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This report describes the long-term follow-up of 56 patients with refractory partial epilepsy who, within 3 months of vigabatrin add-on therapy (3 g/day), showed a reduction in monthly seizure frequency of more than 50%. The short-term (6 months) and long-term (5 years) effects of vigabatrin on seizure frequency in this patient cohort have been published separately. The reduction in seizure frequency appeared to be long-lasting in the patients followed-up (n = 36) and, importantly, a significant number of the patients (n = 7) became seizure-free, especially during long-term treatment. Thus, the efficacy of vigabatrin appears to be progressive, at least in patients who show an early response to treatment. These results are consistent with experimental findings that suggest that vigabatrin may have anti-epileptogenic and neuroprotective effects., (Copyright 1999 BEA Trading Ltd.)

Nitric oxide has been postulated as a retrograde intercellular messenger for long-term potentiation, a form of synaptic plasticity that is associated with learning and memory processes. In the present study we investigated whether the loss or survival of nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase-containing neurons, which are known to synthesize nitric oxide, would be an useful indicator for evaluating the structural and functional state of the rat hippocampus after status epilepticus that is induced by intraperitoneal injection of kainic acid. Besides NADPH diaphorase histochemistry, two other histological parameters were studied: the grade of cell damage evaluated from silver-impregnated sections, and the number of somatostatin-containing neurons in different hippocampal subfields. We found that the number of NADPH diaphorase-containing neurons in the hilus and granule cell layer correlated well with spatial learning and memory performance as assessed by the Morris water-maze test. The extent of cell damage in the CA1 subfield analysed in silver-impregnated sections and the number of hilar somatostatin-containing neurons also significantly correlated with latencies in the water-maze test. Furthermore, linear regression analysis revealed that the number of somatostatin-containing neurons in the hilus explains about 50% of the variation in water-maze learning. These findings emphasize that although general structural preservation is of crucial importance for the function of the hippocampus also interneurons, such as somatostatin- and NADPH diaphorase-containing neurons, may play an important role during the acquisition phase and processing of information in hippocampal circuitry. Therefore, in addition to evaluating general cell damage, analysis of the cell loss that occurs in the interneuron subpopulations will be beneficial in verifying structural and functional deficits of the hippocampus after status epilepticus.

Previous studies have demonstrated formation of recurrent excitatory circuits between sprouted mossy fibers and granule cell dendrites in the inner molecular layer of the dentate gyrus (9, 28, 30). In addition, there is evidence that inhibitory nonprincipal cells also receive an input from sprouted mossy fibers (39). This study was undertaken to further characterize possible target cells for sprouted mossy fibers, using immunofluorescent staining for different calcium-binding proteins in combination with Timm histochemical staining for mossy fibers. Rats were injected intraperitoneally with kainic acid in order to induce epileptic convulsions and mossy fiber sprouting. After 2 months survival, hippocampal sections were immunostained for parvalbumin, calbindin D28k, or calretinin followed by Timm-staining. Under a fluorescent microscope, zinc-positive mossy fibers in epileptic rats were found to surround parvalbumin-containing neurons in the granule cell layer and to follow their dendrites, which extended toward the molecular layer. In addition, dendrites of calbindin D28k-containing cells were covered by multiple mossy fiber terminals in the inner molecular layer. However, the calretinin-containing cell bodies in the granule cell layer did not receive any contacts from the sprouted fibers. Electron microscopic analysis revealed that typical Timm-positive mossy fiber terminals established several asymmetrical synapses with the soma and dendrites of nonpyramidal cells within the granule cell layer. These results provide direct evidence that, in addition to recurrent excitatory connections, inhibitory circuitries, especially those responsible for the perisomatic feedback inhibition, are formed as a result of mossy fiber sprouting in experimental epilepsy.

Our preliminary results showed that mossy fibres do not undergo sprouting after global ischaemia in gerbils, although the pattern of hippocampal cell damage resembled that seen in ischaemic and epileptic rats, where mossy fibre sprouting is known to occur. In order to investigate whether the observed differences in the appearance of mossy fibre sprouting are related to the animal model or species used, this study was undertaken to compare the neuropathological changes induced in gerbils by systemic injection of kainate or by occlusion of carotid arteries with the changes induced in rats by injection of kainate. The pattern of pyramidal cell damage was very similar in each group. Mossy fibre sprouting was present in epileptic rats but not in ischaemic or epileptic gerbils. The number of somatostatin-immunoreactive neurons was decreased in the hilus of epileptic rats and ischaemic gerbils, but not in epileptic gerbils. The analysis of calretinin immunoreactivity in the dentate gyrus revealed differences between the rat and gerbil. The most striking difference between these species was that mossy cells contained calretinin in gerbils but not in rats. Cell counting showed that the calretinin-containing mossy cells had survived both in epileptic and ischaemic gerbils. Therefore, since the mossy cells are known to be highly susceptible to excitotoxic insult in rats and degeneration of these cells is thought to be a key element in the induction of mossy fibre sprouting, we propose that the absence of mossy fibre sprouting in gerbils is related to the survival of the mossy cells.

Objective: To evaluate the efficacy, safety, and cognitive effects of initial vigabatrin monotherapy compared with initial carbamazepine monotherapy in patients with newly diagnosed epilepsy., Design: Open, randomized, controlled design. Follow-up period of 12 months., Setting: University hospital with an epilepsy center., Patients: A total of 100 patients, aged 15 to 64 years, classified as suffering from partial seizures and/or generalized tonic-clonic seizures were randomized to either vigabatrin or carbamazepine monotherapy. Fifty-nine patients with a single epileptic seizure and no antiepileptic drug treatment served as a control population for objective safety measures., Outcome Measures: To evaluate the comparative efficacy and toxicity of vigabatrin and carbamazepine, the drug success rate (ie, the proportion of patients continuing successful treatment with the randomly assigned drug) after 12 months of steady-state treatment was used. To evaluate the safety of the drugs in addition to reported side effects, visual evoked potential recordings and neuropsychological evaluation were performed during follow-up., Results: During the 12-month follow-up period, 60% of patients receiving vigabatrin and carbamazepine were treated successfully. Vigabatrin caused fewer side effects that required discontinuation of therapy. However, vigabatrin had to be discontinuated more often owing to lack of efficacy, and fewer of the successfully treated patients receiving vigabatrin achieved total freedom from seizures. Vigabatrin had no detrimental effects on cognitive functions. Retrieval from both episodic and semantic memory and flexibility of mental processing improved significantly in patients successfully treated with vigabatrin., Conclusion: Vigabatrin seems to be an effective and safe antiepileptic drug as primary monotherapy for epilepsy with fewer cognitive side effects than carbamazepine.

It is a matter of dispute whether or not recurrent epileptic seizures cause neuronal damage in the human brain. We approached this question by measuring the volumes of the amygdala, hippocampus and parahippocampal gyrus with magnetic resonance imaging in 15 controls, 13 unmedicated patients with newly diagnosed epilepsy and 16 patients with chronic drug-refractory epilepsy. In all patients, the seizure origin was in the temporal lobe region and the seizure aetiology was unknown. Newly diagnosed epilepsy patients with seizure lateralization on the left had increased hippocampal right-left difference (p < 0.01) and right/left ratio (p < 0.05) compared with controls. Patients with chronic epilepsy and lateralization on the left had increased hippocampal right-left difference (p < 0.05) and right/left ratio (p < 0.05) compared with controls. In this patient group, the volume of the left hippocampus was 16% smaller than in controls (p < 0.01). The rostral portion of the parahippocampal gyrus was 12% smaller than in controls (p < 0.01). In chronic epilepsy patients with lateralization on the right, we found a statistically non-significant decrease (13%) in the right hippocampal volume compared with controls. In this patient group, the amygdaloid right-left difference (p < 0.05) and right/left ratio (p < 0.05) were decreased compared with controls. The present cross-sectional study provides evidence that mild hippocampal damage is already present in the early stages of epilepsy. Hippocampal damage is more severe in patients with a long history of recurrent generalized seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To study the efficacy and safety of gabapentin in long-term treatment., Design: A 4-year follow-up study of 25 patients with visits at 3-month intervals., Setting: The patients were followed up in the outpatient unit of the University Hospital of Kuopio (Finland)., Patients: We treated 25 patients with drug-resistant complex partial seizures and secondarily generalized seizures in an open-label long-term study, using gabapentin as an additional means of therapy after a 3-month double-blind, placebo-controlled phase. Thirteen patients showed no benefit from gabapentin; the study medication was discontinued after 4 to 6 months of treatment. Of the 12 patients who responded enough to continue treatment, five were withdrawn due to different reasons, one because of loss of response., Main Outcome Measures: The number of patients receiving the study drug in the follow-up and reduction of seizure frequency from baseline level as analyzed by the Wilcoxon test., Results: Seven patients received gabapentin therapy for more than 4 years. The median follow-up time was 54 months. There was a significant reduction in seizure frequency throughout the follow-up period. Five of seven patients had a greater than 50% seizure frequency reduction at 4 years, representing 20% of the 25 patients who entered the study., Conclusions: Gabapentin possesses good efficacy in long-term treatment of patients with partial and secondarily generalized epileptic seizures. It is safe to use, and it is fairly well tolerated even in long-term treatment.

There are several new antiepileptic drugs undergoing extensive clinical investigation. Five new drugs--vigabatrin, lamotrigine, gabapentin, felbamate and oxcarbazepine--appear to be the most widely tested and promising agents. Vigabatrin is most effective in drug-resistant partial epilepsy. Vigabatrin is also effective in infantile spasms, but seems to have negative effects on myoclonic epilepsies and absence seizures. Lamotrigine and felbamate seem to be effective in partial epilepsy and in Lennox-Gastaut syndrome. In addition, lamotrigine and felbamate seem to have efficacy in idiopathic generalised epilepsies. Oxcarbazepine appears to be equally as effective as carbamazepine, but less toxic. Gabapentin has few adverse effects and has efficacy in some patients with drug-resistant partial epilepsy. Some of the new antiepileptic drugs modify excitatory or inhibitory amino acid transmission, but some of them may employ new, still unknown mechanisms of action. Depending on the mechanism of action, the therapeutic effectiveness of the antiepileptic drugs may differ in specific epileptic syndromes. Future antiepileptic drugs may thus give us the possibility to design rational polypharmacy for individual patients by combining agents with different spectra of effectiveness. Considering the goal of good tolerability in the development of the new antiepileptic drugs, polypharmacy with these agents is not expected to increase adverse effects significantly.

Sustained electrical stimulation of the perforant pathway (PP) was used to induce hippocampal seizures in conscious rats. About 4.5 h prior to stimulation, animals were given i.p. injections of either saline or CGP 39551 (10 mg/kg), a competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. When tested 2 weeks later in water maze, the saline pretreated rats showed a severe impairment in spatial learning whereas the animals treated with CGP 39551 had the same escape latencies as the non-stimulated controls. Histological evaluation of cellular degeneration revealed that the number of somatostatin-immunoreactive (SOM-IR) neurons in both stimulated groups was reduced almost equally, but in the CGP 39551 treated animals pyramidal cell damage was partly protected. However, in contrast to the placebo group, NMDA-sensitive [3H]glutamate binding in strata radiatum and oriens of the CA1 area was not significantly reduced in the CGP 39551 group. Thus, the present results suggest that the CGP 39551 treatment was able to protect against the delayed phase of the excitotoxic cell damage, and that the preservation of NMDA receptors partly accounts for the good learning ability of the CGP 39551 pretreated, PP-stimulated rats.

Combining the methods of microdialysis and EEG recording, we have examined the effect of unilaterally, intracortically applied gamma-hydroxybutyrate (GHB) on frontal cortical EEG activity in freely moving rats. GHB, a natural endogenous GABA metabolite, is known to induce rhythmic spike and wave activity, resembling generalized petit mal epilepsy. Without GHB, spontaneous high voltage spindles (HVS, 6-9 Hz) were observed during awake and immobile behavior in most of the animals (HVS rats), while others never had any HVS. In those both groups of animals intracortical application of GHB induced epileptogenic spikes (< 0.5 Hz) behaviorally accompanied by occasional myoclonic jerks and epileptic discharges (< 2 Hz) with behavioral convulsions and contraversive movements towards the left hindlimb (seizures) but did not induce HVS or spike and waves, as reported after systemic application. In the group of rats with spontaneous occurring HVS the amplitude of the HVS on the side of the microdialysis probe was suppressed by GHB and GHB-induced spikes invading the contralateral cortex frequently triggered and terminated local HVS. The results point to different neural mechanisms for the generation of HVS and spikes and epileptic discharges (seizures) induced after local intracortical application of GHB.

We studied the CSF amino acid levels of 42 patients with newly diagnosed epilepsy before treatment with antiepileptic medication and during monotherapy with either vigabatrin or carbamazepine. The present study shows that patients with newly diagnosed epilepsy have elevated levels of the excitatory amino acid glutamate in CSF. Vigabatrin monotherapy effectively prevents the appearance of seizures in patients with high baseline CSF glutamate levels. In these patients, vigabatrin not only elevates the levels of gamma-aminobutyric acid, but also decreases the elevated levels of glutamate in CSF, which may also be important to the antiepileptic efficacy of vigabatrin. Patients with low CSF glutamate levels did not benefit from vigabatrin-induced changes in amino acid levels and successful monotherapy with carbamazepine did not affect CSF amino acid levels. The elevation of gamma-aminobutyric acid is thus not the only way to achieve seizure control and there are several factors underlying the generation and control of seizures. Follow-up of the patients with high baseline glutamate CSF levels will show if the observed abnormalities are related to the severity of epilepsy in individual patients and if early treatment with vigabatrin of these patients could prevent the development of intractable epilepsy.

The long-term clinical, neurophysiologic, and psychological effects of add-on vigabatrin treatment were evaluated in a group of 36 mentally handicapped patients with drug-refractory epilepsy. After an initial 3-month follow-up period, 15 (42%) of 36 patients had at least a 50% decrease in seizure frequency compared with baseline. After a 2-year follow-up period, nine (25%) of 36 patients retained the initially observed antiepileptic effects of vigabatrin, and after 5 years, eight (22%) of 36 patients did so. Five (33%) of the 15 patients who initially exhibited a favorable antiepileptic response to vigabatrin lost that response during a 5-year follow-up. Partial-onset seizures represented the seizure type best controlled by vigabatrin. Side effects were mostly mild, and plasma levels of other antiepileptic medication remained unchanged. No impairment of psychological performance was observed during vigabatrin treatment compared with baseline. Also, no clear change was observed in the background or epileptiform activity in the electroencephalogram during the study. Our findings suggest that vigabatrin as an add-on therapeutic effectively controls seizures in a subpopulation of patients with severe epilepsy. In addition, the antiepileptic response, if achieved, is long lasting in about half of the patients.

We performed neuropathologic examination of cerebral cortex specimens from 4 patients who underwent epilepsy surgery and the brain of 1 patient who died suddenly. All had severe epilepsy and had received gamma-vinyl-GABA (GVG, vigabatrin) for 3-5.5 years. Neither the surgically resected temporal lobe specimens nor the frontal and temporal lobes autopsy specimens showed abnormal white matter vacuolation.

Sustained stimulation of the perforant pathway (PP) offers a model for studying seizure-induced pathology of the hippocampal formation. Using quantitative autoradiography, NMDA-sensitive glutamate binding was evaluated in the rat hippocampus three weeks after PP-stimulation. Decreased receptor binding (38-44%) was found together with pyramidal cell damage and gliosis in the CA1 area, ipsilateral to the stimulation (p < or = 0.001). In the dentate gyrus, however, a 20% increase in receptor density was observed bilaterally within the molecular layer (significant within the outer molecular layer of the contralateral side, on the suprapyramidal location; p < or = 0.05). These results are similar to those found in epileptic patients and suggest a prominent role for NMDA receptors in epilepsy.

Interictal disturbances of memory and attention were evaluated in 74 adults with newly-diagnosed untreated epileptic seizures and no other known brain pathology. In approximately 30% of the patients with cryptogenic seizures, the average memory and attention scores indicated subtle dysfunction compared with normal control group. The patients had difficulties in tasks requiring memory, sustained attention and flexible mental processing, whereas they had normal attention span, simple speed of tracking and simple psychomotor speed. The memory difficulties may be related to attentional dysfunction leading to impaired or slowed initial encoding of memory trace, and also to a deficit in storing process and hippocampal dysfunction. These findings could have important implications for establishing criteria for identifying patients who develop chronic epilepsy and who thereby would benefit from early therapeutic intervention.

We report long-term clinical, neurochemical, and electrophysiologic data of gamma-vinyl GABA (GVG, vigabatrin) in three groups of patients. GVG was started as add-on therapy for 75 patients with refractory complex partial seizures (group A) and for 36 mentally handicapped patients with severe epilepsy (group B). The third group (C) consisted of 20 patients with carbamazepine (CBZ) monotherapy, in half of whom GVG monotherapy was substituted. After 3 months, 55% of patients in group A and 42% in group B were responders (reduction in seizure frequency greater than 50%). After 6 (group A) and 3 years (group B) of follow-up, 27 and 33% of the patients, respectively, still had good response to GVG. Neurochemical measurements showed a twofold increase in CSF GABA concentrations and minimal or no changes in other neurotransmitter-related parameters. In group C, substitution of GVG as medication tended to normalize the lengthened latencies in somatosensory evoked potentials (SEPs) observed during CBZ treatment.

We evaluated the effect of initial oxcarbazepine (OXC) monotherapy on memory, attention and simple psychomotor speed in 14 patients; 15 patients with initial phenytoin (PHT) monotherapy served as reference patients. Neuropsychological assessments were performed before starting the treatment and after 6 and 12 months follow-up with steady-state drug treatment. Differential cognitive effects of OXC and PHT were not apparent in our study. As the efficacy of present antiepileptic drugs in adult epilepsy is analogous, the choice of drug is determined by the comparative side effects of the drugs. In the present study the number of successfully treated patients was similar in both OXC and PHT groups. As far as cognitive side effects are concerned our results revealed no evidence favoring either antiepileptic over the other.

Extensive electrical stimulation of the perforant pathway input to the hippocampus results in a characteristic pattern of neuronal death, which is accompanied by an impairment of cognitive functions similar to that seen in human temporal lobe epilepsy. The excitotoxic hypothesis of epileptic cell death [Olney, J. W. (1978) in Kainic Acid as a Tool in Neurobiology, eds. McGeer, E., Olney, J. W. & McGeer, P. (Raven, New York), pp. 95-121; Olney, J. W. (1983) in Excitotoxins, eds. Fuxe, K., Roberts, P. J. & Schwartch, R. (Wenner-Gren International Symposium Series, Macmillan, London), Vol. 39, pp. 82-96; and Rothman, S. M. & Olney, J. W. (1986) Ann. Neurol. 19, 105-111] predicts an imbalance between excitation and inhibition, which occurs probably as a result of hyperactivity in afferent pathways or impaired inhibition. In the present study, we investigated whether the enhancement of gamma-aminobutyric acid (GABA)-mediated (GABAergic) inhibition of neurotransmission by blocking the GABA-metabolizing enzyme, GABA transaminase, could influence the histopathological and/or the behavioral outcome in this epilepsy model. We demonstrate that the loss of pyramidal cells and hilar somatostatin-containing neurons can be abolished by enhancing the level of synaptically released GABA, and that the preservation of hippocampal structure is accompanied by a significant sparing of spatial memory as compared with placebo-treated controls. These results suggest that enhanced GABAergic inhibition can effectively block the pathophysiological processes that lead to excitotoxic cell death and, as a result, protect the brain from seizure-induced cognitive impairment.

At present, 34 patients aged 15 to 63 years with newly diagnosed epilepsy have been randomly assigned to vigabatrin (n = 17) or carbamazepine (n = 17). Evaluation of clinical data, neuropsychological assessment, quantitative spectral electroencephalogram (EEG), and somatosensory- and visual-evoked potentials at baseline and after a 3 months' maintenance phase are presented for 12 patients on vigabatrin and for 11 patients on carbamazepine. Among these patients, retention rate in the maintenance phase of the study is 75% for vigabatrin patients (two noncompliant patients and one nonresponder dropped out) followed up for a mean of 11 months (range, 5 to 16 months). The retention rate for carbamazepine is 100% for the 11 patients, followed up for a mean of 9 months (range, 3 to 17 months). Patients receiving vigabatrin showed significant improvements in sustained concentration and tasks requiring flexible mental processing after the 3-month maintenance period, compared to baseline. In the carbamazepine group, there was improvement only in delayed list recall, and in contrast, errors in visuomotor tasks requiring processing increased significantly. Patients on carbamazepine demonstrated slowed occipital mean frequencies, but vigabatrin treatment was not associated with any significant quantitative EEG changes. Significant prolongation of somatosensory-evoked potential N19 latencies was seen with both carbamazepine and vigabatrin.

Hippocampal neurons containing somatostatin have been shown to be vulnerable in some experimental models of epilepsy. In this report, we describe our recent findings about the seizure-related changes in somatostatin in brain tissue and cerebrospinal fluid (CSF) in experimental and human epilepsy. These data strengthen the view that the somatostatinergic system is affected in epilepsy.

The duration of an ambulatory electroencephalogram (aEEG) necessary to record epileptic seizures was studied in neurological patients. A total of 2221 aEEG recordings were made for 2035 inpatients. Ambulatory EEG lasting 1 to 8 days (mean, 1.6 days) included seizures or typical undiagnosed symptomatic attacks in 750 recordings (34%), and 266 of them were epileptic in origin. Symptomatic attacks without simultaneous EEG discharges were exhibited in 27% of the epileptic patients. Of the total number of epileptic seizures, 81% were encountered during the first 24 hours, an additional 10% during the next 24 hours, and 7% during the third 24-hour period. Our conclusion was that, in patients exhibiting epileptic seizures during the aEEG recording, the diagnosis will be confirmed by a 2-day recording in the vast majority of the cases.

Clinical features of epilepsy, especially those connected with drug therapy, were evaluated for mentally retarded adult epileptics who were admitted to the neurological out-patient unit during 1977-83. These features were re-evaluated in 1985 and compared with findings from the first visit. During follow-up, the type and frequency of seizures were determined and if possible, medical therapy was either concluded or changed. The therapeutic intervention resulted in the use of fewer and less toxic drugs, for which the serum concentrations were more often within recommended ranges. These aspects may be due to the significant decrease in seizure frequency observed. In order to provide patients with the most efficacious therapy, the therapeutic needs of mentally retarded adult epileptics should be evaluated by a neurologist familiar with epilepsy.

Our report concerns 2 patients who developed delirium after an epileptic attack during mianserin treatment. In both cases the EEG showed a change with periodic sharp slow complexes similar to that seen in Creutzfeldt-Jakob disease. The symptoms subsided, however, and the EEG normalized after the antidepressant was discontinued, suggesting a noxious response to mianserin. If Creutzfeldt-Jakob-like changes in the EEG occur, the possible effect of antidepressant medication should be considered.

Neuropeptides have been proposed to play a role in regulation of the seizure threshold and interictal behavior in experimental models of epilepsy, but there are few studies concerning neuropeptides in human epilepsy. We compared the levels of two peptides, somatostatin (SLI) and beta-endorphin (BEP) in lumbar cerebrospinal fluid (CSF) of unmedicated (N = 18) and medicated (n = 24) epileptic patients with the levels of these peptides in control (n = 20). Peptide levels in the CSF of patients with panic disorder (8) were also evaluated. Patients with chronic medicated epilepsy had a SLl level 80% (p = 0.003, Mann-Whitney U-test) that of the controls, 76% (p = 0.011) that of unmedicated patients, and 84% (p = 0.028) that of the panic group. BEP in the CSF did not differ in unmedicated, medicated and control patients. On the other hand, patients with panic disorder had higher levels of BEP in CSF than did the controls (117%, p = 0.041). In panic patients SLl was at control level. The present study indicates that the peptidergic systems are affected differentially in epilepsy and in panic disorder. Furthermore, there seems to be selectivity in the affect on peptidergic systems during the period when the epilepsy becomes chronic.

Twenty ambulatory outpatients with generalized tonic-clonic seizures with primary generalized discharges and photoconvulsive response on electroencephalogram (EEG) and 11 ambulatory outpatients with partial complex seizures with or without secondary generalization were studied with pattern-reversal light-emitting diode (LED) stimulator visual evoked potential (VEPs) and short-latency median nerve cortical somatosensory evoked potentials (SEPs). The patients with primary generalized epilepsy had significantly prolonged latencies of VEP components P2 and N3 and SEP component P22. The patients with partial epilepsy had significantly prolonged latency of VEP component N3. It is concluded that both functional and structural factors may cause a slowing of central impulse conduction.

1. The anticonvulsant potency of vigabatrin (gamma-vinyl GABA, GVG) was studied in an open trial in a group of 21 mentally handicapped patients with drug-resistant epilepsy. 2. With this treatment one third of these patients had more than 50% reduction in seizure frequency. The anticonvulsant effect appeared during the first month of therapy and was maintained during a 7-month study. The side effects were mild: mainly tiredness, aggressiveness, and ataxia. Other anticonvulsant drugs remained at baseline levels during GVG therapy. GVG was not found to modulate EEG recordings. 3. According to our results, GVG is effective for treating intractable epilepsy in mentally handicapped patients.

The antiepileptic effect, effects on EEG, and tolerability of taltrimide, a new taurine derivative, were studied in this open clinical trial in 27 patients with severe epilepsy resistant to conventional drugs. After the 2-week control phase, taltrimide was given in gradually increasing doses up to 4.0 g/day--this dose used for 12 days. Taltrimide was given over 4 weeks and it was gradually withdrawn over 2 weeks. The frequency of seizures increased statistically significantly during the trial with increasing dose of taltrimide and decreased again in the withdrawal phase of the trial. Of six dropouts, one had status epilepticus, and in two patients increased number or severity of seizures necessitated withdrawal of taltrimide. There were no changes in EEG recordings or in laboratory data for safety evaluation. Taltrimide penetrated well through the blood-brain barrier, with the concentration of its main metabolite, phthalimidoethanesulphonamide, in cerebrospinal fluid, about half that in serum. The concentration of phenytoin increased statistically significantly, and there was a significant decrease in serum carbamazepine concentration during the taltrimide treatment. The anticonvulsive effect of taltrimide observed in animal experiments could not be confirmed in this study; in contrast, the seizures increased statistically significantly during taltrimide treatment. The reason for this remains obscure. The doses used, the significant drug interactions, or the patient material seemingly do not explain totally the noticed increase in seizure frequency. One explanation may be that taltrimide has proconvulsive properties in humans.

Vigabatrin (gamma-vinyl GABA) is a new anticonvulsive drug that irreversibly inhibits the activity of GABA transaminase. The effect of vigabatrin on neurotransmission-related amino acids in CSF of 28 epileptic patients was studied and the relationship between the amino acid pattern and clinical response during 7 months of administration of vigabatrin. Of this study population, 46% had more than 50% decrease in seizure frequency (responders). In 54% the seizures decreased less than 50% (nonresponders). In the whole study group, the levels of total GABA during vigabatrin treatment were 283%, free GABA 197%, homocarnosine 310% and glycine 128% that of the levels at baseline in the same patients. Glutamate, glutamine, aspartate, asparagine, and taurine concentrations did not change. The amino acid pattern in CSF during administration of vigabatrin did not differ significantly in responders and nonresponders. The study suggests that both GABAergic and glycinergic neurotransmission are affected by vigabatrin. The changes in CSF levels of neurotransmitter amino acids are, however, not necessarily related to the clinical response.

The status of bone mineral metabolism was studied in 21 epileptic out-patients receiving carbamazepine as the sole anticonvulsant drug. Hypocalcaemia was found in 3, hypophosphataemia in one and elevated serum alkaline phosphatase in 4 of the cases. Serum 25-hydroxyvitamin D values were significantly lower in the patients than in the controls. No statistically significant difference was observed in bone mineral density between the patients and controls. Histomorphometric analysis of the iliac crest cancellous bone did not reveal any statistically significant difference in the amount of trabecular bone or osteoid between the patients and controls, but the patients had an increased amount of trabecular resorption surfaces. An increased amount of osteoid, suggesting histological osteomalacia, was found in 2 of the 18 biopsies. We conclude that epileptic out-patients receiving carbamazepine therapy have vitamin D deficiency and may develop osteomalacic changes in their skeleton.

The therapeutic action of vigabatrin (gamma vinyl GABA, GVG) has been reported to be mediated by GABAergic neurotransmission. In the present study, we evaluated different neurotransmitter systems in the cerebrospinal fluid (CSF) of patients with complex partial epilepsy, before and during GVG treatment. The markers of the GABAergic system (free GABA, total GABA, homocarnosine) showed a two- to threefold elevation. There was also an increase in glycine during the 6 months of GVG treatment. In contrast, we did not find any constant CSF changes in either excitatory amino acids or in markers of the cholinergic (acetylcholinesterase), dopaminergic (homovanillic acid), serotonergic (5-hydroxyindoleacetic acid), or peptidergic (somatostatin, prolactin, beta-endorphin) systems. This finding (except an elevation in glycine) was in agreement with previous studies which suggest a specific action of GVG on the GABAergic system. The role of glycine in antiepileptic efficacy of GVG needs further evaluation.

We studied the possible role of excitatory and inhibitory amino acids and their balance during generalized convulsions. The levels of amino acids in postictal cerebrospinal fluid (CSF) were compared with amino acid concentrations in interictal CSF of ten patients with generalized tonic-clonic convulsions. Glu, Gln, Asp, Asn, Tau, Gly, total GABA (t-GABA), free GABA (f-GABA), and homocarnosine levels and Glu/Gln, Asp/Asn, t-GABA/Glu, f-GABA/Glu, f-GABA/Asp, and Glu/Asp ratios were similar in both samples (Student's paired t-test). Our results suggest that in humans possible changes in amino acids in brain tissue during the ictal stage are not reflected in the lumbar CSF.

The antiepileptic efficacy and side-effects of oxcarbazepine (OXC), a new carbamazepine derivate, were evaluated in a double-blind study. Forty ambulatory epileptics with unsatisfactory seizure control or unwanted effects due to phenytoin monotherapy were changed to OXC or carbamazepine (CBZ) and were then followed for 48-50 weeks. Thirty-four of the patients completed the study. The seizure frequencies on the trial drugs were not significantly different and the antiepileptic efficacy of OXC was comparable to CBZ. The incidence of side-effects during the initiation phase was lower with OXC suggesting better tolerability of OXC compared to CBZ.

In previous studies of experimental and human epilepsy, defects have been shown in the gamma-aminobutyric acid (GABA) receptors. We further investigated the role of the GABA/benzodiazepine/picrotoxinin receptor complex in the epileptic focus and also in other regions of the rat brain. The focus was induced by cobalt implantation to the right motor cortex, and the brains were dissected 16-19 days after the operation. Benzodiazepine (using [3H]flunitrazepam as a ligand; FLU), GABA [3H]muscimol; MUS), and picrotoxinin [( 35S]t-butylbicyclophosphorothionate; TBPS) receptor bindings were measured in different brain areas and the values were compared with glass-implanted controls. In the focal area, the specific receptor binding decreased in the order TBPS greater than FLU greater than MUS. In the perifocal area only TBPS binding decreased, and Scatchard analysis showed a decrease in the number of binding sites (p less than 0.05) without any effect on binding affinity. No change was seen in the binding characteristics of the other areas studied. According to our results, in cobalt-induced epilepsy the GABA/benzodiazepine/picrotoxinin receptor complex is modulated in the focal area; this may lead to a defect in chloride conductance, which in turn induces disturbed control of neuronal activity in the epileptic focus.

Chronic, mentally subnormal epileptic patients were clinically and neurophysiologically studied in order to determine the occurrence and type of peripheral nerve dysfunction. We observed significant impairment of motor and sensory nerve conduction velocities and H-reflex latencies. Amplitudes of sensory and motor responses were diminished. Motor distal latencies were not prolonged. Conclusive EMG signs of active denervation were not observed. The possible role of anticonvulsive treatment as an underlying noxa is discussed.

The anticonvulsant action of the new anticonvulsant drug gamma-vinyl-GABA (GVG) is obviously mediated by elevation of the concentration of GABA in the brain. The effect of GVG administration on other transmitter systems is not fully known in humans. We studied the possible interactions of GVG administration with peptidergic systems. Included in this study were 67 patients with complex partial epilepsy (CPS). The first CSF sample was taken before GVG administration. The second CSF sample was taken after 3 months of GVG treatment (3 g/day). Thereafter half of the responders (50% decrease in seizure frequency or clear improvement in global performance) received 3 g/day and the other half received 1.5 g/day for the next three months, after which the third CSF sample was taken. Somatostatin (SLI), beta-endorphin (beta-EP), and prolactin (PROL) levels in CSF were measured by radioimmunoassay. Total GABA (tGABA) and GVG levels in CSF were measured by high performance liquid chromatography. After 3 months of GVG treatment there was a slight increase in the beta-EP (p = 0.027, Student's paired t-test), which was not found after 6 months of GVG administration. Both SLI and PROL were stable during the study. Peptide levels were not connected to the clinical response to GVG, GVG dosage, or to tGABA levels in the CSF. In conclusion, the elevation of GABA levels in the brain during GVG treatment apparently does not induce long-term interactions with the peptidergic systems studied.

Incidence of CT abnormalities and their correlation with clinical and EEG features were evaluated in a consecutive series of 202 adult patients with newly diagnosed epileptic seizures. Abnormal CT findings were found in 36% of these patients; the abnormalities consisted of brain tumors (17%), atrophic lesions (11%) and other organic findings (8%) such as arteriovenous malformations. Focal features of seizures, in neurological examination and/or in EEG, correlated significantly with CT abnormalities. The absence of these findings did, however, not exclude the possibility of brain lesions, which in many cases were treatable by surgery.

Epidemiological parameters of epilepsy have been estimated in a large number of studies. Reported annual incidence rates for recurrent seizures vary between 30 and 50/100,000, and prevalence rates in most studies between 500 and 1000/100,000. Varying findings are mostly due to different case ascertainment methods and definitions of epilepsy applied in different surveys. These aspects will be discussed in this paper. A special emphasis is laid on differential diagnosis of seizure disorders, and on the prevalence and causes of complex partial epilepsy. This epileptic disorder is one of the most common forms of epilepsy, and also difficult to treat in many cases. Many recent reports show that prognosis of seizures in patients with epilepsy is better than suggested in earlier studies. However, 25-30% of epileptics seem to have frequent (greater than 1/month) seizures. Our own study, in accordance with earlier findings suggests that prevalence of patients with severe complex partial epilepsy is about 80-90/100,000. Available literature provides several predictive factors for the prognosis of seizures and assessment of prognosis is possible quite early after the onset of seizures. Treatment choices for patients with intractable epilepsy will be discussed.

We studied the antiepileptic potency of vigabatrin (gamma-vinyl GABA, GVG) as an open trial in a group of 36 mentally handicapped patients with drug-resistant epilepsy (30 had seizures of partial onset and 6 had primary generalized [PG] tonic-clonic convulsions). With this treatment, 13 (43%) of the patients with seizures of partial onset and 2 (33%) with PG had more than 50% reduction in seizure frequency. The antiepileptic effect appeared during the first month of therapy and continued throughout the 7-month study. The side effects were mild: tiredness, aggressiveness, and ataxia. Other antiepileptic drugs remained at baseline levels during GVG therapy. GVG did not alter EEG recordings. Our results suggest that GVG is effective for treatment of intractable epilepsy, especially the partial type, in mentally retarded patients. Longer follow-up is needed, however, to determine that the clinical effect is maintained and that no severe side effects appear.

We studied the levels of excitatory and inhibitory amino acids in the cerebrospinal fluid (CSF) of 28 epileptic patients (24 with partial type seizures, 4 with primary generalized seizures) and 12 controls. The levels of aspartate were 63% (p less than 0.01), glutamine 129% (p less than 0.001), and homocarnosine 127% (p less than 0.005) that of controls. The concentrations of glutamate, asparagine, total GABA, free GABA, taurine, and glycine did not differ between epileptic patients and controls. Patients with partial epilepsy had a pattern of amino acids in CSF similar to that in patients with primary generalized seizures. In the present study we did not observe increased excitation or decreased inhibition in the seizure-active brains of epileptics, as far as the CSF levels of amino acids reflect their levels in the brain.

The possible role of different peptidergic systems in the postictal stage of human epilepsy was studied by measuring beta-endorphin, somatostatin, and prolactin levels by radioimmunoassay of cerebrospinal fluid (CSF) from nine epileptic patients. The first sample was taken within 2 hours after generalised tonic-clonic convulsion, and the second sample was obtained interictally after 1-4 days without any kind of clinically observable seizures. beta-endorphin was elevated postictally (p = 0.044) compared with interictal levels. SLI and PROL were similar in both samples. The present study suggests that in humans beta-endorphin is released into CSF during generalised seizures. This may indicate that neurons containing beta-endorphin are activated during a seizure.

In Finland, only limited data exist on the epidemiology of epilepsy in adults. This prompted us to study the incidence and prevalence of epilepsy in a population over 15 years of age, residing in Eastern Finland. In a retrospective study, various medical data sources were used to identify and reexamine all patients with established or suspected epileptic seizures during 1960-1979. A total of 1,233 patients with active epilepsy were identified. Mean annual incidence of epilepsy was 24/100,000. Age-specific incidence ratios tended to increase with advancing age. Prevalence of active epilepsy was 629/100,000. Both prevalence and incidence were higher in males than in females. Age-specific prevalence of active epilepsy increased until 40-50 years of age, and declined in the oldest age groups. Of the various seizure types, highest prevalence ratios were observed for partial secondarily generalized seizures, complex partial seizures, and tonic-clonic seizures. Prevalence of partial seizures and generalized seizures had a different age-related pattern.

The distribution of seizure types was investigated in an epidemiological survey of 1,220 patients over 15 years of age. Classification of clinically dominant seizure type according to the International Classification of Epileptic Seizures (ICES) was possible in 1,005 cases (82.5%). Fifty-six percent of patients had partial seizures and 26.5% had generalized seizures. Subclassification of partial seizures revealed simple partial seizures (SPS) in 7.5% of the cases, complex partial seizures (CPS) in 23%, and partial secondarily generalized seizures (PSGS) in 25.5% of the cases. Simple partial onset was seen in 56% of the patients with CPS, and impairment of consciousness at the onset occurred in the remaining 44%. PSGS started with simple partial onset in 92% of the cases and the remaining 8% started with a complex partial phase. Tonic-clonic seizures were the most common type of generalized seizures, accounting for 23% of all and 88% of generalized seizures. Absence seizures were seen in 1% of the cases. A single seizure type was observed in 737 patients (60%) and the remaining 40% had multiple seizure types. SPS, CPS, and absence seizures were most commonly combined with other seizure types. The study revealed that distribution of seizure type varies as a function of age. Although the present study finds ICES relevant, difficulties in its utilization in epidemiological context are demonstrated.

Taltrimide is a lipophilic taurine derivative with definitive anticonvulsive effects in experimental epilepsy models. In this study, taltrimide was administered for 6 days, and the effects of the treatment on photoconvulsive response in EEG in eight epileptic patients were evaluated. Discharges provoked by intermittent photic stimulation (IPS) were increased by greater than 50% in four patients after taltrimide treatment. Only one patient had reduction of sensitivity. There was only a slight change in discharges after hyperventilation and no change in spontaneous paroxysms. The effects of taltrimide on photosensitivity appear to be rather specific. The study does not reveal anticonvulsive effects of taltrimide in humans.

Twenty-five epileptic outpatients were studied to assess possible effects of the first 6 months of treatment with carbamazepine or oxcarbazepine using serial peripheral nerve conduction measurements. Carbamazepine caused a small slowing effect on the motor conduction of the median nerve after 4 weeks of treatment, and the effect was correlated with the fasting serum concentration of the drug. Slowed motor conduction value of the median nerve was also observed after 6 months of treatment with carbamazepine. Oxcarbazepine did not cause any statistically significant slowing of nerve conduction.

Side effects of sodium valproate during long-term treatment have been evaluated retrospectively in 55 patients suffering from refactory epilepsy. The side effects discovered in the study were slight and transient. In three of the 55 patients CNS side effects were noticed. Gastrointestinal symptoms were uncommon. One patient suffered from loss of hair which could have been attributed to sodium valproate. Severe side effects such as abnormal blood counts or organ damage were not discovered. The frequency of side effects was similar to those already reported in the literature except for gastrointestinal symptoms which were more infrequent than previously reported. No direct correlation could be established between the serum concentration of sodium valproate and the side effects.

Levels of total gamma-aminobutyric acid (TGABA), free GABA (FGABA), and homocarnosine (HC) were studied in CSF taken from 12 controls and 28 patients with drug-refractory epilepsy before and during 7 months of gamma-vinyl-GABA (GVG) administration. At baseline TGABA and FGABA in CSF of epileptic patients did not differ from that of the controls. In epileptic patients HC was 127% of that in controls. During GVG treatment TGABA was 283%, FGABA 197%, and HC 310% of the levels at baseline in the same patients. The patients who had over 50% reduction in seizure frequency during GVG (responders, 46% of the study population) at baseline had higher TGABA and HC in CSF than patients with less than 50% reduction in seizures (non-responders). During GVG the responders and nonresponders had similar levels of different GABAergic markers. The present study shows that in man GVG treatment effectively suppresses seizures in nearly half of the epileptic patients who had previously been drug-refractory. The elevated levels of GABAergic markers in CSF are not, however, necessarily related to good seizure control during GVG.