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The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis
CLINICAL AND LABORATORY OBSERVATIONS
T
The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis
Peter W. Stacpoole, MD, PhD, S. T. Bunch, MD, Richard E. Neiberger, MD, PhD, Leigh Ann Perkins, RN, Ronald Quisling, MD, Alan D. Hutson, PhD, and Melvin Greer, MD
In 27 of 28 children with congenital lactic acidosis, cerebrospinal fluid lactate was higher than venous blood lactate. The mean ± SEM difference between these variables was 2.4 ± 0.3 mmol/L (P = .0001). Girls or patients with pyruvate dehydrogenase deficiency had higher cerebrospinal fluid lactate concentrations than boys or patients with respiratory chain defects or mitochondrial DNA mutations. (J Pediatr 1999;134:99-102)
Enzymatic defects in the pathways of mitochondrial pyruvate oxidation and electron transport are the most common known causes of congenital lactic acidosis.1-3 Sporadic or inherited mutations in genes encoded by nuclear or mitochondrial DNA give rise to deficiencies in the pyruvate dehydrogenase complex or in one or more complexes of the res-
From the Departments of Medicine (Division of Endocrinology and Metabolism), Biochemistry and Molecular Biology, Neurology, Pediatrics, Radiology, and Statistics (Division of Biostatistics), University of Florida, College of Medicine, Gainesville.
Supported by National Institutes of Health grants ES07355, ES07375, and RR00082. Submitted for publication May 8, 1998; revision received Sept 21, 1998; accepted Sept 30, 1998.
Reprint requests: Peter W. Stacpoole, MD, PhD, University of Florida, Health Science Center, PO Box 100226, JHMHC, Gainesville, FL 32610-0336. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/22/94849
piratory chain. Subsequent impairment of mitochondrial oxidative removal of pyruvate fosters reduction in the cytoplasm to lactate. The abnormal accumulation of lactate in tissues and fluids is thus the biochemical hallmark of CLA and is considered a surrogate marker for mitochondrial energy failure.4 The nervous system is uniquely susceptible to inhibition of PDC or the respiratory chain because of its extreme dependence on aerobic glucose metabolism for adenosine triphosphate production. Neurologic defects are the most frequent and devastating clinical manifestations of CLA and are often accompanied by structural abnormalities in the brain and by elevation of brain lactate levels.1,2 Despite the presence of neurologic and/or systemic clinical complications, many patients with biochemically proven CLA exhibit only mild chronic or episodic hyperlactatemia. Although elevated cerebrospinal fluid lactate has been occa-
sionally reported in cases of PDC3,5-7 or respiratory chain3,8,9 deficiency, the frequency of this abnormality and its relevance to systemic lactic acidosis in CLA is uncertain. Moreover, quantitation of CSF lactate is not routinely inCLA CSF MELAS
PDC
Congenital lactic acidosis Cerebrospinal fluid Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Pyruvate dehydrogenase complex
corporated into standard diagnostic paradigms for CLA.1,2 We determined basal venous blood and CSF lactate concentrations in 28 children with CLA caused by PDC or respiratory chain enzyme deficiency.
METHODS Twenty-eight children (15 boys) were investigated as part of a controlled clinical trial of dichloroacetate in CLA (Table). Age at entry, diagnosis, and entry basal venous whole blood and CSF lactate concentrations are given in the Table. Before entry, each patient was required to have, in the preceding 6 months, at least 3 basal lactate levels ≥2.75 mmol/L (venous whole blood or CSF) or ≥2.0 mmol/L 99
STACPOOLE ET AL
THE JOURNAL OF PEDIATRICS JANUARY 1999
Table. Age at entry, diagnosis, and entry basal venous whole blood and CSF lactate concentrations
Lactate concentration (mmol/L) Patient No. Male 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Female 1 2 3 4 5 6 7 8 9 10 11 12 13
Diagnosis
Age (y)
Blood
CSF
OXPHOS RCC I RCC II RCC I, IV RCC IV RCC II RCC I RCC I, IV MELAS PDC RCC I, IV RCC IV RCC IV MELAS RCC 1 Mean Range
1 2⁄12 1 5⁄12 1 6⁄12 1 6⁄12 1 10⁄12 2 10⁄12 3 11⁄12 5 10⁄12 6 6 7⁄12 6 11⁄12 7 1⁄12 7 1⁄12 13 1⁄12 19 3⁄12 5 9⁄12 1 2⁄12-19 3⁄12
5.5 0.4 0.9 4.4 1.5 1.3 1.3 1.2 3.8 5.1 3.7 1.3 1.7 2.4 1.8 2.4 0.4-5.5
PDC PDC RCC I RCC I, III, IV PDC PDC PDC MERRF RCC I, IV RCC IV PDC RCC IV MELAS Mean
⁄12 1 8⁄12 1 9⁄12 1 10⁄12 2 4⁄12 3 9⁄12 3 9⁄12 4 4⁄12 4 7⁄12 5 5⁄12 5 9⁄12 9 8⁄12 19 2⁄12 5 0⁄12
3.5 1.6 2.9 1.7 0.6 1.9 1.5 3.5 2.2 1.0 1.1 1.6 1.1 1.9
7.8 4.6 6.4 5.9 2.4 4.3 5.7 4.4 3.4 3.8 5.3 4.1 2.0 4.6
0.6-3.5
2.0-7.8
Range
10
⁄ -19 2⁄12
10 12
6.5 0.9 1.2 4.8 5.1 1.6 3.0 6.2 5.8 11.4 3.0 3.8 3.6 5.5 4.5 4.5 0.9-11.4
OXPHOS, Generalized depression of respiratory chain enzymes; RCC, respiratory chain complex; MERRF, myotonic epilepsy and ragged red fibers.
(arterial whole blood). In addition, the diagnosis of CLA was established by enzymatic or molecular genetic analysis of cells or DNA obtained from cultured skin fibroblasts, skeletal muscle, or peripheral blood leukocytes. Magnetic resonance imaging of the brain was performed in each patient within 1 year of study entry. Extensive neuro100
logic motor and behavioral evaluations were conducted at entry and were compared with age-appropriate, normative data. Patients were hospitalized in the General Clinical Research Center of Shands Hospital, and the study was approved by the University of Florida Institutional Review Board.
Basal venous blood (0.5 mL) was obtained from an indwelling central or peripheral venous catheter at least 4 hours after a meal and transferred to a chilled Vacutainer tube (Becton Dickinson) containing sodium fluoride and potassium oxalate. The sample was immediately assayed for whole blood lactate with a YSI glucose/lactate analyzer (Yellow Springs Instrument, Yellow Springs, Ohio). Basal CSF (1 mL) was collected by lumbar puncture and was immediately assayed for lactate with a YSI analyzer. No CSF sample obtained for lactate determination had >10 leukocytes or erythrocytes per cubic millimeter. Univariate data are presented as mean ± SEM. Correlations were examined by using Pearson correlation coefficients. Regression analysis and Student paired t tests were used to test for differences between CSF and blood lactate on data from the 28 subjects in whom CSF lactate was measured. Covariate adjustments were made in the regression analysis for age, gender, biochemical defect, and gender by biochemical defect interaction.
RESULTS Seven patients (1 boy) had PDC deficiency, 17 patients (12 boys) had defects in one or more respiratory chain complexes, and 4 patients (2 boys) had an mDNA point mutation commonly associated with the syndromes of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes or myotonic epilepsy and ragged red fibers. All subjects except a 19-year-old woman with MELAS had mild to marked psychomotor retardation. Nine patients had a seizure disorder unrelated to fevers diagnosed before entry into the study, and one had experienced stroke-like episodes. Cortical atrophy (14 patients) and structural brain abnormalities, including hypogenesis or agenesis of the corpus callosum (4 patients), were observed by brain mag-
STACPOOLE ET AL
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 1 netic resonance imaging in the majority of subjects. Only 5 patients had normal findings on brain magnetic resonance imaging at the time of entry. Linear height was below the 5th percentile in 25 patients. Six had elevated levels of serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, or both. Fourteen had findings consistent with proximal renal tubular damage (eg, glycosuria, amino aciduria, hyperphosphaturia), and 7 children had Wolff-ParkinsonWhite conduction abnormality on electrocardiogram. Thus a majority of patients manifested both central nervous system and systemic complications typical of their primary metabolic disease. In healthy adults, or in children without serious neurologic or systemic illness,10 the basal venous blood lactate concentration is usually ≤1.0 mmol/L and the CSF lactate concentration is ~1.3 mmol/L. According to these criteria, 4 children had a normal blood lactate concentration, and one child had a normal CSF lactate concentration (Table). In 27 of the 28 subjects, the lactate concentration was higher in CSF than in blood. The mean ± SEM difference between CSF and blood lactate concentrations was 2.4 ± 0.3 mmol/L (P = .001) for the entire group. Blood and CSF lactate levels were significantly correlated (r = 0.64; P = .0002) for the group. The correlation between blood and CSF lactate concentrations by diagnosis was r = 0.45 (P = .0001) for PDC deficiency and was r = 0.55 (P = .01) for respiratory chain defects (including mDNA mutations). An exploratory analysis was performed on the possible interaction between CSF lactate concentration and biochemical diagnosis. Subjects with PDC deficiency were more likely to have an elevated CSF lactate concentration for a given blood lactate concentration, compared with subjects with respiratory chain defects (Figure). Regression analysis showed that the estimated (CSF-blood) lactate difference was greatest for the single male subject with PDC deficiency. Moreover,
Figure. Correlation between basal venous blood lactate and CSF lactate in patients with PDC deficiency (closed circles, 7 patients) or respiratory chain deficiency (open circles, 21 patients). Also included in this latter category are patients with proven mDNA mutations.
the magnitude of the CSF-blood lactate difference in the PDC deficiency group was larger by 1.82 ± 0.6 mmol/L relative to the CSF-blood lactate difference in the group with respiratory chain defects (P = .0009).
DISCUSSION These data demonstrate, in a large group of children with neurologic and systemic complications of CLA, that the CSF lactate level is more likely to be elevated and to a greater degree than the corresponding basal venous blood level. Although CSF and blood lactate concentrations are highly correlated, the CSF-blood lactate difference is significantly greater in children with PDC deficiency than in the more heterogeneous group of individuals with respiratory chain defects or mDNA mutations (MELAS, myotonic
epilepsy and ragged red fibers) associated with respiratory chain enzyme deficiencies.2 The cause of this discrepancy remains to be determined. CSF lactate is considered to be derived principally from glycolysis by brain cells, rather than from uptake from the circulation, and is thus considered to be a better indicator of brain metabolism than is blood lactate.11 Indeed, blood and CSF lactate equilibrate slowly and vary independently under various physiologic or pathologic conditions, in part because of the apparently low rate of permeation from brain tissue to venous blood and the low rate of lactate extraction from the circulation.12 Our findings and those of others6,8 emphasize several important clinical points regarding the evaluation of patients with CLA. First, CSF lactate is frequently elevated in this disease, regardless of the etiology of the mitochondrial energy failure. Second, CSF 101
STACPOOLE ET AL
THE JOURNAL OF PEDIATRICS JANUARY 1999
lactate, compared with venous blood lactate, is a better discriminator of the presence of central nervous system involvement. Whether it accurately tracks disease progression remains to be elucidated. Third, CSF lactate concentrations are higher in patients with PDC deficiency than in those with respiratory chain defects. Finally, for asyet unknown reasons, CSF lactate appears to correlate significantly with gender in children with CLA; girls average higher metabolite levels than boys. On the basis of these findings, we recommend that the determination of CSF lactate be incorporated into the diagnostic evaluation of patients suspected of having CLA and that patient gender be considered when interpreting CSF lactate concentration.
REFERENCES 1. Robinson BH. Lactic acidemia (disorders of pyruvate carboxylase, pyruvate
2.
3.
4.
5.
6.
dehydrogenase). In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw-Hill; 1995. p. 1479-99. Shoffner JM, Wallace DC. Oxidative phosphorylation diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw-Hill; 1995. p. 1535-609. Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS. Treatment of congenital lactic acidosis with dichloroacetate: a review. Arch Dis Child 1997;77:535-41. Stacpoole PW. Lactic acidosis and other mitochondrial disorders. Metabolism 1997;46:306-21. Prick M, Gabreëls F, Renier W, Trijbels F, Jaspar H, Lamers K, Kok J. Pyruvate dehydrogenase deficiency restricted to brain. Neurology 1981;31:398-404. Brown GK, Haan EA, Kirby DM, Scholem RD, Wraith JE, Rogers JG, Danks DM. “Cerebral” lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis. Eur J Pediatr 1988; 147:10-4.
7. Kerr DS, Berry SA, Lusk MM, Ho L, Patel MS. A deficiency of both subunits of pyruvate dehydrogenase which is not expressed in fibroblasts. Pediatr Res 1988;24:95-100. 8. Kuriyama M, Suehara M, Marume N, Osame M, Igata A. High CSF lactate and pyruvate content in Kearns-Sayre syndrome. Neurology 1984;34:253-5. 9. Jackson MJ, Schaefer JA, Johnson MA, Morris AAM, Turnbull DM, Bindoff LA. Presentation and clinical investigation of mitochondrial respiratory chain disease. A study of 51 patients. Brain 1995;118:339-59. 10. Maaswinkel-Mooij PD, Van den Boget C, Scholte HR, Onkenhaut W, Brederoo P, Poorthuis BJHM. Depletion of mitochondrial DNA in the liver of a patient with lactic acidemia and hypoketotic hypoglycemia. J Pediatr 1996;128:679-83. 11. Plum F, Posner JB. Blood and cerebrospinal fluid lactate during hyperventilation. Am J Physiol 1967;212: 864-70. 12. LaManna JC, Harrington JF, Vendel LM, Abi-Saleh K, Lust WD, Harik SI. Regional blood-brain lactate influx. Brain Res 1993;614:164-70.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of The Journal of Pediatrics for the preceding 5 years are maintained and are available for purchase from Mosby until inventory is depleted, at a cost of $15.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues may be purchased from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.
102
T
The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis
Peter W. Stacpoole, MD, PhD, S. T. Bunch, MD, Richard E. Neiberger, MD, PhD, Leigh Ann Perkins, RN, Ronald Quisling, MD, Alan D. Hutson, PhD, and Melvin Greer, MD
In 27 of 28 children with congenital lactic acidosis, cerebrospinal fluid lactate was higher than venous blood lactate. The mean ± SEM difference between these variables was 2.4 ± 0.3 mmol/L (P = .0001). Girls or patients with pyruvate dehydrogenase deficiency had higher cerebrospinal fluid lactate concentrations than boys or patients with respiratory chain defects or mitochondrial DNA mutations. (J Pediatr 1999;134:99-102)
Enzymatic defects in the pathways of mitochondrial pyruvate oxidation and electron transport are the most common known causes of congenital lactic acidosis.1-3 Sporadic or inherited mutations in genes encoded by nuclear or mitochondrial DNA give rise to deficiencies in the pyruvate dehydrogenase complex or in one or more complexes of the res-
From the Departments of Medicine (Division of Endocrinology and Metabolism), Biochemistry and Molecular Biology, Neurology, Pediatrics, Radiology, and Statistics (Division of Biostatistics), University of Florida, College of Medicine, Gainesville.
Supported by National Institutes of Health grants ES07355, ES07375, and RR00082. Submitted for publication May 8, 1998; revision received Sept 21, 1998; accepted Sept 30, 1998.
Reprint requests: Peter W. Stacpoole, MD, PhD, University of Florida, Health Science Center, PO Box 100226, JHMHC, Gainesville, FL 32610-0336. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/22/94849
piratory chain. Subsequent impairment of mitochondrial oxidative removal of pyruvate fosters reduction in the cytoplasm to lactate. The abnormal accumulation of lactate in tissues and fluids is thus the biochemical hallmark of CLA and is considered a surrogate marker for mitochondrial energy failure.4 The nervous system is uniquely susceptible to inhibition of PDC or the respiratory chain because of its extreme dependence on aerobic glucose metabolism for adenosine triphosphate production. Neurologic defects are the most frequent and devastating clinical manifestations of CLA and are often accompanied by structural abnormalities in the brain and by elevation of brain lactate levels.1,2 Despite the presence of neurologic and/or systemic clinical complications, many patients with biochemically proven CLA exhibit only mild chronic or episodic hyperlactatemia. Although elevated cerebrospinal fluid lactate has been occa-
sionally reported in cases of PDC3,5-7 or respiratory chain3,8,9 deficiency, the frequency of this abnormality and its relevance to systemic lactic acidosis in CLA is uncertain. Moreover, quantitation of CSF lactate is not routinely inCLA CSF MELAS
PDC
Congenital lactic acidosis Cerebrospinal fluid Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Pyruvate dehydrogenase complex
corporated into standard diagnostic paradigms for CLA.1,2 We determined basal venous blood and CSF lactate concentrations in 28 children with CLA caused by PDC or respiratory chain enzyme deficiency.
METHODS Twenty-eight children (15 boys) were investigated as part of a controlled clinical trial of dichloroacetate in CLA (Table). Age at entry, diagnosis, and entry basal venous whole blood and CSF lactate concentrations are given in the Table. Before entry, each patient was required to have, in the preceding 6 months, at least 3 basal lactate levels ≥2.75 mmol/L (venous whole blood or CSF) or ≥2.0 mmol/L 99
STACPOOLE ET AL
THE JOURNAL OF PEDIATRICS JANUARY 1999
Table. Age at entry, diagnosis, and entry basal venous whole blood and CSF lactate concentrations
Lactate concentration (mmol/L) Patient No. Male 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Female 1 2 3 4 5 6 7 8 9 10 11 12 13
Diagnosis
Age (y)
Blood
CSF
OXPHOS RCC I RCC II RCC I, IV RCC IV RCC II RCC I RCC I, IV MELAS PDC RCC I, IV RCC IV RCC IV MELAS RCC 1 Mean Range
1 2⁄12 1 5⁄12 1 6⁄12 1 6⁄12 1 10⁄12 2 10⁄12 3 11⁄12 5 10⁄12 6 6 7⁄12 6 11⁄12 7 1⁄12 7 1⁄12 13 1⁄12 19 3⁄12 5 9⁄12 1 2⁄12-19 3⁄12
5.5 0.4 0.9 4.4 1.5 1.3 1.3 1.2 3.8 5.1 3.7 1.3 1.7 2.4 1.8 2.4 0.4-5.5
PDC PDC RCC I RCC I, III, IV PDC PDC PDC MERRF RCC I, IV RCC IV PDC RCC IV MELAS Mean
⁄12 1 8⁄12 1 9⁄12 1 10⁄12 2 4⁄12 3 9⁄12 3 9⁄12 4 4⁄12 4 7⁄12 5 5⁄12 5 9⁄12 9 8⁄12 19 2⁄12 5 0⁄12
3.5 1.6 2.9 1.7 0.6 1.9 1.5 3.5 2.2 1.0 1.1 1.6 1.1 1.9
7.8 4.6 6.4 5.9 2.4 4.3 5.7 4.4 3.4 3.8 5.3 4.1 2.0 4.6
0.6-3.5
2.0-7.8
Range
10
⁄ -19 2⁄12
10 12
6.5 0.9 1.2 4.8 5.1 1.6 3.0 6.2 5.8 11.4 3.0 3.8 3.6 5.5 4.5 4.5 0.9-11.4
OXPHOS, Generalized depression of respiratory chain enzymes; RCC, respiratory chain complex; MERRF, myotonic epilepsy and ragged red fibers.
(arterial whole blood). In addition, the diagnosis of CLA was established by enzymatic or molecular genetic analysis of cells or DNA obtained from cultured skin fibroblasts, skeletal muscle, or peripheral blood leukocytes. Magnetic resonance imaging of the brain was performed in each patient within 1 year of study entry. Extensive neuro100
logic motor and behavioral evaluations were conducted at entry and were compared with age-appropriate, normative data. Patients were hospitalized in the General Clinical Research Center of Shands Hospital, and the study was approved by the University of Florida Institutional Review Board.
Basal venous blood (0.5 mL) was obtained from an indwelling central or peripheral venous catheter at least 4 hours after a meal and transferred to a chilled Vacutainer tube (Becton Dickinson) containing sodium fluoride and potassium oxalate. The sample was immediately assayed for whole blood lactate with a YSI glucose/lactate analyzer (Yellow Springs Instrument, Yellow Springs, Ohio). Basal CSF (1 mL) was collected by lumbar puncture and was immediately assayed for lactate with a YSI analyzer. No CSF sample obtained for lactate determination had >10 leukocytes or erythrocytes per cubic millimeter. Univariate data are presented as mean ± SEM. Correlations were examined by using Pearson correlation coefficients. Regression analysis and Student paired t tests were used to test for differences between CSF and blood lactate on data from the 28 subjects in whom CSF lactate was measured. Covariate adjustments were made in the regression analysis for age, gender, biochemical defect, and gender by biochemical defect interaction.
RESULTS Seven patients (1 boy) had PDC deficiency, 17 patients (12 boys) had defects in one or more respiratory chain complexes, and 4 patients (2 boys) had an mDNA point mutation commonly associated with the syndromes of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes or myotonic epilepsy and ragged red fibers. All subjects except a 19-year-old woman with MELAS had mild to marked psychomotor retardation. Nine patients had a seizure disorder unrelated to fevers diagnosed before entry into the study, and one had experienced stroke-like episodes. Cortical atrophy (14 patients) and structural brain abnormalities, including hypogenesis or agenesis of the corpus callosum (4 patients), were observed by brain mag-
STACPOOLE ET AL
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 1 netic resonance imaging in the majority of subjects. Only 5 patients had normal findings on brain magnetic resonance imaging at the time of entry. Linear height was below the 5th percentile in 25 patients. Six had elevated levels of serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, or both. Fourteen had findings consistent with proximal renal tubular damage (eg, glycosuria, amino aciduria, hyperphosphaturia), and 7 children had Wolff-ParkinsonWhite conduction abnormality on electrocardiogram. Thus a majority of patients manifested both central nervous system and systemic complications typical of their primary metabolic disease. In healthy adults, or in children without serious neurologic or systemic illness,10 the basal venous blood lactate concentration is usually ≤1.0 mmol/L and the CSF lactate concentration is ~1.3 mmol/L. According to these criteria, 4 children had a normal blood lactate concentration, and one child had a normal CSF lactate concentration (Table). In 27 of the 28 subjects, the lactate concentration was higher in CSF than in blood. The mean ± SEM difference between CSF and blood lactate concentrations was 2.4 ± 0.3 mmol/L (P = .001) for the entire group. Blood and CSF lactate levels were significantly correlated (r = 0.64; P = .0002) for the group. The correlation between blood and CSF lactate concentrations by diagnosis was r = 0.45 (P = .0001) for PDC deficiency and was r = 0.55 (P = .01) for respiratory chain defects (including mDNA mutations). An exploratory analysis was performed on the possible interaction between CSF lactate concentration and biochemical diagnosis. Subjects with PDC deficiency were more likely to have an elevated CSF lactate concentration for a given blood lactate concentration, compared with subjects with respiratory chain defects (Figure). Regression analysis showed that the estimated (CSF-blood) lactate difference was greatest for the single male subject with PDC deficiency. Moreover,
Figure. Correlation between basal venous blood lactate and CSF lactate in patients with PDC deficiency (closed circles, 7 patients) or respiratory chain deficiency (open circles, 21 patients). Also included in this latter category are patients with proven mDNA mutations.
the magnitude of the CSF-blood lactate difference in the PDC deficiency group was larger by 1.82 ± 0.6 mmol/L relative to the CSF-blood lactate difference in the group with respiratory chain defects (P = .0009).
DISCUSSION These data demonstrate, in a large group of children with neurologic and systemic complications of CLA, that the CSF lactate level is more likely to be elevated and to a greater degree than the corresponding basal venous blood level. Although CSF and blood lactate concentrations are highly correlated, the CSF-blood lactate difference is significantly greater in children with PDC deficiency than in the more heterogeneous group of individuals with respiratory chain defects or mDNA mutations (MELAS, myotonic
epilepsy and ragged red fibers) associated with respiratory chain enzyme deficiencies.2 The cause of this discrepancy remains to be determined. CSF lactate is considered to be derived principally from glycolysis by brain cells, rather than from uptake from the circulation, and is thus considered to be a better indicator of brain metabolism than is blood lactate.11 Indeed, blood and CSF lactate equilibrate slowly and vary independently under various physiologic or pathologic conditions, in part because of the apparently low rate of permeation from brain tissue to venous blood and the low rate of lactate extraction from the circulation.12 Our findings and those of others6,8 emphasize several important clinical points regarding the evaluation of patients with CLA. First, CSF lactate is frequently elevated in this disease, regardless of the etiology of the mitochondrial energy failure. Second, CSF 101
STACPOOLE ET AL
THE JOURNAL OF PEDIATRICS JANUARY 1999
lactate, compared with venous blood lactate, is a better discriminator of the presence of central nervous system involvement. Whether it accurately tracks disease progression remains to be elucidated. Third, CSF lactate concentrations are higher in patients with PDC deficiency than in those with respiratory chain defects. Finally, for asyet unknown reasons, CSF lactate appears to correlate significantly with gender in children with CLA; girls average higher metabolite levels than boys. On the basis of these findings, we recommend that the determination of CSF lactate be incorporated into the diagnostic evaluation of patients suspected of having CLA and that patient gender be considered when interpreting CSF lactate concentration.
REFERENCES 1. Robinson BH. Lactic acidemia (disorders of pyruvate carboxylase, pyruvate
2.
3.
4.
5.
6.
dehydrogenase). In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw-Hill; 1995. p. 1479-99. Shoffner JM, Wallace DC. Oxidative phosphorylation diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th ed. New York: McGraw-Hill; 1995. p. 1535-609. Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS. Treatment of congenital lactic acidosis with dichloroacetate: a review. Arch Dis Child 1997;77:535-41. Stacpoole PW. Lactic acidosis and other mitochondrial disorders. Metabolism 1997;46:306-21. Prick M, Gabreëls F, Renier W, Trijbels F, Jaspar H, Lamers K, Kok J. Pyruvate dehydrogenase deficiency restricted to brain. Neurology 1981;31:398-404. Brown GK, Haan EA, Kirby DM, Scholem RD, Wraith JE, Rogers JG, Danks DM. “Cerebral” lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis. Eur J Pediatr 1988; 147:10-4.
7. Kerr DS, Berry SA, Lusk MM, Ho L, Patel MS. A deficiency of both subunits of pyruvate dehydrogenase which is not expressed in fibroblasts. Pediatr Res 1988;24:95-100. 8. Kuriyama M, Suehara M, Marume N, Osame M, Igata A. High CSF lactate and pyruvate content in Kearns-Sayre syndrome. Neurology 1984;34:253-5. 9. Jackson MJ, Schaefer JA, Johnson MA, Morris AAM, Turnbull DM, Bindoff LA. Presentation and clinical investigation of mitochondrial respiratory chain disease. A study of 51 patients. Brain 1995;118:339-59. 10. Maaswinkel-Mooij PD, Van den Boget C, Scholte HR, Onkenhaut W, Brederoo P, Poorthuis BJHM. Depletion of mitochondrial DNA in the liver of a patient with lactic acidemia and hypoketotic hypoglycemia. J Pediatr 1996;128:679-83. 11. Plum F, Posner JB. Blood and cerebrospinal fluid lactate during hyperventilation. Am J Physiol 1967;212: 864-70. 12. LaManna JC, Harrington JF, Vendel LM, Abi-Saleh K, Lust WD, Harik SI. Regional blood-brain lactate influx. Brain Res 1993;614:164-70.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of The Journal of Pediatrics for the preceding 5 years are maintained and are available for purchase from Mosby until inventory is depleted, at a cost of $15.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby, Inc., Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO 63146-3318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues may be purchased from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.
102