Hyperexcitability of the network contributes to synchronization processes in the human epileptic neocortex.

KEY POINTS: Hyperexcitability and hypersynchrony of neuronal networks are thought to be linked to the generation of epileptic activity in both humans and animal models. Here we show that human epileptic postoperative neocortical tissue is able to generate two different types of synchronies in vitro. Epileptiform bursts occurred only in slices derived from epileptic patients and were hypersynchronous events characterized by high levels of excitability. Spontaneous population activity emerged in both epileptic and non-epileptic tissue, with a significantly lower degree of excitability and synchrony, and could not be linked to epilepsy. These results help us to understand better the role of excitatory and inhibitory neuronal circuits in the generation of population events, and to define the subtle border between physiological and pathological synchronies. ABSTRACT: Interictal activity is a hallmark of epilepsy diagnostics and is linked to neuronal hypersynchrony. Little is known about perturbations in human epileptic neocortical microcircuits, and their role in generating pathological synchronies. To explore hyperexcitability of the human epileptic network, and its contribution to convulsive activity, we investigated an in vitro model of synchronous burst activity spontaneously occurring in postoperative tissue slices derived from patients with or without preoperative clinical and electrographic manifestations of epileptic activity. Human neocortical slices generated two types of synchronies. Interictal-like discharges (classified as epileptiform events) emerged only in epileptic samples, and were hypersynchronous bursts characterized by considerably elevated levels of excitation. Synchronous population activity was initiated in both epileptic and non-epileptic tissue, with a significantly lower degree of excitability and synchrony, and could not be linked to epilepsy. However, in pharmacoresistant epileptic tissue, a higher percentage of slices exhibited population activity, with higher local field potential gradient amplitudes. More intracellularly recorded neurons received depolarizing synaptic potentials, discharging more reliably during the events. Light and electron microscopic examinations showed slightly lower neuron densities and higher densities of excitatory synapses in the human epileptic neocortex. Our data suggest that human neocortical microcircuits retain their functionality and plasticity in vitro, and can generate two significantly different synchronies. We propose that population bursts might not be pathological events while interictal-like discharges may reflect the epileptogenicity of the human cortex. Our results show that hyperexcitability characterizes the human epileptic neocortical network, and that it is closely related to the emergence of synchronies.

Are proprioceptive-induced reflex seizures epileptically-enhanced stretch reflex manifestations?

In reflex seizures induced by proprioceptive stimuli, the activated network may be identified as a single anatomo-functional circuit; the sensory-motor network. These seizures may be considered as epileptically-enhanced stretch reflexes. Proprioceptive reflex epilepsies are a good example of the so-called "system epilepsies". We present three cases discussing the clinical features of such epilepsies. [Published with videosequences].

Clinical experiences with Creutzfeldt-Jakob disease: three case studies.

The clinical picture, electroencephalographic, imaging and cerebrospinal fluid parameters as well as the molecular background of Creutzfeldt-Jakob disease have been well explored. The diagnostic criteria, offering clinicians a fair chance to identify these patients in vivo, have recently been updated. However, the diagnosis is still a challenge in everyday neurological routine. We report on three of our Creutzfeldt-Jakob patients for calling attention to the classical and the recently defined features of the disease. We conclude that based on the rapidly progressing neuropsychiatric syndrome Creutzfeldt-Jakob disease may be suspected; follow-up EEG may reveal the typical (pseudo)-periodic pattern with progressive deterioration of the background activity. In addition, diffusion-weighted brain MRI imaging (DWI) has high diagnostic value. Detection of 14-3-3 protein in the cerebrospinal fluid supports the in vivo diagnosis.

[Oligoepilepsy: a real entity or the benign form of epileptic disorder?]. / Oligoepilepszia: onálló entitás vagy az epilepsziás készség benignus formája?

BACKGROUND AND PURPOSE: Although oligoepilepsy (OLE) is a used term in many protocols, guidelines and the everyday routine, it is found practically nowhere in the scientific literature. The aim of our study is to investigate and evaluate of the main characteristics of his subcategory of epilepsy. We try to find answer to the basic question of not only theoretical but also great practical importance whether the OLE does really exist, is it an independent entity of epilepsy or only its general benign clinical presentation. METHODS: We considered OLE if the patients had two seizures maximally in the last year of their course. We counted only the two most severe clinical types, the generalized tonic-clonic and the complex partial seizures. We divided the OLE into two subtypes: those patients who had OLE from the beginning of their epilepsy (OLE1) and those in whom the OLE was the result of the treatment (OLE2). We retrospectively analysed the data of 817 "OLE-suspicious" patients taken from our EPIMED database. RESULTS: We found 47 patients met the inclusion criteria (OLE1 = 34, OLE2 = 13). OLE patients did not differ from the general epileptic population according to the age and gender, the type of seizures, the electro-clinical diagnosis and the possible cause of their first seizure. But we found statistically significant differences in two measures. In OLE, far less seizure provoking factors were found in the sporadic seizures. Concerning the social conditions: while the range of employees was equal, the vast majority of OLE patients were able to work at their level of education. CONCLUSION: We found that more than 5% of people with epilepsy can belong to the OLE category. In the majority of OLE patients the seizure frequency is low from the beginning of the disease. The sporadic seizures in OLE are generally not provoked. The chances of OLE patients in the world of job are better for the OLE patients. In our opinion OLE rather seems to be an independent entity among epilepsy. Therefore larger prospective studies are needed to the exact description of OLE and to establish the special standards for the everyday medical practice.

Laminar analysis of slow wave activity in humans.

Brain electrical activity is largely composed of oscillations at characteristic frequencies. These rhythms are hierarchically organized and are thought to perform important pathological and physiological functions. The slow wave is a fundamental cortical rhythm that emerges in deep non-rapid eye movement sleep. In animals, the slow wave modulates delta, theta, spindle, alpha, beta, gamma and ripple oscillations, thus orchestrating brain electrical rhythms in sleep. While slow wave activity can enhance epileptic manifestations, it is also thought to underlie essential restorative processes and facilitate the consolidation of declarative memories. Animal studies show that slow wave activity is composed of rhythmically recurring phases of widespread, increased cortical cellular and synaptic activity, referred to as active- or up-state, followed by cellular and synaptic inactivation, referred to as silent- or down-state. However, its neural mechanisms in humans are poorly understood, since the traditional intracellular techniques used in animals are inappropriate for investigating the cellular and synaptic/transmembrane events in humans. To elucidate the intracortical neuronal mechanisms of slow wave activity in humans, novel, laminar multichannel microelectrodes were chronically implanted into the cortex of patients with drug-resistant focal epilepsy undergoing cortical mapping for seizure focus localization. Intracortical laminar local field potential gradient, multiple-unit and single-unit activities were recorded during slow wave sleep, related to simultaneous electrocorticography, and analysed with current source density and spectral methods. We found that slow wave activity in humans reflects a rhythmic oscillation between widespread cortical activation and silence. Cortical activation was demonstrated as increased wideband (0.3-200 Hz) spectral power including virtually all bands of cortical oscillations, increased multiple- and single-unit activity and powerful inward transmembrane currents, mainly localized to the supragranular layers. Neuronal firing in the up-state was sparse and the average discharge rate of single cells was less than expected from animal studies. Action potentials at up-state onset were synchronized within +/-10 ms across all cortical layers, suggesting that any layer could initiate firing at up-state onset. These findings provide strong direct experimental evidence that slow wave activity in humans is characterized by hyperpolarizing currents associated with suppressed cell firing, alternating with high levels of oscillatory synaptic/transmembrane activity associated with increased cell firing. Our results emphasize the major involvement of supragranular layers in the genesis of slow wave activity.

Are there real unprovoked/unprecipitated seizures?

Resistant epileptic patients often experience seizure precipitating conditions. Their lack or presence is extremely important not only for the diagnosis of epilepsy but also for the most appropriate treatment of the seizures. Unfortunately, there are a lot of uncertainty in their evaluation occurring in the daily routine and the exact definitions for the practice are still lacking. Based on the consonant and contradictory aspects concerning the consideration of the seizure precipitant factors a new hypothesis is suggested: every clinical epileptic manifestation should need a tonic (chronic cerebral cortical epileptic dysfunction) and a phasic (acute epileptogenic noxa) condition simultaneously. Results of a pilot study aimed to evaluate the possible role of precipitants in the manifestation of habitual seizures of patients strengthened the hypothesis. The (34%) total population might be more sensitive to actual phasic epileptogenic changes and 5.5% who are considered as "seizure precipitant responders". The five most frequent precipitants provoked the patients' "habitual" seizures were: unexpected life events (29.6%), changes in drug intake (23.7%), insomnia (20%), meteoropathological effects (17%) and alcohol consumption (9.5%). The paper lists the evidences and practical experiences supporting the hypothesis and mentions some counter arguments. In conclusion, the acceptance of the hypothesis might open new perspectives in the complex antiepileptic therapy especially for the subpopulation most vulnerable of phasic epileptogenic conditions (about 5-6% of the total). Further investigations are recommended to elucidate the remaining theoretical and practical reservations.

Properties of in vivo interictal spike generation in the human subiculum.

A large proportion of hippocampal afferents and efferents are relayed through the subiculum. It is also thought to be a key structure in the generation and maintenance of epileptic activity; rhythmic interictal-like discharges were recorded in previous studies of subicular slices excised from temporal lobe epilepsy patients. In order to investigate if and how the subiculum is involved in the generation of epileptic discharges in vivo, subicular and lateral temporal lobe electrical activity were recorded under anesthesia in 11 drug-resistant epilepsy patients undergoing temporal lobectomy. Based on laminar field potential gradient, current source density, multiple unit activity (MUA) and spectral analyses, two types of interictal spikes were distinguished in the subiculum. The more frequently occurring spike started with an initial excitatory current (current source density sink) in the pyramidal cell layer associated with increased MUA in the same location, followed by later inhibitory currents (current source density source) and decreased MUA. In the other spike type, the initial excitation was confined to the apical dendritic region and it was associated with a less-prominent increase in MUA. Interictal spikes were highly synchronized at spatially distinct locations of the subiculum. Laminar data showed that the peak of the initial excitation occurred within 0-4 ms at subicular sites separated by 6 mm at the anterior-posterior axis. In addition, initial spike peak amplitudes were highly correlated in most recordings. A subset of subicular and temporal lobe spikes were also highly synchronous, in one case the subicular spikes reliably preceded the temporal lobe discharges. Our results indicate that multiple spike generator mechanisms exist in the human epileptic subiculum suggesting a complex network interplay between medial and lateral temporal structures during interictal epileptic activity. The observed widespread intra-subicular synchrony may reflect both of its intrinsic and extrinsically triggered activity supporting the hypothesis that subiculum may also play an active role in the distribution of epileptiform activity to other brain regions. Limited data suggest that subiculum might even play a pacemaker role in the generation of paroxysmal discharges.

Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures.

PURPOSE: To evaluate the safety and efficacy of zonisamide (ZNS) as adjunctive treatment in patients with refractory localization-related epilepsy. METHODS: This was a double-blind, placebo-controlled study of adjunctive ZNS in 351 patients with refractory partial seizures receiving a stable regimen of one to three antiepileptic drugs (AEDs). Patients were randomized to placebo or ZNS, 100 mg, 300 mg, or 500 mg/day (2:1:1:2) after a 12-week baseline. Dose titration was undertaken over a 6-week titration phase, which was followed by an 18-week fixed-dose assessment phase. Primary efficacy parameters were the differences between ZNS, 500 mg/day, and placebo in the change from baseline in frequency of complex partial (CP) seizures during the fixed-dose assessment phase and in the proportion of CP responders (> or =50% decrease from baseline in seizure frequency). Safety and tolerability also were assessed. RESULTS: Compared with placebo, the highest dose of ZNS (500 mg/day) resulted in a significantly greater decrease in CP seizure frequency from baseline (51.2% vs. 16.3%; p < 0.0001) and a significantly higher proportion of CP responders (52.3% vs. 21.3%; p < 0.001). Both ZNS, 500 mg/day, and 300 mg/day were statistically superior to placebo in reducing the frequency of "all seizures" and simple partial (SP) + CP seizures. For all seizures, a significant dose-response relation was observed (p < 0.0001). The most common adverse events were somnolence, headache, dizziness, and nausea during the titration phase and headache and pharyngitis during the fixed-dose assessment phase. CONCLUSIONS: ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.

[Psychosocial conditions of adult epileptic patients in Hungary]. / A magyarországi felnott epilepsziabetegek pszichoszociális körülményei.

Authors analyze the possible connections among psychosocial, more important epileptological and social conditions in the population of the Hungarian Epilepsy Database. The inclusion criteria were the presence of repeated epileptic seizures, the strict diagnosis of epilepsy and at least three registered control visits. Four hundred and fifty 30 or more years old patients fulfilled the criteria. Based on the answers to four questions in the database considering some conditions potentially modifying the way of life the patients were scored and distributed into 3 subgroups (good, average and bad) concerning their psychosocial conditions. In contrast to previous expectations they found that the type of epilepsy does not influence the attainable psychosocial conditions. Presence of generalized tonic-clonic or complex partial seizure did not exhibit influence either. Analysis of the seizure frequency showed that generalized convulsions, if occurred rarely were accompanied by good psychosocial level and if occurred frequently they were accompanied by a less acceptable level. Psychopathological symptoms independently from their nature and evidenced brain lesion as etiology also made the psychosocial conditions worse. No difference was found concerning the gender of the population. It contradicts the hypothesis that epilepsy has a greater impact on females. Psychosocial conditions are better in patients with higher education and living in pairs. Based on the study authors support the statements of the literature emphasizing that for achieving the best quality of life and psychosocial level an appropriate medical care is not enough. They need also the relative highest level of education and a stable partnership.

Car drivers with epilepsy (Pilot Hungarian EPIMED Database Evaluation).

We investigated aspects of driving among Hungarian patients with epilepsy. Nineteen percent (148/753) of our population had a driving license (DL), including 26% (38/148) who used it. Among persons without a DL, 29% (178/605) desired one. Among those who drove (n=38), 24 worked and 8 had experienced seizures in the last 3 months. Each of these seizures occurred during sleep (5/8), were preceded by known auras and warning signs (2/8) or were provoked by extreme external factors (1/8).