- Email: [email protected]
Mycophenolate mofetil for severe autoimmune haemolytic anemia
THE LANCET
should always be aware of side-effects and complications of methylene blue. Without serious signs of hypoxia, removal of NO is the only therapy required because normal reducing mechanisms within the erythrocyte will usually convert methaemoglobin to haemoglobin within 15 to 20 h.5 1
2
3 4 5
Roberts JJ, Fineman J, Frederick C, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997; 336: 605–10. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full term infants with hypoxic respiratory failure. N Engl J Med 1997; 336: 597–604. Ross JD. Deficient activity of DPNH dependent methomoglobin diaphorase in cord blood erythrocytes. Blood 1963; 21: 51–62. Mansouri A. Review: methemoglobinemia. Am J Med Sci 1985; 289: 200–09. Harris J, Kellermeyer R. The red cell. Cambridge, MA: Harvard University Press, 1970; 267: 447–523.
Department of Paediatrics, Akita University School of Medicine, 1-1-1 Hondo, Akita 010, Japan (W Nakajima)
Methaemoglobin concentration and oxygen saturation after methylene blue infusion
started mechanical ventilation (Hamming II, Senkoikakikai, Tokyo, Japan) and infusion of dopamine, dobutamine, morphine, and a volume expander, and instilled surfactant into the endotracheal tube. Blood oxygen saturation fluctuated 40–100% by pulse oximeter and that at the leg was more than 20% lower than that at the arm. She showed severe cyanosis despite bagging with 100% oxygen. A working diagnosis of persistent pulmonary hypertension of the newborn (PPHN) was made. At 4 h of age nitric oxide (NO) was started from an intended dose of 20 parts per million (ppm). Effective peak inspiratory concentrations of NO were monitored with Ecoline Plus (Nichion-Irikakikai, Chiba, Japan). At 24 h of age, on discontinuing the NO the oxygen saturation dropped immediately, then NO was restarted and increased up to 80 ppm. From 36 h urination was obtained and transcutaneous oxygen pressure began to stabilise at 13·3 kPa but oxygen saturation still fluctuated. At 50 h of age, however, she developed deep central cyanosis although arterial blood gas analysis revealed pH 7·5, pO2 50·7 kPa, and an oxygen saturation of 100%. A methaemoglobin level was 40%. Then NO was decreased and discontinued after 1 h and 1 mg/kg of methylene blue was infused over 8 min, resulting in a reduction in the methaemoglobin concentration to 3·9% over the next 20 min. Blood oxygen saturation transiently decreased from 90 to 65% during the methylene blue infusion (figure), urine of the patient dyed blue for 3 days, and the skin looked dark brown for 1 month. However, discontinuation of NO did not lead to rebound hypoxia or pulmonary hypertension and there were no further episodes of methaemoglobinaemia. Cranial magnetic resonance imaging at 4 weeks of age revealed no finding suggestive of hypoxic damage. She can hold her head up in the supine position at 4 months of age. Although studies indicate that inhaled NO (80 ppm) improves systemic oxygenation in infants with PPHN without development of methaemoglobinaemia,1,2 our patient did develop methaemoglobinaemia. A reason might be that she received 80 ppm of NO for 26 hours. In addition, although NO is short lived, infants are more sensitive than adults to methaemoglobin-producing agents.3 In most cases methaemoglobinaemia is transitory, but it can be occasionally life threatening and must be rapidly diagnosed and treated.4 Although we treated the infant with methylene blue and her general condition improved, we
Vol 350 • October 4, 1997
Mycophenolate mofetil for severe autoimmune haemolytic anemia Barbara Zimmer-Molsberger, Wolfgang Knauf, Eckhard Thiel
Mycophenolate mofetil (MMF) prolongs allograft survival and reverses graft rejection. MMF has also been used to treat rheumatoid arthritis and psoriasis. We used MMF in two patients with severe autoimmune haemolytic anaemia as second-line medication. An 84-year-old man with Coombs-positive warm-reacting autoantibodies type IgG, leucocytosis of 80⫻109/L, anaemia, and thrombocytopaenia was diagnosed as having B prolymphocytic leukaemia in April, 1996. Initial chemotherapy (cyclophosphamide, vincristine, and prednisolone) failed to induce any response. After one cycle of 2-chlorodesoxyadenosine (2-CDA) leucocytes fell below 40⫻109/L, and the thrombocytes stabilised at more than 100⫻109/L. He developed a severe haemolytic anaemia (haemoglobin 4·9–6·2 g/dL), and despite oral prednisolone (5–20 mg per day for 8 weeks), he remained dependent upon red blood cell (RBC) transfusion (2–3 units/week). MMF was started (1 g/day, then 2 g/day) 9 days later, whilst reducing prednisolone. Coombs test became negative within 2 weeks, and haemoglobin rose slowly. He did not need any further blood support after 16 weeks of MMF treatment, and the haemoglobin has been more than 12 g/dL for more than 32 weeks. A 56-year-old patient with a history of chronic B lymphocytic leukaemia since 1991 and previous chemotherapy (2-CDA, and prednisolone with chlorambucil) developed progressive lymphadenopathy and hepatosplenomegaly in May, 1996. He was given another four cycles of 2-CDA, which improved his clinical status but a Coombs-positive haemolytic anaemia with irregular autoantibodies type IgG developed. In October, 1996, he had a haemolytic anaemia (haemoglobin 4·4 g/dL. High-dose oral prednisolone was started, but was complicated by severe insulin-dependent diabetes and varicella zoster infection. Prednisolone dose had to be reduced. In January, 1997, the haemolysis became worse, and MMF (1 g/day, then 2 g/day) was started. Prednisolone was tapered off. Within 4 weeks, the need for RBC transfusions was limited to 8-10 units per month, in contrast with 28 units in January, 1997. The usual second-line management of chronic haemolytic anaemia is azathioprine, danazol, cyclophosphamide, or
1003
THE LANCET
immunoglobulin therapy.1 We used MMF as second-line medication for servere haemolysis after 2-CDA chemotherapy. An association between haemolytic anaemia and chemotherapy with nucleoside-analogues has been described.2 With the increasing interest in nucleosideanalogues to induce remission induction in lymphoproliferative diseases, MMF may be a promising alternative to prednisolone in the event of treatment-related haemolysis. 1 2
Engelfriet CP, Overbeeke MA, von dem Borne AE. Autoimmune hemolytic anemia. Semin Hematol 1992; 29: 3–12. Di Raimondo F, Giustolisi R, Cacciola E, et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia patients treated with fludarabine. Leuk Lymphoma 1993; 11: 63–68.
Department of Hematology, Oncology and Transfusion Medicine, Medical Clinic III, Benjamin Franklin Klinikum, Free University Berlin, Berlin, Germany (Prof E Thiel)
Transient population bypassed by polio vaccination programmes in Yunnan Province, China
Supported in part by the Japan International Cooperation Agency (JICA), the Chinese Government, and a grant for International Health Cooperation Research (8A-4) from the Ministry of Health and Welfare, Japan. We thank Y Chiba and the staff of China polio control programme for their cooperation. 1
2 3
Takashi Nakano, Zheng-Rong Ding, Zhi-Song Liang, Tsuyoshi Matsuba, Wen Xu
4
Efforts to achieve global eradication of poliomyelitis have had considerable success since WHO designated the year 2000 as the deadline. Immunisation programmes, however, may have bypassed certain groups. Four wild strains of polioviruses were isolated between 1995 and April, 1996 around the Myanmar border with China.1 As well as people who cross the border, there is a transient population in China consisting of market tradespeople, construction workers, domestic workers, and others. Rapid economic growth and advances in transport have led to an increase in this population. Market tradespeople are often accompanied by children, and many of these children are not officially registered, even though they may live in the same place for several months or even years. We surveyed four markets in Yunnan Province to determine the proportion of transients in the population and the prevalence of oral polio vaccine (OPV) immunisation in September and October, 1996. We interviewed the parents or custodians of 127 children who appeared to be under the age of 5 years. Data on children aged 1 to 3 years were analysed. 36 children were excluded because of age or incomplete information; 91 were eligible. There were 45 boys and 46 girls. They were classified as: settled people who lived in the same perfecture where their families were registered; transients from within Yunnan Province; transients from other provinces; and transients from abroad. We obtained information on whether the children had received at least one dose of routine OPV vaccination. A BCG scar was looked for. We asked whether the children had ever participated in national immunisation days (NIDs)
Settled population (n=37) Intra-provincial transients (n=15) Extra-provincial transients (n=32) Foreign transients (n=7) All transient (n=54)
or in any of the nine supplementary OPV immunisation campaigns since 1990. 91 eligible children were grouped as 37 settled population, 15 transients within Yunnan, 32 transients from other provinces, and seven foreign transients. There were no significant differences in sex or age between groups. All indices of immunisation were lower in transients (table). Although the sample size of this study is small, this finding is noteworthy because the rate of routine polio immunisation and participation in NIDs in China are high.2–4 Because it is illegal for members to live outside the area in which the family is registered, transients may not participate in immunisation programmes for fear of being identified by the authorities. Furthermore, they often have more children than allowed by the family planning law. Thus, this population may be at high risk of poliomyelitis.
Nakano T, Ding Z, Kyogoku S, et al. Coordination of poliomyelitis immunisation programme in China’s border areas. Lancet 1996; 348: 1097–98. Hull HF, Ward NA, Hull BP, et al. Paralytic poliomyelitis: seasoned strategies, disappearing disease. Lancet 1994; 343: 1331–37. Yang B, Zhang J, Otten MW Jr, et al. Eradication of poliomyelitis: progress in the People’s Republic of China. Pediatr Infect Dis J 1995; 14: 308–14. Chiba Y, Xu A, Li L, et al. Poliomyelitis surveillance in Shandong Province, China, 1990–92. Bull World Health Organ 1994; 72: 915–20.
Department of Pediatrics, Mie National Hospital, 357 Ozato-Kubota, Tsu, Mie, 514-01, Japan (T Nakano); and Yunnan Provincial Epidemic Prevention Station (JICA Polio Control Project in China) Yunnan, China
Vascular headache due to intracranial meningioma: a curable form of headache Andrea Talacchi, Cristina Lombardo, Albino Bricolo
The concurrence of headache and meningioma poses dilemmas in diagnosis and treatment.1 When small meningiomas are found on magnetic resonance imaging (MRI) in patients presenting with headache alone, the association is usually considered coincidental. However, in certain cases, there are some doubts whether incidentallydiscovered meningiomas are asymptomatic. We investigated whether any relation exists between meningioma and headache presenting alone; we also investigated which type of headache may reveal a meningioma, and which type of meningioma may cause headache early in the clinical history. We retrospectively analysed our experience in surgical management of intracranial meningioma during the MRI era (n=514 cases). We selected patients who presented with headache alone, excluding those with papilloedema,
Routine OPV given
BCG scar
NID participation
OPV supplementation other than NID
35 (94·6%) 10 (66·7%) 11 (34·4%) 3 (42·9%) 24 (44·4%)
32 (86·5%) 7 (46·7%) 17 (53·1%) 3 (42·9%) 27 (50·0%)
33 (89·2%) 9 (60·0%) 7 (21·9%) 4 (57·1%) 20 (37·0%)
33 (89·2%) 7 (46·7%) 12 (37·5%) 2 (28–6%) 21 (38·9%)
OPV=oral polio vaccine, NID=national immunisation day.
Immunisation and population status
1004
Vol 350 • October 4, 1997
should always be aware of side-effects and complications of methylene blue. Without serious signs of hypoxia, removal of NO is the only therapy required because normal reducing mechanisms within the erythrocyte will usually convert methaemoglobin to haemoglobin within 15 to 20 h.5 1
2
3 4 5
Roberts JJ, Fineman J, Frederick C, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997; 336: 605–10. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full term infants with hypoxic respiratory failure. N Engl J Med 1997; 336: 597–604. Ross JD. Deficient activity of DPNH dependent methomoglobin diaphorase in cord blood erythrocytes. Blood 1963; 21: 51–62. Mansouri A. Review: methemoglobinemia. Am J Med Sci 1985; 289: 200–09. Harris J, Kellermeyer R. The red cell. Cambridge, MA: Harvard University Press, 1970; 267: 447–523.
Department of Paediatrics, Akita University School of Medicine, 1-1-1 Hondo, Akita 010, Japan (W Nakajima)
Methaemoglobin concentration and oxygen saturation after methylene blue infusion
started mechanical ventilation (Hamming II, Senkoikakikai, Tokyo, Japan) and infusion of dopamine, dobutamine, morphine, and a volume expander, and instilled surfactant into the endotracheal tube. Blood oxygen saturation fluctuated 40–100% by pulse oximeter and that at the leg was more than 20% lower than that at the arm. She showed severe cyanosis despite bagging with 100% oxygen. A working diagnosis of persistent pulmonary hypertension of the newborn (PPHN) was made. At 4 h of age nitric oxide (NO) was started from an intended dose of 20 parts per million (ppm). Effective peak inspiratory concentrations of NO were monitored with Ecoline Plus (Nichion-Irikakikai, Chiba, Japan). At 24 h of age, on discontinuing the NO the oxygen saturation dropped immediately, then NO was restarted and increased up to 80 ppm. From 36 h urination was obtained and transcutaneous oxygen pressure began to stabilise at 13·3 kPa but oxygen saturation still fluctuated. At 50 h of age, however, she developed deep central cyanosis although arterial blood gas analysis revealed pH 7·5, pO2 50·7 kPa, and an oxygen saturation of 100%. A methaemoglobin level was 40%. Then NO was decreased and discontinued after 1 h and 1 mg/kg of methylene blue was infused over 8 min, resulting in a reduction in the methaemoglobin concentration to 3·9% over the next 20 min. Blood oxygen saturation transiently decreased from 90 to 65% during the methylene blue infusion (figure), urine of the patient dyed blue for 3 days, and the skin looked dark brown for 1 month. However, discontinuation of NO did not lead to rebound hypoxia or pulmonary hypertension and there were no further episodes of methaemoglobinaemia. Cranial magnetic resonance imaging at 4 weeks of age revealed no finding suggestive of hypoxic damage. She can hold her head up in the supine position at 4 months of age. Although studies indicate that inhaled NO (80 ppm) improves systemic oxygenation in infants with PPHN without development of methaemoglobinaemia,1,2 our patient did develop methaemoglobinaemia. A reason might be that she received 80 ppm of NO for 26 hours. In addition, although NO is short lived, infants are more sensitive than adults to methaemoglobin-producing agents.3 In most cases methaemoglobinaemia is transitory, but it can be occasionally life threatening and must be rapidly diagnosed and treated.4 Although we treated the infant with methylene blue and her general condition improved, we
Vol 350 • October 4, 1997
Mycophenolate mofetil for severe autoimmune haemolytic anemia Barbara Zimmer-Molsberger, Wolfgang Knauf, Eckhard Thiel
Mycophenolate mofetil (MMF) prolongs allograft survival and reverses graft rejection. MMF has also been used to treat rheumatoid arthritis and psoriasis. We used MMF in two patients with severe autoimmune haemolytic anaemia as second-line medication. An 84-year-old man with Coombs-positive warm-reacting autoantibodies type IgG, leucocytosis of 80⫻109/L, anaemia, and thrombocytopaenia was diagnosed as having B prolymphocytic leukaemia in April, 1996. Initial chemotherapy (cyclophosphamide, vincristine, and prednisolone) failed to induce any response. After one cycle of 2-chlorodesoxyadenosine (2-CDA) leucocytes fell below 40⫻109/L, and the thrombocytes stabilised at more than 100⫻109/L. He developed a severe haemolytic anaemia (haemoglobin 4·9–6·2 g/dL), and despite oral prednisolone (5–20 mg per day for 8 weeks), he remained dependent upon red blood cell (RBC) transfusion (2–3 units/week). MMF was started (1 g/day, then 2 g/day) 9 days later, whilst reducing prednisolone. Coombs test became negative within 2 weeks, and haemoglobin rose slowly. He did not need any further blood support after 16 weeks of MMF treatment, and the haemoglobin has been more than 12 g/dL for more than 32 weeks. A 56-year-old patient with a history of chronic B lymphocytic leukaemia since 1991 and previous chemotherapy (2-CDA, and prednisolone with chlorambucil) developed progressive lymphadenopathy and hepatosplenomegaly in May, 1996. He was given another four cycles of 2-CDA, which improved his clinical status but a Coombs-positive haemolytic anaemia with irregular autoantibodies type IgG developed. In October, 1996, he had a haemolytic anaemia (haemoglobin 4·4 g/dL. High-dose oral prednisolone was started, but was complicated by severe insulin-dependent diabetes and varicella zoster infection. Prednisolone dose had to be reduced. In January, 1997, the haemolysis became worse, and MMF (1 g/day, then 2 g/day) was started. Prednisolone was tapered off. Within 4 weeks, the need for RBC transfusions was limited to 8-10 units per month, in contrast with 28 units in January, 1997. The usual second-line management of chronic haemolytic anaemia is azathioprine, danazol, cyclophosphamide, or
1003
THE LANCET
immunoglobulin therapy.1 We used MMF as second-line medication for servere haemolysis after 2-CDA chemotherapy. An association between haemolytic anaemia and chemotherapy with nucleoside-analogues has been described.2 With the increasing interest in nucleosideanalogues to induce remission induction in lymphoproliferative diseases, MMF may be a promising alternative to prednisolone in the event of treatment-related haemolysis. 1 2
Engelfriet CP, Overbeeke MA, von dem Borne AE. Autoimmune hemolytic anemia. Semin Hematol 1992; 29: 3–12. Di Raimondo F, Giustolisi R, Cacciola E, et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia patients treated with fludarabine. Leuk Lymphoma 1993; 11: 63–68.
Department of Hematology, Oncology and Transfusion Medicine, Medical Clinic III, Benjamin Franklin Klinikum, Free University Berlin, Berlin, Germany (Prof E Thiel)
Transient population bypassed by polio vaccination programmes in Yunnan Province, China
Supported in part by the Japan International Cooperation Agency (JICA), the Chinese Government, and a grant for International Health Cooperation Research (8A-4) from the Ministry of Health and Welfare, Japan. We thank Y Chiba and the staff of China polio control programme for their cooperation. 1
2 3
Takashi Nakano, Zheng-Rong Ding, Zhi-Song Liang, Tsuyoshi Matsuba, Wen Xu
4
Efforts to achieve global eradication of poliomyelitis have had considerable success since WHO designated the year 2000 as the deadline. Immunisation programmes, however, may have bypassed certain groups. Four wild strains of polioviruses were isolated between 1995 and April, 1996 around the Myanmar border with China.1 As well as people who cross the border, there is a transient population in China consisting of market tradespeople, construction workers, domestic workers, and others. Rapid economic growth and advances in transport have led to an increase in this population. Market tradespeople are often accompanied by children, and many of these children are not officially registered, even though they may live in the same place for several months or even years. We surveyed four markets in Yunnan Province to determine the proportion of transients in the population and the prevalence of oral polio vaccine (OPV) immunisation in September and October, 1996. We interviewed the parents or custodians of 127 children who appeared to be under the age of 5 years. Data on children aged 1 to 3 years were analysed. 36 children were excluded because of age or incomplete information; 91 were eligible. There were 45 boys and 46 girls. They were classified as: settled people who lived in the same perfecture where their families were registered; transients from within Yunnan Province; transients from other provinces; and transients from abroad. We obtained information on whether the children had received at least one dose of routine OPV vaccination. A BCG scar was looked for. We asked whether the children had ever participated in national immunisation days (NIDs)
Settled population (n=37) Intra-provincial transients (n=15) Extra-provincial transients (n=32) Foreign transients (n=7) All transient (n=54)
or in any of the nine supplementary OPV immunisation campaigns since 1990. 91 eligible children were grouped as 37 settled population, 15 transients within Yunnan, 32 transients from other provinces, and seven foreign transients. There were no significant differences in sex or age between groups. All indices of immunisation were lower in transients (table). Although the sample size of this study is small, this finding is noteworthy because the rate of routine polio immunisation and participation in NIDs in China are high.2–4 Because it is illegal for members to live outside the area in which the family is registered, transients may not participate in immunisation programmes for fear of being identified by the authorities. Furthermore, they often have more children than allowed by the family planning law. Thus, this population may be at high risk of poliomyelitis.
Nakano T, Ding Z, Kyogoku S, et al. Coordination of poliomyelitis immunisation programme in China’s border areas. Lancet 1996; 348: 1097–98. Hull HF, Ward NA, Hull BP, et al. Paralytic poliomyelitis: seasoned strategies, disappearing disease. Lancet 1994; 343: 1331–37. Yang B, Zhang J, Otten MW Jr, et al. Eradication of poliomyelitis: progress in the People’s Republic of China. Pediatr Infect Dis J 1995; 14: 308–14. Chiba Y, Xu A, Li L, et al. Poliomyelitis surveillance in Shandong Province, China, 1990–92. Bull World Health Organ 1994; 72: 915–20.
Department of Pediatrics, Mie National Hospital, 357 Ozato-Kubota, Tsu, Mie, 514-01, Japan (T Nakano); and Yunnan Provincial Epidemic Prevention Station (JICA Polio Control Project in China) Yunnan, China
Vascular headache due to intracranial meningioma: a curable form of headache Andrea Talacchi, Cristina Lombardo, Albino Bricolo
The concurrence of headache and meningioma poses dilemmas in diagnosis and treatment.1 When small meningiomas are found on magnetic resonance imaging (MRI) in patients presenting with headache alone, the association is usually considered coincidental. However, in certain cases, there are some doubts whether incidentallydiscovered meningiomas are asymptomatic. We investigated whether any relation exists between meningioma and headache presenting alone; we also investigated which type of headache may reveal a meningioma, and which type of meningioma may cause headache early in the clinical history. We retrospectively analysed our experience in surgical management of intracranial meningioma during the MRI era (n=514 cases). We selected patients who presented with headache alone, excluding those with papilloedema,
Routine OPV given
BCG scar
NID participation
OPV supplementation other than NID
35 (94·6%) 10 (66·7%) 11 (34·4%) 3 (42·9%) 24 (44·4%)
32 (86·5%) 7 (46·7%) 17 (53·1%) 3 (42·9%) 27 (50·0%)
33 (89·2%) 9 (60·0%) 7 (21·9%) 4 (57·1%) 20 (37·0%)
33 (89·2%) 7 (46·7%) 12 (37·5%) 2 (28–6%) 21 (38·9%)
OPV=oral polio vaccine, NID=national immunisation day.
Immunisation and population status
1004
Vol 350 • October 4, 1997