John O. Rarick

Incidence and risk factors in sudden unexpected death in epilepsy: A prospective cohort study

Objective: To determine incidence of and risk factors for sudden unexpected death in epilepsy (SUDEP). Methods: Three epilepsy centers enrolled 4,578 patients and prospectively followed these patients for 16,463 patient-years. The cohort was screened for death annually. Deaths were investigated to determine whether SUDEP occurred. Potential risk factors were compared in SUDEP cases and in controls enrolled contemporaneously at the same center. Results: Incidence of SUDEP was 1.21/1,000 patient-years and was higher among women (1.45/1,000) than men (0.98/1,000). SUDEP accounted for 18% of all deaths. Occurrence of tonic-clonic seizures, treatment with more than two anticonvulsant medications, and full-scale IQ less than 70 were independent risk factors for SUDEP. The number of tonic-clonic seizures was a risk factor only in women. The presence of cerebral structural lesions and use of psychotropic drugs at the last visit were not risk factors for SUDEP in this cohort. Subtherapeutic anticonvulsant levels at the last visit were equally common in the two groups. No particular anticonvulsant appeared to be associated with SUDEP. Conclusions: These results support the idea that tonic-clonic seizures are an important proximate cause of SUDEP. This information creates a risk profile for SUDEP that may help direct preventative efforts.

Hyponatremia from oxcarbazepine and carbamazepine

The authors examined sodium concentrations from 97 oxcarbazepine-treated (OXC) and 451 carbamazepine-treated (CBZ) patients with epilepsy using cross-section and follow-up studies. The frequency of hyponatremia (Na+ ≪134 mEq/L) was 29.9% among OXC-treated patients and 13.5% among CBZ-treated patients (p < 0.0001). Hyponatremia (Na+ ≪128 mEq/L) was severe: 12.4% of OXC-treated patients and 2.8% of CBZ-treated patients (p < 0.001). Advanced age was a risk factor for hyponatremia. Hyponatremia, once present, persisted in both groups.

Discontinuation of levetiracetam because of behavioral side effects A case-control study

Background: Levetiracetam (LEV) is a recently approved anticonvulsant with proven efficacy and safety in the treatment of partial seizures. LEV may cause behavioral abnormalities that can be severe and require discontinuation of this drug. Risk factors for discontinuing LEV have not been established. Objective: To determine incidence of behavioral abnormalities severe enough to require discontinuation of LEV and identify risk factors for such behavioral abnormalities. Methods: All patients treated with LEV at MINCEP between January 2000 and February 2002 constituted the study population (n = 553). Patients who had discontinued LEV for behavioral reasons were selected as index cases. Case controls were patients starting LEV immediately after the index case. Potential risk factors for LEV discontinuation included age, gender, cognitive function, history of psychiatric diagnosis, epilepsy syndrome, number of antiepileptic drugs, titration rate, maximum dose of LEV, and LEV level at maximum dose. Results: Thirty-eight patients (6.9%) discontinued LEV because of behavioral abnormalities. Variables associated with LEV discontinuation included faster titration rate to maximal dose, history of a psychiatric disorder, and diagnosis of symptomatic generalized epilepsy. Patients who discontinued LEV owing to behavioral reasons had significantly lower maximum LEV doses than controls. Conclusions: This study identified variables associated with discontinuation of LEV due to behavioral abnormalities. Slower titration of LEV should be considered in those patients at higher risk of discontinuing LEV for behavioral reasons.

Population Pharmacokinetics of Carbamazepine in Adults with Epilepsy

Study Objective. To conduct a population pharmacokinetic analysis of carbamazepine (CBZ).

Steady-State Carbamazepine Pharmacokinetics Following Oral and Stable-Labeled Intravenous Administration in Epilepsy Patients: Effects of Race and Sex

Carbamazepine is a widely prescribed antiepileptic drug. Owing to the lack of an intravenous formulation, its absolute bioavailability, absolute clearance, and half‐life in patients at steady state have not been determined. We developed an intravenous, stable‐labeled (SL) formulation in order to characterize carbamazepine pharmacokinetics in patients. Ninety‐two patients received a 100‐mg infusion of SL‐carbamazepine as part of their morning dose. Blood samples were collected up to 96 hours after drug administration. Plasma drug concentrations were measured with liquid chromatography–mass spectrometry, and concentration–time data were analyzed using a noncompartmental approach. Absolute clearance (l/hr/kg) was significantly lower in men (0.039 ± 0.017) than in women (0.049 ± 0.018; P = 0.007) and in African Americans (0.039 ± 0.017) when compared with Caucasians (0.048 ± 0.018; P = 0.019). Half‐life was significantly longer in men than in women as well as in African Americans as compared with Caucasians. The absolute bioavailability was 0.78. Sex and racial differences in clearance may contribute to variable dosing requirements and clinical response.

Predictors of postoperative memory function after left anterior temporal lobectomy

Patients who undergo left anterior temporal lobectomy (ATL) for intractable epilepsy are at risk of postoperative memory decline. This study attempts to identify the best predictors of memory after ATL using preoperative tests. Thirty-two consecutive patients who underwent left ATL with preoperative and postoperative neuropsychological testing were retrospectively identified. The following independent variables were analyzed by multiple regression: age of onset of seizures, age of temporal lobe damage, gender, MRI results, preoperative memory testing, and intracarotid amytal procedure (IAP) results. Neuropsychological measures of verbal and nonverbal memory served as dependent variables. Male gender (P<0.005), failing the IAP with both left and right hemispheres (P<0.001), and higher logical memory (LM) scores preoperatively (P<0.001) were associated with greater declines in LM after surgery. Our data demonstrate that the IAP predicts postoperative memory independent of other factors known to affect memory after left ATL.

Safety of an IV Formulation of Carbamazepine

An intravenous formulation of carbamazepine (CBZ) was administered to 113 (60 male; 53 female) persons with epilepsy aged 19-87 years. Subjects received 100mg of study drug as replacement for 100mg of their usual morning dose of CBZ. There were no significant changes in blood pressure or heart rate suggesting that this formulation can be developed as replacement therapy for persons unable to take oral CBZ.

Long-term use of felbamate: Clinical outcomes and effect of age and concomitant antiepileptic drug use on its clearance

Purpose:  To determine the effects of long‐term use of felbamate (FBM) on weight, complete blood count, liver function tests, and seizure control, and also to determine the effect of age on FBM clearance.

Steady-state pharmacokinetics and bioavailability of immediate-release and extended-release formulations of lamotrigine in elderly epilepsy patients: Use of stable isotope methodology

A classic 2‐period crossover bioavailability study was conducted to evaluate the relative and absolute bioavailability of immediate‐release (IR) and extended‐release (XR) lamotrigine formulations under steady‐state conditions in elderly patients with epilepsy. On treatment days, each subjects morning dose (IR or XR lamotrigine) was replaced with an intravenous 50‐mg dose of stable‐labeled lamotrigine. Lamotrigine concentrations were measured at 13 points between 0 and 96 hours. XR and IR lamotrigine formulations were similar with respect to steady‐state area under the concentration‐time curve from 0 to 24 hours (AUC0–24 h ss), average concentration (Cavg, ss), and trough concentration (Cτ, ss). A 33% lower fluctuation in concentrations with XR was observed relative to IR lamotrigine. The time to peak concentration (Tmax, ss) was delayed for XR lamotrigine (3.0 vs 1.3 hours) with lower peak concentration (15% lower). The absolute bioavailability for IR and XR formulations was 73% and 92%, respectively. The formulations were bioequivalent with respect to AUC0–24 h ss, Cτ, ss, and Cavg, ss indicating that it may be possible to switch directly from IR to XR lamotrigine without changes in the total daily dose.

Intramuscular and intravenous levetiracetam in humans: Safety and pharmacokinetics

A study in dogs demonstrated that the commercially available formulation of IV levetiracetam (LEV) could be given safely IM and was quickly and completely absorbed. In this crossover study, 5 women and 5 men were given IM and IV LEV. This study demonstrates that administration of 5ml (500mg) IM LEV is well tolerated and its bioavailability is equivalent to an IV injection.