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Cardiomyopathy and abnormal carnitine metabolism
Volumell4 Number5
Editorialcorrespondence
there are artifactual changes related to the assessment process itself, they can be detected during that first week. Administering such a trial requires, first, a pharmacy willing to make up the capsules and, second, teachers who are wiffing to complete a behavioral rating scale on a weekly basis for a 6-week period. In addition to ensuring that stimulant medication is not misused, this method can also help to convince hesitant parents about the true effects of the medication and to assess whether a child will benefit by continuing to receive the medication after the assessment process.
Mark Wolraich, MD Department of Pediatrics Division of Developmental Disabilities The University of Iowa Iowa City, IA 52242
903
administration so that evaluator objectivity could be maintained. Perhaps the ideal approach is to vary the trial design to fit the sophistication and biases of the child, family, and teachers involved.
Margaret C. McBride, MD Departments of Pediatrics and Neurology University of Rochester School of Medicine Rochester, N Y 14642
Cardiomyopathy and abnormal carnitine metabolism
REFERENCE
1.
Kazdin AE. Single-case research designs: methods for clinical and applied settings. New York: Oxford University Press, 1982.
Reply To the Editor." Dr. Wolraich's comments are helpful; certainly any of several trial designs can be used to determine methylphenidate efficacy in children with attention deficit disorder. It is true that a trial using a single dose, as I described, risks overlooking patierits who respond only to higher doses. One approach to that problem would be to retest with a higher dose the two thirds of nonresponders who do not show adverse effects on a standard methylphenidate dosage (such as 0.3 mg/kg/dose). In my series of 70 children, that would have involved 13 retests (19%), which is not a formidable task and is perhaps easier than starting with an open trial to determine an effective dose in all children. Parents and teachers who are opposed to medication might find it more difficult to get beyond their prejudices and admit an effect while trying to arrive at the appropriate dose in an open trial. Families of children for whom an optimal dose was not found might be reluctant to enter a double-blind trial. A trial with more than one changeover might help to sort out inconclusive results. However, I have found a 6-week trial difficult to fit in between school vacations, and on occasion, teachers and parents have become lax in their behavioral ratings before the completion of even 4 weeks. The trial that I described is a compromise between the ideal and the practical. A double-blind trial is a good way to determine the continued need for methylphenidate. It might be best to minimize effects of sudden withdrawal of the medication by tapering the dose to half before starting the trial. It was not clear to me whether Dr. Wolraich uses the same trial pattern for each child or whether the pattern varies. I believe that it is extremely important that the physician evaluator continue to conduct the trim in blinded fashion to avoid bias when reviewing comments and questioning the parents about the trial. It would therefore be necessary to vary the order of drug and placebo
To the Editor." Ino et al. (J PEDIATR 1988;113:511-4) described two interesting cases of dilated cardiomyopathy and abnormal carnitine metabolism. However, the abnormal carnitine metabolism was limited to decreased free plasma carnitine levels, whereas total plasma carnitine concentration was normal. Carnitine therapy resulted in upper normal concentrations of both free and total plasma carnitine. Although the carnitine therapy may have been the cause of the reversal of symptoms, a low-fat, high-carbohydrate diet was also started. The authors gave no carnitine values in liver or muscle, although such results would have been valuable for the characterization of the disorder. Dicarboxylic aciduria is the only mentioned abnormal urinary excretion. A more detailed description of the organic acids excreted, as well as of free and total carnitine levels, is missing. The authors compared their patients with reported patients with cardiomyopathy and systemic carnitine deficiency (their references 1 to 6). However, only the patients described in their references 1, 2, and 5 had severely decreased concentrations of both free and total carnitine in both plasma and muscle. The primary defect in those patients could well be the same as that described by Eriksson et al. 1 and also found by us (unpublished results): a hereditary carnitine transport defect that is also expressed in skin fibroblasts. The defect described by Ino et al. is different and could very well be in the transport or oxidation of fatty acids or their biologic derivatives. An example of such a disorder is described by Hale et al?
Ernst Christensen, PhD Section of Clinical Genetics 4062 Department of Pediatrics Rigshospitalet DK-2100 Copenhagen, Denmark
REFERENCES
1.
2.
Eriksson BO, Lindstedt S, Nordin I. Hereditary defect in carnitine membrane transport is expressed in skin fibrobiasts. Eur J Pediatr 1988;147:6(~2-3. Hale DE,.Bathsaw ML, Coates PM, et al. Long-chain acyl coenzyme A dehydrogenase deficiency: an inherited cause of nonketotic hypoglycemia. Pediatr Res 1985;19:666-71.
Editorialcorrespondence
there are artifactual changes related to the assessment process itself, they can be detected during that first week. Administering such a trial requires, first, a pharmacy willing to make up the capsules and, second, teachers who are wiffing to complete a behavioral rating scale on a weekly basis for a 6-week period. In addition to ensuring that stimulant medication is not misused, this method can also help to convince hesitant parents about the true effects of the medication and to assess whether a child will benefit by continuing to receive the medication after the assessment process.
Mark Wolraich, MD Department of Pediatrics Division of Developmental Disabilities The University of Iowa Iowa City, IA 52242
903
administration so that evaluator objectivity could be maintained. Perhaps the ideal approach is to vary the trial design to fit the sophistication and biases of the child, family, and teachers involved.
Margaret C. McBride, MD Departments of Pediatrics and Neurology University of Rochester School of Medicine Rochester, N Y 14642
Cardiomyopathy and abnormal carnitine metabolism
REFERENCE
1.
Kazdin AE. Single-case research designs: methods for clinical and applied settings. New York: Oxford University Press, 1982.
Reply To the Editor." Dr. Wolraich's comments are helpful; certainly any of several trial designs can be used to determine methylphenidate efficacy in children with attention deficit disorder. It is true that a trial using a single dose, as I described, risks overlooking patierits who respond only to higher doses. One approach to that problem would be to retest with a higher dose the two thirds of nonresponders who do not show adverse effects on a standard methylphenidate dosage (such as 0.3 mg/kg/dose). In my series of 70 children, that would have involved 13 retests (19%), which is not a formidable task and is perhaps easier than starting with an open trial to determine an effective dose in all children. Parents and teachers who are opposed to medication might find it more difficult to get beyond their prejudices and admit an effect while trying to arrive at the appropriate dose in an open trial. Families of children for whom an optimal dose was not found might be reluctant to enter a double-blind trial. A trial with more than one changeover might help to sort out inconclusive results. However, I have found a 6-week trial difficult to fit in between school vacations, and on occasion, teachers and parents have become lax in their behavioral ratings before the completion of even 4 weeks. The trial that I described is a compromise between the ideal and the practical. A double-blind trial is a good way to determine the continued need for methylphenidate. It might be best to minimize effects of sudden withdrawal of the medication by tapering the dose to half before starting the trial. It was not clear to me whether Dr. Wolraich uses the same trial pattern for each child or whether the pattern varies. I believe that it is extremely important that the physician evaluator continue to conduct the trim in blinded fashion to avoid bias when reviewing comments and questioning the parents about the trial. It would therefore be necessary to vary the order of drug and placebo
To the Editor." Ino et al. (J PEDIATR 1988;113:511-4) described two interesting cases of dilated cardiomyopathy and abnormal carnitine metabolism. However, the abnormal carnitine metabolism was limited to decreased free plasma carnitine levels, whereas total plasma carnitine concentration was normal. Carnitine therapy resulted in upper normal concentrations of both free and total plasma carnitine. Although the carnitine therapy may have been the cause of the reversal of symptoms, a low-fat, high-carbohydrate diet was also started. The authors gave no carnitine values in liver or muscle, although such results would have been valuable for the characterization of the disorder. Dicarboxylic aciduria is the only mentioned abnormal urinary excretion. A more detailed description of the organic acids excreted, as well as of free and total carnitine levels, is missing. The authors compared their patients with reported patients with cardiomyopathy and systemic carnitine deficiency (their references 1 to 6). However, only the patients described in their references 1, 2, and 5 had severely decreased concentrations of both free and total carnitine in both plasma and muscle. The primary defect in those patients could well be the same as that described by Eriksson et al. 1 and also found by us (unpublished results): a hereditary carnitine transport defect that is also expressed in skin fibroblasts. The defect described by Ino et al. is different and could very well be in the transport or oxidation of fatty acids or their biologic derivatives. An example of such a disorder is described by Hale et al?
Ernst Christensen, PhD Section of Clinical Genetics 4062 Department of Pediatrics Rigshospitalet DK-2100 Copenhagen, Denmark
REFERENCES
1.
2.
Eriksson BO, Lindstedt S, Nordin I. Hereditary defect in carnitine membrane transport is expressed in skin fibrobiasts. Eur J Pediatr 1988;147:6(~2-3. Hale DE,.Bathsaw ML, Coates PM, et al. Long-chain acyl coenzyme A dehydrogenase deficiency: an inherited cause of nonketotic hypoglycemia. Pediatr Res 1985;19:666-71.