J. Overweg

Acute Effects of Lamotrigine (BW430C) in Persons With Epilepsy

Summary: Sixteen epileptic patients took single doses of lamotrigine, 120 mg or 240 mg. Six photosensitive patients showed reduction (with abolition in two) in photo‐sensitivity after lamotrigine administration. Five subjects with frequent interjetai spikes showed reduction in spike frequency over 24 h after lamotrigine administration. The half‐life (t1/2) of lamotrigine in subjects taking sodium val‐proate was prolonged, whereas the t1/2 in subjects taking carbamazepine and/or phenytoin was reduced. The area under the curve of co‐medication plasma levels was not affected by a single dose of lamotrigine. Five patients reported mild and generally transitory side effects; some of which represented exacerbation of preexisting complaints.

Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy

A double-blind, placebo-controlled trial is reported of lamotrigine as add-on treatment in therapy-resistant epilepsy. A within-patients serial design was used, with two 3-month treatment periods and an intervening 6-week washout/crossover period. An unblinded investigator adjusted lamotrigine dosage to achieve a plasma concentration within a previously predicted therapeutic range. All patients had therapy-resistant partial seizures, some in combination with other seizure types and were without serious neurological or intellectual deficit. Of 34 patients recruited only one was withdrawn because of an adverse experience (maculo-papular rash) probably related to the experimental drug and 30 completed the trial. The other 3 withdrawals were due to default during baseline, dispensing error and cholecystectomy. There was a modest statistically significant reduction in total and partial seizures on lamotrigine compared to placebo treatment. There was no difference in adverse experiences or abnormal biochemical or haematological findings between the lamotrigine and placebo periods. The plasma concentrations of concomitantly administered antiepileptic drugs were not affected by lamotrigine treatment. It is concluded that lamotrigine shows promise as an antiepileptic drug with low toxicity.

Electroencephalographic findings in antiepileptic drug trials: a review and report of 6 studies

A recent survey has shown that the EEG is of doubtful value as an outcome variable in clinical antiepileptic drug (AED) trials. Analysis of findings in 6 trials shows that in only two no consistent effect was seen; that in two power spectral analysis provided additional information to confirm changes in background activity; that in one a close relationship could be established between reduction in frequency of epileptiform discharges and administration of the trial drug (lamotrigine), and that in one, even though no correlation was apparent during use of the AED, there was an increase in frequency of both discharges and seizures on withdrawal (CGP 11952). In general the EEG would appear to be unsuitable as an outcome variable for assessing drug efficacy in AED trials. On the other hand it may give insight into the mode of drug action. Conceivably more efficient use could be made of the EEG if the methodology--including patient selection, consideration of circadian rhythms and of combination AED therapy, and standardized long-term recording--were to be improved and automation and quantification techniques used.

Add-On Therapy in Epilepsy with Calcium Entry Blockers

In view of the known role of Ca2+ in the paroxysmal depolarization shifts of epileptic neurones, the possibility arises that certain Ca2+ entry blockers possess antiepileptic activity. The only drug of the class which readily passes the blood-brain barrier is flunarizine. This is effective in experimental models of epilepsy and produced significant seizure reduction in two therapeutic trials in therapy-resistant patients. It has few and mild side effects at therapeutic blood levels.

A double-blind, placebo-controlled evaluation of the efficacy and safety of loreclezole as add-on therapy in patients with uncontrolled partial seizures

Sixty-two patients with uncontrolled partial seizures participated in a 12-week, double-blind, placebo-controlled add-on-trial. Thirty-two patients received loreclezole and 30 a placebo as add-on therapy. Loreclezole was targeted at a plasma level of 1-2 mg/l. In spite of an antiepileptic therapy, usually with 2 or 3 antiepileptic drugs, these patients had at least 4 seizures a month during the baseline period. At the end of the treatment phase with loreclezole and placebo, individual responses varied widely. The median change in the daily seizure frequency was not significantly different in the 2 groups. However, when individual responses are considered, 6 patients in the verum group (19%) experienced a seizure reduction of 50% or more, compared with no patients in the placebo group. During the trial, only mild adverse events were reported in both the loreclezole and the placebo group, nor were any clinically relevant abnormalities seen in the haematological and biochemical analysis. The efficacy and safety of higher loreclezole plasma concentrations were studied in a long-term follow-up trial, the results of which are presented in the following article.

Quantitative Analysis of 18/FDG-PET in the Presurgical Evaluation of Patients Suffering from Refractory Partial Epilepsy

CT, MRI, 18/FDG-PET and Depth. EEG, performed with subdural and depth electrodes were part of the presurgical evaluation in 22 patients. Statistical analysis of 18/FDG-PET was performed to compare cerebral utilization of glucose to that of normal age matched controls. The findings of CT, MRI, and quantitative analysis of PET are compared with those of ictal Depth. EEG. A positive correlation between CT and Depth. EEG was obtained in 23% of the patients and between MRI and Depth. EEG. in 50%. For both imaging techniques a negative correlation was found in 5%. Regional abnormalities were found with quantified PET in 95% of the patients and were concordant with Depth. EEG. for side of onset in 77% of the patients and for lobe of onset in 59%. A possibly false localising PET result for lobe of onset was obtained in 8 patients (36%). Limitations of PET were most apparent in patients with regional mesiolimbic or bilateral seizure onset. A favourable outcome of surgery was associated usually with positive convergence of both methods. PET may be a valuable contribution to the research and management of partial complex epilepsy, but at present cannot be considered a reliable alternative to invasive EEG methods in patients without clear unilateral focus localization on surface EEG.

Single-dose efficacy evaluation of loreclezole in patients with photosensitive epilepsy

Photosensitivity can be used as a model in short-term studies for assessing the efficacy of new antiepileptic drugs in man. As a quantitative measure of photosensitivity, the photosensitivity range is employed. This is the range between the highest and the lowest flash rate producing a photoparoxysmal response (generalized paroxysmal activity on the EEG). An efficacious new antiepileptic drug should, like all currently available antiepileptic drugs, reduce the photosensitivity range. Single-dose administration of 100-150 mg of loreclezole resulted in a decreased photosensitivity in all patients tested. This effect was attributable to loreclezole as no acute interactions with valproic acid could be demonstrated. The rapid onset of activity indicates that loreclezole readily passes the blood-brain barrier. The doses applied were very well tolerated.

Review of Flunarizine in Epilepsy

A feature of epileptogenesis is burst firing of individual neurons. The burst comprises a slow paroxysmal depolarizing ion shift (PDS) upon which is superimposed a train of action potentials [6, 36]. Bursting depends largely on influx of Ca2+, although other ionic currents are also involved [37, 56].