Michael B. Tennison

Discontinuing Antiepileptic Drugs in Children with Epilepsy: A Comparison of a Six-Week and a Nine-Month Taper Period

BACKGROUND The optimal regimen for discontinuing antiepileptic medications in children with epilepsy is unknown. METHODS We randomly assigned 149 children to either a six-week or a nine-month period of drug tapering, after which therapy was discontinued. Each group was composed of patients who had been seizure-free for either two or four years before drug tapering was begun. Most patients were receiving one antiepileptic drug; none were taking more than two. The children were evaluated periodically during and after the taper period. Sixteen patients were lost to follow-up before the beginning of the taper period. Proportional-hazards regression analysis was used to assess the risk of seizure recurrence among the remaining 133 patients. RESULTS Seizures recurred in 53 patients (40 percent). The mean duration of follow-up was 39 months (range, 11 to 105) for the patients who did not have a recurrence of seizures. Neither the length of the taper period (six weeks vs. nine months, P = 0.38) nor the length of time the patients were free of seizures before the taper period was begun (two years vs. four years, P = 0.20) significantly influenced the risk of seizure recurrence. The presence of mental retardation (relative risk, 3.1, 95 percent confidence interval, 1.5 to 6.2) or spikes in the electroencephalogram at the time of tapering (relative risk, 1.9, 95 percent confidence interval, 1.0 to 3.4) increased the risk of seizure recurrence. CONCLUSIONS The risk of seizure recurrence during drug tapering and after the discontinuation of antiepileptic drug therapy in children with epilepsy is not different whether the medications are tapered over a six-week or a nine-month period.

Movement disorder after withdrawal of fentanyl infusion

ance and physical dependence to a short-acting benzodiazepine, midazolam. J Pharmacol Exp Ther 1990;252:1125-33. 14. Busto U, Sellers EM, Naranjo CA, Cappell H, Sanchez-Craig M, Sykora K. Withdrawal reaction after long-term therapeutic use of benzodiazepines. N Engl J Med 1986;315:854-9. 15. Vree TB, Shimoda M, Driessen J J, et al. Decreased plasma albumin concentration results in increased volume of distribution and decreased elimination of Midazolam in intensive care patients. Clin Pharmacol Ther 1989;46:537-44. 16. Coffey B, Shader RI, Greenblatt D J. Pharmacokinetics of benzodiazepines and psychostimulants in children. J Clin Psychopharmacol 1983;3:217-25. 17. Rail TW: Drugs used in the treatment of asthma: the 18.

Möbius syndrome in infant exposed to cocaine in utero

The pathophysiology of Möbius syndrome has been debated for decades. A vascular etiology is currently favored because it explains the wide clinical spectrum of this syndrome. An infant is reported who was born with Möbius syndrome after a pregnancy complicated by heavy maternal use of cocaine and alcohol. We speculate that cocaine-induced vasoconstriction at a critical time of cerebrovascular development produced a vascular disruption sequence leading to the Möbius syndrome.

Valproate metabolites and hepatotoxicity in an epileptic population.

Summary: Idiosyncratic hepatotoxicity, although rare, is of major concern when one is treating patients with valproate (VPA). Several clinical criteria are associated with an increased risk of developing this complication, but more specific predictors are needed. It has been postulated that 4‐en‐ VPA or one of its further metabolites may be responsible for the hepatic toxicity and that under certain conditions the metabolism of VPA is shifted to this product. We postulated that measurement of serum concentrations of 4‐en‐VPA or another metabolite might be a simple technique that would be predictive of risk for developing idiosyncratic hepatotoxicity. Because this complication is rare, we chose to analyze our data by a multiple linear regression model, exploring associations between VPA or three of its metabolites and clinical risk factors for hepatotoxicity. 4‐en‐VPA correlated with older age and absence of encephalopathy. 4‐en‐VPA was only seen in patients receiving polytherapy; all patients were also receiving CBZ. 2‐en‐VPA correlated with poor nutritional status. We conclude that routine measurement of serum 4‐en‐VPA is unlikely to be a useful predictor of risk for developing fatal hepatotoxicity. Serum concentrations of 4‐en‐VPA may not reflect presence or effects in the liver as it may be metabolized to further intermediates or be bound to tissue. Thus, serum levels of 4‐en‐VPA do not reflect its important role in the pathogenesis of hepatotoxicity. This metabolite was détécted only in patients receiving polytherapy, a potent risk factor for developing this rare complication.

Successful treatment of childhood prolonged refractory status epilepticus with lacosamide

Prolonged, refractory status epilepticus is a rare clinical syndrome that is associated with severe morbidity and mortality. Lacosamide is a newly approved medication for treatment of partial onset seizures in adults, which has a novel mechanism of action. Experimental data and recent reports suggest that lacosamide could be effective in status epilepticus. We report a child with prolonged, refractory status epilepticus that persisted for 10 weeks despite treatment with multiple anti-epileptics and anesthetics and was then aborted with lacosamide. This is the first report of the effect of lacosamide in prolonged refractory status epilepticus, and the first report of lacosamide efficacy in status epilepticus in a child.

Neuropsychologic functioning of human immunodeficiency virus-infected children with hemophilia.

Efforts to detect subtle but objective neuropsychologic deficits could clarify the early involvement of the central nervous system and the progression of human immunodeficiency virus (HIV) infection in older children and young adolescents. Baseline examinations of 63 children and adolescents with hemophilia were conducted by examiners unaware of HIV status or staging or of our studys major hypotheses. They measured six domains of neuropsychologic functioning (motor, language, memory, attention, visual processing, and problem solving), and no differences between groups of similar age, race, and socioeconomic status defined by HIV seropositivity (n = 25) and HIV seronegativity (n = 38) were revealed. A high incidence of subtle neuropsychologic deficits relative to (1) age norms and (2) individual cognitive potential was found on measures of motor performance, attention, and speeded visual processing within both infected and uninfected groups. On the basis of these baseline data, it seems premature to attribute early, subtle neuropsychologic deficits in seropositive children with hemophilia to the central nervous system effects of HIV infection.

Heart rate variability during interictal epileptiform discharges

RATIONALE Seizures may produce a variety of autonomic alterations. These alterations may occur due to evoked autonomic reflexes or as a direct cortical effect on autonomic control. In animal studies, lock step phenomena of interictal discharges to autonomic output have been repeatedly documented. However, the association of interictal discharges and autonomic output is not as well established in humans. METHODS RR intervals timely locked to interictal epileptiform discharge (RR(n)) were compared to RR intervals immediately following (RR(n+1)) interictal discharges in 40 patients with focal onset epilepsy and low baseline heart beat variability. RESULTS In 20 patients with 200 left sided interictal epileptiform discharges, RR(n) shortened in 100 and prolonged in 31 when compared to RR(n+1) intervals. While in 20 patients with 200 right sided interictal epileptiform discharges RR(n) intervals shortened in 17 and prolonged in 116 (Chi square P<0.001). No consistent differences in RR(n) intervals variability between frontal versus temporal localization of the interictal discharges from the same side was found. CONCLUSIONS Interictal discharges, may influence autonomic control over the cardiac cycle and agree with animal studies. Further study of the relationship of interictal discharges to autonomic output is needed to delineate the potential lateralized influences over autonomic nervous system.

Anticonvulsants-induced chorea: a role for pharmacodynamic drug interaction?

Chorea is a rare side effect of anticonvulsants. We describe three patients who developed chorea secondary to anticonvulsant combination use. A mechanism to explain this finding is proposed. After identification of an index case with anticonvulsant-induced chorea, we reviewed the electronic data base records for all patients with seizures followed in the epilepsy clinics at our university-based hospital for cases of dyskinesia associated with anticonvulsants. Two additional patients, one adult and one pediatric patient were identified. Three patients developed chorea while receiving combination anticonvulsants. Two patients had transient chorea that resolved with withdrawal of one of the drugs. All three patients were using phenytoin and lamotrigine in combination when the chorea started, chorea improved with tapering one of the medications. Polytherapy with certain anticonvulsants may predispose patients to drug-induced chorea. A particular increased risk was seen with combinations that have phenytoin and lamotrigine. This could be due to an additive or a synergistic effect on central dopaminergic pathways.

Intraindividual variability of carbamazepine, phenobarbital, and phenytoin concentrations in saliva.

Summary: The intraindividual variability of salivary carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) concentrations was studied in six healthy male volunteers. During three consecutive 1-week phases, subjects took one of the antiepileptic drugs (AED) for 5 days. Nine saliva and nine blood samples were collected simultaneously over the last 4 days of each phase. Salivary, unbound serum, and total serum CBZ, PB, and PHT concentrations were determined by fluorescence polarization immunoassay. Individual mean saliva (Cs)/total serum (Ct), unbound serum (Cu/Ct, and Cs/Cu concentration ratios for CBZ, PB, and PHT were similar to those reported previously. The intraindividual mean (SD) coefficients of variation (%) of the Cs/Ct, Cu/Ct, and Cs/Cu ratios for CBZ were 4.8 ± 2.2%, 4.4 ± 1.8%, and 5.0 ± 1.9%, respectively; for PB they were 5.1 ± 0.8%, 3.6 ± 0.9%, and 6.4 ± 1.0%, respectively; and for PHT they were 7.4 ± 3.1%, 5.5 ± 1.2%, and 8.3 ± 3.2%, respectively. The mean Cs/Ct and Cu/Ct ratios for CBZ and PHT were not significantly different, but they were different for PB (p = 0.01). However, the range of individual coefficients of variation of the Cs/Ct ratio for PB was 4.0–6.2%, which is acceptable for clinical monitoring. We conclude that the intraindividual variability of CBZ, PB, and PHT concentrations in saliva, based upon the saliva/serum concentration ratios of each AED, is not a factor that should dissuade clinicians from using saliva for the therapeutic monitoring of these agents.

Evaluation of the ames seralyzer for the determination of carbamazepine, phenobarbital, and phenytoin concentrations in saliva

The performance of the dry-phase apoenzyme reactivation immunoassay system (ARIS) for the measurement of carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) concentrations in saliva was compared with fluorescence polarization immunoassay (FPIA). Blood and saliva samples were collected from 163 adult and pediatric epilepsy patients, then analyzed using both methods. Regressions between ARIS saliva CBZ, PB, and PHT concentrations, and FPIA unbound and total serum concentrations were highly correlated, but the ARIS technique was somewhat less precise than the FPIA. Valproic acid co-medication did not affect the relationships between ARIS and FPIA saliva concentrations and unbound serum concentrations of PHT, but did disrupt the relationship between ARIS and FPIA saliva PHT and total serum PHT. The sensitivity, specificity, predicted value positive (PV+) of a therapeutic concentration, and predicted value negative (PV-) of a concentration outside the therapeutic range for the ARIS saliva technique compared very well with FPIA for CBZ, PB, and PHT. The ARIS technique for CBZ, PB, and PHT saliva determination provides acceptable accuracy, precision, and sensitivity for therapeutic monitoring. In practice, the benefits of the ARIS saliva technique, including ease of collection, safety, patient/parent acceptance, and short analysis time, are striking.