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25 Indian Journal of Dermatology 2011; 56(1)

Original Article

RETROSPECTIVE ANALYSIS OF STEVENS-JOHNSON SYNDROME AND

TOXIC EPIDERMAL NECROLYSIS OVER A PERIOD OF 10 YEARS

Abarna Devi Sanmarkan, Tukaram Sori, Devinder Mohan Thappa, T J Jaisankar

Abstract

Background: Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), are the acute emergencies in

dermatology practice. Prompt diagnosis and management may reduce the morbidity and mortality in SJS/TEN patients.

Early identication of the offending drug is necessary for early withdrawal and to prevent the recurrences of such a

devastating illness. Aims: To study the demography, offending agents, clinical and laboratory features, treatment,

complications, morbidity and mortality of SJS/TEN in our hospital. Materials and Methods: In this retrospective

study, we reviewed the medical records of SJS, TEN, SJS/TEN overlap of inpatients over a period of 10 years Results:

Maximum number of SJS/TEN cases were in the age group of 1130 years. Males predominated in the SJS group with

a ratio of 1.63:1, whereas females predominated the TEN group with a ratio of 1:2.57. Nonsteroidal anti-inammatory

drugs (NSAIDs) were the commonest group of drugs among the SJS group in 5/21 patients (23.8%). Antimicrobials were

the commonest group of drugs causing TEN in 11/25 patients (44%). Mucosal lesions preceded the onset of skin lesions

in nearly 50%. Our study had one patient each of SJS/TEN due to amlodipine and Phyllanthus amarus, an Indian herb.

The most common morbidity noted in our study was due to ocular sequelae and sepsis leading to acute renal failure

respectively. Kaposis varicelliform eruption was found in three of our patients. Conclusion:Antimicrobials and NSAIDS

are the common offending agents of SJS/TEN in our study.

Key Words:Stevens-Johnson syndrome, retrospective analysis, toxic epidermal necrolysis

Indian J Dermatol 2011:56(1):25-9

From the Department of Dermatology and STD, Jawaharlal

Institute of Postgraduate Medical Education and Research

(JIPMER), Pondicherry - 605 006, India. Address for

correspondence: Dr. Devinder Mohan Thappa, Professor

and Head, Department of Dermatology and STD, JIPMER,

Pondicherry, India. E-mail: [email protected]

Introduction

Stevens-Johnson syndrome (SJS), SJS/TEN overlap, and

toxic epidermal necrolysis (TEN), are variants of acute,

rapidly progressive mucocutaneous reactions which differ

only in their body surface area (BSA) involvement.[1]

Drugs, infections, vaccines, radiological contrasts, vaginal

suppositories,[1] acrylonitrates, graft versus host reaction,[1]

and lupus erythematosus[1] in predisposed individuals result in

immunologically mediated keratinocyte apoptosis, and hence,

extensive necrosis and detachment of epidermis with signicant

morbidity and mortality. Several studies and case reports on

SJS/TEN have been done in India as well as abroad since the

description of SJS case by Stevens and Johnson in 1922[1] and

TEN case by Lyells in 1956.[1] A hospital-based retrospective

study was done to study the demography, offending agents,

clinical and laboratory features, treatment, complications,

morbidity and mortality in SJS/TEN in our hospital.

Materials and Methods

Medical records of all inpatients, admitted with a diagnosis

of SJS, TEN, and SJS/TEN overlap over a period of

10 years from June 98 to July 08, in the Department of

Dermatology, at our institute were reviewed. Of the total

56 medical records, 46 with complete data were selected.

Bastugis criteria[2]

formed the basis for classifying thesesevere mucocutaneous reactions into SJS, TEN and

SJS/TEN overlap. Parameters like age, sex, co-morbid

conditions, etiology, clinical features, past history of drug

reactions, period of hospital stay, investigations, treatment

modalities, course and outcome of these 46 patients were

recorded and analyzed.

Results

Age and gender

The number of patients with SJS and TEN was 21 each and

with SJS/TEN overlap was four. Four patients in overlap

group were included in TEN group. Maximum number of

SJS cases was in the age group of 1120 years and the

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DOI:10.4103/0019-5154.77546

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26Indian Journal of Dermatology 2011; 56(1)

maximum number of TEN cases was in the 2030 years

age group. Males predominated the SJS group with a ratio

of 1.63:1, whereas females predominated in the TEN group

with a ratio of 1:2.57. The youngest patient was a 3-year-

old child and the oldest was a 78-year-old male.

Etiology

Drug as an etiology was established in almost all the casesexcept in one case of SJS which was due to herpes labialis.

The implicated drug was identied in only 36 cases. The

major group of drugs causing SJS/TEN in our study was

antimicrobials 15/46 (32.6%), followed by nonsteroidal

anti-inammatory drugs (NSAIDs) 12/46 (26.08%) and

antiepileptic drugs 8/46 (17.3%). Besides this, there were

two cases of TEN due to paracetamol and one case each

due to nevirapine, isoniazid, fansidar (pyrimethamine

and sulfadoxine), amlodipine, siddha medication, and

Phyllanthus amarus (kizhanelli), a common medicinalplant used for hepatitis B in south India.

Considering the mucocutaneous reactions individually,

NSAIDs were the commonest group of drugs among

the SJS group in 5/21 patients (23.8%). Antimicrobials

like uroquinolones, penicillin group of drugs were the

commonest group causing TEN in 11/25 patients (44%). At

least more than eight patients (17.3%) developed SJS/TEN

following consumption of over-the-counter medications for

analgesia. Anacin, analgen (contains acetylsalicylic acid,

paracetamol, codeine phosphate, and caffeine) and Vicks

action 500 (contains paracetamol, phenylpropanolamine,

and caffeine) were the common over-the-countermedications. The drugs which were implicated in causing

SJS/TEN in our patients are shown in Table 1.

Past history of drug reaction was present in seven cases of

TEN. Nature of past and present reaction in patients with

previous history of drug eruption is shown in Table 2.

The co-morbid conditions for which our patients were taking

these offending drugs were seizures (8), diabetes mellitus (5),

hypertension (3), HIV (2), pulmonary tuberculosis (2), enteric

fever (2), one case each of syphilis, non Hodgkins lymphoma,

hypothyroidism, astrocytoma, hemiparesis, carcinoma cervix,

carcinoma breast, lichen planus and hepatitis B.

Reaction time

The mean duration between the drug intake and the onset

of reaction was 6 days. The reaction time was less than a

week in most of our patients [29/46 (63%)].

Clinical features

Fever, sore throat, myalgia and burning sensation were the

major prodromal symptoms experienced by our patients.

Anaphylaxis was observed in one of the SJS patient. SJS

patients had either blanchable or non blanchable purpuric

macules, typical and atypical targets lesions, vesicles,

Table 1: Agents involved in SJS/TEN

Etiology No. of patients %

Antimicrobials 15 32.6

Gatioxacin 5 10.86

Amoxicillin 3 6.52

Penicillin 1 2.1

Ceftriaxone 1 2.1

Cotrimoxazole 1 2.1

Pyrimethamine and sulfadoxine(Fansidar) 1 2.1

Isoniazid 1 2.1

Chloramphenicol 1 2.1

Nevirapine 1 2.1

NSAIDs 12 26.08

Anacin 3 6.52

Vicks action 500* 2 4.34

Paracetamol 2 4.34

Analgen 1 2.1

Voveran 1 2.1

Nimesulide 1 2.1

Unknown analgesics 2 4.34

Antiepileptics 8 17.3Phenytoin 6 13.04

Carbamazepine 2 4.34

Miscellaneous

Amlodipine 1 2.1

Siddha 1 2.1

P. amarus(kizhanelli) 1 2.1

Unknown drug 7 15.2

Herpes labialis 1 2.1

Total 46 100*Paracetamol + phenylpropanolamine + caffeine; Aspirin +

caffeine; Acetylsalicylic acid, paracetamol, codeine phosphate,

caffeine; Diclofenac sodium

Table 2: Nature of past and present reaction in patients with previous history of drug eruption

Present diagnosis Offending drugs (present) Earlier drug eruptions Offending drugs (earlier episodes)

TEN Analgen Maculopapular rash Cotrimoxazole

TEN Cotrimoxazole Fixed drug eruption Colazal*

TEN Amoxycillin Unknown reaction Sulpha group

TEN Siddha Unknown reaction Cotrimoxazole

TEN Phenytoin Maculopapular rash Carbamazepine

TEN Vicks action 500 Fixed drug eruption Vicks action 500

TEN Carbamazepine SJS Carbamazepine*Balsalazide disodium

Sanmarkan, et al.: Retrospective analysis of SJS and TEN

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bullae and erosions over erythematous and urticated

plaques, involving

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28Indian Journal of Dermatology 2011; 56(1)

Overall, in our study, antimicrobials were the most common

group of drugs causing SJS and TEN. But considering the

mucocutaneous reactions individually, most of our SJS

cases were due to NSAIDs and majority of TEN cases were

due to antimicrobials. This is also in concordance with the

study done in West Germany[6] which showed antibiotics

in 42% of TEN cases and analgesics in 33% of SJS cases.

Antibiotics, mainly beta-lactams, were the most commoncause of SJS/TEN in Wong et al.s study.[9] Though a

study from France[8]showed NSAIDs as the most common

implicated group, some Indian studies[5] have shown

anticonvulsants as the most frequently implicated drugs.

Nanda and Kaur[10] observed that developing countries

have a higher incidence of TEN due to antituberculous

drugs. Chan et al.[11] reported antibacterials such as

aminopenicillins, sulfamethoxazole and trimethoprim as the

commonest causative drugs for SJS and TEN.

Our study had one patient each of SJS/TEN due to

amlodipine and P. amarus (kizhanelli), which is rarely

reported in literature. In the amlodipine induced SJS case,no other etiology was found than amlodipine which the

patient had taken for 3 months. Calcium channel blockers

are known to have a longer reaction time ranging from 2

weeks to 3 months[12,13] as in our case who had a reaction

time of 3 months. A case of TEN induced by kizhanelli

(P. amarus), an Indian herb used more frequently in many

parts of the country for hepatitis, was also observed in our

study. Siddha medication and Chinese herbs induced SJS/

TEN have been reported previously also.[1] Past history of

drug reaction was present in seven TEN cases, of which

only two had drug eruption to the same drug in the past

and the rest had reaction to a different group of drug

and the type of drug reaction was also different. Nearlyfour of our patients had received radiotherapy for their

malignancy prior to occurrence of SJS/TEN as cancer

and/or radiotherapy increases the risk of SJS/TEN to

anticonvulsants.[1]

The mean reaction time in our study was 6 days. Majority

of them had manifested within 7 days of drug intake which

is similar to other studies. Noel et al.[14] observed 23

weeks for TEN and 13 weeks for SJS, and Devi et al.[5]

noticed less than 1 week in 44% of cases, between 1 and

2 weeks in 32% of cases, and between 2 and 3 weeks in

the remaining 24% of cases of SJS/TEN. Yamane et al.[7]

showed that more than half (67.6% of SJS, 80.0% of

TEN) of the patients developed symptomswithin 2 weeks.

Roujeau et al.[8]observed a reaction time of 10.212 days

for TEN cases. The prodromal symptoms were similar as in

other studies. Anaphylaxis was noticed in one of our SJS

patient. Scalp involvement was noticed in four of our TEN

cases.

Mucosal lesions preceded the onset of skin lesion in

nearly half of our patients. In a Taiwanese study, [15]

46.7% of patients had mucosal involvement affecting the

buccal mucosa, pharynx, tongue, lips, anogenital region,

esophagus, colon, nasal cavity and conjunctiva.

Most of our patients had raised ESR and leukocytosis due

to neutrophilia. Only three patients had eosinophilia. Three

of our TEN patients developed thrombocytopenia and

leukopenia, and two patients had neutropenia. Increased

liver enzymes were seen in 18 of our cases. As perYaman et al.s[7]study in SJS/TEN, hepatitis was the most

common complication. Twenty-four cases (46.2%) of SJS

and 41 cases (63.1%) of TEN had hepatitis, suggesting that

SJS could cause more severe hepatitis than TEN. Nearly

50% of the patients had ocular sequelae in the form of

symblepharon, conjunctivitis, corneal scarring and xerosis.

Corneal scarring was treated with amniotic membrane

transplant. Kaposis varicelliform eruption developing

over the lesions of SJS/TEN occurred in three of our

patients, which to our knowledge has not been reported

earlier. Kardaun et al.s[16]study has shown that short-term

dexamethasone pulse therapy, given at an early stage of

the disease, may contribute to a reduced mortality rate in

SJS/TEN without increasing healing time as noticed in our

study. Mortality rate was high in the cases with chronic co-

morbid illnesses like carcinoma, cranial irradiation, diabetes

mellitus, HIV, and abnormal laboratory parameters.

Conclusion

Antimicrobials and NSAIDS are the common offending

agents for SJS/TEN, and hence, patients who have

previous history of drug allergy should strictly avoid

Table 4: The prole of patients who died of complications

Age (years)/

sex

Etiology BSA

(%)

Co-morbid conditions Complications Treatment

32/F Paracetamol 40 Leukopenia, ARF, aspirational

pneumonia, sepsis

Inj. dexamethasone

72/M Siddha 10 Hypothyroidism, bronchial asthma Metabolic encephalopathy,

septicemia, ARF

Prednisolone

78/F Anacin 50 Hypertension, diabetes mellitus ARF, pulmonary edema Inj. dexamethasone45/F Phenytoin 70 Fibrillary astrocytoma,

diabetes mellitus

ARF, sepsis Inj. dexamethasone

26/F Nevirapine 60 HIV ARF, sepsis Inj. dexamethasone

M= male; F= female; BSA=body surface area; ARF=acute renal failure


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over-the-counter medications. Drugs like analgen, Vicks

action 500 are banned globally but are available in India

and hence strict regulations are needed. Early withdrawal

of the offending agent and denitive treatment of SJS/TEN

and multispecialty care may reduce the morbidity, mortality

rates, and thereby, duration of hospital stay.

References

1. Breathnach SM. Erythema multiforme, Stevens-Johnson syndrome

and toxic epidermal necrolysis. In: Burns T, Breathnach S, Cox

N, Grifths C, editors. Rooks Textbook of Dermatology, 7 th ed.

Oxford: Blackwell Science; 2004. p. 53.1-53.47.

2. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L,

Roujeau JC. A clinical classication of cases of toxic epidermal

necrolysis, Stevens-Johnson syndrome, and erythema multiforme

Arch Dermatol 1993;129:92-6.

3. Avakian R, PharmD, Flowers FP, Araujo OE, Ramos-Caro FA.

Toxic epidermal necrolysis: A review. J Am Acad Dermatol

1991;25:69-79.

4. Sharma VK, Sethuraman G, Minz A. Stevens Johnson syndrome,

toxic epidermal necrolysis and SJS-TEN overlap: A retrospective

study of causative drugs and clinical outcome. Indian J DermatolVenereol Leprol 2008;74:238-40.

5. Devi K, George S, Criton S, Suja V, Sridevi PK. Carbamazepine

- The commonest cause of toxic epidermal necrolysis and

Stevens-Johnson syndrome: A study of 7 years. Indian J

Dermatol Venereol Leprol 2005;71:325-8.

6. Schpf E, Sthmer A, Rzany B, Victor N, Zentgraf R, Kapp

JF. Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome

An Epidemiologic Study From West Germany. Arch Dermatol

1991;127:839-42.

7. Yamane Y, Aihara M, Ikezawa Z. Analysis of Stevens-Johnson

syndrome and Toxic epidermal necrolysis in Japan from 2000 to

2006. Allergol Int2007;56:419-25.

8. Roujeau JC, Guillaume JC, Fabre JP, Penso D, Flchet ML, Girre

JP. Toxic epidermal necrolysis (Lyell Syndrome): Incidence and drug

etiology in France, 1981-1985. Arch Dermatol 1990;126:37-42.

9. Wong KC, Kennedy PJ, Lee S. Clinical manifestations and

outcomes in 17 cases of Stevens-Johnson syndrome and toxic

epidermal necrolysis. Australas J Dermatol 1999;40:131-4.

10. Chan HL, Stern RS, Arndt KA, Langlois J, Jick SS, Jick H,et al. The incidence of erythema multiforme, Stevens-Johnson

syndrome and toxic epidermal necrolysis. Arch Dermatol

1990;126:43-7.

11. Nanda A, Kaur S. Drug induced toxic epidermal necrolysis in

developing countries. Arch Dermatol 1990;126:125.

12. Ioulios P, Charalampos M, Efrossini T. The spectrum of

cutaneous reactions associated with calcium antagonists:

A review of the literature and the possible etiopathogenic

mechanisms. Dermatol Online J 2003;9:6.

13. Stern R, Khalsa J, Cutaneous adverse reactions associated with

calcium-channel blockers. Arch Intern Med 1989;149:829-32,

14. Noel MV, Sushma M, Guido S. Cutaneous adverse drug

reactions in hospitalized patients in a tertiary care center. Indian

J Pharmacol 2004;36:292-5.

15. Lam NS, Yang YH, Wang LC, Lin YT, Chiang BL. Clinical

characteristics of childhood erythema multiforme, Stevens-

Johnson syndrome and toxic epidermal necrolysis in Taiwanese

children. J Microbiol Immunol Infect 2004;37:366-70.

16. Kardaun SH, Jonkman MF. Dexamethasone Pulse Therapy for

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis . Acta

Derm Venereol 2007;87:144-8.

Received:February, 2010. Accepted:July, 2010.

Source of support:Nil, Conict of Interest:Nil.


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