GABAA receptor beta3 subunit gene-deficient heterozygous mice show parent-of-origin and gender-related differences in beta3 subunit levels, EEG, and behavior

The homozygous knockout mouse for the beta3 subunit of the GABAA receptor has been proposed as a model for the neurodevelopmental disorder, Angelman syndrome, based on phenotypic similarities of craniofacial abnormalities, cognitive defects, hyperactivity, motor incoordination, disturbed rest-activity cycles, and epilepsy. Since most children with Angelman syndrome are autosomal heterozygotes of maternal origin, apparently through genomic imprinting, we used gabrb3-deficient heterozygote mice of defined parental origin to investigate whether this phenotype is also maternally imprinted in mouse. Whole brain extracts showed greatly reduced beta3 subunit levels in male mice of maternal origin but not in male mice of paternal origin. Females of both parental origin showed greatly reduced beta3 subunit levels. Heterozygotes did not exhibit hyperactive circling behavior, convulsions, or electrographically recorded seizures. EEGs showed qualitative differences among heterozygotes, with male mice of maternal origin demonstrating more abnormalities including increased theta activity. Ethosuximide inhibited theta bursts, suggesting an alteration in the thalamocortical relay. Carbamazepine induced EEG slowing in males and EEG acceleration in females, with a larger effect in paternal-origin heterozygotes. Evidence thus suggests both parent-of-origin and gender-related components in developmental regulation of beta3 expression, in particular, that the maternally-derived male heterozygote may carry a developmental modification resulting in less beta3 protein, which may reflect partial genomic imprinting of the gabrb3 gene in mice.     

Delta oscillation underlies the interictal spike changes after repeated transcranial direct current stimulation in a rat model of chronic seizures

BackgroundTranscranial direct current stimulation (tDCS) provides a noninvasive polarity-specific constant current to treat epilepsy, through a mechanism possibly involving excitability modulation and neural oscillation.ObjectiveTo determine whether EEG oscillations underlie the interictal spike changes after tDCS in rats with chronic spontaneous seizures.MethodsRats with kainic acid-induced spontaneous seizures were subjected to cathodal tDCS or sham stimulation for 5 consecutive days. Video-EEG recordings were collected immediately pre- and post-stimulation and for the subsequent 2 weeks following stimulation. The acute pre-post stimulation and subacute follow-up changes of interictal spikes and EEG oscillations in tDCS-treated rats were compared with sham. Ictal EEG with seizure behaviors, hippocampal brain-derived neurotrophic factor (BDNF) protein expression, and mossy fiber sprouting were compared between tDCS and sham rats.ResultsInterictal spike counts were reduced immediately following tDCS with augmented delta and diminished beta and gamma oscillations compared with sham. Cathodal tDCS also enhanced delta oscillations in normal rats. However, increased numbers of interictal spikes with a decrease of delta and theta oscillations were observed in tDCS-treated rats compared with sham during the following 2 weeks after stimulation. Resuming tDCS suppressed the increase of interictal spike activity. In tDCS rats, hippocampal BDNF protein expression was decreased while mossy fiber sprouting did not change compared with sham.ConclusionsThe inverse relationship between the changes of delta oscillation and interictal spikes during tDCS on and off stimulation periods indicates that an enhanced endogenous delta oscillation underlies the tDCS inhibitory effect on epileptic excitability.     

Relationships between triggered seizures, spontaneous seizures, and interictal spiking in the kindling model of epilepsy

Cats were kindled in the amygdala. After completion of kindling, their EEG was monitored almost continuously by a computer system which allowed the detection of spontaneous seizures and the quantification of interictal spikes. The relationships between seizures triggered by stimulation, spontaneous seizures, and interictal spikes in kindled and contralateral amygdalas were examined. Very few spontaneous seizures were observed; their occurrence appeared facilitated by a few triggered seizures after a long seizure-free interval. Stimulation-triggered seizures were followed first by a decrease in spiking activity during a few hours and then by an increase which could take 3 to 8 days to return to baseline. Spontaneous seizures were also, but less systematically, followed by such a sequence. Spontaneous seizures could occur when the interictal spiking rate was high as well as when it was low. It is concluded that, in the fully kindled cat, interictal spiking appears to be mainly regulated by the occurrence of seizures; the rate of spiking appears to have no bearing on the probability of occurrence of spontaneous seizures. Hence, seizures and interictal spiking could be generated by separate pathophysiologic mechanisms, the seizure-generating mechanism influencing the spike-generating mechanism but not the reverse.     

Epileptiform ictal discharges are prevented by periodic interictal spiking in the olfactory cortex

Interictal potentials are commonly observed between seizures in human epilepsies and in animal models of epilepsy. It is uncertain whether interictal spiking in partial epilepsies is causally related with the onset of an ictal discharge. To analyze the reciprocal correlation between interictal and ictal epileptiform events, we performed extracellular recordings in the limbic system of the in vitro isolated guinea pig brain preparation. Arterial perfusion of bicuculline (50 microM) in vitro consistently induced a focal ictal discharge in the hippocampal-entorhinal region that in one third of the experiments was associated with periodic interictal spikes in the piriform cortex. In the absence of active interictal spiking, the piriform cortex was secondarily invaded by the ictal discharge initiated in the hippocampal-entorhinal region, whereas no secondary ictal entrainment was observed in the presence of periodic piriform cortex spikes at circa 0.1 to 0.2 Hz. Similarly, ictal events never occurred when arterial perfusion of bicuculline was preceded by a local injection of the same drug in the piriform cortex, a procedure that induces a sustained interictal spiking. A reduced responsiveness to incoming paroxysmal discharges generated in the hippocampus was observed during the interval between two interictal spikes in the piriform cortex.     

Temporal lobe epileptiform activity following systemic administration of 4‐aminopyridine in rats

Purpose: The K⁺ channel blocker 4‐aminopyridine (4AP) induces epileptiform synchronization in brain slices maintained in vitro without interfering with γ‐aminobutyric acid (GABA)_A receptor–mediated inhibition and, actually, even enhancing it. The hypothesis that similar electrographic epileptiform patterns occur in vivo following systemic 4AP injection was tested here. Methods: Sprague‐Dawley rats (n = 13) were implanted with bipolar electrodes aimed at the hippocampal CA3 region, entorhinal cortex, subiculum, dentate gyrus, and amygdala. They were then injected with a single dose of 4AP (4–5 mg/kg, i.p.), and video‐monitoring/electroencephalography (EEG) recordings were performed. Key Findings: 4AP induced convulsive or nonconvulsive seizures in 12 of 13 rats, along with generalized fascicular twitching, wet‐dog shakes, and myoclonic jerks. On EEG, we observed in 7 (58.3%) of 12 animals long‐lasting interictal spikes from the subiculum before the occurrence of the first seizure. Once seizures had started, interictal spikes occurred in all areas with no fixed site of origin. Most seizures (41/60, 68.3%) were characterized by a low‐voltage fast‐activity onset pattern and were convulsive (48/60, 80%). 4AP also induced highly rhythmic theta (6–11 Hz) oscillations in CA3 and entorhinal cortex before seizure occurrence. Significance: Our study shows that systemic 4AP administration in vivo can enhance theta oscillations and induce slow interictal spikes and low‐voltage fast‐onset seizures similar to those reported in brain slices. We propose that these effects may reflect, at least in part, enhanced GABA_A receptor–mediated inhibition as reported in in vitro studies.     

Enhanced EEG functional connectivity in mesial temporal lobe epilepsy

PURPOSE: To analyze and compare spectral properties and interdependencies of intracerebral EEG signals recorded during interictal periods from mesial temporal lobe structures in two groups of epileptic patients defined according to the involvement of these structures in the epileptogenic zone (EZ). METHODS: Interictal EEG activity in mesial temporal lobe (MTL) structures (hippocampus, entorhinal cortex and amygdala) was obtained from intracerebral recordings performed in 21 patients with drug-resistant mesial temporal lobe epilepsy (MTLE group). This group was compared with a "control" group of patients (non-MTLE group) in whom depth-EEG recordings of MTL show that seizures did not start from the MTL. Comparison criteria were based on spectral properties and statistical coupling (nonlinear correlation coefficient h(2)) of MTL signals. RESULTS: Power spectral density analysis showed a significant decrease in the theta frequency sub-band (p=0.01) in the MTLE group. Nonlinear correlation (h(2)) values were found to be higher in the MTLE group than in the NMTLE group (p=0.0014). This effect was significant for theta, alpha, beta and gamma frequencies. Correlation values were not correlated with the frequency of interictal spikes (IS) and significant differences between groups were still measureable even when spikes were suppressed from analyzed EEG periods. DISCUSSION: This study shows that, during the interictal state, the EZ in MTLE is characterized by a decrease of oscillations in the theta sub-band and by a general increase of signal interdependencies. This last finding suggests that the EZ is characterized by network of neuronal assemblies with a reinforced functional connectivity.     

Interictal and ictal magnetoencephalographic study in patients with medial frontal lobe epilepsy

PURPOSE: To determine whether magnetoencephalography (MEG) has any clinical value for the analysis of seizure discharges in patients with medial frontal lobe epilepsy (FLE). METHODS: Four patients were studied with 74-channel MEG. Interictal and ictal electroencephalographic (EEG) and MEG recordings were obtained. The equivalent current dipoles (ECDs) of the MEG spikes were calculated. RESULTS: In two patients with postural seizures, interictal EEG spikes occurred at Cz or Fz. The ECDs of interictal MEG spikes were localized around the supplementary motor area. In the other two patients with focal motor or oculomotor seizures, interictal EEG spikes occurred at Fz or Cz. The ECDs of interictal MEG spikes were localized at the top of the medial frontal region. The ECDs detected at MEG ictal onset were also localized in the same area as those of the interictal discharges. CONCLUSIONS: In medial FLE patients, interictal and ictal MEG indicated consistent ECD localization that corresponded to the semiology of clinical seizures. Our findings demonstrate that MEG is a useful tool for detecting epileptogenic focus.     

Systemic overexpression of the alpha 1B-adrenergic receptor in mice: an animal model of epilepsy

PURPOSE: A lack of selective alpha1-adrenergic receptor (alpha1-ARs) agonists and antagonists has made it difficult to clarify the precise function of these receptors in the CNS. We recently generated transgenic mice that overexpress either wild-type or a constitutively active mutant alpha 1B-AR in tissues that normally express the receptor. Both wild-type and mutant mice showed an age-progressive neurodegeneration with locomotor impairment and probable stress-induced motor events, which can be partially reversed by alpha 1-AR antagonists. We hypothesized that the wild-type and mutant mice may exhibit spontaneous epileptogenicity as compared with normal (nontransgenic) mice. METHODS: Normal, wild-type, and mutant mice were studied. Twenty mice (1 year old) underwent prolonged video-EEG monitoring over a 4-week period. Raw EEG data were blindly analyzed by visual inspection for the presence of interictal and ictal epileptic activities. RESULTS: During the acute postoperative period (< or = 3 days), both wild-type (26.1 +/- 8.07 spikes/day) and mutant mice (116.87 +/- 55.13) exhibited more frequent interictal spikes than did normal mice (2.17 +/- 0.75; p value, <0.05), but all three groups showed EEG and clinical seizures. During the later monitoring periods (>3 days), wild-type and mutant mice showed more frequent interictal spikes (15.44 +/- 4.07; p < 0.01; and 6.05 +/- 2.46; p < 0.05, respectively) as compared with normal mice (0.41 +/- 0.41), but only mutant mice had spontaneous clinical seizures (means +/- SEM). CONCLUSIONS: The selective overexpression of the alpha 1B-AR is associated with increased in vivo spontaneous interictal epileptogenicity and EEG/behavioral seizures. These results suggest a possible role (direct or indirect) for the alpha 1B-ARs in the development and expression of epileptogenicity.     

Interictal and ictal EEG activity in the basal ganglia: an SEEG study in patients with temporal lobe epilepsy

PURPOSE: The interictal and ictal EEG activity in the basal ganglia in patients with temporal lobe epilepsy were studied during invasive EEG monitoring. METHODS: Eight epilepsy surgery candidates, each with a proven mesiotemporal seizure-onset zone, participated in the study. We used two invasive EEG methods to determine the seizure-onset zone. In both methods, diagonal electrodes were targeted into the amygdalohippocampal complex via a frontal approach and were passed through the basal ganglia with several leads. We analyzed 16 partial epileptic seizures, four of which became secondarily generalized. RESULTS: No epileptic interictal or ictal discharges were noticed in the basal ganglia. The interictal activity in the basal ganglia was a mixture of low-voltage beta activity and medium-voltage alpha-theta activity. When the ictal paroxysmal activity remained localized to the seizure-onset zone, the activity of the basal ganglia did not change. The spread of epileptic activity to other cortical structures was associated with the basal ganglia EEG slowing to a theta-delta range of 3-7 Hz. This slowing was dependent on the spread of ictal discharge within the ipsilateral temporal lobe (related to the investigated basal ganglia structures); alternatively, the slowing occurred in association with the regional spread of ictal activity from the mesiotemporal region to the temporal neocortex contralaterally to the investigated basal ganglia. Secondary generalization was associated with a further slowing of basal ganglia activity. CONCLUSIONS: The basal ganglia do not generate specific epileptic EEG activity. Despite the absence of spikes, the basal ganglia participate in changing or reflect changes in the distribution of the ictal epileptic activity.     

Beta and gamma range EEG power-spectrum correlation with spiking discharges in DBA/2J mice absence model: role of GABA receptors

PURPOSE: To describe the correlations between spiking pattern and EEG power spectrum frequency in DBA/2J mice, a model for murine absence seizures, after gamma-aminobutyric acid (GABA)(B) modulation. METHODS: The animals were first tested with the GABA(B) agonist l-baclofen followed by the GABA(B) antagonist SCH 50911. Moreover, digital EEGs recorded under experimental conditions were processed at baseline and 10 and 20 min after l-baclofen injection. This procedure was followed by injection of the GABA(B) antagonist SCH50911 and by an additional EEG evaluation at 10 and 20 min from drug administration. The power spectra analysis of signals was obtained for delta (0.5-3 Hz), theta (3.5-7.5 Hz), alpha (8-12 Hz), beta (13-20 Hz), and gamma (21-50 Hz) frequencies. RESULTS: The spiking pattern and power spectrum of beta activity was increased by 80%), whereas gamma power increased (correlation, 0.92; p < 0.001). The remaining frequency bands were unaffected. CONCLUSIONS: This study confirms the potential of GABA(B) antagonists in contrasting seizure absence in rodent models and suggests the application of drugs with a similar mechanism in humans. In addition, because GABA(B) antagonists not only contrast seizure in rodent models of absence but also improve "cognitive" performance, it could be hypothesized that gamma increase, correlated with optimized cortical binding during coherent percepts, may produce potential cognition-enhancing effects.     

The Absence of Interictal Spikes with Documented Seizures Suggests Extratemporal Epilepsy

PURPOSE: To determine the demographic and clinical characteristics of patients who have documented epileptic seizures on long-term video-EEG monitoring who do not have interictal spikes. METHODS: The records of 1,223 monitoring studies from 919 patients who underwent noninvasive long-term video-EEG monitoring were reviewed. In 28 patients (3.0% of monitored patients, 4.4% of patients with electrographic evidence of epilepsy), no interictal spikes were found despite the occurrence of at least one recorded electrographic seizure. The demographic, medical, neuropsychological, and EEG data of these patients were compared with those of 28 matched control patients with documented interictal spikes. RESULTS: Extratemporal seizures were significantly more frequent in the patients with at least one recorded epileptic seizure but without interictal spikes compared with patients with epileptic seizures and interictal spikes (p = 0.031). The only other significant difference between the groups (p = 0.016) was a later age at seizure onset (18.3 vs. 10.7 years) for the patients without interictal spikes. Age at evaluation, gender, handedness, clinical seizure type, family history of epilepsy, history of febrile seizures, neuropsychological testing, and neurologic and psychiatric history did not differ between the two groups. CONCLUSIONS: In patients with documented epilepsy without interictal spikes on EEG monitoring, the possibility of an extratemporal focus should be considered.     

Kainic acid induced hippocampal seizures in rats: comparisons of acute and chronic seizures using intrahippocampal versus systemic injections

Hyppocampal epilepsy is a recently defined syndrome occurring in 65% of all temporal lobe epilepsies as defined by: 1) electrographic (EEG) onset in the hippocampus (HC) prior to EEG seizures elsewhere, 2) post-resection hippocampal sclerosis and mossy fiber synaptic reorganizations and 3) relief of typical complex partial seizures after surgical resection of the hyppocampus. We used intrahippocampal kainic acid injections V² in rats at different developmental ages (postnatal 7 through adult) to develop long term spontaneous HC EEG spikes, EEG seizures, and behavioral seizures. Split-screen video/EEG monitoring demonstrated that this intrahippocampal kainic acid model produced progressive development of: 1) ipsilateral interictal spikes, 2) later polyspike complexes, 3) bilaterally-asynchronous EEG spiking, 4) unilateral HC EEG seizure onsets with occasional secondarily generalized spread to apposite HC and motor cortex to elicit complex partial seizures, and 5) in all seizing rats there was mossy fiber synaptic reorganization, even when injected at age 7 days. These results indicate that the intrahippocampal kainic acid injection model is similar to human hippocampal epilepsy.Supported by NIH Grants NS 02808, NS 31655 (T.L.B.); K08 NS 1603 (G.W.M.); and Fogarty Fellowship TWO 4959 (J.P.L.).     

Benign familial neonatal convulsion: clinical features of the propositus and comparison with the previously reported cases

A patient with benign familial neonatal convulsions was presented. The patient had the first episode of cyanosis on the second day of life. Thereafter, he also experienced focal clonic and/or multifocal clonic seizures. The interictal EEG showed no definite abnormality. Between the seizures he appeared well and physical examination was essentially normal. Treatment with phenobarbital (4 mg/kg/day, P. O.) was started and subsequently he had no further seizures until 3 months. At the age of 4 months, he was admitted to the hospital again because of generalized tonic-clonic seizures. The interictal EEG showed sporadic spikes dominantly in the right central area. The findings of ictal EEG at that time are characterized by fast spiking of increasing amplitude during the tonic phase. During the clonic phase, there are repetitive+ bursts of spikes and sharps mixed with persisting muscle potential. The termination of the convulsion is characterized by general voltage depression. Clinical characteristics such as seizure types, EEG findings, responses to antiepileptic drugs and recurrence of the seizures found in our propositus were compared with those of the patients previously reported in the literature.     

Effects of Antiepileptic Drugs on Absence-Like and Tonic Seizures in the Spontaneously Epileptic Rat, a Double Mutant Rat

Electroencephalographic (EEG) studies were performed to examine the effects of several antiepileptic drugs (AEDS) on absence-like and tonic seizures in the spontaneously epileptic rat (SER: zi(zi), tm/tm,), a double mutant rat, which was obtained by mating the tremor heterozygous animals (tm/ +) with the zitter homozygous animals (zi/zi), and to determine whether the seizures in the SER correspond to human absence and tonic seizures. Spontaneous EEG was continuously recorded from the frontal cortex and hippocampus using implanted electrodes. The SER showed paroxysmal and synchronized 5-7-Hz spike-wave-like complexes in both cortical and hippocampal EEG during the absence-like state, which was characterized by immobility and staring. The animal also exhibited tonic convulsion without external stimulation concomitant with low-voltage fast waves on cortical and hippocampal EEG. In some animals, sporadic low-amplitude spikes appeared in the low-voltage fast waves during tonic convulsion. the absence-like seizures were inhibited by trimethadione (100 mg/kg intraperitoneally, i.p.) and ethosuximide 100 mg/kg i.p.), whereas the tonic convulsion was not affected by these drugs. In contrast, phenytoin (20 mg/kg i.p.) inhibited the tonic seizures without affecting the absence-like seizures. Phenobarbital (10 mg/kg i.p.) and valproate (200 mg/kg i.p.) inhibited both seizures to a similar degree. These results suggest that the SER, with both absence-like and tonic seizures, is a useful model for evaluation of AEDS.     

Gabapentin as add-on therapy in focal epilepsy: a computerized EEG study.

OBJECTIVES: Gabapentin (GBP) possesses a well documented clinical efficacy in those types of focal epilepsy otherwise resistant to conventional antiepileptic drugs (AEDs); on the basis of this, it appears important to investigate the drug effects on the EEG epileptiform and background activity. METHODS: Twenty-five patients with cryptogenic or symptomatic partial epilepsy resistant to conventional AED treatment were included in the study. All patients underwent long-term video-EEG recordings before and after GBP addition (900-1200 mg/day). RESULTS: Quantitative analysis of the interictal EEG paroxysms revealed that GBP had no effect on the rate of occurrence of interictal and ictal EEG abnormalities. GBP was active in delimiting the spatial extent of the interictal spiking activity in those patients who displayed a significant reduction (> or =50%) in seizure occurrence (32% of the patients). EEG background activity recorded under rest condition from 18 out of 25 epileptic patients, before GBP therapy, was characterised by a higher content of the slow spectral components (delta and theta) with respect to control subjects. After GBP addition, the increase of theta relative power was also evident during task performance. CONCLUSIONS: These findings suggest that GBP does not interfere with the generation of interictal EEG spiking while it appears to reduce the susceptibility to seizures concomitantly with a limiting effect on the spiking activity spatial extent. The utilization of GBP in controlling focal seizures is reinforced by the absence of negative influence on cognitive functioning.     

A practical guide for routine EEG studies in epilepsy

Know what is not epilepsy! An electroencephalographer can do much more damage by overinterpreting than by underinterpreting an EEG tracing. Epilepsy is a clinical, not an EEG, diagnosis, but the EEG, when used appropriately, can greatly aid the diagnostic process. Use activating techniques such as hyperventilation, photic stimulation, and natural sleep. Take advantage of seizures in the laboratory--this is a unique opportunity to make a diagnosis. If the ictal event is not accompanied by an EEG abnormality, and pseudoseizures are suspected, remember that patients with hysterical epilepsy often have real seizures as well. Use the EEG to help differentiate between generalized and partial epileptic conditions, and to identify benign epileptic syndromes. These diagnoses have important prognostic and therapeutic implications. The EEG can help determine whether a patient is deteriorating due to increased seizure activity (undermedicated) or increased side effects (overmedicated). Postictal slowing must be differentiated from progressive or drug induced changes. The best candidates for resective surgical therapy are otherwise healthy young adults with medically intractable partial complex seizures, no psychosis, and unilateral or bilaterally independent interictal anterior temporal EEG spike foci. Patients with multifocal or bilaterally synchronous interictal EEG spikes combined with mental retardation are less likely to benefit from resective surgery, although they may be helped by corpus callosum section.     

Ictal Scalp EEG in Unilateral Mesial Temporal Lobe Epilepsy

Summary: Purpose: We wished to determine the predictive significance of unilateral hippocampal atrophy and interictal spikes on localization of ictal scalp EEG changes and assess whether ictal EEG provides information that might change treatment or influence prognosis in patients with such characteristics of epilepsy.
Methods: We analyzed EEG seizure patterns in 118 seizures in 24 patients with unilateral mesial temporal lobe epilepsy (MTLE) defined by typical clinical seizure semiology, unilateral hippocampal atrophy on magnetic resonance imaging (MRI) and unitemporal spikes on interictal EEG. Two blinded electroencephalographers independently determined morphology, location, and time course of ictal EEG changes.
Results: Lateralization was possible in 88.4–92.0% of seizures and always corresponded to the side of the interictal spike focus and of hippocampal atrophy on MRI. Although only 30.4–33.9% of seizures were lateralized at onset, a later significant pattern emerged (12.6–13.3 s after EEG seizure onset) that allowed lateralization in 82.4–91.O% of seizures with non-lateralized onset. Interobserver reliability for lateralization was excellent, with a K-value of 0.85. In most patients, either all (79.2–83.3%) or >50% (8.3–16.7%) of seizures were lateralized. In only a small proportion of patients (4.2–8.3%) were 40% of seizures lateralized. In 1 patient, no seizure could be lateralized by 1 electroencephalographer. The results of ictal EEG recordings did not alter the surgical approach and did not correlate with surgical outcome.
Conclusions: We conclude that unilateral hippocampal atrophy on MRI and unitemporal interictal spikes can predict localization of ictal scalp EEG changes with a high degree of reliability and that ictal EEG provides no additional localizing information in this particular patient group.     

EEG evaluation of children with Sturge-Weber syndrome and epilepsy

To define the contribution of the EEG evaluation in children with seizures and Sturge-Weber syndrome, we reviewed EEG data in 14 radiologically confirmed cases. Thirteen exhibited marked voltage attenuation that was localized to the region of the cerebral angiomatosis. Polymorphic slowing occurred ipsilateral to the lesion in six patients and was bilateral in six. By contrast, interictal spikes were evident in only two patients and did not always correlate with the angiomatosis. Seizures were captured in four patients and consistently revealed ictal discharges only at the periphery of the lesion. These findings indicate that abnormalities of EEG background rather than interictal spikes are consistently present early in the course of Sturge-Weber syndrome and correlate with the region of angiomatosis.     

Electroencephalographic spiking activity, drug levels, and seizure occurrence in epileptic patients

We investigated the relationships among the electroencephalographic spiking rate, drug levels, and seizure occurrence in 44 patients with focal epilepsy. Seizure occurrence was continuously monitored by personnel or videorecording and spiking rate was quantified by an automatic detection method. Results indicate that drug levels do not influence spiking rate, and spiking rate does not change before seizures but increases markedly after them, particularly secondarily generalized seizures. This increase can last several days and is observed during wakefulness and sleep. High or low spiking rates do not influence the occurrence of seizures. We suggest that interictal spikes may passively reflect damage to the brain, a damage which is worsened by further seizures. Spikes may not be directly related to seizure generation.     

Evaluation of the anticonvulsant and biochemical activity of CGS 8216 and CGS 9896 in animal models

Summary CGS 8216, a benzodiazepine-receptor ligand with inverse agonistic properties, and CGS 9896, which possesses partial agonistic or mixed agonist-antagonist properties were compared in a number of epilepsy models. The effect of CGS 9896 on the decrease in GABA levels induced by isoniazid was also investigated. CGS 9896 inhibited the kindling process in rats in that it delayed the development of overt seizures and the increase in the duration of after-discharges. In a genetic rat model characterized by absence-like EEG patterns, CGS 9896 dose-dependently suppressed these spontaneously occurring discharges, while CGS 8216 had no effect. However, CGS 8216 antagonized the anticonvulsant action of CGS 9896. CGS 9896 protected mice against seizures induced by ß-vinyllactic acid, whereas CGS 8216 shortened the latency period before convulsions occurred. CGS 9896 retarded the onset of convulsive fits caused by isoniazid without preventing the decrease in GABA levels produced by that drug. These results confirm the anticonvulsant activity of CGS 9896 and demonstrate the inverse agonistic activity of CGS 8216. The profile of CGS 9896 in the above tests suggests that it might be an effective anticonvulsant, primarily in absence-type seizures.