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Fatal toxic epidermal necrolysis associated with mefloquine antimalarial prophylaxis
THE LANCET 3 4
5
Suzuki Tsuneo. An ultramicroscopic study on rigor mortis. Forensic Sci 1976; 8: 207–16. Patel BD, PArekh Saroj R, Chitale AR. Histopathological evolution of Indian childhood cirrhosis with emphasis on criteria of early diagnosis. Ind Pediatr 1974; 11: 19–28. Boyd William. A textbook of pathology, 8th edition, 1970; 44–45. London, UK.
703-B, Nilesh Apts, Haridas Nagar, Shimpoli Road, Borivli (W), Mumbai 400 092. India (S R Parekh); and Bai Jerbai Wadia Hospital for Children and Institute of Child Health and Seth G S Medical College, Mumbai, India.
to endemic areas, the need for effective and safe prophylaxis is self-evident. We are concerned that antimalarials such as Fansidar and mefloquine with long half-lives may produce severe and potentially life-threatening adverse reactions which persist long after the drug is withdrawn. Mefloquine is now a widely used prophylaxis for chloroquine-resistant falciparum malaria. We emphasise the importance of careful reporting of side-effects if further deaths are to be prevented, as previously experienced with Fansidar. 1
Fatal toxic epidermal necrolysis associated with mefloquine antimalarial prophylaxis S R McBride, C M Lawrence, S A Pape, C A Reid
Mefloquine is the recommended antimalarial for the prevention of falciparum malaria for visitors from the UK to chloroquine-resistant endemic areas.1 Side-effects of mefloquine include gastrointestinal disturbance, cardiac conduction abnormalities, leucopenia, neurological disturbance, and recently highlighted psychiatric disturbances.2 Cases of erythema multiforme and StevensJohnson syndrome have also been reported.3 We report a fatal case of toxic epidermal necrolysis associated with mefloquine prophylaxis. A 6-year-old healthy girl resident in the UK of Nigerian descent visited Nigeria on a 4-week holiday. She commenced mefloquine 125 mg weekly 1 week before travel and was still taking this medication on her return, as recommended in WHO guidelines. She had not taken mefloquine before and was on no other medication. 35 days after starting mefloquine she developed blistering of her lips and oral mucosa with periorbital and facial swelling. She subsequently developed erythema and blistering of her face, trunk, limbs, and perineum which progressed to exfoliation of 95% of her body surface over 48 h. In addition she had ulceration of mucosal surfaces including the cornea, vulva, oropharynx, and nasal mucosa. She shed both hair and nails. Complications over 10 days included pyrexia, hypotension, diarrhoea, neutropenia, anaemia, paralytic ileus, and klebsiella septicaemia. She was managed in a paediatric intensive-care unit with meticulous fluid balance, intravenous cefuroxime and gentamicin, analgesia, and total parental nutrition. Tropical silver sulphadiazine 1% was applied and dressings changed on alternate days under general anaesthesia. Eye care was done twice daily by skilled ophthalmology nurses. In the third week of her admission her condition improved with resolution of pyrexia, negative blood cultures, and evidence of re-epithelialisation. On day 19 of admission she developed cardiac asystole. Resuscitation attempts were unsuccessful. Necropsy was refused. We believe this case of fatal toxic epidermal necrolysis in a previously fit and healthy 6-year-old was due to mefloquine. Extensive investigation revealed no evidence of an alternative drug or other causes. Another weekly dosage antimalarial effective against chloroquine-resistant malaria was introduced in 1974 under the name of Fansidar (pyrimethamine-sulphadoxine). In the first 8 years no severe cutaneous reactions were reported. Subsequently several cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis were reported. Estimation of these reactions was 1 per 5000 to 8000 users with 1 per 11 000–25 000 being fatal.4 Fansidar is no longer recommended for prophylaxis. With the increase in incidence of chloroquine-resistant malaria and ease of travel
Vol 349 • January 11, 1997
2 3
4
Bradley DJ, Warhurst DC, on behalf of a meeting convened by the malaria reference laboratory. Malaria prohylaxis: guidelines for travellers from Britain. BMJ 1995; 310: 709–14. Lench P. Malaria prophylaxis: psychological problems after mefloquine and chloroquine. BMJ 1995; 311: 192. Van den Enden E, Van Gompel A, Colebunders R, Van den Ende J. Mefloquine-induced Stevens-Johnson syndrome. Lancet 1991; 337: 683. Miller KD, Lobel HO, Satriale RF, Kuritsky JN, Stern R, Campbell CC. Severe cutaneous reactions among American travellers using pyrimethamine-sulphadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg 1986; 35: 451–58.
Departments of Dermatology (C M Lawrence), and Plastic Surgery, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK
Aberrant atrioventricular conduction triggered by antimalarial prophylaxis with mefloquine Joachim Richter, Guido Burbach, Urban Hellgren, Andreas Dengler, Ulrich Bienzle
Mefloquine is generally recommended for antimalarial prophylaxis in Plasmodium falciparum-endemic regions with widespread resistance to chloroquine.1 Cardiac quinidine-like side-effects of the chemically related compound quinine are well known.2 Mefloquine, so far, has been considered relatively safe although in therapeutic doses cardiac effects, mainly sinus bradycardia, have been reported. In volunteers receiving mefloquine, a mild but notable prolongation of the We report QTc-interval has been described.3 electrocardiograph (ECG) abnormalities in a 32-year-old colleague who took weekly mefloquine at the recommended dose during a trip to Thailand. 2 days after the fourth tablet he had palpitations, dizziness, and vertigo. These symptoms recurred 2 days after the fifth, sixth, and seventh doses, and were so intense that he lay down in order not to collapse. On all four occasions the symptoms disappeared within 2 days. On his return to Germany, 3 days after the seventh dose, an ECG was done. It showed aberrantly conducted beats followed by an aberrantly conducted premature echo-beat (figure).4 The QTc-interval was not prolonged. The patient, who had no previous cardiac history, was admitted to hospital and continuously monitored. Clinical and routine laboratory examinations, including serum enzymes, tests for cardiotropic viruses, adrenal and thyroid hormones, chest radiograph, and echocardiography were all normal. Because the frequency of aberrantly conducted beats did not increase, and a relation to mefloquine was suspected, no therapy was given. The coupled aberrantly conducted beats occurred with gradually decreasing frequency from about 60 to 30 per h during the first day in hospital. The following day coronary insufficiency was excluded by a stress ECG and ECG telemetry, on which only some coupled supraventricular premature beats and one ventricular ectopic were recorded. Arterial blood pressure response was normal. Serum levels of mefloquine (1·2 mol/L) and its carboxylic acid metabolite
101
5
Suzuki Tsuneo. An ultramicroscopic study on rigor mortis. Forensic Sci 1976; 8: 207–16. Patel BD, PArekh Saroj R, Chitale AR. Histopathological evolution of Indian childhood cirrhosis with emphasis on criteria of early diagnosis. Ind Pediatr 1974; 11: 19–28. Boyd William. A textbook of pathology, 8th edition, 1970; 44–45. London, UK.
703-B, Nilesh Apts, Haridas Nagar, Shimpoli Road, Borivli (W), Mumbai 400 092. India (S R Parekh); and Bai Jerbai Wadia Hospital for Children and Institute of Child Health and Seth G S Medical College, Mumbai, India.
to endemic areas, the need for effective and safe prophylaxis is self-evident. We are concerned that antimalarials such as Fansidar and mefloquine with long half-lives may produce severe and potentially life-threatening adverse reactions which persist long after the drug is withdrawn. Mefloquine is now a widely used prophylaxis for chloroquine-resistant falciparum malaria. We emphasise the importance of careful reporting of side-effects if further deaths are to be prevented, as previously experienced with Fansidar. 1
Fatal toxic epidermal necrolysis associated with mefloquine antimalarial prophylaxis S R McBride, C M Lawrence, S A Pape, C A Reid
Mefloquine is the recommended antimalarial for the prevention of falciparum malaria for visitors from the UK to chloroquine-resistant endemic areas.1 Side-effects of mefloquine include gastrointestinal disturbance, cardiac conduction abnormalities, leucopenia, neurological disturbance, and recently highlighted psychiatric disturbances.2 Cases of erythema multiforme and StevensJohnson syndrome have also been reported.3 We report a fatal case of toxic epidermal necrolysis associated with mefloquine prophylaxis. A 6-year-old healthy girl resident in the UK of Nigerian descent visited Nigeria on a 4-week holiday. She commenced mefloquine 125 mg weekly 1 week before travel and was still taking this medication on her return, as recommended in WHO guidelines. She had not taken mefloquine before and was on no other medication. 35 days after starting mefloquine she developed blistering of her lips and oral mucosa with periorbital and facial swelling. She subsequently developed erythema and blistering of her face, trunk, limbs, and perineum which progressed to exfoliation of 95% of her body surface over 48 h. In addition she had ulceration of mucosal surfaces including the cornea, vulva, oropharynx, and nasal mucosa. She shed both hair and nails. Complications over 10 days included pyrexia, hypotension, diarrhoea, neutropenia, anaemia, paralytic ileus, and klebsiella septicaemia. She was managed in a paediatric intensive-care unit with meticulous fluid balance, intravenous cefuroxime and gentamicin, analgesia, and total parental nutrition. Tropical silver sulphadiazine 1% was applied and dressings changed on alternate days under general anaesthesia. Eye care was done twice daily by skilled ophthalmology nurses. In the third week of her admission her condition improved with resolution of pyrexia, negative blood cultures, and evidence of re-epithelialisation. On day 19 of admission she developed cardiac asystole. Resuscitation attempts were unsuccessful. Necropsy was refused. We believe this case of fatal toxic epidermal necrolysis in a previously fit and healthy 6-year-old was due to mefloquine. Extensive investigation revealed no evidence of an alternative drug or other causes. Another weekly dosage antimalarial effective against chloroquine-resistant malaria was introduced in 1974 under the name of Fansidar (pyrimethamine-sulphadoxine). In the first 8 years no severe cutaneous reactions were reported. Subsequently several cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis were reported. Estimation of these reactions was 1 per 5000 to 8000 users with 1 per 11 000–25 000 being fatal.4 Fansidar is no longer recommended for prophylaxis. With the increase in incidence of chloroquine-resistant malaria and ease of travel
Vol 349 • January 11, 1997
2 3
4
Bradley DJ, Warhurst DC, on behalf of a meeting convened by the malaria reference laboratory. Malaria prohylaxis: guidelines for travellers from Britain. BMJ 1995; 310: 709–14. Lench P. Malaria prophylaxis: psychological problems after mefloquine and chloroquine. BMJ 1995; 311: 192. Van den Enden E, Van Gompel A, Colebunders R, Van den Ende J. Mefloquine-induced Stevens-Johnson syndrome. Lancet 1991; 337: 683. Miller KD, Lobel HO, Satriale RF, Kuritsky JN, Stern R, Campbell CC. Severe cutaneous reactions among American travellers using pyrimethamine-sulphadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg 1986; 35: 451–58.
Departments of Dermatology (C M Lawrence), and Plastic Surgery, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK
Aberrant atrioventricular conduction triggered by antimalarial prophylaxis with mefloquine Joachim Richter, Guido Burbach, Urban Hellgren, Andreas Dengler, Ulrich Bienzle
Mefloquine is generally recommended for antimalarial prophylaxis in Plasmodium falciparum-endemic regions with widespread resistance to chloroquine.1 Cardiac quinidine-like side-effects of the chemically related compound quinine are well known.2 Mefloquine, so far, has been considered relatively safe although in therapeutic doses cardiac effects, mainly sinus bradycardia, have been reported. In volunteers receiving mefloquine, a mild but notable prolongation of the We report QTc-interval has been described.3 electrocardiograph (ECG) abnormalities in a 32-year-old colleague who took weekly mefloquine at the recommended dose during a trip to Thailand. 2 days after the fourth tablet he had palpitations, dizziness, and vertigo. These symptoms recurred 2 days after the fifth, sixth, and seventh doses, and were so intense that he lay down in order not to collapse. On all four occasions the symptoms disappeared within 2 days. On his return to Germany, 3 days after the seventh dose, an ECG was done. It showed aberrantly conducted beats followed by an aberrantly conducted premature echo-beat (figure).4 The QTc-interval was not prolonged. The patient, who had no previous cardiac history, was admitted to hospital and continuously monitored. Clinical and routine laboratory examinations, including serum enzymes, tests for cardiotropic viruses, adrenal and thyroid hormones, chest radiograph, and echocardiography were all normal. Because the frequency of aberrantly conducted beats did not increase, and a relation to mefloquine was suspected, no therapy was given. The coupled aberrantly conducted beats occurred with gradually decreasing frequency from about 60 to 30 per h during the first day in hospital. The following day coronary insufficiency was excluded by a stress ECG and ECG telemetry, on which only some coupled supraventricular premature beats and one ventricular ectopic were recorded. Arterial blood pressure response was normal. Serum levels of mefloquine (1·2 mol/L) and its carboxylic acid metabolite
101