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Mannheimer B, Lindh JD, Fahlén CB, Issa I, Falhammar H, Skov J. Drug-induced hyponatremia in clinical care. Eur J Intern Med 2025:S0953-6205(25)00175-X. [PMID: 40328519 DOI: 10.1016/j.ejim.2025.04.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/08/2025]
Abstract
PURPOSE Over the last decades, advances in understanding of previously described associations have important implications for diagnosis and workup of hyponatremia. In addition, new drug groups potentially affecting sodium balance and water homeostasis have evolved. The aim of this review is to summarize current evidence on drug-induced hyponatremia in clinical care. METHODS We searched PubMed using the string "Inappropriate ADH Syndrome/chemically induced"[Mesh] OR "Inappropriate ADH Syndrome/diagnosis"[Mesh]) OR ("Hyponatremia/chemically induced"[Mesh] OR "Hyponatremia/diagnosis"[Mesh]), January 1st, 2008, to September 2nd 2024. In total 2003 articles were found and reviewed. Relevant articles referenced herein were subsequently traced backwards and also reviewed. RESULTS Drugs associated with hyponatremia, including selective serotonin reuptake inhibitors, antipsychotics, antiepileptic drugs and proton pump inhibitors, typically cause hyponatremia shortly after initiation of treatment. For thiazide diuretics, the number one culprit in drug-induced hyponatremia, the risk for hyponatremia is highest the first weeks after initiation and then gradually decreases to a stable but still increased level after around 3 months. Several drugs that promote a negative water balance such as loop diuretics, lithium and of sodium-glucose cotransporter-2 inhibitors appear to decrease the risk for hyponatremia. Treatment with immune checkpoint inhibitors is associated with an increased risk of hypophysitis and adrenalitis resulting in hyponatremia due to secondary and primary cortisol deficiency. CONCLUSION For most drugs associated with hyponatremia, including thiazides, the cause-effect relationship is tightly linked to newly initiated treatment. Further research is warranted to characterize the association between hyponatremia and newly developed drugs such as sodium-glucose cotransporter-2 inhibitors and immune checkpoint inhibitors.
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Affiliation(s)
- Buster Mannheimer
- Department of Clinical Science and Education at Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Södersjukhuset, Stockholm, Sweden.
| | - Jonatan D Lindh
- Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Bergh Fahlén
- Department of Clinical Science and Education at Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Södersjukhuset, Stockholm, Sweden
| | - Issa Issa
- Department of Clinical Science and Education at Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Södersjukhuset, Stockholm, Sweden
| | - Henrik Falhammar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
| | - Jakob Skov
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Medicine, Karlstad Central Hospital, Region Värmland, Sweden
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Bembenick KN, Mathew J, Heisler M, Siddaiah H, Moore P, Robinson CL, Kaye AM, Shekoohi S, Kaye AD, Varrassi G. Hyponatremia With Anticonvulsant Medications: A Narrative Review. Cureus 2024; 16:e57535. [PMID: 38707045 PMCID: PMC11066697 DOI: 10.7759/cureus.57535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/03/2024] [Indexed: 05/07/2024] Open
Abstract
Hyponatremia is an adverse effect of many antiseizure medications (ASMs). It occurs with interference with the normal balance of electrolytes within the body. Various risk factors associated with the development of hyponatremia in patients taking these medications include age, gender, dosage, and combinations with other drugs. ASMs such as carbamazepine (CBZ), oxcarbazepine (OXC), and valproic acid have a higher risk of hyponatremia. Hyponatremia induced by an antiseizure medication can occur through various mechanisms depending on the drug's specific mechanism of action. Hyponatremia can be a potentially fatal side effect. Patients taking these medications need to be monitored closely for the signs and symptoms of hyponatremia. Acute hyponatremia, defined as developing in <48 hours, is more likely to show symptoms than chronic hyponatremia. Signs of acute hyponatremia include delirium, seizures, decerebrate posturing, and cerebral edema with uncal herniation. Chronic hyponatremia, defined as developing in >48 hours, can cause lethargy, dizziness, weakness, headache, nausea, and confusion. Hyponatremia is associated with longer hospital stays and increased mortality. Treatment varies based on the degree of severity of hyponatremia. Choosing a treatment option should include consideration of the drug causing the electrolyte disturbance, the patient's risk factor profile, and the severity of symptoms as they present in the individual patient. Healthcare providers should be aware of hyponatremia as a potential side effect of ASMs, the signs and symptoms of hyponatremia, the different treatment options available, and the potential complications associated with rapid correction of hyponatremia.
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Affiliation(s)
| | - Jibin Mathew
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Michael Heisler
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Harish Siddaiah
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Peyton Moore
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Christopher L Robinson
- Department of Anesthesiology, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Adam M Kaye
- Department of Pharmacy Practice, Thomas J. Long School of Pharmacy and Health Sciences University of the Pacific, Stockton, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Alan D Kaye
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
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Elsaid AM, Zahran RF, Elmetwaly SM, Wahba Y, Megahed H, Elshazli RM. The potential impact of CYP2D6 (*2/*4/*10) gene variants among Egyptian epileptic children: A preliminary study. Gene 2022; 832:146585. [PMID: 35597526 DOI: 10.1016/j.gene.2022.146585] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/18/2022] [Accepted: 05/16/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND The cytochrome P450 (CYP) isoenzymes have an indispensable role in the metabolic phase of different medications during the treatment of multiple neuropsychiatric disorders. The foremost goal of this study is to evaluate the correlation of the allelic variants within CYP2D6 (*2/*4/*10) gene with the susceptibility for epileptic syndrome as well as the assessment the degree of resistance towards antiepileptic drugs (AEDs). METHODS This work was designed based on the involvement of 200 participants [100 unrelated healthy controls, 50 AEDs responsive, and 50 AEDs resistant]. Genomic DNA for the CYP2D6 variants was genotyped utilizing the T-ARMS-PCR technique. RESULTS The distributions of the CYP2D6*2 (rs16947; c.886C > T) and CYP2D6*4 (rs3892097; c.506-1G > A) variants were significantly correlated with elevated risk among epileptic patients compared to healthy controls (P-value < 0.05). Furthermore, the CYP2D6*2 variant was statistically associated with disease risk among AEDs responsive patients, while the CYP2D6*4 variant was statistically correlated with disease risk among AEDs resistant patients (P-value < 0.05). Interestingly, the allelic variants of the CYP2D6*4 (A allele) and CYP2D6*10 (T allele) were associated with elevated risk among AEDs resistant compared to AEDs responsive patients (P-value = 0.008 and 0.040, respectively). CONCLUSIONS The CYP2D6*2 and CYP2D6*4 variants were recognized as independent risk factors among epileptic patients, but not the CYP2D6*10 variant.
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Affiliation(s)
- Afaf M Elsaid
- Genetics Unit, Children Hospital, Mansoura University, Mansoura, Egypt
| | - Rasha F Zahran
- Department of Chemistry, Biochemistry Division, Faculty of Science, Damietta University, New Damietta, Egypt
| | - Samar M Elmetwaly
- Department of Chemistry, Biochemistry Division, Faculty of Science, Damietta University, New Damietta, Egypt
| | - Yahya Wahba
- Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hisham Megahed
- Clinical Genetics Department, National Research Centre, Cairo, Egypt
| | - Rami M Elshazli
- Biochemistry and Molecular Genetics Unit, Department of Basic Sciences, Faculty of Physical Therapy, Horus University - Egypt, New Damietta, Egypt.
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Wu PM, Cho HY, Chiang CW, Chuang TH, Wu SN, Tu YF. Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na + and Erg-Mediated K + Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line. Int J Mol Sci 2022; 23:7892. [PMID: 35887240 PMCID: PMC9321339 DOI: 10.3390/ijms23147892] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/15/2022] [Accepted: 07/15/2022] [Indexed: 12/18/2022] Open
Abstract
Carbamazepine (CBZ, Tegretol®) is an anticonvulsant used in the treatment of epilepsy and neuropathic pain; however, several unwanted effects of this drug have been noticed. Therefore, the regulatory actions of CBZ on ionic currents in electrically excitable cells need to be reappraised, although its efficacy in suppressing voltage-gated Na+ current (INa) has been disclosed. This study was undertaken to explore the modifications produced by CBZ on ionic currents (e.g., INa and erg-mediated K+ current [IK(erg)]) measured from Neuro-2a (N2a) cells. In these cells, we found that this drug differentially suppressed the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa in a concentration-dependent manner with effective IC50 of 56 and 18 μM, respectively. The overall current-voltage relationship of INa(T) with or without the addition of CBZ remained unchanged; however, the strength (i.e., ∆area) in the window component of INa (INa(W)) evoked by the short ascending ramp pulse (Vramp) was overly lessened in the CBZ presence. Tefluthrin (Tef), a synthetic pyrethroid, known to stimulate INa, augmented the strength of the voltage-dependent hysteresis (Hys(V)) of persistent INa (INa(P)) in response to the isosceles-triangular Vramp; moreover, further application of CBZ attenuated Tef-mediated accentuation of INa(P)'s Hys(V). With a two-step voltage protocol, the recovery of INa(T) inactivation seen in Neuro-2a cells became progressively slowed by adding CBZ; however, the cumulative inhibition of INa(T) evoked by pulse train stimulation was enhanced during exposure to this drug. Neuro-2a-cell exposure to CBZ (100 μM), the magnitude of erg-mediated K+ current measured throughout the entire voltage-clamp steps applied was mildly inhibited. The docking results regarding the interaction of CBZ and voltage-gate Na+ (NaV) channel predicted the ability of CBZ to bind to some amino-acid residues in NaV due to the existence of a hydrogen bond or hydrophobic contact. It is conceivable from the current investigations that the INa (INa(T), INa(L), INa(W), and INa(P)) residing in Neuro-2a cells are susceptible to being suppressed by CBZ, and that its block on INa(L) is larger than that on INa(T). Collectively, the magnitude and gating of NaV channels produced by the CBZ presence might have an impact on its anticonvulsant and analgesic effects occurring in vivo.
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Affiliation(s)
- Po-Ming Wu
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan;
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Hsin-Yen Cho
- Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan; (H.-Y.C.); (T.-H.C.)
| | - Chi-Wu Chiang
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan;
| | - Tzu-Hsien Chuang
- Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan; (H.-Y.C.); (T.-H.C.)
| | - Sheng-Nan Wu
- Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan; (H.-Y.C.); (T.-H.C.)
- Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 70101, Taiwan
| | - Yi-Fang Tu
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan;
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
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Oxcarbazepine and Hyponatremia. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58050559. [PMID: 35629976 PMCID: PMC9147388 DOI: 10.3390/medicina58050559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/14/2022] [Accepted: 04/16/2022] [Indexed: 11/22/2022]
Abstract
Background and Objectives: Hyponatremia is one of the most common adverse effects in patients treated with oxcarbazepine (OXC). Different risk factors for OXC-induced hyponatremia have been described as age, female gender, dosage, and combination with other drugs During our clinical practice, we noticed that a longer duration of treatment with OXC could be associated with a higher risk of hyponatremia, therefore, in this study, we aimed to evaluate factors that may increase the risk of OXC-induced hyponatremia. Materials and Methods: Data were retrospectively collected from our clinical database at the Department of Neurology of the Hospital of Lithuanian University of Health Sciences Kaunas Clinics. The sample was divided into three groups: OXC consumers (n = 31), other anti-seizure medications (ASMs) consumers (n = 43), and controls absent ASMs (n = 31). All groups were matched by age and gender. Hyponatremia was defined as <136 mmol/L. Results: The frequency of hyponatremia was significantly higher among OXC patients (61.3%) compared to other ASM patients (5.4%) and controls (3.2%). The mean serum sodium concentration in the OXC group was 133.1 ± 5.1 mmol/L. The frequency of severe hyponatremia among OXC-treated patients was 19.4%; this subgroup was older than patients with moderate hyponatremia and normonatremia and had a longer OXC treatment duration compared to a subgroup of normonatremia. The average duration of OXC therapy was 8.7 ± 5.5 years with a range from 1 to 21 years. Serum sodium concentration and duration of treatment with OXC demonstrated a significant negative correlation (r = −0,427, p = 0.017). Each year of therapy with OXC increased the risk of hyponatremia 1.3 times (OR = 1.326, 95% Cl 1.027−1.712, p = 0.031). Other factors (gender, age, polypharmacy, OXC dosage, and serum concentration) did not show a significant association with the development of hyponatremia. Conclusions: Longer duration of treatment with OXC is an important factor in the development and severity of hyponatremia.
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Habib MB, Elshafei M, Ali E, Sardar S, Ali K, Haddad N, Abdelaty M. Eslicarbazepine-induced severe hyponatremia resulted in generalized tonic-clonic seizure. Clin Case Rep 2021; 9:e04851. [PMID: 34765195 PMCID: PMC8572345 DOI: 10.1002/ccr3.4851] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/16/2021] [Accepted: 08/30/2021] [Indexed: 01/29/2023] Open
Abstract
Although eslicarbazepine is an anti-seizure medication, it may result in seizure worsening if its use is complicated by severe hyponatremia, even long time after commencing this medication. The treatment is a replacement for another ASM.
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Affiliation(s)
| | | | - Elrazi Ali
- Internal MedicineHamad Medical CorporationDohaQatar
| | | | - Khaled Ali
- Community MedicineHamad Medical CorporationDohaQatar
| | - Naim Haddad
- NeurologyHamad Medical CorporationDohaQatar
- Weill Cornell Medicine‐QatarDohaQatar
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Oxcarbazepine for Behavioral Disorders after Brain Injury: Factors Influencing Efficacy. Brain Sci 2021; 11:brainsci11070949. [PMID: 34356183 PMCID: PMC8305975 DOI: 10.3390/brainsci11070949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 12/19/2022] Open
Abstract
Carbamazepine and oxcarbazepine are used for behavioral disorders following organic diseases. After severe acquired brain injury, patients may develop frontal symptoms. In our neurological rehabilitation routine, oxcarbazepine is used for better safety over carbamazepine, although its efficacy is not clarified. We aimed to improve knowledge on this use of oxcarbazepine, by probing clinical factors associated with response. We retrospectively examined the clinical records of our patients, collecting clinical variables and outcomes of efficacy, both clinician-rated and caregiver/self-rated. We described the distribution of clinical variables and examined their associations via logistic regressions. Patients in our cohort were predominantly pediatric, with frontal lobe damage and irritable/reactive. With an oxcarbazepine median dose of 975 mg, almost half of patients improved. We found several clinical factors associated with clinician-rated efficacy: absence of frontal damage and absence of irritability/reactivity symptoms; clinical factors associated with caregivers/patients-rated efficacy were: higher DRS score at baseline and higher patient age. In this retrospective study, we observed that oxcarbazepine was differentially efficacious in patients with specific characteristics. Our study could not examine drug therapy separately from neuropsychological therapy, nor the influence of dose. Our associative results should be verified experimentally, also assessing causality and establishing dose-related efficacy and safety.
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Kim S, Jo CH, Kim GH. Psychotropic drugs upregulate aquaporin-2 via vasopressin-2 receptor/cAMP/protein kinase A signaling in inner medullary collecting duct cells. Am J Physiol Renal Physiol 2021; 320:F963-F971. [PMID: 33843270 DOI: 10.1152/ajprenal.00576.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 04/07/2021] [Indexed: 12/17/2022] Open
Abstract
Psychotropic drugs may be associated with hyponatremia, but an understanding of how they induce water retention in the kidney remains elusive. Previous studies have postulated that they may increase vasopressin production in the hypothalamus without supporting evidence. In this study, we investigated the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis using haloperidol, sertraline, and carbamazepine. Haloperidol, sertraline, or carbamazepine were treated in inner medullary collecting duct (IMCD) suspensions and primary cultured IMCD cells prepared from male Sprague-Dawley rats. The responses of intracellular cAMP production, aquaporin-2 (AQP2) protein expression and localization, vasopressin-2 receptor (V2R) and AQP2 mRNA, and cAMP-responsive element-binding protein (CREB) were tested with and without tolvaptan and the protein kinase A (PKA) inhibitors H89 and Rp-cAMPS. In IMCD suspensions, cAMP production was increased by haloperidol, sertraline, or carbamazepine and was relieved by tolvaptan cotreatment. In primary cultured IMCD cells, haloperidol, sertraline, or carbamazepine treatment increased total AQP2 and decreased phosphorylated Ser261-AQP2 protein expression. Notably, these responses were reversed by cotreatment with tolvaptan or a PKA inhibitor. AQP2 membrane trafficking was induced by haloperidol, sertraline, or carbamazepine and was also blocked by cotreatment with tolvaptan or a PKA inhibitor. Furthermore, upregulation of V2R and AQP2 mRNA and phosphorylated CREB was induced by haloperidol, sertraline, or carbamazepine and was blocked by tolvaptan cotreatment. We conclude that, in the rat IMCD, psychotropic drugs upregulate AQP2 via V2R-cAMP-PKA signaling in the absence of vasopressin stimulation. The vasopressin-like action on the kidney appears to accelerate AQP2 transcription and dephosphorylate AQP2 at Ser261.NEW & NOTEWORTHY It is unclear whether antipsychotic drugs can retain water in the kidney in the absence of vasopressin. This study demonstrates that haloperidol, sertraline, and carbamazepine can produce nephrogenic syndrome of inappropriate antidiuresis because they directly upregulate vasopressin-2 receptor and aquaporin-2 (AQP2) via cAMP/PKA signaling. We showed that, in addition to AQP2 trafficking, AQP2 protein abundance was rapidly increased by treatment with antipsychotic drugs in association with dephosphorylation of AQP2 at Ser261 and accelerated AQP2 transcription.
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Affiliation(s)
- Sua Kim
- Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Chor Ho Jo
- Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Gheun-Ho Kim
- Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
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Karlov VA, Vlasov PN, Kozhokaru AB, Orlova AS. [The efficacy and tolerability of extended release carbamazepine in adult patients with new-onset epilepsy using epileptiform activity index]. Zh Nevrol Psikhiatr Im S S Korsakova 2021; 121:31-38. [PMID: 33834715 DOI: 10.17116/jnevro202112103131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To evaluate the efficacy and tolerability of extended release carbamazepine (finlepsin-retard and tegretol CR) in adult patients with new-onset focal epilepsy (FE) with the assessment of epileptiform activity index (EAI). MATERIAL AND METHODS The study included 62 patients (38 (61.3%) men and 24 (38.7%) women) with new-onset FE aged ≥18 years (mean age 42.9±18.4 years). All patients underwent video-ECG-monitoring with EAI assessment at each visit. Treatment efficacy was assessed using the criteria of seizure absence (medically induced remission), seizure rate decrease by >50% (responders), seizure rate decrease by <50% - insufficient efficacy, retention on treatment and seizure rate increase compared to baseline and/or development of new type of seizures (aggravation). Overall study period was 12 months. RESULTS By the end of the 12-month follow-up period, there was a 4.3-fold decrease of the total EAI compared to baseline (p<0.001). Retention on carbamazepine treatment during 12 months was achieved in 61.3% (n=38) patients; medically induced remission - in 40.3% (n=25); seizure rate decrease by >50% - in 21.0% (n=13). In 29.1% (n=18) of patients, treatment change was performed; double-drug therapy, including carbamazepine, was prescribed in 9.6% (n=6) of patients. Incidence of adverse events was 29.1% (n=18). CONCLUSIONS Carbamazepine is an effective and promising drug for initial monotherapy of FE. Its use in the treatment of FE results in a 4.3-fold decrease of EAI (p<0.001), which reflects the efficacy of treatment. EAI is an additional objective measure of treatment efficacy.
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Affiliation(s)
- V A Karlov
- Evdokimov Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - P N Vlasov
- Evdokimov Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - A B Kozhokaru
- State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow, Russia
| | - A S Orlova
- Sechenov First Moscow State Medical Univesity, Moscow, Russia
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10
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Wang Y, Li X, He P, Yin J, Dong R, Fu Y, Zhang H. Characteristics and outcome-related factors of seizure at the first onset of autoimmune encephalitis: A retrospective study. CNS Neurosci Ther 2021; 27:694-701. [PMID: 33683811 PMCID: PMC8111501 DOI: 10.1111/cns.13633] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 02/02/2021] [Accepted: 02/18/2021] [Indexed: 01/17/2023] Open
Abstract
Aims Seizure outcome of autoimmune encephalitis (AE) varies from seizure‐free to refractory epilepsy, and the associated factors remain unclear. We aimed to describe seizure characteristics, identify seizure outcome‐related factors, and discuss the medication strategy of antiepileptic drugs (AEDs) at the first onset of AE. Methods We retrospectively studied the data of 86 patients with clinically diagnosed AE. The clinical characteristics were described using a chi‐square test. Seizure outcome‐related factors were assessed using multivariable logistic regression analysis. Results 56 patients were finally enrolled, with antibodies to N‐methyl‐D‐aspartate receptor found in 29, to γ‐aminobutyric acid receptor B found in 13, and to leucine‐rich glioma‐inactivated protein 1 found in 14. Status epilepticus occurrence and onset with seizure lead to a poor seizure outcome, while administration of human gamma globulin and a low antibody titer contributed to a good seizure outcome. Conclusions In the acute phase, seizure characteristics may be considered in the utilization of AEDs. For patients with seizure‐free status in the acute phase, clinical manifestation (onset with seizure or not, whether status epilepticus occurs or not), therapy regimen (human gamma globulin administered or not), and antibody titer may be considered when formulating the strategy for withdrawal of AEDs post‐acute phase.
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Affiliation(s)
- Yilin Wang
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xin Li
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Pingping He
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jiangning Yin
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ruofei Dong
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu Fu
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hong Zhang
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
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Berghuis B, Hulst J, Sonsma A, McCormack M, de Haan GJ, Sander JW, Lindhout D, Koeleman BPC. Symptomatology of carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy. Epilepsia 2021; 62:778-784. [PMID: 33576502 PMCID: PMC8248112 DOI: 10.1111/epi.16828] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/08/2021] [Accepted: 01/12/2021] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To ascertain whether adverse effects experienced by people taking carbamazepine or oxcarbazepine could be attributed to carbamazepine- or oxcarbazepine-induced hyponatremia (COIH). METHODS We performed an observational study, collecting data between 2017 and 2019 on serum sodium levels and adverse effects retrospectively in people with epilepsy while receiving treatment with either carbamazepine (CBZ) or oxcarbazepine (OXC). We defined hyponatremia as sodium level ≤134 mEq/L and severe hyponatremia as sodium level ≤128 mEq/L. Adverse effects experienced were compared between groups of individuals with and without hyponatremia. RESULTS A total of 1370 people using CBZ or OXC were identified, of whom 410 had at least one episode of hyponatremia. We checked for symptoms related to the use of CBZ and OXC in 710 people (410 with and 300 without hyponatremia) and found relevant information in 688. Adverse effects occurred in 65% of people with hyponatremia compared to 21% with normal sodium levels (odds ratio [OR] 7.5, P ≤ .001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (P ≤ .001). Significant predictors of adverse effects were the drug (OXC vs CBZ), and the number of concomitant anti-seizure medications. Dizziness (28% vs 6%), tiredness (22% vs 7%), instability (19% vs 3%), and diplopia (16% vs 4%) were reported more often in the hyponatremia group than in patients with normal levels. SIGNIFICANCE People with COIH had a 7-fold increased risk of developing adverse effects during treatment. Clinicians should consider ascertainment of sodium levels in patients taking CBZ and OXC and act upon findings.
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Affiliation(s)
- Bianca Berghuis
- Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands
| | - Janic Hulst
- Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands
| | - Anja Sonsma
- Centre of Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mark McCormack
- Centre of Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Gerrit-Jan de Haan
- Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands
| | - Josemir W Sander
- Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands.,NIHR UCL Hospitals Biomedical Research Centre, UCL Institute of Neurology, Queen Square, London WC1N 3BG & Chalfont Centre for Epilepsy, Chalfont, UK
| | - Dick Lindhout
- Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands.,Department of Human Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Bobby P C Koeleman
- Centre of Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
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Asghar MA, Rehman AA, Raza ML, Shafiq Y, Asghar MA. Analysis of treatment adherence and cost among patients with epilepsy: a four-year retrospective cohort study in Pakistan. BMC Health Serv Res 2021; 21:72. [PMID: 33468110 PMCID: PMC7816349 DOI: 10.1186/s12913-021-06085-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 01/13/2021] [Indexed: 09/03/2023] Open
Abstract
BACKGROUND The adherence pattern of antiepileptic drugs (AEDs) among patients with epilepsy is relatively lower in the United States and different European countries. However, adherence and cost analysis of AEDs in Asian countries have not been thoroughly studied. Therefore, the present study aimed to analyze the cost and adherence of AEDs and its associated factors in patients followed in Pakistan. METHODS Data from prescriptions collected from patients with epilepsy who have visited the Outpatient Department (OPD) of different tertiary care hospitals at the cosmopolitan city of Karachi, Pakistan from December 2015 to November 2019. The mean follow-up period for each participant was about 22 months. Pairwise comparisons from Cox regression/hazard ratios were used to assess the predictors of adherence. Direct costs of AEDs were calculated and presented as the annual cost of drugs. RESULTS A total of 11,490 patients were included in this study, 51.2 % were male and 48.8 % were female with a mean age of 45.2 ± 15.8 y. Levetiracetam was found as the most prescribing AED in all study participants (32.9 %). Of them, 49.1 % of patients continued their initial recommended treatment. However, 31.3 % of patients have discontinued the therapy, while, 19.6 % were switched to other AED. Adherence with initial treatment was more profound in male (57.4 %) patients, compared to female with a mean age of 44.2 years. Lamotrigine users (60.6 %) showed a higher tendency to retain on initially prescribed drugs. The total cost of epilepsy treatment in the entire study cohort was 153280.5 PKR ($941.9). By applying the Cox regression analysis, it can be observed that the patients with increasing age (OR, 2.04), migraine (OR, 2.21), psychiatric disorders (OR, 4.28), other comorbidities (OR, 1.52) and users of other than top five prescribing AEDs (2.35) were at higher risk of treatment discontinuation. However, levetiracetam (OR, 0.69), valproic acid (OR, 0.52), carbamazepine (OR, 0.81), lamotrigine (OR, 0.80) or lacosamide (OR, 0.65) users have more chances to continue their initial therapy. CONCLUSIONS Similar to western countries, the majority of patients with epilepsy exhibited low adherence with AEDs. Various associated factors for improving adherence were identified in this study.
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Affiliation(s)
- Muhammad Arif Asghar
- Department of Pharmaceutics, Institute of Pharmaceutical Sciences, Jinnah Sindh Medical University Karachi, Karachi, Pakistan.
| | - Ahad Abdul Rehman
- Department of Pharmacology, Institute of Pharmaceutical Sciences, Jinnah Sindh Medical University Karachi, Karachi, Pakistan
| | - Muhammad Liaquat Raza
- Department of Pharmacology, Faculty of Pharmacy, Shaheed Benazir Bhutto Dewan University, Karachi, Pakistan.,Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Yousra Shafiq
- Department of Pharmaceutics, Institute of Pharmaceutical Sciences, Jinnah Sindh Medical University Karachi, Karachi, Pakistan
| | - Muhammad Asif Asghar
- Food and Feed Safety Laboratory, Food and Marine Resources Research Centre, PCSIR Laboratories Complex, Shahrah-e-Salimuzzaman Siddiqui, Off University Road, 75280, Sindh, Pakistan
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Abstract
OBJECTIVES To examine the effectiveness of low-dose lithium carbonate for managing carbamazepine-induced hyponatremia. METHODS Single case study in an 88 year old man with bipolar illness and vascular dementia who had failed to respond to other mood stabilizers. RESULTS The patient had developed hyponatremia on two separate occasions when treated with carbamazepine. Introduction of low-dose lithium resulted in prompt normalization of serum sodium levels, which was maintained for the subsequent 8 weeks. CONCLUSIONS Carbamazepine may sometimes be the best or only viable treatment option for patients with bipolar illness or other conditions. When its use is complicated by syndrome of inappropriate ADH, dose reduction and fluid restriction are the simplest options but, if ineffective, addition of lithium may be a feasible, albeit somewhat complicated, alternative.
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Pharmacokinetic Monitoring of Levetiracetam in Portuguese Refractory Epileptic Patients: Effect of Gender, Weight and Concomitant Therapy. Pharmaceutics 2020; 12:pharmaceutics12100943. [PMID: 33019727 PMCID: PMC7601255 DOI: 10.3390/pharmaceutics12100943] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/26/2020] [Accepted: 09/29/2020] [Indexed: 11/24/2022] Open
Abstract
Levetiracetam is a second-generation antiepileptic drug, widely used in the treatment of focal and generalized epilepsy due to its pharmacokinetic and safety profiles. Its pharmacokinetic monitoring is ascribed as useful to personalize its dosing regimen. The aim of the present study was to describe, for the first time, the pharmacokinetics of levetiracetam in Portuguese refractory epileptic patients. Therefore, a retrospective study was carried out on 65 Portuguese refractory epileptic patients (pharmacokinetic study: 48; validation study: 17) admitted to the Refractory Epilepsy Centre of the Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. The pharmacokinetic parameters of levetiracetam were estimated by applying a one-compartment model with first-order absorption and elimination analysis. Male patients showed higher distribution volume (Vd/F) and oral clearance (CL/F) than female patients (median Vd/F: 52.40 L in males and 38.60 L in females, p = 0.011; median CL/F: 4.71 L/h in males and 3.91 L/h in females, p = 0.028). Higher values of Vd/F (p = 0.026) and CL/F (p = 0.003) were also found in overweight patients relative to normal weight and obese patients. Carbamazepine was the co-administered antiepileptic drug that mostly affected the pharmacokinetics of levetiracetam, increasing both Vd/F (61.30 L with carbamazepine and 39.10 L without carbamazepine, p = 0.007) and CL/F (6.71 L/h with carbamazepine and 3.91 L/h without carbamazepine, p < 0.001). The pharmacokinetics of levetiracetam was affected by gender, body mass index, and co-administration of carbamazepine. This study highlights the impact of several factors on the CL/ and Vd/F of levetiracetam when administered to refractory epileptic patients. The importance of its pharmacokinetic monitoring in clinical pharmacy stands out, thereby enabling the optimization of antiepileptic drug therapy.
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15
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Song HG, Nahm FS. Oxcarbazepine for trigeminal neuralgia may induce lower extremity weakness: A case report. World J Clin Cases 2020; 8:922-927. [PMID: 32190628 PMCID: PMC7062623 DOI: 10.12998/wjcc.v8.i5.922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/22/2020] [Accepted: 02/11/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Although few studies have reported hyponatremia due to carbamazepine or oxcarbazepine in patients with epilepsy, no study has investigated cases of carbamazepine- or oxcarbazepine-induced hyponatremia or unsteady gait in patients with neuropathic pain. Herein, we report a case of oxcarbazepine-induced lower leg weakness in a patient with trigeminal neuralgia and summarize the diagnosis, treatment, and changes of clinical symptoms.
CASE SUMMARY A 78-year-old male with a history of lumbar spinal stenosis was admitted to the hospital after he experienced lancinating pain around his right cheek, eyes, and lip, and was diagnosed with trigeminal neuralgia at the right maxillary and mandibular branch. He was prescribed oxcarbazepine (600 mg/d), milnacipran (25 mg/d), and oxycodone/naloxone (20 mg/10 mg/d) for four years. Four years later, the patient experienced symptoms associated with spinal stenosis, including pain in the lower extremities and unsteady gait. His serum sodium level was 127 mmol/L. Assuming oxcarbazepine to be the cause of the hyponatremia, oxcarbazepine administration was put on hold and the patient was switched to topiramate. At subsequent visit, the patient’s serum sodium level had normalized to 143 mmol/L and his unsteady gait had improved.
CONCLUSION Oxcarbazepine-induced hyponatremia may cause lower extremity weakness and unsteady gait, which should be differentiated from those caused by spinal stenosis.
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Affiliation(s)
- Hyun-Gul Song
- Department of Anesthesiology and Pain Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul 07061, South Korea
| | - Francis Sahngun Nahm
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam 13620, South Korea
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Araya EI, Claudino RF, Piovesan EJ, Chichorro JG. Trigeminal Neuralgia: Basic and Clinical Aspects. Curr Neuropharmacol 2020; 18:109-119. [PMID: 31608834 PMCID: PMC7324879 DOI: 10.2174/1570159x17666191010094350] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/17/2019] [Accepted: 10/01/2019] [Indexed: 12/27/2022] Open
Abstract
The trigeminal nerve is the largest of all cranial nerves. It has three branches that provide the main sensory innervation of the anterior two-thirds of the head and face. Trigeminal neuralgia (TN) is characterized by sudden, severe, brief, and stabbing recurrent episodes of facial pain in one or more branches of the trigeminal nerve. Pain attacks can occur spontaneously or can be triggered by non-noxious stimuli, such as talking, eating, washing the face, brushing teeth, shaving, a light touch or even a cool breeze. In addition to pain attacks, a proportion of the patients also experience persistent background pain, which along with autonomic signs and prolonged disease duration, represent predictors of worse treatment outcomes. It is now widely accepted that the presence of a neurovascular compression at the trigeminal root entry zone is an anatomic abnormality with a high correlation with classical TN. However, TN may be related to other etiologies, thus presenting different and/or additional features. Since the 1960s, the anticonvulsant carbamazepine is the drug of choice for TN treatment. Although anti-epileptic drugs are commonly used to treat neuropathic pain in general, the efficacy of carbamazepine has been largely limited to TN. Carbamazepine, however, is associated with dose-limiting side-effects, particularly with prolonged usage. Thus, a better understanding and new treatment options are urgently warranted for this rare, but excruciating disease.
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17
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Prevalence and risk factors for hyponatremia in adult epilepsy patients: Large-scale cross-sectional cohort study. Seizure 2019; 73:26-30. [PMID: 31707295 DOI: 10.1016/j.seizure.2019.10.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 10/15/2019] [Accepted: 10/17/2019] [Indexed: 12/14/2022] Open
Abstract
PURPOSE To evaluate the risk factors and prevalence of hyponatremia among epilepsy patients in relation to use of antiepileptic drugs (AEDs). METHODS We retrospectively reviewed 14,620 adult patients (aged 18-103 years) and classified them into the following 3 groups: patients without AED treatment (n = 2165, Group I), patients receiving antiepileptic drugs other than carbamazepine (n = 7442, Group II), and patients treated with carbamazepine (n = 5013, Group III). This study did not include the patients receiving oxcarbazepine or eslicarbazepine acetate because these AEDs are not marketed in Japan. Severe hyponatremia was defined as a serum sodium level < 130 mEq/L. RESULTS In Groups I, II, and III, the mean sodium level was 140, 139, and 137 mEq/L, respectively. The highest frequency of severe hyponatremia was observed in Group III (7%), and it was much higher than in Group I (0.8%) or Group II (1.2%). In Groups II and III, old age, low body weight, and concomitant use of phenobarbital, benzodiazepines, or antipsychotics were risk factors for hyponatremia. In Group III, the sodium level decreased as the carbamazepine dose increased. At a carbamazepine dose exceeding 600 mg/day, there was 10.9-fold higher prevalence of hyponatremia, and the risk was potentiated by concomitant use of valproate. CONCLUSION The serum sodium level should be monitored carefully when patients are receiving AED polypharmacy combined with antipsychotics. In particular, concomitant administration of valproate enhances the risk of hyperammonemia in patients receiving carbamazepine. These findings may help clinicians to avoid hyponatremia in patients with epilepsy.
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18
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Vogrig A, Joubert B, André‐Obadia N, Gigli GL, Rheims S, Honnorat J. Seizure specificities in patients with antibody‐mediated autoimmune encephalitis. Epilepsia 2019; 60:1508-1525. [DOI: 10.1111/epi.16282] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 06/15/2019] [Accepted: 06/18/2019] [Indexed: 12/22/2022]
Affiliation(s)
- Alberto Vogrig
- French Reference Center for Paraneoplastic Neurological Syndromes Hospital for Neurology and Neurosurgery Pierre Wertheimer Lyon University Hospital Lyon France
- SynatAc Team NeuroMyoGene InstituteINSERM U1217/CNRSUMR5310 Lyon France
- University Claude Bernard Lyon 1, University of Lyon Lyon France
- Clinical Neurology Unit Santa Maria della Misericordia University Hospital Udine Italy
| | - Bastien Joubert
- French Reference Center for Paraneoplastic Neurological Syndromes Hospital for Neurology and Neurosurgery Pierre Wertheimer Lyon University Hospital Lyon France
- SynatAc Team NeuroMyoGene InstituteINSERM U1217/CNRSUMR5310 Lyon France
- University Claude Bernard Lyon 1, University of Lyon Lyon France
| | - Nathalie André‐Obadia
- Department of Functional Neurology and Epileptology Hospital for Neurology and Neurosurgery Pierre Wertheimer Lyon University Hospital Lyon France
- Lyon's Neurosciences Research Center INSERM U1028/CNRSUMR 5292University of Lyon Lyon France
| | - Gian Luigi Gigli
- Clinical Neurology Unit Santa Maria della Misericordia University Hospital Udine Italy
- Department of Medicine (DAME) University of Udine Medical School Udine Italy
- Department of Mathematics, Informatics and Physics (DMIF) University of Udine Udine Italy
| | - Sylvain Rheims
- Department of Functional Neurology and Epileptology Hospital for Neurology and Neurosurgery Pierre Wertheimer Lyon University Hospital Lyon France
- Lyon's Neurosciences Research Center INSERM U1028/CNRSUMR 5292University of Lyon Lyon France
| | - Jérome Honnorat
- French Reference Center for Paraneoplastic Neurological Syndromes Hospital for Neurology and Neurosurgery Pierre Wertheimer Lyon University Hospital Lyon France
- SynatAc Team NeuroMyoGene InstituteINSERM U1217/CNRSUMR5310 Lyon France
- University Claude Bernard Lyon 1, University of Lyon Lyon France
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Wechsler RT, Radtke RA, Smith M, Vossler DG, Strom L, Trinka E, Cheng H, Grinnell T, Blum D, Vieira M, Moreira J, Rocha F. Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy. Epilepsia 2019; 60:1341-1352. [PMID: 31260089 PMCID: PMC6852335 DOI: 10.1111/epi.16069] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/15/2019] [Accepted: 05/20/2019] [Indexed: 12/15/2022]
Abstract
Objective To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal‐ (partial‐) onset seizures. Methods This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400‐1200 mg once daily), two phase 3 trials of ESL monotherapy (1200‐1600 mg once daily), and their open‐label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+]), incidences of hyponatremia‐related treatment‐emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. Results The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open‐label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+] measurement ≤125 mEq/L, <9% had a >10 mEq/L decrease in [Na+] from baseline, <6% had a hyponatremia‐related TEAE, and <2% discontinued the controlled trials due to a hyponatremia‐related TEAE. Hyponatremia appeared to be more frequent in the monotherapy (vs adjunctive therapy) trials; in the controlled trials of adjunctive ESL and ESL monotherapy, incidence generally increased with increasing ESL dose. The majority of patients with an investigator‐reported TEAE of “hyponatremia” or “blood sodium decreased” did not have a corresponding laboratory [Na+] measurement ≤125 mEq/L. Some symptoms potentially related to hyponatremia (including nausea and vomiting) were more frequent in patients with a minimum postdose [Na+] measurement ≤125 mEq/L. Significance Reductions in serum sodium concentrations and hyponatremia‐related TEAEs occurred in a small number of patients taking ESL. Suspected hyponatremia should be confirmed and monitored via [Na+] measurements.
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Affiliation(s)
| | | | | | - David G Vossler
- University of Washington, Valley Medical Center, Renton, Washington
| | - Laura Strom
- University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Eugen Trinka
- Uniklinikum Salzburg, Christian-Doppler-Klinik, Salzburg, Austria
| | - Hailong Cheng
- Sunovion Pharmaceuticals, Inc., Marlborough, Massachusetts
| | - Todd Grinnell
- Sunovion Pharmaceuticals, Inc., Marlborough, Massachusetts
| | - David Blum
- Sunovion Pharmaceuticals, Inc., Marlborough, Massachusetts
| | - Mariana Vieira
- BIAL - Portela & Cª., S.A., Coronado (S. Romão e S. Mamede), Portugal
| | - Joana Moreira
- BIAL - Portela & Cª., S.A., Coronado (S. Romão e S. Mamede), Portugal
| | - Francisco Rocha
- BIAL - Portela & Cª., S.A., Coronado (S. Romão e S. Mamede), Portugal
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Kaur U, Chauhan I, Gambhir IS, Chakrabarti SS. Antiepileptic drug therapy in the elderly: a clinical pharmacological review. Acta Neurol Belg 2019; 119:163-173. [PMID: 30953298 DOI: 10.1007/s13760-019-01132-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 03/28/2019] [Indexed: 01/02/2023]
Abstract
Seizure disorder is the third most common neurological disorder in the elderly after stroke and dementia. With the increasing geriatric population, the situation of clinicians seeing more and more elderly epilepsy patients is very likely. Not only is the diagnosis of epilepsy tedious in the elderly, its management raises many challenging issues for the treating physicians. Altered physiology, age-related decline in organ function, and plasma protein binding and altered pharmacodynamics make the elderly patients with seizure disorder a difficult group to treat. This is further complicated by the presence of comorbidities and polypharmacy which increase the chances of drug interactions. The adverse effects that might be tolerated well in younger populations may be disastrous for the aged. Although the newer antiepileptic drugs are found to have a favorable safety profile, there is relative scarcity of randomized-controlled trials involving older and newer antiepileptics in the geriatric population. This review tries to compile the available literature on management of epilepsy in the elderly population including evidence of safety and efficacy of newer and older antiepileptics with special reference to the 'geriatric giants'. It also deals with the interactions between antiepileptic medications and other commonly prescribed drugs in the elderly such as anti-hypertensives and antiischemic agents. The recommended guidelines of various international bodies are also analyzed from the perspective of elderly with seizure disorder.
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Affiliation(s)
- Upinder Kaur
- Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Indal Chauhan
- Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Indrajeet Singh Gambhir
- Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Sankha Shubhra Chakrabarti
- Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
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Berghuis B, Stapleton C, Sonsma ACM, Hulst J, de Haan G, Lindhout D, Demurtas R, Krause R, Depondt C, Kunz WS, Zara F, Striano P, Craig J, Auce P, Marson AG, Stefansson H, O'Brien TJ, Johnson MR, Sills GJ, Wolking S, Lerche H, Sisodiya SM, Sander JW, Cavalleri GL, Koeleman BPC, McCormack M. A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine. Epilepsia Open 2019; 4:102-109. [PMID: 30868120 PMCID: PMC6398103 DOI: 10.1002/epi4.12297] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 12/02/2018] [Accepted: 12/06/2018] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. METHODS We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. RESULTS Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. SIGNIFICANCE Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.
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Affiliation(s)
- Bianca Berghuis
- Stichting Epilepsie Instellingen Nederland (SEIN)ZwolleThe Netherlands
| | - Caragh Stapleton
- Molecular and Cellular TherapeuticsRoyal College of Surgeons in IrelandDublinIreland
| | - Anja C. M. Sonsma
- Department of GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Janic Hulst
- Stichting Epilepsie Instellingen Nederland (SEIN)ZwolleThe Netherlands
| | | | - Dick Lindhout
- Stichting Epilepsie Instellingen Nederland (SEIN)ZwolleThe Netherlands
- Department of GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Rita Demurtas
- Department of Clinical and Experimental EpilepsyInstitute of NeurologyUniversity College LondonLondonUK
| | - Roland Krause
- Luxembourg Centre for Systems BiomedicineUniversity of LuxembourgEsch‐sur‐AlzetteLuxembourg
| | - Chantal Depondt
- Laboratory of Experimental NeurologyHôpital ErasmeUniversité Libre de BruxellesBrusselsBelgium
| | - Wolfram S. Kunz
- Institute of Experimental Epileptology and Cognition Research and Department of EpileptologyUniversity of BonnBonnGermany
| | - Federico Zara
- Laboratory of Neurogenetics and NeuroscienceInstitute G. GasliniGenovaItaly
| | - Pasquale Striano
- Pediatric Neurology and Muscular Diseases UnitDINOGMI‐Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child HealthUniversity of GenovaInstitute “G. Gaslini”GenovaItaly
| | - John Craig
- Department of NeurosciencesBelfast Health and Social Care TrustBelfastUK
| | - Pauls Auce
- Department of Molecular and Clinical PharmacologyInstitute of Translational MedicineUniversity of LiverpoolLiverpoolUK
| | - Anthony G. Marson
- Department of Molecular and Clinical PharmacologyInstitute of Translational MedicineUniversity of LiverpoolLiverpoolUK
| | | | - Terence J. O'Brien
- The Departments of Medicine and NeurologyThe Melbourne Brain CentreThe University of MelbourneThe Royal Melbourne HospitalMelbourneAustralia
| | | | - Graeme J. Sills
- Department of Molecular and Clinical PharmacologyInstitute of Translational MedicineUniversity of LiverpoolLiverpoolUK
| | - Stefan Wolking
- Department of Neurology and EpileptologyUniversity of TübingenHertie Institute for Clinical Brain ResearchTübingenGermany
| | - Holger Lerche
- Department of Neurology and EpileptologyUniversity of TübingenHertie Institute for Clinical Brain ResearchTübingenGermany
| | - Sanjay M. Sisodiya
- Department of Clinical and Experimental EpilepsyInstitute of NeurologyUniversity College LondonLondonUK
- Chalfont Centre for EpilepsyChalfont St. PeterUK
| | - Josemir W. Sander
- Stichting Epilepsie Instellingen Nederland (SEIN)ZwolleThe Netherlands
- Department of Clinical and Experimental EpilepsyInstitute of NeurologyUniversity College LondonLondonUK
- Chalfont Centre for EpilepsyChalfont St. PeterUK
| | - Gianpiero L. Cavalleri
- Molecular and Cellular TherapeuticsRoyal College of Surgeons in IrelandDublinIreland
- The FutureNeuro Research CentreRoyal College of Surgeons in IrelandDublinIreland
| | | | - Mark McCormack
- Molecular and Cellular TherapeuticsRoyal College of Surgeons in IrelandDublinIreland
- Department of GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
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22
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Maister AJ, Bogart GT. Acute hyponatremia with accompanying hyperammonemia secondary to divalproex sodium: A case report. Ment Health Clin 2018; 8:191-194. [PMID: 30155395 PMCID: PMC6063457 DOI: 10.9740/mhc.2018.07.191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Divalproex sodium (DVP) is an antiepileptic medication that also has mood stabilizing properties for patients with mental health disorders. Currently, there are a small number of case reports discussing the incidence of hyponatremia that occurs as an adverse effect of DVP. After completion of a thorough literature search, we present the first case report describing acute hyponatremia with accompanying hyperammonemia secondary to DVP use. This case describes a 44-year-old male patient who experienced hyponatremia with accompanying hyperammonemia following initiation of DVP for schizoaffective disorder. This case highlights the need for clinicians to consider monitoring electrolytes, in addition to liver function and platelets, with the initiation of therapy or increase in daily dosage. Given the drug's action at voltage-gated sodium channels, changes in serum sodium could be expected.
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Affiliation(s)
- Ashley J Maister
- PGY1 Pharmacy Practice Resident, Penn Presbyterian Medical Center, Philadelphia, Pennsylvania
| | - Gregory T Bogart
- (Corresponding author) Clinical Pharmacist - Behavioral Health, Jefferson Health New Jersey, Cherry Hill, New Jersey,
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23
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Galiana GL, Gauthier AC, Mattson RH. Eslicarbazepine Acetate: A New Improvement on a Classic Drug Family for the Treatment of Partial-Onset Seizures. Drugs R D 2018; 17:329-339. [PMID: 28741150 PMCID: PMC5629137 DOI: 10.1007/s40268-017-0197-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Eslicarbazepine acetate is a new anti-epileptic drug belonging to the dibenzazepine carboxamide family that is currently approved as adjunctive therapy and monotherapy for partial-onset (focal) seizures. The drug enhances slow inactivation of voltage-gated sodium channels and subsequently reduces the activity of rapidly firing neurons. Eslicarbazepine acetate has few, but some, drug–drug interactions. It is a weak enzyme inducer and it inhibits cytochrome P450 2C19, but it affects a smaller assortment of enzymes than carbamazepine. Clinical studies using eslicarbazepine acetate as adjunctive treatment or monotherapy have demonstrated its efficacy in patients with refractory or newly diagnosed focal seizures. The drug is generally well tolerated, and the most common side effects include dizziness, headache, and diplopia. One of the greatest strengths of eslicarbazepine acetate is its ability to be administered only once per day. Eslicarbazepine acetate has many advantages over older anti-epileptic drugs, and it should be strongly considered when treating patients with partial-onset epilepsy.
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Affiliation(s)
- Graciana L Galiana
- Department of Neurology, Yale Comprehensive Epilepsy Center, Yale School of Medicine, PO Box 208018, New Haven, CT, 06520, USA
| | - Angela C Gauthier
- Department of Neurology, Yale Comprehensive Epilepsy Center, Yale School of Medicine, PO Box 208018, New Haven, CT, 06520, USA.
| | - Richard H Mattson
- Department of Neurology, Yale Comprehensive Epilepsy Center, Yale School of Medicine, PO Box 208018, New Haven, CT, 06520, USA
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24
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Fricke-Galindo I, LLerena A, Jung-Cook H, López-López M. Carbamazepine adverse drug reactions. Expert Rev Clin Pharmacol 2018; 11:705-718. [PMID: 29898616 DOI: 10.1080/17512433.2018.1486707] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Carbamazepine (CBZ) is used for the treatment of epilepsy and other neurological and psychiatric disorders. The occurrence of adverse reactions (ADRs) to CBZ can negatively impact the quality of life of patients, as well as increase health-care costs. Thus, knowledge of CBZ-induced ADRs is important to achieve safer treatment outcomes. Areas covered: This review describes the clinical features, known mechanisms, and clinical management of the main CBZ-induced ADRs. In addition, pharmacogenetic studies focused on ADRs induced by CBZ are cited. Expert commentary: CBZ-induced ADRs are well known in the literature. The metabolite CBZ-10,11-epoxide plays an important role in the mechanism that underlies the ADRs induced by CBZ. Several factors should be considered for a safer use of CBZ, such as monotherapy prescription when possible, an adequate dose titration, knowledge of previous ADRs in the patient, and routine monitoring of CBZ plasma concentrations in symptomatic patients. Pharmacogenetics is a potential tool for CBZ therapy improvement, and the design of multicenter studies focused on the identification of biomarkers for CBZ-induced ADRs could provide useful information for a safer CBZ therapy.
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Affiliation(s)
- Ingrid Fricke-Galindo
- a Doctorate in Biological and Health Sciences , Metropolitan Autonomous University , Coyoacán, Mexico City , Mexico
| | - Adrián LLerena
- b CICAB Clinical Research Centre , Extremadura University Hospital and Medical School , Badajoz , Spain
| | - Helgi Jung-Cook
- c Department of Pharmacy, Chemistry Faculty , National Autonomous University of Mexico , Mexico City , Mexico.,d Department of Neuropharmacology , National Institute of Neurology and Neurosurgery Manuel Velasco Suárez , Mexico City , Mexico
| | - Marisol López-López
- e Department of Biological Systems , Metropolitan Autonomous University , Coyoacán, Mexico City , Mexico
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25
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Falhammar H, Lindh JD, Calissendorff J, Farmand S, Skov J, Nathanson D, Mannheimer B. Differences in associations of antiepileptic drugs and hospitalization due to hyponatremia: A population-based case-control study. Seizure 2018; 59:28-33. [PMID: 29730273 DOI: 10.1016/j.seizure.2018.04.025] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 04/27/2018] [Accepted: 04/29/2018] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Hyponatremia induced by antiepileptic drugs is common, but detailed evidence is lacking. This can be problematic for the treating neurologist confronted with a patient with severe hyponatremia in need of an alternative drug. The objective of this study was to examine the association between individual antiepileptic drugs and hospitalization due to hyponatremia. METHODS This was a register-based case-control study of patients in the general Swedish population. We included 14,359 individuals with a principal diagnosis of hyponatremia and 57,383 matched controls. The association between newly initiated (≤90 days) and ongoing antiepileptic treatment was investigated using multivariable logistic regression adjusting for concomitant drugs, medical conditions, previous hospitalizations and sociaoeconomic factors. RESULTS For newly initiated antiepileptic drugs, adjusted ORs (95% CI) for hospitalization due to hyponatremia, compared to controls, were: carbamazepine 9.63 (6.18-15.33); phenytoin 4.83 (1.14-25.76); valproate 4.96 (2.44-10.66); lamotrigine 1.67 (0.70-4.08); levetiracetam 9.76 (4.02-27.59) and gabapentin 1.61 (1.08-2.38). Newly initiated oxcarbazepine treatment was only found in the hyponatremia group and not in controls. Adjusted ORs (CI) for individuals with ongoing treatment ranged from 7.97 (3.70-18.50) for oxcarbazepine to 0.83 (0.64-1.06) for gabapentin. CONCLUSION There was a strong association between newly initiated treatment with carbamazepine, oxcarbazepine and levetiracetam, and hospitalization due to hyponatremia. The corresponding association for phenytoin and valproate was moderate. The risk for hyponatremia was lower during ongoing treatment. Lamotrigine and gabapentin had the lowest risk both during initiation and ongoing treatment and may be advantageous in patients at risk of developing hyponatremia.
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Affiliation(s)
- Henrik Falhammar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
| | - Jonatan D Lindh
- Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Jan Calissendorff
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
| | - Shermineh Farmand
- Department of Clinical Science and Education at Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Jakob Skov
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - David Nathanson
- Department of Clinical Science and Education at Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Buster Mannheimer
- Department of Clinical Science and Education at Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
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26
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Antiepileptic drugs-induced hyponatremia: Review and analysis of 560 hospitalized patients. Epilepsy Res 2018; 143:7-10. [PMID: 29631131 DOI: 10.1016/j.eplepsyres.2018.03.023] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 03/27/2018] [Accepted: 03/28/2018] [Indexed: 12/31/2022]
Abstract
Recent evidence suggests that eslicarbazepine acetate (ESL) might be an appropriate alternative to carbamazepine (CBZ) and oxcarbazepine (OXC) due to its better safety profile. Hyponatremia may be one of the limiting safety problems in CBZ and OXC whereas it has been indicated that ESL is less sensitive for the adverse event. Since our clinical experience is different we investigated the incidence of hyponatremia in 560 consecutive adult inpatients treated at our center in 2015 by reviewing their medical records. Only CBZ, OXC and ESL were associated with hyponatremia. The incidence of hyponatremia induced by ESL was not statistically different from that induced by OXC (43% of patients with OXC and 33% with ESL, p > 0.05). Both were associated with hyponatremia more often than CBZ (16%). OXC-induced hyponatremia was dose-related, ESL-induced hyponatremia was not. Furthermore, both OXC- and ESL-induced hyponatremia occurred particularly often in elderly epilepsy patients. Thus, for elderly patients, both OXC and ESL should be considered with caution.
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27
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Affiliation(s)
- A H V Schapira
- Clinical Neurosciences, UCL Institute of Neurology, London, UK
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28
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Berghuis B, van der Palen J, de Haan GJ, Lindhout D, Koeleman BPC, Sander JW. Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy. Epilepsia 2017; 58:1227-1233. [PMID: 28542738 DOI: 10.1111/epi.13777] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2017] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To ascertain possible determinants of carbamazepine (CBZ)- and oxcarbazepine (OXC)-induced hyponatremia in a large cohort of people with epilepsy. METHODS We collected data on serum sodium levels in people with epilepsy who were attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L and severe hyponatremia as Na+ ≤128 mEq/L. RESULTS We identified 1,782 people who had used CBZ (n = 1,424) or OXC (n = 358), of whom 50 were treated with both drugs. Data on sodium level measurements were available in 1,132 on CBZ and in 289 on OXC. Hyponatremia occurred in 26% of those taking CBZ and 46% of those taking OXC. This was severe in 7% in the CBZ group and 22% in the OXC group. Hyponatremia was symptomatic in 48% and led to admissions in 3%. Age over 40 years, high serum levels of CBZ and OXC, and concomitant use of other antiepileptic drugs were the main risk factors for hyponatremia in both treatment groups. Female patients on OXC were at a higher risk than male patients of hyponatremia. The risk of hyponatremia on CBZ was significantly associated with the risk of hyponatremia on OXC within a subgroup that used both drugs consecutively. SIGNIFICANCE Hyponatremia is a common problem in people taking CBZ or OXC. Regular ascertainment of sodium levels in those taking either drug is recommended and results should be acted on.
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Affiliation(s)
- Bianca Berghuis
- Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands
| | - Job van der Palen
- Department of Epidemiology, Medical School Twente, Enschede, The Netherlands.,Department of Research Methodology, Measurement and Data Analysis, University of Twente, Enschede, The Netherlands
| | - Gerrit-Jan de Haan
- Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands
| | - Dick Lindhout
- Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands.,Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Bobby P C Koeleman
- Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Josemir W Sander
- Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands.,NIHR UCL Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, United Kingdom.,Chalfont Centre for Epilepsy, Chalfont St. Peter, United Kingdom
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29
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Turning down the volume: Astrocyte volume change in the generation and termination of epileptic seizures. Neurobiol Dis 2017; 104:24-32. [PMID: 28438505 DOI: 10.1016/j.nbd.2017.04.016] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 04/18/2017] [Accepted: 04/20/2017] [Indexed: 12/20/2022] Open
Abstract
Approximately 1% of the global population suffers from epilepsy, a class of disorders characterized by recurrent and unpredictable seizures. Of these cases roughly one-third are refractory to current antiepileptic drugs, which typically target neuronal excitability directly. The events leading to seizure generation and epileptogenesis remain largely unknown, hindering development of new treatments. Some recent experimental models of epilepsy have provided compelling evidence that glial cells, especially astrocytes, could be central to seizure development. One of the proposed mechanisms for astrocyte involvement in seizures is astrocyte swelling, which may promote pathological neuronal firing and synchrony through reduction of the extracellular space and elevated glutamate concentrations. In this review, we discuss the common conditions under which astrocytes swell, the resultant effects on neural excitability, and how seizure development may ultimately be influenced by these effects.
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30
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Yang HJ, Cheng WJ. Antipsychotic use is a risk factor for hyponatremia in patients with schizophrenia: a 15-year follow-up study. Psychopharmacology (Berl) 2017; 234:869-876. [PMID: 28078393 DOI: 10.1007/s00213-017-4525-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 01/02/2017] [Indexed: 01/05/2023]
Abstract
RATIONALE Hyponatremia affects 10% of patients with chronic schizophrenia and can lead to severe consequences. However, the role of antipsychotics and other risk factors in hyponatremia occurrence has remained inconsistent. OBJECTIVE This study examined the association between antipsychotic use and hyponatremia occurrence in patients with schizophrenia. METHODS We utilized the National Health Insurance Research Database to follow 2051 patients with schizophrenia from 1998 to 2013. Among them, 137 (6.7%) developed hyponatremia. Sociodemographic characteristics, physical comorbidities, and psychiatric treatment experiences were compared between those who had hyponatremia and those who did not. A Cox proportional hazards model was used to examine the hazard ratios (HRs) of these characteristics. RESULTS In patients with hyponatremia, the mean age at first hyponatremia occurrence was 54.7 ± 13.9 years, an average of 9.5 ± 4.0 years after schizophrenia diagnosis, and 32.9% of them were off antipsychotics before hyponatremia occurrences. Age at schizophrenia diagnosis (HR = 1.1), low-income household (HR = 2.4), comorbidities (HR = 1.2), and psychiatric admissions (HR = 1.04) were associated with the risks of hyponatremia. Compared with no antipsychotic use, atypical (HR = 2.1) and typical antipsychotics (HR = 3.1) were associated with an elevated risk of hyponatremia, after adjustment for age, sex, and physical comorbidities. Carbamazepine use (HR = 2.9) was also a significant risk factor for hyponatremia (p < 0.05). CONCLUSIONS Antipsychotic use in patients with schizophrenia with polypharmacy should be monitored for hyponatremia occurrences. Clinicians should pay attention to the impact of poor living conditions on hyponatremia occurrence.
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Affiliation(s)
- Hang-Ju Yang
- Department of Emergency Medicine, Jen-Ai Hospital, 483 Dong Rong Road, Taichung, 41265, Taiwan
| | - Wan-Ju Cheng
- Department of Psychiatry, China Medical University Hospital, 2 Yude Road, Taichung, 40447, Taiwan. .,Department of Public Health, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan.
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31
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Pharmacokinetic variability, efficacy and tolerability of eslicarbazepine acetate-A national approach to the evaluation of therapeutic drug monitoring data and clinical outcome. Epilepsy Res 2016; 129:125-131. [PMID: 28043062 DOI: 10.1016/j.eplepsyres.2016.12.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/29/2016] [Accepted: 12/03/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED), still insufficiently studied regarding pharmacokinetic variability, efficacy and tolerability. The purpose of this study was to evaluate therapeutic drug monitoring (TDM) data in Norway and relate pharmacokinetic variability to clinical efficacy and tolerability in a long-term clinical setting in patients with refractory epilepsy. METHODS This retrospective observational study included TDM-data from the main laboratories and population data from the Norwegian Prescription Database in Norway, in addition to clinical data from medical records of adult patients using ESL for up to three years, whenever possible. RESULTS TDM-data from 168 patients were utilized for assessment of pharmacokinetic variability, consisting of 71% of the total number of patients in Norway using ESL, 2011-14. Median daily dose of ESL was 800mg (range 400-1600mg), and median serum concentration of ESL was 53μmol/L (range 13-132μmol/L). Inter-patient variability of ESL was extensive, with 25-fold variability in concentration/dose ratios. Additional clinical data were available from 104 adult patients out of the 168, all with drug resistant focal epilepsy. After 1, 2 and 3 years follow-up, the retention rate of ESL was 83%, 72% and 64%, respectively. ESL was generally well tolerated as add-on treatment, but sedation, cognitive impairment and hyponatremia were reported. Hyponatremia (sodium <137mmol/L) was present in 36% of the patients, and lead to discontinuation in three. CONCLUSION Pharmacokinetic variability of ESL was extensive and the demonstration of usefulness of TDM requires further studies. In patients with drug resistant focal Epilepsy, the high retention rate indicated good efficacy and tolerability. Hyponatremia was observed in one third of the patients. The present results point to a need for individualization of treatment and TDM may be useful.
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32
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Abstract
INTRODUCTION Hyponatremia induced by antiepileptic drugs (AEDs) has not received sufficient attention in patients with epilepsy. Areas covered: We reviewed articles between 1966 and 2015 about hyponatremia as an adverse effect of AEDs in patients with epilepsy. The incidence, clinical symptoms, onset times of AEDs-induced hyponatremia are discussed in detail, as are the risk factors associated with AEDs-induced hyponatremia and mechanisms underlying its development. We also briefly describe strategies for treating AED-induced hyponatremia. Expert opinion: Carbamazepine and oxcarbazepine are the most common AEDs which induce hyponatremia in patients with epilepsy. Recently, other AEDs, such as eslicarbazepine, sodium valproate, lamotrigine, levetiracetam and gabapentin have also been reported to cause hyponatremia. Understanding the risk associated with AED-induced hyponatremia and taking effective measures to combat serum sodium imbalance induced by AED therapy are necessary.
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Affiliation(s)
- Xi Lu
- a Department of Neurology, Chongqing Key Laboratory of Neurology , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China
| | - Xuefeng Wang
- a Department of Neurology, Chongqing Key Laboratory of Neurology , The First Affiliated Hospital of Chongqing Medical University , Chongqing , China.,b Center of Epilepsy , Beijing Institute for Brain Disorders , Beijing , China
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