Annals of Burns and Fire Disasters - vol. XII - n. 1 - March 1999

SUMMARY. Toxic epidermal necrolysis (TEN) defines a group of disease processes characterized by mucoepidermal lysis and necrosis. The condition is rare and may be associated with a wide range of aetiol.ogies, one of which is direct toxicity of a given agent on the epidermal keratinocytes. In its severe form, the outcome is usually dismal. Although many workers in the field have recommended managing patients presenting with this clinical picture in a similar manner to that adopted for burn patients, a comprehensive comparison between burn injury and TEN is still lacking in the literature. Moreover, the term "toxic epidermal necrolysis", coined by Lyell in 1956, is a confusing neologism that does not reflect the exact aetiology of the condition or hint at the way the clinical affliction should be managed. Since TEN shares with burn injuries several features, the most important of which is the treatment recommended during both the acute and the late stages, we propose the term "burn-like syndromes" to describe the wide range of diseases manifested by extensive epidermal blistering and sloughing, as well as cutaneous necrosis requiring hospitalization and special intensive care management.

Skin disorders manifested by blistering and exfoliation mimic burn injuries in their clinical presentation and behaviour as they are characterized by sloughing of the epidermal layers, which uncovers the underlying dermis. When extensive epidermal loss occurs, the condition exceeds the capacity of general medical wards as well as medical intensive care units, necessitating transfer of the patient to a surgical intensive care facility or even to a burn unit. Such burn-like syndromes may be congenitally inherited, such as epidennolysis bullosa, or they may be a manifestation of severe viral, bacterial, or fungal infections. They may also be a post-vaccination reaction or a manifestation of a neoplastic process such as Hodgkin's and non-Hodgkin's lymphoma, leukaemia, or ovarian and prostatic carcinoma. Similar conditions have been observed in graft-versus-host disease, in severe forms of lupus erythernatosis, and following black widow spider bite. In infants, the staphylococcal scalded skin syndrome has a similar clinical presentation. Cutaneous eruptions are also one of the most frequent presentations of adverse drug reactions and are the commonest type of adverse event in hospitalized patients, accounting for 19% of such events. Serious cutaneous manifestations of allergic drug reaction are responsible for about 3% of all disabling injuries during hospitalization. Although the rate of acute severe cutaneous reactions to medications is low, the reactions can affect any patient taking medications and result in serious disability and even death.
In 1922, Stevens and Johnson described a syndrome in children characterized by febrile erosive stomatifis, severe ocular involvement, and disseminated cutaneous eruptive macules, sometimes with a necrotic centre.' In 1956, Lyell described toxic epidermal necrolysis (TEN), with reference to patients with extensive loss of epidermis due to necrosis and a scalded-looking skin.' Although precise diagnostic boundaries between the two disorders have not been established, patients with less than 10% of epidermal detachment are classified as Stevens-Johnson syndrome, while those with more than 30% of TBSA involvement are classified as TEN Not infrequently, patients may present with a clinical picture of Stevens Johnson syndrome that within a few days evolves to one of TEN.
TEN is the most serious of drug-related skin eruptions, with a mortality rate ranging between 11 and 70%. The incidence of TEN is reported to be 1 per million and is slightly commoner in females. It most commonly occurs in adults, but has been reported in neonates and children. It is characterized clinically by a febrile prodrome simulating an upper respiratory tract infection, followed by a diffuse morbilliform eruption or confluent erythema that progresses into the acute phase of persistent fever, mucous membrane involvement, and generalized epidermal sloughing. Total epiden-nal loss within 24 h is not infrequent. Pneumonia often complicates aspiration of sloughed tracheobronchial mucosa. Massive gastrointestinal haemorrhage may also occur, complicating the serious hypovolaemia and electrolyte imbalance resulting from loss of the cutaneous barrier. Septicaemia is the most frequent cause of death in patients with TEN, usually due to Staphylococcus aureus or Pseudomonas.
Even though the overwhelming majority of cases are drug-induced, many aetiological factors have been associated with TEN, including immunizations, malignancies, infections, food substances, and even autogenous antigens Among the most commonly implicated medications are non-steroidal anti-inflammatory drugs, anticonvulsants, and antibiotics such as penicillins and sulphonamides. By 1974, 100 different drugs had been implicated with the TEN syndrome. The immunological pattern of lesions suggests a cell-mediated cytotoxic reaction against epidermal cells rather than any direct toxic effect. Despite the overwhelming evidence supporting the importance of immunological mechanisms, it is still possible that TEN may be the consequence of non-immunological factors.

Over the last two years, three patients have been referred to the care of the senior author with a diagnosis of TEN. All three patients were males. One was 16 years old, the second was an infant whose extensive skin lesions complicated a viral infection (most probably chickenpox) (Fig. 1), while the third was an elderly person in whom an allergic reaction to a non-steroidal anti-inflammatory drug was the most likely causative factor.

In these two last patients the diagnosis was readily reached and adequate therapy was swiftly implemented; the skin lesions healed within the expected time with no or minimal residual scarring. The course of the first patient was, however, more complicated and the outcome more serious (Figs. 2a,b).

The young man was originally admitted to the medical ward. Despite a dermatological consultation, the proper diagnosis was not immediately made. The cutaneous lesions were mismanaged and became desiccated, and the patient also developed ischaemia in both feet secondary to lower extremity compartment syndrome. Fasciotomy, however, was performed late by the vascular surgeon. Subsequently, transmetatarsal amputation of one foot had to be carried out.
Postoperatively the patient had to be kept intubated and he was transferred to the intensive care unit because of severe aspiration pneumonia. It was only then, and after a previously performed skin biopsy hinted at the possibility of TEN, that the plastic surgery team was consulted. At that point, all the cutaneous lesions that originally were salvageable had developed into full-thickness skin necrosis and had to be serially debrided and skin-grafted. After a long and protracted course, with an episode of cardiac arrest, the patient gradually recovered and was discharged home. Retrospectively, the patient's illness was most likely due to anti-epileptic therapy.

Adequate diagnosis and prompt appropriate therapy could have prevented the terrible complications encountered in the first patient described. rrespective of the exact aetiological factors, the acute, generalized, sheet-like loss of epidermis described by Lyell to a large extent resembles a scald burn. Although it is now generally agreed that patients presenting with such a clinical picture are better managed in a specialized burn unit, some differences do exist between the "burn-like" syndrome and burn injury itself. These differences deserve a better understanding as they may have great implications for the type of management that patients should receive.
Severe thermal or chemical burn injury produces damage to both the epidermal and the dermal layers. The thickness of the zone of damage is determined by the intensity of the injurious agent as well as by the duration of exposure, irrespective of the anatomical peculiarities of the area of skin affected. In patients presenting with TEN, histologically there is full-thickness epidermal sloughing with the cleavage plane at the epidermaldermal junction. Vacuolar alterations at the dermalepidermal junction rapidly progress, forming a subepidermal bulla containing virtually acellular fluid. The separated epidermis contains individual as well as groups of necrotic keratinocytes that may also be encountered along the external sheath of the pilosebaceous apparatus"as well as along the straight dermal duct of the sweat glands. The basement membrane becomes disrupted, allowing extravasation of all intravascular components. Although a moderate degree of oedema is present in the papillary dermis, the reticular dermis is normal. 24 Collagen and reticular fibres are preserved. Regeneration of the epidermis proceeds from the epithelial remnants of the sweat glands and the hair follicles, similarly to what is observed in second-degree burns.
It is worth nothing that since in TEN the dermis is preserved and remains completely viable (unlike second degree burns), less scarring is to be expected following spontaneous healing, which usually takes 14 days. It is hence crucial during the healing phase to protect the preserved dermis from infection, desiccation, and subsequent injury U' by judicious and carefully executed dressing changes. It is logical that surgical tangential excision is absolutely contraindicated in TEN and that biological dressings and skin substitutes must be favoured' rather than classical burn dressings that have an inherent mechanical debriding capacity.
As in burns, silver sulphadiazine cream has been widely used for topical treatment of TEN. Its use should however be restricted to patients with no previous history of hypersensitivity to sulphonamides. Pemphigus-like eruptions were described as early as 1942 in association with sulphadiazine therapy. Short courses of corticosteroids early in the disease have been advocated by some, but their effectiveness has never been demonstrated. Peters et al. recommended complete avoidance of steroids in the management of TEN patients.
As in burn injury, TEN causes massive transepidermal fluid loss with associated electrolyte imbalance proportional to the extent of skin necrosis. The amount of intravenous fluid resuscitation is however considerably smaller than that given to patients with a comparable burn injury. This observation needs further investigation. A probable explanation is that there is less intradermal vascular injury and that the state of generalized vascular permeability observed early following a burn injury is absent in TEN. As a corollary, fluid resuscitation formulas and protocols set for burn injury are not applicable to patients presenting with TEN. Only two-thirds to three-quarters of the fluids calculated by most standard burn formulas for the first 24 h may be needed.
In contradistinction to the majority of burn injuries, mucosal involvement is a constant in TEN. Consequently, endotracheal intubation and insertion of nasogastric tubes or Foley catheters should be avoided if possible for fear of producing more damage to the structures involved. Endotracheal intubation may traumatize the friable mucosa of the pharynx, thus contaminating the bronchotracheal tree and precipitating pneumonia.
A peculiarly frequent lesion in patients presenting with TEN, encountered to a lesser extent also in some face burns, is damage to the cornea associated with severe photophobia. This type of lesion deserves special attention and extra care that is not routinely applied to burn patients, if serious ocular complications are to be avoided.
On the other hand, TEN shares with burn injury the necessity to provide the patient with appropriate nutritional and psychological support as well as adequate narcotic medication and nursing care in order to minimize suffering, promote non-delayed healing, and prevent late sequelae and scarring. It is clear that such care can best be provided in a specialized burn unit.

Although TEN shares many aspects with burn injury, the peculiarity of the condition deserves special care and attention. TEN patients should not be managed blindly as burn patients. Health personnel in burn units should be aware of this fact. Moreover, there is a lot of confusion in the literature concerning the diagnostic criteria of related conditions presenting with cutaneous sloughing and necrosis. The argument whether Stevens-Johnson syndrome and TEN are distinct entities or fall within the spectrum of a single disease process is pointless. Also, the term "toxic epidermal necrolysis" coined by Lyell in 1956 is a confusing neologism that does not reflect the exact syndromes may be a better descriptive classification aetiology of the condition or hint at the way this clinical heading for the numerous conditions that share in common affliction should be managed. The term burn-like important features of burn injury.

RESUME. La nécrolyse épidermique toxique (sigle anglais, TEN) définit un groupe de processus morbides caractérisés par la lyse mucoépidennique et la nécrose. Cette condition est rare et peut être associée à une vaste gamme d'étiologies, y inclus la toxicité directe d'un agent déterminé sur les kératinocytes épidermiques. Dans la forme la plus sévère, le résultat est normalement funeste. Bien que beaucoup de chercheurs dans ce champ recommandent pour les patients qui présentent cette condition clinique une gestion du cas similaire au traitement des patients brûlés, il n'existe pas dans la littérature scientifique une comparaison approfondie de la maladie des brûlés et de la TEN. D'ailleurs, le terme TEN, inventé par Lyell en 1956, est un néologisme trompeur qui ne reflète pas l'étiologie précise de la maladie et ne suggère rien pour ce qui concerne sa gestion clinique. Puisque la TEN partage avec les brûlures diverses caractéristiques, dont la plus importante est le traitement recommandé pendant les phases aiguë et tardives de la maladie, les Auteurs proposent le terme "burn-like syndromes" ("syndromes semblables aux brûlures") pour décrire la vaste gamme de maladies qui se manifestent avec la formation étendue d'ampoules épidermiques, le dépouillement de la peau et la nécrose cutanée qui nécessitent l'hospitalisation et une gestion spécifique dans un service de réanimation.

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