Pharmacodynamics of temazepam in primary insomnia: assessment of the value of quantitative electroencephalography and saccadic eye movements in predicting improvement of sleep.

BACKGROUND AND OBJECTIVE: Quantitative electroencephalographic parameters and saccadic eye movements are frequently used as pharmacodynamic measures of benzodiazepine effect. We investigated the relationship between these measures and the hypnotic effect. METHODS: The correlation between the pharmacodynamic measures and sleep quality was determined in 21 patients with primary insomnia. The pharmacokinetic-pharmacodynamic relationships were characterized after administration of 20 mg oral temazepam. The hypnotic effect was determined on the basis of polysomnographic sleep recordings and a subjective sleep evaluation questionnaire. Correlations between pharmacodynamic measures and the improvement of sleep were investigated. RESULTS: The pharmacokinetic-pharmacodynamic relationships for the parameters derived from electroencephalography and saccadic eye movements showed considerable interindividual variability. Administration of temazepam led to a significant improvement in the objective parameters sleep period efficiency, wake time after sleep onset, and sleep efficiency and in the subjective assessment of sleep quality. No significant correlations were observed between the pharmacokinetic-pharmacodynamic-derived parameters and the improvement in objective or subjective sleep parameters. CONCLUSION: In subjects with primary insomnia the administration of 20 mg oral temazepam results in changes in both the pharmacodynamic measures and in quality of sleep. No individual correlations between the pharmacodynamic measures and quality of sleep were observed. We concluded that the investigated pharmacodynamic measures are of value in the first assessment of clinical efficacy and for the selection of the dose(s) to be investigated in subsequent trials that aim at showing clinical efficacy. However, the conclusive quantification of clinical efficacy should be performed only on the basis of the clinical end point itself.

Sleep disruption in Parkinson's disease. Assessment by continuous activity monitoring.

OBJECTIVE: To assess differences in activity and immobility during sleep between patients with Parkinson's disease (PD) and healthy subjects and to evaluate the relations of clinical variables with the motor activity measures in patients with PD. DESIGN: Survey, case series. SETTING: University hospital outpatient neurology department and urban population in Leiden, the Netherlands. Motor activity was recorded during 6 successive nights at home with a wrist-worn activity monitor. PARTICIPANTS: Eighty-nine patients with PD and 83 age-matched healthy controls. MAIN OUTCOME MEASURES: For each subject, three mean measures reflecting activity or immobility during the nocturnal period were calculated. RESULTS: Compared with the healthy elderly subjects, patients with PD have an elevated nocturnal activity level and an increased proportion of time with movement, indicating a more disturbed sleep. The mean duration of nocturnal immobility periods was similar for both groups. This measure, however, did reflect the self-reported disturbed sleep maintenance in both groups. The daily dose of levodopa or the use of dopamine agonists in patients not receiving levodopa, rather than disease severity, proved to be the best predictors of nocturnal activity. CONCLUSIONS: We hypothesize that in mildly to moderately affected patients with PD, levodopa or dopamine agonists cause sleep disruption by their effects on sleep regulation. In more severely affected patients, the beneficial effects of these drugs on nocturnal disabilities that cause sleep disruption in PD prevail.

Simulation of human hypnograms using a Markov chain model.

A Markov chain model has been proposed as a mechanism that generates human sleep stages. A method for estimating the parameters of the model, i.e., the transition probabilities (rates) between sleep stages, has been introduced and applied to 95 hypnograms taken from 23 subjects. The rates characterize interindividual differences and nightly variations of the sleep mechanism, related to sleep-onset behavior, to the decreasing amount of slow wave sleep in the course of the night, and to the REM-NREM periodicity. The model simulates both probabilistic and the above-mentioned predictable dynamics of sleep, but only if these time-varying, individual rates are applied.

Age and gender affect different characteristics of slow waves in the sleep EEG.

Low-frequency EEG was analyzed quantitatively during 2 nights in 40 females and 34 males aged 26 to 101 years. Analyses were based on Rechtschaffen and Kales NREM sleep stages, on absolute low-frequency amplitude (i.e. power in the range of 0.2-2.0 Hz) and on low-frequency continuity. The latter parameter describes how much (0-100%) of the current slow-wave activity is continued in the near-future EEG. Such continuation can occur through closed loops in the underlying neuronal network and cells. These loops are slow, thus corresponding to slow-wave frequencies, and can consist of electrophysiological, chemical and/or other pathways. The continuity percentage then monitors the relative activity of these loops. It does not depend directly on absolute EEG amplitudes. All analyzed parameters, including amplitude-independent continuity, decreased substantially and significantly with increasing age. The amplitudes of low-frequency EEG in females were significantly and substantially (40%) larger than those in males. However, the amplitude-independent continuity percentage did not differ between the genders. These findings support the notion that gender-related anatomical differences have a general effect on EEG amplitude, including during slow-wave sleep. Aging, however, specifically affects the neurophysiological slow-wave-generating mechanism.

Alternative electrode placement in (automatic) sleep scoring (Fpz-Cz/Pz-Oz versus C4-A1).

The purpose of this study is to investigate whether the international standard electrode placement (C4-A1) can be replaced by an alternative placement (Fpz-Cz/Pz-Oz) in an automatic sleep monitoring system without losing Rechtschaffen and Kales (R-K) balances. Single night-sleep polygraphic recordings of 10 patients, screened in a clinical sleep disorder setting, were recorded simultaneously with both placements, and visual sleep classification was performed separately by two independent observers. Interobserver and interplacement agreement were evaluated by way of average (dis)agreement matrices and kappa values computed for overall and individual stage scoring. Interobserver agreement for both the test and the standard electrode placements and interplacement agreement for both observers were assessed as fair to good or excellent. Scoring differences were evaluated by the rank sign test applied to clinical and theoretical difference scores. It appears that the interplacement differences are about equal to the interobserver differences, except for a slight tendency for sleep to be scored in a deeper stage with the proposed alternative placement. The data are presented and discussed in relation to current literature concepts.

Ritanserin, a 5-HT2 receptor blocker, as add-on treatment in narcolepsy.

In a double-blind placebo-controlled trial, ritanserin (a 5-HT2 receptor blocker) 5 mg/day or placebo was added to the usual medication in 28 patients with narcolepsy during 4 wk. The effect was assessed by means of polysomnography, daily and weekly subjective evaluations, and Multiple sleep latency tests (MSLT). During the night ritanserin increased the amount of nonrapid eye movement slow wave sleep and reduced wakefulness after sleep onset. It improved the feeling of being refreshed in the morning after awakening and reduced subjective daytime sleepiness. The drug did not significantly influence sleep latency in the MSLT.

Ambulatory activity monitoring during sleep: an evaluation of internight and intrasubject variability in healthy persons aged 50-98 years.

The aim of this study was to assess the internight and intrasubject variability of nocturnal activity and immobility measures of 99 healthy subjects aged 50-98 years. Motor activity was recorded at home during 6 successive nights with a wrist-worn activity monitor. The occurrence of suprathreshold motor activity was recorded over 15-second epochs. For each subject, six mean measures reflecting activity or immobility during sleep and their coefficient of variation were calculated. Our results revealed no first-night effect or day-of-week effect of the activity and immobility measures over the 6 nights across all subjects. On the other hand, for all nocturnal activity and immobility measures, a considerable intrasubject variability across the 6 nights was found. Females had a greater intrasubject variability of the mean duration of immobility periods and the movement index than males. The intrasubject variability of all nocturnal activity and immobility measures across the successive age groups remains stable. These findings emphasize that although a first-night effect may be lacking, the intrasubject variability of activity and immobility measures across several nights may still be considerable.

Ambulatory monitoring of sleep-wakefulness patterns in healthy elderly males and females (greater than 88 years): the "Senieur" protocol.

OBJECTIVE: The study was designed to investigate sleep-wake patterns in healthy elderly men and women (greater than 88 years) using ambulatory recording techniques. DESIGN: Cross-sectional observations on 2 consecutive days. METHODS: Two consecutive 24-hour recordings were made. Each 30-second period of the recording was scored as characteristic of wakefulness, REM, and non-REM sleep (stages 1-4). SETTING: Interviews and recordings were done in the home of the elderly, not interfering with the habitual routine. PARTICIPANTS: Among eligible members of the "Senieur" protocol, screened for wellness, seven females (88-102 years) and seven males (88-98 years) volunteered to participate. MAIN OUTCOME MEASURES: Organization of sleep, sleep structure, and daytime mapping. RESULTS: There was no difference between the first and second night recording. Important gender differences were observed: males had significantly less total sleep, shorter REM latency, more transitions to wake from REM, less NREM 3 sleep, and virtually no NREM 4. Daytime napping, REM amount, and distribution did not show sex differences. Although the variability in the amount of napping was considerable, it occupied less than 10 percent of the total sleep time in both women and men. Daytime napping was unrelated to sleep characteristics. CONCLUSIONS: Ambulatory sleep-wake recordings allow an objective and critical evaluation of sleep function in normal aging. Interesting findings include a shift of REM sleep to the first part of the sleep period an increased cycle variability, and non-correlation of night-time sleep with daytime napping. In contrast to earlier findings in elderly persons, a polygraphic and subjective first-night effect was lacking.

Nocturnal activity and immobility across aging (50-98 years) in healthy persons.

OBJECTIVE: To measure the influence of age on measures of nocturnal activity and immobility in 100 healthy subjects aged 50 to 98 years. DESIGN: Cross-sectional study. SETTING: Urban population in Leiden. Recordings were performed at home while the subjects maintained their habitual 24-hour pattern of activities. PARTICIPANTS: 100 subjects without a history of major medical disorders and a normal neurological examination and performance-oriented assessment of gait (Tinetti). MEASUREMENTS: Motor activity was recorded during six successive nights with a wrist-worn activity monitor. The occurrence of supra-threshold motor activity was recorded over 15-second epochs. A questionnaire was used to evaluate sleep habits and the occurrence of sleep disturbances. Four mean measures reflecting activity or immobility during the nocturnal period were calculated for each subject. RESULTS: Only one out of four measures, (ie, the nocturnal proportion of time with movement, increased with age for females. For males, no age effects emerged. The mean duration of nocturnal immobility periods was higher in females than in males. Also, for females, the use of hypnotics increased with successive decades. Sex and the use of hypnotics were significantly related to the mean duration of immobility periods. CONCLUSION: If care is taken not to confound aging with illness, measures of nocturnal activity and immobility reveal only marginal effects of aging.

Subjective sleep characteristics of 1,485 males and females aged 50-93: effects of sex and age, and factors related to self-evaluated quality of sleep.

BACKGROUND: This epidemiologic study cross-sectionally examined the effects of sex and age on subjective characteristics of sleep and the factors related to self-evaluated sleep quality in a Dutch noninstitutionalized elderly population. METHODS: 1,692 sleep questionnaires were mailed to all attenders of the general practice serving Krimpen aan de Lek, The Netherlands, aged 50 or over. Both target population and responders (1,485 subjects) were virtually representative of the Dutch population regarding sex and age (50 +) characteristics. RESULTS: Overall, females reported significantly poorer quality of sleep, longer sleep latencies, more nighttime awakenings, less frequent napping, and more frequent use of sedative-hypnotic drugs when compared to males. Additionally, there was a female predominance in the prevalence of disturbed sleep onset and sleep maintenance, whereas a male predominance was observed in the prevalence of excessive daytime sleepiness. Across subjects, a significant age-related increment was found for sleep latency time and time spent in bed. The number of nighttime awakenings increased significantly with age only in males. No significant correlations were found between health status and sex, age, or subjective sleep quality. The most frequently reported causes of disturbed sleep onset and sleep maintenance were worries and nocturia, respectively. Subjective quality of sleep was mostly associated with self-estimated sleep latency. CONCLUSIONS: Our findings extend those of previous epidemiologic studies reporting that sleep disorders are common in the general elderly population. Future studies should further elucidate the nature and extent of geriatric sleep disorders to satisfy the increasing need for its accurate diagnosis and treatment.

Ambulatory first night sleep effect recording in the elderly.

The concept of a first night effect on sleep patterns, specifically in relation to age is a controversial topic in the literature. Our data are obtained during two consecutive 24-h ambulatory home sleep-wake recording in 10 elderly persons with a mean age of 85.5 years. Polysomnographic recordings indicated that a first night effect is present in old age, even using home recording, and that several types of insomnia can be differentiated, stressing that sleep cycle parameters should be taken into account. It is suggested that the first night effect is a 'miniature' replication of a psychophysiological insomnia.

Multi-centre comparison of five eye movement detection algorithms.

Although various investigators have suggested algorithms for the automatic detection of eye movements during sleep, objective comparisons of the proposed methods have previously been difficult due to different recording arrangements of different investigators. In this study the results of five eye movement detection algorithms applied to the same data were compared to visually scored data. The percentages of true and false detections are given for various threshold levels in rapid and slow eye movement detections. The methods gave best results when they were used with the same electrode montage they were designed for but the performance decreased when other montages were used. Subtracting the cross-talk of EEG delta activity improved the correctness of eye movement detections.

Alpha coma.

Six personal cases of alpha coma are reported: 3 following a cerebrovascular accident and 3 resulting from cerebral concussion. Two patients survived. On the basis of differences in pathogenesis, EEG characteristics and prognosis, the following classification is proposed: alpha coma resulting from brain stem vascular accident; cerebral concussion; diffuse cerebral hypoxia; drug intoxication. The clinical course of each of the classes of alpha coma is outlined. The alpha coma state is not restricted to cases with structural brain stem lesions c.q. lesions of the pontomesencephalic region.

Periodic nocturnal myoclonus in a patient with hyperexplexia (startle disease).

The periodic nocturnal myoclonus of a patient with hyperexplexia has been studied. Evidence has been given that the jerks are spontaneous arousal reactions. The temporal characteristics of the jerks have been analysed. The jerks appear to be correlated with the respiratory rhythm and the data suggest a correlation of the jerks with circulatory and respiratory higher order waves. The results are discussed with relation to the literature concerning spontaneous sleep jerks.

Respiration during sleep in Huntington's chorea.

In view of recent reports on lower brainstem dysfunction in Huntington's chorea, we studied respiration during sleep in 12 patients with Huntington's chorea (HC) and in controls. There were no statistically significant differences between patients and controls with respect to apnea periods, respiratory frequency and time elapsed between minimal and maximal value of the respiratory curve. No statistically significant differences in respiratory variability were observed between patients and controls. In the present study, no indication was found for dysfunction of lower brainstem structures involved in respiration in HC.

The validity of the Dutch Sleep Disorders Questionnaire (SDQ).

The Sleep Disorders Questionnaire (SDQ) is a 176-item questionnaire designed to diagnose the presence of common sleep disorders. This study set out to assess the validity of a Dutch translation of the SDQ. Scores on 145 questionnaires were analyzed. A cluster analysis of these scores revealed the following clusters: healthy, depression, insomnia, narcolepsy, and apnea. The cluster classification proved correct for 67% of the subjects, as determined on the basis of polysomnography. These results show that the Dutch SDQ is a reasonably valid instrument for diagnosing sleep disorders.

Analysis of a sleep-dependent neuronal feedback loop: the slow-wave microcontinuity of the EEG.

Increasing depth of sleep corresponds to an increasing gain in the neuronal feedback loops that generate the low-frequency (slow-wave) electroencephalogram (EEG). We derived the maximum-likelihood estimator of the feedback gain and applied it to quantify sleep depth. The estimator computes the fraction (0%-100%) of the current slow wave which continues in the near-future (0.02 s later) EEG. Therefore, this percentage was dubbed slow-wave microcontinuity (SW%). It is not affected by anatomical parameters such as skull thickness, which can considerably bias the commonly used slow-wave power (SWP). In our study, both of the estimators SW% and SWP were monitored throughout two nights in 22 subjects. Each subject took temazepam (a benzodiazepine) on one of the two nights. Both estimators detected the effects of age, temazepam, and time of night on sleep. Females were found to have twice the SWP of males, but no gender effect on SW% was found. This confirms earlier reports that gender affects SWP but not sleep depth. Subjectively assessed differences in sleep quality between the nights were correlated to differences in SW%, not in SWP. These results demonstrate that slow-wave microcontinuity, being based on a physiological model of sleep, reflects sleep depth more closely than SWP does.

Ambulatory monitoring in sleep apnoea presenting with nocturnal episodic phenomena.

Episodic nocturnal phenomena represent a separate cluster of disturbances within the classification of sleep disorders. The reported case history covers paroxysmal signs occurring secondary to a REM-dependent mixed sleep apnoea syndrome. The pathophysiology of similar episodes in elderly (non)epileptic patients is discussed. Ambulatory monitoring is an appropriate technique for investigation if respiratory and motor activity, and EEG and ECG are recorded simultaneously.

Management in the carpal tunnel syndrome: clinical and electromyographical follow-up in 62 patients.

Sixty-two patients suffering from carpal tunnel syndrome (CTS) were followed for an average period of 36 months, and clinical and electromyographical assessments were carried out repeatedly before and after treatment. Treatment was either conservative (25 patients) or surgical (37 patients). The use of repeated electromyographical examinations to supplement the clinical data proved to reveal more objective information on which to determine the choice of therapy. This type of management leads to the choice of medical treatment for patients showing a decrease in an initially prolonged distal motor latency time of the median nerve, whereas surgery may be preferred in patients showing progressively increasing latency times. In this way, a valuable guideline, i.e. the correlation between distal latency times and natural course, can provide a more objective basis for management of CTS patients. The similar final outcome in both groups in our opinion favours the proposed management.

Long-term sleep deprivation as a game. The wear and tear of wakefulness.

We report here the first sleep deprivation study done on a group of 5 healthy students (1 female, 4 males, 23-24 years of age) while playing a game (Triviant). In 2 persons an EEG was recorded for 6 consecutive 24 h periods with an ambulatory monitor from the baseline night until 72 h after deprivation. The baseline night showed normal hypnograms. The students were deprived of sleep for 65 h following the baseline night. Sleep deprivation was complete and resulted in bradyphrenia, loss of memory and contact with reality, ataxia, decrease in body temperature and loss of body weight. The main sign of recuperation was a strongly increased slow-wave sleep synchronization during the first recuperation period (day-time sleep) only. There were no signs of REM rebound.