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Absence of rigor mortis in Indian childhood cirrhosis
THE LANCET
reported in tonsils of experimental scrapie-infected sheep long before the occurrence of clinical signs.5 It is possible therefore that Western blot analysis of human tonsil material may allow early clinical, or possibly pre-clinical, diagnosis of CJD and nvCJD although extensive prospective studies of suspected cases will be necessary to assess the clinical usefulness of this investigation. Tonsil tissue can be easily obtained by biopsy under local anaesthetic in most patients and complications are most unusual. Although many adults will have had childhood tonsillectomy, lymphoreticular tissue may still be obtained from the lingual tonsillar remnants. As a result of the extreme resistance of prions to normal sterilisation procedures, current UK recommendations are that neurosurgical instruments from patients with CJD are destroyed. While infective titres of prions in tonsil may be much lower than in brain, similar precautions to avoid cross contamination and iatrogenic transmission of CJD would seem prudent at present. The development of a disposable tonsil-biopsy kit should be feasible. 1 2
3
4
5
Will RG, Ironside JW, Zeidler M, et al. A new variant of CreutzfeldtJakob disease in the UK. Lancet 1996; 347: 921–25. Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis of prion stain variation and the aetiology of “new variant” CJD. Nature 1996; 383: 685–90. Kimberlin RH, Walker CA. Incubation periods in six models of intraperitoneally injected scrapie depend mainly on the dynamics of agent replication within the nervous system and not the lymphoreticular system. J Gen Virol 1988; 69: 2953–60. Brown P, Gibbs CJJ, Rodgers Johnson P, et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994; 35: 513–29. Schreuder BEC, van Keulen LJM, Vromans MEW, Langeveld JPM, Smits MA. Preclinical test for prion diseases. Nature 1996; 381: 563.
Neurogenetics Unit, Imperial College School of Medicine at St Mary’s, London W2 1PG, UK (J Collinge); National CJD Surveillance Unit, Western General Hospital, Edinburgh, UK; and Department of Neurology, St Mary’s Hospital, London, UK
Absence of rigor mortis in Indian childhood cirrhosis B D Patel, Saroj R Parekh
Indian childhood cirrhosis (ICC) is an enigmatic liver disease which mainly affects rural Indian children under the age of 3 years. Around 1000 BC, Sushruta documented in his Samhita an ICC-like syndrome “Mukhamandika Graha”: “The child has a yellow complexion, oedema over the face and limbs, network of veins on the abdomen, voracious appetite, urine-like smell of the body, fever, and dyspepsia.”1 Since its earliest description by Sen in 1887,2 its aetiology has remained unknown. During an epidemiological field study of ICC, an intriguing observation was made by a social worker who organised funeral ceremonies for bereaved families. He remarked on the total absence of body stiffness in children who died from ICC. A study was undertaken to validate this observation. Parents of 32 patients who died from ICC between the ages of 10 months and 2 years in whom the funeral was delayed 12 hours were interviewed about postmortem stiffness in their children. Information was sought from social workers and health personnel about children with ICC and those dying of other unrelated causes. Observations of rigor mortis in five ICC patients in hospital were recorded. Visual impressions were confirmed by attempting passive flexionextension movements at various joints including the spine (figure). Parents and social workers reported absence of body stiffness in all the 32 patients for a minimum of 12 h to a maximum of 30 h postmortem. Children who died from
100
Photograph of child 36 h after death There is no evidence of rigor mortis and the joints are mobile.
other causes developed body stiffness within 4 to 6 hours. In five hospital patients, the authors observed absence of rigor mortis for from 22 to 36 h after death. Absence of rigor mortis in children dying of ICC has not been referred to in the many publications on ICC and on other liver diseases in children (Medline search to August 1996). Absence of rigor mortis has been reported in obese patients and in fetuses less than 7 months old. A 66% fall in adenosine triphosphate (ATP) concentration in muscles initiates muscle contraction and precipitates rigor mortis.3 Energy for resynthesis of ATP is derived from phosphocreatine with high-energy phosphate bonds; from carbrohydrates, fats, and proteins; as well as from breakdown of glucose and glycogen. Clinical features of ICC include the precirrhotic symptom complex, with irritability, disturbed sleep, sticky stools, and increased appetite with excessive glycogen storage in the liver.4 There is no evidence for increased glycogen storage at other sites, but we consider that there probably is in skeletal muscles. Excess glycogen in muscles would facilitate resynthesis of ATP and so delay rigor. There may be long delay in the onset of rigor in wellfed animals with increased muscle glycogen.5 It would be interesting, to look at glycogen content of muscle biopsy specimens in patients with ICC before and after death and to see if rigor mortis develops in patients who died from glycogen-storage diseases. We thank Anita Borges; Jyotindra Parekh; G M Thanki; N K Memorial Hospital, Porbandar, Gujarat; Jaslok Hospital and Research Centre, Mumbai; and Bai Jerbai Wadia Hospital for Children and Institute of Child Health, Parel, Mumbai, India 1
2
Sushruta. Mukhmandika Graha. Sushruta Samhita. 1000 BC; Uttar Tantra, Chapter 27, verse 15, Kanpur Saraswati Publications (1952): Kanpur, India. Sen BC. Enlargement of liver in children. Indian Medical Gazette 1887; 22: 338.
Vol 349 • January 11, 1997
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
reported in tonsils of experimental scrapie-infected sheep long before the occurrence of clinical signs.5 It is possible therefore that Western blot analysis of human tonsil material may allow early clinical, or possibly pre-clinical, diagnosis of CJD and nvCJD although extensive prospective studies of suspected cases will be necessary to assess the clinical usefulness of this investigation. Tonsil tissue can be easily obtained by biopsy under local anaesthetic in most patients and complications are most unusual. Although many adults will have had childhood tonsillectomy, lymphoreticular tissue may still be obtained from the lingual tonsillar remnants. As a result of the extreme resistance of prions to normal sterilisation procedures, current UK recommendations are that neurosurgical instruments from patients with CJD are destroyed. While infective titres of prions in tonsil may be much lower than in brain, similar precautions to avoid cross contamination and iatrogenic transmission of CJD would seem prudent at present. The development of a disposable tonsil-biopsy kit should be feasible. 1 2
3
4
5
Will RG, Ironside JW, Zeidler M, et al. A new variant of CreutzfeldtJakob disease in the UK. Lancet 1996; 347: 921–25. Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis of prion stain variation and the aetiology of “new variant” CJD. Nature 1996; 383: 685–90. Kimberlin RH, Walker CA. Incubation periods in six models of intraperitoneally injected scrapie depend mainly on the dynamics of agent replication within the nervous system and not the lymphoreticular system. J Gen Virol 1988; 69: 2953–60. Brown P, Gibbs CJJ, Rodgers Johnson P, et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994; 35: 513–29. Schreuder BEC, van Keulen LJM, Vromans MEW, Langeveld JPM, Smits MA. Preclinical test for prion diseases. Nature 1996; 381: 563.
Neurogenetics Unit, Imperial College School of Medicine at St Mary’s, London W2 1PG, UK (J Collinge); National CJD Surveillance Unit, Western General Hospital, Edinburgh, UK; and Department of Neurology, St Mary’s Hospital, London, UK
Absence of rigor mortis in Indian childhood cirrhosis B D Patel, Saroj R Parekh
Indian childhood cirrhosis (ICC) is an enigmatic liver disease which mainly affects rural Indian children under the age of 3 years. Around 1000 BC, Sushruta documented in his Samhita an ICC-like syndrome “Mukhamandika Graha”: “The child has a yellow complexion, oedema over the face and limbs, network of veins on the abdomen, voracious appetite, urine-like smell of the body, fever, and dyspepsia.”1 Since its earliest description by Sen in 1887,2 its aetiology has remained unknown. During an epidemiological field study of ICC, an intriguing observation was made by a social worker who organised funeral ceremonies for bereaved families. He remarked on the total absence of body stiffness in children who died from ICC. A study was undertaken to validate this observation. Parents of 32 patients who died from ICC between the ages of 10 months and 2 years in whom the funeral was delayed 12 hours were interviewed about postmortem stiffness in their children. Information was sought from social workers and health personnel about children with ICC and those dying of other unrelated causes. Observations of rigor mortis in five ICC patients in hospital were recorded. Visual impressions were confirmed by attempting passive flexionextension movements at various joints including the spine (figure). Parents and social workers reported absence of body stiffness in all the 32 patients for a minimum of 12 h to a maximum of 30 h postmortem. Children who died from
100
Photograph of child 36 h after death There is no evidence of rigor mortis and the joints are mobile.
other causes developed body stiffness within 4 to 6 hours. In five hospital patients, the authors observed absence of rigor mortis for from 22 to 36 h after death. Absence of rigor mortis in children dying of ICC has not been referred to in the many publications on ICC and on other liver diseases in children (Medline search to August 1996). Absence of rigor mortis has been reported in obese patients and in fetuses less than 7 months old. A 66% fall in adenosine triphosphate (ATP) concentration in muscles initiates muscle contraction and precipitates rigor mortis.3 Energy for resynthesis of ATP is derived from phosphocreatine with high-energy phosphate bonds; from carbrohydrates, fats, and proteins; as well as from breakdown of glucose and glycogen. Clinical features of ICC include the precirrhotic symptom complex, with irritability, disturbed sleep, sticky stools, and increased appetite with excessive glycogen storage in the liver.4 There is no evidence for increased glycogen storage at other sites, but we consider that there probably is in skeletal muscles. Excess glycogen in muscles would facilitate resynthesis of ATP and so delay rigor. There may be long delay in the onset of rigor in wellfed animals with increased muscle glycogen.5 It would be interesting, to look at glycogen content of muscle biopsy specimens in patients with ICC before and after death and to see if rigor mortis develops in patients who died from glycogen-storage diseases. We thank Anita Borges; Jyotindra Parekh; G M Thanki; N K Memorial Hospital, Porbandar, Gujarat; Jaslok Hospital and Research Centre, Mumbai; and Bai Jerbai Wadia Hospital for Children and Institute of Child Health, Parel, Mumbai, India 1
2
Sushruta. Mukhmandika Graha. Sushruta Samhita. 1000 BC; Uttar Tantra, Chapter 27, verse 15, Kanpur Saraswati Publications (1952): Kanpur, India. Sen BC. Enlargement of liver in children. Indian Medical Gazette 1887; 22: 338.
Vol 349 • January 11, 1997
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