Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis - ClinicalKey

Stevens-Johnson syndrome and toxic epidermal necrolysis- ClinicalKey 07/03/21 19.
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CLINICAL OVERVIEW
Stevens-Johnson syndrome and toxic epidermal

necrolysis
Elsevier Point of Care (see details)
Updated 2 Februari 2021. Copyright Elsevier BV. All rights reserved.
Synopsis
Key Points Urgent Action
Stevens-Johnson syndrome and toxic epidermal
Consult appropriate organ
necrolysis are acute mucocutaneous reactions that differ
system specialist to treat
by severity
complications
In Stevens-Johnson syndrome, extensive blisters can
lead to skin detachment affecting less than 10% of Monitor for secondary
BSA; in toxic epidermal necrolysis, more than 30% of infections and sepsis
BSA is affected; intermediate levels represent an
Monitor prognosis parameters
overlap of the entities 1
Initial symptoms may resemble a viral syndrome with

rash, but in a few days, skin and mucosal eruption lead to rapid deterioration of clinical
condition, and ICU or burn unit admission is required
Most often Stevens-Johnson syndrome or toxic epidermal necrolysis is caused by drug

therapy; however, Mycoplasma pneumoniae and HSV have been identified in cases without
drug exposure
Punch biopsy analysis confirms diagnosis, showing necrotic epidermis and effects that involve
all layers of skin
Erythema multiforme, staphylococcal scalded skin syndrome, autoimmune blister disorders,

and drug reaction with eosinophilia and systemic symptoms need to be ruled out before the
diagnosis of Stevens-Johnson syndrome or toxic epidermal necrolysis can be made
Treatment goals are to protect skin from irritations and infections, to control pain using
medications, and to provide electrolytes and nutrition as needed in supportive care
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Stevens-Johnson syndrome and toxic epidermal necrolysis- ClinicalKey 07/03/21 19.15
Complications may arise in multiple organ systems, including skin and mucosal surfaces
(especially genital), eyes, respiratory system, and gastrointestinal tract
Pitfalls
Avoid misdiagnosis of other cutaneous eruptions as Stevens-Johnson syndrome or toxic
epidermal necrolysis
These conditions are rare (on the order of a handful of cases per million person-years) 2
Terminology
Clinical Clarification
Stevens-Johnson syndrome and toxic epidermal necrolysis are rare, life-threatening skin
conditions involving blistering, skin loss, and multiorgan damage; they are usually caused by
drug therapy
Classification
Stevens-Johnson syndrome exists at the less severe end of a clinical spectrum of acute
mucocutaneous reactions; toxic epidermal necrolysis represents a higher level of severity 3
Severity is defined primarily by extent of blistering 1

In Stevens-Johnson syndrome, extensive blisters lead to skin detachment affecting less than
10% of BSA
In toxic epidermal necrolysis, eruption and scalding lead to skin detachment affecting more
than 30% of BSA
Stevens-Johnson syndrome and toxic epidermal necrolysis may overlap with skin
detachment at 10% to 30% of BSA
Diagnosis
Clinical Presentation
History
Initial symptoms may be nonspecific 2

Fever, conjunctival irritation, rhinitis, cough, sore
throat, and malaise
Areas of painful skin and/or mucosa may occur in the

absence of visible changes
Within several days, skin and mucus membrane lesions

appear

First appear on face and trunk, spreading quickly to Stevens-Johnson syndrome. - Large
rest of body, including mucosae of eyes, nose, desquamation in Stevens-Johnson
oropharynx, and perineum syndrome.
Mucositis and pain at mouth, lips, and tongue may

limit oral intake
Involvement of gastrointestinal mucosa may result in Ocular surface involvement in acute

abdominal distention and sometimes diarrhea, which Stevens-Johnson syndrome/toxic
epidermal necrolysis. - A, Conjunctival
may be bloody 4
hyperemia and membrane. B, Eyelid
Involvement of perineum and urinary tract may lead margin sloughing (arrow) as evident
to dysuria, hematuria, or urinary retention 4 with fluorescein staining under cobalt

blue light. C, Corneal epithelial defect
Involvement of respiratory tract may cause cough, (arrow) stained with fluorescein.
dyspnea, or hemoptysis 4
Medication history may provide important clues to cause

2
More than 100 drugs have been implicated; the

frequency with which a drug has been implicated is
important in determining its potential role, especially
in patients taking multiple medications
Timing of start of drug administration is also an Stevens-Johnson syndrome

important factor in determining causality; drug- associated with afatinib treatment. - A
induced cases usually begin within 8 weeks of start of and B, before treatment. C and D,
the inciting agent, and most often within 4 weeks (eg, after 2 weeks of treatment. Cutaneous
5
a mean of 15 days in one study) lesions improve slowly.
Physical examination
Findings depend on stage at which patient is seen, as
extent and nature of lesions evolve
Inspection of skin and mucosae to determine

morphology and extent of lesions and characteristics of
erosion 6
Lesions generally originate on face and trunk, then Typical crusted lips in a patient with
form peripherally; extremities are less affected than Stevens-Johnson syndrome.
face and trunk, although palms and soles may be
involved

Lesions begin as erythematous macules that enlarge, and they often have a target-like
appearance; the lesions coalesce and develop flaccid blisters that may break, oozing serous
or bloody fluid
Positive Nikolsky sign is suggestive but not confirmatory 6

Tangential mechanical pressure on intact lesion induces epidermal detachment
Oral lesions and purulent conjunctivitis are usually present
Perineal mucosa is typically involved
Assessment of general health and status of internal organs

Vital signs
Fever is a common feature and does not necessarily imply presence of infection
Elevation of pulse and respiratory rate, and decrease in blood pressure, may occur with
superimposed infections or sepsis
Sloughing of respiratory mucosa may impair respiration; cough, wheezing, or rhonchi may
be audible
Causes and Risk Factors

Causes
Medications are the usual causative agents (75% 7-85% 1 of cases)
High-risk drugs 6 8
Allopurinol is the most common cause in Europe and Israel; risk is increased with
coadministration of an ACE inhibitor 2
Antibiotics are among the most common causes 9

Trimethoprim-sulfamethoxazole and other sulfonamide antibiotics 2
Aminopenicillins 10
Antituberculosis drugs 10
Anticonvulsants
Carbamazepine
Phenytoin
Phenobarbital

Lamotrigine (especially in conjunction with valproic acid) 2
NSAIDs of the oxicam class (eg, meloxicam, piroxicam, tenoxicam)
Nevirapine 2
Biologic agents 8
Reexposure to previously implicated medications may result in a recurrence
Other causes include infections

Mycoplasma pneumoniae
HSV
HIV
Annual incidence of toxic epidermal necrolysis is 1000-fold higher in patients with HIV
than in the general population 6
20% of cases are idiopathic 2
Risk factors and/or associations

Age
Stevens-Johnson syndrome and toxic epidermal necrolysis can occur at any age, with higher
prevalence in adults 11
Sex
Predominance in women versus men was reported in the past 7 11
With HIV epidemic, current incidence is approximately the same in men and women 7
Genetics
Increased risk of hypersensitivity reaction to specific drugs is linked to certain HLA antigens 8
12
Numerous HLA alleles have been associated with this disease, and some have higher
prevalence in people with Asian ancestry
Lamotrigine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis are
associated with presence of HLA-B*15:02 allele in people with Han Chinese ancestry 13
Increased risk of phenytoin-induced Stevens-Johnson syndrome and toxic epidermal

necrolysis occurs with HLA-B*15:02 allele, which is inherited mostly via Asian ancestry and

not as much via European ancestry or African ancestry 10 14
HLA-B*58:01 is associated with allopurinol-induced severe cutaneous adverse reactions 15

16
HLA-B*15:02 is associated with phenytoin-induced and carbamazepine-induced Stevens-

Johnson syndrome and toxic epidermal necrolysis 14
HLA-B12 is associated with a higher risk for toxic epidermal necrolysis 9
Ethnicity/race
HLA-B*15:02 allele is inherited mostly via Asian ancestry and not as much via European
ancestry or African ancestry 13 14
Other risk factors/associations

Systemic lupus erythematosus has been reported as a predisposing condition
Some authorities distinguish the blistering skin condition associated with this disease from
Stevens-Johnson syndrome and toxic epidermal necrolysis, attributing it to a different
process 10
Bone marrow transplant recipients are at increased risk for the disease 9
Presence of malignancy or collagen vascular disease increases risk 17
Diagnostic Procedures
Primary diagnostic tools
Diagnosis is often based on details from history and physical examination
Skin biopsy is recommended to confirm diagnosis and rule out differential diagnoses 1
Because of possible complications due to fluid losses, systemic involvement, and

superimposed infection, comprehensive laboratory evaluation is warranted and should be
based on clinical circumstances and degree of illness
CBC, electrolyte levels, serum or plasma glucose level, renal function tests (eg, BUN and
creatinine levels), liver function tests, coagulation studies, and arterial blood gas levels
are recommended in all patients 1 4 10
Elements of a basic metabolic profile are factored into the SCORTEN score, a validated
tool for assessing severity 10 18

Obtain serology or skin or ocular swabs for the following infections if clinical suspicion
exists: 4
Mycoplasma pneumoniae
HSV
HIV
Chlamydia
Varicella-zoster virus
Adenovirus
HLA testing for alleles known to predispose to the disease may help to identify a possible
cause 10
Associations are quite specific; certain alleles predispose to reactions to specific drugs and
are more prevalent via Asian ancestry than via other ancestries
Testing should be guided by an expert
Laboratory
Functional testing
Procedures
Differential Diagnosis
Acute generalized exanthematous pustulosis. - Edematous and erythematous pustular eruption on the back.

Bullous pemphigoid. - Tense bullae on an erythematous urticarial base of skin.
Burns: depth of thermal injury. - A, Patient with sunburn on lower extremity (a superficial or first-degree burn
with associated blisters on anterior tibial surface). B, Partial-thickness injury of hand (superficial second-
degree burn). C, Partial-thickness injury extending beyond subcutaneous layers (deep second-degree burn).
D, Full-thickness (third-degree) burn. E, Full-thickness injury with extensive tissue loss (fourth-degree burn).
Erythema multiforme with typical target lesions.

Staphylococcal scalded skin syndrome. - Blisters are expression of toxin-related (exfoliative toxin A or B)
distant disease and usually do not contain microorganisms.
General
Rarity of Stevens-Johnson syndrome and toxic epidermal necrolysis informs the effort to avoid
misdiagnosis of other cutaneous eruptions
Stevens-Johnson syndrome: 1 to 6 cases per million person-years 2
Toxic epidermal necrolysis: 0.4 to 1.2 cases per million person-years 2
Most common
Erythema multiforme 20
Formerly sometimes equated with Stevens-Johnson syndrome, but now distinguished from it
Presents as target lesions having 3 or more concentric rings in a symmetrical distribution with or
without blisters
Nikolsky sign is not present in erythema multiforme major (ie, no exfoliation of outermost layer
of skin just from slight rubbing)
Differentiated histologically by mononuclear cell infiltration and less necrosis than in Stevens-
Johnson syndrome
Acute generalized exanthematous pustulosis 20

Presents as widespread erythematous and edematous rash with fever and abrupt onset
Distinguished by small nonfollicular whitish pustules that disappear spontaneously in a couple

of days
Differentiated histologically by migration of PMNs within epidermis and paucity of necrotic

keratinocytes

Drug reaction with eosinophilia and systemic symptoms (drug-induced hypersensitivity

syndrome) 21
Like Stevens-Johnson syndrome and toxic epidermal necrolysis, it is a severe cutaneous adverse
reaction occurring usually several weeks after introduction of causative drug
Presents as a pruriginous maculopapular rash (usually starting on face and then generalized),
with edema of face and extremities, fever, and peripheral lymphadenopathy; mucosal
involvement is unusual
Systemic involvement, particularly in liver and kidneys, is nearly always present
Laboratory tests find high eosinophil count, atypical lymphocytes, and sometimes elevated liver
enzyme levels and/or decreased GFR
Differentiated by pattern of dermatologic features, high eosinophil count, and atypical

lymphocytes
Second-degree burn (Related: Thermal burns)
Presents as partial-thickness loss of skin from heat injury
Distinguished by localization of lesions and complete absence of lesions in unaffected areas
Differentiated by history and size of lesions (often quite large)
Staphylococcal scalded skin syndrome
Clinical presentation is blistering skin lesions in an infant
Nikolsky sign is positive, as in Stevens-Johnson syndrome and toxic epidermal necrolysis
Differentiated histologically by subcorneal split with or without mild acantholysis (loss of cell to
cell adhesion)
Autoimmune bullous disorders 202223
Present as blisters of variable character (eg, papular, urticariform, pruritic)
Distinguished by autoantibodies arising in epidermis, dermal-epidermal junction, and basement

membrane
Differentiated histologically by linear deposition of immunoglobulin (IgG and C3, identified by

fluorescent antibodies) at basement membrane
Treatment

Goals
Discontinue or remove inciting agent, if identified
Protect skin and provide supportive care to promote healing
Avoid infections and complications
Disposition
Admission criteria
Hospitalize all patients with confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis
19
Criteria for ICU admission
Patients with SCORTEN score of 3 or higher should be managed in ICU or burn unit 6
Recommendations for specialist referral

Consult dermatologist for specialized biopsy and skin treatment techniques
Consult ophthalmologist to assess and treat ocular involvement
Additional specialists may be needed as clinical status dictates
Treatment Options
Treatment is supportive and similar to that for major burns
Guidelines are available, but evidence base is limited 1 4 19 24

NIH recommendation to begin standardized case reporting reflects an effort to collect more
data 25
Discontinue any possible offending agents and nonessential medications promptly 10
General principles of treatment for all patients in ICU setting
Meticulous wound care 10

Debridement of detached epidermis is not recommended; blisters should be decompressed
4
Regularly clean wounds and intact skin with warm sterile water, saline, or chlorhexidine 4
Apply a greasy emollient all over skin, including lesions, during acute phase; use of an
aerosolized form may limit epidermal trauma 4

Apply nonadhesive dressings to wounds and uninvolved skin (eg, pressure points, friction
sites) 4
Fluid replacement to maintain urine output of 0.5 to 1 mL/kg/hour 10

Crystalloids are recommended; potassium supplementation is often needed 6
Supplemental albumen is recommended by some authorities 10
Pain control 10
May require opioids if pain is severe
Nutritional support
Enteral is preferred (ie, liquid or soft diet) 10
Ventilatory support if needed
Ambient temperature should be maintained at 28 °C to 32 °C 10
Antihistamines may be administered for pruritus from Stevens-Johnson syndrome
Very high potency topical corticosteroids may be applied to affected areas of noneroded skin
once infection has been excluded 4
Mouth care for patients with involvement of oropharyngeal mucosa
Antiseptic mouthwash is recommended
Antiinflammatory mouthwash or oral spray may be used, particularly before eating 4
Potent topical corticosteroid mouthwash may be used 4
Eye care for patients with ocular involvement 4
Daily ophthalmology review
Daily saline irrigation
Ocular lubricants and dressings to prevent corneal exposure
Consider topical corticosteroid eye drops, provided infection has been excluded
Consider amniotic membrane transplantation for conjunctival epithelial defects
Consider topical antibiotic prophylaxis for corneal erosion or ulceration

Consider immunomodulatory therapy 26
Commonly used, but evidence of benefit is limited and use is controversial 26
In a small case series, IV immunoglobulin appeared to improve survival, especially at doses of

2 g/kg or higher; however, large studies have found no survival advantage 27 28
Systemic corticosteroids are frequently used, but studies have not consistently found benefit;
29 consider use in combination with IV immunoglobulin or in combination with cyclosporine
30 31 32
Several other systemic therapies (eg, cyclosporine, tumor necrosis factor antagonists) have
been used, but there is no clear drug or regimen of choice 6 10 29 33
Ideally start within first 24 to 48 hours after presentation if used 32
Surgical debridement is indicated for necrotic or infected epidermis 4
Comorbidities that may have a role in the outbreak (eg, infections) should be addressed (eg,
acyclovir for HSV infection)
Drug therapy
IV immunoglobulin
Immune Globulin (Human) Solution for injection; Infants, Children, and Adolescents:
Efficacy data are limited and variable; reported dosage regimens vary. Total dose of 2 g/kg
IV divided over 1 to 4 days has been used. Reported dosage range: 1.5 to 5.8 g/kg IV total
dose (given in divided doses).
Immune Globulin (Human) Solution for injection; Adults: Total dose of 2 to 3 g/kg IV
divided over 3 to 4 days has been used. 6
Dexamethasone
For Stevens-Johnson syndrome:
Dexamethasone Sodium Phosphate Solution for injection; Adolescents, Children, and
Infants: 0.02 to 0.3 mg/kg/day or 0.6 to 9 mg/m2/day IV or IM given in 3 to 4 divided
doses is the FDA-approved general dosage range. Adjust according to patient response.
Dexamethasone Sodium Phosphate Solution for injection; Adults: Initially, 0.5 to 9

mg/day IV or IM, in 2 to 4 divided doses. Adjust according to patient response.
For toxic epidermal necrolysis:

Dexamethasone Sodium Phosphate Solution for injection; Adults: 1.5 mg/kg IV given

over 30 to 60 minutes daily for 3 days. 10
Methylprednisolone 26 31
Pulse therapy
Methylprednisolone Sodium Succinate Solution for injection; Adults, Adolescents and

Children: 250 to 1,000 mg IV given once daily or on alternate days for 3 to 5 doses. 31
Cyclosporine 26
Cyclosporine Oral capsule; Adults, Adolescents, and Children: 3 to 5 mg/kg/day PO in
divided doses for up to 21 days has been recommended. The average duration is 7 days; may
be given intravenously if needed. 34
Nondrug and supportive care

Limit skin trauma by avoidance or careful use of medical items such as blood pressure cuffs,
tourniquets, ECG electrodes, and dressings 4
Cover areas of desquamation with nonadherent dressings; also apply to noninvolved sites if
protection is required (eg, friction areas) 4
Dressings may be biologic or biosynthetic 1

Dressings may be silver- or antibiotic-impregnated
Frequent changes are not recommended
Encourage mobilization under supervision of physical therapist 4
Comorbidities
Comorbidities that may have a role in the outbreak (eg, infections) should be addressed (eg,
acyclovir for HSV infection)
Special populations
Children
Mortality rate is lower in children 35
Half of affected children have long-term complications 35
A guideline focused on children and adolescents is available from the British Association of
Dermatologists 4
Older adults (eg, those older than 60 years)

In adults older than 60 years, underlying diseases may contribute to mortality 36
Monitoring
Monitor for secondary infections and sepsis
Monitor prognosis parameters
Complications and Prognosis

Complications
Secondary infections
Sepsis
Permanent skin damage 35

Hypopigmentation or hyperpigmentation 37
Scarring of skin
Photosensitivity 37
Chronic pruritis 37
Ocular complications
Keratitis
Corneal defects
Chronic conjunctivitis
Vision loss
Severe dry eye 37
Phimosis or urethral strictures (Related: Phimosis and paraphimosis)
Vaginal adhesions, stenosis, dryness, and dyspareunia 37
Sclerosing cholangitis
Bronchiolitis obliterans
Stridor
Recurrence of Stevens-Johnson syndrome

Death
Prognosis
Prognosis is correlated with SCORTEN score for severity of illness 29
Age 40 years or older
Heart rate 120 beats per minute or higher
Malignancy present
Epidermal detachment affecting 10% or more of BSA
BUN level more than 28 mg/dL (10 mmol/L)
Serum bicarbonate level less than 20 mEq/L (20 mmol/L)
Serum glucose level more than 252 mg/dL (14 mmol/L)
Score 1 point for each item; mortality rate increases as score increases; 26 a score of 5 or more
may indicate 90% predicted mortality 18
Mortality is predominantly caused by multiorgan failure due to sepsis 38
Mortality rate for adults at 1 year 39

For Stevens-Johnson syndrome: 24%
For toxic epidermal necrolysis: 49%
For Stevens-Johnson syndrome/toxic epidermal necrolysis overlap: 43%
Mortality rates for children range from 0% to 16%, depending on severity 40
Among survivors, long-term complications are common 26
Screening and Prevention

Prevention
HLA-B genotype screening before prescribing anticonvulsants 14
HLA-B*15:02 screening before prescribing phenytoin or carbamazepine
HLA-B screening before prescribing allopurinol for gout 15 16

HLA-B*58:01 is linked to severe cutaneous adverse reactions

Patients should be made aware of the risk of a recurrence with reexposure to the inciting
agent; reexposure should be avoided
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Stevens-Johnson syndrome and toxic epidermal necrolysis- ClinicalKey 07/03/21 19.

Stevens-Johnson syndrome and toxic epidermal

Initial symptoms may resemble a viral syndrome with

Most often Stevens-Johnson syndrome or toxic epidermal necrolysis is caused by drug

Erythema multiforme, staphylococcal scalded skin syndrome, autoimmune blister disorders,

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Severity is defined primarily by extent of blistering 1

Initial symptoms may be nonspecific 2

Areas of painful skin and/or mucosa may occur in the

Within several days, skin and mucus membrane lesions

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Mucositis and pain at mouth, lips, and tongue may

Involvement of gastrointestinal mucosa may result in Ocular surface involvement in acute

to dysuria, hematuria, or urinary retention 4 with fluorescein staining under cobalt

Medication history may provide important clues to cause

More than 100 drugs have been implicated; the

Timing of start of drug administration is also an Stevens-Johnson syndrome

Inspection of skin and mucosae to determine

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Positive Nikolsky sign is suggestive but not confirmatory 6

Oral lesions and purulent conjunctivitis are usually present

Perineal mucosa is typically involved

Assessment of general health and status of internal organs

Causes and Risk Factors

Medications are the usual causative agents (75% 7-85% 1 of cases)

Antibiotics are among the most common causes 9

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Lamotrigine (especially in conjunction with valproic acid) 2

NSAIDs of the oxicam class (eg, meloxicam, piroxicam, tenoxicam)

Reexposure to previously implicated medications may result in a recurrence

Other causes include infections

20% of cases are idiopathic 2

Risk factors and/or associations

Predominance in women versus men was reported in the past 7 11

Increased risk of phenytoin-induced Stevens-Johnson syndrome and toxic epidermal

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not as much via European ancestry or African ancestry 10 14

HLA-B*58:01 is associated with allopurinol-induced severe cutaneous adverse reactions 15

HLA-B*15:02 is associated with phenytoin-induced and carbamazepine-induced Stevens-

HLA-B12 is associated with a higher risk for toxic epidermal necrolysis 9

Other risk factors/associations

Presence of malignancy or collagen vascular disease increases risk 17

Diagnosis is often based on details from history and physical examination

Because of possible complications due to fluid losses, systemic involvement, and

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Testing should be guided by an expert

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Bullous pemphigoid. - Tense bullae on an erythematous urticarial base of skin.

Erythema multiforme with typical target lesions.

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Stevens-Johnson syndrome: 1 to 6 cases per million person-years 2

Toxic epidermal necrolysis: 0.4 to 1.2 cases per million person-years 2

Acute generalized exanthematous pustulosis 20

Distinguished by small nonfollicular whitish pustules that disappear spontaneously in a couple

Differentiated histologically by migration of PMNs within epidermis and paucity of necrotic

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Drug reaction with eosinophilia and systemic symptoms (drug-induced hypersensitivity

Systemic involvement, particularly in liver and kidneys, is nearly always present

Differentiated by pattern of dermatologic features, high eosinophil count, and atypical

Second-degree burn (Related: Thermal burns)

Presents as partial-thickness loss of skin from heat injury

Distinguished by localization of lesions and complete absence of lesions in unaffected areas

Differentiated by history and size of lesions (often quite large)