Carbamazepine dose-concentration relationship in elderly nursing home residents

PURPOSE: To describe the dose-concentration relationships of carbamazepine (CBZ) in elderly nursing home residents and the effect of sex, age, and type of co-medications. RESULTS: This is a cross-sectional study of elderly (> or = 65 years) nursing home residents across the United States (N=92). Data collection was from 1 June 1998 to 31 December 2000. The mean CBZ dose was 9.2+/-5.4 mg/(kg day(-1)) (+/-Standard Deviation) and serum concentration was 5.9+/-2.2mg/L. The daily dose was significantly lower in the oldest-old age group (> or = 85 years, mean 476.9 mg/day (95% confidence interval CI) 326.5-627.3) as compared to the dose in the young-old (65-74 years, mean 724.4 mg/day (CI) 603.4-845.4) (p=0.016). Adjusted for body weight, doses were similar on a mg/(kg day(-1)) basis. The majority of observed CBZ serum concentrations were at the lower end (67.4%) or below (20.7%) the suggested therapeutic range for younger adult outpatients. CONCLUSIONS: Total daily CBZ doses and patient weight decreased with age. The average dose for elderly nursing home residents was approximately 9 mg/(kg day(-1)). Carbamazepine serum concentrations were lower than those used for younger adults, suggesting that these patients may be more sensitive to CBZ.     

Carbamazepine-risperidone interactions in patients with epilepsy

Because concomitant administration of psychoactive and antiepileptic drugs is increasing progressively in neurologic and psychiatric practice, the aim of the current study was to evaluate the pharmacokinetic interactions between risperidone (RISP) and carbamazepine (CBZ) plasma concentrations in a group of patients with epilepsy with behavioral disturbances. The authors assessed eight patients on CBZ monotherapy (CBZ extended-release capsules) at a mean dosage of 625 +/- 253 mg/day (range, 400-1,200 mg/day) for at least 1 year. RISP (1 mg in one daily dose) was added to CBZ therapy for the occurrence of behavior disturbances. CBZ blood levels were assessed before (T0), 24 hours after (T1), and 2 weeks after (T2) RISP administration. Steady-state plasma concentrations of CBZ increased from 6.67 +/- 0.41 microg/mL at baseline to 7.37 +/- 0.59 microg/mL (p < 0.01) at T1, to 7.95 +/- 0.47 microg/mL (p < 0.0001) at T2. The pharmacokinetic data suggest either a possible role of RISP in inhibiting the cytochrome P450 microsomal enzyme system (CYP)-3A4 pathway or a potential role of CYP2D6 in CBZ metabolism.     

脑胶质瘤术后晚期癫痫发生的危险因素分析

目的 探讨胶质瘤术后晚期癫痫发生的危险因素.方法 回顾分析接受手术并有完整临床资料的胶质瘤病例305例,以性别、年龄、主要症状、阳性体征、术前癫痫、病变部位、手术入路、动静脉损伤、肿瘤残留、术后水肿、病理性质、早期癫痫、病变复发、手术次数、放射治疗等15项可能的影响因素为自变量,设定术后“发生晚期癫痫”为因变量,使用Logistic逐步回归分析研究相关的影响因素.结果 术前癫痫、病变部位、肿瘤残留、病变复发、术后水肿5个因素是术后晚期癫痫发生的危险因素.结论 胶质瘤患者术后晚期癫痫的发生影响患者的生活质量,针对晚期癫痫发生危险因素的防治,有利于减少胶质瘤术后晚期癫痫的发生,从而改善患者的生活质量.     

Evaluation of Carbamazepine and Carbamazepine-Epoxide Protein Binding in Patients Undergoing Epilepsy Surgery

Carbamazepine (CBZ) serum concentrations increase after epilepsy surgery. A possible mechanism may be acute changes in protein binding, specifically those involving the acute phase reactant α₁-acid glycoprotein (AAG). We prospectively evaluated 16 adults (11 receiving CBZ) with epilepsy (mean age 30 ± 8.9 years, 8 women and 8 men) undergoing temporal lobe resections and characterized AAG, albumin, CBZ, and CBZ-epoxide (CBZ-E) free fractions over time. AAG, ALB, CBZ, and CBZ-E free fractions were determined before surgery (baseline) and on postoperative days 1–5, 14, and 30. AAG was measured with a radial immunodiffusion assay method, CBZ and CBZ-E serum concentrations were determined by high-performance liquid chromatography (HPLC). Free fractions of CBZ and CBZ-E were calculated as the ratio of unbound (determined after ultracentrifugation) to total serum drug concentrations. Statistical analysis included analysis of variance (ANOVA) and Student's t test for paired data when appropriate, with significance assigned at p < 0.05. All data are mean ± SD. AAG concentrations increased significantly from baseline (61.9 ± 21.3 mg/dl), peaking at postoperative day 3 (116.8 ± 20.6 mg/dl) and decreasing to baseline levels between days 14 and 30. CBZ serum concentrations were significantly increased in the immediate postoperative period (day 3), but albumin concentrations and CBZ and CBZ-E free fractions did not differ significantly between baseline and the postoperative time points. Temporal lobe resection results in an acute phase reaction which is manifested in part by significant changes in AAG. Although CBZ and CBZ-E total serum concentrations increased significantly in the immediate postoperative period, epilepsy surgery did not appear to result in significant overall changes in drug binding to plasma proteins.     

Aspects of antiepileptic drug therapy in children

During the past 10 years, better results in the treatment of epilepsy have been obtained through the application of pharmacokinetic data to drug therapy of epilepsy. However, pediatric drug therapy is complicated by the continuous change in body weight and body composition with the growth and development, especially during infancy. Younger children require a higher dose per kilogram of body weight than older children in order to achieve comparable plasma concentrations. Plasma levels and seizure control were investigated in a prospective randomized study when phenytoin, carbamazepine (CBZ) or sodium valproate (VPA) was given as a single drug to pediatric patients with several types of epileptic seizures. Studies on newly referred, previously untreated children suggest that both partial and generalized tonic-clonic seizures can be prevented by each of the three drugs. No significant differences in clinical efficacy were found among the three drugs, when optimum plasma concentration ranges were maintained with blood level monitoring. Clonazepam (CZP) may be effective in partial seizures. However, as a wide range of plasma levels was associated with complete freedom from seizures, it was not possible to define a therapeutic range for CZP. Any patient who receives multiple-drug therapy is at risk to develop a drug-drug interaction. Simultaneous administration of VPA was associated with a raised plasma level of carbamazepine-10,11-epoxide (CBZ-E), a major metabolite of CBZ, relative to the CBZ dose, whereas the plasma CBZ level remained unaltered. High plasma concentration of CBZ-E may be responsible for side effects in some patients. Drug-protein binding interactions are another source of side effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipoprotein(a) concentration increases during treatment with carbamazepine

PURPOSE: Treatment with carbamazepine (CBZ) is known to affect apolipoprotein B-containing lipoprotein concentrations in serum. However, little is known about the effects of anticonvulsant drugs (AEDs) on lipoprotein(a) [Lp(a)], although Lp(a) has been characterized as independent cardiovascular risk factor. We investigated prospectively the effect of CBZ on lipoprotein(a) concentration in normolipidemic healthy adults. METHODS: Twenty male volunteers were included in the study. Lp(a) levels were determined before and 69 +/- 19 days after CBZ administration by using an enzyme-linked immunoassay. RESULTS: CBZ (mean plasma concentration, 6.6 +/- 0.6 microg/ml) caused a significant increase in Lp(a) concentrations, with a median change of +19.5% (95% CI: +8.2, +53.3; p < 0.001). Total cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides also increased significantly. CONCLUSIONS: Although the precise mechanism of action of CBZ on Lp(a) elevation remains uncertain, it might be related to its enzyme-inducing properties. During treatment with CBZ, special focus should be given to elevated LDL cholesterol and Lp(a) concentrations with regard to increased risk for atherosclerotic vascular diseases.     

Congenital malformations due to antiepileptic drugs

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.     

Reproductive effects of valproate, carbamazepine, and oxcarbazepine in men with epilepsy

BACKGROUND: Recent observations have indicated that reproductive endocrine disorders are common among women taking valproate (VPA) for epilepsy, but it is not known whether respective abnormalities develop in men taking VPA for epilepsy. Carbamazepine (CBZ) may induce endocrine disorders in men with epilepsy, but the endocrine effects of oxcarbazepine (OXC) are not known. METHODS: Reproductive endocrine function was evaluated in 90 men taking VPA (n = 21), CBZ (n = 40), or OXC (n = 29) as monotherapy for epilepsy and in 25 healthy control men. RESULTS: Twelve men (57%) taking VPA had increased serum androgen levels. The mean serum level of androstenedione was high in patients taking VPA. Serum levels of dehydroepiandrosterone sulfate were low, and serum concentrations of sex hormone-binding globulin (SHBG) were high in men taking CBZ. The endocrine effects of OXC seemed to be dose-dependent, because serum hormone levels were normal in patients with low OXC doses (< 900 mg/day), but serum concentrations of testosterone, gonadotropins, and SHBG were high in patients with a daily OXC dose > or = 900 mg. CONCLUSIONS: VPA increases serum androgen concentrations in men with epilepsy. The endocrine effects of CBZ and OXC were different, because CBZ appears to decrease the bioactivity of androgens, whereas OXC does not.     

Drug-resistant epilepsy in children with partial onset epilepsy treated with carbamazepine

Objective: To evaluate the outcome, including drug-resistant epilepsy (DRE) in children with newly diagnosed partial onset epilepsy treated with carbamazepine (CBZ). Methods: A retrospective medical records review and telephone questionnaire were undertaken on a total of 100 subjects. Results: Long-term follow-up was obtained on 79 children with a mean duration of 7.1 years from CBZ initiation. A total of 66 (83.5%) subjects achieved 2-year seizure remission, 48 (72.7%) subjects did so with CBZ monotherapy. Seven (10.6%) had seizure recurrence after 2-year seizure remission. DRE was diagnosed in seven (8.9%) subjects and five subjects had epilepsy surgery. The mean duration from seizure onset to epilepsy surgery was 5.3 (±2.1) years. Contributing factors for the prolonged duration from seizure onset to epilepsy surgery were identified including: relapsing–remitting course of seizure, family reluctance for epilepsy surgery and uncontrolled psychological problems. Conclusions: Over 80% of children with newly diagnosed partial onset epilepsy who were initially treated with CBZ achieved 2-year seizure remission, and more than 70% of this group did so with CBZ monotherapy. The majority of these patients maintained seizure remission overtime. However, 8.9% of this population met the criteria for DRE and most of them had epilepsy surgery. The duration from seizure onset to epilepsy surgery is an important potential area for improvement in DRE patient care.     

抗癫痫药血药浓度监测结果的分析

目的 探讨用药剂量、年龄、性别及合并用药对3种抗癫痫药卡马西平(CBZ)、苯妥英钠(PHT)和苯巴比妥(PB)血药浓度的影响，评价血药浓度监测对癫痫患临床用药的指导意义。方法 采用化学发光法对我院333例癫痫患用药后的血药浓度进行了578次监测，对监测结果进行分析与评价。结果 服用PHT的100例次其血药浓度达到有效范围的占32．0％，使用PB的136例次和使用CBZ的342例次该值分别为44．1％和41．5％。结论 血药浓度监测对于临床用药的科学合理化、安全有效性有重要价值。     

Post-operative hematoma after surgery for intracranial meningiomas: causes, avoidable risk factors and clinical outcome

Intracranial meningiomas are mainly benign lesions amenable for surgical resection. However, removal of an intracranial meningioma carries a higher risk of post-operative hemorrhage compared to surgery for other intracranial neoplasms. Because avoidance of post-operative hematoma is of vital interest for neurosurgical patients, the aim of this retrospective study was to analyze risk factors of post-operative hematoma associated with meningioma surgery. Two hundred and ninety six patients with intracranial meningiomas, operated between June 1998 and June 2002, were included in this study. Patients who developed a space-occupying post-operative intracranial hemorrhage and were treated surgically were identified. Data of patients with and without hematoma were retrospectively analyzed to identify risk factors associated with post-operative hematoma. Variables analyzed included patients' age, invasion of venous sinus by the meningioma, tumor vascularization, arachnoidal infiltration, pre-operative prophylaxis of thromboembolic events, peri-operative coagulation abnormalities, residual tumor, location and histology of the tumor. Outcome of patients with post-operative hematoma was assessed according to the Glasgow Outcome Scale (GOS) at discharge and at three months. 21 patients (7.1 %) of 296 patients developed a post-operative intracranial hematoma requiring surgical evacuation. Age was significantly higher in the hematoma group 62.4 +/- 14.0 years compared to patients without post-operative hematoma 56.1 +/- 12.0 (p < 0.05; t-test). Patients older than 70 years had a six-fold increased risk to develop a post-operative hematoma (Chi2 test, 95% CI 1.949-13.224). Patients with post-operative hemorrhage had significant lower post-operative prothrombin time, fibrinogen and platelets immediately after surgery and lower platelets at day 1. None of the other parameters, including pre-operative routine coagulation values, differed significantly between patients with and without post-operative hemorrhage. Three patients with post-operative hematoma showed platelet dysfunction and three patients showed decreased FXIII activity. Of those patients with post-operative hemorrhage at three months follow up three patients (13%) succumbed from reasons not directly related to hemorrhage, one patient remained GOS 2 (4.3%), four patients (17.4%) were GOS 3 and 15 (65.4%) patients had favorable outcome (GOS 4 [one patient] and GOS5 [14 patients]). Meningioma surgery carries a higher risk for post-operative hematoma in the elderly. Thrombocytopenia and other hemostatic disorders were frequently associated with post-operative hemorrhage after meningioma surgery, while no surgical factors could be defined. Extending coagulation tests and specific replacement therapy may prevent hematoma formation and improve the patients outcome.     

Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin

OBJECTIVE: The objective of the present analysis is to examine lamotrigine (LTG) pharmacokinetics both during polytherapy with enzyme inducing antiepileptic drugs and to evaluate the time course of de-induction following the step-wise withdrawal of enzyme inducers. BACKGROUND: LTG pharmacokinetics can be significantly influenced by concomitant AEDs, and the addition of enzyme inducers can markedly increase LTG clearance, thereby reducing serum concentrations. A clinically relevant question is how will LTG clearance and resulting plasma concentrations be altered during concomitant enzyme inducer withdrawal/conversion process. DESIGN/METHOD: As part of a previously published, active-control, LTG monotherapy trial, dose and plasma concentration data for LTG, carbamazepine (CBZ) or phenytoin (PHT) were obtained. Following the attainment of a LTG target dose of 500 mg/day, CZB or PHT were withdrawn in weekly 20% decrements. Following inducer withdrawal, LTG was then continued as monotherapy for an additional 12 weeks. Plasma concentrations and daily doses of LTG, CBZ, or PHT were obtained at regularly scheduled study visits during inducer withdrawal and during LTG monotherapy. Pharmacokinetic analysis of the plasma concentration data was done to determine the time-course and effect of inducer plasma concentration on LTG oral clearance (Cl(o)), where LTG Cl(o) was estimated as the dose/concentration ratio. RESULTS: Of the 156 patients enrolled in this trial, 76 were assigned to LTG arm, 43 completed the withdrawal to monotherapy phase with 28 successfully completing the study. In a subset analysis of completers, LTG Cl(o) determined prior to withdrawal of the inducers was significantly greater in patients (n=28) on LTG+PHT (160% increase) than in those (n=48) receiving LTG+CBZ (62% increase): 1.77+/-0.77 vs. 1.06+/-0.41 ml/min/kg, respectively, p=0.017. The significant reduction in LTG Cl(o) occurred only when CBZ plasma concentrations reached approximately 2 microg/ml or PHT plasma concentrations reached zero. CONCLUSIONS: Mean LTG plasma concentrations will approximately double following the withdrawal PHT; however increases of only 60% may occur following the withdrawal of CBZ. Importantly, these data suggest that LTG concentrations would not be expected to increase until the concomitant inducer is almost completely removed.     

A once-per-day, drug-in-food protocol for prolonged administration of antiepileptic drugs in animal models

Purpose: Convenient and effective methods for administering potential antiepileptic drugs (AEDs) chronically should facilitate many experiments in animal models of chronic epilepsy with spontaneous recurrent seizures. This proof‐of‐principle study aimed to optimize a once‐per‐day, drug‐in‐food protocol by testing the effect of carbamazepine (CBZ) on the frequency of convulsive seizures in rats with kainate‐induced epilepsy. Methods: Adult male rats were given repeated low‐dose kainate injections until convulsive status epilepticus persisted for >3 h. After the rats developed spontaneous recurrent seizures, food pellets with CBZ (30, 100, or 300 mg/kg/day) were provided once per day in three 2‐week trials (n = 7–9 rats) involving 5 days of CBZ or control treatment, separated by two recovery days within a trial. The total amount of food provided and consumed per day corresponded to a normal caloric diet (60 g/kg/day). Key Findings: When provided once per day, all animals ate the CBZ‐containing food irregularly but continuously throughout the 24‐h day. With this daily feeding protocol, CBZ significantly reduced the frequency of spontaneous convulsive seizures in a dose‐dependent manner. It is important to note that the effect of CBZ was consistent across the 5 days and throughout each day of the trials. With food administered at 9:00 a.m., and blood assayed at 5:00 p.m., higher food levels of CBZ resulted in higher plasma concentrations of CBZ. Significance: This AED‐in‐food protocol is simple, efficient, inexpensive, reliable, and noninvasive; it allows easier long‐term drug administration and is less stressful and more humane than other methods of AED administration.     

Carbamazepine Toxicity with Lamotrigine: Pharmacokinetic or Pharmacodynamic Interaction?

Summary: Purpose: To determine whether the toxicity that occurs in some patients when lamotrigine (LTG) is added to carbamazepine (CBZ) is the result of either a pharmacokinetic or a pharmacokinetic or a pharmcodynamic interaction.
Methods: Escalating LTG doses were added to ongoing CBZ treatmcnt in 47 patients. All patients had blood samples collected for drug concentration measurement, including the epoxide metabolite of CBZ, before starting LTG treatment and after stabilising at each dose escalation. Patients also were examined for signs of toxicity.
Results: After LTG was introduced, nine patients demonstrated clinical signs of CNS toxicity, mainly diplopia and diziness. There was no significant (p = 0.05) change in the serum concentrations of either CBZ or its epoxide metabolite when LTG was added either to the group as a whole or to the nine patients who experienced adverse CNS effects. LTG serum concentrations also were below the level at which the common signs of LTG toxicity, such as nausea, vomiting, or unsteadiness, are more likely to occur. In seven of the nine patients who exhibited CNS toxicity. CBZ serum concentrations were >8 mg/L on LTG introduction.
Conclusions: Toxicity is more likely to occur when LTG is added to CBZ if the initial CBZ level is high. typically >8 mg/L. This appears to be the result of a pharmacodynamic interaction. A reduction of CBZ dose usually resolves the toxicity, allowing the LTG dose to be escalated to maximal effect. It is not usually necessary to stop either drug.     

Quality of life of patients after epilepsy surgery]

Drug resistant epilepsy impairs patients' quality of life making social interaction more difficult. Surgical treatment is an option for seizure control in medically refractory patients. We evaluated pre-operative and post-operative quality of life using a standardized questionnaire based on the QOLIE-10. The questionnaire included ten questions dealing with psychosocial and drug's side effects and was applied before surgery and eight months post-operatively. The studied sample comprised twelve consecutive adult patients with epilepsy treated surgically who were seizure free. Differences were found between the pre-operative and post-operative periods in 70% of the questions, with a better post-operative profile. Successful epilepsy surgery has a great impact in the quality of life of these patients.     

A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy

PURPOSE: To assess the clinical impact of monitoring serum concentrations of antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy. METHODS: One-hundred eighty patients with partial or idiopathic generalized nonabsence epilepsy, aged 6 to 65 years, requiring initiation of treatment with carbamazepine (CBZ), valproate (VPA), phenytoin (PHT), phenobarbital (PB), or primidone (PRM) were randomly allocated to two groups according to an open, prospective parallel-group design. In one group, dosage was adjusted to achieve serum AED concentration within a target range (10-20 microg/ml for PHT, 15-40 microg/ml for PB, 4-11 microg/ml for CBZ, and 40-100 microg/ml for VPA), whereas in the other group, dosage was adjusted on clinical grounds. Patients were followed up for 24 months or until a change in therapeutic strategy was clinically indicated. RESULTS: Baseline characteristics did not differ between the two groups. Most patients with partial epilepsy were treated with CBZ, whereas generalized epilepsies were most commonly managed with PB or VPA. PHT was used only in a small minority of patients. A total of 116 patients completed 2-year follow-up, and there were no differences in exit rate from any cause between the monitored group and the control group. The proportion of assessable patients with mean serum drug levels outside the target range (mostly below range) during the first 6 months of the study was 8% in the monitored group compared with 25% in the control group (p < 0.01). There were no significant differences between the monitored group and the control group with respect to patients achieving 12-month remission (60% vs. 61%), patients remaining seizure free since initiation of treatment (38% vs. 41%), and time to first seizure or 12-month remission. Frequency of adverse effects was almost identical in the two groups. CONCLUSIONS: Only a small minority of patients were treated with PHT, the drug for which serum concentration measurements are most likely to be useful. With the AEDs most commonly used in this study, early implementation of serum AED level monitoring did not improve overall therapeutic outcome. and the majority of patients could be satisfactorily treated by adjusting dose on clinical grounds. Monitoring the serum levels of these drugs in selected patients and in special situations is likely to be more rewarding than routine measurements in a large clinic population.     

Comparison of the cognitive effects of tiagabine and carbamazepine as monotherapy in newly diagnosed adult patients with partial epilepsy: pooled analysis of two long-term, randomized, follow-up studies

PURPOSE: Patients with epilepsy are at greater risk for cognitive impairment than are age- and education-matched controls. Cognitive decline is a significant adverse event associated with many first-generation anticonvulsant drugs (AEDs); however, the past decade has seen the introduction of several new AEDs with more-favorable cognitive profiles. Tiagabine (TGB) is indicated as adjunctive therapy for the treatment of partial seizures. The cognitive effects of TGB and carbamazepine (CBZ) monotherapy were evaluated in adult epilepsy patients with partial seizures. METHODS: This analysis pooled data from two randomized studies with similar populations, dosing, and cognitive assessments. TGB was titrated to 20-30 mg/day and CBZ to 400-800 mg/day over a 6-week period. A control or no-drug group of untreated patients with a single epileptic seizure was included for comparison. Cognitive function was assessed at baseline and 52 weeks. RESULTS: Of the 105 epilepsy patients enrolled, 79 completed the 52 weeks of monotherapy (TGB, 74%; CBZ, 77%). Altogether, 19 untreated patients composed the no-drug group. During the 52-week follow-up, only one statistically significant difference was found between the treatment groups and the no-drug group [verbal fluency task: F(2, 92) = 3.16; p = 0.047]. On further analysis, it was determined that this statistical difference was solely based on the patients receiving CBZ performing worse than the control group (p = 0.048). Statistically significant improvements (p < 0.05) were found on six (26%) of 23 variables with TGB and CBZ, as well as the no-drug group, although the variables differed between the groups. Significant worsening in the test scores was not seen in any of the study groups. CONCLUSIONS: The results of this 52-week, follow-up study show that successful TGB monotherapy with 20-30 mg/day has a cognitive profile similar to that of successful long-term CBZ monotherapy with 400-800 mg/day in newly diagnosed patients with epilepsy and to that of untreated patients with a single seizure. We observed no significant decline in cognitive scores associated with TGB monotherapy.     

Antiepileptic drug therapy and its management in sudden unexpected death in epilepsy: a case-control study

PURPOSE: Because frequent seizures constitute a major risk factor for sudden unexpected death in epilepsy (SUDEP), the treatment with antiepileptic drugs (AEDs) may play a role for the occurrence of SUDEP. We used data from routine therapeutic drug monitoring (TDM) to study the association between various aspects of AED treatment and the risk of SUDEP. METHODS: A nested case-control study was based on a cohort consisting of 6,880 patients registered in the Stockholm County In Ward Care Register with a diagnosis of epilepsy. Fifty-seven SUDEP cases, and 171 controls, living epilepsy patients, were selected from the cohort. Clinical data including data on TDM were collected through medical record review. RESULTS: The relative risk (RR) of SUDEP was 3.7 (95% CI, 1.0-13.1) for outpatients who had no TDM compared with those who had one to three TDMs during the 2 years of observation. RR was 9.5 (1.4-66.0) if carbamazepine (CBZ) plasma levels at the last TDM were above and not within the common target range (20-40 microM). High CBZ levels were associated with a higher risk in patients receiving polytherapy and in those with frequent dose changes. Although the subgroup of patients with high CBZ levels was small (six cases of 33 with CBZ therapy), and the result should be interpreted with caution, no similar associations were demonstrated for phenytoin plasma levels and risk of SUDEP. No association was found between SUDEP risk and within-patient variation in AED levels over time. CONCLUSIONS: Polytherapy, frequent dose changes, and high CBZ levels as identified risk factors for SUDEP all point to the risks associated with an unstable severe epilepsy. It is unclear whether high CBZ levels per se represent a risk factor or just reflect other unidentified aspects of a severe epilepsy. Our results, however, prompt further detailed analyses of the possible role of AEDs in SUDEP in larger cohorts and suggest that reasonable monitoring of the drug therapy may be useful to reduce risks.     

Haemostatic changes following surgery

Changes in factors V, VII and VIII and in fibrinogen were studied in 32 patients undergoing major abdominal surgery. Mean levels of factors V and VII were similar to population-based values preoperatively. Factor V fell following elective surgery and then rose above the mean pre-operative level before returning to it by the tenth post-operative day. Factor VII fell following both elective and emergency surgery and tended to remain depressed throughout the post-operative period. Pre-operative values of factor VIII and fibrinogen were higher than population-based values and higher in the emergency than in waiting-list patients. Both factor VIII and fibrinogen rose following elective surgery but no statistically significant change was seen following emergency surgery. The uncomplicated conditions leading to elective surgery, the acute complications leading to emergency surgery, and surgery itself may each have contributed to increases in factor VIII and fibrinogen levels, whereas the fall in factors V and VII was largely related to surgery itself. The findings may help in the interpretation of associations between clotting factors and thrombotic disease, particularly in the case of factor VII.     

Fluctuations in Salivary Carbamazepine and Carbamazepine-10,11-Epoxide Concentrations During the Day in Epileptic Children

Hourly salivary concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (EP) were studied during 2 consecutive days in a group of epileptic children receiving twice daily CBZ monotherapy either as the tablet or syrup formulation. Relatively large fluctuations were observed for both CBZ (mean, 57%; range, 32-100%) and EP (mean, 97%; range, 19-189%) during a dosage interval. However, concentrations of EP were generally much lower, approximately 34% of corresponding CBZ levels, and in absolute terms the concentration-time curves for EP appeared much less variable. Further evidence supporting extensive CBZ concentration fluctuations during the day was provided by an additional group of 30 epileptic children receiving CBZ monotherapy whose time of dosage was manipulated to achieve peak and trough concentrations during assessment with a psychomotor test battery. Changes in salivary CBZ concentrations within subjects ranged from 4 to 272% (median, 65%), excluding two atypical cases who showed greater than 10-fold increases in the expected high concentration. These results suggest that in children there is a substantial risk of error in the interpretation of CBZ concentrations from a single sample without consideration of the time of last dose. The implications of these findings for clinical treatment with regard to the appearance of side effects and changes in psychomotor function are discussed.