Modification of slow cortical potentials in patients with refractory epilepsy: a controlled outcome study.

PURPOSE: To compare self-regulation of low-frequency EEG components (slow cortical potentials, SCPs) with other methods of seizure control for patients with drug-refractory partial epilepsy and to separate the real anticonvulsive effect from placebo effects. METHODS: Results of a treatment program of SCP self-regulation (experimental group) are compared with two groups of patients, one of which learned self-control of respiratory parameters (end-tidal CO2 and respiration rate: RES group); the other received medication with new anticonvulsive drugs (AEDs) in combination with psychosocial counseling (MED group). Clinical, cognitive, behavioral, and personality measures were assessed before and after treatment. In addition, to control for placebo responses, patients repeatedly estimated their beliefs in the efficiency of the respective treatment, their satisfaction and expectations, and the quality of the relationship with their therapists. RESULTS: SCP and MED groups showed a significant decrease of seizure frequency, but the RES group did not. Clear positive changes in the sociopsychological adjustment were obtained in all three groups, with the maximal improvement being attained in the RES group. CONCLUSIONS: All kinds of therapy result in considerable improvement of patients' emotional state, which may in part be due to potential placebo effects: however, this improvement is not related to the quality of the therapeutic effect proper (i.e., seizure reduction). Traditional double-blind control group designs are inappropriate for behavioral interventions or treatments with psychoactive pharmacologic drugs. Rather, specific tests can be developed to control the placebo effect and to separate it from the genuine therapeutic effects.

Negative potential shifts and the prediction of the outcome of neurofeedback therapy in epilepsy.

About two-thirds of epilepsy patients who learn to control their slow cortical potential shifts (SCP) reduce their seizure rate, but the remaining third does not demonstrate clinical improvement. In the present study, this finding was replicated in a group of 27 patients with focal epilepsy. We found that patients who consistently produced larger negative SCP in all conditions during the first phase of treatment, showed no decrease in seizure frequency during the six-month follow-up, as compared with the three-month baseline phase. The large negative SCP explained about one-third of the variance of the clinical outcome. Age, medication, seizure history, or the localization of focus were found to be unrelated to clinical improvement.

Once-daily versus twice-daily vigabatrin: is there a difference? The results of a double-blind pilot study.

PURPOSE: Vigabatrin (VGB) has been approved in Europe and is prescribed for either once or twice-daily administration. This choice has been based on the pharmacodynamic activity of VGB. The purpose of this study was to compare the efficacy and tolerability of these two different medication regimens. METHODS: The study design was a double-blind randomized two-period cross-over study in adults who had responded to add-on VGB for previously uncontrolled seizures. Each study period consisted of three months. Patients were maintained on the same daily dose of VGB to which they had demonstrated a clinical response. In addition to the primary efficacy criteria of seizure frequency on the two treatment regimens, this study included blinded ratings of overall efficacy and "well being" by both physician and patient. The primary tolerability criterion was the reported incidence of adverse events by phase. RESULTS: Fifty patients were initially entered into the study, and 13 patients withdrew before completion, only one reported as due to an adverse event. There was no statistical difference in seizure frequency or the tolerability of the medication. Blinded physician and patient rating scales for seizure control, and patient well being showed a nonstatistical trend toward once-daily administration as compared with twice-daily administration. CONCLUSIONS: This clinical study provides support for the pharmacological evidence that this preparation may be administered on a once or twice daily basis, depending on the individual patient's preference, total dosage and co-medication.

Comparison of total and free phenytoin serum concentrations measured by high-performance liquid chromatography and standard TDx assay: implications for the prediction of free phenytoin serum concentrations.

The free fraction of phenytoin (PHT) in serum increases considerably in combination with valproic acid (VPA), depending on the VPA concentration. Equations to predict the free PHT concentration (PHTf) from the total PHT concentration (PHTt) and from the VPA concentration were developed by Haidukewych and colleagues. (equation 1: PHTf = 0.095 x PHTt + 0.001 x VPA x PHTt) and May and colleagues (equation 2: PHTf = 0.0792 x PHTt + 0.000636 x VPA x PHTt]; in both equations, PHTf, PHTt, and VPA are given in microg/ml. Obviously, the equations give different predictions. The aim of this study was to investigate whether different methods for the determination of PHTt and PHTf were responsible for the differences; equation 1 was calculated from standard TDx measurements and equation 2 from high-performance liquid chromatography (HPLC) values. A total of 52 samples from patients with VPA (n=26) or without VPA (n=26) were analyzed using HPLC and TDx. The concentrations measured by HPLC and TDx were highly correlated but TDx yields significantly higher PHTt (Y = 0.98 x X + 2.46; X = HPLC, Y = TDx, r2 = 0.957) and, in particular, higher PHTf concentrations (Y = 1.03 x X + 0.30; X = HPLC, Y = TDx, r2 = 0.919), compared with our HPLC method. The accuracy of the predictive equations depends on the method used for the determination of PHTt and PHTf. The best predictions of PHTf were obtained if equation 2 and HPLC measurements were used. However, the differences in the predicted PHTf could only partly be explained by the different methods of determination.

Stability of cortical self-regulation in epilepsy patients.

Biofeedback-supported self-regulation of slow cortical potentials (SCP) is increasingly being used for treatment of intractable epilepsy. However, it is unknown whether the acquired ability to regulate one's own cortical potentials remains stable over time. In this study, 18 patients with drug-resistant partial epilepsy performed 35 training sessions in which they learned to generate slow cortical potential shifts in either positive or negative direction. At the end of training, they differentiated significantly between required cortical positivity and required cortical negativity. Six months after this point, they still demonstrated an unchanged between-condition differentiation. The performance in the booster session was particularly good in trials without continuous SCP feedback. The ability to generate positive SCP shifts was related to decrease of seizure frequency during the 6 months follow-up period compared with the 3 month baseline period. This data indicate that the acquired ability of humans to regulate their cortical potentials did not decrease over a 6 month period but rather, tended to consolidate.

Self-regulation of slow cortical potentials in epilepsy: a retrial with analysis of influencing factors.

Twenty sessions of biofeedback training were carried out with 12 drug-resistant patients with focal epilepsy who learned to produce either negative or positive shifts of their slow cortical potentials (SCPs) at vertex. Feedback trials were interspersed with transfer trials in which only a discriminative stimulus (signalizing whether positivity or negativity was required) was presented, without feedback signal. Patients were able to differentiate significantly between the conditions of cortical positivity and cortical negativity, with larger differentiation scores being obtained in feedback trials than in transfer trials. The amplitude of positivity generated in the positivity condition increased linearly across sessions both in feedback and in transfer trials. The largest negativity was produced in the 5th session; after this, more transient negativities were generated, whose amplitude decreased towards the end of trial. The mean severity of seizures, estimated as the frequency of seizures weighted by their subjective 'strength', decreased significantly after training as compared to the pre-training phase. The data suggest that (1) patients could learn to achieve a state of cortical disfacilitation and (2) with progressed learning, they became less motivated for (or afraid of) producing considerable negative shifts, since extensive negativity may reflect cortical over-excitation and therefore be associated with early signs of seizures. The inability of producing cortical negativity is however not necessarily a bad predictor.

Comparison of phenytoin and carbamazepine serum concentrations measured by high-performance liquid chromatography, the standard TDx assay, the enzyme multiplied immunoassay technique, and a new patient-side immunoassay cartridge system.

Steady-state concentrations of phenytoin (PHT) and carbamazepine (CBZ) were measured by a novel patient-side immunoassay system with a single-use cartridge (Biotrack 516). The Biotrack determinations were performed in whole blood and extrapolated to serum on the basis of the hemoglobin content. The results were compared with serum concentrations measured by high-performance liquid chromatography (HPLC) or the standard TDx and enzyme multiplied immunoassay (EMIT) techniques. A total of 222 samples from epileptic patients on PHT and 322 samples from patients on CBZ were analyzed. In the case of PHT there was a highly linear correlation [r = 0.985, y = 1.113x-0.589; x = HPLC, y = Biotrack] between HPLC and the Biotrack system in the concentration range of 2.5-30 micrograms/ml. In the case of CBZ, the correlation between HPLC and the Biotrack system in the concentration range of 2.0-20 micrograms/ml was somewhat lower [r = 0.931, y = 1.29x-0.136; x = HPLC, y = Biotrack]. Comparable results were also found for the correlation of the Biotrack system with the TDx assay or with the EMIT assay, respectively. Comedication had no influence, or only a minor influence (valproic acid), on the concentration of PHT and CBZ measured by the Biotrack system. Furthermore, the concentration of the metabolite carbamazepine-10, 11-epoxide had no influence on the concentration of CBZ measured by the Biotrack system. Since the automated cartridge system is simple, can be used rapidly, and is performed with only a few drops of blood, this technique offers some advantages for routine clinical use, especially under outpatient conditions.

Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial.

The new antiepileptic drug zonisamide was evaluated in a European multicenter parallel-group double-blind trial as add-on treatment for 139 patients with refractory partial epilepsy. During treatment with zonisamide complex partial seizures decreased by 27.7% compared to placebo (P < 0.05) and the median rate dropped from 12/month to 7.1/month with no changes in the placebo group (P < 0.007). During the 12-week double-blind phase a 50% reduction of all seizures was recorded in 29.9% of the patients treated with zonisamide vs. 9.4% during placebo. Complete remission was observed during treatment with zonisamide in 6.2%. The plasma concentrations of the concomitant antiepileptic drugs did not change markedly when zonisamide was added. Adverse events, mostly fatigue, somnolence, dizziness and ataxia, occurred in 59.2% of the patients compared to 27.9% during placebo. Zonisamide was withdrawn in two patients due to adverse events. Kidney stones were not observed nor any relevant clinical chemistry or hematological changes. Zonisamide is an effective antiepileptic drug for add-on treatment of refractory partial epilepsy.