The first step is to suspect EM, based on clinical features. A skin biopsy and laboratory investigations are useful mainly if the diagnosis is not definite clinically. The second step is to determine whether hospitalization is needed when EM major (EMM) occurs with oral lesions severe enough to impair feeding, when a diagnosis of SJS is suspected, or when severe constitutional symptoms are present. The third step is to establish the cause of EM by identifying a history of recurrent herpes, performing chest radiography, or documenting M. pneumoniae infection (Fig. 39-1).
Prodromal symptoms are absent in most cases. If present, they are usually mild, suggesting an upper respiratory infection (e.g., cough, rhinitis, low-grade fever). In EMM, fever higher than 38.5°C (101.3°F) is present in one-third of cases.2 A history of prior attack(s) is found in at least one-third of patients and thus helps with the diagnosis. The events of the preceding 3 weeks should be reviewed for clinical evidence of any precipitating agent, with a special focus on recurrent herpes.
The skin eruption arises abruptly. In most patients, all lesions appear within 3 days, but in some, several crops follow each other during a single episode of EM. Often there are a limited number of lesions, but up to hundreds may form. Most occur in a symmetric, acral distribution on the extensor surfaces of the extremities (hands and feet, elbows, and knees), face, and neck, and less frequently on the thighs, buttocks, and trunk. Lesions often first appear acrally and then spread in a centripetal manner. Mechanical factors (Koebner phenomenon) and actinic factors (predilection of sun-exposed sites) appear to influence the distribution of lesions. Although patients occasionally report burning and itching, the eruption is usually asymptomatic.
The diversity in clinical pattern implied by the name multiforme is mainly due to the findings in each single lesion; most lesions are usually rather similar in a given patient at a given time. The typical lesion is a highly regular, circular, wheal-like erythematous papule or plaque that persists for 1 week or longer (Fig. 39-2). It measures from a few millimeters to approximately 3 cm and may expand slightly over 24 to 48 hours. Although the periphery remains erythematous and edematous, the center becomes violaceous and dark; inflammatory activity may regress or relapse in the center, which gives rise to concentric rings of color (see Fig. 39-2). Often, the center turns purpuric and/or necrotic or transforms into a tense vesicle or bulla. The result is the classic target or iris lesion.
Mixture of typical targets and papules in a case of EM minor
According to the proposed classification, typical target lesions consist of at least three concentric components: (1) a dusky central disk, or blister; (2) more peripherally, an infiltrated pale ring; and (3) an erythematous halo. Not all lesions of EM are typical; some display two rings only (“raised atypical targets”). However, all are papular, in contrast with macules, which are the typical lesions in epidermal necrolysis (SJS–TEN). In some patients with EM, most lesions are livid vesicles overlying a just slightly darker central portion, encircled by an erythematous margin (Figs. 39-3, 39-4, and 39-5, Fig. 39-8). Larger lesions may have a central bulla and a marginal ring of vesicles (herpes iris of Bateman) (Figs. 39-6 and 39-7).
Typical target lesions on the palm.
Late lesions of EM with nonspecific blisters and erosions but target shapes still visible.
Typical targets around the knee.
Giant targets in a case of recurrent EMM associated to recurrent Mycoplasma pneumoniae infection.
Multiple concentric vesicular rings (herpes iris of Bateman). This pattern may be more frequent in Mycoplasma pneumoniae-related cases of erythema multiforme major.
Unusual presentations include cases in which recurrent EM in the same patient produces typical target lesions in one instance but plaques in a subsequent event. Mucous membranes can be severely involved in some episodes and spared in others (see section “Mucous Membrane Lesions”).
In most cases, EM affects well under 10% of the body surface area. In 88 hospital cases of EMM prospectively included in the Severe Cutaneous Adverse Reactions study, the median involvement was 1% of the body surface area.2 Very rare instances of extensive skin lesions with “giant” targets and prominent involvement of several mucous sites may be difficult to distinguish from SJS.
The duration of an individual lesion is shorter than 2 weeks, but residual discoloration may remain for months. There is no scarring.
Mucosal lesions are present in up to 70% of patients, most often limited to the oral cavity.
Predilection sites for mucosal lesions are the lips (eFig. 39-7.1), on both cutaneous and mucosal sides, nonattached gingivae, and the ventral side of the tongue. The hard palate is usually spared, as are the attached gingivae. On the cutaneous part of the lips, identifiable target lesions may be discernible (see Fig. 39-9). On the mucosa proper there are erosions with fibrinous deposits, and occasionally intact vesicles and bullae can be seen (Fig. 39-10). The process may rarely extend to the throat, larynx, and even the trachea and bronchi.
Erosions of the lips in a case of EMM.
Erythema multiforme major. Involvement of the lips with a target pattern.
Erythema multiforme major (EMM). Mouth lesions of EMM usually manifest as erosions.
Eye involvement begins with pain and bilateral conjunctivitis in which vesicles and erosions can occur (Fig. 39-11).
Erythema multiforme major. Eye lesions. Conjunctivitis with erosions.
The nasal, urethral, and anal mucosae also may be inflamed and eroded.
Ectodermosis pluriorificialis (synonym Fuchs syndrome) is a rare occurrence characterized by severe involvement of two or three mucosal sites in the absence of skin lesions. Its often relapsing nature suggests that it is HSV related. Moreover, typical target lesions may arise on the skin with new attacks.
Relationship to Recurrent Herpes
In more than 70% of patients with recurrent EM, an episode of recurrent HSV infection precedes the rash; the association with herpes labialis predominates over that with genital herpes or herpes in other locations. EM usually follows recurrent herpes but may also occur after primary HSV infection. The average interval is 7 days (range, 2 to 17 days); the duration of the lag period appears to be specific for individual patients. In a small number of patients, HSV recrudescence and EM may occur simultaneously. Not all episodes of EM are preceded by clinically evident HSV infection, and not all HSV episodes are followed by EM. Episodes of recurrent HSV infection may precede the development of HSV-related EM by many years.
Related Physical Findings
Fever and other constitutional symptoms are usually absent in EM minor, and the physical examination is normal. Fever higher than 38.5°C (101.3°F) is present in 32% of cases of EMM. Mouth erosions may be very painful and may impair alimentation. The patient may be unable to close the mouth and may constantly drool bloodstained saliva. Cervical lymphadenopathy is usually present in these patients. The pain of genital erosions may lead to reflex urinary retention. Cough, polypnea, and hypoxia may occur in M. pneumoniae-related cases.