Valproate induced isolated neutropenia
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《美国医学杂志》
Department of Pediatrics, All India Institute of Medical Sciences,New Delhi - 110029, India
Valproate is a commonly used antiepileptic drug. We report a 2-year-old female patient, a known case of cerebral palsy (definite history of birth asphyxia) with developmental delay and infantile spasms (onset at 5 months with frequency of 5-10 clusters/day). She did not respond favorably to ACTH injections. The child was started on valproate 40mg/kg/d and clobazam 1mg/kg/d to control seizures at 1 year of age. Though seizure free, the child had presented to us with extensive oral ulceration which did not respond to multivitamin supplementation. On routine investigations the patient was found to have an absolute neutrophil count of 1000/ul, hemoglobin of 11g/dl and platelet count of 1,50,000/μl. This child had been on 40mg/kg/d of valproate for a year at the time of presentation. The child was extensively investigated for cause of neutropenia. Her immunoglobulin profile was normal, her human immunodeficiency virus serology was negative and her blood culture was sterile. Bone marrow touch preparation and biopsy revealed normalcy of all three cell lines. Keeping in view that there had been rare cases of valproate induced isolated neutropenia the patient's valproate was tapered off and she was started on vigabatrin 50mg/Kg/d.
Four weeks after valproate was discontinued, absolute neutrophil count which was 1000/ul prior to discontinuation, rose to about 3000/ul. Patient's hemoglobin values and platelet counts were normal and did not show any variation. Patient's serum valproate level done during the episode of neutropenia was within normal range (87.7mg/ml).
Valproic acid is one of a series of fatty or carboxylic acids that have anti-seizure activity. The time course of valproate's anticonvulsant activity appears to poorly correlate with its blood or tissue levels. Valproate's broad spectrum of action is probably due to more than one molecular mechanisms but its action against partial seizures is probably a consequence of its action on Na+ channels.[1]
Valproate is well absorbed after an oral dose with bioavailability of greater than 80%, it is fully ionized at body pH and bound to plasma proteins to an extent of 90%. Therapeutic serum levels of valproate vary from 50-100mg/ml. In testing efficacy, drug should not be abandoned until morning trough levels of 80mg/ml have been attained.
Most common drugs related adverse effects of valproate are nausea, vomiting and other gastrointestinal complaints such as abdominal pain and heartburn. High levels of valproate may be associated with a fine tremor. Other reversible adverse effects, seen rarely, include weight gain, increased appetite and hair loss.[2]
Idiosyncratic toxicity of valproate includes hepatotoxicity, which most frequently occurs in children less than 2-year-old who are on multiple drugs and often within 4 months of initiation of therapy.[3] Other documented idiosyncratic reactions to valproate include immune mediated thrombocytopenia,[4], [5] pancreatitis[5] and bone marrow suppression leading to depression of one or more cell lines.[6]
Neutropenia was first described during sodium valproate treatment by Jaeken et al. They reported a single case of a 3-month-old boy who was receiving 40 mg/Kg/day of valproate. This child's absolute neutrophil count improved promptly after stopping valproate. Immunoflourescence studies in this patient failed to detect antibodies against neutrophils.[4] There are a few cases of valproate induced neutropenia in adults as well.[7] Evidence indicates that the probable mechanism is dose related marrow depression,[6] but our child had a normal bone marrow examination. This case highlights this uncommon but serious adverse drug reaction of a commonly used antiepileptic drug and also serves to emphasize the importance monitoring blood counts in patients on valproate therapy.
References
1. Mac Donald R.L, Meldrum B.S. Principles of antiepileptic drug action. In Antiepiletic Drugs , 4th edn , Levy R.L, et al (editors) Raven Press, 1995.
2. Parra J, Iriarte -J, Pierre - Loius S J. Valproate toxicity. Neurology 1996; 47 : 1608.
3. Dreifuss FE, Langer DH. Hepatic considerations in use of antiepileptic drugs. Epilepsia 1987; 28: 523.
4. Jaeken J, Von Goethem C, Casaer P, Devlieger H , Eggermont E, Pilet M. Letter. Neutropenia during Sodium Valproate treatment. Arc Dis Child 1979; 59 : 986-989.
5. Coulter DL, Wuh, Allen RJ. Valproic acid therapy in childhood epilepsy. JAMA 1980; 244 : 785-788.
6. Acharya S, Bussel JB. Hematological toxicity of sodium valproate. J Pediatr Hematol Oncol 2000; 22 : 62-65.
7. Vesta KS, Medina PJ. Valproic acid-induced neutropenia. Ann Pharmacother 2000; 37 : 819-821.(Kohli Utkarsh, Gulati She)
Valproate is a commonly used antiepileptic drug. We report a 2-year-old female patient, a known case of cerebral palsy (definite history of birth asphyxia) with developmental delay and infantile spasms (onset at 5 months with frequency of 5-10 clusters/day). She did not respond favorably to ACTH injections. The child was started on valproate 40mg/kg/d and clobazam 1mg/kg/d to control seizures at 1 year of age. Though seizure free, the child had presented to us with extensive oral ulceration which did not respond to multivitamin supplementation. On routine investigations the patient was found to have an absolute neutrophil count of 1000/ul, hemoglobin of 11g/dl and platelet count of 1,50,000/μl. This child had been on 40mg/kg/d of valproate for a year at the time of presentation. The child was extensively investigated for cause of neutropenia. Her immunoglobulin profile was normal, her human immunodeficiency virus serology was negative and her blood culture was sterile. Bone marrow touch preparation and biopsy revealed normalcy of all three cell lines. Keeping in view that there had been rare cases of valproate induced isolated neutropenia the patient's valproate was tapered off and she was started on vigabatrin 50mg/Kg/d.
Four weeks after valproate was discontinued, absolute neutrophil count which was 1000/ul prior to discontinuation, rose to about 3000/ul. Patient's hemoglobin values and platelet counts were normal and did not show any variation. Patient's serum valproate level done during the episode of neutropenia was within normal range (87.7mg/ml).
Valproic acid is one of a series of fatty or carboxylic acids that have anti-seizure activity. The time course of valproate's anticonvulsant activity appears to poorly correlate with its blood or tissue levels. Valproate's broad spectrum of action is probably due to more than one molecular mechanisms but its action against partial seizures is probably a consequence of its action on Na+ channels.[1]
Valproate is well absorbed after an oral dose with bioavailability of greater than 80%, it is fully ionized at body pH and bound to plasma proteins to an extent of 90%. Therapeutic serum levels of valproate vary from 50-100mg/ml. In testing efficacy, drug should not be abandoned until morning trough levels of 80mg/ml have been attained.
Most common drugs related adverse effects of valproate are nausea, vomiting and other gastrointestinal complaints such as abdominal pain and heartburn. High levels of valproate may be associated with a fine tremor. Other reversible adverse effects, seen rarely, include weight gain, increased appetite and hair loss.[2]
Idiosyncratic toxicity of valproate includes hepatotoxicity, which most frequently occurs in children less than 2-year-old who are on multiple drugs and often within 4 months of initiation of therapy.[3] Other documented idiosyncratic reactions to valproate include immune mediated thrombocytopenia,[4], [5] pancreatitis[5] and bone marrow suppression leading to depression of one or more cell lines.[6]
Neutropenia was first described during sodium valproate treatment by Jaeken et al. They reported a single case of a 3-month-old boy who was receiving 40 mg/Kg/day of valproate. This child's absolute neutrophil count improved promptly after stopping valproate. Immunoflourescence studies in this patient failed to detect antibodies against neutrophils.[4] There are a few cases of valproate induced neutropenia in adults as well.[7] Evidence indicates that the probable mechanism is dose related marrow depression,[6] but our child had a normal bone marrow examination. This case highlights this uncommon but serious adverse drug reaction of a commonly used antiepileptic drug and also serves to emphasize the importance monitoring blood counts in patients on valproate therapy.
References
1. Mac Donald R.L, Meldrum B.S. Principles of antiepileptic drug action. In Antiepiletic Drugs , 4th edn , Levy R.L, et al (editors) Raven Press, 1995.
2. Parra J, Iriarte -J, Pierre - Loius S J. Valproate toxicity. Neurology 1996; 47 : 1608.
3. Dreifuss FE, Langer DH. Hepatic considerations in use of antiepileptic drugs. Epilepsia 1987; 28: 523.
4. Jaeken J, Von Goethem C, Casaer P, Devlieger H , Eggermont E, Pilet M. Letter. Neutropenia during Sodium Valproate treatment. Arc Dis Child 1979; 59 : 986-989.
5. Coulter DL, Wuh, Allen RJ. Valproic acid therapy in childhood epilepsy. JAMA 1980; 244 : 785-788.
6. Acharya S, Bussel JB. Hematological toxicity of sodium valproate. J Pediatr Hematol Oncol 2000; 22 : 62-65.
7. Vesta KS, Medina PJ. Valproic acid-induced neutropenia. Ann Pharmacother 2000; 37 : 819-821.(Kohli Utkarsh, Gulati She)