TOXIC EPIDERMAL NECROLYSIS

PATHOPHYSIOLOGY AND 
MANAGEMENT

PRESENTER    ‐ DR. PANKAJ CHATURVEDI
MODERATOR ‐ DR. B.K. KHAITAN
ALL INDIA INSTITUTE OF MEDICAL SCIENCES(AIIMS), 
ALL INDIA INSTITUTE OF MEDICAL SCIENCES(AIIMS),
NEW DELHI
 INTRODUCTION
TEN and SJS 
TEN and SJS
• Acute  life‐threatening mucocutaneous 
reactions due to drugs
reactions due to drugs.
• Extensive  necrosis and detachment of the 
epidermis. 
id i
• Systemic  toxicity,  generalized, erythematous
rash, bullae, separation of large sheets of 
epidermis, mucosal erosions. 
 INTRODUCTION

SJS TEN
 INTRODUCTION
ERYTHEMA MULTIFORME
ERYTHEMA MULTIFORME
• Acute , self‐limited, mild, often relapsing 
mucocutaneous syndrome
mucocutaneous syndrome. 
• Recurrent  HSV infection.
• Target ‐shaped plaques predominant on the 
acral areas and face.
 INTRODUCTION
• Typical  target lesions consist of three 
concentric components:
ti t
(1) A dusky central disk, or blister
(2) Ring of pale edema
(3) Erythematous halo
• Herpes iris of Bateman.
• Not all lesions of erythema
y multiforme are 
typical, some display two rings only (raised 
atypical targets), but none are flat, which is 
the typical lesion of SJS‐TEN.
INTRODUCTION

EM
 CLASSIFICATION
• No
No generally accepted classification of the 
generally accepted classification of the
erythema multiforme, SJS and TEN spectrum
• Morphology remains the predominant basis 
Morphology remains the predominant basis
for disease definitions
• Controversy exists
C i
 CLASSIFICATION
• Bastuji‐Garin
Bastuji Garin et al, divides the spectrum into five 
et al, divides the spectrum into five
categories
((1) Bullous
) erythema
y multiforme ((EM): epidermal 
) p
detachment involving <10% of the body surface, 
coupled with localized typical targets or raised 
atypical targets.
 CLASSIFICATION
(2) SJS: epidermal detachment of <10% of the body 
surface in association with widespread erythematous
f i i ti ith id d th t
or purpuric macules or flat atypical targets .
 CLASSIFICATION
• 3)
3) SJS/TEN overlap:
SJS/TEN overlap: epidermal detachment of 
epidermal detachment of
10% to 30% of the body surface plus 
widespread purpuric macules or flat atypical 
targets. 

• (4) TEN with spots: epidermal detachment of 
>30% of the body surface coupled with 
widespread purpuric macules or flat atypical 
targets .
 CLASSIFICATION
• (5)
(5) TEN without spots: large sheets of 
TEN without spots: large sheets of
epidermal detachment involving > 10% of the 
body surface without purpuric macules or 
body surface without purpuric macules or
target lesions.
‐ These doesn
These doesn’tt occur due to confluence of    
occur due to confluence of
smaller lesions.
 CLASSIFICATION
Clinical  and management point of view 
Clinical and management point of view
• EM           ‐ Different disorder (HSV, acral
involvement young patients)
involvement,young
• SJS           ‐ <10% BSA
• SJS ‐TEN Overlap ‐ 10‐30% BSA
• TEN         ‐ > 30 % BSA
 INCIDENCE
• SJS   ‐ 1 to 6 cases/million person yrs.
SJS 1 to 6 cases/million person yrs
• TEN  ‐ 0.4 to 1.2 cases/million person yrs.
• Any age (AIIMS study mean age‐
( S d 22 3
22.3±15.4 yrs)
)
• M:F  ‐ 2:3
• High risk ‐ HIV
‐ CTD
‐ Malignancy
 MORTALITY

• SJS                        :   5‐12%
• SJS‐TEN Overlap :   20‐25% (AIIMS‐9%)
SJS TEN Overlap : 20 25% (AIIMS 9%)
• TEN                       :   > 30 %   (AIIMS‐26% )
 ETIOLOGY
• Drugs
Drugs   ‐ Most cases
Most cases
• Others ‐ Infections (Mycoplasma, HSV)
‐ Immunization
i i
‐ BMT
‐ Idiopathic
 ETIOLOGY
DRUGS
• More than 100 drugs implicated.
• 60‐70 % ‐ Importance of 1 medication est.
• Within  8 weeks (usually 4 to 30 days) after 
the onset of drug exposure.
• Drugs taken for a long time 
Drugs taken for a long time – minimal risk 
minimal risk
after 8 wks.
 ETIOLOGY
DRUGS
• Anticonvulsants M/C  ‐ 35% of total cases
Phenytoin ‐ 45%
Carbamazepine ‐30%
L
Lamotrigine
i i 20%
20%        
Phenobarbitone
Valproic acid ‐ safest 
Over all risk ‐ 1 to 10 per 10,000 new users
Risk 10 times more in pt previously treated with anticonvulsants
 ETIOLOGY
DRUGS
• Antibiotics     ‐ 33% cases
Cephalosporins M/C‐ 26% cases
Sulfonamides
Quinolones
Cyclins
 ETIOLOGY
DRUGS
• Cross sensitivity Cephalosporins & Penicillines
• A reaction to sulfonamide antibiotics does not 
mean sensitivity  to sulfonamide nonantibiotic
drugs (thiazide diuretics, sufonylureas, 
furosemide, or cyclooxygenase‐2 inhibitors) 
medications.
• Sulfonamide moiety, but only sulfonamide 
antibiotics have an arylamine group at the N4 
position → highly reactive nitroso
iti → hi hl ti it product
d t
 ETIOLOGY

DRUGS
Allopurinol – Single most common drug in 
Europe
ETIOLOGY
DRUGS
 ETIOLOGY

DRUGS
NEWER DRUGS
Nevirapine : RR‐ 22
Lamotrigine : RR
: RR‐ 14
Sertaline : RR‐11
P
Pantoprazolel : RR‐18
RR 18
Tramadol : RR‐ 20
 PATHOGENESIS
GENETIC FACTORS
GENETIC FACTORS
• Significant  increase in the human leukocyte 
antigen (HLA) B12 phenotype
antigen (HLA)‐B12 phenotype.
• Strong association between HLA‐B*1502 and 
carbamazapine‐induced SJS/TEN.
b i i d d SJS/TEN
 PATHOGENESIS
T CELL ACTIVATION
T‐ CELL ACTIVATION
• Drugs “prohaptens”
Metabolism

Metabolite
Detoxification
Excreted
 PATHOGENESIS
T CELL ACTIVATION
T‐ CELL ACTIVATION
• Drugs “prohaptens”
Metabolism

Metabolite
Detoxification Activation of CD 8
Metabolite + Endogenous proteins
Metabolite + Endogenous proteins

H
Haptens HLA 1
HLA‐1 presentation
i
 PATHOGENESIS
• HIV patients‐ reduced levels  glutathione and cysteine, are 
at risk for developing TEN to sulfonamides because of 
accumulation of the chemically reactive nitroso product.
• Co‐administration of certain drugs ↑chance of reactions
(
(reactions to carbamazapine
ti t b i and lamotrigine
dl t i i are more 
common when given in combination with valproic acid. 
The addition of valproic acid ‘‘overloads’’ detoxifying 
p y)
capacity.)
 PATHOGENESIS
p i concept 
p‐i concept
• pharmacological interaction with       
immunological receptor
immunological receptor. 
• Drug metabolism need not to be abnormal.
 PATHOGENESIS
APOPTOSIS
• Cytotoxic T lymphocytes kill other cells 
by inducing apoptosis.
• “Cell
Cell dies from within
dies from within”
• Immunologically silent.
• Once started‐ can not reversed.
 PATHOGENESIS
APOPTOSIS
1. Fas‐Fas ligand (Fas ‐L) pathway 

2. Perforin and granzyme pathway

3. TRAIL (TNF‐related apoptosis‐inducing ligand)
 PATHOGENESIS
Fas‐FasL
Fas FasL : APOPTOSIS
: APOPTOSIS
   

 
 PATHOGENESIS
PERFORIN‐GRANZYME
PERFORIN GRANZYME PATHWAY
PATHWAY
PATHOGENESIS
TRAIL
 CLINICAL FEATURES
CLINICAL FEATURES
< 10% BSA
< 10% BSA                – SJS

10%‐30% BSA         _         SJS‐TEN Overlap
0% 30% S SS O l

>30% BSA                _         TEN
 CLINICAL FEATURES
CLINICAL FEATURES
History
• Within 8 week (usually 4 to 30 days) after the 
onset of drug exposure.
• Onset delayed in the patients on steroids. 
• Prodromal symptoms ‐
y p 1 to 3 days 
y
• Pain on swallowing and burning or stinging of 
the eyes
the eyes
1/3rd cases begin with ‐ nonspecific symptoms,
1/3rd with symptoms of mucous membrane involvement
1/3rd with an exanthem
 CLINICAL FEATURES
CLINICAL FEATURES
Cutaneous Lesions
Cutaneous Lesions
• Symmetrically distributed on face, upper trunk, 
proximal extremities, skin tenderness.
proximal extremities, skin tenderness. 
• The initial skin lesions ‐ erythematous, dusky red, 
p p
purpuric macules, irregularly shaped
g y p
• Atypical target lesions with dark centers.
• Extensive and diffuse erythema, positive Nikolsky 
y ,p y
sign on erythematous zones  f/b flaccid blisters, 
and large areas of exposed, red, oozing dermis
CLINICAL FEATURES
CLINICAL FEATURES
 CLINICAL FEATURES
CLINICAL FEATURES
Mucosal Involvement
• Mucous membrane involvement (at least two 
sites) in 90% cases
sites) in 90% cases.
• Impaired alimentation, photophobia, 
conjunctival synechiae painful micturition
conjunctival synechiae, painful micturition. 
• Oral cavity ,vermilion border ‐ invariably 
affected. 
ff d
CLINICAL FEATURES
CLINICAL FEATURES
 CLINICAL FEATURES
CLINICAL FEATURES
Mucosal involvement
Mucosal involvement
• 85% of pt ‐ conjunctival lesions (hyperemia, 
erosions chemosis photophobia lacrimation
erosions, chemosis, photophobia, lacrimation, 
corneal ulceration, anterior uveitis, purulent 
conjunctivitis synechiae between eyelids and 
conjunctivitis, synechiae between eyelids and
conjunctiva). 
• Shedding of nails ‐
Sh ddi f il severe forms.
f
 CLINICAL FEATURES
CLINICAL FEATURES
Mucosal Involvement
Mucosal Involvement
 CLINICAL FEATURES
CLINICAL FEATURES
Extra‐Cutaneous Symptoms
• C
Constutional
i l symptoms 
• Visceral involvement ,pulmonary and digestive 
complications. 
li i
• Early pulmonary complications in 25% pt ‐
d
dyspnea, bronchial hyper secretion, 
b hi l h i
hypoxemia, hemoptysis, expectoration of 
bronchial mucosal casts
bronchial mucosal casts. 
• CXR ‐ interstitial syndrome.
• Acute respiratory failure A/W
A i f il A/W poor prognosis. 
i
 CLINICAL FEATURES
CLINICAL FEATURES
Extra‐Cutaneous
Extra Cutaneous Symptoms
Symptoms
• GIT involvement : less common, epithelial 
necrosis of the esophagus small bowel colon
necrosis of the esophagus, small bowel, colon‐
profuse diarrhea with malabsorption, malena, 
colonic perforation
colonic perforation.
• Renal involvement ‐ Proteinuria, 
microalbuminuria, hematuria, and azotemia.
i lb i i h t i d t i
 DIAGNOSIS
• Clinical
• Histopathology
MANAGEMENT
 MANAGEMENT
First and most important step
First and most important step

Stop all the drugs (except the lifesaving drugs)
p g ( p g g )
 MANAGEMENT
Assessment of patients 
Assessment of patients
• Hospitalization (Specialized centre/ Burn care 
unit) & Barrier nursing
unit) & Barrier nursing.
• References ‐ physician, ophthalmologist 
pulmonologist, physiotherapist, and plastic 
l l i h i h i d l i
surgeon  
• BSA ‐ estimated by the rule of nine. 
g , y p , y
• Vital signs, urinary output, any clinical evidence 
of infection or septicemia to be noted
 MANAGEMENT
Lab Investigations
g
• Complete  blood count (N/N , lymphopenia, 
Neutropenia)
• Serum  electrolytes (Na+, K+, Ca++, phosphate)
( )
• Urinalysis  (hematuria, proteinuria)
• Blood  sugar  
Bl d
• Liver function tests (deranged in 50%)
• Renal  function tests
Renal function tests
• Chest X‐ray 
• Blood culture, and skin culture to rule out infection
Blood culture and skin culture to rule out infection
 MANAGEMENT
Histopathology
• Epidermal involvement ‐ sparse apoptotic 
keratinocytes in the suprabasal layers f/b full‐
thickness epidermal necrosis and sub epidermal
thickness epidermal necrosis and sub‐epidermal 
detachment .
• Dense mononuclear cell infiltrate of the papillary 
Dense mononuclear cell infiltrate of the papillary
dermis
• Cell‐mediated immunologic reaction(CD8+ 
g (
lymphocytes with features of cytotoxic cells).
• DIF‐ Negative
 MANAGEMENT
Histopathology
 MANAGEMENT
• Fluid replacemnent
Parklands formula.
Parklands formula.

Fluid requirement = 4 ml/kg body weight x % BSA determined by the rule  
of nine
of nine 
75% of this amount is required by the patient of TEN.
Half amount is given in first 8 hrs.
Half amount is given in next 16 hours.

• Maintenance regimen 
Urine output is maintained > 1000 —1500 ml/daY.
p /
Total replacement = urine output +500ml.
Total fluids = oral (tube feeding)  +  intravenous fluids 
(DNS or normal saline) 
 MANAGEMENT
Nutritional support 
Nutritional support
• Oral  liquid diet, nasogastric tube or total 
parenteral nutrition initiated(oral feeding is
parenteral nutrition initiated(oral feeding is 
always preferred). 
• Caloric requirements ‐
C l i i 30 35 K l/k
30‐35 Kcal/kg per day. 
d
• Proteins (1.5 g/kg per day).
• Liquid and semisolid diet.
 MANAGEMENT

• Dressing
• Temperature regulation(maintained at 30‐
32°C).
)
• Analgesics and antacids
 MANAGEMENT

DISEASE SPECIFIC THERAPY

DISEASE SPECIFIC THERAPY
• No  universal consensus on therapy in SJS and 
TEN. 
• Various drugs ‐ corticosteroids, intravenous 
immunoglobulin (IVIg), cyclosporine, 
cyclophosphamide, pentoxyfylline, thalidomide, 
plasmapheresis.
• Very  few RCTs.
 MANAGEMENT
CORTICOSTEROIDS
• Debatable. 
• Open uncontrolled trials, case series.
O ll d i l i
• Some authors against use d/t
‐ Risk of infection
‐ Delayed healing
Delayed healing
MANAGEMENT

Halebian et al. Annals of Sur 1986;204:5.
 MANAGEMENT
GROUP – 1            n=15 GROUP – 2                  n=15
TREATED WITH STEROIDS TREATED WITHOUT STEROIDS
(HISTORICAL CONTROLS)
5 Survived 10 Survived

11 of 15 cases in gp 2 
received steroids over a 
mean of 3.4 days
 MANAGEMENT

JS Pasricha B K Khaitan et al. IJD 1996;35:523‐7.

JS Pasricha, B.K.Khaitan et al IJD 1996;35:523 7
 MANAGEMENT
• 5
5 cases of TEN treated with short course of 
cases of TEN treated with short course of
high dose steroids, to control the reaction 
within 24‐48
within 24 48 hrs.
hrs
• Steroids withdrawn in next 7‐10 days.
OUTCOME All patient survived.
OUTCOME‐ All i i d
MANAGEMENT

Kardaun et al.Acta Dermatol Venereol 2007;87:144‐8.

 MANAGEMENT
• 12
12 consecutive patients from 1993
consecutive patients from 1993‐2003
2003
(7 TEN, 4 SJS‐TEN, 1 SJS)
• All given Dexamethasone
All given Dexamethasone pulse for 3 days.
pulse for 3 days
• Mean delay between onset & Tt – 2.8 days.
• 1 Patient died (SCORTEN predicted fatal 
1 P ti t di d (SCORTEN di t d f t l
outcome in 4).
• Pt died d/t brain edema d/t metastasis
Pt di d d/t b i d d/t t t i
(Skin healed at the time of death)
MANAGEMENT

Allergology International. 2007;56:419‐425
 MANAGEMENT
• 52
52  cases of SJS, 65 cases of TEN retrospectively 
cases of SJS 65 cases of TEN retrospectively
analysed.
• Most cases treated with steroids (in some 
Most cases treated with steroids (in some
plasmapheresis/IVIG added)
• SJS ‐
SJS 80.8 % steroids alone (30.8% Pulse)
80 8 % id l (30 8% P l )
• TEN‐ 60% steroids alone (29.2% Pulse)
RESULTS ‐ 1 Pt with SJS died (1.9%)
‐ 4 pt with TEN died (6.2%)
4 pt with TEN died (6 2%)
(3 had BSA≥90%, 1 BSA ‐70%)
 MANAGEMENT
Why earlier studies showed poor outcome 
Why earlier studies showed poor outcome
with corticosteroids ??
1) Given too late 
2) In a too low dose
3) Given too long
 MANAGEMENT
• Corticosteroids
Corticosteroids – the most effective drugs in 
the most effective drugs in
stopping the progression of disease.
 MANAGEMENT
BASIC PRINCIPLES FOR GIVING 
CORTICOSTEROIDS
1)Withdrawl of causative drug.
2)Administration of a single large dose to control 
the reaction immediatelyy
(Dexamethasone 8mg‐16mg)
• If doubt in dose , err on higher side.
If doubt in dose err on higher side
 MANAGEMENT
BASIC PRINCIPLES FOR GIVING 
CORTICOSTEROIDS
3) Evaluation of the response to treatment
• Evaluate the response next morning.
Evaluate the response next morning
• Adequate if no new lesions, no increase in size 
of prev
f l i
lesions, lesions has become dusky red, 
l i h b d k d
toxemia disappeared ,patient is alert.
• Inadequate response – increase the dose 
proportionately, evaluate the response next day.
 MANAGEMENT
BASIC PRINCIPLES FOR GIVING      
BASIC PRINCIPLES FOR GIVING
CORTICOSTEROIDS
4) Early withdrawal of corticosteroids.
Early withdrawal of corticosteroids
• Tapered from day 2‐3 when reaction is 
controlled.
ll d
• Stopped within 7 days.
• Daily reduction of 2‐4 mg dexamethasone. 
 MANAGEMENT
INTRAVENOUS IMMUNOGLOBULIN
INTRAVENOUS IMMUNOGLOBULIN
• Interferes  with Fas‐Fas L interaction and 
prevents apoptosis
prevents apoptosis.
• Anti ‐infectious property( maily has IgG)
• Corrects  protein and fluid loss.
 MANAGEMENT
INTRAVENOUS IMMUNOGLOBULIN
INTRAVENOUS IMMUNOGLOBULIN
• No conclusive data regarding efficacy.
• Many studies shown encouraging results.
di h i l
• Dose‐ 2g/kg.
• Can  be given‐ 0.4g/kg/day for 5 days.
• It is available as infusion vial of 100ml with 5g
It is available as infusion vial of 100ml with 5g 
IVIg or 200ml with 10g IVIg.
• High cost (Rs 5 000 for 5g in India)
High cost (Rs 5,000 for 5g in India) 
 MANAGEMENT
CYCLOSPORINE
• Inhibits activated T lymphocytes, macrophages and 
keratinocytes. 
keratinocytes

• Interferes  with metabolism of TNF‐α .

• Possesses  anti‐apoptotic properties.

• 3‐5 mg/kg per day orally or i.v. for up to 2 weeks followed 
35 /k d ll i f t 2 k f ll d
by weaning over another 2 weeks.

• Encouraging results in reports, larger studies awaited.
 MANAGEMENT
THALIDOMIDE
• Proposed  as a treatment for TEN because of 
its potent TNF α inhibition
its potent TNF‐α inhibition. 
• Controlled trial was interrupted because of 
hi h
higher mortality in thalidomide group (10 out 
li i h lid id (10
of 12 patients died) compared with placebo (3 
of 10 patients died). 
f 10 i di d)
• Its use is not recommended.
 MANAGEMENT
PLASMAPHERESIS
PLASMAPHERESIS 
• Removes the drug from the blood.
• Inconclusive data to recommend the use.
Inconclusive data to recommend the use
CYCLOPHOSPHAMIDE
• Not useful.
N t f l
OTHERS USED WITHOUT ANY BENIFIT
: Pentoxiphylline
: N‐Acetyl Cysteine.
 MANAGEMENT
• CONTINUING
CONTINUING MANAGEMENT
MANAGEMENT
‐ Eye care
‐ Oral hygiene
O lh i
‐ Skincare
‐ Antibiotics 
 PROGNOSIS
SCORTEN
• A  mathematical tool to assess severity of 
illness and predict mortality
illness and predict mortality. 
• SCORTEN should be computed within the first 
24 h
24 hours after admission and again on day 
f d i i d i d
three.
PROGNOSIS
 PROGNOSIS
Other than the SCORTEN
• 1)How long the suspected drug continued after the onset 
of SJS‐TEN?
of SJS TEN? (Earlier the drug stopped, better is the 
(Earlier the drug stopped better is the
prognosis)
• 2)Half life of the drug.(Good prog
2)H lf lif f th d (G d with short T1/2 drugs)
ith h t T1/2 d )
• 3)Delay in referral to a specialized centre(Poor prog)
• 4) Early  thrombocytopenia, neutropenia (Poor prog)
• 5)Early antibiotic empirical treatment.(Poor prog)
5)Early antibiotic empirical treatment.(Poor prog)
 SEQUELAE

• Skin usually heals without scarring.
Skin usually heals without scarring
• Mucosal scaring – upto 30% cases
• Eye complications.
li i
 FINDING OUT THE CULPRIT‐ DRUG 
PROVOCATION
GOALS
• Prevent recurrences
• Help patient take drugs safely
l i k d f l
• Help doctors prescribe safely for the patient

The greater the severity of the reaction, 
e g ea e e se e y of e eac o ,
the greater the need to ensure these goals.
 FINDING OUT THE CULPRIT‐ DRUG 
PROVOCATION
If a single drug was ingested, 
If a single drug was ingested
With a consistent time course,
Easily identified.
il id ifi d Unnecessary

Multiple drugs ingested
Names of drugs not known
g
Substitutes not easily available      Necessary
 PREVENTION
• Survivors
Survivors  and their first degree relatives 
and their first degree relatives
should avoid suspected offending agents and 
related compounds
related compounds. 
• Drugs of the same pharmacologic class can be 
used provided they are structurally different
used provided they are structurally different 
from the culprit drug.
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Th k Y
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