Erythema Multiforme is a common Vesiculobullous deramtological condition with mucosal manifestations trigged by Herpes virus infection and certain sulpha containing drugs.

1. Chitwan Medical College
&
Teaching Hospital

2. Department Of
Oral Medicine and Radiology
Submitted to:
Dr. Manish Kumar
Department of
Oral Medicine and Radiology
Submitted by:
Binaya Subedi
BDS 4th Batch
College of Dental Sciences,CMC

3. Binaya Subedi
BDS Final Year (4th Batch)
School of Dental Sciences, Chitwan Medical College

4. 
 Terminologies
 Classification of vesiculobullous lesions
 Erythema Multiforme
 Introductions
 Classification
 Etiology
 Clinical Features
 Oral Manifestations
 Mangement
 Steven- Jhonson Syndrome
 Toxic Epidermal Necrolysis (TEN)
Contents

5. ULCER:
Break in the continuity of the surface epithelium of the skin or the
mucous membrane to involve the underlying connective tissue as a
result of micro molecular cell death of the surface epithelium or its
traumatic removal.
VESICLE:
Elevated blister containing clear fluid that is less than 1 cm in
diameter.
BULLA:
Elevated blister containing clear fluid that is over 1 cm in diameter.
Terminologies

6. PAPULES:
These are the lesions raised above the skin or mucosal surface that are smaller
than 1 cm in diameter.
NODULES:
These lesions are present within the dermis or mucosa. These lesions may also
protrudes above the skin or mucosa forming a characteristic dome shaped
structure.
PUSTULES:
These are blisters containing purulent material and appear yellow.
MACULES:
These are the lesions that are flush with adjacent mucosa and that are
noticeable because of their difference in color from normal skin or mucosa.

7. Classification of
Vesiculobullous lesion

8. 
Based on Clinical Presentation:
Predominantly vesicular:
 HSV infection
 Hand, foot and mouth
disease
 Herpangina
 Varicella infection
 Dermatitis herpetiformis
Predominantly bullous:
 Pemphigus vulgaris
 Bullous pemphigoid
 Benign mucous membrane
pemphigoid
 Erythema multiforme
 Bullous lichen planus
 Epidermolysis bullosa
 Bullous impetigo
 Stevens-johnson syndrome
 Linear IgA disease

9. 
Histopathological Classification
Intraepithelial bullous lesion:
 HSV infection
 Varicella infection
 Herpangina
 Hand foot and mouth
disease
 Pemphigus
 Epidermolysis bullosa
 Mucosal
erythemamultiforme
Subepithelial bullous lesions:
 Bullous pemphigoid
 Cicatricial pemphigoid
 Linear IgA disease
 Dermatitis herpetiformis
 Dermal erythema
multiforme

10. 
 Viral Disease
 Herpetic gingivostomatitis
 Herpetic labialis
 Recurrent Herpes Stomatitis
 Herpangina
 Primary and secondary Varicella Zooster
 Immunological Conditions
 Pemphigus
 Bullous Pemphigoid
 Erythema Multiforme
 Bullous Lichen Planus
Etiologic Classification

11. 
 Hereditary Condition
 Epidermolysis Bullosa
 Hailey Hailey Disease
 Daries Disease
 Miscellaneous Conditions
 Impetigo
 Oral Blood blisters

12. Erythema Multiforme

13. 
 Erythema Multiforme is an acute self limiting dermatitis
characterized by distinctive clinical eruption manifested
as the iris or target lesion.
 Hebra in 1866 described EM as, “a benign condition
characterized by skin lesion with an concentric color
changes which were distributes symmetrically.”
 It has various morphological appearance such as macule,
papule, bullae and crust, hence the name ‘Multiforme’
Introduction

14. 
 It exhibits the spectrum of severity ranging from
 Erthema Multiforme Minor
 Erythema Multiforme Major
 Steven-Johnson Syndrome (Traditionally
considered to be synonymous with EM major)
 Toxic Epidermal Necrolysis (TEN)
Currently, EM major and minor are considered
distinctly different process form the latter two
conditions.

15. 
 Not fully understood but is probably an immunologically
mediated process.
 May be precipitated by some bacterial, fungal and viral
infections:
 Herpes Simplex Virus infections (HSV-1 & HSV-2) trigger
EM- minor in almost 100% of cases
 Besides herpetic infection (55%), Mycoplasma Pneumoniae
appears to be common cause in EM Major and in Children.
 Some other viruses like CMV, VZV and HIV have been
frequently associated with EM.
Etio-pathogenesis

16. 
 Exposure to certain analgesics and antibiotics,
particularly Sulfa- drugs are most common triggers.
 These inculdes:
o NSAIDS : Sulphasalazine
o Antibiotics: Sulfonamides, Penicilline, Ciprofloxacin
o Anti-diabetic: Metformin, Hydantoins
o Barbiturates
o Antipsychotics: Phenothiazines
 It has also been reported to occur after Hepatitis B,
smallpox and DPT vaccinations.

20. Transport of HSV viral DNA fragments to distant skin sites by peripheral
blood mononuclear cells i.e. monocytes
HSV genes within DNA fragments are expressed on keratinocytes
Recruitment of HSV- specific CD4+Th1 cells
Production of INF-γ
Increased antigen presenting capacities of keratinocytes
Recruitment of lymphocytes
Activation of NK cells
Activation of Macrophages
Increased keratinolysis by macrophages and cytotoxic T cells
Pathogenesis of HSV induced Erythema Multiforme

21.  Pathogenesis of Drug induced Erythema Multiforme
 Involves expression of tumor necrosis factor alpha (TNF- α) and not
interferon-γ suggesting a varying mechanism .
 The disease process also often involves an abnormal metabolism of a
responsible drugs.
 Drug metabolism is directed toward the alternative pathway of oxidation by
the cytochrome P-450 enzymes, resulting in increased production of reactive
and potentially toxic metabolites.
 Affected individuals have a defect in the ability to detoxify these reactive
metabolites, which may bind covalently to proteins on the surface of
epithelial cells.
 This may then induce the immune response, leading to the severe skin
reaction Much of the tissue damage in drug-induced lesions appears to be
due to apoptosis by to activation of cytotoxic T cells and NK cells

22. 
 Clinical Presentation
 Age: Young Adults (10-30 Yrs)
 Sex: Males and females are equally affected.
 Common sites: mucous membrane
Oral Cavity, conjunctival, genitourinary, respiratory track
mucous membrane
Involvement of extraoral mucosal areas often associated
with Erythema Multiforme Major.
Clinical Features

23. 
 It seldom present with prodromal symptoms
however sometimes non-specific symptoms such as
low grade fever, diarrhea, malaise, myalgia, cough,
sore throat may be reported approximately 1 week
before the onset.
 It shows varying degree of severity in affected
patients.
Clinical Features

24. 
EM minor
 They usually begin with asymptomatic, round, dusky-red
macules, papules or occasionally vesicles or bullae
distributed in rather symmetrical pattern over the hands
or arms, feet, legs, face and neck.
 Individual lesion will greatly vary in size even in same
person but generally its only few centimeter or less.
 A concentric erythematous ring with varying shades of
erythema resembling a target or bull’s eye is the
characteristics finding referred to as “Target Lesion” or
“iris”.

25. Concentric rings
surrounded by varying
degree of redness
“Target Lesions”

26. Central blister/vesicles with a
concentric ring of varying degree
of erythema
papular lesion on the dorsum of
the arm.

27. 
 These lesions will appear rapidly within a day or
two and persist for several days to a few weeks
gradually fading to eventually clearing.
 Complete recovery from an EM attack typically
occurs within 1 to 4 weeks.
 No scarring occurs. Transient hypopigmentation or
hyperpigmentation may be seen.
 Recurrence is common over a period of year or so.

28. 
 Involvement of two or more mucosal sites along
with widespread skin lesions.
 Involvement of oral mucosa with ocular and genital
mucosa common in most of cases.
EM Major

29. 
 25-70% of cases presents with oral manifestations.
 Pain and discomfort is common complain of the patient.
 Common sites:
Lips, labial Mucosa, buccal mucosa, tongue, floor of mouth
and soft palate
 They emerge quickly and are similar to skin lesions.
Oral Manifestation

30. 
 They begin with erythematous patch that undergo
epithelial necrosis evolving into large, shallow erosions,
and ulceration with irregular borders bleeds freely
 Hemorrhagic crusting of the vermilion zones of lip is
common.
 Ulcerations in oral mucosa will be diffuse and the patients
are unable to ingest liquids due to sore mouth. 
sometimes they become dehydrated.

31. 
 There may be mild to severe oral and perioral pain
that may compromise speech, eating, and fluid
intake.
 Lip and oral lesions heal without scarring.

34. 
Investigations and
Diagnosis

35.  The diagnosis of EM is mainly based on the history
and clinical presentation, as histopathologic features
and laboratory investigations are nonspecific.

36. History:
 acute onset of oral and/or skin lesions, possibly preceded by
an HSV infection or a history of recent drug intake.
 Pain and discomfort during eating, drinking, swallowing or
speech
Clinical Examination:
 Characteristic multiple appearance of the lesion of the skin
and mucous membranes such as macules, papules, even
vesicles and bullae.
 Round, erythematous lesion with varying shades of redness
with rather symmetrical distribution over the the extremities
(dorsal surfaces of hands, feet, elbows, and knees)  Traget
Lesion

37. 
 Histopathological features are characterstic but not
pathnogomic.
Epithelial Changes:
 intercellular and intracellular edema of the overlying
epithelium with focal microvesicle formation
 Necrotic keratinocytes, pooling of an eosinophilic
amorphous coagulum within the epithelium,
 infiltration of mononuclear and polymorphonuclear cells
into all epithelial layers .
 acanthosis and elongation of rete pegs
 Individual necrotic keratinocytes are surrounded by CD8
cells termed as “satellite cell necrosis”.
Histopathology

38. 
Connective Tissue Changes
 generalized diffuse infiltrate of mixed mononuclear
cells on the upper portion of the lamina propria,
 vasodilation of blood vessels
 marked connective tissue edema causing large zone
separation at the basement membrane level.
 Immunofluorescence testing reveals that deep
perivasculitis is positive for immunoglobulin M and
C3

41. 
 Other common Diagnostic methods are;
 Immunofluorescence
 Tzanck Smear
 HSV-PCR
 Serology

42. Tzanck smear Test
Immunofluroscence
Testing

43. 
Differential Diagnosis
Dermal Lesion
 Hypersensitivity
Reaction
 Drug eruptions
 Urticarial lesions
Oral Lesions
 Apthous Stomatitis
 Contact Stomatitis
 ANUG
 Pemphigus
 Varicella Infection

45. 
 Depends upon severity of the disease, with mild
cases not usually requiring treatment as the
condition is self limiting.
Management

46. Mild Cases:
1. General Measures:
• Elimination of offending agents such as drugs, coloring and flavouring agents
etc.
• Maintenance of proper oral hygiene
• Iv rehydration if the patient is dehydrated
2. Topical Therapy:
• should be focused on symptomatic relief using topical anti-inflammatory,
anesthetic, or analgesic agents
• Fluocinonide 0.05% or other topical steroid agents need to be applied to
involved areas 2 to 3 times per day
• Mouthwash containing equal parts of viscous lidocaine 2%, diphenhydramine,
and an aluminum hydroxide and magnesium hydroxide mixture (Maalox) as a
swish-and-spit, up to 4 times per day.
3. Antiviral Therapy
• Oral acyclovir (400 mg BID) will reduce the duration of the condition.

47. Severe Cases:
Steriod therpay
• The most commonly used steroid is Prednisone 40- 60 mg per day, in a
tapering dose over 2 to 4 weeks systemic
• Steroid use only partially suppresses disease activity and may increase the
risk of disease chronicity and prolonged duration of attacks
Antiviral Therapy
• Valacyclovir (500-1000 mg/day) or Famicyclovir (125-250 mg/day)
Recurrent EM
Additional Immunosupressive therapy is used along with antiviral
therapy.
• Dapson or Hydroxychloroquin are primary drugs for recurrent EM
• Azathioprine is effective in suppressing the condition but has
serious side effects.
• Mycophenolate mofetil, newer immunosuppressant is advocated
these days

48. 
 Not usually life threatening except for the severe
cases.
 Usually self limiting but 20% experience recurrent
episodes in springs and autumns due to recurrent
herpes and drug exposure.
Prognosis

50. 
Steven Johnson syndrome
and
Toxic Epidermal Necrolysis

51. 
 Previously considered to be severe form of erythema
multiforme but it is now established fact that these
two represent a separate entity than EM
 They can be distinguished from EM varying only in
the area of involvement of skin surface.
 The acute life threatening condition is characterized
by epidermal sloughing and mucositis secondary to
extensive keratinocytic apoptosis.

52. 
 SJS and TEN is almost always triggered by drug
exposures.
 Common causative drugs are: anticonvulsants,
sulfonamides, NSAIDS, antibiotics (as that of EM so
is the pathogenesis)
Etiopathogenesis

53.  Pathogenesis of SJS and TEN
 Involves expression of tumor necrosis factor alpha (TNF- α) and not
interferon-γ suggesting a varying mechanism .
 The disease process also often involves an abnormal metabolism of a
responsible drugs.
 Drug metabolism is directed toward the alternative pathway of
oxidation by the cytochrome P-450 enzymes, resulting in increased
production of reactive and potentially toxic metabolites.
 Affected individuals have a defect in the ability to detoxify these
reactive metabolites, which may bind covalently to proteins on the
surface of epithelial cells.
 This may then induce the immune response, leading to the severe skin
reaction Much of the tissue damage in drug-induced lesions appears
to be due to apoptosis by to activation of cytotoxic T cells and NK cells

54. 
 Steven-Johnson Syndrome is usually seen in younger
patients annd Toxic Epidermal Necrolysis tends to occur
in people over 60 years.
 A female predominance is observed.
 Usually have flu-like symptoms including fever, malaise,
sore throat, headache, loss of appetite.
 The only difference between them is degree of skin
involvement with SJS involving less than 10% of total
body surface while TEN involving more than 30%.
Clinical Features

55. Skin lesion begins in few days. Unlike EM, skin lesion begins in
trunk presenting as completely flat erythematous macule.
Sloughing of skin and flaccid bullae appears within 1-14 days
Involvement of mucosal sites such as oral mucosa, genital
mucosa, respiratory mucosa and eyes.
Oral mucous membrane lesions: are extremely severe and no
mastication is possible. Vesicles and bullae will rupture leaving
raw eroded areas covered with thick white exudates.
Eye Lesions: Photophobia due to conjunctivitis, corneal
ulcerations, panopthalmitis.
 Genital lesions: may be non-specific urethritis, balanitis
and/or vaginal ulcers.

56. Respiratory infections such as tracheobronchial ulcerations
and penumonia.
Diffuse sloughing of significant proportion of skin and
mucosal surface makes it appear as if the patient had been
badly scalded.
If the patient survives, the cutaneous lesion will lean in 3-5
weeks however oral lesions takes longer to heal and
significant ocular damage is noticed in half of patients.
Differential Diagnosis:
• Staphylococcus scalded skin syndrome

58. Extensive Skin Involvement
Ocular involvement
Genital InvolvementSteven-Johnson Syndrome

59. Severe scalding of skin resembling
thermal burn

60. 
 Shows sub-epithelial blisters characterized by
degenerating, necrotic basal kerainocytes.
 Chronic inflammatory infiltrates in connective tissue
stroma.
Histopathology

61. Investigations may include:
 Urgent frozen sections of skin biopsy: full thickness
skin necrosis
 Direct immune fluorescence: negative
 Complete blood count (CBC): anemia, lymphopenia,
neutropenia, eosinophilia, atypical lymphocytosis
 Liver function tests (LFT): elevated transaminases,
hypoalbuminemia
 Renal function: microalbuminuria, renal tubular
enzymes in urine, reduced glomerular filtration, rising
creatinine and urea, hyponatremia
 Pulmonary function: bronchial mucosal sloughing on
bronchoscopy, interstitial infiltrates on chest x-ray
 Cardiac function: abnormal ECG and imaging

62. Management
General Measures:
Care of a patient with Stevens-Johnson syndrome/toxic epidermal
necrolysis requires supportive care, including:
• Cessation of suspected causative drug(s)
• Hospital admission: preferably to an intensive care and/or burn unit
• Fluid replacement (crystalloid)
• Nutritional assessment: may require nasogastric tube feeding
• Temperature control: warm environment, emergency blanket
• Pain relief
• Supplemental oxygen and in some cases, intubation with mechanical
ventilation
• Sterile/aseptic handling
Skin care requires daily examination of skin and mucosal surfaces for infection,
non-adherent dressings, and avoidance of trauma to the skin. Mucosal surfaces
require careful cleansing and topical anesthetics.
• Gentle removal of necrotic skin/mucosal tissue
• Culture of skin lesions, axillae, and groins every two days

63. • Antibiotics may be required for secondary infection but are best
avoided prophylactically.
• It is unknown whether systemic corticosteroids are beneficial,
but they are often prescribed in high dose for the first three to
five days of admission. Granulocyte colony-stimulating factor
(G-CSF) may be of benefit in patients with severe neutropenia.
• Other drugs reported effective include systemic corticosteroids,
ciclosporin, TNF-alpha inhibitors, N-acetylcysteine, and
intravenous immunoglobulins. Their role remains controversial.

64. Prognosis:
The severity of Stevens-Johnson syndrome/toxic
epidermal necrolysis is assessed using SCORTEN. One
point is scored for each of the following seven criteria at
admission.
Age older than 40 years
Presence of a malignancy
Heart rate more than 120
Initial percentage of epidermal detachment greater
than 10%
Serum urea level greater than10 mmol/L
Serum glucose level greater than 14 mmol/L
Serum bicarbonate level less than 20 mmol/L

65. 
 Shafer’s Textbook of Oral Pathology, 7th edition
 Oral & Maxillofacial Pathology, Neville, 4th edition
 Burket's Oral Medicine - Glick, Michael, 12th edition
 Textbook of Oral Medicine, Oral Diagnosis and Oral
Radiology, Ongole, 2nd edition
 Erythema Multiforme, A Review of Epidemiology,
Pathogenesis, Clinical Features, and Treatment
 Etiopathogenesis of Erythema Multiforme - A Concise
Review, Rakhi Issrani and Namdeo Prabhu
 Stevens Johnson Syndrome (Toxic Epidermal Necrolysis),
Amanda M. Oakley; Karthik Krishnamurthy.
References