 91

Figure 1. Large erosion localized on the sole.

Figure 2. Thumb onychomadesis.
Figure 3. Hemorrhagic crusts on the lips.
Figure 4. Histological examination (H&E, x200).
Little lymphocytic infiltrate in the upper dermis and a fairly pronounced perivascular infiltrate composed largely of mononuclear cells. The
upper dermis shows marked edema resulting in subepidermal blisters and vasodilatation.

cent evaluation produce the answer. The diagnosis were confirmed in this case.
immunophatological differences between autoim- Corticosteroid management is highly debated. They
munological blister diseases and SJS syndrome con- may increase the risk of sepsis (primarily due to
cern deposits of immunoglobulins and complement. Staphylococcus aureus, Pseudomonas spp., Gramm-
In pemphigus deposits are located in intercellular negative bacilli or candida) and delay healing (15).
spaces of epidermis, in Pemphigoid in epidermal- On the other hand, some studies reported that early
dermal junction and in SJS only in mucosal vessels. treatment with high doses of systemic steroids
The deposits consist of IgG and C3 in autoimmuno- ensured a more rapid recovery, mainly in SJS
logical bister diseases and IgM and C3 in SJS. patients where the skin destruction was not too
Dermatitis herpetiformis very rarely has acral and extensive and could be reversed by anti-inflammato-
oral involvement (14). ry effects of steroids (16). Some studies revealed
Systemic corticosteroids were applied (pred- good therapeutic effect after treatment of SJS
nisone given orally) after clinical and histological patients with systemic steroids simultaneously with
92 RAFA£ CZAJKOWSKI et al.

intravenous immunoglobulin therapy (IVIG) and 4. Letko E., Papaliodis D. N., Papaliodis G. N.,
IVIG alone, however, no randomized clinical trial Daoud Y. J., Ahmed A. R., Foster C. S.: Ann.
was published. Other authors have not obtained sim- Allergy Asthma Immunol. 94, 419 (2005).
ilar results, so rational evaluation of the treatment 5. Wolf R., Orion E., Marcos B., Matz H.: Clin.
benefit can not currently be done (17). Our patient Dermatol. 23, 171 (2005).
did not receive prophylactic systemic antibiotics 6. Devi K., George S., Criton S., Suja V., Sridevi
because they may increase both the emergence of P. K.: Indian J. Dermatol. Venerol. Leprol. 71,
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chloramphenicol) were sufficient to avoid bacterial Chang N. C.: Intern. Med. J. 35, 188 (2005).
contamination of the erosions and good wound heal- 8. Mockenhaupt M., Messenheimer J., Tennis P.,
ing. No standard exists about topical treatment of Schlingmann J.: Neurology 64, 1134 (2005).
SJS patients. Possible management may be conser- 9. Frisch P. O., Ruiz-Maldonado R.: Fitzpatrickís
vative or surgical. The best treatment results were dermatology in general medicine, 6th ed. p.
obtained by authors leaving in place the involved 543, McGraw-Hill, New York 2003.
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