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Arousability and reactivity to sensory stimuli are essential features of sleep, discriminating it from coma and keeping the sleeper in contact with the environment. Arousals and oscillations during sleep serve the reversibility of sleep and carry an alarm function awakening the sleeper in danger. In this review, we will explore mechanisms and circuits involved in arousal intrusions within the sleep texture, focusing on the significance of these phenomena in two sleep-related conditions: NREM sleep parasomnias and sleep-related hypermotor epilepsy. Knowledges and gaps in the field are discussed.

Az epileptogenesis útjainak vizsgálata a rend­szerepilepszia-koncepció mentén. Irodalmi áttekintés és saját tapasztalatok alapján ismertetjük a deklaratív memóriarendszer, az alvás/ébredés és a perisylvian kommunikációs rendszer epilepsziás átalakulását, majd az epileptogenesis folyamatát bemutatjuk az agyi sérülések és a poszttraumás epilepszia modelljén is. Az ismertetett rendszer-epilepsziák kiala­kulásában közös lépések ismerhetők fel a plaszticitás és a NREM-alvás alatti szinaptikus homeosztázis felfoko­zó­dásában, ami egyben rávilágít az alvás döntő szerepére epilepsziában. Megkíséreljük körvonalazni a rend­szerepilepszia-koncepciót, és az egymással összefüggő plaszticitás – alvási szinaptikus homeosztázis „kisiklása” formájában rámutatunk az epileptogenesis lehetséges közös patomechanizmusára.

We review the literature on REM parasomnias, and their the underlying mechanisms. Several REM parasomnias are consistent with sleep dissociations, where certain elements of the REM sleep pattern emerge in an inadequate time (sleep paralysis, hypnagogic hallucinations and cataplexy) or are absent/partial in their normal REM sleep time (REM sleep without atonia, underlying REM sleep behavior disorder). The rest of REM parasomnias (sleep related painful erection, catathrenia) may have other still unclear mechanisms. REM parasomnias deserve attention, because in addition to disturbing sleep and causing injuries, they may shed light on REM sleep functions as well as the heterogeneous etiologies of parasomnias. One of them, REM sleep behavior disorder has special importance as a warning sign of evolving neurodegenerative conditions mainly synucleinopathies (some cases synucleinopathies themselves) and it is a model parasomnia revealing that parasomnias may have by autoimmune, iatrogenic and even psychosomatic etiologies.Áttekintjük a REM-parasomniák irodalmát, és röviden foglalkozunk a hátterükben álló mechanizmussal. A csoport tagjainak egy része alvásdisszociációnak felel meg, ahol a REM-alvás egyes elemei inadekvát fázisban (például alvási paralysis, hypnagog hallucinációk) jelennek meg, vagy fordítva, elmaradnak/töredékesek a REM-alvás alatt, amelynek egyébként fiziológiás részei (REM-alvás izomatónia nélkül, a REM-magatartászavar hátterében álló rendellenesség). A többi REM-parasomnia (alvásfüggő fájdalmas erectio, catathrenia) hátterében egyéb, egyelőre tisztázatlan me­chanizmus állhat. A REM-parasomniák alvászavart és sérüléseket okozhatnak, és tanulmányozásuk meg­vilá­gít­hatja a REM-alvás funkcióit és a parasomniák hátterében álló sokszínű etio­lógiát. A REM-magatartászavarnak különleges jelentősége van: neurodegeneratív betegségek, különösen synuclei­no­pathiák előjele (vagy kísérője) lehet, talán maga is az. Egyben modell-rendellenesség, ami autoimmun, iatrogén és pszichoszomatikus zavarok fel­tá­rását teheti lehetővé.

Összefoglaló. Bevezetés és célkitűzés: A terápiarezisztens fokális epilepsziák sebészeti kezelése elterjedten használt kezelési lehetőség. Célunk az epilepsziasebészet-hatékonyság változásának vizsgálata egy évtizednyi távlatból a budapesti centrumban. Módszerek: Az Országos Klinikai Idegtudományi Intézetben reszektív epilepsziasebészeti beavatkozásokon átesett fokális epilepsziás betegek adatai kerültek feldolgozásra. A vizsgált 10 év beteganyagát két periódusra osztottuk a műtét időpontja szerint (2006–2010 és 2011–2016). Vizsgálati szempontjaink: demográfiai adatok, az epilepszia kezdete és típusa, mágnesesrezonancia-lelet, preoperatív rohamfrekvencia, műtéttípus és szövettani lelet. Az epileptológiai kimenetelt az Engel-klasszifikáció alapján értékeltük. Eredmények: Epilepsziasebészeti beavatkozás 187 betegen történt, akik közül 137-nél került sor reszekciós műtétre. A betegek 65%-ában temporalis, 18%-ában frontalis, míg 7%-ában olyan multilobaris epilepszia igazolódott, mely a temporalis vagy a frontalis lebenyt érintette. Teljes rohammentességet (Engel I/A) az 1. évben 68%-ban, a 2. évben 64%-ban, míg az 5. évben 63%-ban mértünk. A két intervallum összehasonlításakor az 1 éves rohammentesség aránya 60%-ról (temporalis: 67%, extratemporalis: 50%) 73%-ra (temporalis: 79%, extratemporalis: 62%) javult a második periódusban. Az etiológia szempontjából a hippocampalis sclerosis aránya 28%-ról 14%-ra csökkent, a fokális corticalis dysplasiák aránya 22%-ról 31%-ra növekedett. Következtetés: A sebészeti kezelés fokális epilepsziák esetén – alapos előzetes kivizsgálást követően – általában biztonságos és a legnagyobb arányban sikeres beavatkozás. A legkedvezőbb kimenetel temporalis lokalizációban érhető el. A hatékonyság az évek során egyre javuló tendenciát mutatott az egyre nehezebb sebészeti esetek ellenére. Ez magyarázható a sebészeti technikák fejlődésével, illetve a jobb, műtét előtti elektrofiziológiai és képalkotó technikákkal, amelyek bevezetésével pontosabb lokalizáció adható. Orv Hetil. 2021; 162(6): 219–226. Summary. Introduction and objective: The surgical treatment of medically intractable focal epilepsies is a well established practice. Our aim was to examine the efficacy of epilepsy surgery within a decade long period in our centre in Budapest. Methods: Data of drug-resistant patients with resective epilepsy surgery in the National Institute of Clinical Neurosciences were evaluated. The examined 10-year period was divided based on the year of the operation in two parts (2006–2010 and 2011–2016). The following data were collected: demography, beginning and type of epilepsy, magnetic resonance, preoperative seizure frequency, type of surgery and histology. Epileptological outcome was based on modified Engel’s classification. Results: Out of 187 surgeries, we identified 137 patients with resective intervention: 65% temporal lobe, 18% frontal, and 7% multilobar epilepsy. Seizure-freedom (Engel I/A) was 68% in the first postoperative year, 64% in the second, and 63% in the fifth year. In the first period, 1-year seizure freedom was 60% (temporal: 67% extratemporal: 50%), while in the second period it was 73% (temporal 79%, extratemporal 62%). Hippocampal sclerosis ratio dropped from 28% to 14%, while focal cortical dysplasia ratio increased from 22% to 31%. Conclusion: Surgical treatment in focal epilepsy – after thorough presurgical evaluation – is generally safe and successful. The most favorable outcome is in temporal localization. The efficacy tended to improve over time despite of the more challenging cases. This can be explained with the development of surgical techniques and improvement of presurgical localization. Orv Hetil. 2021; 162(6): 219–226.

BACKGROUND AND PURPOSE: Some epilepsy syndromes (sleep-related epilepsies, SREs) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life. Our purpose was to define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2).METHODS: The project was conducted under the auspices of the European Academy of Neurology, the European Sleep Research Society and the International League Against Epilepsy Europe. The framework entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For the literature search a stepwise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine's MEDLINE database and Cochrane Library.RESULTS: Scenario 1: Despite a low quality of evidence, recommendations on anamnestic evaluation and tools for capturing the event at home or in the laboratory are provided for specific SREs. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizure control.CONCLUSIONS: Definitive procedures for evaluating patients with SRE are lacking. Advice is provided that could be of help for standardizing and improving the diagnostic approach of specific SREs. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined.

The aim of this review is to summarize and discuss the strong bond between NREM sleep and epilepsy underlain by the shared link and effect on brain plasticity. Beyond the seizure occurrence rate, sleep relatedness may manifest in the enhancement of interictal epileptic discharges (spikes and pathological ripples). The number of the discharges as well as their propagation increase during NREM sleep, unmasking the epileptic network that is hidden during wakefulness. The interictal epileptic discharges associate with different sleep constituents (sleep slow waves, spindling and high frequency oscillations); known to play essential role in memory and learning. We highlight three major groups of epilepsies, in which sleep-related plastic functions suffer an epileptic derailment. In absence epilepsy mainly involving the thalamo-cortical system, sleep spindles transform to generalized spike-wave activity. In mesio-temporal epilepsy affecting the hippocampal declarative memory system, the sharp wave ripples derail to dysfunctional epileptic oscillations (spikes and pathological ripples). Idiopathic childhood epilepsies affecting the perisylvian network may progress to catastrophic status electricus during NREM sleep. In these major epilepsies, NREM sleep has a pivotal role in the development and course of the disorder. Epilepsy is born in-, and exhibits its pathological properties during NREM sleep. Interictal discharges are important causative agents in this process.

Aims - Overview of the new data about the strong link of sleep and epilepsy and conjoining cognitive impairment. Methods - Search for relevant references and summary of our own research activity on the topic. Results - Strong interrealtionship exists between epilepsy and plastic brain functions (memory processing and synaptic homeostasis) and the working modes of NREM sleep. In the most frequent childhood and adult epilepsy networks responsible for plastic functions can be derailed to an epileptic level of excitability, and suffer a transitory or permanent epileptic transformation. Exampling on the three big epilepsies: absence epilepsy; medial temporal lobe epilepsy; and childhood idiopathic focal age dependent epilepsy spectrum we demonstrate the most important features of this epileptic transformation. The association of cognitive impairment to certain sleep dependent epilepsies gains explanation by the epilepsy caused interference with slow wave decline (ICFE) and memory consolidation (MTLE) during NREM sleep. This paper serves also to introduce the concept of sleep dependent system epilepsies. Conclusions - We provide evidences about shared mechanisms among sleep related epilepsies being the derailment of sleep plastic funcions toward exaggerated excitability determined by the inherent possibilities of the signal transduction properties.

Slow waves recorded with EEG in NREM sleep are indicative of the strength and spatial extent of synchronized firing in neuronal assemblies of the cerebral cortex. Slow waves often appear in the A1 part of the cyclic alternating patterns (CAP), which correlate with a number of behavioral and biological parameters, but their physiological significance is not adequately known. We automatically detected slow waves from the scalp recordings of 37 healthy patients, visually identified CAP A1 events and compared slow waves during CAP A1 with those during NCAP. For each slow wave, we computed the amplitude, slopes, frequency, synchronization (synchronization likelihood) between specific cortical areas, as well as the location of origin and scalp propagation of individual waves. CAP A1 slow waves were characterized by greater spatial extent and amplitude, steeper slopes and greater cortical synchronization, but a similar prominence in frontal areas and similar propagation patterns to other areas on the scalp. Our results indicate that CAP A1 represents a period of highly synchronous neuronal firing over large areas of the cortical mantle. This feature may contribute to the role CAP A1 plays in both normal synaptic homeostasis and in the generation of epileptiform phenomena in epileptic patients.

Accumulating evidence suggests that epileptic seizures originating from the temporal lobe (TL) occur in cats. Typically, affected animals have clinically focal seizures with orofacial automatisms including salivation, facial twitching, lip smacking, chewing, licking, and swallowing. Motor arrest and autonomic and behavioral signs also may occur. Many affected cats have magnetic resonance imaging (MRI) changes within the hippocampus or histopathologically confirmed hippocampal sclerosis or necrosis. From the 1950s to the 1980s, cats frequently were used as animal models for neurophysiological experiments and electrophysiological studies, from which important basic knowledge about epilepsy originated, but which has been rarely cited in clinical veterinary studies. These studies were reviewed. Experimental research on cats showed the widespread anatomical connections among TL structures. The ictal clinical signs originating from the hippocampus, amygdala, or lateral temporal cortex are similar, because of their dense interconnections. The ictal signs can be divided into autonomic, somatic, and behavioral. For research purposes, a 6-stage system was established, reflecting the usual sequential progression from focal to generalized seizure: attention response (1), arrest (2), salivation, licking (3), facial twitching (4), head turning or nodding (5), and generalized clonic convulsions (6). Knowledge of this data may help in recognizing low-stage (stage 1 or stage 2) epileptic seizures in clinical practice. Early experimental research data are in accordance with recent clinical observations regarding ictal clinical signs of TL epileptic seizures in cats. Furthermore, the research data supports the idea that TL epilepsy represents a unique clinical entity with a specific seizure type and origin in cats.

Epileptiform activity in various but not all epilepsy and recording types and cerebral areas is more frequent in NREM sleep, and especially during sleep periods with high-amplitude EEG slow waves. Slow waves synchronize high-frequency oscillations: physiological activity from the theta through the gamma band usually appears during scalp-positive upstates while epileptiform activity occurs at transitory phases and the scalp-negative downstate. It has been proposed that interictal discharges (IIDs) are facilitated by the high degree of neuronal firing synchrony during slow wave transitory and downstates. This would suggest that their occurrence increases as a function of slow wave synchronization, indicated by greater amplitude, steeper slopes and higher EEG signal synchronization. We investigated the occurrence of IIDs during NREM sleep slow waves in epileptic patients undergoing presurgical electrophysiological monitoring. Intracranially registered IIDs preferentially occurred during the scalp-negative downstates of frontal scalp slow waves in all subjects. IID occurrence was more frequent during larger slow waves in the pooled sample and a subset of subjects. However, slow wave slope steepness and EEG signal synchronization between two frontal scalp channels was not significantly associated with IID occurrence. Our results indicate that IIDs indeed do not occur at the same slow wave phase as physiological rhythms, but contrary to previous hypotheses their occurrence is not strongly affected by EEG synchronization.

In this paper we reviewed results of sleep research that have changed the views about sleep slow wave homeostasis, which involve use-dependent and experience-dependent local aspects to understand more of the physiology of plastic changes during sleep. Apart from the traditional homeostatic slow-wave economy, we also overviewed research on the existence and role of reactive aspects of sleep slow waves. Based on the results from spontaneous and artificially evoked slow waves, we offer a new hypothesis on instant slow wave homeostatic regulation. This regulation compensates for any potentially sleep-disturbing events by providing instant "delta injections" to maintain the nightly delta level, thus protecting cognitive functions located in the frontal lobe. We suggest that this double (long-term /instant) homeostasis provides double security for the frontal lobes in order to protect cognitive functions. The incorporation of reactive slow wave activity (SWA) makes sleep regulation more dynamic and provides more room for the internalization of external influences during sleep.

The veterinary literature on epilepsy in cats is less extensive than that for dogs. The present review summarizes the most important human definitions related to epilepsy and discusses the difficulties in applying them in daily veterinary practice. Epileptic seizures can have a wide range of clinical signs and are not necessarily typical in all cases. Whether a seizure event is epileptic can only be suspected based on clinical, laboratory, and neuroimaging findings as electroencephalography diagnostic techniques have not yet been developed to a sufficiently accurate level in veterinary medicine. In addition, the present review aims to describe other diagnoses and nonepileptic conditions that might be mistaken for epileptic seizures. Seizures associated with hippocampal lesions are described and discussed extensively, as they seem to be a special entity only recognized in the past few years. Furthermore, we focus on clinical work‐up and on treatment that can be recommended based on the literature and summarize the limited data available relating to the outcome. Critical commentary is provided as most studies are based on very weak evidence.

The article summarises the role of input and consequent phasic events in the dynamism of non-rapid eye movement (NREM) sleep and in homeostatic slow-wave economy during sleep. Then, an overview of the mechanism of how micro-arousals in NREM sleep gate epileptic events in absence epilepsy (AE) and in sporadic and autosomal dominant nocturnal frontal lobe epilepsy (NFLE/ADNFLE) is presented. The ictal type of generalised spike-wave discharges (SWDs) are associated with a special vigilance level in between NREM, rapid-eye movement (REM) and wake state. This transitional state is characterised by input-driven bidirectional fluctuations. Among them, SWDs are linked to A1 type A phases of CAP and therefore seem to be associated with shifts towards NREM sleep (sleep induction). In ADNFLE (and presumably in NFLE), micro-arousals release epileptic events in NREM sleep probably due to epileptic sensitisation of the cholinergic arousal system by the known acetylcholine (ACh) receptor mutations affecting the arousal system, giving rise to the epileptic (and also parasomniac) episodes. In both kinds of these system epilepsies (AE and NFLE), epileptic events can be released by phasic events during NREM sleep. The difference is that absences are activated in reactive states with a sleep-promoting, antiarousal effect, while in NFLE the epileptic disorder is interwoven with the cholinergic arousal function. The role of arousal/antiarousal in NFLE and AE fits nicely with the hypothesis that these epilepsies are disorders of two antagonistic thalamo-frontal systems involved in functions NREM sleep and wakefulness.

Background. The relationship between sleep and epilepsy has been long ago studied, and several excellent reviews are available. However, recent development in sleep research, the network concept in epilepsy, and the recognition of high frequency oscillations in epilepsy and more new results may put this matter in a new light. Aim. The review address the multifold interrelationships between sleep and epilepsy networks and with networks of cognitive functions. Material and Methods. The work is a conceptual update of the available clinical data and relevant studies. Results and Conclusions. Studies exploring dynamic microstructure of sleep have found important gating mechanisms for epileptic activation. As a general rule interictal epileptic manifestations seem to be linked to the slow oscillations of sleep and especially to the reactive delta bouts characterized by A1 subtype in the CAP system. Important link between epilepsy and sleep is the interference of epileptiform discharges with the plastic functions in NREM sleep. This is the main reason of cognitive impairment in different forms of early epileptic encephalopathies affecting the brain in a special developmental window. The impairment of cognitive functions via sleep is present especially in epileptic networks involving the thalamocortical system and the hippocampocortical memory encoding system.

Summary Purpose: To evaluate the efficacy and safety profile of eslicarbazepine acetate (ESL) added to stable antiepileptic therapy in adults with partial-onset seizures. Methods: Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double-blind, randomized, placebo-controlled studies were pooled and analyzed. Following a 2-week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once-daily doses for 12 weeks. Key Findings: Seizure frequency was significantly reduced with ESL 800 mg (p 10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations. Significance: Once-daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs.

Summary Purpose: To evaluate the long-term efficacy and safety of once daily eslicarbazepine acetate (ESL) as adjunctive therapy for partial-onset seizures in adults with epilepsy. Methods: One-year open-label treatment extension with ESL in patients who completed a placebo-controlled pivotal study (Epilepsia 2009; 50: 454–463). Starting dose was 800 mg once daily, for 4 weeks; thereafter, dose could be titrated up or down. Doses of concomitant antiepileptic drugs were to be kept stable. Results: Overall, 314 patients were enrolled. The intent-to-treat population consisted of 312 patients, and 239 (76.6%) completed 1 year of treatment. ESL median dose was 800 mg once daily. Compared to baseline, median seizure frequency decreased by 39% during the first 4 weeks and between 48% and 56% thereafter. The responder rate (≥50% seizure reduction) was 41% during weeks 1–4 and, thereafter ranged between 48% and 53%. The proportion of seizure-free patients per 12-week interval ranged between 8.7% and 12.5%. Quality of life, as measured by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), and depressive symptoms, as measured by the Montgomery Asberg Depression Rating Scale (MADRS), improved significantly compared to baseline. Treatment-emergent adverse events (TEAEs) were reported by 51% of patients. The most frequent TEAEs were headache (10%), dizziness (10%), diplopia (5%), and nasopharyngitis (5%). TEAEs were mostly (97%) of mild to moderate intensity. Eleven patients (3.5%) discontinued due to TEAEs. There were no results of laboratory tests raising safety concerns. Discussion: Sustained therapeutic effect, favorable tolerability and safety, and an improvement in quality of life and depressive symptoms were observed during long-term add-on treatment of partial-onset seizures in adults with once daily ESL.

The endocannabinoid system plays a central role in retrograde synaptic communication, and controls both glutamatergic and GABAergic transmission via type 1 cannabinoid receptors (CB1). Both in sclerotic human hippocampi and in the chronic phase of pilocarpine-induced epilepsy in mice with sclerosis, CB1 receptor-positive interneuron somata were preserved both in the dentate gyrus and in the CA1 area, and the density of CB1 immunostained fibers increased considerably in the dentate molecular layer. This suggests that, while CB1 receptors are known to be reduced in density on glutamatergic axons, the CB1 receptor-expressing GABAergic axons sprout, or there is an increase of CB1 receptor levels on these fibers. The changes of CB1 immunostaining in association with the GABAergic inhibitory system appears to correlate with the severity of pyramidal cell loss in the CA1 subfield. These results confirm the involvement of the endocannabinoid system associated with GABAergic transmission in human TLE, as well as in the chronic phase of the pilocarpine model in mice. Pharmacotherapy aimed at the modulation of endocannabinoid-mediated retrograde synaptic signaling should take into account the opposite change in CB1 receptor expression observed on glutamatergic versus GABAergic axon terminals.

Vagus nerve stimulation (VNS) is a nonpharmacologic therapeutic option for patients with intractable epilepsy. Better clinical outcomes were recorded in nonfocal and Lennox-Gastaut syndrome (LGS). We conducted a 2-year, open label, prospective study to measure the seizure outcome of 26 VNS patients. The seizure numbers were assessed using clinician's global impression scale (CGI) and patient diaries. The average seizure reduction was 23% at the first year and 22% at the second year. Seizure reduction was more pronounced among patients with nonfocal than with focal epilepsy. The response rate was 50% at first year and 30% at the second year. The best CGI record for clinically significant improvement was 15% in the LGS group. The only statistically significant result was the reduction of the generalized tonic-clonic seizures (GTCS). The side-effect profile was good; however, the large number of mild and reversible effects influenced the stimulation parameters and thus probably the effectiveness of the therapy. We suggest that VNS is an optional treatment mostly in cases of therapy-resistant Lennox-Gastaut syndrome. Patients with GTCS may experience improvement such as reduction of seizure severity. We conclude that VNS is a safe neuromodulatory treatment, but future developments of neuromodulatory approaches are needed.

Calretinin is expressed mainly in interneurons that specialize to innervate either principal cell dendrites or other interneurons in the human hippocampus. Calretinin-containing cells were shown to be vulnerable in animal models of ischaemia and epilepsy. In the human hippocampus, controversial data were published regarding their sensitivity in epilepsy. Therefore we aimed to reveal the fate of this cell type in human epileptic hippocampi. Surgically removed hippocampi of patients with drug-resistant temporal lobe epileptic (n = 44) were examined and compared to control (n = 8) samples with different post-mortem delays. The samples were immunostained for calretinin and the changes in the distribution, density and synaptic target selectivity of calretinin-positive cells were analysed. Control samples with post-mortem delays longer than 8 h resulted in a reduced number of immunolabelled cells compared to controls with short post-mortem delay. The number of calretinin-positive cells in the epileptic tissue was considerably decreased in correlation with the severity of principal cell loss. Preserved cells had segmented and shortened dendrites. Electron microscopic examination revealed that in controls, 23% of the calretinin-positive interneuronal terminals targeted calretinin-positive dendrites, whereas in the epileptic samples it was reduced to 3-5%. The number of contacts between calretinin-positive dendrites also dropped. The present quantitative data suggest that calretinin-containing cells in the human hippocampus are highly vulnerable, thus inhibition mediated by dendritic inhibitory cells and their synchronization by interneuron-specific interneurons may be impaired in epilepsy. We hypothesize that reorganization of the interneuron-selective cells may be implicated in the occurrence of seizures in non-sclerotic patients, where the majority of principal and non-principal cells are preserved.

Summary Purpose: To study the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in adults with ≥4 partial-onset seizures (simple or complex, with or without secondary generalization) per 4 weeks despite treatment with 1–2 antiepileptic drugs (AEDs). Methods: This multicenter, parallel-group study had an 8-week, single-blind, placebo baseline phase, after which patients were randomized to placebo (n = 102) or once-daily ESL 400 mg (n = 100), 800 mg (n = 98), or 1,200 mg (n = 102) in the double-blind treatment phase. ESL starting dose was 400 mg; thereafter, ESL was titrated at weekly 400-mg steps to the full maintenance dose (12 weeks). Results: Seizure frequency adjusted per 4 weeks over the maintenance period (primary endpoint) was significantly lower than placebo in the ESL 1,200-mg (p = 0.0003) and 800-mg (p = 0.0028) groups [analysis of covariance (ANCOVA) of log-transformed seizure frequency]. Responder rate was 20% (placebo), 23% (400 mg), 34% (800 mg), and 43% (1,200 mg). Median relative reduction in seizure frequency was 16% (placebo), 26% (400 mg), 36% (800 mg), and 45% (1,200 mg). The most frequent concomitant AEDs were carbamazepine (56–62% of patients), lamotrigine (25–27%), and valproic acid (22–28%). Similar efficacy results were obtained in patients administered ESL with or without carbamazepine as concomitant AED. Discontinuation rates caused by adverse events (AEs) were 3.9% (placebo), 4% (400 mg), 8.2% (800 mg), and 19.6% (1,200 mg). AEs in >10% of any group were dizziness, headache, and diplopia. Most AEs were mild or moderate. Discussion: ESL, 800 and 1,200 mg once-daily, was well tolerated and more effective than placebo in patients who were refractory to treatment with one or two concomitant AEDs.

Summary Purpose: To evaluate the efficacy and safety of lacosamide (200 and 400 mg/day) when added to one to three concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. Methods: This multicenter, double-blind, placebo-controlled trial randomized patients (age 16–70 years) with partial-onset seizures with or without secondary generalization to placebo, lacosamide 200, or lacosamide 400 mg/day. The trial consisted of an 8-week baseline, a 4-week titration, and a 12-week maintenance period. Results: Four hundred eighty-five patients were randomized and received trial medication. Among these, 87% were taking two or more concomitant AEDs. Median percent reduction in seizure frequency per 28 days from baseline to maintenance period (intent-to-treat, ITT) was 20.5% for placebo, 35.3% for lacosamide 200 mg/day (p = 0.02), and 36.4% for 400 mg/day (p = 0.03). In the per protocol population, the reductions were 35.3% for lacosamide 200 mg/day (p = 0.04) and 44.9% for 400 mg/day (p = 0.01) compared to placebo (25.4%). The 50% responder rate for lacosamide 400 mg/day (40.5%) was significant (p = 0.01) over placebo (25.8%), but was not for 200 mg/day (35.0%). In the per protocol population, the 50% responder rate for lacosamide 400 mg/day (46.3%) was significant (p

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.

Summary: Objective: To examine the effects of age on different aspects of temporal lobe seizure semiology. Methods: We performed a video analysis of 605 archived seizures from 155 consecutive patients (age 10 months to 49 years) selected by seizure freedom after temporal lobectomy. Eighty patients had hippocampal sclerosis (HS). Beside semiological seizure classification, we assessed age dependency of several axes of seizure semiology: (1) aura, (2) number of different lateralizing signs, occurrence of ictal (3) emotional signs, (4) autonomic symptoms, (5) automatisms, and (6) secondary generalization as well as (7) the ratio of motor seizure components. Results: From the 155 patients, 117 reported aura, 39 had ictal emotional signs, 51 had autonomic symptoms, 130 presented automatisms, while 18 patients showed secondary generalization at least once during their seizures. Altogether 369 (median: 2/patient) different lateralizing signs were recorded. Frequency of HS (p < 0.001), ictal automatisms (p < 0.001), secondary generalization (p = 0.014), number of different lateralizing signs (p < 0.001) increased while the ratio of motor seizure component (p = 0.007) decreased by age. Auras, emotional symptoms, and autonomic signs occurred independently of patients’ ages. Hippocampal sclerosis adjusted linear models revealed that the frequency of automatisms and secondarily generalized seizures as well as the number of different lateralizing signs are HSindependent significant variables. Conclusion: Our findings support that brain maturation significantly influences the evolution of some important aspects (motor seizures, lateralizing signs) of temporal lobe seizure semiology. Conversely, other aspects (aura, emotional, and autonomic signs) are independent of the maturation process. This is the first report investigating age dependency of epileptic seizure semiology comparing all age groups. Key Words: Temporal lobe epilepsy—Seizure semiology—Age.

Summary Objective To describe clinical characteristics and lateralizing value of peri-ictal electrode manipulation automatism (EMA) in patients with temporal lobe epilepsy (TLE) and compare our data with ictal manual automatisms described in the literature. Methods Two-hundred and five videotaped seizures of 55 consecutive patients with refractory TLE and postoperatively seizure-free outcome were analyzed and EMA (tugging, scratching or adjusting the electrodes and cables) were monitored. Results Twenty-eight (51%) patients showed EMA during 47 (23%) seizures. Ictal start was noted in 22 seizures and in 19/22 cases EMA finished before the end of seizure. Ictal EMAs were always associated with automotor seizure components. During 25 seizures, exclusively postictal EMAs were observed. Electrode manipulation was presented during 24/112 left-sided and 23/93 right-sided seizures ( p =0.742). Peri-ictal EMA was unilateral (completed by one hand) in 24/47 seizures (10 ictal, 14 postictal); it was done by the hand ipsilateral to the seizure onset zone in 17/24 and by contralateral hand in 7/24 cases ( p =0.064). We observed concomitant contralateral dystonic posturing during 3/10 seizures with unilateral ictal EMA. Unilateral hand automatism, temporally independent from the EMA appeared in 30 (64%) of the 47 seizures. Conclusion Peri-ictal EMA is a frequent phenomenon but shows no lateralizing value in TLE. The mechanism of EMA is in many ways dissimilar from that of earlier described manual automatisms.

Arousal systems play a topical neurophysiologic role in protecting and tailoring sleep duration and depth. When they appear in NREM sleep, arousal responses are not limited to a single EEG pattern but are part of a continuous spectrum of EEG modifications ranging from high-voltage slow rhythms to low amplitude fast activities. The hierarchic features of arousal responses are reflected in the phase A subtypes of CAP (cyclic alternating pattern) including both slow arousals (dominated by the

Recent evidence suggests that the sleep-dependent consolidation of declarative memories relies on the non-rapid eye movement (NREM) rather than the rapid eye movement (REM) phase of sleep. Moreover, a few studies both at the cellular and the behavioural levels have suggested the involvement of sleep spindles, the most synchronous oscillatory waveforms during NREM sleep stage 2, in this process. Our previous study showed that overnight verbal memory retention correlates with the total number of sleep spindles in left frontocentral areas, while spindling in other regions did not correlate with mnemonic retention. In the present study, we show that retention of visuospatial memories over a 24-h period correlates with the total number of sleep spindles detected over parietal regions during the intervening night-time sleep. This result provides further evidence for the association between sleep spindle activity and declarative memory consolidation, and suggests that visuospatial and verbal memory retention differ in the topographic distribution of the NREM spindle activity with which they are associated.

This review summarises data gathered on the KC phenomenon over the past 70 yr. The following issues are discussed: definitions, morphology and topography of KC, the regular participation in NREM sleep, elicitability features of evoked KC, autonomic and motor concomitants, relationship of KC with information processing during NREM sleep, relationship of KC and deltas of NREM sleep, and relationship of KC with sleep cyclicity. KC is a complex multifunctional phenomenon of the sleeping brain involved in information processing and defence against the arousal effect of sensory stimuli. To put the old chap in a new garment, the relationship of KC with synchronisation-type and desynchronisation-type micro-arousals, and the 'cyclic alternating pattern', will be discussed, with an emphasis on the sleep-protecting role of KC and synchronisation-type answers in sleep regulation executed by phasic events. Lastly, the role of KC providing gating functions in idiopathic generalized epilepsies and other, different, sleep disorders are characterised. A 'theoretical epilogue' is appended to show some system theoretical and regulational aspects.

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 (

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.

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.

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.

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.