Standard procedures for the diagnostic pathway of sleep-related epilepsies and comorbid sleep disorders: an EAN, ESRS and ILAE-Europe consensus review.

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.

Bilateral Dentate Gyrus Structural Alterations in a Cat Associated With Hippocampal Sclerosis and Intraventricular Meningioma.

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.

Feline Temporal Lobe Epilepsy: Review of the Experimental Literature.

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.

Lateralizing value of postictal automatisms in temporal lobe epilepsy.

PURPOSE: To describe clinical characteristics and lateralizing value of postictal automatisms in patients with temporal lobe epilepsy (TLE). METHODS: One hundred and ninety-three videotaped seizures of 55 consecutive patients with refractory TLE and postoperatively seizure-free outcome were analyzed. Ictal as well as postictal (manual, oral and speech) automatisms were monitored. RESULTS: Thirty-four (62%) of the 55 patients showed PA at least once during their seizures. Postictal automatism was observed in 70 (36%) attacks as manual (21%), oral (13%) or speech (9%) automatisms. Fifteen seizures contained a combination of two different postictal automatisms. The presence of postictal oral automatisms did not lateralize the seizure onset zone (p=0.834). Speech automatisms (repetitive verbal behavior) occurred more frequently after left-sided seizures (p=0.002). Postictal unilateral manual automatism showed no lateralizing value occurring by the ipsilateral hand in 10 and the contralateral upper limb in 6 seizures (p=0.454). CONCLUSION: : Postictal automatism is a relatively frequent phenomenon in TLE. Postictal speech automatism lateralizes the seizure onset zone to the left hemisphere. Our observation can help the presurgical evaluation of TLE because verbal perseveration frequently occurs spontaneously, even in seizures without appropriate postictal language testing.

Surviving CA1 pyramidal cells receive intact perisomatic inhibitory input in the human epileptic hippocampus.

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.

Electrode manipulation automatism during temporal lobe seizures.

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.

Overnight verbal memory retention correlates with the number of sleep spindles.

Despite strong evidence supporting a role for sleep in the consolidation of newly acquired declarative memories, the contribution of specific sleep stages remains controversial. Based on electrophysiological studies in animals, synchronous sleep oscillations have been long proposed as possible origins of sleep-related memory improvement. Nevertheless, no studies to date have directly investigated the impact of sleep oscillations on overnight memory retention in humans. In the present study we provide evidence that overnight verbal memory retention is highly correlated with the number of sleep spindles detected by an automatic algorithm over left frontocentral areas. At the same time, overnight retention of newly learned faces was found to be independent of spindle activity but correlated with non-rapid-eye-movement sleep time. The data strongly support theories suggesting a link between sleep spindle activity and verbal memory consolidation.

Management of epilepsy in Hungary.

The management of epilepsy in Hungary is becoming a science in its own right (epileptology) and clinicians are conforming to international standards of practice. In this paper, the historical background of epileptology and the organization of treatment in Hungary are reviewed, and the current state of epidemiological data, development of diagnostic techniques and pharmacological and surgical therapy summarized. Particular emphasis is placed on: new strategies in morphological and functional neuroimaging; up-to-date electrophysiological diagnosis; clinical use of recently introduced pharmacological regimens. The results from questionnaires about public awareness and attitudes towards epilepsy, and quality of life in Hungarians with epilepsy are presented.

Substance P- and tyrosine hydroxylase-containing neurons in the human dorsal motor nucleus of the vagus nerve.

The aim of this study was to provide a comprehensive account of the topography, morphology, and frequencies of the substance P- and tyrosine hydroxylase-containing neurons in the human dorsal motor nucleus of the vagus nerve. The morphology of immunoreactive neurons was studied and the variations of the cell distributions were presented by three-dimensional computer reconstructions. Three types of substance P-like immunoreactive neurons were identified. They were predominantly located in the dorsointermediate, centrointermediate, caudointermediate, and caudal division of the dorsal motor nucleus of the vagus nerve. The morphology of substance P-like immunoreactive neurons varied according to the subnuclei in which they were found. Three types of tyrosine hydroxylase-like immunoreactive neurons were identified, mainly in the periphery of the dorsal motor nucleus of the vagus nerve, including the medial fringe, ventrointermediate, and dorsointermediate subnuclei of the 10. Many cells throughout the ventrointermediate subnucleus of the dorsal motor nucleus of the vagus nerve are seen ventrally to intermingle with the tyrosine hydroxylase neurons of the intermediate reticular zone. Computer reconstructions provided a three-dimensional view of the positions of substance P- and tyrosine hydroxylase-like immunoreactive neurons within the subdivisions of the dorsal motor nucleus of the vagus nerve. The uneven distribution of substance P- and tyrosine hydroxylase-like immunoreactive neurons within the subdivisions suggests an involvement of these substances in some, but not all, autonomic functions of the dorsal motor nucleus of the vagus nerve.

Serotonergic neurons in the brainstem of the wallaby, Macropus eugenii.

The organisation and cytoarchitecture of the serotonergic neurons in a diprotodont marsupial were examined by using serial sections of the brainstem processed for serotonin immunohistochemistry and routine histology. The topographic distribution of serotonergic neurons in the brainstem of the adult wallaby (Macropus eugenii) was similar to that of eutherian mammals. Serotonergic neurons were divided into rostral and caudal groups, separated by an oblique boundary through the pontomedullary junction. Approximately 52% of the serotonergic neurons in the wallaby brainstem were located in the rostral midline nuclei (caudal linear nucleus, dorsal, median, and pontine raphe nuclei and the interpeduncular nucleus), whereas 21% were found in the caudal midline region (nuclei raphe magnus, obscurus, and pallidus). The remaining serotonergic neurons (27%) were located in more lateral regions such as the pedunculopontine tegmental nuclei, the supralemniscal nuclei (B9 group), and the ventrolateral medulla. The largest serotonergic group, the dorsal raphe, contained one-third of the brainstem serotonergic neurons and showed five subdivisions, similar to that described in other species. In contrast, the median raphe did not show clear subdivisions. The internal complexity of the raphe nuclei and the degree of lateralisation of serotonergic neurons suggest that the wallaby serotonergic system is similar in organisation to that described for the cat and rabbit. This study supports the suggestion that the serotonergic system is evolutionally well conserved and provides baseline data for a quantitative study of serotonergic innervation of the developing cortex in the wallaby.

Orgasmic aura originates from the right hemisphere.

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.

Loss of Calbindin-D28K immunoreactivity from dentate granule cells in human temporal lobe epilepsy.

The loss of the calcium binding protein, Calbindin-D28k, from dentate granule cells has been observed in different animal models of epilepsy and in ischaemia. This decrease is accompanied by alterations of calcium and N-methyl-D-aspartate currents, which may explain the hyperexcitability of the dentate gyrus. In the present study, we found a loss of calbindin immunoreactivity from over 90% of the dentate granule cells in lobectomy samples from four of 10 temporal lobe epilepsy patients. In another four patients, over 50%, of dentate granule cells were devoid of calbindin immunoreactivity, whereas the remaining two cases showed a 20-30% decrease. Electron microscopy revealed a normal ultrastructure both in calbindin-containing and calbindin-negative granule cells. Both calbindin-positive and -negative mossy fibre collaterals participated in supragranular sprouting. As inferred from data in animal models, the lack of calbindin in dentate granule cells of human epileptic subjects is likely to result in hyperexcitability of the dentate gyrus, which may then function as a "motor" for seizures.

Changes in the distribution and connectivity of interneurons in the epileptic human dentate gyrus.

The distribution, size, dendritic morphology and synaptic connections of calbindin-, calretinin- and substance P receptor-positive interneurons and pathways have been examined in control and epileptic human dentate gyrus. In the epileptic dentate gyrus, calbindin-containing interneurons are preserved, but their dendrites become elongated and spiny, and several cell bodies appear hypertrophic. The relative laminar distribution of calretinin-containing cells did not change, but their number was considerably reduced. The calretinin-positive axonal bundle at the top of the granule cell layer originating from the supramammillary nucleus expanded, forming a dense network in the entire width of the stratum moleculare. Substance P receptor-immunopositive cells were partially lost in epileptic samples, and in addition, the laminar distribution and dendritic morphology of the surviving cells differed considerably from the controls. In the control human dentate gyrus, the majority of substance P receptor-positive cells can be seen in the hilus, while most are present in the stratum moleculare in the epileptic tissue. Their synaptic input is also changed. The extent of individual pathological abnormalities correlates with each other in most cases. Our data suggest, that although a large proportion of inhibitory interneurons are preserved in the epileptic human dentate gyrus, their distribution, morphology and synaptic connections differ from controls. These functional alterations of inhibitory circuits in the dentate gyrus are likely to be compensatory changes with a role to balance the enhanced excitatory input in the region.

Synaptic reorganization of calbindin-positive neurons in the human hippocampal CA1 region in temporal lobe epilepsy.

The distribution, morphology, synaptic coverage and postsynaptic targets of calbindin-containing interneurons and afferent pathways have been analyzed in the control and epileptic CA1 region of the human hippocampus. Numerous calbindin-positive interneurons are preserved even in the strongly sclerotic CA1 region. The morphology of individual cells is altered: the cell body and dendrites become spiny, the radially oriented dendrites disappear, and are replaced by a large number of curved, distorted dendrites. Even in the non-sclerotic epileptic samples, where pyramidal cells are present and calbindin-immunoreactive interneurons seem to be unchanged, some modifications could be observed at the electron microscopic level: they received more inhibitory synaptic input, and the calbindin-positive excitatory afferents - presumably derived from the CA1, the CA2 and/or the dentate gyrus - are sprouted. In the strongly sclerotic tissue, with the death of pyramidal cells, calbindin-positive terminals (belonging to interneurons and the remaining excitatory afferents) change their targets. Our data suggest that an intense synaptic reorganization takes place in the epileptic CA1 region, even in the non-sclerotic tissue, before the death of considerable numbers of pyramidal cells. Calbindin-positive interneurons participate in this reorganization: they show plastic changes in response to epilepsy. The enhanced inhibition of inhibitory interneurons may result in the disinhibition of pyramidal cells or in an abnormal synchrony in the output region of the hippocampus.

Preservation of perisomatic inhibitory input of granule cells in the epileptic human dentate gyrus.

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 microm synaptic length/100 microm 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.

Are microarousals preceded by electroencephalographic slow wave synchronization precursors of confusional awakenings?

The number of microarousals preceded by electroencephalographic (EEG) slow wave synchronization (MAS) and the number not preceded by EEG slow wave synchronization (K-complexes and/or delta groups) (MA) were analyzed during the first night of sleep in nine young patients with somnambulism and/or sleep terrors and in eight age- and sex-matched controls. While MAs peaked in REM ad intermediate sleep, MASs appeared as a phenomenon of NREM sleep, peaking in stage 2. The number of MASs was significantly greater in all stages of NREM sleep in the patient group, but number and distribution of MAs did not differ between the two groups. In the patient group, the MASs occurred in slow wave sleep (stages 3-4 of each sleep cycle); in controls, MASs occurred infrequently. MASs were frequently associated with automatic chewing movements. The higher frequency of microarousals in the patient group did not result in an increase in time awake during the night. The increase in number of microarousals supports Broughton's hypothesis of the presence of some "arousal disorder" in somnambulism and/or sleep terrors. MASs may be predictive markers of ensuing confusional awakenings.

8-OH-DPAT and MK-801 affect epileptic activity independently of vigilance.

Vigilance and parallel occurrence of epileptic activity after administration of the 5-HT(1A) agonist 8-OH-DPAT and the NMDA receptor antagonist MK-801 were studied in the genetic absence epilepsy model WAG/Rij rats. Spike-wave discharges (SWD) were present predominantly in passive awake and light slow wave sleep (SWS1) either in control animals or after treatments. Injection of 8-OH-DPAT (20.0 microg/rat i.c.v.) caused marked increase and MK-801 (10.0 microg/rat i.c.v.) decrease in SWD densities, thus the ratios of SWD in passive awake and in SWS1. SWD densities of MK-801 plus 8-OH-DPAT in combination were similar to those of CSF+CSF treated control rats. Both 8-OH-DPAT and MK-801 transiently increased the duration of active awake, increased latency and decreased duration of rapid eye movement (REM) sleep. 8-OH-DPAT increased the amount of SWD despite the decrease in the duration of SWS1. MK-801 decreased the amount of SWD despite the lack of significant change in duration of passive awake or SWS1. Pre-treatment with MK-801 reversed 8-OH-DPAT- induced increase in duration of SWD without any effect on 8-OH-DPAT-induced changes in sleep parameters. Our studies provide evidence that 8-OH-DPAT-induced epileptic activity is independent of its effect on sleep, and that interaction of serotonergic and glutamatergic systems plays a role in the generation of SWD, but not in the regulation of vigilance and sleep.

The 5-HT1A agonist 8-OH-DPAT increases the number of spike-wave discharges in a genetic rat model of absence epilepsy.

The effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on the epileptiform activity has been investigated in adult WAG/RIJ rats. Either intraperitoneal (0.1-0.5 mg/kg) or intracerebroventricular (2-20 microg/rat) administration of 8-OH-DPAT caused marked, dose-dependent increases in the number and mean cumulative duration of spike-wave discharges. These effects were attenuated by NAN-190, a 5-HT1A receptor antagonist. These data indicate that serotonergic system regulates the epileptiform activity in this genetic model of human absence epilepsy.

Arousals without awakening--dynamic aspect of sleep.

K complex as an elementary form of arousal was investigated by evoked K complexes. The components building up evoked K complexes and topographical sleep-level differences and influence of the kind of cognitive elaboration were analysed. Evidences are presented supporting that K complex represents a cascade of events originating from sources of different topography and probably by a different kind of elaboration activated in a certain order requested by the nature and context of the eliciting stimuli. The power spectra of evoked arousals--including K complexes--were investigated. The poststimulus spectral pattern is characterized by a short initial power elevation and a following reduction of all frequency bands except a simultaneous but prolonged (5-20 s) and strong (50%) power reduction at the 13-14 Hz sigma spindle band. This phenomenon seems to be a common feature in different stages of slow wave sleep. This stimulus-related microstate could serve as a transitory stand-by state ready to reach higher arousal rapidly while maintaining the continuity of sleep; hence, the inhibition of spindle activity could provide a phasically improved thalamocortical sensory inflow after environmental stimuli. A microstructural scheme of arousals without awakening has been delineated.

Disabling erratic myoclonus during lamotrigine therapy with high serum level--report of two cases.

We present two patients with epilepsy who experienced disabling myoclonic jerks during lamotrigine treatment. Both were young males who had intractable cryptogenic generalized epilepsy since childhood. They received a lamotrigine-valproate combination resulting in an excellent improvement; however, after 2-3 years of therapy, both patients were hospitalized because of continuous disabling myoclonic jerks. The dosage of lamotrigine was the same before and at the onset of myoclonus. When the severe myoclonus started, both patients had a higher serum lamotrigine level (16.5 and 17.7 mg/L, respectively) than in previous findings. Disabling myoclonus was also present during lamotrigine monotherapy with 15 mg/L serum level. Lamotrigine may severely worsen myoclonic phenomena in generalized epilepsies, in which adverse events may be dependent on drug serum level.