[Social and economic aspects of administration of new antiepileptic drugs]. / Stosowanie nowych leków przeciwpadaczkowych w aspekcie ekonomiczno-spolecznym.

The necessity of analysis of the cost of treatment of patients with epilepsy becomes of primary importance in Poland as a consequence of recent economic transformations affecting the efficiency of health service. The reasons are: high number of patients with epilepsy (approaching 400,000 in a population of about 40 mln) and long time course of illness, taking into account steady, gradual rise of the cost of treatment, even if we accept greater efficiency of the new antiepileptic drugs. However, the analysis of questionnaires provided by patients with epilepsy indicates that optimation of their treatment with introduction of new antiepileptic drugs may be a procedure leading to diminution of the global expenses associated with care of epileptic patients. Identification of factors influencing cost of antiepileptic treatment before and after introduction of new antiepileptic drugs. A group of 150 people chosen at random from a population of persons taking new antiepileptic drugs (vigabatrin, lamotrygin, topiramate, gabapentin, tiagabine) received anonymous questionnaires concerning the time course of their illness. 80 questionnaires were returned. The questions concerned the situation before and after treatment. Statistical analysis included t test for dependent samples-including items such as: number of epileptic seizures and number and days of hospitalization, etc. per year of observation. Significant decrease of the number of epileptic seizures (p < 0.05), number of hospitalizations (p < 0.001), days of hospitalizations (p < 0.001) and neurological consultations (p < 0.001) occurred after optimalization of treatment. Results of our research illustrate significant reduction of direct costs of treatment associated with introduction of new antiepileptic drugs.

Effect of vigabatrin addition on carbamazepine blood serum levels in patients with epilepsy.

Because vigabatrin (VGB) is not metabolized by liver enzymes and does not bind with serum proteins, there is little theoretical chance of it interacting with other antiepileptic drugs. However, our observations have shown that if VGB is added to carbamazepine (CBZ) monotherapy, some patients respond with adverse, toxic symptoms suggesting possible carbamazepine-vigabatrin interaction. This article presents the results of a study of 66 epileptic patients (27 women and 39 men), age 10-66 years (mean, 28.2 years), with focal seizure onset with or without secondary generalization. In these patients, in addition to CBZ therapy with an average dose of 16.7 mg/kg per day (8.6-26.8), VGB, average dose 31.1 mg/kg per day (7.1-57.9), was added. CBZ concentration was measured twice: prior to VGB introduction and 5-12 weeks after the final dose of VGB was reached. In our study 69.7% of patients responded to VGB addition with a significant increase (by at least 10%) in CBZ concentration. A correlation between the value of the increase and the initial level of CBZ prior to VGB addition was found also. Correlational analysis (Pearson's r) revealed a negative correlation between CBZ concentration and increased concentration after VGB addition (r = -0.47, df = 64, P < 0.001). This negative correlation means that if the initial CBZ level is lower, its concentration value after VGB addition is higher.

Carbamazepine effects on afterdischarge, memory retrieval, and conditioned avoidance response latency in hippocampally kindled cats.

Carbamazepine (CBZ) effects on (a) complex partial seizures and afterdischarges (AD), (b) memory retrieval, and (c) conditioned avoidance response (CAR) latencies were studied in a group of 9 hippocampally kindled cats. Significant AD and epileptic seizure suppression was observed in kindled cats after administration of CBZ concurrent with significant improvement in percentage scores on the memory retrieval test. The CAR latencies were longer in kindled cats with or without CBZ than in the conditioned group of cats without both kindling and CBZ. CAR latencies were not significantly different between kindled and kindled-CBZ-treated cats. Thus, the longer latencies in kindled animals cannot be due to CBZ but apparently are related to the effects of kindling. In some kindled animals, longer CAR latencies were reversed by CBZ.

Memory restoration or memory block: differential effects of physostigmine depend on the age of the memory trace.

The authors investigated the effect of physostigmine (Ph) on short-term memory underlying the response-to-change test in rats. In the first test trial (acquisition) the rat could observe the white-black T-maze arms through transparent partitions which prevented the entrance to the arms. In the subsequent trial the rat was allowed a free choice between two identical maze arms, one of them being changed from white to black or vice versa. Physostigmine or saline (NaCl) was injected i.p. 1 min after the acquisition trial. When the retention interval between the two trials was short (10 min), NaCl rats showed a significant preponderance of the changed arm choices, whereas after a longer retention interval (20 min) they selected the changed arm in low percentage. This indicated a rapid decline of memory traces underlying the response to the change of brightness. Physostigmine in a dose of 0.1 mg/kg blocked responding to change after 10 min retention interval, when the memory was strong. However, when tested after a 20 min interval, Ph injected rats showed restoration of memory. After a 15 min interval, retention in both NaCl and Ph injected rats was on a similar, intermediate level. A higher dose of Ph (0.3 mg/kg) had no effect on responding to change after any retention interval examined in this experiment.

EEG afterdischarge patterns and performance of the avoidance response in hippocampally kindled cats.

The relation between EEG limbic afterdischarge patterns and the performance of avoidance response was studied in eight hippocampally kindled cats. Five basic types of EEG afterdischarge patterns were identified in the hippocampal formation: (i) continuous 2-4/s high amplitude spikes or spike and wave complexes; (ii) continuous, 4.5-12/s high amplitude spikes or spike and wave complexes; (iii) dysrhythmic pattern: disorganized irregular spiking, mixed with slow waves at 3-20/s frequency; (iv) continuous, 20-30/s comb-like shaped spiking of moderate amplitude, and (v) trains of high amplitude and frequency irregular spikes, lasting for 0.2-1 s. followed by EEG depression lasting 0.3-1 s. The performance of conditioned response was tested during first 10 s. of afterdischarge development after kindling electrical stimulation of the hippocampus. A statistically significant relation was observed between the EEG afterdischarge patterns seen at the beginning of afterdischarge formation (basically types I, II and III) and the performance of avoidance response, with greatest probability of the response failure with type III of afterdischarge pattern. Latencies of the avoidance responses were prolonged during afterdischarges, in comparison to latencies observed before and after kindling hippocampal stimulation.

Effect of after-discharge EEG patterns on performance and latency of the conditioned avoidance response in hippocampally kindled cats.

The relation between different EEG after-discharge patterns and memory retrieval of the conditioned avoidance response was studied in 8 hippocampally kindled cats. The after-discharge patterns were classified into 5 basic EEG types. The relation was analyzed in three different situations: A, at the conditioning stimulation onset, B, at the conditioning stimulus termination, and C, when conditioning stimulus onset and termination were studied within the same type of EEG pattern of after-discharge. The moment of presentation of the conditioning stimulus was determined by the type of EEG after-discharge pattern. Significant relation was observed between reflex performance and type II and III EEG AD types. The type II (4.5-12/s spiking activity) was associated with a greater proportion of positive responses if presented on the uniform background of EEG after-discharge patterns. During the type III pattern (EEG dysrhythmia), there were more negative than positive responses in all the three experimental situations, especially if the type III EEG pattern was observed at the time of conditioned stimulus termination. The latency of reflex performance measured in the experimental condition C (the same pattern of EEG during conditioning stimulus onset and termination) was longer during the type II EEG pattern of after-discharges than the latencies found during type III EEG activity and in the control group. During type III pattern associated with greatest proportion of response failures there was, however, no increase of reflex latencies. The results suggest differential effect of different EEG after-discharge patterns on memory retrieval of the well established conditioned avoidance response in cats.

The role of body turn-brightness associations in the effect of scopolamine on response-to-change in the rat.

We explored further the different effects of anticholinergics on response-to-change in the passive and active tests. We hypothesized that body turn-brightness associations are formed in the active but not in the passive test, where the turns were prevented by transparent partitions blocking maze arm entrance. This difference might account for the resistance of the active test performance to anticholinergic drugs. To examine this idea, the passive test conditions were modified so that body turns were possible. However, scopolamine (1.0 mg/kg) interfered with response-to-change performance to the same extent as observed previously in the typical passive test procedure. Thus, body turn-brightness associations are not the source of resistance of active test performance to cholinergic receptor blockade.

Cue distinctiveness and response-to-change in scopolamine injected or hippocampal rats.

Our previous findings indicated that hippocampal lesions (H) or scopolamine' injections (Sc) affected stimulus information acquired by distant observation of the white-black T-maze arms (the passive test), but left the information intact when it was gained by T-maze exploration (the active test). Because this difference might reflect the attentional deficit in H or Sc rats, in the present experiment we attempted to investigate the effect of lowered distinctiveness of cues (dark grey vs black T-maze arms) on the performance of rats in the active test. A total of 75 rats were assigned to four groups: (i) damaged in the dorsal hippocampus (H); (ii) sham operated (C); (iii) scopolamine (Sc) injected (1.0 mg/kg i. p.) and (iv) saline injected (NaCL). Each group showed a significant preponderance of choices of the arm which was changed in brightness between the two consecutive trials, separated by 1 min break. The groups did not differ markedly among themselves in the percentage of changed arm choices (H group, 85 percent; C, 74 percent; Sc -72 percent; NaCL, 72 percent). This result indicates that H or Sc rats are able to perceive a slight difference of brightness and to retain it over a period of 1 min. Therefore, the different performance of H as well as Sc rats in the passive and active test, observed previously, cannot be accounted for by the attentional deficit hypothesis.

Effects of atropine on response-to-change.

The effect of atropine on rats response to the change of brightness was investigated in a T-maze, in two procedural test versions differing in the exposure of visual stimuli. In the passive test the rats could observe the white and black arms through clear partitions which blocked the entrance to the arms, while in the active test they were allowed to explore the maze arms. In the subsequent free choice trial, when both arms were of the same brightness (either white or black) atropine in a dose of 16 mg/kg, injected 10 min prior to the exposure of stimuli, affected the rats' performance in the passive test. The druged rats showed random selection of the arms, whereas 80 percent of saline controls chose the arm whose brightness had been changed. In the active test the same dose of atropine had no effect on the choice behavior. Both atropine and saline groups showed a closely similar preference for the changed arm. The effect of atropine on response-to-change was compared to that of scopolamine investigated by us in the previous study.

Scopolamine impairs the response-to-change following observation of the environment but not after its exploration by the rat.

The tendency to select the T-maze arm that has been changed in brightness between two successive trials (response-to-change) was investigated in rats injected with scopolamine (Sc) or saline (NaCl) 20 min before the test. In the "passive" version of the test, when in trial 1 rats could inspect the white-black arms through clear partitions blocking the entrance to the arms, a dose of when in trial 1 rats could inspect the white-black arms through clear partitions blocking the entrance to the arms, a dose of 1.0 mg/kg Sc decreased significantly the number of changed arm choices in trial 2, as compared to saline controls. A lower dose of Sc (0.5 mg/kg) was ineffective. In the "active" test version, when in trial 1 the rats were allowed to explore the white-black arms, doses of 1.0 and 2.0 mg/kg Sc did not affect the preference for the changed arm in trial 2. NaCl rats showed a significant preference for the changed arm choices in both tests. The scopolamine effects on response-to-change, i.e., impairment of performance in the passive but not in the active version, were essentially the same as those found by us previously in hippocampal rats.

How long do rats remember the spatial arrangement of visual stimuli?

The responses to stimulus change consisting in the choice of maze arm where the brightness was changed between two consecutive trials were studied in an enclosed T maze with varying exposure times and retention intervals. The strength of memory involved in the response-to-change test depended on both variables. Memory acquired in 10 min exposure survived around 25 min, while after 1 min exposure memory decayed in less than 15 min. Under conditions of paucity of memory traces rats relied on their directional preferences.