European Journal of
Letters to the editors
Pediatrics
Eur J Pediatr (1992) 151 : 619-620
9 Springer-Verlag 1992
Fatal pancytopenia during high-dose valproate monotherapy J. Rajantie, M. Kajosaari, and V. Ylitalo Aurora Hospital, SF-00250Helsinki, Finland Received October 8, 1991 / Accepted in revised form January 10, 1992 Sir: Liver and pancreatic toxities are the best known side-effects of valproic acid, a widely used anticonvulsant [2], but alterations in blood cells have also been described [1-8]. Immune thrombocytopenia is the most frequent haematological finding [1], but dose-related suppression of haematopoiesis has also been reported [8]. We describe a serious haematological disorder associated with valproic acid monotherapy. Intractable epilepsy in a 3-year-old, severely handicapped girl with cerebral palsy had been treated for 5 months with high-dose (150 mg/kg per day) valproic acid [7]. Immune thrombocytopenia (platelets 27 x 109/1, normal marrow megakaryocytosis and presence of antiplatelet antibodies) appeared during an acute infection. Serum valproate concentration was inappropriately low to the dose (460 gmol/1; recommended therapeutic range 340-700 gmol/1), possibly because of poor drug intake. The dose was reduced to 100 mg/kg per day, and a keen follow up was ordered. However, the family did not contact the hospital until 2 months later when the child became critically ill. Her blood haemoglobin (Hb) was 22 g/l, mean corpuscular volume 104fl, corrected reticulocyte count 0.0, WBC 3.5 • 109/1 with 24% neutrophils, and platelets 31 x 109/1. Hb binding capacity of haptoglobin was zero, suggesting haemolysis. Serum bilirubin was not increased. The direct Coombs test, measured after several red cell transfusions, was negative. No evidence of bleeding or infection was found. Activated partial thromboplastin time was 29 s, thromboplastin time 45%. Serum aspartate aminotransferase activity was 68 units/1. Vitamin B12 level was 1200pmol/1; erythrocyte folate concentration was normal. Bone marrow examination now showed low cellularity, impaired erythropoiesis, arrested myeloid maturation and few megakaryocytes. In this agonal state, the serum valproate concentration was very high (1378 gmol/1). Repeated transfusions only temporarily corrected the anaemia and the child died on the 4th day after admission. The parents did not allow autopsy. Valproic acid doses higher than those considered standard are known to be useful for recalcitrant childhood epilepsies [7]. The haematologicat side-effects of valproate are usually mild and respond to a dose decrease. However, the present case of severe aplastic anaemia with shortened red cell life span, presumably due to immunological mechanisms, indicates that even fatal bone marrow toxicity can occur. Therefore, high dosage of valproate should be avoided and, in cases of persisting epilepsy, other medications should be tried. During valproate treatment haematological parameters should be closely followed. If anything other than a pure thrombocytopenia is observed, then valproate therapy should be promptly discontinued. References 1. Barr RD, CopelandSA, StockwellML, Morris N, Kehon JC (1982)Valproic acid and immunethrombocytopenia.Arch Dis Child 57 : 681-684
2. Dreifuss FE, Langer DH (1988) Side effects of valproate. Am J Med 84 : 34-41 3. Ganick DJ, Sunder T, Finley JL (1990) Severe hematologic toxicityof valproic acid. A report of four patients. Am J Pediatr Hematol Oncol 12: 80-85 4. Jaeken J, Van Goethem C, Casaer P, DevliegerH, Eggermont E, Pilet M (1979) Neutropenia during sodium valproate treatment. Arch Dis Child 54: 986-987 5. Kaya IS, Dilmen U, Toppare M, Senses DA, Prentice HG (1991) VaIproic acid-induced pancytopenia and Coombs test positivity. Lancet 337:1227-1228 6. MacDougallLG (1982) Pure red cell aplasiaassociated with sodiumvalproate therapy. JAMA 247 :53-54 7. Prats JM, Garaizar C, Rua MJ, Garcia-NietoML, Madoz P (1991) Infantile spasms treated with high doses of sodiumvalproate: initial response and follow-up. Dev Med Child Neurol 33 : 617-625 8. Watts RG, Emanuel PD, Zuckerman KS, Howard TH (1990) Valproic acid-induced cytopenias. Evidence for a dose-related suppression of hematopoiesis. J Pediatr 117 :495-499
Acute phosphorus intoxication in very low birth weight infant J.N. van den Anker, W. P. F. Fetter, and P. J.J. Sauer Department of Paediatrics, Divisionof Neonatology,Erasmus University and UniversityHospital Rotterdam/Sophia Children's Hospital, Rotterdam, The Netherlands Received February 26, 1992/ Accepted February 26, 1992 Sir: The improved survival of very low birth weight infants has been accompanied by an increased incidence of metabolic bone disease in this population [1]. It is clear that a disturbance in phosphorus and calcium homeostasis has an important pathophysiological role [2]. Provision of sufficient phosphorus and calcium to meet desired requirements is necessary whether an infant is being fed enterally or parenterally. Our policy is to provide our very low birth weight infants, in addition to their special formula feeding with an additional 46 mg phosphorus and 90 mg calcium enterally every day to prevent metabolic bone disease. We describe a case of acute phosphorus intoxication in a very low birth weight infant. A Caucasian female was delivered by caesarean section (gestational age: 28 1/7 weeks; weight 665 g) and showed signs of respiratory insufficiency necessitating artificial ventilation for 7 weeks. Her clinical course was complicated by the development of bronchopulmonary dysplasia and retinopathy of prematurity. She was supplemented with phosphorus and calcium as described above. At age 62 days she was transferred to a regional hospital (postconceptional age: 37 weeks; weight 1325 g). There were no changes in therapy but I day after transferral the child deteriorated. Apnoeic attacks with cyanosis, compromised circulation and a distended abdomen were the presenting symptoms. Septicaemia was suspected and after blood, urine and cerebrospinal fluid cultures were taken broad spectrum antibiotics were started. She was transferred back to our hospital and on admission we saw a child with severe apnoeic attacks, based on severe laryngospasm. There were also generalized muscle spasms in both arms and legs. The abdomen was distended but non-tender. Rapid biochemical determinations showed an extreme hypocalcaemia (1.03mmol/1).
620 This was directly supplemented intravenously and there was a rapid i m p r o v e m e n t in her condition together with normalisation of the serum calcium concentration. Phosphate determination showed an abnormal high concentration of 6.66mmol/1 (n = 1.62-3.07mmol/1), which also normalised in a couple of days. A thorough investigation revealed a mistake in the prescribed phosphorus supplementation. In stead of the administration of 46 mg phosphorus daily, 460 mg phosphorus was administered to the child, which caused the rapid increase in serum phosphate and dangerous drop in serum calcium. She is now 3 years old and her psychomotor development is excellent, indicating no long-term side-effects of the acute intoxication at this moment. This case report of an acute phosphorus intoxication clearly demonstrates that we should always consider iatrogenic causes of sudden deterioration of infants, especially when they receive drugs.
References
1. Kulkarni PB, Hall RT, Rhodes OG, et al. (1980) Rickets in very low birth weight infants. J Pediatr 96: 249 2. McIntosch N, Livesey A, Brooke OG (1983) Plasma-25-hydroxyvitamin D and rickets in low birth weight babies. Arch Dis Child 58 : 476
Prenatal diagnosis of Canavan disease C. J a k o b s 1, H . J . ten B r i n k s , P. D i v r y 2, a n d M . O . R o l l a n d 2
~Department of Paediatrics, Free University Hospital, Amsterdam, The Netherlands 2Centre d'Etude des Maladies M6taboliques, H6pital Debronsse, Lyon, France Received March 17, 1992 / Accepted in revised form March 17, 1992 Sir: Ozand et al. [4] described the prenatal detection of Canavan disease in a pregnancy at risk by determination of Nacetylaspartic acid ( N A A ) in maternal urine and N A A in amniotic fluid. In maternal urine the N A A concentration increased at 6 months of gestation to 450 m m o l / m o l creatinine (control values < 30 mmol/mol creat.) and in the amniotic fluid sample at 8.5 months gestation to 1050gmol/1 (control values < 2 0 gmol/1). The child born from this pregnancy indeed showed increased N A A excretion in urine and an aspartoacylase deficiency was established in the child's fibroblasts. Ozand et al. suggested that in future pregnancies N A A concentrations in amniotic fluid should be measured at 10-18 weeks gestation to find out whether the rise in amniotic fluid precedes the increase in the maternal urine when the fetus is affected, allowing early termination of the pregnancy. We recently monitored two pregnancies at risk for Canavan disease. In the first family the index case was shown to have Canavan disease by elevated excretion of N A A in urine and deficiency of aspartoacylase in fibroblasts. In the next pregnancy, amniocentesis was performed at 14 weeks of gestation, Aspartoacylase activity was measured according to Matalon et al. [3] in cultured amniotic fluid cells, but gave ambiguous results due to low activities in control cells. N A A was assayed in am-
I Abbreviation:NAA = N-acetylaspartic acid
]
Table 1. NAA values in amniotic fluid of controls and the pregnancies at
risk Amniotic fluid
NAA (gmol/l) First family
Second family
14 weeks
5.9a
18 weeks
7.9"
4.2" 4.1b 7.2a 6.5b 154b
At term Controls (16-18 weeks) (n = 30)a range = 0.3-2.6" (n = 5)b range = 1 . 0 - 1 . 6 b a Amsterdam b Lyon
niotic fluid with a stable isotope dilution m e t h o d using D3labelled N A A as internal standard and with chemical ionization gas chromatography mass fragmentography [2]. The concentration of N A A in the pregnancy at risk was considered elevated (Table 1), but because we did not have experience with proven affected pregnancies the amniocentesis was repeated at 18 weeks of gestation. The N A A excretion in amniotic fluid had increased further and the parents decided to terminate the pregnancy. Unfortunately, fetal fibroblasts failed to grow and final confirmation of the aspartoacylase defect was not possible, Maternal urine was not available for N A A measurement. In the second family two previous children were shown to have Canavan disease (Divry et al. [1]). Chorionic villus biopsy and amniocentesis were p e r f o r m e d at 14 weeks gestation. Unfortunately, the villus sample was too small for direct analysis of aspartoacylase activity, N A A in amniotic fluid was assayed in duplicate in two laboratories using a similar isotope dilution m e t h o d [2] and was moderately elevated (Table 1). A m n i o c e n tesis was repeated at 18 weeks. Again the concentrations were considered elevated (Table 1), but the parents decided to continue the pregnancy. The baby was born by caesarean section and now a massive urinary excretion of N A A (650mmol/mol creat.) indicates an affected child. In amniotic fluid taken at birth, the N A A concentration (154gmol/1) was elevated but less than that reported by Ozand et al. N A A values in maternal urine did not increase significantly ( 2 4 m m o l / m o l creat, at 7 months of pregnancy) and were not helpful in the diagnosis. F r o m our experience it is suggested that the N A A concentration is indeed elevated in amniotic fluid from the affected Canavan fetus between 14 and 18 weeks. The relatively mild increase can only be adequately discriminated from control values when a sensitive stable isotope dilution assay is used.
References
Divry P, Vianey-Liaud C, Gay C, Macabeo V, Rapin F, Echenne B (1988) N-acetylaspartic aciduria: report of three new cases in children with a neurological syndrome associating maerocephaty and leukodystrophy. J Inherited Metab Dis 11:307-308 Jakobs C, Brink HJ ten, Langelaar SA, Zee T, Stellaard F, Macek M, Srsnova K, Srsen S, Kleijer WJ (1991) Stable isotope dilution analysis of N-acetylaspartic acid in CSF, blood, urine and amniotic fluid: accurate postnatal diagnosis and the potential for prenatal diagnosis of Canavan disease. J Inherited Metab Dis 14 : 653-660 3, Matalon R, Michals KM, Sebesta D, Deanching M, Gashkoff P, Casanova J (1988) Aspartoacylase deficiency and N-acetylaspartic aeiduria in patients with Canavan disease. Am J Hum Genet 29 : 463-471 4. Ozand PT, Gascon GG, A1 Aqeel MJ, Nester MJ, Feryal RR, Gleispach H, Cook JD, A10daib A (1991) Prenatal detection of Canavan Disease. Lancet 335 : 735-736
Letters to the editors
Pediatrics
Eur J Pediatr (1992) 151 : 619-620
9 Springer-Verlag 1992
Fatal pancytopenia during high-dose valproate monotherapy J. Rajantie, M. Kajosaari, and V. Ylitalo Aurora Hospital, SF-00250Helsinki, Finland Received October 8, 1991 / Accepted in revised form January 10, 1992 Sir: Liver and pancreatic toxities are the best known side-effects of valproic acid, a widely used anticonvulsant [2], but alterations in blood cells have also been described [1-8]. Immune thrombocytopenia is the most frequent haematological finding [1], but dose-related suppression of haematopoiesis has also been reported [8]. We describe a serious haematological disorder associated with valproic acid monotherapy. Intractable epilepsy in a 3-year-old, severely handicapped girl with cerebral palsy had been treated for 5 months with high-dose (150 mg/kg per day) valproic acid [7]. Immune thrombocytopenia (platelets 27 x 109/1, normal marrow megakaryocytosis and presence of antiplatelet antibodies) appeared during an acute infection. Serum valproate concentration was inappropriately low to the dose (460 gmol/1; recommended therapeutic range 340-700 gmol/1), possibly because of poor drug intake. The dose was reduced to 100 mg/kg per day, and a keen follow up was ordered. However, the family did not contact the hospital until 2 months later when the child became critically ill. Her blood haemoglobin (Hb) was 22 g/l, mean corpuscular volume 104fl, corrected reticulocyte count 0.0, WBC 3.5 • 109/1 with 24% neutrophils, and platelets 31 x 109/1. Hb binding capacity of haptoglobin was zero, suggesting haemolysis. Serum bilirubin was not increased. The direct Coombs test, measured after several red cell transfusions, was negative. No evidence of bleeding or infection was found. Activated partial thromboplastin time was 29 s, thromboplastin time 45%. Serum aspartate aminotransferase activity was 68 units/1. Vitamin B12 level was 1200pmol/1; erythrocyte folate concentration was normal. Bone marrow examination now showed low cellularity, impaired erythropoiesis, arrested myeloid maturation and few megakaryocytes. In this agonal state, the serum valproate concentration was very high (1378 gmol/1). Repeated transfusions only temporarily corrected the anaemia and the child died on the 4th day after admission. The parents did not allow autopsy. Valproic acid doses higher than those considered standard are known to be useful for recalcitrant childhood epilepsies [7]. The haematologicat side-effects of valproate are usually mild and respond to a dose decrease. However, the present case of severe aplastic anaemia with shortened red cell life span, presumably due to immunological mechanisms, indicates that even fatal bone marrow toxicity can occur. Therefore, high dosage of valproate should be avoided and, in cases of persisting epilepsy, other medications should be tried. During valproate treatment haematological parameters should be closely followed. If anything other than a pure thrombocytopenia is observed, then valproate therapy should be promptly discontinued. References 1. Barr RD, CopelandSA, StockwellML, Morris N, Kehon JC (1982)Valproic acid and immunethrombocytopenia.Arch Dis Child 57 : 681-684
2. Dreifuss FE, Langer DH (1988) Side effects of valproate. Am J Med 84 : 34-41 3. Ganick DJ, Sunder T, Finley JL (1990) Severe hematologic toxicityof valproic acid. A report of four patients. Am J Pediatr Hematol Oncol 12: 80-85 4. Jaeken J, Van Goethem C, Casaer P, DevliegerH, Eggermont E, Pilet M (1979) Neutropenia during sodium valproate treatment. Arch Dis Child 54: 986-987 5. Kaya IS, Dilmen U, Toppare M, Senses DA, Prentice HG (1991) VaIproic acid-induced pancytopenia and Coombs test positivity. Lancet 337:1227-1228 6. MacDougallLG (1982) Pure red cell aplasiaassociated with sodiumvalproate therapy. JAMA 247 :53-54 7. Prats JM, Garaizar C, Rua MJ, Garcia-NietoML, Madoz P (1991) Infantile spasms treated with high doses of sodiumvalproate: initial response and follow-up. Dev Med Child Neurol 33 : 617-625 8. Watts RG, Emanuel PD, Zuckerman KS, Howard TH (1990) Valproic acid-induced cytopenias. Evidence for a dose-related suppression of hematopoiesis. J Pediatr 117 :495-499
Acute phosphorus intoxication in very low birth weight infant J.N. van den Anker, W. P. F. Fetter, and P. J.J. Sauer Department of Paediatrics, Divisionof Neonatology,Erasmus University and UniversityHospital Rotterdam/Sophia Children's Hospital, Rotterdam, The Netherlands Received February 26, 1992/ Accepted February 26, 1992 Sir: The improved survival of very low birth weight infants has been accompanied by an increased incidence of metabolic bone disease in this population [1]. It is clear that a disturbance in phosphorus and calcium homeostasis has an important pathophysiological role [2]. Provision of sufficient phosphorus and calcium to meet desired requirements is necessary whether an infant is being fed enterally or parenterally. Our policy is to provide our very low birth weight infants, in addition to their special formula feeding with an additional 46 mg phosphorus and 90 mg calcium enterally every day to prevent metabolic bone disease. We describe a case of acute phosphorus intoxication in a very low birth weight infant. A Caucasian female was delivered by caesarean section (gestational age: 28 1/7 weeks; weight 665 g) and showed signs of respiratory insufficiency necessitating artificial ventilation for 7 weeks. Her clinical course was complicated by the development of bronchopulmonary dysplasia and retinopathy of prematurity. She was supplemented with phosphorus and calcium as described above. At age 62 days she was transferred to a regional hospital (postconceptional age: 37 weeks; weight 1325 g). There were no changes in therapy but I day after transferral the child deteriorated. Apnoeic attacks with cyanosis, compromised circulation and a distended abdomen were the presenting symptoms. Septicaemia was suspected and after blood, urine and cerebrospinal fluid cultures were taken broad spectrum antibiotics were started. She was transferred back to our hospital and on admission we saw a child with severe apnoeic attacks, based on severe laryngospasm. There were also generalized muscle spasms in both arms and legs. The abdomen was distended but non-tender. Rapid biochemical determinations showed an extreme hypocalcaemia (1.03mmol/1).
620 This was directly supplemented intravenously and there was a rapid i m p r o v e m e n t in her condition together with normalisation of the serum calcium concentration. Phosphate determination showed an abnormal high concentration of 6.66mmol/1 (n = 1.62-3.07mmol/1), which also normalised in a couple of days. A thorough investigation revealed a mistake in the prescribed phosphorus supplementation. In stead of the administration of 46 mg phosphorus daily, 460 mg phosphorus was administered to the child, which caused the rapid increase in serum phosphate and dangerous drop in serum calcium. She is now 3 years old and her psychomotor development is excellent, indicating no long-term side-effects of the acute intoxication at this moment. This case report of an acute phosphorus intoxication clearly demonstrates that we should always consider iatrogenic causes of sudden deterioration of infants, especially when they receive drugs.
References
1. Kulkarni PB, Hall RT, Rhodes OG, et al. (1980) Rickets in very low birth weight infants. J Pediatr 96: 249 2. McIntosch N, Livesey A, Brooke OG (1983) Plasma-25-hydroxyvitamin D and rickets in low birth weight babies. Arch Dis Child 58 : 476
Prenatal diagnosis of Canavan disease C. J a k o b s 1, H . J . ten B r i n k s , P. D i v r y 2, a n d M . O . R o l l a n d 2
~Department of Paediatrics, Free University Hospital, Amsterdam, The Netherlands 2Centre d'Etude des Maladies M6taboliques, H6pital Debronsse, Lyon, France Received March 17, 1992 / Accepted in revised form March 17, 1992 Sir: Ozand et al. [4] described the prenatal detection of Canavan disease in a pregnancy at risk by determination of Nacetylaspartic acid ( N A A ) in maternal urine and N A A in amniotic fluid. In maternal urine the N A A concentration increased at 6 months of gestation to 450 m m o l / m o l creatinine (control values < 30 mmol/mol creat.) and in the amniotic fluid sample at 8.5 months gestation to 1050gmol/1 (control values < 2 0 gmol/1). The child born from this pregnancy indeed showed increased N A A excretion in urine and an aspartoacylase deficiency was established in the child's fibroblasts. Ozand et al. suggested that in future pregnancies N A A concentrations in amniotic fluid should be measured at 10-18 weeks gestation to find out whether the rise in amniotic fluid precedes the increase in the maternal urine when the fetus is affected, allowing early termination of the pregnancy. We recently monitored two pregnancies at risk for Canavan disease. In the first family the index case was shown to have Canavan disease by elevated excretion of N A A in urine and deficiency of aspartoacylase in fibroblasts. In the next pregnancy, amniocentesis was performed at 14 weeks of gestation, Aspartoacylase activity was measured according to Matalon et al. [3] in cultured amniotic fluid cells, but gave ambiguous results due to low activities in control cells. N A A was assayed in am-
I Abbreviation:NAA = N-acetylaspartic acid
]
Table 1. NAA values in amniotic fluid of controls and the pregnancies at
risk Amniotic fluid
NAA (gmol/l) First family
Second family
14 weeks
5.9a
18 weeks
7.9"
4.2" 4.1b 7.2a 6.5b 154b
At term Controls (16-18 weeks) (n = 30)a range = 0.3-2.6" (n = 5)b range = 1 . 0 - 1 . 6 b a Amsterdam b Lyon
niotic fluid with a stable isotope dilution m e t h o d using D3labelled N A A as internal standard and with chemical ionization gas chromatography mass fragmentography [2]. The concentration of N A A in the pregnancy at risk was considered elevated (Table 1), but because we did not have experience with proven affected pregnancies the amniocentesis was repeated at 18 weeks of gestation. The N A A excretion in amniotic fluid had increased further and the parents decided to terminate the pregnancy. Unfortunately, fetal fibroblasts failed to grow and final confirmation of the aspartoacylase defect was not possible, Maternal urine was not available for N A A measurement. In the second family two previous children were shown to have Canavan disease (Divry et al. [1]). Chorionic villus biopsy and amniocentesis were p e r f o r m e d at 14 weeks gestation. Unfortunately, the villus sample was too small for direct analysis of aspartoacylase activity, N A A in amniotic fluid was assayed in duplicate in two laboratories using a similar isotope dilution m e t h o d [2] and was moderately elevated (Table 1). A m n i o c e n tesis was repeated at 18 weeks. Again the concentrations were considered elevated (Table 1), but the parents decided to continue the pregnancy. The baby was born by caesarean section and now a massive urinary excretion of N A A (650mmol/mol creat.) indicates an affected child. In amniotic fluid taken at birth, the N A A concentration (154gmol/1) was elevated but less than that reported by Ozand et al. N A A values in maternal urine did not increase significantly ( 2 4 m m o l / m o l creat, at 7 months of pregnancy) and were not helpful in the diagnosis. F r o m our experience it is suggested that the N A A concentration is indeed elevated in amniotic fluid from the affected Canavan fetus between 14 and 18 weeks. The relatively mild increase can only be adequately discriminated from control values when a sensitive stable isotope dilution assay is used.
References
Divry P, Vianey-Liaud C, Gay C, Macabeo V, Rapin F, Echenne B (1988) N-acetylaspartic aciduria: report of three new cases in children with a neurological syndrome associating maerocephaty and leukodystrophy. J Inherited Metab Dis 11:307-308 Jakobs C, Brink HJ ten, Langelaar SA, Zee T, Stellaard F, Macek M, Srsnova K, Srsen S, Kleijer WJ (1991) Stable isotope dilution analysis of N-acetylaspartic acid in CSF, blood, urine and amniotic fluid: accurate postnatal diagnosis and the potential for prenatal diagnosis of Canavan disease. J Inherited Metab Dis 14 : 653-660 3, Matalon R, Michals KM, Sebesta D, Deanching M, Gashkoff P, Casanova J (1988) Aspartoacylase deficiency and N-acetylaspartic aeiduria in patients with Canavan disease. Am J Hum Genet 29 : 463-471 4. Ozand PT, Gascon GG, A1 Aqeel MJ, Nester MJ, Feryal RR, Gleispach H, Cook JD, A10daib A (1991) Prenatal detection of Canavan Disease. Lancet 335 : 735-736
