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PubMed1977

Effects of antiepileptic drugs on thalamocortical excitability.

Comparative effects of anticonvulsant drugs on the thalamocortical system were analyzed quantitatively. Paired stimuli were delivered to the ventrolateral thalamus with evoked responses recorded from the ipsilateral sensorimotor cortex in the cat. Threshold and excitability profiles were developed with an on-line computer. Effects of phenytoin and diazepam were generally similar, with depression of excitability and slight elevation of thresholds. Ethosuximide produced a pronounced pair-interval dependent effect of unchanged or increased excitability and lowered threshold at shorter intervals, with depressed excitability and raised threshold at longer intervals. These data demonstrate a marked difference in effect of the petit mal and grand mal agents tested and suggest a basis for the effectiveness of ethosuximide in controlling 3-per-second repetitive activity.

Animals↗
PubMed1978

Sodium valproate in the treatment of intractable seizure disorders: a clinical and electroencephalographic study.

A 12-week study of clinical response, EEG changes and serum antiepileptic drug (AED) levels using sodium valproate (VAL) was undertaken. The study showed that VAL is a powerful adjunct in the treatment of intractable epilepsy. It was most effective in patients with generalized seizures, but no seizure type was totally resistant. No serious adverse effects were encountered; nausea was easily overcome by readjusting the drug dosage. In most cases the only EEG change was decrease of epileptiform activity, and this correlated well with decreased frequency of clinical seizures. These two features in turn were most often seen with a serum VAL level of 40 microgram per milliliter or greater. Intoxication with VAL was accompanied by marked slowing of the background rhythms, but no increase in beta activity. Other modifications of the EEG were probably due to changes in the plasma levels of other drugs. Interactions between VAL and conventional antiepileptic drugs occur, so that serum concentrations of all drugs must be monitored in patients receiving VAL.

Adult↗
PubMed1978

Proglonged epileptic twilight states: continuous recordings with nasopharyngeal electrodes and videotape analysis.

Confusion, speech arrest, automatic behavior, and amnesia characterize the prolonged twilight states of both petit mal and psychomotor status. However, in psychomotor status two electroclinical phases were differentiated: (1) A continuous twilight state with partial responsiveness and reactive automatisms interrupted by (2) staring, total loss of responsiveness, and stereotyped automatisms. During the first phase, with reactive behavior, the EEG showed bilateral diffuse slowing. During the second phase, with stereotyped automatisms, there were spreading right temporal 4- to 12-Hz discharges. Petit mal status had one continuous twilight state, during which both stereotyped and reactive automatisms merged as 1.5- to 4-Hz spike-wave complexes, and bimedial temporal 4-Hz discharges' appeared in the EEG.

Adult↗
PubMed1981

The hospital experience and seizure control.

We studied 30 patients who were admitted to the hospital because of intractable seizures. Twenty-three had fewer seizures during one or both of the first 2 hospital weeks than before admission, although medication was not changed. The role of environment in seizure control is difficult to measure, but hospital admission itself is a form of environmental manipulation. When seizure control is achieved in the hospital, the hospital experience itself must be considered in addition to other therapeutic interventions.

Anticonvulsants↗
PubMed1993

Prognostic factors of pentobarbital therapy for refractory generalized status epilepticus.

Pentobarbital coma (PBC) is a treatment for patients with refractory status epilepticus, but there are currently few guidelines for choosing when to initiate or continue this therapy. To identify potential prognostic factors in this setting, we reviewed the course of 17 adult patients treated with a standardized protocol of PBC for refractory status epilepticus over the past 6 years. PBC was extremely effective in aborting seizures in 16 of 17 patients, but 11 of the patients developed severe hypotension that required therapy with vasopressors. Six of the patients had full recoveries or developed only minimal residual deficits following PBC, two developed severe neurologic deficits, and nine died. Survival was associated with a history of epilepsy, absence of multiorgan failure before or during PBC, age < 40 years, and absence of hypotension requiring vasopressors during PBC. Long-term follow-up in seven of eight survivors (mean, 2.9 years; range, 1 to 5 years) showed that patients' conditions remained stable after discharge from the hospital. Thus, although PBC is effective in controlling ongoing seizures, the therapy frequently leads to significant hypotension. This side effect may be especially troublesome in patients with the negative prognostic indicators identified in this study. These findings highlight the need for alternative approaches in the management of these patients.

Adult↗
PubMed1997

GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities.

Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, is widely distributed throughout the brain and spinal cord. Two major families of GABA receptors have been identified, GABAA and GABAB. While much is known about the pharmacological and molecular properties of GABAA receptors, it is only within the last few years that potent and selective antagonists have been developed for the GABAB site, and only within the past few months that this receptor has been cloned. Thus, tools are now available to define more fully the GABAB receptor in terms of its biology and the therapeutic potential of manipulating this site. Data suggest that, in addition to their established use as muscle relaxants, GABAB receptor agonists possess analgesic and antitussive properties, and may be useful for treating bladder dysfunction. While there is less clinical data on GABAB receptor antagonists, preclinical results indicate that they may be of value in treating absence epilepsy, cognitive dysfunction and, possibly, pulmonary and intestinal disorders. However, for this potential to be fully exploited, it is necessary to identify and characterise molecularly and pharmacologically distinct GABAB receptor subtypes.

Editorial↗
PubMed2006

Distinct electrical and chemical connectivity maps in the thalamic reticular nucleus: potential roles in synchronization and sensation.

GABAergic neurons of the thalamic reticular nucleus (nRt) provide thalamocortical relay neurons with feedback inhibition that influences sensory processing and thalamocortical rhythm generation. Mutual interactions between reticular neurons coordinate oscillatory activities developed within the network during normal sleep and in absence epilepsy, but the chemical versus electrical nature of these connections and their functional influence remain controversial. Here, we investigated the incidence and spatial extent of intra-nRt connectivity in vitro in horizontal and coronal thalamic slices from rat. Laser scanning photostimulation activated presynaptic nRt cells during patch-clamp recordings of postsynaptic neurons. Photolysis of caged glutamate evoked GABAergic IPSCs and/or depolarizing events (spikelets, mediated via electrical coupling) in a large proportion of neurons, thus indicating connectivity with presynaptic cell(s). Synaptic inputs were organized along the major axis of the nucleus in the same orientation as, but commonly exceeding the extent of, dendritic arborization of the postsynaptic neuron. In the anteroposterior (horizontal) plane, chemical connectivity had higher incidence (60% of recorded neurons vs 40% in vertical plane) and longer spatial extent, whereas in the dorsoventral (vertical) plane, electrical coupling dominated (47% incidence vs 37% in horizontal plane) and was more widely distributed. These data demonstrate that both electrical and chemical synapses are prominent within nRt and suggest different roles for the two types of connections. We thus propose that, along the vertical plane, electrical connectivity will promote coordinated rhythmic activity of sleep and/or thalamocortical epilepsy, whereas along the horizontal plane, chemical connectivity will oppose widespread thalamocortical synchronization and modulate sensory throughput.

Animals↗
PubMed2006

The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression.

The mouse mutant ducky and its allele ducky(2J) represent a model for absence epilepsy characterized by spike-wave seizures and cerebellar ataxia. These mice have mutations in Cacna2d2, which encodes the alpha2delta-2 calcium channel subunit. Of relevance to the ataxic phenotype, alpha2delta-2 mRNA is strongly expressed in cerebellar Purkinje cells (PCs). The Cacna2d2(du2J) mutation results in a 2 bp deletion in the coding region and a complete loss of alpha2delta-2 protein. Here we show that du(2J)/du(2J) mice have a 30% reduction in somatic calcium current and a marked fall in the spontaneous PC firing rate at 22 degrees C, accompanied by a decrease in firing regularity, which is not affected by blocking synaptic input to PCs. At 34 degrees C, du(2J)/du(2J) PCs show no spontaneous intrinsic activity. Du(2J)/du(2J) mice also have alterations in the cerebellar expression of several genes related to PC function. At postnatal day 21, there is an elevation of tyrosine hydroxylase mRNA and a reduction in tenascin-C gene expression. Although du(2J)/+ mice have a marked reduction in alpha2delta-2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tyrosine hydroxylase gene expression. However, du(2J)/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in alpha2delta-2. A hypothesis for future study is that effects on gene expression occur as a result of a reduction in somatic calcium currents, whereas effects on PC firing occur as a long-term result of loss of alpha2delta-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.

Animals↗
PubMed2006

Intrinsic and synaptic dynamics interact to generate emergent patterns of rhythmic bursting in thalamocortical neurons.

Rhythmic inhibition entrains the firing of excitatory neurons during oscillations throughout the brain. Previous work has suggested that the strength and duration of inhibitory input determines the synchrony and period, respectively, of these oscillations. In particular, sleep spindles result from a cycle of events including rhythmic inhibition and rebound bursts in thalamocortical (TC) neurons, and slowing and strengthening this inhibitory input may transform spindles into spike-wave discharges characteristic of absence epilepsy. Here, we used dynamic clamp to inject TC neurons with spindle-like trains of IPSCs and studied how modest changes in the amplitude and/or duration of these IPSCs affected the responses of the TC neurons. Contrary to our expectations, we found that prolonging IPSCs accelerates postinhibitory rebound (PIR) in TC neurons, and that increasing either the amplitude or duration of IPSCs desynchronizes PIR activity in a population of TC cells. Tonic injection of hyperpolarizing or depolarizing current dramatically alters the timing and synchrony of PIR. These results demonstrate that rhythmic PIR activity is an emergent property of interactions between intrinsic and synaptic currents, not just a passive reflection of incoming synaptic inhibition.

Action Potentials↗
PubMed1977

Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy.

Sodium valproate has a broad spectrum of anticonvulsant activity, but is structurally unrelated to conventional antiepileptic drugs. Its proposed mode of action is mediated through effects on the function of brain gamma-aminobutyric acid (GABA). However, the elevations in brain and cerebellar GABA, and the concomitant reductions in levels of cyclic guanosine monophosphate, occur in animals at dose levels which are unlikely to be achieved during treatment of epileptic patients.

Administration, Oral↗
PubMed1997

Occurrences of electroencephalographic (EEG) patterns that resemble epileptiform discharges in background EEG in epileptic patients.

The relationships of background EEG to epileptiform discharge development were studied in 9 epileptic patients having generalized spike and wave complexes (SWCs) with a maximum at the frontal location on either side. The instantaneous power spectrum of EEGs at F3, F4, C3, C4, P3, P4, O1, O2, T3 and T4 was estimated with wavelet transform. Subsequently, the similarity of power spectra between SWCs and background EEG was determined by use of Kullback-Leibler information and artificial neural network in each patient. Both similarity measures revealed that EEG patterns similar to SWCs occurred in the background activity just before SWCs at frontal locations. These findings suggested that these SWC-like EEG events occurred as poorly developed epileptiform discharges buried in the background activity.

Adolescent↗