Feline generalized penicillin epilepsy

Feline generalized penicillin epilepsy represents an experimental model of generalized spike-and-wave discharges occurring during clinical absence attacks. Spike-and-wave discharges of feline generalized penicillin epilepsy also have a pharmacological profile that is similar to that encountered in human absence attacks. Studies on the respective roles played by the thalamus and cortex in the generation of spike-and-wave discharges indicate that both structures are important in the elaboration of such generalized activity. Moreover, GABA_A-mediated, intracortical inhibitory mechanisms are preserved and eventually enhanced at a time when generalized spike-and-wave discharges of feline generalized penicillin epilepsy are recorded. A preservation of GABA-mediated mechanisms in pure absence epilepsy might explain the differences in prognostic outlook that characterizes this type of epilepsy from seizures in which GABAergic mechanisms break down (e.g., generalized convulsive and partial epileptic attacks).This work was supported by MRC of Canada grant MT-8109 to Dr. Avoli.     

Dopaminergic mechanism in generalized photosensitive epilepsy

Apomorphine, a dopamine receptor agonist, blocked epileptic photosensitivity in patients with primary corticoreticular epilepsy. This effect was not modified by naloxone, a narcotic antagonist, suggesting that apomorphine acts on cerebral dopaminergic receptors. Apomorphine did not block spontaneous spike-and-wave discharges in patients with nonphotosensitive primary corticoreticular epilepsy. The different actions of apomorphine on spontaneous and photically induced spike-and-wave activity suggest that there is a selective dopaminergic mechanism in human epileptic photosensitivity.     

Lateral geniculate kindling and long-lasting photosensitivity in cats

The kindling response of the lateral geniculate body (GL) was compared with that of the amygdala, using cats. Daily electrical stimulation in the GL group led to the generalized tonic-clonic convulsion in most subjects and the resulting state of seizure susceptibility was long-lasting, as in the amygdala group. The kindling response of the GL differed from that of the amygdala in some respects, i.e., rapid kindling, short latency for seizure generalization, a different pattern of behavioral seizure development, and seizure regression during the course of kindling. The effects of photic stimulation with pentylenetetrazol administration were also examined before and after kindling in both groups. This study revealed that the photically induced myoclonus, at times proceeding to the generalized tonic-clonic convulsion, was provoked repeatedly as a result of GL kindling, whereas none of the amygdala-kindled cats showed such marked photosensitivity. These photically induced seizures were invariably observed for at least 4 weeks after GL kindling. Our results suggest that a neural mechanism participating in GL kindling is different from that in amygdala kindling, and that there might be cross-sensitization between seizure susceptibility resulting from GL kindling and photosensitivity.     

Feline generalized penicillin epilepsy: changes of glutamic acid and taurine parallel the progressive increase in excitability of the cortex

A coinciding temporal sequence of electrophysiological and biochemical correlates of developing generalized penicillin epilepsy in cats may indicate a "cause and effect" relationship between the two phenomena. After intramuscular injection of penicillin, in the pre-epileptic state prior to the onset of spike-and-wave discharge, the cortical content of glutamic acid decreases. This change occurs when an increased amplitude of visual evoked potentials in association cortex heralds the approach of spike-and-wave activity. The decrease of glutamic acid and that of aspartic acid occur in parallel with an almost stoichiometric increase of glutamine, gamma-aminobutyric acid (GABA), or both, while taurine levels in the pre-epileptic state remain near normal. As the pre-epileptic progresses to the epileptic state, characterized by generalized 4-5 cycles/s spike-and-wave discharges, a failure of the glial capture mechanisms for taurine and glutamate appears to occur, since both amino acids are lost from the tissue and glutamine levels fall while GABA levels are maintained or become elevated but increasingly at the expense of aspartic acid. A presumed increase in interstitial glutamic acid concentration possibly in combination with subsequent failure of GABA inhibition appears the most plausible explanation for the increasing hyperexcitability during the development of feline generalized penicillin epilepsy.     

Suppressive effects of L-5-hydroxytryptophan in a feline model of photosensitive epilepsy

We recently demonstrated that long-lasting photosensitivity is acquired as a result of kindling of the lateral geniculate nucleus (LGN), and that the LGN-kindled cat pretreated with D, L-allylglycine represents a useful model of epilepsy for drug studies. The present experiments studied anticonvulsant effects of a serotonin precursor, L-5-hydroxytryptophan (5-HTP), on photosensitivity in the LGN-kindled cat under D,L-allylglycine and on LGN-kindled seizures. 5-HTP suppressed both myoclonic responses and paroxysmal EEG discharges induced by photic stimulation in a dose-related manner. Photically-induced seizures were completely blocked 1.5-2 h after injection of 20 mg/kg 5-HTP. 5-HTP was also effective in reducing the afterdischarge duration and behavioral seizure stage in LGN-kindled seizures; following 40 mg/kg administration, no electroclinical seizures were elicited in the LGN-kindled cats. Serotonergic mechanisms may play an important role in epileptic photosensitivity; the 5-HTP suppressive effect on photosensitivity is at least partly due to reduced neuronal activity at the level of the LGN via serotonergic inhibition.     

Pathophysiology of generalized penicillin epilepsy in the cat: the role of cortical and subcortical structures. I. Systemic application of penicillin.

The mechanism of precipitation of generalized epileptiform discharges in feline generalized penicillin epilepsy, a model of human generalized corticoreticular ('centrencephalic') epilepsy, was studied in acute and chronic experiments in cats with implanted skull and intracerebral electrodes. Single shock and low frequency repetitive stimulation of subcortical sites from which prior to penicillin administration spindle activity and recruiting responses could be elicited, readily triggered epileptiform discharges in the same animals after penicillin. These structures comprised the intralaminar and midline thalamic nuclei, the neostriatum, and some posterior thalamic association nuclei (Pulvinar and nucleus lateralis posterior). Subcortical and cortical structures which prior to penicillin elicited neither spindle activity nor recruiting responses were significantly less effective in triggering generalized epileptic bursts after penicillin injection. The probability with which such bursts were elicited from these structures was still, however, in many instances above chance level. It is concluded that the generalized epileptiform discharges in feline generalized penicillin epilepsy can be triggered from a large number of brain sites, but most reliably so from subcortical nuclei involved in spindle generation and recruiting responses. The experimental evidence presented still does not allow one to determine whether epileptic alteration of neuronal function in this form of epilepsy primarily resides in cortical or subcortical nerve cells or in both.     

Suppressive effects ofl-5-hydroxytryptophan in a feline model of photosensitive epilepsy

We recently demonstrated that long-lasting photosensitivity is acquired as a result of kindling of the lateral geniculate nucleus (LGN), and that the LGN-kindled cat pretreated withd,l-allylglycine represents a useful model of epilepsy for drug studies. The present experiments studied anticonvulsant effects of a serotonin precursor,l-5-hydroxytryptophan (5-HTP), on photosensitivity in the LGN-kindled cat underd,l-allylglycine and on LGN-kindled seizures. 5-HTP suppressed both myoclonic responses and paroxysmal EEG discharges induced by photic stimulation in a dose-related manner. Photically-induced seizures were completely blocked 1.5–2 h after injection of 20 mg/kg 5-HTP. 5-HTP was also effective in reducing the afterdischarge duration and behavioral seizure stage in LGN-kindled seizures; following 40 mg/kg administration, no electroclinical seizures were elicited in the LGN-kindled cats. Serotonergic mechanisms may play an important role in epileptic photosensitivity; the 5-HTP suppressive effect on photosensitivity is at least partly due to reduced neuronal activity at the level of the LGN via serotonergic inhibition.     

Incidence of photosensitive epilepsy in unselected Indian epileptic population

The recognition of photosensitivity depends upon the finding of an abnormal EEG response to intermittent photic stimulation (IPS). Photosensitive epilepsy being the most common form of reflex epilepsy, has been studied most extensively and is reported to account for 5–10% of the epileptic population in general. One thousand unselected epileptics hailing from different parts of Northern India were screened for photosensitivity, both clinically and on a standard protocol of IPS-provoked EEG recordings. Six patients (mean age 14.5 ± 3.56 yr) were found to be photosensitive: 4 had generalized, 1 had complex partial and 1 mixed seizures; 3 had history of seizures provoked by visual stimuli. The baseline EEG in 4 patients showed generalized and 2 partial, with secondary generalized, epileptiform discharges. On IPS, similar EEG findings were obtained with a wide range of stimulus frequency (6–60 cycles/s). There is a low incidence of photosensitivity in our epileptic population, for which we believe, genetic factors are responsible.     

Clinical and EEG phenotypes of epilepsy in the baboon (Papio hamadryas spp.)

Spontaneous seizures have been reported in several baboon subspecies housed at the Southwest Foundation for Biomedical Research (SFBR), including Papio hamadryas anubis as well as cynocephalus/anubis and other hybrids. This study classified clinical and electroencephalographic (EEG) phenotypes in these subspecies based upon interictal and ictal findings, as well as photosensitivity, by scalp EEG. One hundred baboons underwent 1-h EEG studies with photic stimulation (PS), 49 with previously witnessed seizures and 51 without. The animals were classified according to these electroclinical phenotypes: presence or absence of interictal epileptic discharges (IEDs), seizures and photoparoxysmal or photoconvulsive responses. Effects of age, gender, and species on EEG phenotypes were also examined. Six discrete electroclinical phenotypes were identified. Generalized IEDs of 2-3, 4-6, and/or 6-7Hz were identified in 67 baboons. Epileptic seizures were recorded in 40 animals, including myoclonic and generalized tonic-clonic seizures. Thirty-three animals were photosensitive. Although the prevalence of IEDs and seizures were similar in seizure and asymptomatic animals, photosensitivity was more prevalent in the seizure animals (p=0.001). P.h. anubis/cynocephalus hybrids were more likely to be photosensitive than P.h. anubis (p=0.004). The reliable characterization of distinct epileptic phenotypes in this pedigreed colony is critical to the success of future genetic analyses to identify genetic factors underlying their epilepsy.     

Effects of allylglycine on photosensitivity in the lateral geniculate-kindled cat

The effects of DL-allylglycine, an inhibitor of GABA synthesis, on the responses to photic stimulation were studied in the cat kindled in the lateral geniculate body (GL). For 3 to 8 h after the injection of DL-allylglycine at a subconvulsant dose (30 or 40 mg/kg, i.v.), the kindled cat showed a stable level of photosensitivity without any toxic effects and responded with various degrees of myoclonus or a generalized tonic-clonic convulsion when photic stimulation was repeated at hourly intervals. The incidence of photically induced myoclonus reached its plateau during this period. Our results suggest that photosensitivity of the lateral geniculate-kindled cat is related to the modification of GABAergic mechanisms, and that when the GL-kindled cat is pretreated with DL-allylglycine it is a reliable model of photosensitive epilepsy.     

Potentiation and modification of recruiting responses precedes the appearance of spike and wave discharges in feline generalized penicillin epilepsy

Recruiting responses (RR) were evoked by stimulation of nucleus centralis medialis in awake and painlessly immobilized cats. Following the administration of sodium penicillin G (350,000 IU/kg i.m.) and at a time preceding the development of generalized spike-and-wave discharge we observed a strong potentiation of RR in 10 out of 15 experiments (50-200% increase in amplitude). The major feature of wave form modification consisted mainly of a development or increase of positive phases of individual recruiting waves. In between such large amplitude negative-positive recruiting waves a slow negative wave developed. One of every two recruiting waves was often diminished when the preceding recruiting wave had reached considerable amplitude. The changes in the RR were antagonized by barbiturates and by caffeine. In conjunction with previous evidence these results support the hypothesis that spikes of spike-and-wave discharges in FGPE are generated by similar thalamocortical volleys as those creating RR and spindles. They further suggest that the crucial neuronal mechanism underlying this effect of penicillin is a shift in the emphasis from distal apical dendritic thalamocortical synapses on cortical pyramidal neurons to more proximal ones.     

Baboon model of generalized epilepsy: continuous intracranial video-EEG monitoring with subdural electrodes

The baboon provides a natural non-human primate model for photosensitive, generalized epilepsy. This study describes an implantation procedure for the placement of subdural grid and strip electrodes for continuous video-EEG monitoring in the epileptic baboon to evaluate the generation and propagation of ictal and interictal epileptic discharges. Subdural grid, strip and depth electrodes were implanted in six baboons, targeting brain regions that were activated in functional neuroimaging studies during photoparoxysmal responses. The baboons were monitored with continuous video-EEG monitoring for 2-21 (mean 9) days. Although the animals were tethered, the EEG signal was transmitted wirelessly to optimize their mobility. Spontaneous seizures, interictal epileptic discharges (IEDs), and responses to intermittent light stimulation (ILS) were assessed. Due to cortical injuries related to the electrode implantation and their displacement, the procedure was modified. Habitual myoclonic and generalized tonic-clonic seizures were recorded in three baboons, all associated with a generalized ictal discharge, but were triggered multiregionally, in the frontal, parietal and occipital cortices. IEDs were similarly expressed multiregionally, and responsible for triggering most generalized spike-and-wave discharges. Generalized photoparoxysmal responses were activated only in one baboon, while driving responses recorded in all three photosensitive baboons were 2.5 times the stimulus rate. In contrast to previous intracranial investigations in this model, generalized ictal and interictal epileptic discharges were triggered by parietal and occipital, in addition to the frontocentral cortices. Furthermore, targeted visual areas responded differently to ILS in photosensitive than nonphotosensitive baboons, but further studies are required before mechanisms can be implicated for ILS-induced activation of the epileptic networks.     

Photosensitivity in Idiopathic Generalized Epilepsies

Summary:  Photosensitivity is an abnormal visual sensitivity of the brain in reaction to flickering light sources or patterns and is expressed in the electroencephalogram as generalized spike-and-wave discharge and in more susceptible individuals as clinical seizures. The most common types of seizures are generalized tonic-clonic, followed by myoclonic and absence. The photosensitive epilepsies are classified as pure photosensitive , where seizures occur only with the flickering light source/pattern or during intermittent photic stimulation (IPS) in the laboratory, and epilepsy with photosensitivity , where spontaneous seizures also occur. Positive response to IPS in idiopathic epilepsy syndromes, which are included in the International Classification or are in development, is reported to range from 7.5% in juvenile absence epilepsy to 100% in pure photosensitive epilepsy.
The treatment of photosensitivity and pure photosensitive epilepsy with rare seizures includes general and specific protective measures. For most patients, however, combination treatment with antiepileptic drugs is necessary. Valproic acid monotherapy has a success rate of 73–86%. Levetiracetam appears to be a new alternative therapeutic option. Clobazam, lamotrigine, ethosuximide, and topiramate also have been recommended as second-choice therapies.     

Role of the thalamus in generalized penicillin epilepsy: Observations on decorticated cats

Experiments in bilaterally and unilaterally decorticated cats determined whether or not the thalamus plays a primary role in the production of spike and wave (SW) discharge in feline generalized penicillin epilepsy (FGPE). In bilaterally decorticated cats an i.m. dose of penicillin sufficient to induce FGPE in intact cats did not change thalamic spindles appreciably; it failed to induce thalamic SWs or any other form of epileptic activity in the decorticated thalamus. Low-frequency spindles bearing some resemblance to SWs were often seen in the nucleus lateralis posterior (LP) before penicillin administration and showed some slight increase thereafter. This may have some bearing on earlier evidence suggesting that the thalamocortical sector comprising the LP and suprasylvian gyrus plays a leading role in the elaboration of SWs in FGPE. In unilaterally decorticated cats the SW discharges in the intact hemisphere were associated with lower voltage synchronous discharges in the decorticated thalamus which persisted after transection of the massa intermedia or of the mesencephalic reticular formation, but disappeared after section of the anterior commissure. This pathway thus seemed to be responsible for transmitting rhythmic activity at the SW frequency from the intact hemisphere to the decorticated thalamus. These findings support earlier conclusions that the development of generalized SW discharge in FGPE primarily depends on a change in cortical excitability, even though a thalamic trigger is essential. Thalamic SW activity appearing in intact animals after penicillin thus seems to be imposed upon the thalamus by the cortex.     

Postsynaptic reactions of neurons of the sensomotor cortex of the cat during evoked and self-sustained rhythmic activity of the "peak-wave" type

Intracellular correlates of evoked rhythmic cortical "spike-and-wave" potentials produced in sensorimotor cortex during 3/s stimulation of the thalamic relay nucleus (VPL) and of self-sustained "spike-and-wave" afterdischarges following 8-14/s stimulation of the same nucleus were studied in acute experiments on cats immobilized by myorelaxants. Intracellular recordings of pyramidal tract neurons revealed that different components of evoked "spike-and-wave" potentials, i. e. the spike-like negative wave and the long lasting negative wave, are postsynaptic in origin: the first is due to EPSPs with spike discharges, and the latter--to IPSPs of cortical neurons. Components of "spike-and-wave" afterdischarge mostly reflect the paroxysmal depolarizing shifts of the membrane potential of cortical neurons. After cessation of sustained "spike-and-wave" activity the long-lasting hyperpolarization accompanied by inhibition of spike discharges and subsequent recovery was observed in cortical neurons. It is presumed that the negative wave of the evoked "spike-and-wave" potential as well as slow negative potentials of direct cortical and primary responses reflect IPSPs of deeper parts of pyramidal tract neurons, while the waves of the sustained "spike-and-wave" afterdischarges are due to paroxysmal depolarizing shifts in cortical neurons.     

Participation of cortical recurrent inhibition in the genesis of spike and wave discharges in feline generalized penicillin epilepsy

Cortical recurrent inhibition (RI) evoked in pericruciate cortex by antidronic stimulation of the cerebral peduncle (CP) was studied in normal cats and in cats exhibiting the signs of feline generalized penicillin epilepsy (FGPE) following the i.m. injection of penicillin. Two measures of RI evoked by antidromic CP stimulation were used: (i) the averaged focal potential in the pericruciate gyrus: and (ii) the duration of the suppression or diminution of extracellularly recorded action potential (ap) discharge of antidromically activated pericruciate neurons measured in peristimulus time histograms (PSTHs). After i.m. injection of 350,000 IU/kg of penicillin RI remained preserved as long as only generalized spike and wave (SW) discharges appeared in the EEG, although in 5/17 neurons a modest to moderate reduction in the duratuon of RI occurred once SW discharges had appeared in the EEG. This inconstant reduction was probably not caused by a direct anti-inhibitory action of penicillin, but is a consequence of the increased number of ap discharges curtailing RI. At the small concentrations of penicillin existing in brain in FGPE its anti-inhibitory action evident with larger concentrations cannot be demonstrated.When focal or generalized tonic-clonic (T-C) seizured occurred, RI was reduced in slightly more than half of the instances for a few minutes before the onset of these seizures. This suggests that the transition from SW discharge to T-C seizure may be caused by a breakdown of RI.     

Dynamic fMRI and EEG recordings during spike-wave seizures and generalized tonic-clonic seizures in WAG/Rij rats.

Generalized epileptic seizures produce widespread physiological changes in the brain. Recent studies suggest that "generalized" seizures may not involve the whole brain homogeneously. For example, electrophysiological recordings in WAG/Rij rats, an established model of human absence seizures, have shown that spike-and-wave discharges are most intense in the perioral somatosensory cortex and thalamus, but spare the occipital cortex. Is this heterogeneous increased neuronal activity matched by changes in local cerebral blood flow sufficient to meet or exceed cerebral oxygen consumption? To investigate this, we performed blood oxygen level-dependent functional magnetic resonance imaging (fMRI) measurements at 7T with simultaneous electroencephalogram recordings. During spontaneous spike-wave seizures in WAG/Rij rats under fentanylhaloperidol anesthesia, we found increased fMRI signals in focal regions including the perioral somatosensory cortex, known to be intensely involved during seizures, whereas the occipital cortex was spared. For comparison, we also studied bicuculline-induced generalized tonic-clonic seizures under the same conditions, and found fMRI increases to be larger and more widespread than during spike-and-wave seizures. These findings suggest that even in regions with intense neuronal activity during epileptic seizures, oxygen delivery exceeds metabolic needs, enabling fMRI to be used for investigation of dynamic cortical and subcortical network involvement in this disorder.     

Coexistence of symptomatic focal and absence seizures: Video-EEG and EEG-fMRI evidence of overlapping but independent epileptogenic networks

The distinction between typical absences and hypomotor seizures in patients having frontal lesions is difficult. In focal epilepsy, generalized-like interictal discharges can reflect either a coexistent generalized epileptic trait or a secondary bilateral synchrony. Using combined measures of the EEG and blood oxygenation level dependent (BOLD) activity, we studied a 50-year-old patient with both absence-like and symptomatic focal motor seizures. Focal activity induced activation in the lesional area and deactivation in the contralateral central cortex. Generalized spike-and-wave discharges (GSWDs) resulted also in perilesional activation, and multifocal symmetrical cortical and thalamic activations, and deactivation in associative cortical areas. Although the central cortex was involved during both types of epileptic activity, electroencephalography (EEG)–functional magnetic resonance imaging (fMRI) revealed distinct neuronal networks at the time of the focal or generalized discharges, allowing a clear-cut differentiation of the generators. Whether the patient had distinct epileptic syndromes or distinct electrographic patterns from the lesional trigger remains debatable.     

Dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome): a condition unrelated to mitochondrial encephalomyopathies.

Thirteen patients with dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome) had full clinical and neurophysiological study as well as muscle biopsy. The patients had action myoclonus, generalised epileptic seizures, and mild cerebellar syndrome. The disease was inherited in an autosomal recessive pattern in five patients, and occurred as isolated cases in the remaining eight patients. The age at onset of symptoms ranged from 6 to 15 years (mean, 10.4 years). The EEG and polygraphic findings included normal background activity in most patients, spontaneous fast generalised spike-and-wave discharges, photosensitivity, no activation during slow sleep, and vertex and rolandic spikes in REM sleep. Results of muscle biopsy, performed an average of 14 years after onset of the disease, were normal and showed no mitochondrial abnormalities. These findings suggest that Ramsay Hunt syndrome is a condition with distinctive clinical and neurophysiological features and unrelated to mitochondrial encephalomyopathies.     

氟桂利嗪对青霉素致痈效应和海马神经元单位放电的影响

目的：探讨Ca^2＋拮抗剂氟桂利嗪对青霉素致效应和海马神经元单位放电的影响.方法：Wistar大鼠随机分成3组.正常对照组;癫癎模型组：用青霉素钠按6 000 000 U·kg^-1腹腔注射;癫癎预处理组：造模前用盐酸氟桂利嗪 20 mg·kg^-1每隔12 h灌胃,共2次,于第2次给药2 h后制作模型.观察癫癎发作并记录海马神经元单位放电.结果： ①正常对照组大鼠共记录到24个单位海马神经元放电;②癫癎模型组共记录到78个单位海马神经元放电,癫癎发作程度强,发作频率高;③癫癎预处理组共记录到47个单位海马神经元放电,癫癎发作程度减轻,发作频率减少.结论：氟桂利嗪可抑制青霉素致效应,减少海马神经元的单位放电.