Erythema Multiforme |
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Recently ruptured blister of the buccal mucosa. |
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Quick Review for Patients
| Erythema multiforme is an unusual allergic reaction which results in red rashes, blisters and ulcers of the mouth membranes and the skin, either together or separately. Some cases are very severe and may be fatal, but most persons have a much more mild, self-limiting form of the disease. Recurring examples do occur, especially when recurring herpes virus infection (fever blisters on the lip) is the triggering event. Erythema multiforme has an abrupt onset and typically resolves without scarring in 2-6 weeks. Systemic or topical corticosteroids are usually effective. |
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Erythema multiforme is an acute, self-limiting, blistering and ulcerative allergic response of the skin and mucous membranes. Some authorities separate the disease into minor and major (Stevens-Johnson syndrome) subtypes, and an extreme subtype referred to as toxic epidermal necrolysis (Lyell's disease), first described in 1956. Most cases are minor, but death has resulted from severe involvement. Infection appears to be the triggering event in at least half of the cases, usually with Herpes simplex virus or Mycoplasma pneumoniae. Medications, especially sulfonamides, and foods may also initiate an attack, and those associated with medications tend to be among the most severe cases.
Immune complexes associated with the subepithelial microvasculature have been implicated in its pathophysiology. The disease may represent a type III immune complex-mediated hypersensitivity reaction with impaired histamine metabolism and with a portion of the pathology arising from a type IV delayed hypersensitivity reaction. Endothelial cells appear to be the target of injury in these reactions. Persons with HLA-DQB1 may be especially susceptible to the disease, while recurrences are associated with HLA-B62 and HLA-B35. Herpes simplex DNA has been demonstrated in patients with recurrent erythema multiforme.
Usually a dermal problem, erythema multiforme also often affects the mucous membranes of the mouth, eyes, nasal/paranasal sinuses, and genitalia. Major forms of the disease have an average annual incidence rate of 0.5/100,000 persons. Toxic epidermal necrolysis is much more rare, occurring only once in every 1,000,000 persons each year.
Clinical Features
Erythema multiforme typically affects teenagers and young adults, but onset may be as late as 50 years or more of age. Toxic epidermal necrolysis typically occurs in older individuals. There is a male predilection, although toxic epidermal necrolysis shows a rather strong female predilection.
Skin or mucosal lesions occur abruptly and may be rather localized or may cover most of the body surfaces. Oral lesions tend to affect the labial and buccal mucosa, but any mucosal surface may be involved, although lesions of the gingiva and hard palate are rare. Fever, lymphadenopathy, malaise, headache, cough, sore throat, and polyarthralgia may present as prodromal signs and symptom as much as a week prior to the onset of the surface erythema or blisters.
On the skin, a wide variety of irregular red macular, papular and vesicular lesions may occur, either separately or in combination. A unique lesion, the target or bull's-eye lesion appears as concentric rings of affected skin interspersed with rings of clinically normal skin, often with a bullous lesion at the center.
Cases called to the attention of the dental profession often present with only oral involvement or oral and conjunctival involvement. Whether alone or in conjunction with dermal disease, oral lesions begin as erythematous macules which go on to form bullae with irregular outlines and a strong inflammatory halo. Blisters readily rupture to leave a flat white ulcer bed. The erythema which may be the only manifestation of skin involvement is less pronounced when it occurs in the mouth and often it is not present at all. Some patients experience only shallow ulceration, not bullous formation. Bullous and ulcerative oral lesions are moderately painful or tender, and this is usually the patient's main complaint, but severe involvement, such as that seen in toxic epidermal necrolysis, may lead to sloughing of large portions of the oral mucosa, giving the patient the appearance of having been badly scalded. Secondary infection of skin lesions may cause additional destruction or septicemia. Significant ocular scaring and synechiae formation occurs in half of affected patients from bullous lesions of the conjunctiva, often with loss of eye lashes and perhaps with fusion of the bulbar and lid conjunctivae.
Pathology and Differential Diagnosis
The microscopic appearance of mucosal lesions of erythema multiforme varies considerably, depending on the stage of lesional development, the amount of local trauma and the site of biopsy. The classic appearance is that of a vacuolar interface mucositis with vacuolization of the basal epithelial cells and with lymphocytes coating the basement membrane (tagging lymphocytes); additional lymphocytes sparsely surround subepithelial vessels. The lymphocytes consist largely of CD4+ (helper) cells in the connective tissue and CD8+ (cytotoxic) lymphocytes in the epithelium. The latter cells are similar to those associated with graft-vs.-host disease.
Spongiosis and exocytosis may be seen but are seldom pronounced. Necrotic keratinocytes (apoptotic keratinocytes) in the spinous layer is a hallmark feature and affected cells often show adjacent or surrounding lymphocytes (satellite cell necrosis). In bullous lesions there may be full-thickness epithelial necrosis, subepithelial bullae or intraepithelial bullae, or a combination of all three, but subepithelial involvement is usually the only type noted. Extravasated erythrocytes are often seen within the blister.
Connective tissue papillae usually show edema and mild to moderate inflammatory cell infiltration, predominantly by chronic cells. It is not unusual to see nuclear dust from ruptured neutrophils, and eosinophils are often present. Pigment incontinence may be seen in the subepithelial stroma, with melanophages additionally found in older lesions. The basement membrane may be smudged and often seems poorly demarcated.
Direct and indirect immunofluorescence studies are not usually useful in the diagnosis, but deposits of IgM and C3 in the walls of superficial blood vessels can usually be identified. Granular deposits of IgM, C3 and fibrinogen may also be present along the basement membrane. Circulating immune complexes are often demonstrated with a monoclonal rheumatoid faction inhibition assay or a C1q binding radioassay.
Correlation between pathologist and clinician is often the key to the
diagnosis of erythema multiforme. Oral lesions are often quite necrosed by
the time of biopsy and may show secondary inflammation from recurring trauma
or from contact with the oral flora. It is important to remember, moreover,
that necrotic keratinocytes are also found in fixed drug eruption, acute graft-vs.-host disease, viral vesicles, radiation mucositis and some lichenoid
reactions.
Treatment and Prognosis
Erythema multiforme is usually self-limiting and runs its course in 2-6 weeks, but one in five patients will experience recurrent episodes, usually in the spring and autumn. Management includes the use of systemic corticosteroids, topical corticosteroids for less severe and more localized lesions. These two therapies may be more effective when used in combination. Topical anesthetic agents may be needed to reduce the pain, especially during mealtimes, and intravenous rehydration may be necessary because of the pain of eating and drinking fluids.
Usually there is healing without scar formation and without recurrence. Recurrent cases, when they occur, typically have a recurrence every 1-6 months, or may only manifest on additional contact with the initiating factor, such as recurrent herpes labialis or new drug contact. For those with recurring disease the continuous use of oral acyclovir or another antiviral medication may help to control the Herpes simplex outbreaks, thereby preventing the onset of additional episodes of erythema multiforme.
Patients with toxic epidermal necrolysis have a one in three chance of
dying of their disease, while the Stevens-Johnson syndrome carries a 2-10%
mortality rate. Normally, however, erythema multiforme is not a life-threatening
disease.
References (Chronologic Order)
Note: Click on underlined author's names for additional detail.
General references:
Neville BW, Damm DD, Allen CM, Bouquot JE. Oral and maxillofacial pathology. Philadelphia, W. B. Saunders; 1995.
Elder D, Elenitsas R, Jaworsky C, Johnson B Jr. Lever's Histopathology of the skin, 8th edition. Philadelphia; Lippincott-Raven, 1997.
Sapp JP, Eversole LR, Wysocki GP. Contemporary oral and maxillofacial pathology. Mosby; St. Louis, 1997.
Odell EW, Morgan PR. Biopsy pathology of the oral tissues. London; Chapman & hall Medical, 1998.
Specific references:
Lyell A. Toxic epidermal necrolysis: An eruption resembling scalding of the skin. Br J Dermatol 68:355-361, 1956.
Hurwitz S. Erythema multiforme: A review of its characteristics, diagnostic criteria, and management. Pediatr Rev 11:217-222, 1990.
Schopf E, et al. Toxic epidermal necrolysis and Stevens-Johnson syndrome: An epidemiologic study from West Germany. Arch Dermatol 127:839-842, 1991.
Aslanzadeh J, et al. Detection of HSV-specific DNA in biopsy tissue of patients with erythema multiforme by polymerase chain reaction. Br J Dermatol 126:19-23, 1992.
Lozada-Nur F, Cram D, Gorsky M. Clinical response to levamisole in thirty-nine patients with erythema multiforme: An open prospective study. Oral Surg Oral Med Oral Pathol 74:294-298, 1992.
Parsons JM. Toxic epidermal necrolysis. Int J Dermatol 31:749-768, 1992.Stampien TM, Schwartz RA. Erythema multiforme. Am Faro Physician 46:1171-1176, 1992.
Wilkins J, Morrison L, White CR. Oculocutaneous manifestations of the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Dermatol Clin 10:571-582, 1992.
Barone CM, et at. Treatment of toxic epidermal necrolysis and Stevens-Johnson syndrome in children. J Oral Maxillofac Surg 51:264-268, 1993.
Bastuji-Garin S, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129:92-96, 1993.
Roujeau J-C, et al. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 23:1039-1058, 1990.
Schofield JK, Tatnail FM, Leigh IM. Recurrent erythema multiforme: Clinical features and treatment in a large series of patients. Br J Dermatol 128:542-545, 1993.
