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Adverse behavioral reactions in children treated with carbamazepine (Tegretol)
Volume 101 Number 5
tion of carnitine in the picomol range, Clin Chim Acta 37:235, 1972. 12. Michell ME: Carnitine metabolism in human subjects. I. Normal metabolism, Am J Clin Nutr 31:293, 1978. 13. Coulter DL, and Allen RJ" Secondary hyperammonemia: A possible mechanism for valproate encephalopathy, Lancet 1:1310, 1980.
Carnitine deficiency and hyperammonemia
785
14. Grusky JA, and Rosenberg LE: Inhibition of hepatic mitochondrial carbamylphosphate synthetase (CPS I) by acyl CoA esters: Possible mechanism of hyperammonemia in the organic acidemias, Pediatr Res 13:475, 1979. 15. Coude FX, Ravier D, Cathelineau L, Grimber G, Parvy P, and Kamoun PP: Letter to editor: A mechanism for valproateinduced hyperammonemia, Pediatr Res 15:974, 1981.
Clinical and laboratory observations Adverse behavioral reactions in children treated with carbamazepine (Tegretol) Faye S. Silverstein, M.D.C.M., Mary Ann Parrish, R.N., P.N.P., and Michael V. Johnston, M.D. A n n Arbor, Mich. CARBAMAZEPINE (Tegretol) is an effective anticonvulsant for generalized and partial seizures. Its use in children has grown considerably since it was given approval by the Food and Drug Administration in 1974.1,2 Major commonly cited advantages of the drug include its relative freedom from cosmetic and behavioral side effects? Indeed; earbamazepine has been reported to have beneficial effects on mood and cognitive functioning,4,5 especially when it can be substituted for more sedating barbiturate drugs. As a result Of a survey of parents' attitudes about various drugs administered to their children with epilepsy, we became aware of several children who displayed episodes of bizarre behavior while taking carbamazepine. Subsequently, we reviewed our clinic's experience with more than 200 children given this drug. We identified seven patients in whom introduction of the drug was From the Section of Pediatric NeurOlogy, University of Michigan Medical Center and Center for Human Growth and Developmont. Supported by TIDA Award NS 06054-02 (M. V. J.) and United Cerebral Palsy Research and Education Foundation Fellowship CF 106-81 (F. S. S.). Reprint address: Michael V. Johnston, M.D,, Neuroscience Laboratory Bldg., University of Michigan, 1103 E. Huron, Ann Arbor, MI 48109.
0022-3476/82/110785+03500.30/0 9 1982 The C. V. Mosby Co.
followed by acute adverse behavioral changes. Although the children had no obvious lasting effects, the episodes were sometimes dramatic and alarming to parents and physicians. RESULTS The clinical data describing these patients are summarized in the Table. Most had difficulty sleeping and were agitated. Several noticed difficulty thinking clearly. Three of the reactions were particularly dramatic: Patient 1 had developmental regression and irritability, Patient 2 had psychotic features, and Patient 3 had delirium. It is noteworthy that these relatively severe reactions occurred in children who were mentally retarded; The clinical presentations were confusing in the first three patients and in several others, because the abnormal behavior occurred at carbamezepine concentrations not usually considered to be in the toxic range (> 12~g/ml.) The difficulties this unexpected reaction may cause are evident in Patient 3. Carbamazepine therapy was initiated for seizures poorly controlled by phenobarbital, and the patient was admitted to a hospital one week later. On admission the carbamazepine concentration was 2.5 #g/ml and the phenobarbital concentration was 18 #g/ml. The dose of carbamazepine was raised from 300 to 600 mg/day when the low carbamazepine concentration was noted.
786
Clinical and laboratory observations
The Journal of Pediatrics November 1982
Table. Patients who experienced adverse behavioral reactions to carbamazepine (Tegretol)
Patient
Age ( y r ) Sex
Diagnosis
Onset after starting CBZ
Dose (mg/kg)
CBZ concentration* (~g/ml)
Several weeks
10
9.3, 7.3
Absence seizures, mental retardation
10 days
10
8.9
M
Generalized tonic-clonic seizures, mild mental retardation
8 days
6 for l wk; then 12
6.0
14
M
Generalized tonic-clonic seizures
5
12
F
Partial complex seizures
6
18
M
7
9
F
Generalized tonic-clonic SeizUres, mental retardation Mixed seizure disorder
1
6
F
Mixed seizure disorder, mental retardation
2
17
F
3
i1
4
Third week
4 days
10 for 4 days; then 20
11.8
8
ND
Several weeks
10
ND
Several weeks
10 for 2 wk, then 20
5.8
Behavioral changes and course
Extreme irritability, developmental regression; returned to baseline on CBZ withdrawal Agitation, obsessive thoughts, auditory hallucinations; resolved, on withdrawal Incoherent, agitated, combative; resolved on CBZ withdrawal; CBZ was reintroduced slowly later without problems Felt "spaced out," had to "strain to think," marked personality change; resolved when dose lowered Insomnia, looked "bewildered," felt like "'feet weren't attached to the ground"; resolved at lower dose Aggressive outbursts, biting and fighting; resolved on withdrawal Hyperactivity, insomnia, anger and "paranoia"; resolved on withdrawal
CBZ, carbamazepine;ND, not done. *Usual therapeutic range 4 to 12 t~g/rnl.
Within 24 hours the patient became delirious and combative. He was given 360 mg phenobarbital intravenously Without effect, but he did become calmer after 2 mg haloperidol was given intramuscularly. The carbamazepine concentration 36 hours after the dose increase was 6 # g / m l , and a lumbar puncture yielded normal fluid. Withdrawal of carbamazepine was associated with rapid clearing of the delirium, although seizures became more frequent. These were eventually partially controlled with mephobarbital and valproic acid. In addition to these seven patients, we are aware of two children, cared for by other pediatricians, with similar behavioral changes probably related to carbamazepine. DISCUSSION These patients all had a relatively acute disturbance of neuropsychologic functioning temporally related to introduction or increase in the dose of carbamazepine. Several children had reacted adversely to other anticonvulsant drugs, but the parents identified the reactions to carbamazepine as distinct from the previous experiences. Although
transient dizziness, drowsiness, and incoordination have been described in patients of all ages starting treatment with the drugr this more complex and severe reaction in children has not been described. Its recognition is importanic because the symptoms might otherwise prompt extensive diagnostic evaluation for other causes of encephalopathy (e.g., complex partial status epilepticus). Furthermore, failure tO recognize this reaction promptly may cause considerable confusion in parents who expect the drug to be "good" for behavior. These seven patients were gathered from a total group of approximately 200 children receiving carbamazepine, an incidence of about 3%; however, the exact incidence remains to be determined. Four of the patients were mentally retarded, so these reactions may be more frequent in patients with preexisting central nervous system problems. 7 The pharmacologic mechanism for behavioral toxicity could be related to the tricyclic structure of carbamazepine, which makes it unique among clinically useful anticonvulsants. Chemically related tricyclic antidepres-
Volume 10l Number 5
sant drugs may produce a similar state of confusion, with hallucinations, disorientation, anxiety, agitation, insomnia, and exacerbation of psychosis in a few susceptible individuals. 8 Many studies have suggested that carbamazepine has beneficial psychotr0Pic actions, so it is not surprising that it may also produce occasional adverse emotional reactions. Until it is more clear which factors may predispose children to behavioral toxicity, it may be prudent to initiate therapy cautiously and at a low dose in certain patients, especially those with preexisting psychopathologic problems or retardation. Five of our seven patients were eventually able to tolerate the drug when it was reintroduced slowly. This experience suggests that if carbamazepine is needed for seizure control, a previous adverse behavioral reaction is not an absolute contraindication to another careful trial.
Clinical and laboratory observations
787
REFERENCES 1. Huf R, and Schain R: Long-term experiences with carbamazepine (Tegretol) in children with seizures, J PEDIATR97:310, 1980. 2. Wallace S: Carbamazepine in childhood seizures, Dev Med Child Neurol 20:223, 1978. 3. Johnston MV, and Freeman JM: Pharmacologic advances in seizure control Pediatr Clin North Am 28:179, 1981. 4. Dodrill CB, and Troupin AS: Psychotropic effects of carbamazepine in epilepsy: A double blind comparison with phenytoin, Neurology 27:1023, 1977. 5. Sillanpaa M: Carbamazepine: Pharmacology and clinical uses, Acta Neurol Scand [Suppl] 88:97, 1981. 6. Livingston S, Pauli LL, and Berman W: Carbamazepine (Tegretol) in epilepsy, Dis Nerv Syst 35:103, 1974. 7. Stores A: Behavioral effects of antiepileptic drugs, Dev Med Child Neurol 17:647, 1975. 8. Goodman A, and Gilman L: The pharmacologic basis of therapeutics, New York, 1980, Macmillan, Inc.
Tolmetin sodium in the management of nephrogenic diabetes
insipidus Robert L. Chevalier, M.D., and Alan D. Rogol, M.D., Ph.D., Charlottesville, Va.
NEPHROGENIC DIABETES INSIPIDUS, a congenital disorder characterized by a lack of response of the collecting duct to circulating antidiuretic hormone, is a rare but debilitating condition in the small child. The generally recommended management with sodium restriction and diuretic therapy is usually unsuccessful because compliance with the low-salt diet is poor and diuretics are often ineffective, x Recent studies of the mechanism of renal water handling have shown that prostaglandins exert an inhibitory effect on the action of vasopressin to enhance collecting duct permeability. 2 Prostaglandin synthesis inhibitors have been tested in patients with NDI, with encouraging results? 4 However, virtually all nonsteroidal anti-inflammatory drugs have significant systemic toxicity and are not recommended for use in children. This From the Departments of Pediatrics and Pharmacology, University of Virginia School of Medicine. Reprint address: Robert L. Chevalier, M.D., Department of Pediatrics, Box 386, University of Virginia Medical Center, Charlottesville, VA 22908.
0022-3476/82/110787+03500.30/0 @ 1982 The C. V. Mosby Co.
prompted us to treat a child with N D I using tolmetin sodium (Tolectin), an inhibitor of prostaglandin synthesis with proved safety in children 2 years of age and older. 6
I
NDI: cAMP:
nephrogenic diabetes insipidus cyclic adenosine monophosphate
|
]
I
CASE REPORT The patient, a 39/12-year-old white boy, was diagnosed as having NDI at 6 months of age, but showed no response to a saltrestricted diet and hydrochlorothiazide. At 29/12 years of age he was admitted to the University of Virginia Medical Center for evaluation. Physical examination revealed a thin child with a height of 80 cm (below the fifth percentile), weight of 11 kg (below the fifth percentile), weight-for-height at the tenth percentile, blood pressure of 95/50 mm Hg, and pulse 105. There were no physical abnormalities. Urinalysis revealed a specific gravity of 1.002, pH 6, negative protein and glucose, and a benign sediment. Hematocrit was 37%, and electrolyte values were sodium 139 mEq/L, potassium 3.7 mEq/L, chloride 105 mEq/L, CO2 26 mEq/L, blood urea nitrogen 9 mg/dl, creatinine 0.7 mg/dl, calcium 10.3 mg/dl, and phosphate 4.4 mg/dl. Renal sonogram
tion of carnitine in the picomol range, Clin Chim Acta 37:235, 1972. 12. Michell ME: Carnitine metabolism in human subjects. I. Normal metabolism, Am J Clin Nutr 31:293, 1978. 13. Coulter DL, and Allen RJ" Secondary hyperammonemia: A possible mechanism for valproate encephalopathy, Lancet 1:1310, 1980.
Carnitine deficiency and hyperammonemia
785
14. Grusky JA, and Rosenberg LE: Inhibition of hepatic mitochondrial carbamylphosphate synthetase (CPS I) by acyl CoA esters: Possible mechanism of hyperammonemia in the organic acidemias, Pediatr Res 13:475, 1979. 15. Coude FX, Ravier D, Cathelineau L, Grimber G, Parvy P, and Kamoun PP: Letter to editor: A mechanism for valproateinduced hyperammonemia, Pediatr Res 15:974, 1981.
Clinical and laboratory observations Adverse behavioral reactions in children treated with carbamazepine (Tegretol) Faye S. Silverstein, M.D.C.M., Mary Ann Parrish, R.N., P.N.P., and Michael V. Johnston, M.D. A n n Arbor, Mich. CARBAMAZEPINE (Tegretol) is an effective anticonvulsant for generalized and partial seizures. Its use in children has grown considerably since it was given approval by the Food and Drug Administration in 1974.1,2 Major commonly cited advantages of the drug include its relative freedom from cosmetic and behavioral side effects? Indeed; earbamazepine has been reported to have beneficial effects on mood and cognitive functioning,4,5 especially when it can be substituted for more sedating barbiturate drugs. As a result Of a survey of parents' attitudes about various drugs administered to their children with epilepsy, we became aware of several children who displayed episodes of bizarre behavior while taking carbamazepine. Subsequently, we reviewed our clinic's experience with more than 200 children given this drug. We identified seven patients in whom introduction of the drug was From the Section of Pediatric NeurOlogy, University of Michigan Medical Center and Center for Human Growth and Developmont. Supported by TIDA Award NS 06054-02 (M. V. J.) and United Cerebral Palsy Research and Education Foundation Fellowship CF 106-81 (F. S. S.). Reprint address: Michael V. Johnston, M.D,, Neuroscience Laboratory Bldg., University of Michigan, 1103 E. Huron, Ann Arbor, MI 48109.
0022-3476/82/110785+03500.30/0 9 1982 The C. V. Mosby Co.
followed by acute adverse behavioral changes. Although the children had no obvious lasting effects, the episodes were sometimes dramatic and alarming to parents and physicians. RESULTS The clinical data describing these patients are summarized in the Table. Most had difficulty sleeping and were agitated. Several noticed difficulty thinking clearly. Three of the reactions were particularly dramatic: Patient 1 had developmental regression and irritability, Patient 2 had psychotic features, and Patient 3 had delirium. It is noteworthy that these relatively severe reactions occurred in children who were mentally retarded; The clinical presentations were confusing in the first three patients and in several others, because the abnormal behavior occurred at carbamezepine concentrations not usually considered to be in the toxic range (> 12~g/ml.) The difficulties this unexpected reaction may cause are evident in Patient 3. Carbamazepine therapy was initiated for seizures poorly controlled by phenobarbital, and the patient was admitted to a hospital one week later. On admission the carbamazepine concentration was 2.5 #g/ml and the phenobarbital concentration was 18 #g/ml. The dose of carbamazepine was raised from 300 to 600 mg/day when the low carbamazepine concentration was noted.
786
Clinical and laboratory observations
The Journal of Pediatrics November 1982
Table. Patients who experienced adverse behavioral reactions to carbamazepine (Tegretol)
Patient
Age ( y r ) Sex
Diagnosis
Onset after starting CBZ
Dose (mg/kg)
CBZ concentration* (~g/ml)
Several weeks
10
9.3, 7.3
Absence seizures, mental retardation
10 days
10
8.9
M
Generalized tonic-clonic seizures, mild mental retardation
8 days
6 for l wk; then 12
6.0
14
M
Generalized tonic-clonic seizures
5
12
F
Partial complex seizures
6
18
M
7
9
F
Generalized tonic-clonic SeizUres, mental retardation Mixed seizure disorder
1
6
F
Mixed seizure disorder, mental retardation
2
17
F
3
i1
4
Third week
4 days
10 for 4 days; then 20
11.8
8
ND
Several weeks
10
ND
Several weeks
10 for 2 wk, then 20
5.8
Behavioral changes and course
Extreme irritability, developmental regression; returned to baseline on CBZ withdrawal Agitation, obsessive thoughts, auditory hallucinations; resolved, on withdrawal Incoherent, agitated, combative; resolved on CBZ withdrawal; CBZ was reintroduced slowly later without problems Felt "spaced out," had to "strain to think," marked personality change; resolved when dose lowered Insomnia, looked "bewildered," felt like "'feet weren't attached to the ground"; resolved at lower dose Aggressive outbursts, biting and fighting; resolved on withdrawal Hyperactivity, insomnia, anger and "paranoia"; resolved on withdrawal
CBZ, carbamazepine;ND, not done. *Usual therapeutic range 4 to 12 t~g/rnl.
Within 24 hours the patient became delirious and combative. He was given 360 mg phenobarbital intravenously Without effect, but he did become calmer after 2 mg haloperidol was given intramuscularly. The carbamazepine concentration 36 hours after the dose increase was 6 # g / m l , and a lumbar puncture yielded normal fluid. Withdrawal of carbamazepine was associated with rapid clearing of the delirium, although seizures became more frequent. These were eventually partially controlled with mephobarbital and valproic acid. In addition to these seven patients, we are aware of two children, cared for by other pediatricians, with similar behavioral changes probably related to carbamazepine. DISCUSSION These patients all had a relatively acute disturbance of neuropsychologic functioning temporally related to introduction or increase in the dose of carbamazepine. Several children had reacted adversely to other anticonvulsant drugs, but the parents identified the reactions to carbamazepine as distinct from the previous experiences. Although
transient dizziness, drowsiness, and incoordination have been described in patients of all ages starting treatment with the drugr this more complex and severe reaction in children has not been described. Its recognition is importanic because the symptoms might otherwise prompt extensive diagnostic evaluation for other causes of encephalopathy (e.g., complex partial status epilepticus). Furthermore, failure tO recognize this reaction promptly may cause considerable confusion in parents who expect the drug to be "good" for behavior. These seven patients were gathered from a total group of approximately 200 children receiving carbamazepine, an incidence of about 3%; however, the exact incidence remains to be determined. Four of the patients were mentally retarded, so these reactions may be more frequent in patients with preexisting central nervous system problems. 7 The pharmacologic mechanism for behavioral toxicity could be related to the tricyclic structure of carbamazepine, which makes it unique among clinically useful anticonvulsants. Chemically related tricyclic antidepres-
Volume 10l Number 5
sant drugs may produce a similar state of confusion, with hallucinations, disorientation, anxiety, agitation, insomnia, and exacerbation of psychosis in a few susceptible individuals. 8 Many studies have suggested that carbamazepine has beneficial psychotr0Pic actions, so it is not surprising that it may also produce occasional adverse emotional reactions. Until it is more clear which factors may predispose children to behavioral toxicity, it may be prudent to initiate therapy cautiously and at a low dose in certain patients, especially those with preexisting psychopathologic problems or retardation. Five of our seven patients were eventually able to tolerate the drug when it was reintroduced slowly. This experience suggests that if carbamazepine is needed for seizure control, a previous adverse behavioral reaction is not an absolute contraindication to another careful trial.
Clinical and laboratory observations
787
REFERENCES 1. Huf R, and Schain R: Long-term experiences with carbamazepine (Tegretol) in children with seizures, J PEDIATR97:310, 1980. 2. Wallace S: Carbamazepine in childhood seizures, Dev Med Child Neurol 20:223, 1978. 3. Johnston MV, and Freeman JM: Pharmacologic advances in seizure control Pediatr Clin North Am 28:179, 1981. 4. Dodrill CB, and Troupin AS: Psychotropic effects of carbamazepine in epilepsy: A double blind comparison with phenytoin, Neurology 27:1023, 1977. 5. Sillanpaa M: Carbamazepine: Pharmacology and clinical uses, Acta Neurol Scand [Suppl] 88:97, 1981. 6. Livingston S, Pauli LL, and Berman W: Carbamazepine (Tegretol) in epilepsy, Dis Nerv Syst 35:103, 1974. 7. Stores A: Behavioral effects of antiepileptic drugs, Dev Med Child Neurol 17:647, 1975. 8. Goodman A, and Gilman L: The pharmacologic basis of therapeutics, New York, 1980, Macmillan, Inc.
Tolmetin sodium in the management of nephrogenic diabetes
insipidus Robert L. Chevalier, M.D., and Alan D. Rogol, M.D., Ph.D., Charlottesville, Va.
NEPHROGENIC DIABETES INSIPIDUS, a congenital disorder characterized by a lack of response of the collecting duct to circulating antidiuretic hormone, is a rare but debilitating condition in the small child. The generally recommended management with sodium restriction and diuretic therapy is usually unsuccessful because compliance with the low-salt diet is poor and diuretics are often ineffective, x Recent studies of the mechanism of renal water handling have shown that prostaglandins exert an inhibitory effect on the action of vasopressin to enhance collecting duct permeability. 2 Prostaglandin synthesis inhibitors have been tested in patients with NDI, with encouraging results? 4 However, virtually all nonsteroidal anti-inflammatory drugs have significant systemic toxicity and are not recommended for use in children. This From the Departments of Pediatrics and Pharmacology, University of Virginia School of Medicine. Reprint address: Robert L. Chevalier, M.D., Department of Pediatrics, Box 386, University of Virginia Medical Center, Charlottesville, VA 22908.
0022-3476/82/110787+03500.30/0 @ 1982 The C. V. Mosby Co.
prompted us to treat a child with N D I using tolmetin sodium (Tolectin), an inhibitor of prostaglandin synthesis with proved safety in children 2 years of age and older. 6
I
NDI: cAMP:
nephrogenic diabetes insipidus cyclic adenosine monophosphate
|
]
I
CASE REPORT The patient, a 39/12-year-old white boy, was diagnosed as having NDI at 6 months of age, but showed no response to a saltrestricted diet and hydrochlorothiazide. At 29/12 years of age he was admitted to the University of Virginia Medical Center for evaluation. Physical examination revealed a thin child with a height of 80 cm (below the fifth percentile), weight of 11 kg (below the fifth percentile), weight-for-height at the tenth percentile, blood pressure of 95/50 mm Hg, and pulse 105. There were no physical abnormalities. Urinalysis revealed a specific gravity of 1.002, pH 6, negative protein and glucose, and a benign sediment. Hematocrit was 37%, and electrolyte values were sodium 139 mEq/L, potassium 3.7 mEq/L, chloride 105 mEq/L, CO2 26 mEq/L, blood urea nitrogen 9 mg/dl, creatinine 0.7 mg/dl, calcium 10.3 mg/dl, and phosphate 4.4 mg/dl. Renal sonogram