The place of stereotactic depth electrode recording in epilepsy

A series of 70 patients studied with stereotactically implanted depth electrodes is analyzed. Indications and grouping fall into three main categories: the bitemporal series (52 patients), where there is ambiguity as to the lateralization of the focus; the unilateral series (6 patients), where the main problem is one of localization within one hemisphere, and the generalized and/or multifocal series (12 patients), where a primary focus is suspected. The best indication is represented by the group of 'bitemporal cases' which turned out to have a well-lateralized onset with intracerebral recording.     

The role of stereotactic amygdalotomy in the treatment of temporal lobe epilepsy associated with behavioral disorders

The efficacy of bilateral stereotactic amygdalotomy for the treatment of aggressive behavioral disorders has been evaluated in a retrospective study of 67 cases. In addition 4 cases with complex partial seizures accompanied by aggressive outbursts revealing a unilateral epileptogenic focus in the amygdala or periamygdala region during preoperative stereoelectroencephalographic (SEEG) evaluation received a unilateral stereotactic amygdalotomy. Long-term follow-up of these 4 cases shows that 3 patients had considerable improvement in seizure frequency and severity as well as behavioral disturbances. The results in the remaining patients evaluated by surface EEG were inconclusive.     

Intracerebral site of convulsant action of bicuculline

Bicuculline was injected intracerebrally in several forebrain sites of the rat. In a discrete area in the vicinity of prepiriform cortex, a single, unilateral injection of bicuculline (49 pmol) produced generalized clonic seizures documented behaviorally and electroencephalographically. This is the first identification of an anatomical site from which generalized seizures can be elicited by low doses of a chemoconvulsant.     

Vagus nerve stimulation in the treatment of patients with pharmacoresistant epilepsy: our experiences

Vagus nerve stimulation (VNS) for the treatment of refractory partial epileptic seizures with or without secondary generalisation in patients older than 12 years was approved in Europe in 1994 and in the United States in 1997. We have studied the efficacy of VNS in patients with pharmacoresistant epilepsy hospitalized in the Neurology Department of the University Hospital Centre Zagreb. From 1997 to 2001 we have implanted VNS in 11 patients with pharmacoresistant epilepsy, who were magnetic resonance imaging (MRI) negative and from May 2007 to May 2009 in 11 patients with pharmacoresistant epilepsy, 9 of them were MRI positive, and were inoperable due to localisation of the pathomorphologic changes (ganglioglioma, hamartoma, various types of cortical dysplasia, porencephalic cysts), 2 were MR negative. In the group of MRI negative patients 1 patient had complex partial seizures (CPS), 6 patients had CPS with secondary generalisation, 2 patients had primary generalized epilepsy (PGE) including myoclonic, absence, atonic and tonic-clonic seizures, one patient had PGE and CPS, and 3 patients had Lennox-Gastaut syndrome (LGS). In the group of MRI positive patients one patient had elementary partial seizures (EPS) and CPS, two patients had EPS and CPS with secondary generalisation, one patient had CPS, 3 patients had CPS with secondary generalisation, and 2 patients had CPS with secondary generalisation as well as atonic seizures. After continuous follow-up of 11 MRI negative patients during 5 years and 2 MRI negative patients during one year there was decrease in mean-seizure frequency of 51.67%. After continuous follow-up of 9 MRI positive patients during 2 years there was decrease in mean-seizure frequency of 61.9%. The most frequent side effects were hoarseness, throat pain and cough in the "on phase" of the VNS, but they were mild and transitory. We can conclude that VNS was effective mode of therapy in our group of patients with pharmacoresistant epilepsy.     

The Characterization of Childhood Occipital Epilepsy of Gastaut: A Study of Seven Patients

Characterization of the electroclinical features and evolution of childhood occipital epilepsy of Gastaut (COE-G). Seven children were retrospectively identified as having COE-G and were followed-up clinically using EEGs. Visual manifestations were the most common ictal event. Eye-associated ictal deviation was associated with ipsilateral turning of the head and migraine-like symptoms were frequent. Hemiconvulsions occurred in two children, and only one child had secondary generalized tonic–clonic seizures. In all patients, seizures occurred while awake, while two patients also had seizures while sleeping. EEG showed five patients with occipital spike-wave discharges when their eyes were closed which disappeared once their eyes were opened. Two cases continued having frequent seizures despite antiepileptic drug treatment. These patients also displayed learning difficulties and behavioral impairments after seizure onset. COE-G is a distinctive epileptic syndrome; however, the long-term prognosis for patients with the condition is unclear.     

Detection of germline mutations in argentine retinoblastoma patients: low and full penetrance retinoblastoma caused by the same germline truncating mutation

Constitutional RB1 gene mutations were studied in a series of 21 families with unilateral and bilateral retinoblastoma patients. Peripheral blood lymphocytes were analyzed by "exon by exon" PCR-heteroduplex and sequencing. Mutations were identified in 6 (29%) of the patients. One mutation corresponded to an intronic polymorphism in g.174351T > A. The other five mutations resulted C to T exonic transitions, four were CGA sequences (g.65386, g.150037 in two patients, and g.162237), creating stop codons and presumably truncated proteins. The fifth one was new and resulted in alanine to valine substitution (g.73774). Two patients had the same the germline truncated mutation (g.150037C > T), one with a familial bilateral early onset retinoblastoma and one with a sporadic unilateral late onset retinoblastoma. The later type has not been previously described. This finding is discussed in the genotype/phenotype correlation context. Additionally, a single nucleotide change was found in six studied samples, where a C to T homozygous transversion was identified in intron 26 (IVS26 + 28). It is worthy the non concordance of the nucleotide with the published sequence. This analysis proved to be a useful method for the detection of mutations in the RB1 gene, and contributed to the adequate genetic counseling to patients and relatives.     

The head-eye-body turning behavior induced by electrical or cholinergic stimulation of the pulvinar-lateralis posterior nucleus complex is not dependent on the catecholaminergic system

Two experimental designs were developed in cats in order to analyze the role of the catecholaminergic system in the turning response evoked by cholinergic or electrical stimulation of the pulvinar-lateralis posterior nucleus complex (P-LP). Twenty one adult cats were employed. In one series of experiments, nine cats had a cannula implanted in one P-LP, and through it, apomorphine alone or mixed with carbachol were microinjected. The behavior was observed and the EEG was recorded. In the second experimental design, a cannula and bipolar electrodes were implanted unilaterally in the P-LP of nine cats, and a series of electrical stimulations were performed before and after 6-OHDA administration into the P-LP, and apomorphine was injected parenterally in order to induce turning behavior. Finally three cats received 16 micrograms of 6 OHDA into the P-LP, through a Hamilton syringe and no electrodes or cannula were implanted, to study the histological damage. No evidence of involvement of the catecholaminergic system was found in either of these two experimental series. These results contrast with what has been found in the nigrostriatal dopaminergic system, where an imbalance in dopamine concentration induces turning behavior. High doses (16 micrograms) of 6-OHDA induced minimal damage in the P-LP.     

De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy

Severe myoclonic epilepsy of infancy (SMEI) is a rare disorder that occurs in isolated patients. The disease is characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Later, patients also manifest other seizure types, including absence, myoclonic, and simple and complex partial seizures. Psychomotor development stagnates around the second year of life. Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel alpha-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ is a mild type of epilepsy associated with febrile and afebrile seizures. Because both GEFS+ and SMEI involve fever-associated seizures, we screened seven unrelated patients with SMEI for mutations in SCN1A. We identified a mutation in each patient: four had frameshift mutations, one had a nonsense mutation, one had a splice-donor mutation, and one had a missense mutation. All mutations are de novo mutations and were not observed in 184 control chromosomes.     

Epileptic dizziness.

Clinical and electroencephalographic features and the response to treatment of 30 patients with episodic dizziness due to epilepsy were noted. The symptom consisted of a brief episode of disequilibrium, often with a sensation of rotation, without evident precipitating factors or sequelae. A history of "absences" or other features suggestive of temporal lobe epilepsy was elicited in over half the patients, and seven (almost a quarter) had had one or more generalized seizures before presentation. Electroencephalography showed a posterior temporal lobe focus in all but two patients, and there was a family history of epilepsy in six. Response to treatment with phenytoin or carbamazepine was good in most patients. Epilepsy should be considered in the differential diagnosis of episodic dizziness or vertigo, especially in young people.     

Kindling of the limbic structures with a shortened interstimulus interval

We investigated the possibility to produce hippocampal or amygdala kindling syndrome in rabbits which had been electrically stimulated at a fixed interval between stimuli at 5 min. Animals were prepared with chronically implanted electrodes (neocortex, hippocampus, amygdala, nucleus caudatus). The initial stimuli produced only localized effect, but repeated applications of the stimuli progressively increased the seizure activity resulting in generalized kindled convulsions after 2-4 h period. At the first stage generalized seizures were followed by long lasting refractory period, but at the end of the procedure almost all stimuli evoke major motor seizures and recurrent widely spread electrographic epileptic changes. The most noteworthy findings emerging from this study is the inhibition of postictal seizure inhibition period. This effect was independent of whether stimulated the electrode was positioned in the hippocampus or amygdala, but the hippocampal formation occupied the central position for the once and propagation of the seizure activity in all cases. When established this syndrome persisted without any attenuation for some weeks. It was concluded that this model of rapid development of kindling syndrome is useful for investigation of the nature of epilepsy and postictal seizure inhibition.     

Chronic theophylline administration has no apparent effect on theophylline concentrations required to produce seizures in rats

Theophylline, the widely used antiasthmatic drug, can cause life-threatening, generalized seizures when administered in excessive doses. The plasma concentrations of theophylline associated with these seizures vary widely among patients, thereby complicating efforts to prevent seizures by timely initiation of appropriate treatment. Some investigators suspect that chronic administration increases the neurotoxicity of theophylline but others have suggested the opposite. We have studied this problem in an animal model of theophylline-induced seizures. Osmotic pumps containing theophylline solution or drug-free solvent (for the surgical control group) were implanted in adult female Lewis rats, yielding almost constant serum theophylline concentrations of about 14 mg/liter for 7 days in the treated group. On the seventh day, theophylline was administered by much more rapid iv infusion to the two groups of animals and to one nonimplanted (nonsurgical) control group until onset of maximal seizures. There were no statistically significant differences between the three groups with respect to the concentrations of theophylline in serum, serum water, brain, and cerebrospinal fluid at onset of seizures. The concentrations of theophylline metabolites were either very low or undetectable. Under the experimental conditions, preexposure of rats for 7 days to theophylline in the human therapeutic concentration range had no apparent effect on the acute neurotoxicity of the drug.     

The course of untreated epilepsy.

As little is known about the course of untreated epilepsy the time intervals between untreated tonic clonic seizures were examined retrospectively in a series of 183 patients presenting to a neurological department having had two to five seizures. After the first seizure a second attack had occurred within one month in 56 patients, within three months in 93, and within one year in 159. The median interval between the first two seizures was 12 weeks (95% confidence interval 10 to 18 weeks), between the second and third eight weeks (four to 12 weeks), between the third and fourth four weeks (two to 20 weeks), and between the fourth and fifth three weeks (one to four weeks). When patients who had had three, four, or five untreated seizures were considered separately a similar pattern of decreasing intervals was seen. Successive intervals between seizures could be compared in 82 patients. In 48 the interval decreased, in 16 it did not change, and in 18 it increased. These results suggest that in many patients there is an accelerating disease process in the early stages of epilepsy.     

Lipoplasty of the calves and ankles

The author details his experience over the past 6 years with 53 patients who had lipoplasty of the calves and ankles. The patient selection and diagnosis are critical. Determining whether the problem is localized or circumferential (generalized) influences the approach. The incisions are outlined as well as the best technique to provide excellent access to the entire leg. Although the results take a considerable period of time to appear because of long-lasting edema, after 3 months in the localized cases and 6 months in the generalized cases, an excellent configuration of the lower leg may be obtained. The author has had no significant complications in this series.     

In-vivo 3-Dimensional gait symmetry analysis in patients with bilateral total hip arthroplasty

Although three-dimensional (3D) asymmetry has been reported in unilateral THA patients during gait, it is not well understood whether asymmetric hip kinematics during gait persist in bilaterally operated THA patients. The purpose of this study was to compare the in vivo 3D kinematics and component placement between bilateral and unilateral THA patients during gait. Eight bilateral and thirty-three unilateral THA patients were evaluated for both hips during treadmill gait using a validated combination of 3D computer tomography-based modeling and dual fluoroscopic imaging system (DFIS). The in vivo 3D kinematics of the unilateral THA group was first assessed. The magnitudes of kinematics and component placement difference between implanted hips in the bilateral THA group and between the implanted and non-implanted hips in the unilateral THA group were compared. The study results showed asymmetric gait kinematics in the unilateral THA group. Although the magnitude of kinematics differences between sides for both the bilateral and unilateral THA groups did not change significantly for hip rotations (p > 0.05), the bilaterally operated THA group has significantly lower magnitude of hip gait translation difference. Significant reduction in the magnitude of the acetabular cup adduction, stem adduction, and combine hip anteversion and adduction difference was observed in the bilateral THA group (p < 0.05). Our findings demonstrated that despite significant improvements of component placement and reduced magnitude of hip gait translation difference between implanted hips in the bilateral THA group, asymmetric hip kinematic rotations persisted in patients with bilateral THA during gait.     

The role of the temporal neocortex in the origin of convulsive activity]

Experiments on cats with cooling capsules implanted over different areas of the neocortex have shown that cooling of different intensity applied to the temporal neocortex may result in both stimulation and switching off effects. Cold stimulation (temperature dropping to 27-33 degrees C) manifested in generalized epileptiform brain electrical activity and paroxysmal states. The functional switching off the temporal area observed during its deeper cooling (20-21 degrees C) discontinues the paroxysmal state already developed and prevents the appearance of seizures, regrardless of the localization of the epileptogenic focus. The paroxysmal state weakens and ceases after repeated cooling of the temporal neocortex. The temporal neocortex, involved in the integrated activating brain system, plays a decisive role in the emergence of paroxysmal states.     

Excess of multifocal tumors in nephroblastoma: implications for mechanisms of tumor development and genetic counseling

Referring to the mutational theory of carcinogenesis in embryonal tumors, it is commonly accepted that patients with multifocal tumors are hereditary cases. This is based on the implicit assumption that each tumor results from a single mutational event occurring in a cell that has already inherited a mutation, and that these tumors are independent. We studied the distribution of tumors in 1,868 cases where the focality was known (SIOP 1, 2, 5 and 6). Using all the supposed gene carriers (bilateral and unilateral multifocal cases), and assuming a Poisson distribution of tumors, we estimated the mean number m of tumors in each kidney to be 0.37. Comparing the observed distribution of cases to the expected one, we found a very bad fit to this hypothesis (P<10^-9). This is due to an excess of multifocal tumors, particularly in unilateral cases. These findings have important implications in genetic counseling, since the usual practice of considering multifocal tumor patients as hereditary cases may result in a large overestimate of the recurrence risk in such cases. The implications for the mechanisms of tumor development are also discussed.     

Vitamins E and C prevent the impairment of retention of an inhibitory avoidance task caused by arginine administration

S-adenosylmethionine (SAMe) is present in all tissues and functions as the sole donor of methyl groups in over 100 different methylation reactions. Recent reports suggest that direct intraventricular injection of SAMe induces Parkinsonian like symptoms in rats including seizures, tremors, hyperkinesia and abnormal posture. In order to assess the influence of SAMe on rat behavior we have undertaken a study to examine the effect of 3 different forms of SAMe. Guide cannulae were sterotaxically implanted into the lateral ventricle of male SD rats ( n = 5 for each group) using either ketamine or chloral hydrate anesthesia. 48 h post surgery the rats received a 5-μL injection containing 1 μmol of either SAMe-toluenedisulfonate, SAMe-butanedisulfonate, SAMe-chloride, or vehicle (butanedisulfonate, toluenedisulfonate or saline). Locomotor activity was monitored using the TruScan monitoring system and by videotape recording for 1 h. The videotape was reviewed by one of the authors (RD-A) who is experienced with animal models of epilepsy. SAMe injected animals had frequent myoclonic and tonic seizures, and occasional generalized clonic seizures. SAMe induced behavioral seizures and tremors occurred only in rats that had previously been anesthetized with chloral hydrate, and not in rats that received ketamine. The number of movements recorded during the 1-h period were significantly increased in SAMe injected animals compared to control groups in both chloral hydrate and ketamine anethetized rats. Our studies indicate that there is an anesthetic dependency for SAMe induced seizures and tremors.     

Plasma and Cerebrospinal Fluid Amino Acids in Epileptic Patients

Altered plasma and cerebrospinal fluid amino acid levels may be associated with human epilepsy. We studied three groups of patients, those with a generalized epileptic syndrome, juvenile myoclonic epilepsy, patients with refractory localization-related epilepsies, and patients with acute seizures (within 24 h). Plasma levels of amino acids were studied in all patient groups, as were those in the cerebrospinal fluid (CSF) of patients with acute seizures. After acute seizures, the amino acid changes in the CSF were limited to a reduction in the level of taurine, whereas the levels of most amino acids in plasma were decreased. On the other hand, levels of the excitatory amino acids glutamate and aspartate were increased. The most notable finding in the juvenile myoclonic epilepsy patients was an increase in glutamate level in the plasma. Our study supports the conception of an altered metabolism of glutamate in generalized epilepsies.     

Artificial Cardiac Pacemakers

Nine patients with complete heart block and Stokes-Adams disease were treated with subcutaneously implanted, fixed-rate, artificial cardiac pacemakers. All of these patients were refractory to medical treatment and confined to bed by the frequency of their attacks. One patient died in uremia one month after operation; in the remaining eight, the implanted pacemakers are providing adequate stimulation at present. These patients are free of seizures and show an improvement in the amount of their physical activity. A fixed rate of 60 to 65 per minute was adequate in all cases. The results of our clinical experience with cardiac pacemakers is satisfactory, but the possibility of mechanical failure limits their use to situations in which the patient is incapacitated despite medical treatment.     

Poster Sessions AP10: Learning,Memory and Behavior. S‐adenosylmethionine induced seizures are anesthetic dependant

S‐adenosylmethionine (SAMe) is present in all tissues and functions as the sole donor of methyl groups in over 100 different methylation reactions. Recent reports suggest that direct intraventricular injection of SAMe induces Parkinsonian like symptoms in rats including seizures, tremors, hyperkinesia and abnormal posture. In order to assess the influence of SAMe on rat behavior we have undertaken a study to examine the effect of 3 different forms of SAMe. Guide cannulae were sterotaxically implanted into the lateral ventricle of male SD rats (n = 5 for each group) using either ketamine or chloral hydrate anesthesia. 48 h post surgery the rats received a 5‐μL injection containing 1 μmol of either SAMe‐toluenedisulfonate, SAMe‐butanedisulfonate, SAMe‐chloride, or vehicle (butanedisulfonate, toluenedisulfonate or saline). Locomotor activity was monitored using the TruScan monitoring system and by videotape recording for 1 h. The videotape was reviewed by one of the authors (RD‐A) who is experienced with animal models of epilepsy. SAMe injected animals had frequent myoclonic and tonic seizures, and occasional generalized clonic seizures. SAMe induced behavioral seizures and tremors occurred only in rats that had previously been anesthetized with chloral hydrate, and not in rats that received ketamine. The number of movements recorded during the 1‐h period were significantly increased in SAMe injected animals compared to control groups in both chloral hydrate and ketamine anethetized rats. Our studies indicate that there is an anesthetic dependency for SAMe induced seizures and tremors.