Secondary Seizures Research Articles

Epileptic-like activity induces multiple forms of plasticity in hippocampal area CA1

Mesial temporal lobe epilepsy is a relatively common form of epilepsy that afflicts many thousands of people. It has been suggested that the development of primary and secondary foci may involve mechanisms similar to long-term potentiation (LTP). In vitro seizure models typically involve an increase in spontaneous asynchronous bursting activity (epileptiform activity) induced either by increasing excitation or decreasing inhibition. Previous experiments have indicated that these models often generate bursting activity that closely resembles epileptic activity. LTP is often observed following epileptiform activity. In area CA1 of the hippocampus two forms of LTP that are dependent on the activation of either the L-type voltage dependent calcium channel (vdccLTP) or the N-methyl- d-aspartate receptor/channel (nmdaLTP) have been described. It is unclear from previous experiments which type of LTP results from epileptiform activity. Recent evidence indicates that nmdaLTP is most likely a short-term type of plasticity while vdccLTP may be a long-lasting form of synaptic plasticity. Given the characteristics of vdccLTP it is a likely candidate mechanism to underlie the development and formation of secondary seizure foci. We have therefore tested the ability of epileptiform activity induced by elevated potassium chloride to induce multiple forms of LTP in area CA1 of the rat hippocampus. Elevation of extracellular potassium chloride resulted in spontaneous asynchronous bursting. The net result of the spontaneous asynchronous bursting was to induce a compoundLTP consisting of nmdaLTP and vdccLTP components.

Prognostic implication of contralateral secondary electrographic seizures in temporal lobe epilepsy.

Interhemispheric propagation of seizures in temporal lobe epilepsy is frequently noted during intracranial EEG monitoring. We hypothesized that a distinct secondary electrographic seizure (DSES) in the temporal lobe contralateral to primary seizure onset may be an unfavorable prognostic indicator. We reviewed intracranial depth electrode EEG recordings, 1-year outcome, and medical records of 51 patients (M 29, F 22: age 15-64 years) who underwent anterior temporal lobectomy during 1988-96. We defined DSES as a seizure that spread to the contralateral temporal lobe and produced distinct contralateral EEG features. The distinct feature was focal involvement of one or two electrode contacts at onset, which starts and evolves independently from the ipsilateral temporal lobe. We considered DSES as the predominant seizure pattern when it occurred in more than one half of the patients' recorded seizures. Only nine of 19 (47%) patients with predominant DSES had a 1-year seizure-free outcome, whereas 27 of 32 (84%) patients without predominant DSES had a 1-year seizure-free outcome (p < 0.01). Bitemporal independent seizures were more common in patients with predominant DSES (9/19 versus 0/32; p < 0.001). Our results suggest that distinct contralateral secondary electrographic seizure is a predictor of unfavorable outcome and is also more likely to be associated with bitemporal seizures.

Childhood secondary (symptomatic) epilepsy, seizure control, and intellectual handicap in a nontropical region of South Africa.

To determine the prevalence of secondary (symptomatic) epilepsy and to ascertain levels of seizure control and intellectual function in a clinic population of children drawn from a poor community in a temperate region of South Africa. Detailed review of the records of every child with recurrent seizures who attended a special epilepsy outpatient clinic during 1995. A total of 1,017 children was studied. In 432 (43%), there was historic, clinical, and radiologic evidence to suggest that epilepsy was symptomatic of underlying brain damage or defect. Acceptable seizure control was maintained with a single standard anticonvulsant drug (AED) in 65% of cases. In the 6 months preceding the study, 37% of the subjects had remained seizure free. Forty-seven percent of the study population were considered to be of subnormal intelligence. In a children's hospital outpatient population in the Western Cape region of South Africa, the prevalence of secondary epilepsy is higher than is found in developed countries. There is need within the community for preventive measures aimed at reducing the prevalence of perinatal insults, meningitis, tuberculosis, neurocysticercosis, and cerebral trauma.

Brain imaging in neonatal hypoglycaemia

Magnetic resonance imaging studies in two cases of neonatal hypoglycaemia showed cortical and white matter cerebral damage that was most obvious in the occipital lobes. Both cases showed oedema in...

The effects of focal N-methyl- d-aspartate pretreatment on the parameters of amygdaloid electrical kindling

Evidence is accumulating for a role of glutamate in both the development (epileptogenesis) and spread of epileptic neuronal hyperactivity in the brain. In the present investigation we examined the influence of daily focal pretreatment with the selective glutamate receptor agonist N-methyl- d-aspartate (NMDA) on the parameters of amygdaloid electrical kindling, an animal model of human complex partial and secondary generalised focal seizures. Pretreatment with NMDA significantly increased the electrical afterdischarge threshold in this model. With subsequent daily suprathreshold electrical stimulation, however, NMDA pretreatment enhanced the kindling process as shown by both electroencephalographic and motor seizure responses. Marked reductions in the number of stimulations required to reach each distinct stage of kindling development were evident. The number of stimulations required to achieve the fully kindled state was approximately halved by pretreatment with NMDA (6.8±1.6 stimulations) compared with control, buffer-pretreated animals (11.6±1.4 stimulations; mean±S.E.M.; P<0.05). Consistent with this, the mean durations of the electrically-evoked afterdischarges on most NMDA pretreatment days were significantly increased compared to those recorded in control animals. Importantly, fully kindled animals showed a markedly enhanced sensitivity to focally applied NMDA. The results of the present experiments provide strong in vivo evidence to support the concept that ion fluxes through NMDA receptor-linked cation channels play a major role in the mechanisms of kindling epileptogenesis. Extracellular glutamate at abnormally raised levels, acting at least in part via NMDA receptors, may be the principal agent triggering many forms of epilepsy.

Twenty-Year Experience with Early Surgery for Craniosynostosis

As the second of a two-part series, 76 patients with pansynostosis and craniofacial synostosis syndromes were retrospectively analyzed. Diagnoses included pansynostosis (7), craniofrontonasal dysplasia (8), and Apert (24), Crouzon (15), and Pfeiffer (15) syndromes. All patients underwent primary fronto-orbital advancement-calvarial vault remodeling procedures at less than 18 months of age (mean 6.1 months). Twenty-eight patients (36.8 percent) required a secondary cranial vault operation (mean age 28.4 months). Additionally, a major tertiary procedure was necessary in 5 patients to deal with persistent unacceptable craniofacial form. To address the associated finding of midface hypoplasia, 64.8 percent (n = 35) of patients underwent Le Fort III midface advancement or had that procedure recommended for them. The remainder were awaiting appropriate age for this reconstruction. The more extensive pathologic involvement of the pansynostosis and craniofacial syndrome group is illustrated. As compared with the isolated craniofacial synostosis group previously reported, the incidence of major secondary procedures (36.8 versus 13.5 percent), perioperative complications (11.3 versus 5.0 percent), follow-up complications (44.7 versus 7.7 percent), hydrocephalus (42.1 versus 3.9 percent), shunt placement (22.4 versus 1.0 percent), and seizures (11.8 versus 2.9 percent) was significantly increased. Complex problems including those of increased intracranial pressure, airway obstruction, and recurrent turricephaly or cranial vault maldevelopment are repeatedly encountered. In addition, that early fronto-orbital advancement-cranial vault remodeling failed to promote midface development and hypoplasia of this region is almost a consistent finding in the craniofacial syndromic group. The average length of postoperative follow-up was 6 years. According to the classification of Whitaker et al., which assesses surgical results, 73.7 percent of patients were considered to have at least satisfactory craniofacial form (category I-II) at latest evaluation. An algorithmic approach to the treatment of all patients with craniosynostosis is presented utilizing early surgical intervention as the key element.

Seizure classification in dogs from a nonreferral-based population

Summary On initial evaluation for onset of seizure disorders at nonreferral veterinary practices, 50 previously healthy dogs were enrolled in a study to determine the probability of identifying a specific cause for the seizures. Treatment was not administered prior to entry of dogs in the study. On the basis of antemortem and postmortem test results, 22 dogs (44%) were classified as having primary epileptic seizures (pes; idiopathic or without identifiable cause), 23 (46%) had secondary epileptic seizures (ses; identifiable intracranial cause), and 5 (10%) had reactive epileptic seizures (res; metabolic or transient noxious cause). Forty-one dogs (82%) had 2 or more seizures before evaluation, with 37 (90%) of these dogs classified as having epilepsy on the basis of an underlying chronic brain disorder. For these 41 dogs, 17 (41%) had pes, 20 (49%) had ses, and 4 (10%) had res. Among the 9 dogs (18%) with nonrecurring seizures, 5 had pes, 3 had ses, and 1 had res. Generalized seizures were the most common first-observed seizure type associated with all etiologic classifications in all dogs with recurring and nonrecurring seizures. Diagnosis of ses was statistically more probable when the dog was less than 1 or more than 7 years old at the first seizure, when the first seizure was a partial seizure, or when the first seizure occurred between midnight and 8 am. A diagnosis of res was statistically more probable only when the interval between the first and second seizure was brief (≤ 4 weeks). A diagnosis of pes was statistically more probable when the dog was between 1 and 5 years of age at the first seizure, when the dog was a large breed (&gt; 15 kg), when the seizure occurred between 8 am and midnight, or when the interval between the first and second seizure was long (&gt; 4 weeks).

Changes in Neurofilament Protein NF‐L and NF‐H Immunoreactivity Following Kainic Acid‐Induced Seizures

Postlesion plasticity of neuronal processes might contribute to secondary spontaneous seizures after kainic acid administration. In this study, neurofilament (NF) proteins were examined following intraperitoneal injection of kainic acid, and special reference was given to temporal changes in quantity and quality of the NF light (NF-L) and heavy (NF-H) subunits. A pronounced decrease in phosphorylation-related immunoreactivity of NF-H occurred as early as 1 day after the injection in the amygdala/pyriform cortex, hippocampus, striatum, and dorsal cerebral cortex. A shift of NF-H from the phosphorylated to nonphosphorylated form was evident in immunoblots, suggesting dephosphorylation contributed to the decrease. Decreases in NF-L and phosphorylated NF-H contents in the limbic structure at 3 days were correlated with the increasing kainic acid doses from 2.5 to 10 mg/kg. The degradation pattern in immunoblots with antibodies against NF-L indicated that the decrease in NF-L was probably due to calcium-activated proteolysis. NF-L and phosphorylated NF-H contents secondarily increased from 9 days onward, with approximately 20% above the control level of phosphorylated NF-H immunoreactivity at 27 days in the amygdala/pyriform cortex and ventral hippocampus. Immunohistochemical examination of the hippocampus revealed that an increase of NF staining in the mossy fiber system may contribute to the NF recovery in this region. Furthermore, the temporal changes of NF-L and phosphorylated NF-H contents were positively correlated with those of the neuronal cell adhesion molecule, a neuritic growth cone marker, substantiating postlesion regenerative reactions of NF proteins. Functional consequences of the NF plasticity remain to be identified.

Pathophysiology of Perinatal Asphyxia

Following a severe asphyxial episode many cells can recover metabolically, and a cascade of processes are triggered in which intervention, even some hours later, can allow rescue of some cells that would otherwise die. A number of principles, however, needs to be carefully considered before extrapolating from animal to human trials. In particular, the effects on long-term outcome and on those who are compromised by intrauterine growth retardation need to be determined. It is critical to be able to identify rapidly those infants in terms of nature and severity of injury who are most likely to benefit from treatment. The dimension of time and phase of injury or recovery are key factors to effective intervention. Novel continuous cerebral function monitoring techniques such as those based on real-time spectral analysis of the EEG activity, cortical impedance monitoring, and near-infrared spectroscopy have considerable potential for determining the severity and pathophysiologic phase of injury on line.

Clinical manifestations in children with occipital spike-wave paroxysms.

The pattern of occipital-posterotemporal spike-wave paroxysms (O-PT SWPs), is a distinctive EEG abnormality observed primarily with occipital epilepsy of childhood and basilar artery migraine. We studied EEG and clinical features in 30 children and young adults with this EEG pattern. Prolonged and brief O-PT SWPs were observed. Prolonged discharges (greater than 6 s) were observed only in children with seizures (p less than 0.001), and brief discharges (1-6 s) were observed immediately after eye closure. Generalized SWPs (11 patients, 37%) and background abnormalities (17 patients, 57%) were common. Photic activation of O-PT SWPs was not observed. Twenty-four patients (80%) manifested paroxysmal phenomena-seizures (20 patients, 67%) and migraine (12 patients, 40%, 4 alone and 8 with seizures). Fifteen patients (75%) had partial seizures, and 5 (25%) had absence seizures. In 7 patients with partial seizures, an etiology was evident. Neurologic examination was more often abnormal in patients with secondary partial seizures than in those with idiopathic partial seizures (p less than 0.05) and absence seizures. Conversely, migraine was more often associated with idiopathic partial seizures than with secondary partial seizures (p less than 0.05) and absence seizures. Six children (20%) had no paroxysmal events. Generalized SWPs were uncommon in patients with idiopathic partial seizures. We conclude that O-PT SWPs is a nonspecific epileptiform abnormality that may occur in children with (a) idiopathic partial, (b) symptomatic partial, and (c) absence epilepsies, but it may also occur in patients with no evidence of seizures.

Lasting nature of both transfer and interference in amygdaloid kindling in cats: observation upon stimulation with 11-month rest following primary site kindling.

Eleven months after the completion of primary site amygdaloid (AM) kindling, three cats experienced kindling of the secondary site AM. At the secondary site, animals developed kindled seizure with a mean of eight stimulations, which was significantly fewer than the 29 required at the primary site, indicating a presence of a positive transfer effect. However, the ictal architecture of the secondary site-kindled seizure was significantly different from that of the primary site: in the former, there was a marked delay in secondary generalization, with individual kindled seizure having a significantly prolonged seizure duration. Both the transhemispheric positive and negative transfer effects observed with the secondary site AM kindling reflect the lasting nature of the neural remodeling induced by the primary site AM kindling. This finding may have clinical relevance.

Corpus Callosotomy for Intractable Seizures in the Pediatric Age Group

The results of corpus callosotomy in 18 patients 16 years old and younger are presented. Eighty-three percent of our patients have had a significant improvement from the surgery (a decrease in seizure frequency of greater than 80% or no longer having generalized atonic, tonic, or tonic-clonic seizures). The procedure seems to be well tolerated in young patients, and we have not noted a postoperative deterioration in behavior, memory, or language function in our patients. One of our patients died in status epilepticus 3 months after surgery. Nevertheless, we have not encountered any serious morbidity in our other patients. Corpus callosotomy can be considered for children with intractable seizures, especially when generalized atonic, tonic, or tonic-clonic (whether primary or secondary) seizures are the major seizure type.

Estradiol replacement to female rats facilitates dorsal hippocampal but not ventral hippocampal kindled seizure acquisition

Estradiol replacement facilitates amygdala and neocortical kindling. This study determined if estradiol also interacts with kindling of additional limbic sites, the dorsal (dH) and ventral (vH) hippocampus. During dH stimulations, ovariectomized female rats with estradiol (E) replacement required 29.7 ± 3.5 trials to kindle and accumulated 1170 ± 90 s of afterdischarge (AD), significantly less than the 40.6 ± 3.7 trials and 1620 ± 225 s in rats without estradiol (nE). E did not significantly alter the long series of partial limbic seizures preceding generalized seizures despite the early appearance of AD in the contralateral amygdala. E significantly advanced the onset of generalized seizures compared to nE (22.7 ± 2.3 versus 27.9 ± 3.2 trials), an event coincident with neocortical AD development. Following secondary seizure generalization, E rats rapidly completed late-kindled seizure acquisition. In contrast, nE rats required an almost twofold greater number of AD trials and AD s to complete late kindling compared to E rats. One factor in the slower late kindling of nE rats was the instability of generalized seizures which frequently regressed to focal or partial responses. In marked contrast to dH kindling, vH kindling was uneffected by E replacement. The results provide further experimental evidence for a role for estradiol in catamenial epilepsy and support our previous work suggesting that the focal origin of seizure development is critical to E facilitation of kindling and that secondary generalization of seizures is especially sensitive to estradiol.

Kindled Seizures Elevate Blood Pressure and Induce Cardiac Arrhythmias

The effect of kindled seizures on the cardiovascular system was examined in amygdaloid kindled rats. The most prominent cardiovascular response during a generalized kindled seizure was an abrupt 50% increase in mean arterial pressure (MAP) lasting 20-30 s after initiation of the seizure. Superimposed on this change in blood pressure (BP) was a profound bradycardia characterized by a rate about half that recorded before stimulation. Changes in heart rate (HR) and BP observed during amygdaloid kindled seizures were similar to those observed during secondary spontaneous seizures. These effects apparently are independent of the kindling stimulus because stimulus-induced cardiovascular changes were not present at the beginning of the kindling process. These results suggest that the kindling seizure model is useful to study the underlying mechanisms of seizure-induced cardiac arrhythmias and possibly the clinical phenomenon of sudden unexplained death in epileptic patients.

Estradiol replacement facilitates the acquisition of seizures kindled from the anterior neocortex in female rats

Estradiol replacement facilitates kindling from a limbic region, the amygdala. This study determined if estradiol also interacts with kindling from a non-limbic region, the anterior neocortex. Ovariectomized female rats with estradiol replacement required 24 ± 1.6 trials to kindle and accumulated 434 ± 28 sec of afterdischarge (AD), significantly less than the 38 ± 2.2 trials and 840 ± 93 sec in rats without estradiol. Estradiol replacement did not significantly alter the long series of focal cortical seizures preceding generalized seizures in spite of the early appearance of AD in the contralateral amygdala. Estradiol significantly advanced the onset of generalized seizures compared to rats without estradiol (19 ± 0.6 versus 24 ± 1.9 trials). Following secondary seizure generalization, estradiol rats rapidly completed late kindled seizure acquisition. In contrast, late kindling in rats without estradiol was slower as reflected by a 3-fold greater number of AD trials and AD seconds to complete kindling compared to rats with estradiol. One factor in the slower late kindling of rats without estradiol was the instability of generalized seizures which frequently regressed to focal or partial responses. The results provide further experimental evidence for a role for estradiol in catamenial epilepsy and suggest that the process of secondarily generalization of seizures is especially sensitive to estradiol.

8-Cyclopentyl 1,3-dimethylxanthine prolongs epileptic seizures in rats

We tested the effects of 8-cyclopentyl-1,3 dimethylxanthine (8-CPT) on electrically induced seizures in rats. 8-CPT prolonged secondary seizures and converted partial seizures into generalized motor seizures, but did not affect primary seizure duration. Because 8-CPT is a potent and specific adenosine antagonist, these results add further support to the hypothesis that endogenous adenosine prevents the spread of epileptic seizures.

Proconvulsant effects of theophylline on hippocampal afterdischarges

We tested the effects of the adenosine antagonist, theophylline, on electrically induced afterdischarges in the hippocampus of rats. Theophylline did not significantly alter the threshold for afterdischarge initiation or the duration of the initial afterdischarge. However, theophylline greatly prolonged the duration of secondary afterdischarges, and permitted generalization to motor seizures. Because theophylline antagonizes adenosine, and the hippocampus is a region rich in adenosine binding sites, we interpret these results to mean that endogenous adenosine has little action on focal seizure initiation, but a strong action to suppress secondary seizures and to inhibit seizure generalization.

Postictal events in amygdala-kindled female rats with and without estradiol replacement

This study investigated the effect of estradiol on ictal and postictal events in ovariectomized female rats kindled by daily amygdala stimulation during the presence or absence of estradiol replacement. Although ictal components of kindled seizures were not altered by estradiol, several postictal events such as myoclonic jerks were significantly increased by estradiol. Twelve days after kindling, estradiol-replaced rats with electrodes in the basal, lateral, or cortical amygdala nuclei developed brief postictal “bursts” of behavioral and EEG activity which developed into a secondary seizure in some rats. Rats without estradiol never displayed these postictal events. Pretreatment of rats with pentylenetetrazol, 20 mg/kg, 15 days after kindling, resulted in a further increase in the incidence of bursts and secondary seizures in the presence of estradiol; these events were most prominent in rats kindled in the absence of estradiol. Pentylenetetrazol also caused a significant increase in myoclonic jerks in estradiol-replaced rats, and postictal spikes in all rats. A series of five consecutive generalized seizures at 48-h intervals caused an increase in bursts in rats with estradiol replacement, but not in rats without estradiol. The results indicate that estradiol exerts excitatory effects during the postictal period following amygdala-kindled seizures and suggest that multiple regions mediate the postictal effects of estradiol, perhaps depending on the intraamygdala site of kindling stimulations.

Thalamic kindling: Electrical stimulation of the lateral geniculate nucleus produces photosensitive grand mal seizures

Kindling is traditionally viewed as a chronic, focal epilepsy model which consistently induces complex partial seizures from limbic structures in animals. This study revealed that primary or exceedingly rapid secondary generalized seizures could also be kindled when stimulation was applied to the lateral geniculate nucleus, a thalamic region involved in sleep regulation and possibly also photosensitive epilepsy. Two experiments were conducted in cat. Experiment 1 compared the development of generalized tonic-clonic convulsions and associated sleep disorders following electrical stimulation of the lateral geniculate nucleus ( N = 4) and the amygdala ( N = 4). Experiment 2 described the effects of intermittent light stimulation on seizure thresholds in both groups. Three primary findings distinguished the epileptogenic process in those two brain regions. First, generalized electroencephalographic and clinical seizures accompanied the first afterdischarge obtained with thalamic stimulation. In contrast, focal seizures with secondary generalization appeared during a 3- to 4-week period of afterdischarge elicitations from the amygdala. Second, amygdala-kindled cats showed fewer sleep spindles during slow-wave sleep whereas cats kindled in the lateral geniculate nucleus had abnormal sleep spindles approaching spike wave-like activity. Third, only the latter cats showed reduced seizure thresholds in response to photic stimulation. Based on the anatomic substrates involved, the clinical and electrographic profiles observed during kindling and the type of sleep disturbance shown, we concluded that lateral geniculate nucleus kindling may represent primary generalized epilepsy, possibly of a photosensitive nature; alternatively, the rapid propagation of abnormal discharge was also consistent with the important role of the thalamus in secondary seizure generalization.

Choosing anticonvulsants.

In considering the type of drug to be given to control epilepsy one must take into account the type of epilepsy, the age and sex of the patient, and schooling or jobs. Tonic-clonic seizures and partial seizures are all suppressed to some extent by phenobarbitone, primidone, phenytoin, carbamazepine, and sodium valproate. Of all of the drugs used, none has been shown to be free of teratogenic effects. The long half-lives of phenobarbitone of 72-120 hours, ethosuximide of 30-40 hours in children, and phenytoin of over 20 hours in adults mean that they may be taken as a single daily dose. Interactions between anticonvulsants are common and numerous interactions with other drugs are reported, some of which are important, such as the enhancement of the metabolism of oral contraceptives and warfarin by carbamazepine and phenytoin. No anticonvulsant is free from drug interactions. The advantages and disadvantages of the various drugs are presented. Recommendations are: 1) where only absence attacks occur, use ethosuximide; 2) if there are absence attacks together with other types of attacks use valproate; 3) for partial and secondary tonic-clonic seizures in children and young adults, use carbamazepine; 4) for primary tonic-clonic seizures in young adults, use valproate as a frist choice and carmamazepine as the 2nd; 5) for older patients phenytoin is satisfactory; and 6) for mycoclonus, valproate is chosen.