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Blood flow velocities and neonatal asphyxia
The Journal of Pediatrics Volume 126, Number 4
Editorial correspondence
Opsoclonus-myoclonus, ataxia, and coincident neuroblastoma
675
AP. Use of intravenous gamma globulin therapy for postinfectious acute cerebellar ataxia/opsoclonus of childhood [Abstract]. Ann Neurol 1992;32:440.
To the Editor: Koh et al. 1 describe 10 children with neuroblastoma and the paraneoplastic opsoclonus-myoclonus syndrome. The long survival of children so affected appeared to be a consequence of the following factors: ( 1) favorable fiistologic characteristics according to the Shimada classification, (2) tumors with a single copy of the N-myc oncogene, (3) localized tumor, and (4) a high percentage of extraabdominal tumors. Several points regarding this article are instructive. First, paraneoplastic neurologie syndromes are most often associated with long survival in children and adults. This phenomenon has been explained by the findings in patients with neurologic paraneoplastic syndromes, limited disease, and favorable tumor biology. The authors elegantly expand on this thesis by demonstration of a single copy of N-mye, an oncogene which, when amplified, independently predicts unfavorable prognosis. Second, paraneoplastic syndromes are clinically defined, and the definition is augmented by laboratory demonstration of syndromespecific autoantibodies. This laboratory tool is frequently used in diagnosing paraneoplastic disorders in adults; however, I know of no similar pediatric experience. An autoantibody associated with the opsoclonus-myoclonus syndrome in women with breast cancer is termed anti-Ri. 2 Anti-Ri appears to be a specific marker of the opsoclonus-myoclonus syndrome and warrants investigation in children with neuroblastoma both with and without the paraneoplastic disorder. Finally, common themes in neurologic paraneoplastic disorders are the presence of fixed neurologie deficits notwithstanding early diagnosis and, often, curative treatment of the underlying cancer. No effective therapies for neurologic paraneoplastic syndromes have been identified. The data supporting the presence of adrenocorticotropic hormone in children with opsoclonus-myoclonus are not compelling, given the poor outcome reflected by the high incidence of encephalopathy and variable response time to treatment. Edmondson et al. 3 suggested intravenous immune globulin therapy, but no long-term follow-up was available; this therapy may warrant further study.
Blood flow velocities and neonatal asphyxia To the Editor." The report by Akinbi et al. (J PEDIATR 1994;125:625-7) claims that blood flow velocity profiles correlate with birth asphyxia. To meet the authors' diagnostic criteria for birth asphyxia, infants had to have a cord blood pH <7.20 or a 5-minute Apgar score _<_7.The literature is replete with evidence that neither of these is diagnostic of asphyxia. In 1986 the American Academy of Pediatrics Committee on the Fetus and Newborn noted that Apgar scores at 1 and 5 minutes correlate poorly with either cause or outcome, that scores alone should not be considered evidence of asphyxia, and that a score of 7 is normal. 1 Similar problems exist when cord pH values are misused as singular indicators of asphyxia. In the study by Ruth and Raivio, 2 positive predictive value and sensitivity of cord pH values <7.16 (i.e., more than 2 SD below the mean) for adverse outcomes linked to asphyxia were 8% and 21%, respectively. This is not surprising because nearly 15% of all live-born singletons delivered at term have cord arterial pH values <7.20, the value used by Akinbi et aL to diagnose birth asphyxia. 3 Furthermore, the correlation between Apgar score and cord pH is poor. Only 19% of low Apgar scores are associated with significant acidosis, and only 27% of infants with acidosis have low Apgar scores. 4 A joint statement by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists noted that the term asphyxia should be reserved for clinical situations characterized by "damaging acidemia, hypoxia and metabolic acidosis. ''5 Most causes of asphyxia predate parturition and have little to do with intrapartum events. In this regard, the term birth asphyxia is imprecise and should not be used. 5 It is a label that implies causality, has substantial medicolegal implications, and befies the scientific investigations that have been performed during the last 25 years.
Stephen J. Elliott, MD Department of Pediatrics Baylor College of Medicine Houston, TX 77030
Marc C. Chamberlain, MD Department of Neuroseiences Division of Neurology/Oncology University of California, San Diego La Jolla, CA 92093-0812 9/35/62447 REFERENCES
1. Koh PS, Raffensperger JG, Berry S, et al. Long-term outcome in children with opsoclonus-myoclonus and ataxia and coincident neuroblastoma. J PEDIATR 1994;125:712-6. 2. Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29:241-51. 3. Edmondson JC, Nichter CA, Selman JE, DeVivo DC, Gold
9/35/62449 REFERENCES
1. American Academy of Pediatrics. Use and abuse of the Apgar score. Pediatrics 1986;78:1148-9, 2. Ruth V J, Raivio KO. Perinatal brain damage: predictive value of metabolic acidosis and the Apgar score. Br Med J 1988; 297:24-7. 3. Gilstrap LC, Leveno K J, Burris J, Williams ML, Little BB. Diagnosis of birth asphyxia on the basis of fetal pH, Apgar score, and newborn cerebral dysfunction. Am J Obstet Gynecol 1989;161:825-30.
676
Editorial correspondence
The Journal of Pediatrics April 1995
4. Sykes GS, Molloy PM, Johnson P. Do Apgar scores indicate asphyxia? Lancet 1982;1:494-6. 5. American Academy of Pediatrics, and American College of Obstetricians and Gynecologists. Guidelines for perinatal care. 3rd ed. Elk Grove Village, Illinois: American Academy of Pediatrics, 1992:221-4.
Reply
the risk of dystocia in nulliparous women. N Engl J Med 1993;328:1145-9. 5. Sykes GS, Molloy PM, Johnson P, et al. Do Apgar score indicate asphyxia? Lancet 1982;1:494-6. 6. Ruth VJ, Raivio KO. Perinatal brain damage: predictive value of metabolic acidosis and Apgar score. BMJ 1988;297: 24-7. 7. Gilstrap LC, Leveno K J, Burris J, Williams LM, Little BB. Diagnosis of birth asphyxia on the basis of fetal pH, Apgar score, and newborn cerebral dysfunction. Am J Obstet Gyncol 1989;161:825-30.
To the Editor: We appreciate Dr. Elliott's comment about the stringency of our diagnostic criteria for diagnosis of birth asphyxia. Although the joint statement by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists relates specifically to neurologic outcome, his point is well taken. Our study was not intended as a validation of either the Apgar score or umbilical cord blood pH. Neither of these two measurements, singly or in combination, accurately predicts morbidity. The cutoff point for the 5-minute Apgar score used in our study was actually <7. Many studies have used the same criteria that we used1-4; two of the studies cited by Dr. Elliott used a 5-minute Apgar score of 7 as one of their criteria. 5, 6 However, this was neither our rationale nor a justification. The fact that only 0.6% of live births will meet the criterion of pH _<7.00,7 as Dr. Elliott would have preferred for us to use, would preclude most studies that attempt to correlate clinical conditions that engender anxiety in caretakers of newborn infants (in this case, timing of enteral feedings) with established means of assessing neonatal physiologic status. The point in our report--that the two indexes we examined, peak systolic blood flow and pulsatility index, were worse with worsening cord blood pH and lower Apgar scores--should not be obfuscated by this distinction of the American Academy of Pediatrics definition of birth asphyxia from acidemia at birth.
H. Akinbi, MD V. Bhutani, MD S. Abbasi, MD Section on Newborn Pediatrics Pennsylvania Hospital Philadelphia, PA 19107 9/35/62448
REFERENCES
1. Thilaganathan B, Athanasiou S, Ozmen S, Creighton S, Watson NR, Nicholaides KH. Umbilical cord blood erythroblast count as an index of intrauterine hypoxia. Arch Dis Child 1994;70:F192-4. 2. Samueloff A, Langer O, Berkus M, Field N, Xenakis E, Ridgway L. Is fetal heart variability a good predictor of fetal outcome? Aeta Obstet Gynecot Scand 1994;73:39-44. 3. Bruner JB, Levy DW, Arger PH. Doppler ultrasonography of the umbilical cord in complicated pregnancies. South Med J 1993;86:418-22. 4. Fraser WD, Marcoux S, Moutquin JM, Christen A, Canadian Early Amniotomy Study Group. Effect of early amniotomy on
A new defect in vitamin D metabolism To the Editor: We read with interest the article by Casella et al. 1 and the Editor's Column 2 on a possible new defect ~n vitamin D metabolism. The importance of a singular observation is enforced if more patients with similar findings are disclosed. Thus we describe two Turkish sisters with similar findings (i.e., rickets at the age of 3 years and reappearance of the rickets after successful treatment with vitamin D). The initial observations included difficulties in walking, low 25hydroxyvitamin D concentration and low calcium and phosphate levels in serum, elevated alkaline phosphatase activity, and signs of rickets by x-ray examination. After treatment with vitamin D, normalization of all described abnormal findings occurred 6 to 12 months later. Between the ages of 8 to 13 years, after discontinuation of vitamin D therapy, both patients several times had mild to severe symptoms of active rickets (difficulties in walking, pain in the knees, typical x-ray findings, elevated alkaline phosphatase activity, and low serum values for 25-hydroxyvitamin D). Treatment with orally administered vitamin D (5000 to 10,000 U daily) led each time to the disappearance of clinical symptoms and the abnormal laboratory findings. There is no consanguinity and no evidence of metabolic bone disease in the parents or the five siblings. The patients both received vitamin D supplementation (500 U daily) during the first year of life. Nutritional intake and outdoor activity were comparable with those of other children, and there was no treatment with anticonvulsive drugs. Growth and weight gain were normal, as were results of liver and kidney function tests and examinations for malabsorption. The patients of Casella et al. and ours have in common late-onset rickets that can be treated successfully with vitamin D but reappears without further vitamin D supplementation, and there is evidence that they require the supplementation for an extended period or even for life. They do not fulfill the diagnostic criteria of vitamin D-dependent rickets type I or II. 3 The early symptoms and the first response to vitamin D treatment resemble the condition of late-onset vitamin D deficiency, but reappearance and familial occurrence distinguish it from a simple form of vitamin D deficiency. The cause of the enhanced vitamin D requirement remains obscure; the proposed defect in 25-hydroxylation is possible but still
Editorial correspondence
Opsoclonus-myoclonus, ataxia, and coincident neuroblastoma
675
AP. Use of intravenous gamma globulin therapy for postinfectious acute cerebellar ataxia/opsoclonus of childhood [Abstract]. Ann Neurol 1992;32:440.
To the Editor: Koh et al. 1 describe 10 children with neuroblastoma and the paraneoplastic opsoclonus-myoclonus syndrome. The long survival of children so affected appeared to be a consequence of the following factors: ( 1) favorable fiistologic characteristics according to the Shimada classification, (2) tumors with a single copy of the N-myc oncogene, (3) localized tumor, and (4) a high percentage of extraabdominal tumors. Several points regarding this article are instructive. First, paraneoplastic neurologie syndromes are most often associated with long survival in children and adults. This phenomenon has been explained by the findings in patients with neurologic paraneoplastic syndromes, limited disease, and favorable tumor biology. The authors elegantly expand on this thesis by demonstration of a single copy of N-mye, an oncogene which, when amplified, independently predicts unfavorable prognosis. Second, paraneoplastic syndromes are clinically defined, and the definition is augmented by laboratory demonstration of syndromespecific autoantibodies. This laboratory tool is frequently used in diagnosing paraneoplastic disorders in adults; however, I know of no similar pediatric experience. An autoantibody associated with the opsoclonus-myoclonus syndrome in women with breast cancer is termed anti-Ri. 2 Anti-Ri appears to be a specific marker of the opsoclonus-myoclonus syndrome and warrants investigation in children with neuroblastoma both with and without the paraneoplastic disorder. Finally, common themes in neurologic paraneoplastic disorders are the presence of fixed neurologie deficits notwithstanding early diagnosis and, often, curative treatment of the underlying cancer. No effective therapies for neurologic paraneoplastic syndromes have been identified. The data supporting the presence of adrenocorticotropic hormone in children with opsoclonus-myoclonus are not compelling, given the poor outcome reflected by the high incidence of encephalopathy and variable response time to treatment. Edmondson et al. 3 suggested intravenous immune globulin therapy, but no long-term follow-up was available; this therapy may warrant further study.
Blood flow velocities and neonatal asphyxia To the Editor." The report by Akinbi et al. (J PEDIATR 1994;125:625-7) claims that blood flow velocity profiles correlate with birth asphyxia. To meet the authors' diagnostic criteria for birth asphyxia, infants had to have a cord blood pH <7.20 or a 5-minute Apgar score _<_7.The literature is replete with evidence that neither of these is diagnostic of asphyxia. In 1986 the American Academy of Pediatrics Committee on the Fetus and Newborn noted that Apgar scores at 1 and 5 minutes correlate poorly with either cause or outcome, that scores alone should not be considered evidence of asphyxia, and that a score of 7 is normal. 1 Similar problems exist when cord pH values are misused as singular indicators of asphyxia. In the study by Ruth and Raivio, 2 positive predictive value and sensitivity of cord pH values <7.16 (i.e., more than 2 SD below the mean) for adverse outcomes linked to asphyxia were 8% and 21%, respectively. This is not surprising because nearly 15% of all live-born singletons delivered at term have cord arterial pH values <7.20, the value used by Akinbi et aL to diagnose birth asphyxia. 3 Furthermore, the correlation between Apgar score and cord pH is poor. Only 19% of low Apgar scores are associated with significant acidosis, and only 27% of infants with acidosis have low Apgar scores. 4 A joint statement by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists noted that the term asphyxia should be reserved for clinical situations characterized by "damaging acidemia, hypoxia and metabolic acidosis. ''5 Most causes of asphyxia predate parturition and have little to do with intrapartum events. In this regard, the term birth asphyxia is imprecise and should not be used. 5 It is a label that implies causality, has substantial medicolegal implications, and befies the scientific investigations that have been performed during the last 25 years.
Stephen J. Elliott, MD Department of Pediatrics Baylor College of Medicine Houston, TX 77030
Marc C. Chamberlain, MD Department of Neuroseiences Division of Neurology/Oncology University of California, San Diego La Jolla, CA 92093-0812 9/35/62447 REFERENCES
1. Koh PS, Raffensperger JG, Berry S, et al. Long-term outcome in children with opsoclonus-myoclonus and ataxia and coincident neuroblastoma. J PEDIATR 1994;125:712-6. 2. Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 1991;29:241-51. 3. Edmondson JC, Nichter CA, Selman JE, DeVivo DC, Gold
9/35/62449 REFERENCES
1. American Academy of Pediatrics. Use and abuse of the Apgar score. Pediatrics 1986;78:1148-9, 2. Ruth V J, Raivio KO. Perinatal brain damage: predictive value of metabolic acidosis and the Apgar score. Br Med J 1988; 297:24-7. 3. Gilstrap LC, Leveno K J, Burris J, Williams ML, Little BB. Diagnosis of birth asphyxia on the basis of fetal pH, Apgar score, and newborn cerebral dysfunction. Am J Obstet Gynecol 1989;161:825-30.
676
Editorial correspondence
The Journal of Pediatrics April 1995
4. Sykes GS, Molloy PM, Johnson P. Do Apgar scores indicate asphyxia? Lancet 1982;1:494-6. 5. American Academy of Pediatrics, and American College of Obstetricians and Gynecologists. Guidelines for perinatal care. 3rd ed. Elk Grove Village, Illinois: American Academy of Pediatrics, 1992:221-4.
Reply
the risk of dystocia in nulliparous women. N Engl J Med 1993;328:1145-9. 5. Sykes GS, Molloy PM, Johnson P, et al. Do Apgar score indicate asphyxia? Lancet 1982;1:494-6. 6. Ruth VJ, Raivio KO. Perinatal brain damage: predictive value of metabolic acidosis and Apgar score. BMJ 1988;297: 24-7. 7. Gilstrap LC, Leveno K J, Burris J, Williams LM, Little BB. Diagnosis of birth asphyxia on the basis of fetal pH, Apgar score, and newborn cerebral dysfunction. Am J Obstet Gyncol 1989;161:825-30.
To the Editor: We appreciate Dr. Elliott's comment about the stringency of our diagnostic criteria for diagnosis of birth asphyxia. Although the joint statement by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists relates specifically to neurologic outcome, his point is well taken. Our study was not intended as a validation of either the Apgar score or umbilical cord blood pH. Neither of these two measurements, singly or in combination, accurately predicts morbidity. The cutoff point for the 5-minute Apgar score used in our study was actually <7. Many studies have used the same criteria that we used1-4; two of the studies cited by Dr. Elliott used a 5-minute Apgar score of 7 as one of their criteria. 5, 6 However, this was neither our rationale nor a justification. The fact that only 0.6% of live births will meet the criterion of pH _<7.00,7 as Dr. Elliott would have preferred for us to use, would preclude most studies that attempt to correlate clinical conditions that engender anxiety in caretakers of newborn infants (in this case, timing of enteral feedings) with established means of assessing neonatal physiologic status. The point in our report--that the two indexes we examined, peak systolic blood flow and pulsatility index, were worse with worsening cord blood pH and lower Apgar scores--should not be obfuscated by this distinction of the American Academy of Pediatrics definition of birth asphyxia from acidemia at birth.
H. Akinbi, MD V. Bhutani, MD S. Abbasi, MD Section on Newborn Pediatrics Pennsylvania Hospital Philadelphia, PA 19107 9/35/62448
REFERENCES
1. Thilaganathan B, Athanasiou S, Ozmen S, Creighton S, Watson NR, Nicholaides KH. Umbilical cord blood erythroblast count as an index of intrauterine hypoxia. Arch Dis Child 1994;70:F192-4. 2. Samueloff A, Langer O, Berkus M, Field N, Xenakis E, Ridgway L. Is fetal heart variability a good predictor of fetal outcome? Aeta Obstet Gynecot Scand 1994;73:39-44. 3. Bruner JB, Levy DW, Arger PH. Doppler ultrasonography of the umbilical cord in complicated pregnancies. South Med J 1993;86:418-22. 4. Fraser WD, Marcoux S, Moutquin JM, Christen A, Canadian Early Amniotomy Study Group. Effect of early amniotomy on
A new defect in vitamin D metabolism To the Editor: We read with interest the article by Casella et al. 1 and the Editor's Column 2 on a possible new defect ~n vitamin D metabolism. The importance of a singular observation is enforced if more patients with similar findings are disclosed. Thus we describe two Turkish sisters with similar findings (i.e., rickets at the age of 3 years and reappearance of the rickets after successful treatment with vitamin D). The initial observations included difficulties in walking, low 25hydroxyvitamin D concentration and low calcium and phosphate levels in serum, elevated alkaline phosphatase activity, and signs of rickets by x-ray examination. After treatment with vitamin D, normalization of all described abnormal findings occurred 6 to 12 months later. Between the ages of 8 to 13 years, after discontinuation of vitamin D therapy, both patients several times had mild to severe symptoms of active rickets (difficulties in walking, pain in the knees, typical x-ray findings, elevated alkaline phosphatase activity, and low serum values for 25-hydroxyvitamin D). Treatment with orally administered vitamin D (5000 to 10,000 U daily) led each time to the disappearance of clinical symptoms and the abnormal laboratory findings. There is no consanguinity and no evidence of metabolic bone disease in the parents or the five siblings. The patients both received vitamin D supplementation (500 U daily) during the first year of life. Nutritional intake and outdoor activity were comparable with those of other children, and there was no treatment with anticonvulsive drugs. Growth and weight gain were normal, as were results of liver and kidney function tests and examinations for malabsorption. The patients of Casella et al. and ours have in common late-onset rickets that can be treated successfully with vitamin D but reappears without further vitamin D supplementation, and there is evidence that they require the supplementation for an extended period or even for life. They do not fulfill the diagnostic criteria of vitamin D-dependent rickets type I or II. 3 The early symptoms and the first response to vitamin D treatment resemble the condition of late-onset vitamin D deficiency, but reappearance and familial occurrence distinguish it from a simple form of vitamin D deficiency. The cause of the enhanced vitamin D requirement remains obscure; the proposed defect in 25-hydroxylation is possible but still