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limbs, especially the dorsal and ventral surfaces of the hands and feet, and, furthermore, at least one mucous membrane is almost always affected, which seems not to have been the case in this

patient. Ackerman did not support a diagnosis of erythema multiforme and thought the condition to be an "interface dermatitis". He suggested, further, that even in the unlikely event of this eruption being an unusual presentation of erythema multiforme, he would regard the associated infection by herpesvirus to be the likely cause. He concluded that "all of the evidence fails to convince me that this patient had erythema multiforme". Furthermore, it is noteworthy that the original histological report of this lesion was not erythema multiforme but rather a "toxic process", not further specified. We remained concerned that the evident causal association of HSV with possible erythema multiforme was not sufficiently addressed in the case report. We therefore also consulted Professor M. Longson, previously from Manchester (UK) and now the United Arab Emirates. Longson believed that the arguments used to implicate a cause other than HSV (the consistently high IgG titres and the cited time-lapse between the clinical vulvar herpes infection and the rash) were equivocal, and were, in fact, consistent with HSV. He concluded that herpesvirus was thus the most probable cause of the skin reaction and that no data to the contrary were

presented.

Thus we believe that the diagnosis of erythema multiforme in this patient is not beyond reasonable doubt. Further, we believe that, even were this a rather atypical case of erythema multiforme, the most probable cause remains the well-documented preceding herpes attack, and that there are no convincing arguments to suggest the contrary. Lastly, very little, if any, evidence was provided that acamprosate was the cause of this skin reaction. International Clinical

Development Department,

Groupe Lipha, 69379 Lyon, France

to

GL, Douglas RG, Bennett JE,

Principles and practice of infectious diseases. Edinburgh: Churchill Livingstone, 1990: 1149. 2. Shelley WB. Herpes simplex virus as a cause of erythema multiforme. JAMA 1967; eds.

201: 153.

** This letter has been shown to Dr Fortier-Beaulieu and colleagues, whose reply follows.-ED L. SiR,—The two major points that Dr Potgieter and Dr Opsomer raise are that the case was not really erythema multiforme, and that, if it had been, the chances are it was caused by herpes and not acamprosate. We have also seen Dr Ackerman’s report. Professor Longson thinks that herpes would be the first cause of the erythema multiforme. We do not deny herpes as a possible cause (and state so in our report), but we see no reason to exclude thereby acamprosate as an equally reasonable cause, in view of the temporal relation between the drug and the event, and the regression after drug withdrawal. Another possibility is that of an interaction or potentiation between acamprosate and herpes. Since most adults have been in contact at one time or another with herpes, one wonders how to analyse all the reported cases of drug-induced multiforme, in which recent herpes eruption may have gone unnoticed, and the potential role of herpes infection in drug-related erythema multiforme. As clinicians, however, and whatever the arguments, we would hesitate before reintroducing the drug in this

patient. Ackerman states that the slides he saw and the case description are

"those of an interface dermatitis which may have been induced by a

drug but could have been caused by a virus other than herpesvirus but the condition is not necessarily erythema multiforme". Although we may have overdiagnosed the skin condition, which resembled a mild case of erythema multiforme, Ackerman’s opinion in fact reinforces the role of the drug in the skin condition. If the condition is not erythema multiforme, then Longson’s arguments for herpes fall, and acamprosate is left as the best suspect. M. FORTIER-BEAULIEU E. THOMINE N. MOORE

epidermal necrosis due omeprazole

SIR,-A 72-year-old woman started omeprazole 20 mg daily for dyspeptic symptoms unresponsive to antacids. She was disabled by a previous hemiplegia, cardiac failure, agoraphobia, and travel sickness, and she was taking long-term medication for heart failure and depression. 2 weeks after starting omeprazole she developed a rash

on

the

arms

which became very extensive

on

trunk and

proximal limbs over the following 4 weeks, at which stage she was referred here. The omeprazole had not been discontinued at an early stage in view of the beneficial effect on the gastro-oesophageal symptoms. Clinical examination revealed widespread erythematous plaques, confluent on the upper back, with sheets of crusting and erosions and a few flaccid non-haemorrhagic blisters. There was crusting of the lower lip but no buccal or other mucosal erosion; the clinical features were of intra-epidermal blistering and suggested pemphigus, but the timing suggested a drug reaction. Examination of a skin biopsy specimen demonstrated a sparse dermal mononuclear cell infiltrate and necrotic epidermal keratinocytes, suggestive of erythema multiforme. Negative direct immunofluorescence and serum indirect immunofluorescence excluded pemphigus. These features indicated a drug side-effect. We stopped omeprazole and treatment was with oral prednisolone. Toxic epidermal necrolysis is caused by drugs in about two-thirds of patients, occurs more often in women, and the frequency increases with age,’ all features of the present case. The precise diagnosis and the relation between bullous erythema multiforme and toxic epidermal necrolysis is arguable. Our patient did not have the large sheets of blistering typical of toxic epidermal necrolysis but had more

blistering ADRIAAN S. POTGIETER LUC OPSOMER

1. Straus SE. Introduction to herpes viridae. In: Mandell

Medical Clinic, Hôpital de Boisguillaume, 76233 Boisguillaume Cedex, France

Acute disseminated

and less discrete lesions than those of

multiforme, and the eruption fits best into

an

typical erythema entity described as

disseminated epidermal necrosis type 3.2 There are no published reports of this type of eruption with omeprazole, but the Committee on Safety of Medicines has received 223 reports of cutaneous reactions to omeprazole up to August, 1992 (CSM, personal communication), including 6 of erythema multiforme and 8 of other patterns of blistering. None of the reports has been of this severity. acute

Department of Dermatology, Cumberland Infirmary, Carlisle CA2 7HY, UK 1. 2.

N. H. Cox

Roujeau J-C, Chosidow O, Saiag P, Guillaume J-C Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 1990; 23: 1039-58. Ruiz-Maldonado R. Acute disseminated epidermal necrosis types 1, 2, and 3: study of 60 cases. J Am Acad Dermatol 1985; 13: 623-35.

Didanosine as probable cause of Stevens-Johnson syndrome SIR,-We report a case of Stevens-Johnson syndrome associated with didanosine 2’,3’-dideoxyinosine (ddI). A 35-year-old white HIV-positive man was admitted in July, 1992, for Stevens-Johnson syndrome that started on July 16. He had a history of intravenous drug addiction and was classified as group IVCI (Centers for Disease Control criteria). Previous opportunistic infections were pulmonary pneumocystosis, candidal oesophagitis, central nervous system toxoplasmosis, and visceral leishmaniasis. Admission temperature was 39°C. His skin was erythematous and papular with some purpuric eruption nearly all over. Erosions were present on his mouth and genitalia, associated with a right superficial keratitis. A skin biopsy specimen supported the diagnosis of Stevens-Johnson syndrome. There was no recent herpetic infection. The chest radiograph was normal and the

Mycobacterium pneumoniae serology was negative, making an infectious cause unlikely. Recent drugs included clindamycin, pyrimethamine, itraconazole, valproic acid, and aerosolised pentamidine for several months. His drug history also included ofloxacine from June 17 to July 6 (ie, discontinued 10 days before the first cutaneous signs) and didanosine 400 mg orally daily from June 26 to July 17. Zidovudine had been discontinued several months before because of haematological toxicity. Results from the

858

algorithm used in France for adverse drug monitoring’ were: probably excluded relation for ofloxacin; doubtful for clindamycin, pyrimethamine, itraconazole, valproic acid, and pentamidine; and probable relation for didanosine. After discontinuation of this therapy, his temperature and cutaneous lesions improved rapidly and the patient was discharged on July 30. In three phase I trials,2-4 the major toxic effects related to didanosine were pancreatitis and peripheral neuropathy. Both seemed to be dose-related and resolved or improved3,4 after discontinuation of therapy. Other toxic effects included hyperuricaemia related to high dose/-4 elevated liver enzymes/,3 and abnormalities in cardiac conduction.2 Adverse cutaneous drug reactions were uncommon. In these trials, 4 patients had a rash: 1/34/ 2/37,3and 1/37. The rash was morbilliform’ and maculopapular.3 In 1 case,2 the rash recurred with more intensity on rechallenge. In 2 other cases,3 didanosine was not discontinued and the rash resolved spontaneously. The manufacturer (Bristol) had similar case. Patients with AIDS have an increased risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis when treated with antibacterial sulphonamides and other drugs.s Our case suggests that didanosine might be another not heard of any

cause.

Department of Dermatology and Immunopathology, Hôpital Henri-Mondor, Université Paris XII, 94010 Créteil, France

A. PARNEIX-SPAKE S. BASTUJI-GARIN Y. LEVY M-L. DUBREUIL-LEMAIRE

J-C. ROUJEAU

1. Moore N, Paux G, Begaud B, et al. Adverse drug reaction monitoring: doing it the French way. Lancet 1985; ii: 1056-58. 2 Cooley TP, Kunches LM, Saunders CA, et al. Once-daily administration of 2’,3’

didanosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. N Engl J Med 1990; 322: 1340-45. 3. Lambert J S, Seidlin M, Reichman RC, et al. 2’,3’-didanosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. N Engl J Med 1990; 322: 1333-40. 4. Yarchoan R, Mitsuya H, Pluda JM, et al. The national cancer institute phase I study of 2’,3’-didanosine administration in adults with AIDS and AIDS-related complex: analysis of activity and toxicity profiles. Rev Infect Dis 1990; 12: 522-23. 5. Coopman SA, Stem RS. Cutaneous drug reactions in human immunodeficency virus infection. Arch Dermatol 1991; 127: 714-17.

Bradycardia due to anthracyclines SIR,-Dr Walker and colleagues describe (Aug 8, p 380) bradycardia following administration of amphotericin after cancer chemotherapy. We report a further three patients with bradycardia after treatment with cytotoxic drugs, including anthracyclines. Patient 1-A 48-year-old man had lobar pneumonia as the first manifestation of acute myeloblastic leukaemia. He was given antibiotics and started on daunorubicin, cytarabine, and thioguanine. The total dose of daunorubicin was less than 150 mg/m2. Amphotericin was added afr t-n days because pneumonia had not resolved. A month after treatment finished he developed symptomatic bradycardia. Electrocardiography (ECG) before chemotherapy had been normal. ECG now showed Mobitz type I

second-degree atrioventricular block, and substantial pauses with periods of rapid atrial flutter on ambulatory electrocardiography. A permanent pacemaker was inserted and he was given digoxin. Patient 2-A 56-year-old woman presented with renal failure. ECG was normal. Renal biopsy showed a plasma-cell infiltrate and positive amyloid staining. Myeloma was diagnosed and she was given vincristine, dexamethasone, and doxorubicin. The cumulative dose of doxorubicin was less than 36 mg/m2. Four days after the last drug administration she was syncopal. A rhythm strip showed atrial fibrillation with a ventricular rate of 60 per min and pauses of more than 2 s; a few hours later she developed a junctional rhythm. After a further 6 h ECG showed complete heart block, and a permanent pacemaker was inserted. Two days later ventricular fibrillation was followed by unsuccessful resuscitation. Necropsy showed no myocardial amyloid. Patient 3-A 47-year-old man with Wegener’s granulomatosis received 7 years treatment with cyclophosphamide and developed erythroleukaemia, which was treated with cytarabine, etoposide, and daunorubicin. He was also given antibiotics, including

amphotericin for otitis interna. Two months later he was given a second course of chemotherapy. The total dose of daunorubicin was 300 mg/m2. He received further amphotericin for a second infection, to which he responded, but three weeks later he became syncopal. The ECG now showed complete heart block, and a permanent pacemaker was inserted; ECG was normal before chemotherapy. These three patients were younger than most who develop bradyarrhythmias requiring pacemakers, and none had a history of cardiac disease. All developed symptomatic bradycardia after chemotherapy. Each of the patients received intravenous anthracyclines but the dose given was below that (> 550 mg/m2) usually associated with cardiotoxicity. Two patients also received amphotericin, which may have precipitated the clinical presentation. Unlike Walker and colleagues’ patient, there was no evidence of bradycardia during the administration of amphotericin, with the last dose being given at least one month before presentation. Rhythm disturbances during anthracycline treatment have been reported in conjunction with left ventricular dysfunction,l of which there was no clinical evidence in our patients. Arrhythmias, such as atrial flutter, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation,2,3may also arise after acute exposure to the drug, but the development of symptomatic bradycardia has not been reported after anthracyclines alone. Wegener’s granulomatosis and amyloidosis seem unlikely causes of the bradyarrhythmias. The most probable trigger in our patients is an adverse effect due to anthracyclines with a further possible contribution in two patients from co-administered amphotericin. Patients presenting with syncopal spells should be investigated at an early stage to identify arrhythmias so that appropriate management can be provided. H. BETHELL Papworth Hospital, Cambridge CB3 8RE, UK

A. A. GRACE

M.C.PETCH P. M. SCHOFIELD

J. A. HALL

Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukaemia in childhood. N Engl J Med 1991; 324: 808-14. 2. Bristow MR, Billingham ME, Mason JW, Daniels JR. Clinical spectrum of anthracycline antibiotic cardiotoxicity. Cancer Treat Rep 1978; 62: 873-79. 3. Bristow M, Thompson P, Martin R, Mason J, Billingham M, Harrison D Early anthracycline toxicity Am J Med 1978; 65: 823-32. 1.

Susceptibility of low-density lipoproteins to oxidation in coronary bypass patients SIR,-Dr Regnstrom and colleagues (May 16, p 1183) report that the susceptibility of low-density lipoprotein (LDL) to oxidation is associated with the severity of atherosclerosis in male survivors of myocardial infarction. Their finding supports the hypothesis on the pathological importance of oxidised LDL as an atherogenic particle.’ We attempted to relate the severity of atherosclerosis in coronary arteries and grafts to the susceptiblity of LDL to oxidative modification in vitro. 1766 patients underwent aortocoronary bypass surgery with insertion of 1-6 grafts. 158 were selected randomly and blindly for recatheterisation. This study was approved by the ethics committee of the Academic Hospital, University of Leiden, and patients gave written informed consent before angiography was done. The mean interval between surgery and angiographic reexamination was 72 years. Randomly, 28 of these 158 patients were divided into two groups (group A with progression; group B without progression). Progression was defined as: occurrence of a new lesion leading to 50% or more stenosis, increment of an existing lesion by 30% or more, or progression to occlusion. After isolation from plasma by density-gradient ultracentrifugation, LDL was used within 2 h to determine the susceptibility to in-vitro oxidation.2 The table shows patients’ details and laboratory findings. LDL isolated from group A patients was less resistant to oxidation than was LDL from group B patients, as shown by a shorter lag time (table). The reduced lag time could not be attributed to a lower a-tocopherol content in LDL. The protective effect of &agr;-tocopherol against oxidative modification of lipids can be prolonged by ascorbate. However, blood ascorbate

Didanosine as probable cause of Stevens-Johnson syndrome.

857 limbs, especially the dorsal and ventral surfaces of the hands and feet, and, furthermore, at least one mucous membrane is almost always affected...
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