toxic epidermal necrolysis caused by flurazepam?

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loping various complications including ophthalmo- logic: corneal ulceration, anterior uveitis, panophthalmitis, blindness; gastroenterologic: esophageal strictures ...

Case report

Psychiatria Danubina, 2005; Vol. 17, No. 3-4, pp 236-239

Caslav Loncar, Tomislav Franic & Marijo Bilusic: TOXIC EPIDERMAL NECROLYSIS CAUSED BY FLURAZEPAM? ________________________ Psychiatha Danubina, 2005; Vol. 17, No. 3-4, pp 236-239 ________________________

© Medicinska naklada - Zagreb, Croatia

TOXIC EPIDERMAL NECROLYSIS CAUSED BY FLURAZEPAM? Caslav Loncar1, Tomislav Franic2 & Marijo Bilusic3


department of Psychiatry, University Hospital, Split, Croatia 2 Department of Psychiatry, University Hospital, Split, Croatia Department of Physiology, Medical College Wisconsin, Milwaukee, US

SUMMARY Stevens-Johnson syndrome and toxic epidermal necrolysis are rare, but severe cutaneous reactions. Beside cutaneous manifestations, the syndrom is characterised by constitutional sypmtoms with even lethal consequences. Toxic epidermal necrolysis is usually drug-hypersensitivity syndrome. More than a hundred drugs were suspected to cause toxic epidermal necrolysis. Although benzodiazepines had been suspected in some cases, there had not been such implication for flurazepam. The autors report severe, life threatening case of toxic epidermal necrolysis in young women suffering from schizophrenia. The most probable cause was flurazepam, a hypnotic agent from benzodiazepine class. Key words: Stevens-Johnson syndrome - toxic epidermal necrolysis - drug hypersensitivity -flurazepam

Key points: Toxic epidermal necrolysis (TEN) is severe life threatening condition. The TEN is drug hypersensitivity related. This case for the first time presents flurazepam as the cause of TEN. * * * * *

INTRODUCTION Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but severe cutaneous reactions, which are thought to be two distinct diseases. Today is accepted the opinion that SJS and TEN are the same disease with different extent of skin lesions (Roujeau 1997). We are talking about SJS, if the skin lesions cover less than 10 percent of body surface (Roujeau et al. 1995, Knowles et al. 2000). The most prominent feature is the rash which can begin as macules that develop into papules, vesicles, bullae, urticarial plaques, or confluent erythema. In some cases, the rash is folowed by the epidermal necrosis, which causes erosions of the mucous membranes and extensive detachment of the epidermis (Layell 1979). Beside cutaneous manifestations, the

syndrom is characterized by constitutional sypmtoms such as high fever, malaise, multiorgan sequelae, infections, and even lethal fluid and electrolyte imbalance. Death rate may increase depending upon the extent of skin lesions, up to 40 percent (Roujeau et al. 1995). The SJS/TEN has significant risk for developing various complications including ophthalmologic: corneal ulceration, anterior uveitis, panophthalmitis, blindness; gastroenterologic: esophageal strictures; genitourinary: renal tubular necrosis, renal failure, penile scarring, vaginal stenosis; pulmonary: tracheobronchial shedding with resultant respiratory failure; cutaneous: scarring and cosmetic deformity, recurrences of infection through slow-healing ulcerations (Power etal. 1995, Foster etal. 1988).

The incidence of toxic epidermal necrolysis is estimated at 0.4 to 1.2 cases per million personyears (Hart et al. 2002, Roujeau et al. 1990, Schopf et al. 1991, Chan et al. 1990) and of StevensJohnson syndrome, at 1 to 6 cases per million person-years (Schopf et al. 1991, Chan et al. 1990). Toxic epidermal necrolysis is usually drugrelated (Roujeau et al. 1990). Drugs are the most important cause, but infections or a combination of infections and drugs have also been implicated. In case reports and studies, more than 100 drugs have been implicated as causes of Stevens-Johnson syndrome or toxic epidermal necrolysis (Roujeau et al. 1995, Roujeau et al. 1990). Drughypersensitivity syndrome generally occurs during first exposure to the drug, with initial symptoms starting 2-6 weeks later. In the patients with a history of drug-hypersensitivity reaction, reexposure after previous reaction may cause symptoms within one day (Knowles et al. 2000). Altough benzodiazepines had been suspected in some cases (Roujeau et al. 1995), according to our knowledge, there had not been such implication for flurazepam.

CASE REPORT A 29-year-old white female was admitted to psychiatry ward because of decompensation of schizophrenia (paranoid-halucinatory form). It was her fourth hospitalization during last year. Before that, she had been under succesful outpatient psychiatric treatment for four years. Beside psychiatric disorder, she did not have previous history of severe illnesses. She was born as a premature heterozygot twin; her early psychomotor development was normal. During childhood, she has suffered from bronchitis and constipation. There was not any information about allergies; for different reasons (noncompliance, exstrapyramidal symptoms, bad therapeutical response) she changed several psychotropic medications: risperidone, promazine, diazepam, clozapine, alprazolam, fluephenazine. Her therapy, few weeks prior to the admission, included olanzapine and promazine.

During physical examination, she did not show any symptom of physical illness. Her body temperature, blood pressure, and pulse rate were within normal limits. Laboratory examination detected slightly increased ESR (erythrocyte sedimentation rate) of 18 mm/h. Total serum proteins were 80, 5 g/1, and creatine kinase was 382 U/l. Furthermore, levels of glucose, urea, creatinine, total bilirubin, aspartate aminotransferaze (AST), alanine aminotransferaze (ALT), gammaglutariltransferaze (GGT), potassium, sodium and chloride were within normal limits. CBC shows: hemoglobin 11.9 g/dL, hematocrit 36.5%, MCHC 32.4 g/dl, WBC, RBC, MCV, MCH, RDW, HDW, PLT, MPV were normal. Differential WBC count did not show any abnormalities. After the admission to hospital, her therapy was changed to fluphenazine, promazine and diazepam due to noncompliance. During first three weeks of hospitalization her physical condition was unremarcable, while her mental status showed fluctuations; consequetly, the existing therapy was modified in order to optimize the treatment. New medications were included: biperiden at the day 8, carbamazepine at the day 14, and flurazepam at the day 24 of hospitalization. At the day 27, the maculo papulous rash was noticed on the patient's chest region. In the next 24 hours, the rash became generalized with the appearance of vesicles and bullae on the sites where the maculae and papulae first appeared. At the same time the patient became highly febrile, up to 39.9°C, and unable to urinate. She was transfered to intensive care unit, in order to receive adequate treatment. The skin and mucous lesions affected the chest, back, face, neck, both hands and legs, mouth, eyes, ears and vagina. The extent of skin lesions was higher than 40 percent and also mucous membranes were affected so diagnosis of toxic epidermal necrolysis was established as working diagnosis. The laboratory tests were performed daily and included: erythrocyte sedimentation rate C reactive protein complete blood count, differential blood

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Caslav Loncar, Tomislav Franic & Marijo Bilusic: TOXIC EPIDERMAL NECROLYSIS CAUSED BY FWRAZEPAM? ________________________ Psychiatria Danubina, 2005; Vol. 17, No. 3-4, pp 236-239 _______________________

Buy Now to Create PDF without Trial Watermark!! Caslav Loncar, Tomislav Franic & Marijo Bilusic: TOXIC EPIDERMAL NECROLYSIS CAUSED BY FLURAZEPAM? _______________________ Psychiatria Danubina, 2005; Vol. 17, No. 3-4, pp 236-239 _______________________

count, blood biochemistry with total serum proteins, creatine kinase, glucose, urea, creatinine, total bilirubin, aspartate aminotransferaze, alanine aminotransferaze, gammaglutariltransferaze, potassium, sodium, chloride calcium, magnesium phosphorus. Although she was high febrile up to 39.9°C between days 27 and 31 of hospitalization, ESR and C reactive protein were within normal limits and WBC were decreased (2.94). Differential blood count shows increased ratio of eosinophils (9%). Six days after rash appeared the albumin was sligtly decreased, probably due to large surface of denuded areas. Other laboratory values were clinicaly unremarcable. Hemocultures were sterile and the content of blisters, we found pseudomonas aeruginosa in urinoculture, and mixed microorganisms on the denuded areas (Pseudomonas aeruginosa, Staphylococus aureus MRSA, Enterobacter clocae, Klebsiela pneumoniae) probably due to secondary infection. The erosions on bucal and nasal mucousa were painful and the nasogastric tube was introduced. The patient was unable tu urinate until urinary cateterization, while the reasons of urinar y retention were probably hyperemic changes and erosions of urethral mucousa. Additionally the laboratory investigation of renal function did not show any abnormality. Oftalmologic, dermatologic, gynecologic, otorinolaryngologic and psychiatrists' consultation were obtained each day. The patient was treated as those with severe burns, by protecting the skin and denuded areas from trauma and infection and replacing fluid and electrolyte losses. Beside these suportive measures she was treated with metilprednizolone lmg/kg intravenous for five days with dramaticall y positive therapeutic response DISCUSSION

The patient presented by the autors was diagnosed and treated as a severe form of toxic epidermal necrolysis. It was working diagnosis which was firmly confirmed by clinical aspect


(Correia et al. 1993), epidemiologic facts and some laboratory values. The question arised: "What was the cause?" As we said, toxic epidermal necrolysis is usually drug-related so the main suspects were the medications consumed by the patient. Drughypersensitivity syndrome generally occurs during first exposure, so in the focus of our interest were carbamazepine and flurazepam, the first one already known as the most frequent cause of SJS/TEN syndrome (Rzany et al. 1999). We tested the medication sensitivity of the patient with the test of indirect degranulation of basofile mastocytes. The tested medications were biperiden, carbamazepine, flurazepam, fluphenazine, promazine and diazepam. Only flurazepam was found as the cause of hypersensitivity in our patient. The presented case is an example that the SJS/TEN, although very rarely, could be very severe. The second important conclusion is that there is no such medication which could not be the cause of TEN, even in the presence of already convicted suspect.

7. Naldi L, Locati F, Marchesi L, Cainelli T: Incidence of toxic epidermal necrolysis in Italy. Arch Dermatol 1990; 126:1103-4. 8. Power W, Ghoraishi M, Merayo-Lloves J, Neves R, Foster C: Analysis of the acute ophthalmic manifestations of the erythema multiforme/StevensJohnson syndrome/ toxic epidermal necrolysis disease spectrum. Ophthalmology 1995; 102(11): 1669-1676. 9. Roujeau JC, Chosidow O, Saiag P, Guillaume JC: Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 1990; 23: 1039-58. 10. Roujeau J-C, Guillaume J-C, Fabre J-P, Penso D, Flechet ML, Girre JP: Toxic epidermal necrolysis (Lyell syndrome): incidence and drug etiology in France, 1981-1985. Arch Dermatol 1990; 126:3742.

11. Roujeau JC, Kelly JP, Naldi L, et al: Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995; 333(24): 1600-7. 12. Roujeau JC: Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol 1997; 24(11): 726-9. 13. Rzany B, Correia O, Kelly P J, Naldi L, Auquier A, Stern R: Risk of Stevens-Johnson syndrome and toxic epidermal necrol ysis during first weeks of antiepileptic therapy: a case control study. The Lancet 1990; 353: 2190-94. \4.SchopfE, Stuhmer A, Rzany B, Victor N, ZentgrafR, Kapp JF: Toxic epidermal necrolysis and StevensJohnson syndrome: an epidemiologic study from West Germany. Arch Dermatol 1991; 127:839-42.

REFERENCES 1. Chan HL, Stern RS, Arndt KA, et al: The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: a population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990; 126:43-7. 2. Correia O, Chosidow O, Saiag P, Bastuji-Garin S, Revuz J, Roujeau J-C: Evolving pattern of druginduced toxic epidermal necrolysis. Dermatology 1993; 186:32-7. 3. Foster CS, Fong LP, Azar D, Kenyon KR: Episodic conjunctival inflammation after Stevens-Johnson syndrome. Ophthalmology 1988; 95(4): 453-62 4. Hart R, Minto C, Creighton S: Vaginal adhesions caused by Stevens-Johnson syndrome. J Pediatr Adolesc Gynecol2002; 15:151-152. 5. Knowles RS, Uetrecht J, Shear HN: Idiosyncratic drug reactions: the reactive metabolite syndromes. The Lancet 2000; 356: 1587-1591. 6. Lay ell A: Toxic epidermal necrolysis (the scaled skin syndrome): a reappraisal. Br J dermatol 1979; 100:69-86.


Correspodence: (aslav Loncar MD, Depertment of Psychiatry, University Hospital Split Syinciceva 1, 22 000 Split, Croatia l-mil: [email protected]

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