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Levetiracetam-associated hyponatremia
Seizure (2008) 17, 389—390
www.elsevier.com/locate/yseiz
LETTER TO THE EDITOR Levetiracetam-associated hyponatremia KEYWORDS Levetiracetam; Side effects; Hyponatremia
Hyponatremia has been associated with several antiepileptic drugs (AEDs), such as carbamazepine, oxcarbazepine, and occasionally with valproate and lamotrigine.1,2 To date, there is only a report of hyponatremia associated with levetiracetam in a 65-year-old patient predisposed to the development of syndrome of inappropriate antidiuretic hormone secretion (SIADH).3 We recently observed a patient developing hyponatremia following two challanges with levetiracetam in absence of any evident predisposition to SIADH. This 76-year-old man suffered from complex partial seizures, occasionally followed by secondarily generalization, started 4 months before. Initial treatment with phenobarbital (100 mg daily) was soon discontinued due to diurnal somnolence and replaced with levetiracetam (1000 mg twice daily). Six months later the man was admitted to our Neurology Clinic due to a tonic—clonic seizure. His previous medical history included hypertension and anxiety for which he was receiving amlodipine and lorazepam. At admission, an EEG revealed lateralized temporal epileptiform activity. Brain MRI and chest CT scan were unremarkable. Haematological tests showed serum sodium level of 127 mM (normal, 135—145) and osmolality of 290 mOsm/kg (normal, 280—300). Urine sodium and osmolality were 6 mM (normal, <10) and 190 Osm/kg (normal, 250—1200). Other serum electrolytes, glycemia, urea, creatinine, bicarbonate, liver transaminases, T4, T3, and TSH were normal. Renal, cardiac, and hepatic function were normal. Due to the poor clinical efficacy, levetiracetam was discontinued and valproic acid (600 mg daily) was initiated. A week later, his serum sodium level was 136 mM and the patient was discharged. However, at home his wife erroneously
restarted levetiracetam treatment (500 mg twice daily). No further seizures did occur. A week later, serum sodium level were 130 mM, and osmolality of 290 mOsm/kg. Urine sodium and urine osmolality were within the normal limits. The patient was asymptomatic. Levetiracetam was discontinued, and the sodium level normalized after 4 days. Levetiracetam is an increasingly used AED with apparently low profile of toxicity. The most common adverse events mentioned in clinical trials include somnolence, asthenia, headache, dizziness, and nervousness.4 This patient developed asymptomatic hyponatremia after two levetiracetam challenges, one of which in monotherapy. Amlodipine, which was a comedication in our patient, has been previously associated with hyponatremia in a single case report.5 However, it is unlikely that amlodipine induced low serum sodium as its dose remained stable during the two levetiracetam trials. Other causes of hyponatremia were excluded. There was a clear temporal association between the introduction and discontinuation of levetiracetam as previously reported,3 likely due to the rapid (1 h after administration) peak effect of the drug and its short (6—8 h) half-life elimination.4 Our patient developed low serum sodium levels at different levetiracetam doses (i.e., 500 and 1000 mg twice daily), according to the absence of association between the AED dose and hyponatremia.1,2 A peripheral process (i.e., the excessive water reabsorption in the collecting tubule) is generally suggested for hyponatremia induced by other AEDs2; however, the mechanism whereby levetiracetam may induce this effect remains speculative. Although hyponatremia is rarely associated to levetiracetam treatment,3 it can occur in asymptomatic patients. In our case, advanced age was the only factor predisposing to hyponatremia. However, the risk is greatly increased by polypharmacy, surgery, underlying renal and psychiatric comorbidity, and female gender.1 Thus, subjects taking levetiracetam and presenting these risk factors should be particularly monitored for laboratory evidence of hyponatremia.
1059-1311/$ — see front matter # 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2007.10.007
390 Further observations are needed to confirm the frequency of levetiracetam-associated hyponatremia as well as the additional risk factors for developing this effect.
References 1. Castilla-Guerra L, del Carmen Fernandez-Moreno M, LopezChozas JM, Fernandez-Bolanos R. Electrolytes disturbances and seizures. Epilepsia 2006;47:1990—8. 2. Dong X, Leppik IE, White J, Rarick J. Hyponatremia from oxcarbazepine and carbamazepine. Neurology 2005;65:1976—8. 3. Nasrallah K, Silver B. Hyponatremia associated with repeated use of levetiracetam. Epilepsia 2005;46:972—3. 4. Arroyo S, Crawford P. Safety profile of levetiracetam. Epileptic Disorders 2003;5:S57—63. 5. Malaterre HR, Kallee K, Daver LM. Hyponatremia and amlodipine therapy. Cardiovasc Drugs Ther 1999;13:171—2.
Letter to the editor Vincenzo Belcastro* Cinzia Costa Neurologic Clinic, University of Perugia, S. Andrea delle Fratte, 06156 Perugia, Italy Pasquale Striano Epilepsy Center, Federico II University, Napoli, Italy *Corresponding author. Fax: +39 075 5784229 E-mail address: [email protected] (V. Belcastro) 18 October 2007
www.elsevier.com/locate/yseiz
LETTER TO THE EDITOR Levetiracetam-associated hyponatremia KEYWORDS Levetiracetam; Side effects; Hyponatremia
Hyponatremia has been associated with several antiepileptic drugs (AEDs), such as carbamazepine, oxcarbazepine, and occasionally with valproate and lamotrigine.1,2 To date, there is only a report of hyponatremia associated with levetiracetam in a 65-year-old patient predisposed to the development of syndrome of inappropriate antidiuretic hormone secretion (SIADH).3 We recently observed a patient developing hyponatremia following two challanges with levetiracetam in absence of any evident predisposition to SIADH. This 76-year-old man suffered from complex partial seizures, occasionally followed by secondarily generalization, started 4 months before. Initial treatment with phenobarbital (100 mg daily) was soon discontinued due to diurnal somnolence and replaced with levetiracetam (1000 mg twice daily). Six months later the man was admitted to our Neurology Clinic due to a tonic—clonic seizure. His previous medical history included hypertension and anxiety for which he was receiving amlodipine and lorazepam. At admission, an EEG revealed lateralized temporal epileptiform activity. Brain MRI and chest CT scan were unremarkable. Haematological tests showed serum sodium level of 127 mM (normal, 135—145) and osmolality of 290 mOsm/kg (normal, 280—300). Urine sodium and osmolality were 6 mM (normal, <10) and 190 Osm/kg (normal, 250—1200). Other serum electrolytes, glycemia, urea, creatinine, bicarbonate, liver transaminases, T4, T3, and TSH were normal. Renal, cardiac, and hepatic function were normal. Due to the poor clinical efficacy, levetiracetam was discontinued and valproic acid (600 mg daily) was initiated. A week later, his serum sodium level was 136 mM and the patient was discharged. However, at home his wife erroneously
restarted levetiracetam treatment (500 mg twice daily). No further seizures did occur. A week later, serum sodium level were 130 mM, and osmolality of 290 mOsm/kg. Urine sodium and urine osmolality were within the normal limits. The patient was asymptomatic. Levetiracetam was discontinued, and the sodium level normalized after 4 days. Levetiracetam is an increasingly used AED with apparently low profile of toxicity. The most common adverse events mentioned in clinical trials include somnolence, asthenia, headache, dizziness, and nervousness.4 This patient developed asymptomatic hyponatremia after two levetiracetam challenges, one of which in monotherapy. Amlodipine, which was a comedication in our patient, has been previously associated with hyponatremia in a single case report.5 However, it is unlikely that amlodipine induced low serum sodium as its dose remained stable during the two levetiracetam trials. Other causes of hyponatremia were excluded. There was a clear temporal association between the introduction and discontinuation of levetiracetam as previously reported,3 likely due to the rapid (1 h after administration) peak effect of the drug and its short (6—8 h) half-life elimination.4 Our patient developed low serum sodium levels at different levetiracetam doses (i.e., 500 and 1000 mg twice daily), according to the absence of association between the AED dose and hyponatremia.1,2 A peripheral process (i.e., the excessive water reabsorption in the collecting tubule) is generally suggested for hyponatremia induced by other AEDs2; however, the mechanism whereby levetiracetam may induce this effect remains speculative. Although hyponatremia is rarely associated to levetiracetam treatment,3 it can occur in asymptomatic patients. In our case, advanced age was the only factor predisposing to hyponatremia. However, the risk is greatly increased by polypharmacy, surgery, underlying renal and psychiatric comorbidity, and female gender.1 Thus, subjects taking levetiracetam and presenting these risk factors should be particularly monitored for laboratory evidence of hyponatremia.
1059-1311/$ — see front matter # 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2007.10.007
390 Further observations are needed to confirm the frequency of levetiracetam-associated hyponatremia as well as the additional risk factors for developing this effect.
References 1. Castilla-Guerra L, del Carmen Fernandez-Moreno M, LopezChozas JM, Fernandez-Bolanos R. Electrolytes disturbances and seizures. Epilepsia 2006;47:1990—8. 2. Dong X, Leppik IE, White J, Rarick J. Hyponatremia from oxcarbazepine and carbamazepine. Neurology 2005;65:1976—8. 3. Nasrallah K, Silver B. Hyponatremia associated with repeated use of levetiracetam. Epilepsia 2005;46:972—3. 4. Arroyo S, Crawford P. Safety profile of levetiracetam. Epileptic Disorders 2003;5:S57—63. 5. Malaterre HR, Kallee K, Daver LM. Hyponatremia and amlodipine therapy. Cardiovasc Drugs Ther 1999;13:171—2.
Letter to the editor Vincenzo Belcastro* Cinzia Costa Neurologic Clinic, University of Perugia, S. Andrea delle Fratte, 06156 Perugia, Italy Pasquale Striano Epilepsy Center, Federico II University, Napoli, Italy *Corresponding author. Fax: +39 075 5784229 E-mail address: [email protected] (V. Belcastro) 18 October 2007