Sndrome exfoliativo

plurifocal
INTRODUCCIN
El sndrome se ha asociado con administracin de frmacos, agentes infecciosos (herpes
simples y mycoplasmas), conectivopatas neoplasias o sin causa aparente, las drogas
pueden estar involucradas falsamente, ya que se han administrado en el curso de la
enfermedad para tratar los sntomas prodrmicos. Su etiopatogenia es desconocida, aunque
se ha sugerido que puede ser una combinacin de inmunocomplejos y reacciones mediadas
por linfocitos.
Los frmacos que con ms frecuencia han sido implicados en la etiologa medicamentosa de
este sndrome son: sulfonamidas (sobre todo las de accin prolongada, diurticos o
hipoglucemiantes) hidantoinas, carbamacepina, pirazolanas, barbitricos, penicilinas y
tetraciclinas. Tambin se han incriminado en algunos casos piroxicam, alopurinol,
griseofulvina y captopril.

EPIDEMIOLOGA
Se encuentra el SSJ-EM (eritema multiforme) en aproximadamente un 0,2% de todos los
pacientes dermatolgicos y en el 0,01 a 0,1% de los pacientes internados.

MANIFESTACIONES CLINICAS
Los pacientes con sndrome de Stevens Johnson presentan vesculas hemorrgicas y
ulceras en labios y paladar que son muy dolorosas y les interfieren con la nutricin. En el
borde de los labios les aparece una costra sero-sanguinolenta que es tpica de este sndrome
en ms de 95%. De cada 100 de los enfermos existe conjuntivitis purulenta y edema
palpebral, puede haber afectacin de la mucosa traqueo bronquial y esofgica.

DIAGNSTICO
Es inminentemente clnico, junto con el antecedente de ingesta de frmacos
sealado anteriormente y confirmar el diagnstico. Las lesiones extensas con erupcin
maculopapular, ampollas afectando al menos el 10% de la superficie corporal.
Se debe realizar una biopsia de piel para descartar otras enfermedades y confirmar el
diagnstico, los resultados seran queratinositos necrticos en toda la epidermis,
degeneracin vacuolar de la unin dermo-epidrmica que determinan la extensin de la
afeccin cutnea y mucosa; y si las formas clnicas son muy severas se deben realizar
exmenes de laboratorio para determinar el grado de reaccin y la afeccin de rganos
internos.

Se debe buscar la magnitud de la reaccin inmunolgica (reflejado por la presencia

de linfocitos activados e indirectamente, por el nivel de eosinofilia de la circulacin) y la
afeccin a rganos internos (niveles de transaminasas o creatinina). Los signos de dao
heptico deberan ser un argumento vlido para evitar el frmaco, posteriormente aun si se
present un exantema leve en la piel.
La protena C reactiva se eleva en algunas formas de hipersensibilidad, no obstante
tambin se ha encontrado en valores normales.

TRATAMIENTO
Hoy en da se est de acuerdo que el tratamiento de los pacientes debe realizarse en
unidades de grandes quemados, en combinacin con un equipo multidisciplinario, que
incluya bsicamente, personal de enfermera especializado, medico intensivista, cirujano
plstico, dermatlogo y oftalmlogo.
Es fundamental identificar el agente etiolgico y suspender su accin de forma
inmediata.
Se han ensayado algunos tratamientos especficos, que han sido tiles en ocasiones,
la base fundamental es proporcionar a los pacientes un soporte vital adecuado, los cuidados
cutneos mucosos locales y el prevenir y tratar adecuadamente los sntomas y
complicaciones que puedan surgir.

INTRODUCTION AND TERMINOLOGY Stevens-Johnson syndrome (SJS) and toxic epidermal

necrolysis (TEN) are severe mucocutaneous reactions, most commonly triggered by medications,
characterized by extensive necrosis and detachment of the epidermis. According to a widely accepted
classification, SJS and TEN are considered variants of a disease continuum and are distinguished chiefly
by severity, based upon the percentage of body surface involved with blisters and erosions (table 1) [1,2]:
SJS is the less severe condition, in which skin detachment is <10 percent of the body surface
(picture 1A-C). Mucous membranes are affected in over 90 percent of patients, usually at two or
more distinct sites (ocular, oral, and genital).
TEN involves detachment of >30 percent of the body surface area (picture 2A-D). Mucous
membranes are involved in the majority of cases.
SJS/TEN overlap describes patients with skin detachment of 10 to 30 percent of body surface
area.
We will use the term "SJS/TEN" to refer collectively to SJS, TEN, and SJS/TEN overlap syndrome.
The pathogenesis, clinical manifestations, and diagnosis of SJS/TEN are discussed in this topic.
Treatment, prognosis, and long-term complications are discussed separately. Other drug eruptions are
reviewed elsewhere.
EPIDEMIOLOGY Estimates of incidence for Stevens-Johnson syndrome (SJS), toxic epidermal
necrolysis (TEN), and SJS/TEN overlap range from two to seven cases per million people per year [3-7].
SJS is more common, outnumbering TEN by as much as three cases to one [8]. The incidence

of SJS/TEN is approximately 100-fold higher among HIV-infected individuals than in the general
population [9]. SJS/TEN can occur in patients of any age. It is more common in women than in men, with
a male to female ratio of 0.6 [10].
The overall mortality rate among patients with SJS/TEN is approximately 30 percent, ranging from
approximately 10 percent for SJS to more than 30 percent for TEN. Mortality continues to increase up to
one year after disease onset.
In a survival analysis of a large cohort of SJS/TEN patients, the overall mortality rate was 23 percent at
six weeks, 28 percent at three months, and 34 percent at one year [10]. When distinguishing patients by
severity, the mortality rates at six weeks were 12 percent for SJS, 29 percent for SJS/TEN overlap, and
46 percent for TEN and increased at one year to 24 percent for SJS, 43 percent for SJS/TEN overlap,
and 49 percent for TEN. Older age (>70 years) and presence of severe comorbidities, but not disease
severity, were associated with mortality beyond three months of disease onset. (See "Stevens-Johnson
syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)
ETIOLOGY
Drugs Medications are the leading trigger of Stevens-Johnson syndrome/toxic epidermal
necrolysis (SJS/TEN) in both adults and children. The risk of SJS/TEN seems to be limited to the first
eight weeks of treatment. Drugs used for a longer time are unlikely to be the cause of SJS/TEN.
Approximately 20 to 25 percent of cases and probably an even higher proportion of pediatric cases
cannot be clearly attributed to a drug [11].
In a large multinational case-control study including 379 cases of SJS/TEN and 1505 controls, the
following agents or groups of agents were most commonly implicated (table 2) [12,13]:
Allopurinol
Aromatic anticonvulsants
Antibacterial sulfonamides
Lamotrigine
Nevirapine
Oxicam NSAIDs
In children, the medications most often associated with SJS/TEN are sulfonamide
antimicrobials, phenobarbital, carbamazepine, and lamotrigine. An association
with acetaminophen/paracetamol has also been reported [14,15].
Infection Mycoplasma pneumoniae and cytomegalovirus infections are the next most common trigger
of SJS/TEN, particularly in children [16-19]. A review of case series and single-case reports suggests
that M. pneumoniae-associated cases may be characterized more often by moderate to severe
involvement of two or more mucosal sites and sparse or even absent skin involvement [20]. Between
September and November 2013, an outbreak of eight pediatric cases of M. pneumoniaeassociated SJS/TEN was reported in Colorado, likely related to high levels of M. pneumoniae infection in
the region [21]. At least seven more cases of SJS occurred in the same area in the first months of 2014
[22]. All children had severe oropharyngeal mucositis, seven also had conjunctival involvement, and five
genital mucosal involvement. Mild skin involvement was present in all cases. However, it is uncertain
whether M. pneumoniae-associated mucositis with minimal or no skin involvement represents an atypical
SJS variant or is a distinct entity [23,24].

Other Rare causes of SJS/TEN include vaccinations, systemic diseases, contrast medium, external
chemical exposure, herbal medicines, and foods [2,25,26]. Cases of SJS/TEN have been reported after
bone marrow transplantation. Radiotherapy in addition to treatment with antiepileptic drugs
(eg, phenytoin, phenobarbital, carbamazepine) or amifostine can trigger SJS/TEN, with lesions localized
predominantly at sites of radiation treatment [27].
PREDISPOSING FACTORS Risk factors for Stevens-Johnson syndrome/toxic epidermal
necrolysis (SJS/TEN) include HIV infection, genetic factors, underlying immunologic diseases, and
possibly physical factors.
HIV infection Patients with HIV infection have been reported to have 100-fold higher risk
of SJS/TEN than the general population [9]. The reasons for this susceptibility are not fully understood,
although exposure to multiple medications, polymorphisms of genes involved in drug metabolism,
immune dysregulation, and the presence of concomitant infections may contribute [28-32].
Genetic factors Genetic factors associated with an increased risk of SJS/TEN include the following:
Certain HLA-types (table 3) Patients with HLA-B*15:02 phenotype are at increased risk
for SJS/TEN due to carbamazepine and other aromatic anticonvulsants
(eg, phenytoin, phenobarbital). The prevalence of this allele is significant, approximately 7 to 10
percent, in patients of Asian and South Asian ancestry.
Genome-wide studies have also found an association between the HLA-A*31:01 allele
and carbamazepine-induced severe cutaneous drug reactions, including SJS/TEN, in Japanese and
in persons of European descent [33,34]. However, a subsequent multinational study and metaanalysis found that HLA-A*31:01 is strongly associated with carbamazepine-induced drug reaction
with eosinophilia and systemic symptoms (DRESS) in European and Asian patients, but shows only
a weaker association with SJS/TEN [35].
A systematic review and meta-analysis found a significant association between HLAB*58:01 and allopurinol-induced SJS/TEN in both Asian and non-Asian populations [36].
Genetic polymorphisms Polymorphisms in the CYP2C19 gene, coding for a cytochrome P450
isoform, may confer an increased risk of SJS/TEN following the administration
of phenobarbital, phenytoin, orcarbamazepine [37]. Other CYP2C variants, including CYP2C9*3,
known to be associated with reduced phenytoin clearance, may be associated with an increased risk
of severe cutaneous adverse reactions to phenytoin, including SJS/TEN and DRESS [38]. Other
polymorphisms potentially associated with SJS/TEN include those in the IL-4 receptor gene [39,40],
prostaglandin E receptor 3 gene [41], and a group of genes located in the 6p21 region
(BAT1, HCP5, MICC, and PSORS1C1), which are in linkage disequilibrium with HLA-B*58:01 [42].
However, larger studies are needed to assess the role of genetic polymorphism in the pathogenesis
of SJS/TEN.
Genetic screening The US Food and Drug Administration has suggested screening patients of Asian
and South Asian ancestry for HLA-B*15:02 if use of carbamazepine is under consideration [43-46]. One
consensus panel has recommended screening all carbamazepine-nave patients for the HLAA*31:01 allele prior to starting treatment, regardless of race or ethnicity, since the allele is prevalent in
most ethnic groups [47].
The clinical utility of testing for HLA-B*58:01 allele prior to treatment with allopurinol has not been
demonstrated in any population [48]. However, the Clinical Pharmacogenetics Implementation

Consortium (CPIC) recommends that allopurinol should not be prescribed to patients who are known
carriers of HLA-B*58:01 [49]. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse
effects", section on 'Carbamazepine' and "Antiseizure drugs: Mechanism of action, pharmacology, and
adverse effects", section on 'Role of HLA testing' and "Prevention of recurrent gout: Pharmacologic uratelowering therapy and treatment of tophi", section on 'Allopurinol'.)
Other factors
Malignancy may increase the risk of SJS/TEN, although data are conflicting as to whether
malignancy truly increases the risk, or is simply associated with increased exposure to causative
medications [50,51].
High doses and rapid introduction of medications [13,52].
Patients with systemic lupus erythematosus (SLE) appear to be at an increased risk
of SJS/TEN [53]. In a retrospective review of 1366 patients with SJS/TEN, the prevalence of SLE
was 1.2 percent, whereas the estimated prevalence in the general population is approximately 0.02
to 0.05 percent [54]. However, in lupus patients the differentiation between SJS/TEN and an
extreme phenotype of acute cutaneous lupus ("TEN-like" lupus erythematosus) may be difficult and
requires accurate clinicopathologic correlation [54,55].
Physical stimuli, such as ultraviolet light or radiation therapy, may be co-factors in some cases [5658].
PATHOGENESIS The pathologic mechanisms that induce skin damage in StevensJohnson syndrome/toxic epidermal necrolysis (SJS/TEN) are incompletely understood. Early studies of
the immunophenotype of lymphocytes detected in the blister fluid of SJS/TEN lesions suggested a cellmediated cytotoxic reaction against keratinocytes leading to massive apoptosis [59]. Subsequent studies
demonstrated that cytotoxic T-cells are drug-specific and directed against the native form of the drug
rather than against a reactive metabolite [60-62].
Drugs can stimulate the immune system by directly binding to the major histocompatibility complex (MHC)
I and the T-cell receptor. This results in the clonal expansion of a population of drug-specific cytotoxic Tcells that kill keratinocytes directly and indirectly through the recruitment of other cells that release soluble
death mediators, including granulysin [63]. (See "Drug allergy: Pathogenesis", section on 'Interaction of
drugs with the immune system'.)
Mediators of keratinocyte apoptosis Drug-specific CD8+ cytotoxic T cells, along with natural killer
(NK) cells are thought to be the major inducers of keratinocyte apoptosis [60,61]. Various cytotoxic
proteins and cytokines such as soluble Fas ligand, perforin/granzyme, tumor necrosis factor (TNF)-alpha,
and TNF-related apoptosis inducing ligand (TRAIL) have been proposed as mediators for the extensive
keratinocyte apoptosis in SJS/TEN. However, it is now accepted that granulysin, a cytolytic protein found
in cytotoxic T cells and natural killer (NK) cells plays a key role in the pathogenesis of SJS/TEN [64].
Granulysin Granulysin is a cytolytic protein produced and secreted by cytotoxic T lymphocytes,
natural killer (NK) cells, and NK/T cells. The gene expression profiling of cells from five patients with SJS
or TEN identified granulysin as the most highly expressed cytotoxic molecule [65]. Both fluid and cells
from SJS/TEN patient blisters demonstrated cytotoxicity when incubated with keratinocytes, but the effect
was reduced by depletion of granulysin. Control fluid or cells from patients with burns did not show such
activity. The levels of granulysin in blister fluid correlated with the severity of disease. In addition, injection
of granulysin from patient blisters into mouse skin caused dose-dependent blistering and necrosis.

The mechanism through which cytotoxic T lymphocytes and natural killer cells are stimulated to release
granulysin is unknown. The results of one study suggest that the interaction between
the CD94/NKG2Creceptor on cytotoxic T lymphocytes and HLA-E, an MHC class Ib molecule, expressed
by keratinocytes in patients with SJS or TEN, may promote degranulation [66].
Other factors Soluble Fas-ligand, perforin, TNF-alpha, TNF-related apoptosis-inducing ligand
(TRAIL), and granzyme B, which are involved in distinct non-apoptotic cell death pathways, are also
found in high concentrations in the peripheral mononuclear cells and blister fluid of SJS/TEN patients [6769]. However, elevations in these mediators are not specific to SJS/TEN.
HISTOPATHOLOGY The hallmark of Stevens-Johnson syndrome/toxic epidermal
necrolysis (SJS/TEN) is the keratinocyte necrosis, ranging from partial to full-thickness necrosis of
epidermis. In early lesions, apoptotic keratinocytes are scattered in the basal layer of the epidermis, but in
established lesions full-thickness epidermal necrosis and subepidermal bullae may be seen [8]. A scant
perivascular lymphohistiocytic inflammatory infiltrate containing a variable amount of eosinophils is
present in the superficial dermis (picture 3).
CLINICAL PRESENTATION
Prodrome Fever, often exceeding 39C (102.2F), and influenza-like symptoms precede by one to
three days the development of mucocutaneous lesions [70]. Photophobia and conjunctival itching or
burning, and pain on swallowing may be early symptoms of mucosal involvement. Malaise, myalgia, and
arthralgia are present in most patients.
In some patients, an exanthematous eruption can be the heralding sign of SJS/TEN. Signs and symptoms
that should alert the clinician to the possibility of Stevens-Johnson syndrome/toxic epidermal
necrolysis(SJS/TEN) include fever >38C (100.4F), mucositis, skin tenderness, and blistering (table 4)
[70,71]. (See "Exanthematous (morbilliform) drug eruption", section on 'Early signs of severe reaction'.)
Cutaneous lesions The skin lesions typically begin with ill-defined, coalescing erythematous macules
with purpuric centers, although many cases of SJS/TEN may present with diffuse erythema (picture 1A,
2A, 2C-D) [72,73]. The skin is often tender to the touch and skin pain can be prominent and out of
proportion to the cutaneous findings.
Lesions start on the face and thorax before spreading to other areas and are symmetrically distributed
[74]. The scalp is typically spared, and palms and soles are rarely involved [75,76]. Atypical target lesions
with darker centers may be present. As the disease progresses, vesicles and bullae form and within days
the skin begins to slough.
Nikolsky sign (ie, the ability to extend the area of superficial sloughing by applying gentle lateral pressure
on the surface of the skin at an apparently uninvolved site) may be positive. The Asboe-Hansen sign or
"bulla spread sign" (a lateral extension of bullae with pressure) may also be present. The ultimate
appearance of the skin has been likened to that of extensive thermal injury [77]. (See "Approach to the
patient with cutaneous blisters", section on 'Nikolsky sign'.)
Mucosal lesions Mucosal involvement occurs in approximately 90 percent of cases of SJS/TEN and
can precede or follow the skin eruption [78]. Painful crusts and erosions may occur on any mucosal
surface [70,79].

Oral The oral mucosa and the vermilion border are almost invariably involved, with painful
hemorrhagic erosions covered with a grayish-white membrane (picture 1C-D). Stomatitis and mucositis
lead to impaired oral intake with consequent malnutrition and dehydration.
Ocular Ocular involvement is reported in approximately 80 percent of patients. The most common
change in the eyes is a severe conjunctivitis with a purulent discharge (picture 1E), but bullae may
develop. Corneal ulceration is frequent, and anterior uveitis or panophthalmitis may occur. Pain and
photophobia are accompanying symptoms. The eye changes often regress completely, but scarring with
the development of synechiae between the eyelids and conjunctiva may be late sequelae [80,81].
(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and longterm sequelae", section on 'Long-term sequelae'.)
Urogenital Urethritis develops in up to two-thirds of patients, and may lead to urinary retention. Genital
erosions are frequent. In women, vulvovaginal involvement may present with erosive and ulcerative
vaginitis, vulvar bullae, and vaginal synechiae, and may lead to long-term anatomic sequelae. These
include labial and vaginal adhesions and stenosis, obstructed urinary stream and urinary retention,
recurrent cystitis, or hematocolpos [82-86]. Vulvovaginal adenosis (presence of metaplastic cervical or
endometrial glandular epithelium in the vulva or vagina) also has been reported in women
with SJS/TEN [87-89].
Other Pharyngeal mucosa is affected in nearly all patients; tracheal, bronchial, and esophageal
membranes are less frequently involved [90,91]. Intestinal involvement is rare [92].
Laboratory abnormalities Hematologic abnormalities, particularly anemia and lymphopenia, are
common in SJS/TEN [74]. Eosinophilia is unusual; neutropenia is present in about one-third of patients,
and is correlated with a poor prognosis [74,93]. However, the administration of systemic corticosteroids
can cause demarginalization and mobilization of neutrophils into the circulation, and this may obscure
neutropenia.
Hypoalbuminemia, electrolyte imbalance, and increased blood urea nitrogen and glucose may be noted in
severe cases, due to massive transdermal fluid loss and hypercatabolic state. Serum urea nitrogen
>10mmol/L and glucose >14 mmol/L are considered markers of disease severity [94]. Mild elevations in
serum aminotransferase levels (two to three times the normal value) are present in about one-half of
patients with TEN, while overt hepatitis occurs in approximately 10 percent [79].
CLINICAL COURSE The acute phase of Stevens-Johnson syndrome/toxic epidermal
necrolysis (SJS/TEN) lasts 8 to 12 days and is characterized by persistent fever, severe mucous
membrane involvement, and epidermal sloughing that may be generalized and result in large, raw, painful
areas of denuded skin. Reepithelialization may begin after several days, and typically requires two to four
weeks [95]. Skin that remained attached during the acute process may peel gradually and nails may be
shed.
COMPLICATIONS
Acute phase In severe cases with extensive skin detachment, acute complications may include
massive loss of fluids through the denuded skin, electrolyte imbalance, hypovolemic shock with renal
failure, bacteremia, insulin resistance, hypercatabolic state, and multiple organ dysfunction syndrome.
Abdominal compartment syndrome secondary to excessive replacement fluid therapy has been reported
in a few patients [96]. (See "Abdominal compartment syndrome in adults".)

Patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are at high risk of
bacterial infection. Sepsis and septic shock, most often caused by S. aureus and P. aeruginosa, are the
main cause of death in these patients. In a study of 179 patients with SJS/TEN, bacteremia was detected
in 48 (27 percent) [97]. The main pathogens implicated were S. aureus, P. aeruginosa, and
Enterobacteriaceae organisms. The risk of bacteremia was higher in patients older than 40 years, in
those with skin detachment on more than 30 percent of BSA, and in those with greater than 10,000 white
blood cell count. (See"Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation,
diagnosis, and prognosis".)
Pulmonary complications (eg, pneumonia, interstitial pneumonitis) are frequent. Presenting symptoms
include cough and elevated respiratory rate. Strict clinical surveillance is necessary for these patients,
due to the risk of progression to acute respiratory distress syndrome. Acute respiratory failure requiring
mechanical ventilation has been reported in approximately 25 percent of patients with SJS/TEN [90].
(See "Acute respiratory distress syndrome: Clinical features and diagnosis in adults".)
Gastrointestinal complications may result from epithelial necrosis of the esophagus, small bowel, or colon.
Diarrhea, melena, small bowel ulcerations, colonic perforation, and small bowel intussusception have
been reported in a few patients [98-101].
Long-term sequelae Long-term sequelae of SJS/TEN are discussed separately. (See "StevensJohnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae",
section on 'Long-term sequelae'.)
PATIENT EVALUATION AND DIAGNOSIS
Clinical findings and history There are no universally accepted diagnostic criteria for StevensJohnson syndrome/toxic epidermal necrolysis (SJS/TEN), and histologic findings are neither specific nor
diagnostic. Despite these limitations, the diagnosis of SJS or TEN would be appropriate in a patient with
the following clinical features [102] (see 'Clinical presentation' above):
A suggestive history of drug exposure or illness. Drug exposure commonly precedes the onset of
symptoms by one to four weeks (average 14 days), but reexposure may result in onset of symptoms
in as little as 48 hours [103].
A prodrome of acute-onset febrile illness and malaise
Erythematous macules, targetoid lesions, or diffuse erythema progressing to vesicles and bullae
(picture 1A)
Positive Nikolsky sign and/or "bulla spread sign"
Oral, ocular, and/or genital mucositis with painful mucosal erosions (picture 1C, 1E)
Necrosis and sloughing of the epidermis of varying degree (picture 2C)
Assessment of drug causality For patients suspected to have SJS/TEN, the identification of the
causative drug is essential because early withdrawal of the offending agent may improve the prognosis
[104]. In addition, the identification of the culprit drug is of paramount importance to prevent reexposure in
patients recovering from SJS/TEN.
The assessment of drug causality is based upon detailed history and clinical judgement. Information
about the drugs that are most frequently associated with SJS/TEN is helpful (table 2). An algorithm of
drug causality for epidermal necrolysis (ALDEN) has been developed as a tool for rapid assessment of
drug causality in patients presenting with SJS/TEN, particularly in those exposed to multiple medications

[11]. Each potentially offending drug is assigned a score from -11 to 10 based upon six parameters (table
5):
Time delay from initial drug intake to onset of reaction
Probability of drug presence in the body on the index day
A previous history of exposure to the same drug, with or without reaction
Presence of the drug beyond the progression phase of the disease
Drug notoriety as a cause of SJS/TEN based upon previous studies
Presence or absence of other etiologic causes
The score is categorized as very probable (6), probable (4 to 5), possible (2 to 3), unlikely (0 to 1), and
very unlikely (0).
Assessment of severity The severity and prognosis of SJS/TEN depends upon the amount of skin
detachment or "detachable" skin (ie, skin with positive Nikolsky sign). Based upon the percentage of the
body surface area (BSA) involved, patients can be classified into three severity groups [1]:
SJS skin detachment of <10 percent of BSA
TEN skin detachment of >30 percent of BSA (picture 2A-D)
SJS/TEN overlap skin detachment of 10 to 30 percent of BSA
The correct evaluation of the extent of lesions may be difficult in areas with spotty lesions. It is useful to
remember that in both children and adults the surface of the patients hand, including palm and fingers,
corresponds to approximately one percent of the total body surface area. (See "Classification of burns",
section on 'Percent body surface area estimates'.)
The prognosis of individual patients can be rapidly evaluated in the early stages of disease by applying a
prognostic scoring system called SCORTEN, based upon seven clinical and laboratory variables (table 6)
[94]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and
long-term sequelae", section on 'SCORTEN score'.)
Skin biopsy A skin biopsy for routine histopathologic examination and possibly direct
immunofluorescence is useful in confirming the diagnosis and excluding other conditions that may
mimic SJS/TEN. An appropriate sample may be obtained by performing a large (>4 mm) punch biopsy or
a deep shave biopsy ("saucerization").
In the early stages of disease, apoptotic keratinocytes are scattered in the basal layer of the epidermis
and there is a perivascular mononuclear inflammatory infiltrate in the papillary dermis composed primarily
of T-lymphocytes [8]. This infiltrate is not diagnostic, and may be seen in a wide variety of conditions,
including a simple drug-induced exanthem. As the lesions progress, frank subepidermal bullae develop,
with full thickness epidermal necrosis (picture 3). Direct immunofluorescence is always negative.
Cultures Because of the high risk of bacterial superinfection and sepsis, appropriate cultures should
be performed from blood, wounds, and mucosal lesions. In children, PCR and/or serologies
for Mycoplasma pneumoniae infection should also be obtained in the early stage of disease and three
weeks later. (See "Mycoplasma pneumoniae infection in children", section on 'Diagnosis'.)
Investigational tests Candidate serum markers of SJS/TEN, including soluble Fas ligand, soluble
CD40 ligand, granulysin, and high-mobility group box 1 protein (HMGB1, a nonhistone nuclear protein

released by necrotic and apoptotic cells) have been evaluated in a few small studies [67,105-107].
However, further studies are necessary to determine whether these markers may be helpful in the early
diagnosis of SJS/TEN. (See 'Pathogenesis' above.)
DIFFERENTIAL DIAGNOSIS The differential diagnosis of Stevens-Johnson syndrome/toxic epidermal
necrolysis (SJS/TEN) includes:
Erythema multiforme Erythema multiforme usually presents with typical target lesions, or raised
atypical targetoid lesions that are predominantly located on the extremities (picture 4). Bullae and
epidermal detachment are usually limited and involve less than 10 percent of the body surface area.
Erythema multiforme is in most cases associated with infection with herpes simplex virus (table 1).
(See "Pathogenesis, clinical features, and diagnosis of erythema multiforme".)
Erythroderma and erythematous drug eruptions The generalized and symmetric
maculopapular erythema of a drug eruption can mimic early SJS/TEN. However, exanthematous
drug eruptions lack mucosal involvement and the prominent skin pain of TEN. Histology shows only
a mild interface dermatitis with a perivascular inflammatory infiltrate of lymphocytes, neutrophils, and
eosinophils. (See"Erythroderma in adults" and "Exanthematous (morbilliform) drug eruption".)
Acute generalized exanthematous pustulosis Severe cases of acute generalized
exanthematous pustulosis (AGEP) may be difficult to differentiate from SJS/TEN (picture 5). AGEP
typically develops within a few days of exposure to the offending drug, most often a beta lactam
antibiotic, and resolves without treatment in one to two weeks after drug discontinuation. The
histologic hallmark of AGEP is a spongiform subcorneal and/or intraepidermal pustule (picture 5).
(See "Acute generalized exanthematous pustulosis (AGEP)".)
Phototoxic eruptions Severe phototoxic eruptions may be confused with SJS/TEN. Important
clues to the correct diagnosis include recent sun exposure, known phototoxic properties of certain
medications, and location of the lesions on sun-exposed areas. (See "Photosensitivity disorders
(photodermatoses): Clinical manifestations, diagnosis, and treatment".)
Staphylococcal scalded skin syndrome Staphylococcal scalded skin syndrome (SSSS) is
caused by epidermolytic toxins produced by certain strains of Staphylococci and is usually seen in
neonates and young children. SSSS presents with generalized erythema rapidly followed by the
development of flaccid blisters and desquamation (picture 6). The mucous membranes are not
involved. Histology reveals sloughing of only the upper layers of the epidermis, in contrast with the
subepidermal split with full thickness epidermal necrosis observed in SJS/TEN.
(See "Vesiculobullous and pustular lesions in the newborn", section on 'Staphylococcal scalded skin
syndrome'.)
Paraneoplastic pemphigus Paraneoplastic pemphigus is a rare disorder that can represent the
initial presentation of a malignancy or occur in a patient with a known neoplastic process, such as
non-Hodgkin lymphoma in adults or Castleman's disease in children. Patients may develop severe
mucocutaneous disease with ocular and oral blisters and skin lesions (picture 7A-C).
(See "Paraneoplastic pemphigus".)
Linear IgA bullous dermatosis Linear IgA bullous dermatosis (LABD) is a rare autoimmune
blistering disease that may mimic toxic epidermal necrolysis (picture 8). Histology reveals a
subepidermal blister with an underlying neutrophil-predominant dermal infiltrate. Direct
immunofluorescence shows linear deposits of IgA along the basement membrane. (See "Linear IgA
bullous dermatosis".