a case of toxic epidermal necrolysis (ten) -burns-and-fire-disasters-23-81

8/3/2019 A Case of Toxic Epidermal Necrolysis (Ten) -Burns-And-fire-disasters-23-81

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Annals of Burns and Fire Disasters - vol. XXIII - n. 2 - June 2010

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Introduction

Toxic epidermal necrolysis (TEN), also known as

Lyells syndrome, is a severe adverse drug reaction char-acterized by extensive destruction of the epidermis andmucosal epithelia.1-3 This entity was first described by Lyellin 1956, who termed the condition toxic epidermal necrol-ysis, pointing out that drug sensitization was generallyconsidered to be the mechanism leading to this syndrome.4,5

Although the incidence of TEN is very low, i.e. approxi-mately 1 to 6 cases per million persons, it can affect any-

one at any time at any age, usually as a consequence ofan adverse idiosyncratic drug reaction.3,6-8

The mortality rate for TEN is still high (approximate-ly 25-35%),1,6,9,10 mainly due to secondary septicaemia andionic and metabolic disturbances following loss of epider-mal integrity.11,12

Drugs appear to be the predominant causative agent, particularly antibacterials, anticonvulsivants, and non-

steroidal anti-inflammatory agents. More than 220 med-

ications have been implicated, of which a few are thosemost commonly involved.10-12

The generally proven cause of TEN is an adverse drug

reaction resulting from a specific formation of toxic drugmetabolite, perhaps in the skin itself. Reactive metabolitesgenerated from cutaneous sources can exert a direct cyto-toxic effect. They also stimulate stress signals promotingthe cell surface expression of stress molecules, as well asthe release of cytokines and the expression of adhesionmolecules initiating lymphocyte and macrophage infiltra-tion and activation.10,13

However, the precise pathomechanisms involved re-main unknown. The majority of studies focus on the role

of T cells, but recently, there is growing evidence that inthe pathogenetic scenario of TEN, T cells, particularlyCD4+ in the dermis and CD8+ in the epidermis, mono-cytes, macrophages, and keratinocytes play different important roles directly or with the mediation of cy-tokines.10,11,14-17

Dysregulation of the tumour necrosis factor (TNFa)

A CASE OF TOXIC EPIDERMAL NECROLYSIS (TEN) WITH

SEVERE CHRONIC OCULAR COMPLICATIONS IN A HEALTHY

46-YEAR-OLD WOMAN

Voltan A.,* Azzena B.

Department of Plastic and Reconstructive Surgery, Burns Unit, University Hospital of Padua, Padua, Italy

SUMMARY. Toxic epidermal necrolysis (TEN), also known as Lyells syndrome, is a severe drug reaction characterized by ex-tensive destruction of the epidermis and mucosal epithelia. The eyes are typically involved in TEN. The precise pathomechanismsinvolved remain unknown. We present a case of toxic epidermal necrolysis in a healthy 46-yr-old female patient who had inhaledglycophosphate (herbicide) and was treated with paracetamol, aspirin, and chlorpheniramine. Thirty-five per cent of the skin areawas affected by the syndrome, with involvement of conjunctival, gastrointestinal, and respiratory mucous membranes. Topical treat-ment was performed every day and the patient did not undergo surgery. Complete wound healing was achieved in 47 days. Therewere acute complications, consisting of infection of the skin areas (Candida), gastrointestinal bleeding, pleural effusion, and severeocular mucous membrane damage. The most serious chronic complication was the presence of significant opacity of the cornealepithelium, causing almost complete loss of vision. According to the data in the literature, ocular complications in TEN are fre-quent and are present in the majority of the patients studied, but are not often severe. Risk factors for the development of ocularcomplications are not known. Ocular sequelae may appear after the acute period and they can be extremely disabling, even caus-ing almost complete loss of vision. Treatment includes corticosteroids and topical antibiotic therapy in the acute phase and if nec-essary corneal transplantation in the event of chronic damage to the corneal epithelium.

Keywords: toxic epidermal necrolysis, severe ocular involvement, chronic complication

* Corresponding author: Dr Anna Voltan, Divisione di Chirurgia Plastica e Ricostruttiva, Centro Ustioni, via Giustiniani 2, Padua, Italia. Tel. +39 349 3229687;

fax +39 049 8218199; e-mail: [email protected]


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system is also likely to be involved in TEN pathogenesis.Functional studies showed that Fas-L was typically activeon keratinocytes in TEN. The expression of Fas-L on hu-

man keratinocytes is upregulated by cytokines including

IL-1b, IL-15, IFN-g, and TNF-a released by keratinocytesthemselves and also by skin-infiltrating immunocompetentcells.10,18,19

The eyes are typically involved in TEN. The ten dis-ease spectrum remains an important cause of severe visu-al loss in a significant number of patients.20

According to the data in the literature, ocular compli-

cations occur in more than 50% of the patients affected,with ocular surface inflammation developing rapidly in theacute stage.6,20,21

The common clinical course after the acute stage in-cludes persistent epithelial defects, ulceration, and perfo-ration, finally developing into corneal cicatricial changessuch as neovascularization, opacification, keratinization,

and symblepharon.6,22,23

Even when the acute stage impairments subside, per-manent visual impairment or blindness remains and con-junctival inflammation becomes chronic.

After the acute period, ocular sequelae may appear.These are not rare but only a few outcome studies have been published. About 40% of survivors of TEN haveresidual potentially disabling lesions that in some cases

cause blindness.11,24-27

Case report

An otherwise healthy 46-yr-old woman was admittedto Padua Burns Unit (Italy) with the following history. Afew hours after exposure to a glycophosphate herbicide shedeveloped the sensation of slight sore throat together with

conjunctival hyperaemia, eyelid oedema, lacrimation, andfever. During the night she took a drug based on acetyl-salicylic acid, paracetamol, and chlorpheniramine, withscarce relief. The following morning, noticing aggravationof her symptoms and an itchy skin rash in her the faceand trunk, she went immediately to the nearest hospital.She was first treated with corticosteroids, antihistamines,and liquid infusion with mild relief and she returned home.

After worsening of symptomatology and increasing of fever(>38 C), she was hospitalized in an intensive care unitand vigorous antibiotic therapy was set up. She was as-sessed by a specialist dermatologist and otorhinolaryngol-ogist for multiple lesions of the skin and mucosal epithe-lia of the respiratory tract and, in the end, a diagnosis oftoxic epidermal necrolysis was confirmed.

Three days after the onset of her symptoms, the woman

was admitted to our burns unit and all general and topi-cal measures were established.

When the patient was admitted to the burns unit, 35%of the skin area was affected by the syndrome, with in-

Fig. 1 - Patient on admission with typical skin lesions involving the face.

Fig. 3 - Skin lesions on legs.

Fig. 2 - Peeled skin on patients back on admission.


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volvement of conjunctival, gastrointestinal, and respirato-ry mucous membranes.

Flaccid bullae developed on the patients trunk, face,and upper and lower limbs (Figs. 1-5). These lesions ex-

hibited a positive Nikolsky sign with spreading of the bul-lae on pressure. The patients skin took on the appearanceof a second-degree scald (Fig. 6).

The patient was immediately positioned on an air-fluidized therapy unit. Drugs suspected of being incitingagents were immediately discontinued. Intravenous re-placement of fluid losses, administration of high-title IgM

enriched intravenous immunoglobulin (Pentaglobin) at adosage of 0.2g/kg daily for three days, and enteral nutri-tion were initiated. Antibacterials were administered on the basis of the results of microbiological exams performed

on blood, urine, and skin lesions. A blood culture takenon day 14 after admission resulted positive for Staphylo-coccus Warneri and Staphylococcus saprophyticus andtreatment with gentamicin, vancomycin, and piperacillinwas established (after consulting an infectious diseases spe-cialist). Microbiological tests performed on skin lesionserum resulted once positive forEscherichia coli.

Topical treatment was performed every day and the

patient did not undergo surgery. Medical dressing was per-formed by washing with saline solution, application of paraffin gauze on eroded skin areas, and ointment withoils and vitamin E preparations. Dressings were changeddaily. We preferred not to use aggressive agents such assilver sulphadiazine, clorhexidine, or other topical antimi-crobial agents. We did not use skin substitutes (ker-atinocytes, homografts, xenografts, etc.).

Fig. 4 - Typical le-sions on right arm.

Fig. 5 - Maximum involvement of face, four days after admission.

Fig. 6 - Positive Nikolsky sign on patients back. The skin appearedto have suffered a second-degree burn.


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A skin biopsy was taken and histological tests con-firmed the diagnosis of TEN. A cytological examinationof the serum of the lesions showed the presence of typi-cal inflammatory cells such as macrophages and lympho-

Fig. 8 - Almost complete healing of anterior part of the trunk onday 20.

Fig. 7 - Partial wound healing of facial skin, 20 days after admission.

Fig. 9 - Re-epithelialization beginning on patients back, 20 days af-

ter admission.

cytes. On admission of the patient we had already carriedout toxic investigations in haematics, which were positivefor paracetamol and chlorpheniramine but not for alcoholor other drugs.

Respiratory mucous membrane involvement was con-firmed by bronchoscopy, which revealed acute inflamma-tion of the upper respiratory tract, with moderate bleeding

of mucous membranes, while the trachea and bronchialtube, in the tract visible with endoscopy, were open.

The patient soon started assisted physiokinesitherapyin the upper and lower limbs and to both eyelids in order

to prevent symblepharon.Three weeks after the onset of the symptoms, skin re-

epithelialization of the face and anterior part of the trunk

was almost complete ( Figs. 7, 8) and wound healing ofthe back was beginning ( Fig. 9).

Anamnesis. The patient, a healthy housewife, marriedwith two healthy children, did not report any previouspathology or allergy, she had never undergone surgery, andshe was not receiving any home pharmacological therapyat the time of admission.

Ocular involvement. The first examination of the eyes

by a specialist oculist on admission found the presence ofcopious conjunctival secretions and disepithelialization ofthe borders of the eyelids, while the corneal epitheliumwas still in good condition ( Fig. 10). Artificial tear re-placement to prevent keratoconjunctivitis sicca syndromeand daily washing with saline solution were initiated.

Six days after hospitalization, the patient developedconjunctival synechiae with partial corneal disepithelial-ization in both eyes and was therefore treated daily withwashing with saline solution, debridement of the forniceswith a sterile spatula, and topical antibiotic therapy.


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Fifteen days after the onset of the symptoms corneal

opacity occurred. Five days later, a diagnosis was madeof bilateral corneal leucoma (Fig. 11).

The final examination by an oculist found severe oc-ular impairment, conjunctival synechiae still present, andbilateral neovascularized corneal opacity.

Fever pattern. From admission, and for 24 days, the

patient had high fever, with a temperature of over 39 Cand peaks above 40 C. The fever abated on day 24, andall antibiotics were stopped, the patient being treated on-ly with fluconazole for Candida esophagitis with a goodresponse. On the following days the patient was feverlessand remained so until she was discharged.

Acute complications. Ocular damage was the first acute

complication the patient developed, followed by Candidaesophagitis, gastrointestinal bleeding, and pleural effusion.

Chronic complications. Complete wound healing wasachieved in 47 days. The most serious chronic complica-tion was significant opacity of the corneal epithelium,which caused almost complete loss of vision. The patientis now waiting to undergo surgery for corneal membrane

transplantation.

Discussion

Toxic epidermal necrolysis is a rare but potentially fa-tal skin disorder. Even if much has been learned in thelast fifty years about the management of TEN, the diffi-culty of making a prompt and accurate diagnosis at the

onset of the disease and the controversy about a treatmentregimen that could be universally accepted represent animportant limitation on the correct approach to this severepathology.6,28-30

TEN is a severe adverse drug reaction, characterizedby low incidence but high mortality (25-50%). Elderly pa-tients and patients with extensive lesions have a highermortality rate. Septicaemia is the commonest cause of death

in patients, usually due to Staphylococcus aureus or Pseudomonas aeruginosa.11,12 TEN is heralded by a pro-dromal phase (48-72 h) progressing into the acute phase.

A typical feature of TEN is epidermolysis, character-

ized by the presence of flaccid bullae formed by the necro-sis of epidermal cells, determining a positive Nikolsky sign.

After the acute phase, cutaneous and ocular sequelaemay appear. According to the data in the literature, ocu-lar complications in TEN are frequent and are present in

the majority of the patients studied. They result in entro-pion, symblepharon, and synechiae.

The skin lesions usually completely heal in 4 to 10weeks, but up to 40% of survivors have residual poten-tially disabling lesion that may cause blindness.10,24,26 How-ever, the exact percentage of blindness as a chronic com-plication among the population of survivors is unknown.

The pathomechanism that leads to severe ocular com-plications has been variously hypothesized. Some reports6

maintain that the loss of corneal epithelial stem cells lo-

cated in the limbal region plays an important role in thepathophysiological mechanism of the ocular damage. Whenthe corneal epithelial stem cells are lost, the corneal ep-

ithelium no longer regenerates, resulting in conjunctivalepithelial invasion into the cornea (conjunctivalization) andcicatricial changes in the ocular surface. It is also believed31

that severe and prolonged acute ocular inflammation pro-motes the development of late ocular complications. A con-

tinued inflammatory reaction involving the ocular surfacedestroys goblet cells and results in decreased secretion ofmucin, which impairs tear distribution and stability. Cica-trization may lead to dry eye, corneal opacification, andeyelid deformities.

The risk factors for the development of ocular com-plications are not known. Early ophthalmological consul-tation is recommended for ocular lesions.

Treatment must be prompt and accurate to prevent se-vere complications - it includes general and local meas-ures. The patient is usually admitted to a burns unit andtreated with systemic corticosteroids, although the benefitsof this are controversial. The patient should be placed ina warm environment, avoiding any skin trauma. Support-ive therapies and antiseptics used in burn patients are sim-ilarly applied to TEN patients.10,32-34

General measures include control of fluid and elec-trolyte balance, nutritional support, and close monitoringto detect any signs of internal organ failure and systemic

Fig. 10 - Involvement of eyes at time of admission: conjunctival hy-peraemia, eyelid oedema, lacrimation.

Fig. 11 - Severe involvement of eyes on day 20: conjunctival synechi-ae still present, corneal leucoma.


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infection. Antibacterials should be administered only incase of infection. Local measures for skin involvement in-clude dressings for wound coverage, performed every dayin order to prevent infectious sequelae.

In patients affected by this syndrome, skin loss isusually superficial and spontaneous re-epithelializationoccurs in a few weeks. However, it has been suggested 35

that surgical treatment should be performed with skin al-

lografts to prevent infection and protein/fluid loss andprovide immediate pain relief. However, it has also beenfound that keratinocyte allografts offered no improvementin re-epithelialization and did not prevent abnormal scar-ring.36

Local measures for ocular involvement include corti-costeroids and topical antibiotic therapy in the acute phaseand if necessary corneal transplantation for chronic dam-

age to the corneal epithelium.It is universally accepted that as long-term ophthalmic

sequelae can be catastrophic, early recognition and thera-py of this acute oculocutaneous disease spectrum are crit-ically important.

Local measures should be instituted at the very onsetof ocular involvement. First, tear replacement and frequentirrigation of the conjunctival fornices have to be performed

with a preservative-free solution. The superior and infe-rior fornices must be debrided daily in order to removemembranes. Despite early local measures, late surgicaltherapy is often required to correct structural defects suchas symblepharon, entropion, ectropion, and lagophthal-mos.4,10

The outcome of TEN, not only as regards the eyes, isin all cases difficult to predict because it depends on age,

co-morbidity, and the extent of skin involvement.11

Conclusion

As in the literature and in our own experience, themajority of patients affected by TEN suffer acute ocular

complications. Between 2000 and 2008, 26 patients (17female, 9 male) were admitted to our burns unit with aconfirmed diagnosis of TEN. Of these, nineteen (73%)developed acute ocular complications but no chronic se-

quelae.To our knowledge, in our burns unit, the patient de-

scribed in this paper is the first reported case of TENamong all the patients affected by the syndrome present-ing severe ocular complications, with almost complete lossof vision. Given the limited data in the literature, mainlydue to the syndromes rarity, we think it is important topublicize the individual experiences of various burns units

as a way of improving our knowledge of this severe pathol-ogy.

We decided to present this case because of the par-ticular manner of the onset of the disease (exposure to her-bicide and drugs) and because of the severe damage to thecorneal epithelium, which was the worst chronic compli-cation.

While the importance of a prompt and accurate diag-

nosis and of correct and rapid therapy to prevent severechronic complications is generally known, the pathologi-cal mechanism that causes the progression from acute tochronic lesions is still unknown.

We are convinced of the need to increase as much as possible the amount of information available in the liter-ature about toxic epidermal necrolysis if we are to improvediagnosis and therapy, together with help and suggestions

from the experience of others.

RSUM. Le syndrome de Lyell, galement appel lpidermolyse ncrosante suraigu, est une grave raction pharmacologiquecaractrise par la destruction tendue de lpiderme et des pithliums muqueux. Les yeux sont gnralement atteints. Les mca-nismes pathologiques prcis impliqus restent inconnus. Nous prsentons un cas du syndrome de Lyell chez une patiente saine de46 ans qui avait inhal glycophosphate (herbicide) et a t traite avec paractamol, aspirine, et chlorphniramine. Trente-cinq pourcent de la surface cutane a t atteinte par le syndrome, avec limplication des membranes muqueuses conjonctivales, gastro-in-testinales et respiratoires Un traitement topique a t administr tous les jours et la patiente na pas t opre. La gurison com-

plte des lsions a t obtenue aprs 47 jours. Nous avons observ des complications aigus, cest--dire infection des surfaces cu-

tanes (Candida), hmorragie gastro-intestinale, effusion pleurale, et de graves dommages aux membranes muqueuses oculaires. Lacomplication chronique la plus grave a t la prsence dune opacit importante de lpithlium cornen, qui a provoqu la perte presque complte de la vue. Selon les donnes de la littrature, les complications oculaires sont frquentes dans les cas de syn-drome de Lyell et sont prsentes dans la majorit des patients tudis, mais elles ne sont pas souvent trs graves. Les facteurs derisque qui portent au dveloppement des complications oculaires ne sont pas connus. Les squelles oculaires peuvent se manifes-ter aprs la priode aigu et peuvent tre extrmement invalidantes, causant mme la perte presque complte de la vue. Le traite-ment comprend les corticostrodes et la thrapie antibiotique topique dans la phase aigu et, si ncessaire, la transplantation cor-nenne en cas de dommages chroniques de lpithlium cornen.

Mots-cls: syndrome de Lyell, atteinte oculaire svre, complication chronique


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a case of toxic epidermal necrolysis (ten) -burns-and-fire-disasters-23-81

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