Richard D. Scheyer

Clinical and electrographic effects of acute anticonvulsant withdrawal in epileptic patients

We retrospectively investigated the effects of acute antiepileptic drug (AED) withdrawal on seizure symptomatology—including frequency, clinical features, and electrical onset—by studying 35 patients during evaluation for epilepsy surgery. The highest risk for both partial and secondary generalized seizures occurred during absent or subtherapeutic, and not during rapidly falling, AED levels. AED withdrawal had minimal effect on clinical symptomatology or electrographic onset.

Differentiation of temporal lobe ictal behavior associated with hippocampal sclerosis and tumors of temporal lobe.

Summary: Ictal behavioral characteristics may reflect seizure spread patterns and provide a clue to seizure onset location, between or within specific cerebral lobes. Sequential symptomatology might therefore distinguish patients with hippocampal sclerosis from patients with temporal lobe tumors. To determine ictal behavioral differences in patients of these groups, we analyzed 145 seizures of 33 patients with hippocampal sclerosis (group I) and 79 seizures of 22 patients with temporal lobe tumors (group 11). First appearance of a variety of ictal behavioral characteristics was determined in three phases (first 5 s, 5–60 s, and from 60 s to mental clearing) for patients in both groups. Ipsilateral hand automatisms were significantly more frequent in the first 60 s in group I (p < 0.005). Onset of contralateral head turning was observed in the first 5 s only in group Il (p < 0.05). First appearance of leg automatisms in group I and of oral automatisms in group Il were very rare in phase 2 (p < 0.01, p < 0.005). Time of onset of other ictal behavioral characteristics and duration of seizures were not statistically different between the two groups. Ictal behavioral characteristics varied among and within patients and patient groups, but certain behavioral characteristics were helpful in differentiating these two groups of temporal lobe epilepsy (TLE) patients.

Phenytoin concentrations in the human brain: An in vivo microdialysis study

We report the first human study of phenytoin concentration using in vivo microdialysis, which permits sampling the extracellular environment of the brain. This technique has been applied to patients undergoing intracranial electrode investigation for intractable epilepsy. By varying the rate of perfusion (from 2.5 to 0.25 microliters/min), it is possible to quantify the concentration of drug in the extracellular fluid (ECF), which reflects the concentration on the outer neuronal cell membrane. Samples were obtained from four catheters in two patients, in whom serum phenytoin (PHT) concentrations were held constant. Unbound serum concentrations were measured following ultrafiltration at 37 degrees C. In one patient, with left and right hippocampal probes, steady state ECF/unbound serum ratios were 87 and 84% respectively. In the second patient, with hippocampal and frontal probes, ECF/unbound serum ratios were 87 and 85% respectively. Flow rate for 50% maximal recovery averaged 1.65 microliters/min (1.5-1.7 microliters/min). We found that steady state ECF PHT concentrations corresponded closely to unbound serum concentrations. No differences are observed between different sites within the brain. Flow rates needed for equilibration of dialysate with the extracellular space were slower than reported for carbamazepine, but faster than those we found for carbamazepine-epoxide and valproate.

Measurement of carbamazepine and carbamazepine epoxide in the human brain using in vivo microdialysis

We report the first study of carbamazepine and carbamazepine-10,11-epoxide concentrations determined by using intracerebral microdialysis in three patients undergoing depth electrode studies for the evaluation of medically intractable epilepsy. Very small microdialysis catheters, affixed to and inserted with the depth electrodes, sampled drug concentration in the extracellular environment. We perfused artificial extracellular fluid continuously, and varied the perfusion rate to permit estimation of the absolute drug concentration in the extracellular space. Serum samples were obtained simultaneously. The relation between dialysate and extracellular concentration (recovery fraction) depended, in vivo but not in vitro, on the relative lipophilicity of the compounds, suggesting that diffusion of the drug within the brain is a major determinant of microdialysate drug concentration. When this is taken into account, the steady-state extracellular concentrations of these compounds closely mirror their unbound serum concentrations.

In vivo determination of valproate binding constants during sole and multi-drug therapy.

Valproate (VPA) is present in humans and is largely bound to protein. Only free drug is metabolized, and antiepileptic and toxic effects are probably related to free concentrations. By measuring serial free and total serum VPA levels after routine oral doses, we have determined individual in vivo protein binding parameters for 37 patients after a total of 49 separate drug administrations. Binding site concentrations and dissociation constants were fitted using a nonlinear algorithm. On sole VPA (n = 28) the mean dissociation constant was 91 mumol/L, and the mean concentration of binding sites was 1,176 mumol/L. Evidence suggests a second, nonsaturable binding site. Fraction of unbound VPA ranged from 5.4% at low levels up to 38.7%, rising with increasing total concentration. Concurrent therapy with phenytoin (n = 7) or carbamazepine (n = 8) did not cause displacement of VPA. Changes in free fraction were consistently observed during the interdose interval. The data demonstrate that the binding changes are not a factor in decreased VPA levels during coadministration of other antiepileptic drugs.

Chapter 23 Involvement of glutamate in human epileptic activities

Publisher Summary Epilepsy may be described as a disruption of the normal balance between excitation and inhibition. Much effort has been devoted toward understanding the role of perturbations of the excitatory neurotransmitter glutamate. Glutamatergic abnormalities are well established for certain human epilepsies. In the past, elevated brain glutamate was found in the brain of a child who died because of the status epilepticus related to pyridoxine dependency; a genetic condition in which glutamic acid decarboxylase (GAD)—the enzyme that converts glutamate to gamma-aminobutyric acid (GABA)—does not function normally. In this patient, the effect of dysfunctional GAD could not be isolated from the effects of status epilepticus. Several antiepileptic drugs have anti-glutamatergic actions that may account for a part of their antiepileptic effects. Felbamate inhibits binding of glycine at the NMDA receptor. Lamotrigine and perhaps carbamazepine may decrease presynaptic glutamate release by blocking sodium and perhaps calcium channels. The concept of epilepsy as an excess of excitatory activity has made glutamate an appealing target for study. Most evidence of its involvement is indirect, as elevated glutamate levels in brain or cerebrospinal fluid (CSF) of individuals with frequent seizures could be a result of metabolic, rather than neurotransmitter, glutamate.

Simultaneous HPLC Analysis of Carbamazepine and Carbamazepine Epoxide in Human Brain Microdialysate

Abstract Intracerebral microdialysis has become a standard method for neurochemistry studies and is becoming recognized as an important new method for pharmacological studies. The technique permits repeated measurement of drug concentrations in the brain extracellular fluid with minimal disturbance of the neuronal environment. The sample volumes are exceedingly small, on the order of tens of microliters. This is countered by the purity of the samples, reducing the need for extraction prior to assay. We present a HPLC assay capable of reliably measuring the concentrations of the antiepileptic drug carbamazepine and its metabolites carbamazepine-10,11-epoxide and carbamazepine-10,11trans-diol.

Review of new antiepileptic drugs (AEDs)

zures (3). If these results are borne out when the clinical trials have been completed, then Drs. Kamin and colleagues are correct that the lhAh model fails to predict the antiabsence efficacy of TPM. Nevertheless, we stand by our statement that the lWlh model is superior to the high-dose PTZ model in predicting the effects of AEDs against human absence seizures. To date, 10 AEDs (ethosuximide, clonazepam, valproate, phenytoin, carbamazepine, lamotrigine, vigabratin, tiagabine, gabapentin, and TPM) have been tested against seizures in both the lWlh and high-dose PTZ models. Even assuming that the ZWlh model failed to correctly predict the effects of TPM, this model correctly predicted the effect of the other 9 AEDs, yielding a predictive rate of 90%. By comparison, the high-dose PTZ model yielded a predictive rate of only 60%. Moreover, if the preliminary report of antiabsence efficacy of TPM in humans is not supported by the final results of clinical trials, then the predictive rate of lWlh will be loo%, compared to 50% for the high-dose PTZ model. We agree with Drs. Kamin and colleagues that there “is a need for more animal models that can predict pharmacological efficacy in specific types of epilepsy.” Patients with absence seizures comprise a clinically heterogeneous population, and so the use of several different animal models may improve the likelihood of detecting new AEDs that will be efficacious against subgroups of human patients. For this reason, it would appear reasonable to use both genetic and pharmacologic models to screen putative antiabsence AEDs.

Near-patient rapid assay of phenytoin concentration.

Summary: The Biotrack 516 is a simple, automated whole blood phenytoin (PHT) assay that reports corresponding total serum concentrations in 3 min. We compared Biotrack results in 58 patients with the total and unbound serum PHT concentrations measured by the standard TDx fluorescence polarization immunoassay. Correlation with total TDx concentration was high (r = 0.98); median absolute error was 1.4 μg/ml. Correlation of unbound PHT with Biotrack (r = 0.95) was comparable to correlation of unbound and total TDx (r = 0.94). The Biotrack assay is a promising method for clinical monitoring of PHT concentrations.