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Summary: Purpose: Malformations of cortical development (MCDs) are usually highly epileptogenic, and their hyperexcitability could facilitate the occurrence of reflex seizures. We sought to characterize reflex seizures in patients with MCDs and refractory epilepsy. Methods: Clinical, electrographic, and neuroimaging data were reviewed in eight patients with MCDs who had reflex seizures reproduced during presurgical evaluation. Results: All eight patients had both reflex and spontaneous seizures. In six, however, drop attacks or axial myoclonic seizures occurred only upon specific sensory stimulation. Reflex seizures were induced by more than one type of stimulus in most patients, but anatomofunctional correlations could usually be invoked. Six patients had significant intellectual impairment. Surgical resection controlled seizures in two patients. Conclusions: Reflex seizures in patients with MCDs may be medically refractory and may often manifest as drop attacks or axial myoclonus. Surgical resection of focal lesions can bring reflex seizures under control. Putative mechanisms related to the relatively low frequency of reflex seizures in MCDs are discussed. Ke yW ords: Reflex seizures—Malformations of cortical development—High degrees of epileptogenicity.

The covert-rapid-eye-movement (REM) sleep hypothesis of dreaming suggests that elements of REM sleep emerge during sleep onset, leading to vivid hypnagogic imagery. Based on parahippocampal electrocorticography of epileptic patients we found an increase in REM-like 1.5-3.0 Hz parahippocampal activity during wake-sleep transition, which peaks after on average 30s of sleep onset, and reaches 82% of REM sleep value. The increase in 1.5-3.0 Hz parahippocampal activity followed alpha dropout, but did not relate to short-term fluctuations in alpha waves or sleep spindles. Non-REM sleep-specific slow (

Temporal lobe epilepsy (TLE) is known to be linked to an impaired balance of excitation and inhibition. Whether inhibition is decreased or preserved in the human epileptic hippocampus, beside the excess excitation, is still a debated question. In the present study, quantitative light and electron microscopy has been performed to analyse the distribution, morphology and input-output connections of parvalbumin (PV)-immunopositive interneurons, together with the entire perisomatic input of pyramidal cells, in the human control and epileptic CA1 region. Based on the degree of cell loss, the patients with therapy-resistant TLE formed four pathological groups. In the non-sclerotic CA1 region of TLE patients, where large numbers of pyramidal cells are preserved, the number of PV-immunopositive cell bodies decreased, whereas axon terminal staining, and the distribution of their postsynaptic targets was not altered. The synaptic coverage of CA1 pyramidal cell axon initial segments (AISs) remained unchanged in the epileptic tissue. The somatic inhibitory input is also preserved; it has been decreased only in the cases with patchy pyramidal cell loss in the CA1 region (control, 0.637; epileptic with mild cell loss, 0.642; epileptic with patchy cell loss, 0.424 microm synaptic length/100 microm soma perimeter). The strongly sclerotic epileptic CA1 region, where pyramidal cells can hardly be seen, contains a very small number of PV-immunopositive elements. Our results suggest that perisomatic inhibitory input is preserved in the epileptic CA1 region as long as pyramidal cells are present. Basket and axo-axonic cells survive in epilepsy if their original targets are present, although many of them lose their PV content or PV immunoreactivity. An efficient perisomatic inhibition is likely to take part in the generation of abnormal synchrony in the non-sclerotic epileptic CA1 region, and thus participate in the maintenance of epileptic seizures driven, for example, by hyperactive afferent input.

Laminar multiple microelectrodes have been developed to sample cortical and hippocampal activity in animals. If these measurements are adequately co-registered with the anatomy of the region, they can yield important information about its function and structure. In vivo laminar electrophysiological recordings from the human epileptic hippocampus are rare. However, histological and immunohistochemical analyses are widely used to determine the structural changes associated with temporal lobe epilepsy (TLE). Here we present data obtained by a combined approach: intraoperative recording of laminar field potentials, single and multiple unit activity under anesthesia, accompanied by histology and immunohistochemistry from the same hippocampal region of epileptic patients undergoing temporal lobectomy for drug-resistant TLE. The stability of the electrophysiology and the accuracy of its co-registration with histology were tested successfully. We have found large field potential spikes associated with bursting single units in CA1. Intracortical and subdural strip recordings from the lateral temporal cortex showed similar field potential activation patterns. A prominent oscillatory activity was present in the dentate gyrus with highly localized field potential gradient and multiple unit activity. This pattern could be used as a landmark defining the position of the electrode in the hippocampus. Our findings indicate that some aspects of the local and network epileptiform activity in the hippocampal formation are likely preserved under anesthesia. Electrophysiological identification of the functional state of the hippocampus together with its local structural correlates could further enhance our understanding of this disease.

We investigated the nature of preictal subjective phenomena and whether they had any effect on the seizure frequency in 95 adult patients with medial temporal lobe epilepsy. Seventy-three (77%) patients indicated that they experienced seizure-provoking factors. Ten patients (11%) had prodromas independent of auras, while auras occurred in 89%. Forty-four patients (46%) reported that that they had tried to stop their seizures in the presence of prodroma or aura and this action had resulted in success at least once. Twenty-one patients (22%) regularly tried to stop their seizures because this effort was often successful according to their interpretation. Patients who reported that they could frequently inhibit their seizures had 1.8±1.6 seizures/month, a significantly lower mean seizure frequency than those 74 patients who did not do it regularly (4.6±4.8 seizures/month, P

The role of arousals in sleep is gaining interest among both basic researchers and clinicians. In the last 20 years increasing evidence shows that arousals are deeply involved in the pathophysiology of sleep disorders. The nature of arousals in sleep is still a matter of debate. According to the conceptual framework of the American Sleep Disorders Association criteria, arousals are a marker of sleep disruption representing a detrimental and harmful feature for sleep. In contrast, our view indicates arousals as elements weaved into the texture of sleep taking part in the regulation of the sleep process. In addition, the concept of micro-arousal (MA) has been extended, incorporating, besides the classical low-voltage fast-rhythm electroencephalographic (EEG) arousals, high-amplitude EEG bursts, be they like delta-like or K-complexes, which reflects a special kind of arousal process, mobilizing parallely antiarousal swings. In physiologic conditions, the slow and fast MA are not randomly scattered but appear structurally distributed within sleep representing state-specific arousal responses. MA preceded by slow waves occurs more frequently across the descending part of sleep cycles and in the first cycles, while the traditional fast type of arousals across the ascending slope of cycles prevails during the last third of sleep. The uniform arousal characteristics of these two types of MAs is supported by the finding that different MAs are associated with an increasing magnitude of vegetative activation ranging hierarchically from the weaker slow EEG types (coupled with mild autonomic activation) to the stronger rapid EEG types (coupled with a vigorous autonomic activation). Finally, it has been ascertained that MA are not isolated events but are basically endowed with a periodic nature expressed in non-rapid eye movement (NREM) sleep by the cyclic alternating pattern (CAP). Understanding the role of arousals and CAP and the relationship between physiologic and pathologic MA can shed light on the adaptive properties of the sleeping brain and provide insight into the pathomechanisms of sleep disturbances. Functional significance of arousal in sleep, and particularly in NREM sleep, is to ensure the reversibility of sleep, without which it would be identical to coma. Arousals may connect the sleeper with the surrounding world maintaining the selection of relevant incoming information and adapting the organism to the dangers and demands of the outer world. In this dynamic perspective, ongoing phasic events carry on the one hand arousal influences and on the other elements of information processing. The other function of arousals is tailoring the more or less stereotyped endogenously determined sleep process driven by chemical influences according to internal and external demands. In this perspective, arousals shape the individual course of night sleep as a variation of the sleep program.

Objective: To describe psychosis-like hallucinatory states in unrecognized narcolepsy. Method: Two patients with hypnagogic/hypnapompic hallucinations are presented. Results: Both patients had realistic and complex – multi-modal and scenic-daytime sexual hallucinations leading, in the first case, to a legal procedure because of false accusation, and in the second, to serious workplace conflicts. Both patients were convinced of the reality of their hallucinatory experiences but later both were able to recognize their hallucinatory character. Clinical data, a multiple sleep latency test, polysomnography, and HLA typing revealed that both patients suffered from narcolepsy. Conclusion: We suggest that in unrecognized narcolepsy with daytime hypnagogic/hypnapompic hallucinations the diagnostic procedure may mistakenly incline towards delusional psychoses. Daytime realistic hypnagogic/hypnapompic hallucinations may also have forensic consequences and mislead legal evaluation. Useful clinical features in differentiating narcolepsy from psychoses are: the presence of other narcoleptic symptoms, features of hallucinations, and response to adequate medication.

The 25-year-old right-handed woman suffering from temporal lobe epilepsy (TLE) was referred to our centre for presurgical evaluation. MRI showed a right-sided hippocampal sclerosis. During video-EEG-recorded seizures, abdominal aura was followed by oral automatisms, during which she was completely reactive to external stimuli, although she was unable to speak. Ictal EEG showed right temporal seizure pattern, without contralateral propagation. She had abnormal speech postictally. Speech-activated functional transcranial Doppler sonography revealed right-sided speech dominance. She has become seizure free after a right-sided amygdalo-hippocampectomy. In our patient, contradictory clinical ictal lateralising signs (automatisms with preserved responsiveness vs. ictal and postictal dysphasia) occurred during right-, speech-dominant-sided seizures. This is the first report when automatisms with preserved consciousness occurred during a seizure originating and involving the speech-dominant hemisphere.

Background Treatment-resistant complex partial seizures (CPS) with orofacial involvement recently were reported in cats in association with hippocampal pathology. The features had some similarity to those described in humans with limbic encephalitis and voltage-gated potassium channel (VGKC) complex antibody. Hypothesis/Objectives The purpose of this pilot study was to evaluate cats with CPS and orofacial involvement for the presence of VGKC-complex antibody. Animals Client-owned cats with acute orofacial CPS and control cats were investigated. Methods Prospective study. Serum was collected from 14 cats in the acute stage of the disease and compared with 19 controls. VGKC-complex antibodies were determined by routine immunoprecipitation and by binding to leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), the 2 main targets of VGKC-complex antibodies in humans. Results Five of the 14 affected cats, but none of the 19 controls, had VGKC-complex antibody concentrations above the cut-off concentration (>100 pmol/L) based on control samples and similar to those found in humans. Antibodies in 4 cats were directed against LGI1, and none were directed against CASPR2. Follow-up sera were available for 5 cats in remission and all antibody concentrations were within the reference range. Conclusion and Clinical Importance Our study suggests that an autoimmune limbic encephalitis exists in cats and that VGKC-complex/LGI1 antibodies may play a role in this disorder, as they are thought to in humans.

A 13-year-old cat had a history of seizures for 3 years that resembled temporal lobe epilepsy. Histologic examination of the brain revealed bilateral hippocampal alterations, including hypergyration and broadening of the dentate gyrus associated with hippocampal sclerosis and an intraventricular meningioma near the hippocampal region. The findings in the dentate gyrus were interpreted as a congenital malformation; however, it could not be ruled out that the alterations were induced by the seizures. Similar changes of the dentate gyrus have not been previously described in cats.

After a short description of general attitude toward serialism in Hungary in the 1960s a detailed analysis of serial procedures in movements II and V of Gyorgy Kurtag's StringQuartet, op. 1 is given. Differences between handling 12-tone aggregates and rows, motivic connections between adjacent and non-adjacent tones, and symmetrical and non-symmetrical partitions of the row are examined. Through these means, serial parts prove to harmonise with the overall narrative context of a generally non-serial, atonal work.

Frequency and severity of sleep apnoeas, snoring history, standard clinical stroke scale were assessed in 106 acute (73 ischaemic, 33 haemorrhagic) stroke patients. Thirty-seven patients with ischaemic stroke and 14 patients with cerebral bleeding, each having pathological oxygen desaturation index during sleep, were re-tested in 3 months for sleep apnoeas and clinical stroke scale. In haemorrhagic strokes, the apnoea frequency decreased parallel with clinical improvement; but it remained as frequent as in the acute phase in the ischaemic stroke group (p = 0.0002). Apnoea frequency decreased mostly during the course of posterior stroke (p = 0.0001). It is concluded that pathological sleep apnoea frequency remains stable after ischaemic stroke indicating a concomitant obstructive sleep apnoea syndrome and sleep apnoea is a transitory symptom of haemorrhagic strokes.

Introduction The brain process of short term storage of multimodal information is called generally as working memory. This is thought to be located in the frontal and parietal lobes, however recent evidences show that the temporal lobe has important function in maintaining short-term and spatial information. Among multiple neuropsychological tests used for short term memory, the N-back test (NBT) has the advantage, that higher values of memory load can be set by increasing the recall distance (value n ). Methods We involved therapy resistant epilepsy patients undergoing video-EEG with scalp and invasive intracranial electrodes for visual and verbal NBT. The stimuli were presented gradually from 0 to 2 backs. The EEG graphs were filtered and averaged, and time-frequency analysis was performed (EEGLAB). Results Verbal NBT showed significant left-sided increase in gamma power, while during visual NBT right-sided gamma power increase was observed. The power correlated with the elevation of memory load. Intracranial data showed less increase in frontal regions compared to temporal. Conclusions Increase of gamma power seemed to be a good psychoneural correlate of memory processes during verbal and visual NBT. It showed appropriate lateralization and correlation with memory load. Based on our preliminary data the role of temporal lobe in short term memory can be hypothesized. We plan to include more patients.

Temporal lobe epilepsy is the most prevalent type of epileptic syndrome, and also the most frequent type of surgically treatable epilepsy. But in many cases the laterality is difficult to prove based on non-invasive investigations and scalp EEG. There is broad evidence that suggest that the seizure onset zone may be on the opposite side compared to where the seizure is seen on the scalp EEG due to rapid spread to the contralateral side. Based on these data a technique was developed first by Wieser et al., which allowed direct corticographic recordings from the medial temporal structures without performing invasive surgery. The implantation of foramen ovale (FO) electrode proved to be safe, efficient and very useful in many cases where the seizure onset zone could not be determined on non-invasive data alone. In the last 20 years we have implanted FO electrodes in more tha 100 patients with success. We find using FO electrodes useful in answering the following questions: • Is there an unilateral onset? (laterality vs. Bilateral indenpendent onset?). • Evidence of seizure start in the mediobasal region? (localisation?). • Where is the seizure onset zone over the mediobasal. surface along the anterior – posterior axis? • Seizure propagation routes?

Objectives The traditional method for seizure onset zone determination is based on the temporal order in the appearance of pathological waveforms. However, this method assumes, that the well observable pathological waveforms are really the first signs of those processes, which play important role in the seizure generation. Our objective is to develop and apply new mathematical methods to identify the causal relations between brain areas during epileptic activity. Methods The Convergent Cross Mapping method of Sugihara was modified to reveal temporal dynamics of causal connections, and applied to current source density distribution data calculated from multichannel foramen ovale electrode recordings. Results The causality analysis revealed directed connections between the two hippocampi and specific changes in intra and inter-hippocampal connections comparing interictal and ictal periods: intrahippocampal connections get stronger and spread away spatially, while inter-hippocampal connections show more complex temporal development patterns during the seizures: the functional connectivity decreases during initial phase of the seizures in some cases, while increases during the full blown seizures. Onset of the tonic phases accompanied by temporal increase of the causal connections between the two hippocampi as well. Conclusions New mathematical analysis method, such as Convergent Cross Mapping raise the possibility of objective determination the causal relationships at the initiation of the seizure, without specific assumptions about the waveforms. Significance Causality analysis can support more precise identification of seizure onset zones, thus results in better surgical outcome.

NREM sleep has a highly dynamic structure, with rich variables of phasic events. These phasic events appear as spontaneous changes and can be elicited in the same form by external stimuli (best explored by applying acoustic ones). The response to external stimuli as well the spontaneous changes have two types. One is the traditional arousal response with fast frequencies and amplitude attenuation conjoined by heart rate acceleration and muscle artefacts. The second type is the so called sleep like answer, paradoxically characterized by slow waves and/or K-complexes, with less participation of autonomic signs and muscles. The same interrelationship is reflected by the cylic alternating pattern (CAP), a myrocyclicity recognised by the Parma School. The CAP A1 phase an analogue of the sleep like response concommits the high pressure, while the A2-3 CAP phases the low pressure periods throughout the sleep cylicity. The microshifts are the promoters of any up-and down shifts building up lastly the ascending and descending slopes of the sleep cycles and that way the macro-states of sleep cyclicity. Spindle activity have a separate regulation being related more to the cortico-thalamic system. The relationship between dynamic changes on the level of sleep phases (and sleep cycles) is probably in a close connection with both the up-bottom regulation originating in the brainstem/hypothalamic regulatory influence and by the bottom-up peripheral demands. Therefore NREM sleep has a multiple regulation: partially driven by metabolic (from the bottom) and central (from the top) regulation, nevertheless by the stimuli of the external world influencing sleep as a flexible open system.

SUMMARYAim.The aim of this article is to review criticaly the Electrical Status Epilepticus in Slow Sleep (ESES) phenomenon from a neurophysiological mechanisms aspect as well as terminological and classification issues.Methods.The review includes all the relevant papers published during the last 43 years on the subject of ESES and Continous Spike – Wave in Sleep (CSWS).These papers were identified in various large databases via the internet.Rewiev and remarks.ESES/CSWS phenomena can be held as a common final pathway originating from different etiologies, including patients with early brain damage (probably involving thalamic structures), but also patients without structural pathology as in atypical evolution of idiopathic regional childhood hyperexcitability syndromes (with Rolandic epilepsy as a prototype). There are hints that genetic predisposition might be an important factor in the development of this process. The two large patient groups (lesional and non-lesional) show the same EEG evolution and encephalopathic cognitive consequences. The sleep EEG activation can be held as a common endophenotype. ESES represents an extreme sleep activation/potentiation of the local/regional interictal discharges, enhancing them in frequency, territorial extension, intra and trans-hemispherial propagation, synchrony and continuity. This process is most probably not identical with the development of bilateral spike-wave pattern in „generalized” epilepsies which involves primarily or secondarily the thalamocortical system as it had been explored by Gloor (1979) for idiopathic generalized rpilepsy and Steriade and Amzica (2003) for different types of generalized spike and wave discharges.Conclusions and syndromological embedding of ESES.In an overwhelming majority of the investigated cases, the maps of the single discharges constituting sleep activation are identical; with focal/regional interictal spikes followed by slow closing wave, as it is seen in childhood regional age dependent hyperexcitability syndromes (prototype of the centro-temporal spikes of Rolandic epilepsy). The main mechanism of the developing cognitive impairment is most probably the consequence of interference with plastic function of slow wave sleep by obliterating synaptic decline during sleep. Presently, the consensus and co-operative research is highly obstacled by the terminological chaos, the controversial definitions and views around this still striking and enigmatic phenomenon.

Temporal lobe epilepsy is known to be associated with hyperactivity that is likely to be generated or amplified in the hippocampal formation. The majority of granule cells, the principal cells of the dentate gyrus, are found to be resistant to damage in epilepsy, and may serve as generators of seizures if their inhibition is impaired. Therefore, the parvalbumin-containing subset of interneurons, known to provide the most powerful inhibitory input to granule cell somata and axon initial segments, were examined in human control and epileptic dentate gyrus. A strong reduction in the number of parvalbumin-containing cells was found in the epileptic samples especially in the hilar region, although in some patches of the granule cell layer parvalbumin-positive terminals that form vertical clusters characteristic of axo-axonic cells were more numerous than in controls. Analysis of the postsynaptic target elements of parvalbumin-positive axon terminals showed that they form symmetric synapses with somata, dendrites, axon initial segments and spines as in the control, but the ratio of axon initial segment synapses was increased in the epileptic tissue (control: 15.9%, epileptic: 31.3%). Furthermore, the synaptic coverage of granule cell axon initial segments increased more than three times (control: 0.52, epileptic: 2.10 μm synaptic length/100 μm axon initial segment membrane) in the epileptic samples, whereas the amount of somatic symmetric synapses did not change significantly. Although the number of parvalbumin-positive interneurons is decreased, the perisomatic inhibitory input of dentate granule cells is preserved in temporal lobe epilepsy. Basket and axo-axonic cell terminals – whether positive or negative for parvalbumin – are present, moreover, the axon collaterals targeting axon initial segments sprout in the epileptic dentate gyrus. We suggest that perisomatic inhibitory interneurons survive in epilepsy, but their somadendritic compartment and partly the axon loses parvalbumin or immunoreactivity for parvalbumin. The hyperinnervation of axon initial segments might be a compensatory change in the inhibitory network, but at the same time may lead to a more effective synchronization of granule cell firing that could contribute to the generation or amplification of epileptic seizures.

To correlate the extent of the leptomeningeal angiomatosis with clinical features in Sturge-Weber syndrome (SWS).The study group consisted of 86 consecutive patients aged two months to 56 (mean 7.9 +/- 10.3) years with SWS and epilepsy. Clinical and MRI data were analyzed.Based on the extent of leptomeningeal angiomatosis, patients were divided into two subgroups: 43 patients had hemispheric angiomatosis and atrophy, whereas, another 43 had focal involvement. Nine of the 43 hemispherial patients (10%) showed bilateral involvement: all of these bilateral cases demonstrated dominance in a single side with hemispheric leptomeningeal angiomatosis and contralateral focal extension. Hemispheric and focal subgroups were clinically different. Patients with hemispheric SWS were younger at the age of epilepsy onset (p0.001) and age at MRI examination (p0.05). Neither gender, lateralization, duration of epilepsy, appearance of secondarily generalized seizures, nor seizure frequency revealed a significant difference between subgroups.Bilateral involvement is frequent and occurs in cases with a hemisperic involvement on one side. The age of epilepsy onset is related to the extent of leptomeningeal angiomatosis. Patients with hemispheric form of SWS presented with earlier age of seizure onset. Focal pial angiomatoses do not tend to progress (a longer duration is not associated with more frequent hemispheric involvement). Other variables including seizure frequency and secondary generalized tonic-clonic seizures are not associated with the extent of angiomatosis.

Hippocampal theta or rhythmic slow activity (RSA) occurring during exploratory behaviors and rapid-eye-movement (REM) sleep is a characteristic and well-identifiable oscillatory rhythm in animals. In contrast, controversy surrounds the existence and electrophysiological correlates of this activity in humans. Some argue that the human hippocampal theta occurs in short and phasic bursts. On the contrary, our earlier studies provide evidence that REM-dependent mesiotemporal RSA is continuous like in animals but instead of the theta it falls in the delta frequency range. Here we used a virtual navigation task in 24 epilepsy patients implanted with foramen ovale electrodes. EEG was analyzed for 1-Hz wide frequency bins up to 10 Hz according to four conditions: resting, non-learning route-following, acquisition and recall. We found progressively increasing spectral power in frequency bins up the 4 Hz across these conditions. No spectral power increase relative to resting was revealed within the traditional theta band and above in any of the navigation conditions. Thus the affected frequency bins were below the theta band and were similar to those characterizing REM sleep in our previous studies providing further indication that it is delta rather than theta that should be regarded as a human analog of the animal RSA.

The homeostatic sleep regulation idea underwent important development. Sleep homeostasis was first connected to the duration of the preceding awake time. Due to increasing innovative research in this field with convincing evidences on local sleep regulation, it seems that beyond the length of waking time, use-dependent afferent stimulation and synaptic upscaling (learning) are the main factors regulating the NREM sleep slow-wave activity (SWA). Further achievement of the same research line was to obtain evidences that plastic modulation of local slow-wave power during NREM sleep is closely related to the recreation of cognitive functions in the cortex, mainly in the frontal lobes. Slow-wave homeostasis and use-dependent plasticity are probably two sides of the same coin representing the biological function of slow-wave sleep.

In this chapter, we will deal with data accumulated about the arousal-driven spontaneous and evoked phasic events. We are looking for characteristics of spontaneous and elicited phasic changes, regularities in their occurrence, and the impact of their existence on the course of sleep. Summarizing the results of earlier works about PAT, K-complexes, and CAP phenomena, a new approach has been used in their systematization. First, we have differentiated arousal-like and sleep-like spontaneous and elicited responses and investigated the relation of these two types with dynamic changes in the course of night sleep. We differentiated these phasic changes from tonic states of sleep and analyzed the interrelationships of the phasic and tonic changes.

We are dealing with the relationship between macrostructural (slope of the sleep cycles) and the microstructural dynamics. Descending (“D”) and ascending (“A”) slopes of cycles show opposite trends: “D” slope shows sleep promoting, while “A” slope shows wake/REM-promoting tendencies. Arousal-like phasic changes (PAT and CAP A2–3 phases) turned out to be overwhelming during the “A” slopes of sleep cycles, and their amount is increased from evening to morning. Within the “A” slopes their frequency increases before REM sleep periods. Sleep-like phasic changes have a different course. They are prevalent during the “D” slopes of the first sleep cycles and follow the homeostatic decay of slow wave oscillation. Accordingly, the elicitability of the two types of phasic events has opposite tendencies during night sleep from evening to morning: Arousal-like responses are prevalent during the “A” slopes and their responsivity increases, while sleep-like responses are prevalent during the “D” slopes and their elicitability decreases. Lastly, we point out the double nature of the forces behind tonic and phasic regulation: There are alternating chemical influences behind the tonic one and faster reciprocal sleep- and wake-promoting inputs behind the phasic regulation. Due to the intermingled phasic and tonic regulation, the sleeper is connected with the surrounding world and is able to execute two seemingly contradictory tasks: (1) separation for trophotropic (use dependent homeostatic) functions and (2) reactivity in form of state-dependent responses.

The significance of reactive (input-related) slow wave responses has remained hidden for a long time. The recognition of this phenomenon started with the discovery of K-complexes and continued with the description of the A1 phase of cyclic alternating pattern (CAP); however, their biological role and importance is not yet fully understood. We propose here that these phenomena represent an instant (short-term) slow wave homeostasis to ensure the necessary amount of slow waves of a night. We propose that this instant slow wave homeostatic regulation is a supplementary regulation tool of slow wave economy as a response to any perturbation threatening the realization of the necessary slow wave amount especially during the first cycles, when homeostatic sleep pressure is high. There we have the link between the arousal-related microstructural sleep regulation and the sleep slow wave homeostasis, believed hitherto to be different issues.

In this chapter we provide an overview about those NREM sleep ­regulation models which take into consideration the effects of external and internal input factors apparently unrelated to the core sleep regulatory mechanisms but deeply influencing their dynamism. McCarley and Massaquoi (J Sleep Res 1(2):132–137, 1992) have begun to incorporate the influence of external noise according to the observations showing frequent brief nonbehavioral EEG and ­polygraphic “awakenings” in sleep. Lo et al. (Proc Natl Acad Sci USA 101(50):17545–1758, 2004) studying brief sleep-wake transitions were able to show that these events can be commonly observed across different species with different sleep patterns. The universality of the distributions of short wake episodes strikingly contrasts the species-specific distributions of sleep bouts. Lo concludes that this relationship reveals a universal regulatory mechanism shaping the dynamism of sleep. Behn et al. (J Neurophysiol 97(6):3828–3840, 2007) created a model of sleep-wake network composed of coupled relaxation oscillation equations. This model could be considered as a crucial one in trying to explain the dual nature of sleep-regulation: gross sleep-wake regulatory mechanisms depending on the already described neural circuitry of the flip-flop switch and fine structure shaped by short bouts of wakefulness. We have hypothesized a parallel regulation of sleep in our model (Halasz et al. J Sleep Res 13(1):1–23, 2004). Tonic processes were hypothesized to involve mainly intracerebral, slow, and chemical influences, while the phasic ones extracerebral, fast, and neuronal-synaptic ones tailoring the interaction of the reciprocal antagonistic influence between the sleep and arousal centers depicted in the flip-flop model of Saper et al. (Trends Neurosci. 24(12):726–731, 2001). The specificity of our model relied in the differential analysis of the descending and ascending slopes of the sleep cycles, which are usually undifferentiated in current models of sleep regulation.

A main part of fundamental knowledge about sleep regulation roots in the recognition of reciprocally antagonistic sleep-wake-promoting influences originating in brainstem/hypothalamic neuronal networks and in their dynamic interplay. All the presently known concepts and models of sleep regulation are essentially based on the anatomy and function of these subcortical networks. From the beginning of this century, the Harvard School of sleep research and the Lyon sleep research group have introduced important concepts about the working of the flip-flop model of “sleep switch” governing sleep/wake alternations and tried to connect these views with the earlier ideas explaining sleep cyclicity. These results have suggested that the subcortical neuronal assemblies have indeed a governing role in the EEG and behavioral changes during the sleep/wake cycle. However, within the NREM sleep period, robust dynamical changes take place, about which the flip-flop model has nothing to say about. NREM sleep cannot be taken as a “stable” state. Growing evidences about the “microstructure” of NREM sleep present sleep as an ever-changing fluctuating state intermingled with microarousals, strongly ­contradicting to this simple model.

During the last 15–20 years, a new knowledge accumulated about NREM slow wave oscillations that have become the key issue of homeostatic regulation. A frequency-based classification of slow waves has been developed, differentiating between 0.1–1- and 1–4-Hz groups. The cortical

According to the synaptic homeostasis hypothesis of Tononi and Cirelli (Sleep Med Rev 10(1):49–62, 2006), the homeostatic regulation of sleep slow wave activity is related to the amount of the synaptic potentiation that has accumulated during the preceding waking state. The homeostatic increase of slow wave activity is shown to be valid for regional involvement in special localization related tasks, especially true for the frontal lobe.

The main aim of this study was to identify interictal epileptiform discharges in a group of dogs with seizures of known aetiology (symptomatic epilepsy, SE) and in dogs with idiopathic epilepsy (IE). Propofol was used for chemical restraint in all dogs. We found electroencephalographic (EEG) changes that could be considered epileptiform discharges (EDs) in 5 out of 40 dogs (12.5%). The EEG changes identified were spikes in four cases and periodic epileptiform discharges in one case. All EDs were seen in the SE group. We conclude that the interictal electroencephalographic examinations of propofolanaesthetised dogs suffering from IE and SE rarely show epileptic discharges and that the diagnostic value of such EEGs in the work-up for epilepsy seems to be low as epileptic discharges were unlikely to be detected. However, positive findings are more likely to be connected with SE. We found frequent, transient EEG phenomena (spindles, K-complexes, vertex waves, positive occipital sharp transients of sleep, cyclic alternating patterns), which are non-epileptic but their differentiation from epileptic phenomena is challenging.

Aims. To build up a coherent shared pathophysiology of NFLE and AP and discuss the underlying functional network. Methods. Reviewing relevant published data we point out common features in semiology of events, relations to macro- and microstructural dynamism of NREM sleep, to cholinergic arousal mechanism and genetic aspects. Results. We propose that pathological arousals accompanied by confused behavior with autonomic signs and/or hypermotor automatisms are expressions of the frontal cholinergic arousal function of different degree, during the condition of depressed cognition by frontodorsal functional loss in NREM sleep. This may happen either if the frontal cortical Ach receptors are mutated in ADNFLE (and probably also in genetically not proved nonlesional cases as well), or without epileptic disorder, in AP, assuming gain in receptor functions in both conditions. This hypothesis incorporates the previous “liberation theory” of Tassinari and the “state dissociation hypothesis” of Bassetti and Terzaghi). We propose that NFLE and IGE represent epileptic disorders of the two antagonistic twin systems in the frontal lobe. NFLE is the epileptic facilitation of the ergotropic frontal arousal system whereas absence epilepsy is the epileptic facilitation of burst-firing working mode of the spindle and delta producing frontal thalamocortical throphotropic sleep system. Significance. The proposed physiopathogenesis conceptualize epilepsies in physiologically meaningful networks.

The first part of the chapter describes the activating effect of sleep on epileptic syndromes and underlying epileptic networks. The most important sleep-activated idiopathic epileptic disorders are addressed according to their vigilance-related symptomatology, underlying circuits, and the association of sleep activation and the degree and type of cognitive impairment. In the light of recent sleep research data, sleep activation of epileptic discharges has been shown to interfere with the physiological functions of nonrapid eye movement (NREM) sleep, explaining how epilepsy exerts an important influence on cognitive function, mainly during developmental windows. According to the role of sleep in cognitive impairment, epilepsies can be divided into two groups: (1) those with the involvement of the thalamocortical system, in which cognitive impairment via interference of sleep function is important; and (2) those in which the thalamocortical system is not a key factor in determining how epilepsy may induce cognitive impairment. The second part of the chapter is devoted to the role of sleep activation as a diagnostic tool.

The authors present a patient with right mesiotemporal epileptogenic region who experienced orgasmic epileptic aura. Twenty-two similar published cases were also evaluated. Among 15 patients with unilateral EEG foci, 13 (87%) had right and 2 (13%) had left focus. All of the nine patients who had sufficient data on ictal onset area had right-sided seizure onset. The authors suggest that orgasmic aura is an ictal lateralizing sign to the right hemisphere.

Prolonged EEG monitoring and video-EEG monitoring are basic methods on the level of epilepsy centers. These methods are able to make differences between epilepsy and non epileptic paroxysmal manifestations like psychogenic non epileptic seizures, parasomniac phenomena, narcolepsy. The application of the method, at least the video-EEG variant, needs team work, high level organisation, highly educated staff and high tech electrographic devices. Running the method even with these requirements is beneficial from the cost-benefit aspect as well.

The paper is aimed to introduce the neuronal network basis of dynamic sleep processes, including the micro-structure of sleep and the relationship of sleep dynamics with homeostatic regulation and plastic changes during sleep. Newer studies tend to show that beyond the wellknown long-term homeostatic and circadian regulation of NREM sleep, sleep is regulated by a stimulus and arousal dependent flexible defense system, the elements of which participate in sleep delta homeostasis. Within the EEG elements of sleep a more larger amount represents reactible type as it was thought previously. Both the events of wake state and sensory input during sleep are shaping the sleep EEG in a function- and localisation specific way and the next day cognitive functios are determined by these changes.

Zonisamide is licensed in the European Union for adjunctive therapy for partial epilepsy, but its efficacy in generalized epilepsy was less explored.This prospective observational study included 47 patients (mean age 29 years, range 3-50) with different resistant generalized epilepsy syndromes: idiopathic generalized syndromes (IGE) 15 patients, (juvenile myoclonic epilepsy four, absence epilepsy four, myoclonic absence two, unclassified IGE five), progressive myoclonic epilepsy type 1 (PME1) four, severe myoclonic epilepsy of infancy (SMEI) three, borderline SMEI three, Lennox-Gastaut syndrome/secondary generalized epileptic encephalopties 23 patients. All patients were followed up for at least six months. The mean dose given was 367 mg/day (range 100-600 mg/day), the patients received at least one and no more than two concomitant AE. Response was defined as more than 50% seizure reduction or seizure freedom.The best effect was achieved in PME one, all the patients were responders. Myoclonic seizures were reduced 80%, none of the patients had generalized tonic clonic (GTC) seizures. In two of the four patients all other antiepileptics were tapered of (including piracetam), so they were GTC seizure and almost myoclonia free on zonisamide only. Responder rates were in GEFS +/- SME 62.5%, in resistant IGE 62.5%, and in epileptic encephalopathies 33.3% patients. Tolerance after initial efficacy developed in six patients. Adverse effects were mild: weight loss, somnolence and confusion were repeatedly reported. Three patients reported cognitive improvement.Clinical benefit of a broad spectrum antiepileptic zonisamide extends across seizure types, ages and epilepsy syndromes. The efficacy in PME proved to be excellent.

To evaluate the pharmacokinetics of eslicarbazepine acetate (ESL) at steady-state in adults with partial-onset seizures who have taken ESL for at least 1 year with one or two concomitant antiepileptic drugs (AEDs).Blood samples for the pharmacokinetic assessment were taken at pre-dose, and 1, 2, 3, 4, 6, 8, 12 and 24h post-dose at steady-state in 51 patients stabilised on chronic (beyond 1 year) treatment with ESL 400mg (n=7), 800mg (n=26) or 1200mg (n=18) once-daily. Most patients (n=29, 56.9%) were receiving 2 concomitant AEDs, and most frequent co-medications were carbamazepine (n=34, 66.7%) and valproic acid (n=19, 37.3%). Plasma concentrations of ESL and its metabolites eslicarbazepine, R-licarbazepine and oxcarbazepine (OXC) were determined by a validated chiral method using liquid chromatography coupled to mass spectrometry.Similarly to earlier findings in healthy subjects, plasma ESL concentrations were consistently below the lower limit of quantification (50ng/mL). The major compound in plasma was the active metabolite eslicarbazepine, which reached maximum concentrations (C(max)) 2h post-dose; thereafter, its plasma concentrations declined with a mean apparent half-life of 13, 14, and 20h in patients receiving ESL doses of 400, 800, and 1200mg once daily, respectively. Eslicarbazepine C(max) were 9.7, 15.5 and 23.0μg/mL, and areas under the plasma concentration-time curve over the dosing interval (AUC(0-24)) were 132.5, 205.4 and 336.1μgh/mL in patients receiving ESL doses of 400, 800 and 1200mg once-daily, respectively. Eslicarbazepine main pharmacokinetic parameters (C(max) and AUC(0-24)) were dose-proportional. R-licarbazepine and OXC were minor metabolites.Following once-daily oral administration of ESL 400mg, 800mg and 1200mg to epilepsy patients treated concomitantly with one or two other AEDs, ESL was rapidly converted to eslicarbazepine, which was the primary active compound found in plasma. Systemic exposure to eslicarbazepine was dose-proportional.

According to our opinion several ideas, trends and aims of the traditional neurology became outworn. (So together with all the romantic beauty and hierarchic relations: Adieu!). The specialisation within the main body of the profession is unavoidable. A new, high quality, cost-benefit sensitive, institutional system should be built up, non essentially on inpatient, but on outpatient basis, supported by a personal and partnership oriented patient/doctor relationship, with multidisciplinatory co-operations and team-work. Education should be also rebuilt accordingly. This analysis of the present situation and recommendations for the future plans was given--since our ages--without any personal interest or attraction. We tried to keep before us only the future of our beloved profession, the preservation of worths, and the exploration of the withdrawing dogmatic views. We invite everybody who is interested in the current questions of our profession to share their opinion with the whole neurological society and take part in open discussion of these important questions.

In this paper we investigate evidences supporting the network concept of epilepsies from different approaches. Firstly the functions of cortical networks in which most of the epileptic networks are embedded, are treated. Then the tentative characteristics of an epileptic network are enumerated and the conversion mechanisms from physiological to epileptic networks are analyzed. Later the role of neuronal oscillations in epileptic networks and aspects of epilepsies provoked by sensory and cognitive tasks is studied. Lastly new fMRI data in mapping BOLD networks underlying spike and seizure discharges are used as arguments in favour of the epileptic network hypothesis. In a second part the well-known epilepsies related, or probably related to physiological networks are shown. Finally consequences of the network approach for creating a new unified epilepsy classification are discussed.

Seventeen cats were presented with acute onset of complex partial seizures with orofacial involvement (salivation, facial twitching, lip smacking, chewing, licking or swallowing), motor arrest (motionless starring) and behavioural changes. In 11 cats hippocampal necrosis (HN) was confirmed by histopathology. In a further six cats hippocampal changes were suggested by magnetic resonance imaging. The mean monitoring time of eight cats which were not euthanased in the acute phase of the disease, was 408 days (60–908): four cats are still alive. In all surviving cases, the owners reported a good quality of life. We conclude that an acute cluster of complex partial seizures with orofacial involvement are often associated with HN and that HN is not necessarily a fatal condition. Supportive and antiepileptic therapy can result in remission. The long-term outcome can be good to excellent; therefore, euthanasia should be avoided in the acute phase of the signs.

Sleep-associated memory consolidation is thought to rely on coordinated information transfer between the hippocampus and neocortex brought about during slow wave sleep (SWS) by distinct local field potential oscillations. Specifically, findings in animals have led to the concept that ripples originating from hippocampus combine with spindles to provide a fine-tuned temporal frame for a persistent transfer of memory-related information to the neocortex. The present study focused on characterizing the temporal relationship between parahippocampal ripple activity (80-140 Hz) and spindles recorded from frontal, parietal and parahippocampal cortices in 12 epilepsy patients implanted with parahippocampal foramen ovale electrodes. Overall, parietal and parahippocampal spindles showed closer relationships to parahippocampal ripple activity than frontal spindles, with the latter following parietal and parahippocampal spindles at a variable delay of up to 0.5 s. On a timescale of seconds, ripple activity showed a continuous increase before the peak of parietal and parahippocampal spindles, and decreased thereafter. At a fine timescale of milliseconds, parahippocampal ripple activity was tightly phase-locked to the troughs of these spindles. The demonstration of spindle phase-locked ripple activity in humans is consistent with the idea of a temporally fine-tuned hippocampus-to-neocortex transfer of information taking place during SWS.