Sodium valproate - Induced skeletal myopathy
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《美国医学杂志》
Department of Pediatrics, Bhabha Atomic Research Centre Hospital, Anushaktinagar, Mumbai, India
Abstract
The authors report a case of skeletal myopathy in a four-year-old boy on long-term sodium valproate therapy for secondary epilepsy due to neurocysticercosis. He presented with clinical features of limb girdle weakness. EMG revealed features of myopathy. Carnitine deficiency due to sodium valproate was suspected and plasma carnitine levels were found to be low. Sodium valproate was withdrawn. L-carnitine supplementation resulted in marked clinical recovery as well as rise in plasma carnitine levels.
Keywords: Carnitine; Sodium valproate
Sodium valproate is a broad-spectrum anticonvulsant. Nausea, vomiting, anorexia, amenorrhoea, sedation, tremor, weight gain, alopecia, and hepato-toxicity are its most common side effects.[1] However, one should also be aware of the uncommon side effects of this drug. It is known to cause carnitine deficiency, which usually is asymptomatic in most of the cases or can have varied manifestations. The authors report a case of skeletal myopathy in a four-year-old child who was on long-term sodium valproate.
Case report
A four-year-old male child, a case of secondary epilepsy due to neurocysticercosis was on sodium valproate. The initial dose was 20 mg/kg that was gradually increased to 40mg/kg over one year because of the recurrence of seizures. Four months later while on 40mg/kg of valproate, he developed weakness in both the lower limbs. He had difficulty in running, jumping, climbing up the stairs and getting up from sitting position.
His symptoms were progressive. Clinical examination revealed hypotonia and weakness in the proximal group of muscles of all four limbs, which was more pronounced in the lower limbs. There was no hypertrophy or atrophy of any group of muscles. Sensory system examination and the deep tendon reflexes were normal. He had marked lordosis and a waddling gait, suggesting the diagnosis of myopathy.
The routine investigations, Serum Sodium Valproate levels and Serum CPK levels were normal. EMG revealed findings suggestive of myopathy as there was significant increase in the polyphasic potentials of normal amplitude and duration intermixed with brief amplitude small duration, biphasic and triphasic waves.
The child being on long-term sodium valproate, myopathy due to secondary carnitine deficiency was suspected. Plasma carnitine level estimation revealed lower value, i.e. 16 umoles/L (Normal 20 - 43 umoles/L), thus confirming carnitine deficiency. Valproate was discontinued and replaced with Carbamazepine. The child was also supplemented with L-carnitine in the dose of 100 mg/kg/day. This resulted in rapid clinical improvement within ten days and the child had complete clinical recovery within two months. Investigations done three months later revealed normal Plasma Carnitine level, and features of recovery on the EMG. Repeat EMG six months later was absolutely normal thus confirming the diagnosis of valproate-induced skeletal myopathy.
Discussion
Sodium valproate is the widely used an anti-epileptic drug in the pediatric population. Nausea, vomiting, anorexia, amenorrhoea, sedation, tremor, weight gain, alopecia, and hepato-toxicity are the most common side effects of this drug.[1] The hepatotoxicity may manifest in several ways: transient elevation of transaminase values, reversible hyperammonemia with liver disease, or Reye syndrome - like syndrome, or progressive hepatitis.[2] Patients with epilepsy who are on sodium valproate have been reported to have low serum carnitine levels and this secondary carnitine deficiency has been reported in the literature. Prolonged treatment with sodium valproate more than other anticonvulsants, enhances renal losses of carnitine esters, lowers serum carnitine levels, and results in secondary carnitine deficiency.[2], [3], [4], [5] It also may cause a decrease in serum free carnitine levels by inhibition of plasmalemmal carnitine uptake.[1]
Carnitine (beta-hydroxy-gamma-trimethylammonium butyrate) is a protein synthesized naturally in the body from lysine and methionine. The major biochemical function of camitine is to act as a trans-membrane carrier of long - chain fatty acids to the interior of mitochondria. Consequently carnitine plays a major role in energy production, especially involving the utilization of fats as an energy source.
In most cases these decreased carnitine levels have no obvious pathologic significance, and most children manifest no symptoms of camitine deficiency. However literature has revealed cases of sodium valproate induced carnitine deficiency manifesting in the form of cardiac dysfunction,[6] encephalopathy,[7] hepato-toxicity,[8] malignant cerebral edema,[9] and fatigue.[5] Valproate induced myopathy has been reported by Shapira et al,[10] and Coulter DL.[11] Shapira et al[10] in their study observed six patients on valproate therapy with low muscle carnitine content who had hypotonia. Three of the patients had below normal serum carnitine levels. Muscle biopsy in them revealed lipid droplets accumulation on electron microscopy. Melegh et al[12] in their study also reported that valproate treatment induces lipid globule accumulation with ultrastructural abnormalities of mitochondria in skeletal muscle.
The present case also presented with hypotonia, and as the clinical manifestations along with the EMG were suggestive of myopathy, muscle biopsy was not done in the case. Also low plasma carnitine levels along with positive response to carnitine supplementation and valproate-withdrawal confirmed the diagnosis of valproate induced skeletal myopathy.
Various risk factors have been implicated for valproate-induced carnitine deficiency. The risk factors which have been identified so far, include young age (less than two years of age), multiple neurological disabilities (mental retardation, cerebral palsy, blindness, microcephaly), non-ambulatory status, underweight, diet, tube feedings, taking multiple anticonvulsant drugs, hyperammonemia, or metabolic acidosis.[7] It is important to mention here that none of the above risk factor was present in the patient.
The treatment of carnitine deficiency is carnitine supplementation. In all the reported cases of carnitine deficiency carnitine supplementation resulted in subjective and objective improvement along with the increase in carnitine serum concentrations. Similar result was observed in the patient.
There was no clear consensus on carnitine supplementation in children on valproate therapy but Pediatric Neurology Advisory Committee in 1996 provided more concrete indications on L-carnitine supplementation in childhood epilepsy.[13] Intravenous L-carnitine supplementation is clearly indicated for valproate-induced hepatotoxicity, overdose, and other acute metabolic crisises associated with carnitine deficiency. Oral supplementation is clearly indicated for the primary plasmalemmal carnitine transporter defect. The panelists concurred that oral L-carnitine supplementation is strongly recommended for the following groups as well: patients with certain secondary carnitine deficiency syndromes, symptomatic valproate- associated hyperammonemia, multiple risk factors for valproate hepatotoxicity, or renal- associated syndromes; infants and young children taking valproate; patients with epilepsy using the ketogenic diet who have hypocarnitinemia; patients receiving dialysis; and premature infants who are receiving total parental nutrition. Intravenous supplementation for medical emergency situations usually exceeds this recommended dosage. The panel recommended an oral L-carnitine dosage of 100 mg/kg/day, upto a maximum of 2gm/day. Thus it is recommended that L-carnitine supplementation be provided to those children at greatest risk for hepatotoxicity. In older children on valproate therapy, L-carnitine supplementation should be administered if there are clinical symptoms suggestive of carnitine deficiency (weakness, lethargy, hypotonia) or if a significant decrease in the serum free carnitine levels is measured on a periodic basis.[1]
References
1. Michael V. Johnston. Seizures in childhood. In Behrman RE, Kleigman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th edn. Philadelphia, WB Saunders Co. 2003; 1993-2005.
2. Coulter DL. Prevention of hepatotoxicity recurrence with valproate monotherapy and carnitine. (
Abstract). Ann Neuro 11998; 24: 301.
3. Castro -Gago M, Eiris-Punal J, Novo- Rodriguez MI, Couceiro J, Camina F, Rodriguez-Segade S. Serum carnitine levels in epileptic children before and during treatment with valproic acid, carbamazepine, and phenobarbital. J Child Neurol 1998;13 : 546-549.
4. Zelnik N, Fridkis I, Gruener N. Reduced carnitine and antiepileptic drugs: cause relationship or co-existence. Acta Paediatr 1995; 84: 93-95.
5. Van Wouwe JP. Carnitine deficiency during valproic acid treatment. Intenat J Vit Nutr Res 1995; 65 : 211-214.
6. Bratton SL, Garden AL, Bohan TP, French JW, Clarke WR. A child with valproic acid-associated carnitine deficiency and carnitine-responsive cardiac dysfunction. J Child Neurol 1992; 7: 413-416.
7. Beversdorf D, Allen C, Nordgren R. Valproate induced encephalopathy treated with carnitine in an adult. J Neurol Neurosurg Psyciatry 1996; 61: 211.
8. Dreifuss FE, Santilli N, Langer DR, Sweeny KP, Moline KA, Menander KB.Valproic acid hepatic fatalities: a retrospective review. Neurology 1987; 37 : 379-385.
9. Triggs WJ, Gilmore RL, Millington DS, Cibula J, Bunch TS, Harman E. Valproate- associated carnitine deficiency and malignant cerebral edema in the absence of hepatic failure. Int J Clin Pharmacol Ther 1997; 35 : 353-356.
10. Shapira Y, Gutman A Muscle carnitine deficiency in patients using valproic acid. J Pediatr 1991; 118 : 646-649.
11. Coulter DL. Carnitine, valproate and toxicity. Child Neurol 1991; 6 : 7-14.
12. Melegh B, Trombit AK. Valproate treatment induces lipid globule accumulation with ultrastructural abnormalities of mitochondria in skeletal muscle. Neuropediatrics 1998; 28 : 257-261.
13. De Vivo DC, Bohan TP, Coulter DL, Dreifuss FE, Greenwood RS, Nordli DR Jr et al. L - carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998; 39: 1216-1225.(Kasturi L, Sawant Sangeet)
Abstract
The authors report a case of skeletal myopathy in a four-year-old boy on long-term sodium valproate therapy for secondary epilepsy due to neurocysticercosis. He presented with clinical features of limb girdle weakness. EMG revealed features of myopathy. Carnitine deficiency due to sodium valproate was suspected and plasma carnitine levels were found to be low. Sodium valproate was withdrawn. L-carnitine supplementation resulted in marked clinical recovery as well as rise in plasma carnitine levels.
Keywords: Carnitine; Sodium valproate
Sodium valproate is a broad-spectrum anticonvulsant. Nausea, vomiting, anorexia, amenorrhoea, sedation, tremor, weight gain, alopecia, and hepato-toxicity are its most common side effects.[1] However, one should also be aware of the uncommon side effects of this drug. It is known to cause carnitine deficiency, which usually is asymptomatic in most of the cases or can have varied manifestations. The authors report a case of skeletal myopathy in a four-year-old child who was on long-term sodium valproate.
Case report
A four-year-old male child, a case of secondary epilepsy due to neurocysticercosis was on sodium valproate. The initial dose was 20 mg/kg that was gradually increased to 40mg/kg over one year because of the recurrence of seizures. Four months later while on 40mg/kg of valproate, he developed weakness in both the lower limbs. He had difficulty in running, jumping, climbing up the stairs and getting up from sitting position.
His symptoms were progressive. Clinical examination revealed hypotonia and weakness in the proximal group of muscles of all four limbs, which was more pronounced in the lower limbs. There was no hypertrophy or atrophy of any group of muscles. Sensory system examination and the deep tendon reflexes were normal. He had marked lordosis and a waddling gait, suggesting the diagnosis of myopathy.
The routine investigations, Serum Sodium Valproate levels and Serum CPK levels were normal. EMG revealed findings suggestive of myopathy as there was significant increase in the polyphasic potentials of normal amplitude and duration intermixed with brief amplitude small duration, biphasic and triphasic waves.
The child being on long-term sodium valproate, myopathy due to secondary carnitine deficiency was suspected. Plasma carnitine level estimation revealed lower value, i.e. 16 umoles/L (Normal 20 - 43 umoles/L), thus confirming carnitine deficiency. Valproate was discontinued and replaced with Carbamazepine. The child was also supplemented with L-carnitine in the dose of 100 mg/kg/day. This resulted in rapid clinical improvement within ten days and the child had complete clinical recovery within two months. Investigations done three months later revealed normal Plasma Carnitine level, and features of recovery on the EMG. Repeat EMG six months later was absolutely normal thus confirming the diagnosis of valproate-induced skeletal myopathy.
Discussion
Sodium valproate is the widely used an anti-epileptic drug in the pediatric population. Nausea, vomiting, anorexia, amenorrhoea, sedation, tremor, weight gain, alopecia, and hepato-toxicity are the most common side effects of this drug.[1] The hepatotoxicity may manifest in several ways: transient elevation of transaminase values, reversible hyperammonemia with liver disease, or Reye syndrome - like syndrome, or progressive hepatitis.[2] Patients with epilepsy who are on sodium valproate have been reported to have low serum carnitine levels and this secondary carnitine deficiency has been reported in the literature. Prolonged treatment with sodium valproate more than other anticonvulsants, enhances renal losses of carnitine esters, lowers serum carnitine levels, and results in secondary carnitine deficiency.[2], [3], [4], [5] It also may cause a decrease in serum free carnitine levels by inhibition of plasmalemmal carnitine uptake.[1]
Carnitine (beta-hydroxy-gamma-trimethylammonium butyrate) is a protein synthesized naturally in the body from lysine and methionine. The major biochemical function of camitine is to act as a trans-membrane carrier of long - chain fatty acids to the interior of mitochondria. Consequently carnitine plays a major role in energy production, especially involving the utilization of fats as an energy source.
In most cases these decreased carnitine levels have no obvious pathologic significance, and most children manifest no symptoms of camitine deficiency. However literature has revealed cases of sodium valproate induced carnitine deficiency manifesting in the form of cardiac dysfunction,[6] encephalopathy,[7] hepato-toxicity,[8] malignant cerebral edema,[9] and fatigue.[5] Valproate induced myopathy has been reported by Shapira et al,[10] and Coulter DL.[11] Shapira et al[10] in their study observed six patients on valproate therapy with low muscle carnitine content who had hypotonia. Three of the patients had below normal serum carnitine levels. Muscle biopsy in them revealed lipid droplets accumulation on electron microscopy. Melegh et al[12] in their study also reported that valproate treatment induces lipid globule accumulation with ultrastructural abnormalities of mitochondria in skeletal muscle.
The present case also presented with hypotonia, and as the clinical manifestations along with the EMG were suggestive of myopathy, muscle biopsy was not done in the case. Also low plasma carnitine levels along with positive response to carnitine supplementation and valproate-withdrawal confirmed the diagnosis of valproate induced skeletal myopathy.
Various risk factors have been implicated for valproate-induced carnitine deficiency. The risk factors which have been identified so far, include young age (less than two years of age), multiple neurological disabilities (mental retardation, cerebral palsy, blindness, microcephaly), non-ambulatory status, underweight, diet, tube feedings, taking multiple anticonvulsant drugs, hyperammonemia, or metabolic acidosis.[7] It is important to mention here that none of the above risk factor was present in the patient.
The treatment of carnitine deficiency is carnitine supplementation. In all the reported cases of carnitine deficiency carnitine supplementation resulted in subjective and objective improvement along with the increase in carnitine serum concentrations. Similar result was observed in the patient.
There was no clear consensus on carnitine supplementation in children on valproate therapy but Pediatric Neurology Advisory Committee in 1996 provided more concrete indications on L-carnitine supplementation in childhood epilepsy.[13] Intravenous L-carnitine supplementation is clearly indicated for valproate-induced hepatotoxicity, overdose, and other acute metabolic crisises associated with carnitine deficiency. Oral supplementation is clearly indicated for the primary plasmalemmal carnitine transporter defect. The panelists concurred that oral L-carnitine supplementation is strongly recommended for the following groups as well: patients with certain secondary carnitine deficiency syndromes, symptomatic valproate- associated hyperammonemia, multiple risk factors for valproate hepatotoxicity, or renal- associated syndromes; infants and young children taking valproate; patients with epilepsy using the ketogenic diet who have hypocarnitinemia; patients receiving dialysis; and premature infants who are receiving total parental nutrition. Intravenous supplementation for medical emergency situations usually exceeds this recommended dosage. The panel recommended an oral L-carnitine dosage of 100 mg/kg/day, upto a maximum of 2gm/day. Thus it is recommended that L-carnitine supplementation be provided to those children at greatest risk for hepatotoxicity. In older children on valproate therapy, L-carnitine supplementation should be administered if there are clinical symptoms suggestive of carnitine deficiency (weakness, lethargy, hypotonia) or if a significant decrease in the serum free carnitine levels is measured on a periodic basis.[1]
References
1. Michael V. Johnston. Seizures in childhood. In Behrman RE, Kleigman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th edn. Philadelphia, WB Saunders Co. 2003; 1993-2005.
2. Coulter DL. Prevention of hepatotoxicity recurrence with valproate monotherapy and carnitine. (
Abstract). Ann Neuro 11998; 24: 301.
3. Castro -Gago M, Eiris-Punal J, Novo- Rodriguez MI, Couceiro J, Camina F, Rodriguez-Segade S. Serum carnitine levels in epileptic children before and during treatment with valproic acid, carbamazepine, and phenobarbital. J Child Neurol 1998;13 : 546-549.
4. Zelnik N, Fridkis I, Gruener N. Reduced carnitine and antiepileptic drugs: cause relationship or co-existence. Acta Paediatr 1995; 84: 93-95.
5. Van Wouwe JP. Carnitine deficiency during valproic acid treatment. Intenat J Vit Nutr Res 1995; 65 : 211-214.
6. Bratton SL, Garden AL, Bohan TP, French JW, Clarke WR. A child with valproic acid-associated carnitine deficiency and carnitine-responsive cardiac dysfunction. J Child Neurol 1992; 7: 413-416.
7. Beversdorf D, Allen C, Nordgren R. Valproate induced encephalopathy treated with carnitine in an adult. J Neurol Neurosurg Psyciatry 1996; 61: 211.
8. Dreifuss FE, Santilli N, Langer DR, Sweeny KP, Moline KA, Menander KB.Valproic acid hepatic fatalities: a retrospective review. Neurology 1987; 37 : 379-385.
9. Triggs WJ, Gilmore RL, Millington DS, Cibula J, Bunch TS, Harman E. Valproate- associated carnitine deficiency and malignant cerebral edema in the absence of hepatic failure. Int J Clin Pharmacol Ther 1997; 35 : 353-356.
10. Shapira Y, Gutman A Muscle carnitine deficiency in patients using valproic acid. J Pediatr 1991; 118 : 646-649.
11. Coulter DL. Carnitine, valproate and toxicity. Child Neurol 1991; 6 : 7-14.
12. Melegh B, Trombit AK. Valproate treatment induces lipid globule accumulation with ultrastructural abnormalities of mitochondria in skeletal muscle. Neuropediatrics 1998; 28 : 257-261.
13. De Vivo DC, Bohan TP, Coulter DL, Dreifuss FE, Greenwood RS, Nordli DR Jr et al. L - carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998; 39: 1216-1225.(Kasturi L, Sawant Sangeet)