Sleep and Epilepsy

Summary: Epileptic mechanisms in the brain are subject to long-duration, time-ordered neuromodulatory processes controlled by endogenous oscillators which are responsible for appropriately phased modulation of various normal physiological processes, including the 24-h sleep/wakefulness cycle and the ultradian 100-min cycle of rapid eye movement/non-rapid eye movement sleep. Both focal and generalized types of epileptiform activity in humans are subject to biorhythmic modulation, and the various modulation patterns observed are in accord with a model which explains these patterns as a consequence of the interaction of two endogenous modulatory processes: one with a period of about 24 h, the other with a period of about 100 min. Differences in the phase angle between the two cyclic processes, determined by time of sleep onset, explain the various modulatory patterns observed. The mechanisms involved in the genesis and elaboration of electrical epileptiform activity in animal models are examined in relation to known processes involved in the physiology of sleep, and compared with data derived from long-term studies of the time distribution of epileptic events in humans. In infantile spasms, clinical seizure activity and the ictal and interictal EEG patterns in relationship to the phases of the sleep cycle, the significant defects in the quality and quantity of sleep in this disorder, and the changes that take place in all of these when seizures are abolished by effective treatment, suggest that pontine mechanisms responsible for the sleep cycle may be involved in the elaboration of infantile spasms and hypsarrhythmia.     

Ectopic Overexpression of Orexin Alters Sleep/Wakefulness States and Muscle Tone Regulation during REM Sleep in Mice

Orexins (also called hypocretins), which are neuropeptides exclusively expressed by a population of neurons specifically localized in the lateral hypothalamic area, are critically implicated in the regulation of sleep/wake states. Orexin deficiency results in narcoleptic phenotype in rodents, dogs, and humans, suggesting that orexins are important for maintaining consolidated wakefulness states. However, the physiological effect of constitutive increased orexinergic transmission tone, which might be important for understanding the effects of orexin agonists that are promising candidates for therapeutic agents of narcolepsy, has not been fully characterized. We report here the sleep/wakefulness abnormalities in transgenic mice that exhibit widespread overexpression of a rat prepro-orexin transgene driven by a β-actin/cytomegalovirus hybrid promoter (CAG/orexin transgenic mice). CAG/orexin mice exhibit sleep abnormalities with fragmentation of non-rapid eye movement (REM) sleep episode and a reduction in REM sleep. Non-REM sleep was frequently disturbed by short episodes of wakefulness. EEG/EMG studies also reveal incomplete REM sleep atonia with abnormal myoclonic activity during this sleep stage. These results suggest that endogenous orexinergic activity should be appropriately regulated for normal maintenance of sleep states. Orexinergic transmission should be activated during wakefulness, while it should be inactivated or decreased during sleep state to maintain appropriate vigilance states.     

Combined influence of cyclic arousability and EEG synchrony on generalized interictal discharges within the sleep cycle

PURPOSE: to analyze the activating role of cyclic alternating pattern (CAP) and EEG synchrony on generalized interictal paroxysms in the first part of the night, when all sleep patterns are represented. METHODS: nocturnal polysomnographic investigation was accomplished on a randomized series of 18 subjects with an active form of primary generalized epilepsy (PGE), but only six patients showed a complete and regular profile of the first two sleep cycles (SCs). Completeness and regularity of the selected SCs consisted in the absence of intervening wakefulness, in the presence of all sleep stages, and in the identification of three main units, (a) a descending branch, dominated by the build-up of EEG synchrony in the transition from light to deep non-rapid eye movement (NREM) sleep; (b) a trough, where the magnitude of EEG synchrony is greatest and gives rise to stages 3 and 4; (c) an ascending branch characterized by a decrease of EEG synchrony preceding the onset of rapid eye movement (REM) sleep. Generalized paroxysms were evaluated in terms of discharge rates (number of interictal bursts per minute of sleep) and distribution within the investigated sleep parameters. RESULTS: the discharge rates decreased from SC1 to SC2, with higher values quantified during NREM sleep (mean, 2.8) compared with REM sleep (mean, 0.8). Both SCs showed a progressive decrease of activation across the three units, from the highest discharge rates reached during the descending branches (mean, 3.6) to the more attenuated discharge rates during the troughs (mean, 2.4) down to the lowest rates during the ascending limbs (mean, 1.1). The magnitude of activation during the descending branches was closely related to the CAP condition (mean, 5.2) and to the powerful effect of phase A (mean, 13.9). The great majority (82%) of EEG discharges occurring in phase A were distributed within the A1 subtypes (identified by sequences of k-complexes or delta bursts). CONCLUSIONS: within the first two SCs, the features of NREM sleep endowed with the major activating power on generalized bursts are represented by the rise of EEG synchrony (descending branch) and by the A phases of CAP involved in the regulation of its build-up.     

Sleep modulation of interictal spike configuration in untreated children with partial seizures

Spontaneous changes in interictal spike morphology were evaluated before initiation of antiepileptic drug (AED) therapy in 38 children with uncontrolled partial seizures. Nonrapid eye movement (NREM) sleep during the first third of the night was associated with spikes of higher amplitude, longer duration, and lower degree of sharpness than those observed in wakefulness or REM sleep. Spike amplitude decreased in subsequent NREM epochs, but duration and sharpness remained relatively consistent. A NREM/REM modulatory pattern was identified, with REM periods exhibiting spikes of decreased amplitude, shorter duration, and increased sharpness as compared with NREM periods in each third of the night. The spike changes associated with REM sleep are similar to the alterations previously described as occurring coincidentally with attainment of seizure control and thus may reflect inherent modulation of epileptogenicity in synchrony with sleep cycles.     

Influence of ACTH therapy on overnight sleep polygrams in infantile spasms

Overnight sleep polygrams were recorded before and during therapy in nine patients with infantile spasms. Results showed that ACTH therapy increased the waking time and decreased rapid eye movement sleep. Thus it caused sleep disturbance in patients with infantile spasms. During ACTH therapy the number of rapid eye movements/min and the pulse rate decreased significantly. Body movements/min also decreased, but not significantly. These results suggest that ACTH therapy may inhibit functions of the central nervous system. The respiratory rate increased during ACTH and clonazepam therapy, probably in association with the decrease or the absence of seizures. These findings indicate the necessity for further studies on whether ACTH therapy is really of value in patients with infantile spasms, and show that if ACTH is given, the period of therapy should be as short as possible.     

The diagnostic value of power spectra analysis of the sleep electroencephalography in narcoleptic patients

ObjectiveManifestations of narcolepsy with cataplexy (NC) include disturbed nocturnal sleep – hereunder sleep–wake instability, decreased latency to rapid eye movement (REM) sleep, and dissociated REM sleep events. In this study, we characterized the electroencephalography (EEG) of various sleep stages in NC versus controls.MethodsEEG power spectral density (PSD) was computed in 136 NC patients and 510 sex- and age-matched controls. Features reflecting differences in PSD curves were computed. A Lasso-regularized regression model was used to find an optimal feature subset, which was validated on 19 NC patients and 708 non-NC patients from a sleep clinic. Reproducible features were analyzed using receiver operating characteristic (ROC) curves.ResultsThirteen features were selected based on the training dataset. Three were applicable in the validation dataset, indicating that NC patients show (1) increased alpha power in REM sleep, (2) decreased sigma power in wakefulness, and (3) decreased delta power in stage N1 versus wakefulness. Sensitivity of these features ranged from 4% to 10% with specificity around 98%, and it did not vary substantially with and without treatment.ConclusionsEEG spectral analysis of REM sleep, wake, and differences between N1 and wakefulness contain diagnostic features of NC. These traits may represent sleepiness and dissociated REM sleep in patients with NC. However, the features are not sufficient for differentiating NC from controls, and further analysis is needed to completely evaluate the diagnostic potential of these features.     

West Syndrome and its Related Epileptic Syndromes

Summary: The purpose of this project was to study the relationship between West syndrome (WS) and its related epileptic syndromes, and reconsider the nosological limits of WS. The electroclinical features of 45 patients who experienced spasms in series were investigated, as well as some features not common in patients with WS. All patients were mentally retarded. The patients were divided into three groups: Group 1 consisted of 12 patients with refractory epilepsies with onset in early infancy, group 2 consisted of 5 patients with symptomatic localization-related epilepsies associated with spasms in series, and group 3 consisted of 28 patients with generalized epilepsies who had spasms in series after age 2 years. Partial seizures were the dominant symptom throughout the clinical course and spasms in series associated with atypical hypsarrhythmia appeared transiently during infancy in a significant number of the patients in group 1. In group 2, complex partial seizures (CPS) were the main seizure type and hypsarrhythmia was not observed during the clinical course. The EEGs in group 3 patients showed diffuse slow spike-waves or multifocal epileptic discharges in all but 1 patient. The EEG of the remaining patient still showed hypsarrhythmia at age 8 years. Therefore, group 1 patients should be classified as having WS although cortical mechanisms play a critical role in the occurrence of their seizures. Group 2 patients should be considered as having a type of localization-related epilepsy even though they share a similar pathophysiological mechanism with group 1. In group 3, 1 patient whose EEG still showed hypsarrhythmia was classified as having WS. The other patients should be classified as having generalized epilepsies other than WS.     

Participation of histaminergic H1 and noradrenergic alpha 1 receptors in orexin A-induced wakefulness in rats

The participation of histaminergic H(1) and noradrenergic alpha(1) receptors in orexin A-induced wakefulness was studied by examining the sleep-wakefulness cycle in rats. Intracerebroventricular infusion of orexin A (1 nmol) caused an increase in the wakefulness state, while non-rapid eye movement sleep (NREM sleep) and rapid eye movement sleep (REM sleep) states were decreased. Prazosin (150 nmol) showed no significant antagonistic effect on the orexin A-induced increase in the wakefulness state and decrease in NREM and REM sleep. On the contrary, pyrilamine (150 nmol) was effective in antagonizing orexin A-induced increase in wakefulness and decrease in NREM sleep. When prazosin (150 nmol) and pyrilamine (150 nmol) were simultaneously perfused into the lateral ventricle, an almost complete antagonistic effect was observed with the increase in the wakefulness state and decrease in NREM sleep. Orexin A (1 nmol) caused a significant decrease in the histamine contents of the cortex, hippocampus and hypothalamus, whereas noradrenaline contents were decreased only in the hypothalamus. From these results, we concluded that the arousal effect induced by orexin A occurs through histaminergic H(1) and noradrenergic alpha(1) receptors, although participation of the H(1) receptor was more important than the alpha(1) receptor.     

EEG findings in an adult with severe case of alobar holoprosencephaly

Holoprosencephaly is a category of congenital brain malformation that is frequently associated with epilepsy. Epileptic spasms and partial seizures are reported with a variety of electrographic ictal and interictal EEG findings. We report a case of severe alobar holoprosencephaly with cortical tissue limited to inferior–anterior–frontal areas and a thin mantle over the posterior areas, and no appreciable connective fibers to the subcortical structures. Interictal EEG consisted mainly of 2–3 Hz irregular delta activity during wakefulness and sleep. Clinical seizures had two different semiologies: (1) epileptic spasms lasting 0.5 s during state change and (2) prolonged tonic spasms lasting 5–8 s followed by appendicular clonic activity, abnormal nystagmoid eye movements and eye flutter lasting 5–8 s. Preceding the epileptic spasms, there was 1–2 s of electrodecrement in the EEG. During prolonged tonic spasms there was also electrodecrement in the EEG. No other electrographic activity was seen. Due to lack of any appreciable connecting fibers between cortical and subcortical structures, these findings suggest an increase in brain stem excitability with inefficient (or lack of) cortical modulation as a possible underlying mechanism for epileptic spasms in this patient.     

Polysomnographic characteristics of young manic patients. Comparison with unipolar depressed patients and normal control subjects.

Although sleep disturbance is a prominent feature of mania, its polysomnographic (PSG) features have received little study. To investigate more systematically the PSG characteristics of sleep in mania, all-night PSG evaluations were performed for two to four consecutive nights in 19 young manic patients (age range, 18 to 36 years), 19 age-matched patients with major depression, and 19 age-matched normal control subjects. Manic and depressed patients displayed nearly identical profiles of PSG abnormalities compared with normal control subjects, including disturbed sleep continuity, increased percentage of stage 1 sleep, shortened rapid eye movement latency, and increased rapid eye movement density. These results are similar to those reported in previous studies of major depression, and they are consistent with the possibility that the sleep disturbance in mania and major depression is caused by the same mechanism.     

Electroencephalographic sleep in psychotic depression. A valid subtype?

Electroencephalographic (EEG) sleep patterns were examined in 27 psychotic and 79 nonpsychotic subjects with major depression to evaluate the validity of the psychotic-nonpsychotic subtype dichotomy. Sleep in psychotic depression was characterized by increased wakefulness, decreased rapid eye movement (REM) sleep percentage, and decreased REM activity even after controlling for clinical differences in age, severity, and agitation. Psychotic depressive subjects also were more likely to have extremely short sleep-onset REM latencies. In psychotic depression EEG sleep varied as a function of total illness duration. Patients with recent-onset syndromes had profiles characterized by marked initial insomnia, increased stage 1 sleep percentage, and long REM latency; patients with illnesses of longer duration had extremely short REM latencies. Demonstration of selected EEG sleep variables discriminating between psychotic and nonpsychotic depression further supports psychotic depression as a distinct subtype of major affective disorder.     

Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy

BACKGROUND: Patients with brief, complex partial seizures frequently suffer from tiredness and decreased productivity that continue well beyond the postictal period. A possible explanation is that seizures, even when occurring during the day, disrupt sleep the following night. OBJECTIVE: To determine the effect of temporal lobe complex partial seizures on sleep structure and daytime drowsiness. METHODS: Patients with temporal lobe epilepsy were admitted for video-electroencephalography monitoring. All-night polysomnography was recorded under the following 3 conditions: seizure free, seizure during the day before the recording, and seizure during the recording. Percentage of time in each sleep stage, sleep efficiency, and time to first and second rapid eye movement (REM) period were compared for seizure vs control conditions. Daytime drowsiness was also measured, using a modified maintenance of wakefulness test and 2 subjective drowsiness tests. RESULTS: Daytime seizures reduced REM from 18%+/-1% to 12%+/-2% (P = .003). Night seizures reduced REM from 16%+/-1% to 6.8%+/-2% (P<.001). Night seizures also significantly reduced stages 2 and 4 while increasing stage 1 sleep. Night seizures, but not day seizures, significantly reduced sleep efficiency, increased time to first REM period, and increased drowsiness as measured by the maintenance of wakefulness test. CONCLUSIONS: Temporal lobe complex partial seizures decrease REM sleep, particularly when occurring during sleep but also when occurring on the previous day. This may, in part, be responsible for the prolonged impairment of functioning that some patients report following seizures.     

Effects of clozapine on sleep measures and sleep-associated changes in growth hormone and cortisol in patients with schizophrenia.

There have been limited reports on the effect of the atypical anti-psychotic agent clozapine on sleep measures and hormone secretion. The goal of this study was to determine the type, rate, and extent of changes in sleep measures and nighttime secretion of growth hormone (GH) and cortisol during clozapine treatment. Five schizophrenic patients (age: 32.4+/-7.4) and five age- and sex-matched normal subjects (age: 33.0+/-5.1) underwent nocturnal polysomnography (NPSG) before clozapine therapy (S1), and during early and late clozapine therapy (S2 and S3). Serum GH and cortisol levels were monitored during each NPSG. NPSG findings showed that the mean total sleep time, sleep efficiency, and duration of awakening were increased at S2, and maintained until S3. The mean amounts of stage 2 sleep at S2 and S3 increased significantly compared with that of S1. In unmedicated schizophrenic patients, the mean plasma GH level in rapid eye movement sleep was lower than during the waking stage, and the mean level of plasma cortisol was higher during the waking stage. Plasma cortisol levels did not differ between control subjects and patients at any time, but clozapine treatment decreased plasma cortisol levels at S2 compared with S1 and S3. Plasma GH levels were unchanged by clozapine treatment. Clozapine improved sleep continuity and increased stage 2 sleep time from the beginning of therapy. These effects were maintained through at least 7 weeks of therapy. However, clozapine did not affect the relationship of plasma GH and cortisol levels with sleep stages in schizophrenic patients.     

The influence of sex, age and sleep/wake state on characteristics of periodic leg movements in restless legs syndrome patients.

Restless legs syndrome (RLS) patients experience periodic stereotyped leg movements while awake and during sleep. The aim of the present study was to measure the effects of sex, age and the sleep/wake state on several characteristics (frequency, duration and periodicity) of these periodic leg movements (PLM). One hundred unrelated patients diagnosed with primary RLS were studied. During wakefulness, frequency of PLM increased and the mean inter-movement interval decreased with advancing age. The modal value of inter-movement interval distribution was also altered suggesting that aging influences rhythm-generation mechanisms. Sleep/wake states had a profound effect on leg movement characteristics. Movements of longer duration were seen during wakefulness, while REM sleep was characterized by the shorter duration and the lowest frequency of PLM, due most likely to the inhibition of spinal motoneurons that prevails in REM sleep. States of vigilance also modulated the periodicity of PLM. Intervals were shorter during wakefulness and increased progressively from stage 1 to stage 2 sleep, and to slow wave sleep (SWS). During REM, the duration of sleep intervals returned to values obtained in stage 1 sleep; these two stages sharing similar patterns of EEG activity. These results indicate that a single state dependent mechanism may be responsible for the periodicity of PLM noted both during sleep and wakefulness.     

Eye movement-related modulation of trigeminal neuron activity during active sleep and wakefulness

The amplitude of electrically-evoked mass action potentials recorded in the spinal cord and brainstem has been reported to decrease only during eye movement events of active sleep. In contrast, we have reported that the response of trigeminal sensory neurons to peripheral stimuli is modulated throughout the behavioral state of active sleep. It is unclear whether eye movement events contribute to the modulation of trigeminal sensory neuron activity during active sleep. In the present study, eye movement events were demarcated in order to investigate how these events affect peripheral input to trigeminal sensory neurons in chronic, intact, behaving cats. When compared with wakefulness, the mean response of 45 trigeminal sensory neurons to low-intensity electrical stimulation of the canine tooth pulp was significantly suppressed by 28% during periods of active sleep where no eye movement activity was present and by 41% during periods of active sleep with eye movement events. Hence, during active sleep, tooth pulp-evoked responses were significantly decreased by 16% during eye movement events when compared with non-eye movement active sleep. To investigate whether presynaptic inhibition played a role in this phenomenon, the excitability of eight individual tooth pulp afferent terminals during eye movement periods was compared with non-eye movement periods of active sleep. No evidence of eye movement-related depolarization of tooth pulp terminals was detected. When compared to wakefulness, the responses of six trigeminal sensory neurons to air puff stimulation of facial hair mechanoreceptors were significantly increased by 96% during periods of active sleep where no eye movement activity was present but were significantly decreased by 15% during eye movement events when compared with non-eye movement active sleep. The results of the present study indicate that neuronal responses to both tooth pulp and facial hair mechanoreceptor stimulation are significantly attenuated during eye movement events of active sleep.     

Sleep-Wakefulness Alterations in Amygdala-Kindled Rats

Summary: Purpose: Our aim was to study the relation between epilepsy and sleep–wakefulness cycles in the amygdalakindling model of temporal lobe epilepsy.
Methods: Adult male Wistar rats were electrically kindled through bipolar electrodes implanted in the anterior amygdala. Polysomnographic recordings were taken before and after kindled seizures for 6 h. For the studies on the effects of a single, full-blown seizure, recordings were taken immediately after the seizure and daily thereafter until the recordings returned to baseline values. For studies on the effects of five full-blown seizures, recordings were taken immediately after the fifth seizure and then on day 1, 2, 3, 5, 7, 14, 21, and 28.
Results: Polysomnographic recordings taken immediately after the first full-blown seizure revealed an initial increase in the duration of deep slow-wave sleep (SII), a decrease in the light slow-wave sleep (SI) stage of non-rapid eye movement (NREM) sleep, and a decrease in the quiet wakefulness (W,) stage of wakefulness. All these parameters returned to baseline values after 24 h. The duration of rapid eye movement (REM) sleep increased and returned to the baseline value after 48 h. Five consecutive full-blown seizures caused an increase in the duration of SII from the day the seizures occurred until day 28, whereas the duration of SI decreased for 72 h. The duration of REM sleep, decreased only on the day of the seizures and day 1, while decreases in the number of REM episodes were observed on the day of the seizure, day 2 and day 14.
Conclusions: Our study indicates that even a single, full-blown seizure can cause alterations in the architecture of sleep–wakefulness cycles for a short duration, and that multiple seizures produce long-term effects.     

Sleep disorders in Wilson’s disease

Background: Wilson’s disease (WD) is an autosomal recessive inherited disease with copper accumulation; neurodegeneration is associated with dopaminergic deficit. The aim of the study is to verify sleep co‐morbidity by questionnaire and objective sleep examinations (polysomnography, multiple sleep latency test). Methods: Fifty‐five patients with WD (22 hepatic, 28 neurological, five asymptomatic form) and 55 age‐ and sex‐matched control subjects completed a questionnaire concerning their sleep habits, sleep co‐morbidity, Epworth sleepiness scale (ESS), and answered screening questions for rapid eye movement (REM) behaviour disorder (RBD‐SQ). Twenty‐four patients with WD and control subjects underwent polysomnographic examination. Results: Unlike the controls, patients with WD were more prone to daytime napping accompanied by tiredness and excessive daytime sleepiness, cataplexy‐like episodes and poor nocturnal sleep. Their mean ESS as well as RBD‐SQ was higher than that of the controls. Total sleep time was lower, accompanied by decreased sleep efficiency and increased wakefulness. Patients with WD had lower latency of stage 1 and stage 2 of non‐rapid eye movement (NREM) sleep and less amount of NREM sleep stage 2. One‐third of the patients with WD were found to have short or borderline multiple sleep latency test (MSLT) values independent of nocturnal pathology (sleep apnoea, periodic leg movements and/or restless leg syndrome). Conclusions: Patients with WD often suffer from sleep disturbances (regardless of the clinical form). The spectrum of sleep/wake symptoms raises the suspicion that altered REM sleep function may also be involved.     

Quantification of diffuse and focal delta activity in hypsarrhythmia

In order to determine whether or not there is any correlation between the various aspects of hypsarrhythmia and the etiology, we studied one of the major components of this pattern, delta activity, in patients with infantile spasms. In 3 different etiologic groups of patients (prenatal, perinatal and cryptogenic) we divided this activity into 2 types: diffuse (DSA) and focal slow activity (FSA). These two activities were quantified in 3 consecutive minute periods of wakefulness, drowsiness and slow sleep. The mean values of DSA and FSA remained unchanged during the 3 consecutive minute periods and in the different stages of vigilance. DSA and FSA differed significantly according to the etiology, with a predominance of DSA in the cryptogenic group and of FSA in the prenatal group. DSA was not correlated with either sex or age. The focal component seems to be related to brain lesions, whereas the diffuse component appears to be as a stereotyped neurophysiological phenomenon independent of brain lesions, sex or age.     

The neurobiology,diagnosis, and treatment of narcolepsy

Narcolepsy is a common cause of chronic sleepiness distinguished by intrusions into wakefulness of physiological aspects of rapid eye movement sleep such as cataplexy and hallucinations. Recent advances provide compelling evidence that narcolepsy may be a neurodegenerative or autoimmune disorder resulting in a loss of hypothalamic neurons containing the neuropeptide orexin (also known as hypocretin). Because orexin promotes wakefulness and inhibits rapid eye movement sleep, its absence may permit inappropriate transitions between wakefulness and sleep. These discoveries have considerably improved our understanding of the neurobiology of sleep and should foster the development of rational treatments for a variety of sleep disorders.