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Background and Purpose: Treatment of chronic insomnia with nightly hypnotics is efficacious, but discontinuation is recommended after 1 month, less than the average disease duration. This study was undertaken to determine the efficacy of intermittent administration. Patients and Methods: A double-blind study was carried out on 8 patients (age, 32.8 ± 9 years; 3 men) with primary sleep maintenance insomnia longer than 1 month. Polysomnography of conventional sleep parameters, cyclic alternating patterns (CAPs), and arousals was performed. Perception of sleep quality was assessed on a visual analog scale. After an adaptation night, baselines were recorded followed by 6 consecutive nights of alternating treatment with zolpidem (10 mg) or placebo. Results: Significant improvements on baseline values (P < 0.0001) were observed on all 3 active treatment nights for total sleep time, sleep efficiency, CAP time, CAP rate, subtype A2, arousals, and arousal index. Deep non-rapid eye movement sleep increased with the second and third doses of active treatment (P < 0.0001). Rapid eye movement sleep increased during the last 3 polysomnographic recordings (P < 0.014). Sleep quality (visual analog scale) improved on all nights after the initial dose of active treatment (P < 0.0001). There was no evidence of rebound insomnia with placebo. Conclusions: Intermittent treatment with zolpidem in primary insomnia patients improves CAP parameters and arousals, as well as sleep duration and quality, in the absence of rebound insomnia.

In each non-REM (NREM) sleep stage, the aggregation of the arousal-related phasic events permits identification of periods of arousal fluctuation (cyclic alternating pattern or CAP) and periods of long-lasting arousal stability (non-CAP or NCAP). As the ratio CAP time to NREM sleep time (CAP/NREM) measures the instability of arousal during sleep, any perturbing event determines an increase of CAP/NREM. On the basis of these premises, 6 healthy volunteers underwent 5 sleep recordings at increasing intensities of sound pressure level (basal condition followed by continuous white noise at 45 dBA, 55 dBA, 65 dBA and 75 dBA, respectively). Besides a remarkable enhancement of CAP/NREM (P less than 0.00001), acoustic perturbation induced a significant linear increase of waking time after sleep onset, stage 2, NREM sleep, stage shifts and a significant linear decrease of stage 4, deep sleep, REM sleep and total sleep time. At each step of environmental disturbance, the values of the CAP ratio were consistent with the gradual changes of sleep organization. Although the Multiple Sleep Latency Test was unremarkable during the day following the sleep recording, CAP/NREM was significantly correlated with the personal evaluation of sleep quality (P less than 0.01). Through this model of transient situational insomnia it was possible to outline different degrees of subjective complaint depending on 3 ranges of CAP/NREM. A crucial role of CAP in the pathophysiological mechanisms of clinical insomnia is hypothesized.

We describe the case of a patient with nocturnal frontal lobe epilepsy, presenting with periodic leg movements during sleep and complaining of excessive daytime sleepiness. With the support of intracerebral electroencephalogram recordings and the corroboration of the postoperative outcome, periodic leg movements during sleep and excessive daytime sleepiness appeared to be associated to enhanced arousal instability induced by by recurrent epileptic discharges not detectable on scalp electroencephalogram.

There is growing evidence that cyclic alternating pattern (CAP) and arousals are woven into the basic mechanisms of sleep regulation. In the present study, the overnight sleep cycles (SC) of 20 normal subjects were analyzed according to their stage composition, CAP rate, phase A subtypes and arousals. Individual SC were then divided into 10 normalized temporal epochs. CAP parameters and arousals were measured in each epoch and averaged in relation to the SC order. Subtypes A2 and A3 of CAP in non-rapid eye movement (NREM) sleep, and arousals, both in REM and NREM sleep when not coincident with a A2 or A3 phases, were lumped together as fast electroencephalographic (EEG) activities (FA). Subtypes A1 of CAP, characterized by slow EEG activities (SA), were analyzed separately. The time distribution of SA and FA was compared to the mathematical model of normal sleep structure including functions representing the homeostatic process S, the circadian process C, the ultradian process generating NREM/REM cycles and the slow wave activity (SWA) resulting from the interaction between homeostatic and ultradian processes. The relationship between SA and FA and the sleep-model components was evaluated by multiple regression analysis in which SA and FA were considered as dependent variables while the covariates were the process S, process C, SWA, REM-on and REM-off activities and their squared values. Regression was highly significant (P < 0.0001) for both SA and FA. SA were prevalent in the first three SC, and exhibited single or multiple peaks immediately before and in the final part of deep sleep (stages 3 + 4). The peaks of FA were delayed and prevailed during the pre-REM periods of light sleep (stages 1 + 2) and during REM sleep. SA showed an exponential decline across the successive SC, according to the homeostatic process. In contrast, the distribution of FA was not influenced by the order of SC, with periodic peaks of FA occurring before the onset of REM sleep, in accordance with the REM-on switch. The dynamics of CAP and arousals during sleep can be viewed as an intermediate level between cellular activities and macroscale EEG phenomena as they reflect the decay of the homeostatic process and the interaction between REM-off and REM-on mechanisms while are slightly influenced by circadian rhythm.

Publisher Summary This chapter describes the cyclic alternating pattern (CAP) in human sleep. The CAP is a specific type of periodic activity in which both phase A and phase B can range between 2–60 seconds. Phase A and the following phase B compose a CAP cycle. In the history of EEG practice, CAP was initially considered as an EEG sign of cerebral disturbance. A prolonged cyclic alternation of high-voltage slow waves (phase A) and low-voltage irregular activity (phase B) can be recorded in comatose patients and correlates with the clinical outcome. In lighter stages of coma, the A phases are closely related to hyperventilation and increased pulse rate and can be associated with greater muscle activity, restlessness and pressure variations of the cerebrospinal fluid. In contrast, autonomic and muscle activities are attenuated during the B phases. This two-fold behavior indicates during CAP the comatose patient shifts repeatedly between more aroused (during phase A) and less aroused (during phase B) states that entrain also vegetative and motor functions under a common oscillatory process.

Objective: To define a unified method for the automatic recognition and quantitative description of EEG phasic events of sleep microstructure occurring during NREM sleep, particularly arousals, phase A subtypes of cyclic alternating pattern and spindles. Methods: The NREM sleep EEG of 10 normal young subjects was examined in order to recognize formal phasic events of sleep microstructure. The following 'formal' events (i.e. events defined exclusively on the basis of automatic analysis criteria) were classified: arousals, A1-phases (A-phases not including arousals) and A2- and A3-phases (A-phases including arousals). Spindle bursts, corresponding to visually recognized spindles, were also formally defined. The identification of these events was carried out following a three-step procedure: (1) computation of band-related descriptors derived from the EEG signal, (2) introduction of suitable thresholds and (3) application of simple logical principles, i.e. an exclusion principle and an overlapping principle. Results: Formal A-phases, arousals and spindle bursts showed spectral characteristics which were consistent with visual inspection. The value of the parameter Correctness for the recognition of the A-phases was 83.5%. In particular, the different physiological distribution of the A-phases in Stage 2 preceding slow wave sleep with respect to Stage 2 preceding REM sleep was confirmed. Conclusions: The proposed method provides a unified quantitative approach to the study of sleep microstructure. Visually defined events can be reliably identified by means of automatic recognition. (C) 2004 Elsevier B.V. All rights reserved.

Objective : Polysomnographic (PSG) measures consistently reflect poor sleep quality and effective treatment in insomniac patients. Methods : The PSG findings of 47 patients (18 M and 29 F, 42.5±10 years) meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for a diagnosis of primary insomnia were compared with those of 25 age- and gender-balanced healthy subjects (controls) without sleep complaints. After one adaptation night to the sleep lab, each patient underwent two randomized double-blind PSG recordings. Twenty-four patients followed a placebo-drug sequence and 23 a drug-placebo succession. Active treatment consisted of widely used hypnotic drugs, i.e. zolpidem, triazolam, zopiclone, brotizolam. Conventional PSG measures, electroencephalogram (EEG) arousals and CAP variables (including phase A subtypes) were quantified and statistically analyzed. Results : Compared to controls, insomniac patients under placebo showed a significant increase of CAP rate, subtypes A1 and A2, EEG arousals, nocturnal wakefulness and stage 1, associated with reduced values of total sleep time and slow wave sleep (stages 3 and 4). In insomniac patients, sleep quality was significantly improved by hypnotic treatment. Compared to placebo, active medication significantly reduced CAP rate, subtypes A1 and A2, but had only marginal effects on subtypes A3 and on EEG arousals. Under hypnotic treatment total sleep time, nocturnal awakenings, stage 1 and slow wave sleep recuperated normal values. The most significant correlation between sleep quality and PSG variables was found for CAP rate ( P Conclusions : PSG investigation extended to CAP variables and EEG arousals can be an important procedure for the diagnosis of primary insomnia and evaluation of treatment efficacy.

Insomnia affects 30-35% of people living in developed countries. The impact of insomnia on daytime functioning and its relationship with medical and psychiatric illnesses necessitate early treatment to prevent insomnia becoming persistent and to avoid the development of complications. However, pharmacological strategies must achieve a balance between sedative and adverse effects. In the last 30 years, benzodiazepines have been the preferred drugs for the treatment of insomnia. Benzodiazepines act nonselectively at two central receptor sites, named omega(1) and omega(2), which are located in different areas of the CNS. The sedative action of benzodiazepines is related to omega(1) receptors, whereas omega(2) receptors are responsible for their effects on memory and cognitive functioning. According to their pharmacokinetic profile, benzodiazepines can be classified into three groups: short half-life (3 hours), medium half-life (8-24 hours) and long half-life (24 hours). The newer non-benzodiazepine agents zopiclone, zolpidem and zaleplon have a hypnosedative action comparable with that of benzodiazepines, but they display specific pharmacokinetic and pharmacodynamic properties. These three 'Z' agents all share a short plasma half-life and limited duration of action. In addition, these agents are selective compounds that interact preferentially with omega(1) receptors (sedative effect), whereas benzodiazepines also interact with omega(2) receptors (adverse effects on cognitive performance and memory). Zaleplon is characterised by an ultrashort half-life (approximately 1 hour). Zolpidem and zopiclone have longer half-lives (approximately 2.4 and 5 hours, respectively). These properties, together with the low risk of residual effect, may explain the limited negative influences of these agents on daytime performance. Psychomotor tasks and memory capacities appear to be better preserved by non-benzodiazepine agents than by benzodiazepines. When present, cognitive deficits almost exclusively coincide with the peak plasma concentration. In particular, impairment can emerge in the first hours after drug administration, whereas psychomotor and memory tests carried out 7-8 hours later (i.e. in the morning) generally show no relevant alterations. As with benzodiazepines, the three 'Z' non-benzodiazepine agents should be used for a limited period, even in chronic relapsing conditions. Further evaluation is needed of the safety of hypnosedative medications in the long-term management of insomnia.

This article reviews the 15 years of studies conducted on the cyclic alternating pattern (CAP), the electro- encephalogram (EEG) marker of arousal instability during sleep. Starting from the limits and drawbacks of conventional sleep parameters (macrostructure), investigation of the underground world (microstructure) is extensively carried out with particular attention to K-complexes and other arousal-related phasic events of non-rapid eye movement (NREM) sleep. The continuity between conventional and non-conventional arousals is stressed in the light of autonomic function and motor activity evidence. The similarities and differences between CAP and arousals are thoroughly illustrated as well as the putative biological bases of these phenomena. The oscillatory nature of CAP, the involvement of CAP in the modulation of EEG synchrony, the sleep-maintenance properties of CAP in response to arousing stimuli, the clinical applications of CAP parameters and the promising availability of automatic scoring systems are highlighted.

Introduction Restless legs syndrome (RLS) is a frequent pathology, yet underrated and underestimated, affecting inasmuch as 5–10% of the population as a whole. However the pathophysiology has not been completely understood. The dopaminergic system has certainly a primary role, and some studies have highlighted a condition of spinal hyper-excitability. The aim of our study is to explore this hypothesis throughout the electrophysiological evaluation of the spinal and peripheral nervous system in primitives RLS patients. Materials and methods Among the patients affected by primitive RLS admitted to our Sleep Centerlab, we selected 15 women, and compared them with 17 control subjects of the same sex and age. All subjects had undergone ENG evaluation to exclude any secondary causes of lower limb paresthesia and to evaluate spinal excitability. According to a previous study, we considered two parameters which can be easily extracted from the routine tests normally carried out in the neurophysiopathology labs, the duration of F waves (FWD) of the Internal Popliteal (IPN) and ulnar nerves, and the relationship between FWD and the duration of the corresponding CMAP (CMAPD). Results None of the subjects (RLS and controls) included in our study presented alterations in the nerve conduction velocity. Compared to the control group, significantly higher values were found in the RLS patients for the FWD/CMAPD ratio average (p 0.001 test Mann–Whitney) and for the FWD average for both nerves ulnar (p 0.05 unpaired t-test) and IPN (p 0.01 unpaired t-test). Conclusion The results of our study confirm the absence of peripheral involvement in primitive RLS, while they indicate a spinal motorneuronal hyper-excitability, which seems widespread, as both IPN and ulnar nerve stimulation indicators are altered. Such condition could be due mainly to an alteration of the modulation in the interneuronal system. Presently, RLS diagnosis is based exclusively on clinical criteria. The FWD/CMAPD ratio can help to shed light on the pathogenesis of RLS, and can be used as an instrumental diagnostic indicator, easily obtainable and useful especially in cases of lower leg discomfort at night of unclear interpretation. Acknowledgements The authors would like to thank Prof. F. Marrosu and Dr. M. Fraschini, University of Cagliari, Italy, and Prof. L. Parrino, University of Parma, Italy, for their important contribution.

This review summarises all the evidences about the influence of different vigilance states on the occurrence of spike wave discharge (SWD) in idiopathic generalised epilepsy (IGE) patients. Numerous converging observations showed that full REM-sleep and alert wakefulness exert strong inhibition. A critical zone of vigilance which is a transitional state between waking and non-REM (NREM) sleep, and NREM sleep and REM sleep, has a promoting effect on the absence type spike wave discharge. Spike wave discharges are associated with phasic arousals without awakening and are attached to oscillation son the microstructural level of sleep, perpetuated by cyclic arousal events known as 'cyclic alternating pattern' (CAP), especially within the critical zone, but also along the whole sleep process. More specifically SWD seems to be attached to the 'A-phase' of CAP which is a reactive one and reflects synchronised NREM sleep EEG elements, like K-complexes, spindles and delta groups. The more slow wave elements are found in phase A--like in subtype A1--the more the coincidence with SWD occurs, and the more it is characterised by fast rhythms--as in subtype A2 and A3--the less the association with SWD could be observed. Since subtype A1 is associated with the first sleep cycle and with the descending branches of cycles, it is concluded that SWD appear in those dynamic moments of vigilance level oscillations which were characterised by strong sleep-like answers to arousal influences in high sleep pressure periods of sleep cyclicity. These data harmonize with another line of evidence suggesting that SWD represent the epileptic variant of the complex thalamocortical system function which is the substrate of NREM sleep EEG phenomena. In idiopathic generalised epilepsy there is a growing body of evidence that--as it was assumed by Gloor--spindles transform to SWD pattern. These data explain why those dynamic changes which evoke sleep responses are promoting for the occurrence of SWD. Adapting these data we offer a new interpretation to explain the strong activation effect of sleep deprivation in this kind of epilepsy. We assume that it is mainly due to the forced vigilance level oscillations, especially in morning, when elevated sleep pressure and circadian wake promoting forces, representing opposite tendencies, increase the amount of oscillations.

The objective of this work was to study the non-linear aspects of sleep EEG, taking into account the different sleep stages and the peculiar organization of its phasic events in ordered sequences (CAP) by applying a series of new non-linear measures (non-linear cross prediction or NLCP), which appear more reliable for the detection and characterization of non-linear structures in experimental data than the commonly used correlation dimension. Eight healthy subjects aged 18-20 years participated in this study. Polysomnography was performed in all subjects; signals were sampled at 128 Hz and stored on hard disk. The C3 or C4 derivation was used for all the subsequent computational steps, which were performed on EEG epochs (4096 data points) selected from sleep stage 2 (S2) and slow-wave sleep (SWS), in both CAP and non-CAP (NCAP) conditions. Also, epochs from sleep stage 1 (S1), REM and wakefulness preceding sleep were recorded. The dynamic properties of the EEG were assessed by means of the non-linear cross-prediction test, which uses three different 'model' time series in order to predict non-linearly the original data set (Pred, Ama, and Tir). Pred is a measure of the predictability of the time series, and Ama and Tir are measures of asymmetry, indicating non-linear structure. The non-linear measures applied in this study indicate that sleep EEG tends to show non-linear structure only during CAP periods, both during S2 and SWS. Moreover, during CAP periods, non-linearity can only be detected during the phase A1 subtypes (and partially A2) of CAP. The A3 phases show characteristics of non-stationarity and bear some resemblance to wakefulness. Based on the results of this study, sleep might be considered as a dynamically evolving sequence of different states of the EEG, which we could track by detecting non-linearity, mostly in association with CAP. Our results clearly show that detectable non-linearity in the EEG is closely related to the occurrence of the phase A of CAP.

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.

Publisher Summary The variations of the arousal level across the 24 hour rhythm play an important role in the modulation of epileptic events. The sleep–wake cycle, and particularly the conditions of instability that occur during sleep, affect the appearance of interictal electroencephalography discharges and epileptic seizures significantly. An important modulation of the sleep–wake rhythm is mediated by the endogenous circadian system. Both human and animal studies have demonstrated that the mammalian circadian oscillator is located in the suprachiasmatic nuclei of the anterior hypothalamus and serves as a topical source for the timing boundaries of sleep and wakefulness in the 24 hour cycle. The variations of sleep propensity over time are not only affected by the biological clock but are also influenced by the subject's prior sleep–wake history. Experimental investigation has ascertained that the intrinsic alternation between non-rapid eye movement and rapid eye movement sleep is under the control of an oscillatory process generated by a particular rhythmicity of neurotransmission and by the reciprocal interaction between two neuronal groups. The variations of the arousal level across the 24 hour rhythm play an important role in the modulation of epileptic events.

Objectives: Epileptic susceptibility is triggered by the sleeping condition. However, both ictal and interictal events are not equally affected by the different sleep states. Besides the well-known dichotomy between non-REM sleep (high activation) and REM sleep (low activation), epileptic phenomena are deeply sensitive to the ongoing level of arousal. Methods: During non-REM sleep the arousal level can be either unstable, as expressed by the repetitive sequences of the cyclic alternating pattern (CAP), or stable, as reflected by non-CAP. Phase A (arousal complex) and phase B (post-arousal rebound response) are the two basic components of the CAP cycle, which presents a 20–40 s periodicity. Three subtypes of A phases can be recognized: the A1 subtypes, which are thoroughly composed of K-complexes and delta bursts, and subtypes A2 and A3 dominated by moderate (A2) or prominent (A3) EEG desynchrony. Results: As a manifestation of unstable sleep, CAP offers a favorable background for the occurrence of nocturnal motor seizures that in most cases arise in concomitance with a phase A. In primary generalized epilepsy (PGE) and in lesional epilepsies with fronto-temporal focus, activation of interictal discharges is high during CAP reaching the climax during phase A and the strongest inhibition during phase B. A lack of modulation is observed instead in epilepsy with benign rolandic spikes. In PGE, the interictal bursts are mostly associated with the highly synchronized phase A1 subtypes. Conclusions: The analysis of sleep microstructure based on CAP parameters offers a sensitive framework for exploring the linkage between dynamic EEG events and epileptic phenomena.

Objective: To measure the readjustments of sleep macro- and microstructure in patients with obstructive sleep apnea syndrome (OSAS) after acute nasal continuous positive airway pressure (NCPAP) treatment. Background: The conventional polysomnographic analysis (macrostructure of sleep) does not necessarily provide the best measures of sleep disruption associated with OSAS. In contrast, microstructural methods of analyzing sleep (i.e., arousals and cyclic alternating pattern) may improve evaluation of patients with OSAS. Method:— Ten patients with OSAS were monitored polygraphically before and during the first night of NCPAP therapy. The results were compared with those of 10 age- and sex-matched controls without sleep-related breathing disorders. Each nocturnal recording was followed by daytime observation using the multiple sleep latency test and Visual Analogue Scale (VAS). Results: The first night of ventilatory therapy was characterized by a remarkable expansion of stages 3 and 4 and of REM sleep. In addition, NCPAP suppressed the presence of cyclic alternating pattern (CAP) in REM sleep and induced an impressive rebound of arousals and of certain CAP variables—i.e., CAP rate, CAP time, number of CAP cycles—which dropped well below the physiologic values expressed by controls. A normal duration of phases A and B was re-established starting the first treatment night. When we matched sleep variables with the indices of daytime function, a significant correlation emerged only between the variations of CAP rate and VAS scores. In particular, improvement of daytime sleepiness was less evident when the ventilatory-induced drop of CAP rate was more pronounced. Conclusions: The application of CAP variables to the microstructural analysis of sleep may expand our knowledge regarding sleep and respiration.

Objective: There is consolidated evidence that stage changes in sleep are closely related to spontaneous EEG fluctuations centered on the 20–40 periodicity of the cyclic alternating pattern (CAP). The present investigation aimed at assessing the involvement of the different components of CAP in the process of build-up, maintenance and demolition of deep non-REM (NREM) sleep. Methods: CAP parameters were quantified in the first 3 sleep cycles (SC1, SC2, SC3), selected from polysomnographic recordings of 25 healthy sound sleepers belonging to an extensive age range (10–49 years). Only ideal SCs were selected, i.e. the ones uninterrupted by intervening wakefulness and in which all stages were represented and linked in a regular succession of a descending branch, a trough and an ascending branch. Results: Among the first 3 SCs, a total amount of 45 (SC1, 16; SC2, 13; SC3, 16) met the inclusion requirements. SC1 contained the highest amount of slow wave sleep (43.7 min) and the lowest values of CAP rate (31.6%). The number of phase A1 subtypes remained unmodified across the 3 SCs (SC1, 48; SC2, 48; SC3, 48), whereas both subtypes A2 (SC1, 9; SC2, 14; SC3, 14) and A3 (SC1, 2; SC2, 8; SC3, 10) increased significantly (P

Objectives : The analysis of cyclic alternating pattern (CAP) provides important microstructural information on arousal instability and on EEG synchrony modulation in the sleep process. This work presents a methodology for automatic classification of the micro-organization of human sleep EEG, using the CAP paradigm. Methods : The classification system is composed of 3 parts: feature extraction, detection and classification. The feature extraction part is an EEG generation model-based maximum likelihood estimator. The detector part for the CAP phases A and B is done by a variable length template matched filter, while the classification criteria part is implemented on a state machine ruled-based decision system. Results and conclusions : The preliminary results of the automatic classifier on a group of 4 middle-aged adults are presented. The high agreement between the detector and visual scoring is very promising in the achievement of a fully automated scoring system, although a more exhaustive evaluation program is needed.

We made a polygraphic study of 6 patients with nocturnal paroxysmal dystonia (NPD) in which the cyclic alternating pattern (CAP) parameters were compared with those of a group of age- and sex-matched controls.All patients met the requirements for NPD diagnosis, characterized by generalized stereotyped movements (dystonic-dyskinetic), with a 1-min centered duration but with no clear evidence of epileptic abnormalities in the waking EEG and during nocturnal recordings.Besides the major events, the NPD polysomnograms also showed shorter, repeated episodes of shorter duration (generally20 s) consisting of abrupt movements involving one or more body segments. Overall, the motor events in patients with NPD were closely related to periods of unstable non-REM (NREM) sleep, as evidenced by the sequences of CAP, and began during an A phase. According to the conventional scoring parameters, NPD and controls differed only in sleep latency (+14 min in the NPD patients: p0.04). However, the architecture of sleep in the group with NPD was characterized by prolonged and irregular NREM/REM cycles. In addition, the NPD recordings showed significantly higher values of CAP rate (p0.0001). When major motor attacks were suppressed by medication, sleep was characterized by a decrease in the excessive amounts of CAP rate and by a more regular architecture.The modulatory role of CAP on nocturnal motor events is reported.

To test the effects of a hypnotic drug administered on a regular basis, six adults (four women and two men; mean age 37 years) who complained of transient or short-term insomnia, took zolpidem 10 mg at bedtime for 4 consecutive weeks. The period of active treatment, preceded by a baseline placebo night, ended with a 4-night gradual tapering phase followed by 3 nights of placebo administration. After adaptation to the sleep laboratory, all subjects underwent five polysomnographic recordings; baseline placebo (night 1); 1st, 7th and 28th nights of hypnotic medication (nights 2, 3, and 4 respectively); 3rd placebo night after complete tapering (night 5) and completed a morning visual analogue scale (VAS) for evaluating sleep quality. The sleep recordings were scored according to the conventional procedures (macrostructure) and to the cyclic alternating pattern (CAP) rules (microstructure). Data analysis was based on a repeated-measures analysis of variance integrated by post-hoc comparisons. At the macrostructural level, significant overall modifications (p < 0.035) emerged only from slow-wave sleep (SWS). The amounts of SWS were enhanced along the entire drug period, but a significant difference was found only between the baseline night (10%) and the first night of drug administration (20%). At the microstructural level, CAP rate (the ratio of CAP time to non-rapid eye movement sleep time) showed overall significant variations throughout the entire protocol period (p < 0.0001). Compared with baseline night 1 (59%), the CAP rate was significantly lower on drug nights 2 (32%), 3 (37%), and 4 (38%). The increase in the CAP rate found on night 5 (43%) was still significantly below the baseline value. The VAS scores showed significant overall changes (p < 0.0001), with improved values during the active treatment period.

This review aims at providing a critical assessment of the effects of the most widely used benzodiazepine (flurazepam, flunitrazepam, temazepam, triazolam) and non-benzodiazepine (zopiclone and zolpidem) hypnotic drugs, based on the recording of polysomnographic variables. In the light of newly acquired neurophysiological data on the microstructure of sleep, this paper reconsiders the problem of insomnia and the current ideas on polysomnography and hypnotic drugs.

Obstructive sleep apnea syndrome (OSAS) is characterized by multiple interruptions of airflow between periods of arousals. A key feature of OSAS is the 20- to 40-s cyclic pattern of electrophysiologic parameters. The periodicity of the OSAS-related phenomena is reminiscent of the natural electroencephalographic (EEG) arousal rhythm of non-rapid eye movement (NREM) sleep known as the cyclic alternating pattern (CAP). Morphologically, CAP consists of transient arousals (phase A) that periodically interrupt the tonic theta/delta activities of NREM sleep (phase B). Functionally, CAP translates a condition of sustained arousal instability oscillating between a greater arousal level (phase A) and a lesser arousal level (phase B). CAP is also related to the controls of the motor and autonomic mechanisms. On the basis of the information simultaneously derived from EEG activities, muscle tone, and neurovegetative responses, it is possible to distinguish three subtypes of A phases corresponding to different levels of arousal power: A1 (dominated by EEG synchronization and weak activation of polygraphic variables); A2 (mixture of EEG synchronization/desynchronization and intermediate activation of polygraphic variables); and A3 (dominated by EEG desynchronization and strong activation of polygraphic variables). Unlike standard criteria, CAP parameters offer a more suitable perspective for evaluating sleep pathologies in which brief and frequent arousals appear as a prominent feature. The present study aimed at (a) assessing CAP parameters in OSAS patients and (b) investigating the reciprocal interactions between CAP and the cyclic variations in respiratory rate. Twelve obese middle-aged OSAS subjects complaining of daytime sleepiness were polygraphically compared with age-matched and gender-matched volunteers in good health and with no complaints about sleep and wakefulness (controls). In OSAS patients, conventional parameters showed predictable decrements in total sleep time, slow wave sleep, and REM sleep and increases in stage 1 and nocturnal awakenings. Sleep fragmentation was associated with a significant enhancement of CAP and of the A phases with longer and more desynchronized EEG patterns (especially A3). The increase of A3 subtypes permitted scoring and detecting CAP also in REM sleep. The great majority of respiratory pauses (96% in NREM and 80% in REM sleep) were coupled with CAP. All CAP-related respiratory events rose in close temporal connection with a phase B, while effective breathing was always recovered during phase A (especially A2 and A3 subtypes). These data suggest that (a) phase B of CAP offers a vulnerable background for upper airway collapse and for attenuation of biochemical and neural mechanisms in the control of the ventilatory drive and (b) survival in OSAS patients is effected by the enhancement of the strongest components of the natural arousal rhythm at sleep quality's expense.

Fig. 1. A profile of Tiberius Claudius Germanicus appears on the obverse of this silver denarius struck during the Imperial Roman Era (ca. first century CE; photo provided courtesy of A Pangerl of www.romancoins.info). To the Editor We would like to thank Dr. Sacchetti and co-workers for their interest in our article [1]. Sacchetti et al. raise the question whether a stroke may transform, in selected patients, an obstructive sleep apnea syndrome (OSAHS) into a complex-sleep apnea syndrome (Comp-SAS) and postulate that the appearance of central respiratory events may represent a stable consequence of stroke, and may complicate the treatment approach to sleep apnea. This hypothesis is supported by their preliminary data showing mixed (obstructive and central) apneas four months after the stroke. This high prevalence of central and mixed respiratory events in stable phase after stroke is higher than that found in other studies, about the time course of sleep breathing disorders and central periodic breathing in stroke patients [2,3]. These data also contradict in part the attenuation of central respiratory events within week or a few months after the stroke described by the same authors or in OSAHS patients with CompSAS [4]. In OSAHS patients some predictive factors for appearance of CompSAS during CPAP treatment have been proposed [5], which include atrial fibrillation, use of opioids, sleep disruption and features of initial sleep apnea syndrome (in term of severity of obstructive apneas and presence of relevant mixed/central events). The last two factors are probably strictly related to the fluctuations of ventilatory control system and CO2 levels, that we documented in our paper [1], as well as, the fluctuations of arousal system in NREM sleep that have been described as possible distinctive patterns of some patients with OSAHS [6]. Finally, in our opinion, the question is to clarify if these or other factors can tell us whether initial ‘‘complex’’ cases of OSAHS are more prone to develop a clear CompSAS after a stroke and, whether as suggestedbySacchetti andco-workers, tomerge this ‘‘pre-stroke’’ profile of sleep disordered breathing with ‘‘post-stroke’’ features. Thismay enable us to findout possible factors able to distinguish patientswith a transient CompSAS frompatientswith a persistent one.

The standardized scoring criteria of sleep can serve as a rough tool for monitoring the effects of psychoactive compounds, both in normal sleepers and in insomniac patients. More sensitive information on the impact of perturbing factors and drugs during sleep is supplied by the cyclic alternating pattern (CAP) parameters. In particular, CAP rate, which measures the amount of arousal instability during NREM sleep, has been proved of high reliability in a variety of clinical and pharmacological settings. The present study aimed at evaluating the activity of brotizolam (Br) 0.25 mg and triazolam (Tr) 0.25 mg on both conventional and CAP parameters in a model of situational insomnia of intermediate severity. Six middle-aged healthy subjects (three males and three females, aged 40-55 years) with no complaints about sleep, underwent a polysomnographic investigation according to a double-blind crossover design: placebo without noise (night 1), placebo with noise (night 2), brotizolam or triazolam without noise (nights 3 and 5), brotizolam or triazolam with noise (nights 4 and 6). The unperturbed nights consisted of standard recording conditions in a sound-protected sleep laboratory, whereas situational insomnia was accomplished by means of continuous white noise at 55 dBA delivered throughout the night. Subjects received medication orally at bedtime. An interval of at least 48 h was secured between consecutive recordings in the same individual. Compared to baseline conditions, situational insomnia was characterized by a shorter amount of total sleep (-40 min) and by an extension of intrasleep awakenings (+62 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Six middle aged subjects complaining of chronic insomnia associated with dysthymia were investigated in a 2-month single blind study: a 7-day placebo treatment period, followed by a 6-week phase with increasing doses of trazodone controlled release (CR) formulation (50 mg through days 8-10; 75 mg through days 11-13; 150 mg through days 14-49) and then a final 7-day withdrawal period under placebo. Medication was always administered at bedtime. Five polysomnographic recordings were accomplished by each subject (sleep 1: under baseline placebo; sleep 2-3-4; under active treatment; sleep 5: after drug discontinuation). A "blind" EEG reader analysed the traditional polysomnographic variables (macrostructure of sleep) and the amount and percentage ratio (CAP rate) of cyclic alternating pattern (CAP), the microstructural parameter that measures the instability of arousal during sleep. Visual analogue scales (VAS) for the evaluation of subjective sleep quality and the Hamilton rating scale for depression (HAM-D) were regularly assessed across the study. Statistical analysis was based on an ANOVA test with repeated measures completed by means of Bonferroni adjusted probabilities. No significant differences emerged from the macrostructural parameters referred to sleep initiation and maintenance, while significant overall modifications emerged from stage 2 (P < 0.0005), slow wave sleep (P < 0.0001), total CAP time (P < 0.0001) and CAP rate (P < 0.0001). Compared to the placebo baseline night, a significant increase of slow wave sleep (+40 min) and significant reductions of stage 2 (-67 min), CAP time (-90 min) and CAP rate (-23%) were already found on day 4 of treatment (sleep 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep-related disorders are revisited in the light of the physiological modality of NREM sleep expressed by the cyclic alternating pattern (CAP). Owing to its fluctuating properties on vigilance, muscle tone, and vegetative activities, CAP represents a highly favorable condition for the occurrence of interictal generalized and focal lesional EEG discharges, for motor seizures, and for periodic jerks in nocturnal myoclonus. All these manifestations are significantly associated with the components of activation during CAP, i.e., the A phases. On the contrary, the B phases of CAP appear chronologically linked to inhibitory phenomena in epileptic patients and in nocturnal myoclonus. The two phases of CAP seem especially involved in sleep apnea syndrome, where respiration is interrupted during a phase B and restored during a phase A. CAP rate, that measures the effort of the brain to maintain sleep, is increased by all conditions that induce vigilance instability such as noise, clinical insomnia, interictal EEG paroxysms, nocturnal seizures, periodic leg movements, and in certain extreme pathologic conditions such as Creutzfeldt-Jakob disease and stage 2 coma.

Summary: Twenty epileptic patients (10 male and 10 female) were polygraphically recorded during nocturnal sleep. Ten subjects, with a wide age range, were affected by focal lesional epilepsy, and 10 were children affected by benign epilepsy with rolandic spikes (BERS). In five cases a bihemispheric expression of the focal lesional bursts emerged occasionally during the night recordings. The behavior of interictal electroencephalographic (EEG) paroxysms were analyzed with respect to the two arousal states of non-rapid-eye-movement (REM) sleep: (a) the cyclic alternating pattern (CAP), expressed by biphasic EEG periodic activities and related to long-lasting fluctuations between greater (phase A) and lesser (phase B) arousal levels; and (b) the non-CAP (NCAP), manifested by EEG stationarities that reflect a sustained relative stability of arousal. The CAP/NCAP modality affected the spiking activity and distribution of the focal lesional EEG paroxysms, which appeared enhanced during CAP and which were mostly collected in phase A. The even more powerful influence of CAP and especially phase A on the secondary bisynchronous bursts suggests a crucial integration among thalamocortical circuits, arousal modulation, and epileptic generalization mechanisms. Conversely, in the BERS recordings no significant differences emerged throughout CAP and NCAP. The intense activity of the rolandic foci induced by sleep as such could be explained on the basis of the greater dependence of these functional cortical EEG abnormalities on the degree of synchronization during sleep.

Twelve patients with episodes of acute confusional migraine (ACM) are reported. Prolonged agitation and mental confusion characterized the headache attacks, occurring mostly among adolescents. The ictal EEG showed diffuse, slow abnormalities and a peculiar pattern known as FIRDA (frontal intermittent rhythmic delta activity). Neuroradiologic examinations and laboratory tests were unremarkable. After the acute stage, EEG gradually tended to show normalization. Apart from the noticeable similarities to the “juvenile head trauma syndrome”, the authors assume that ACM represents a peculiar clinical form among the different types of migraine associated with disorders of higher mental functions.

Summary: Because arousal plays a critical role in activation of epileptic phenomena, we analyzed the behavior of interictal generalized spike-and-waves (S-W) during the two recently identified modalities of arousal control during NREM sleep: (a) the cyclic alternating pattern (CAP), expressed by successive biphasic (phase A and phase B) fluctuations of arousal; and (b) non-CAP (NCAP), characterized by prolonged stable periods of EEG and arousal level. Within the single NREM stages, phase A consists of clusters of phasic events associated with transient arousal activation, whereas phase B is represented by the periodic reappearance of the EEG background and reflects a rebound inhibitory condition. The polysomnograms of 10 subjects with a wide age range and affected by primary generalized epilepsy displayed significant differences (all at p < 0.01) between the spike indexes (S-W/min) of CAP (2.9) and NCAP (1.3), of phase A (7.4) and phase B (0.3), and of NCAP and phase B. For distribution of S-W, a significant prevalence of EEG paroxysms was detected during CAP as compared with NCAP (68 vs. 32%, p < 0.001), and 93% of all the interictal bursts that occurred in CAP occurred in phase A (p < 0.001). Our data stress the arousal-dependent influence of CAP and NCAP on modulation of generalized epileptic mechanisms during sleep. RESUME Comme allegement du sommeil joue un role important dans activation des phenomenes epileptiques, les auteurs ont analyse le comportement des decharges de pointes-ondes generaees intercritiques pendant deux modalites allegement du sommeil survenant en sommeil lent, identification recente: 1o) le pattern cyclique alternant (PAC), exprime par des fluctuations bi-phasiques successives (phase A et phase B) de allegement, 2o) le type non-PAC (NPAC), caracterise par un etat stationnaire prolonge de EEG et du niveau allegement. A interieur des stades individuels du sommeil lent, la phase A consiste en une accumulation evenements phasiques associes a une activation transitoire de eveil, tandis que la phase B est representee par la reapparition periodique de activite de fond EEG, et temoigne un etat inhibition rebond. Les polysomnographies de dix sujets presentant une epilepsie generalisee primaire, âges tres variables, ont montre des differences significatives, toutes avec p < 0.01, entre les index de pointes (P-O/min) DPAC (2,9) et DNPAC (1,3). de la phase A (7,4) et de la phase B (0,3), des NPAC et de la phase B. La distribution des P-O a montre une prevalence significativement plus elevee des paroxysmes EEG pendant les PAC par comparaison avec les NPAC (68% contre 32%: p < 0.001), 93% de toutes les decharges intercritiques qui survenaient en PAC ont ete trouves en phase A (p < 0.001). Ces donnees soulignent influence dependante de eveil des PAC et des NPAC sur la modulation des mecanismes epileptiques generalises pendant le sommeil. RESUMEN Puesto que el despertar juega un papel critico en la activacion de los fenomenos epilepticos hemos analizado el comportamiento de las puntas-onda interictales generalizadas (S-W) durante las dos modalidades del despertar recientemente identificadas durante la fase NREM del sueno: (1) el Patron Ciclico Alternante (CAP), expresado por fluctuaciones sucesivas bifasicas del despertar (fase A y fase B); (2) no-CAP (NCAP) caracterizado por peridos estacionarios prolongados del EEG y del nivel del despertar. En los estadios de NREM linicos la fase A esta constituida por agrupaciones de acontecimientos fasicos asociados a una activacion transitoria del despertar mientras que la fase B esta representada por la reaparicion periodica de la actividad de fondo del EEG y refleja una condition inhibitoria de rebote. Los polisomnogramas de 10 individuos afectados de epilepsia generalizada primaria y pertenecientes a un amplio grupo de edades, mostraron diferencias significativas (todas con p 0.01) entre los indices de puntas (SW/min) del CAP (2.9) y del NCAP (1.3) de la fase A (7.4) y de la fase B (0.3), del NCAP y fase B. En lo que respecta a la distribution de las S-W se registro una prevalencia significativa de los paroxismos en el EEG comparandolos con el NCAP (68% vs 32%: p 0.001); el 93% de todos los brotes interictales que ocurrieron en el CAP se encontraron en la fase A (p 0.001). Nuestra informacion insiste en la influencia, dependiente del despertar, del CAP y del NCAP sobre la modulacion de los mecanismos epilepticos generalizados durante el sueno. ZUSAMMENFASSUNG Arousal spielt eine wichtige Rolle bei der Aktivierung von epileptischen Phanomenen. so das wir das Verhalten von interiktalen Spike und Waves (SW) wahrend der 2 kurzlich identifizierten Modalitaten von Arousal-Kontrolle im NREM Schlaf analysierten: 1. das zyklisch alternierende Muster (CAP), das durch Aufeinanderfolge von biphasischen (Phase A und Phase B) Fluktuationen von Arousal definiert wird und 2. Nicht–CAP, das durch langere Stationaritaten im EEG und Arousal-Level charakterisiert ist. Innerhalb der einzelnen NREM-Stadien be-steht Phase A aus Ansammlungen von phasischen Ereignissen die mit vorubergehender Arousalaktivierung assoziiert sind, wahrend Phase B durch das periodische Wiederauftreten der EEG-Hintergrundaktivitat gekennzeichnet ist und einer inhibitorischen Rebound-Bedingung entspricht. Die Polysomnogramme von 10 Personen mit primar generalisierter Epilepsie und einem grosen Altersunterschied zeigten signifikante Unterschiede (p < 0.01) zwischen den Spike Indice (Spike Waves/min) zwischen CAP (2.9) und NCAP (1.3). zwischen Phase A (7.4) und Phase B (0.3), und zwischen NCAP und Phase B. Bezogen auf die Verteilung von Spike Wave-Entladungen wurde eine signifikante Pravalenz von EEG-Paroxysmen wahrend CAP im Vergleich zu NCAP gefunden (68% gegenuber 32%, p < 0.001). 93% aller interiktalen Ausbruche wahrend CAP ereigneten sich in Phase A (p < 0.001). Unsere Ergebnisse zeigen den Arousal-abhangigen Einflus von CAP und NCAP auf die Modulation generalisierter epileptischer Mechanismen wahrend des Schlafes.

The Cyclic Alternating Pattern (CAP) is an intrinsic component of normal NREM sleep. This periodic activity is organized in biphasic 40-sec cycles clustered in sequences. CAP sequences are functionally correlated to long lasting arousal instability. CAP is induced by endogenous stimuli (change in sleep stage, body movements) but it is considerably increased by exogenous impulses (noise). CAP rate (CAPR) is a novel polysomnographic variable that measures the amount of CAP during sleep, and it may be calculated for total sleep time and total NREM sleep. We demonstrated that all-night exposure to a 45 dB(A) white noise induced a significant CAPR increase, correlated with impaired sleep quality, even without changes in sleep architecture. We hypothesized that administration of an hypnotic should attenuate this CAPR rise. This hypothesis was verified in a double-blind placebo study, in which 12 healthy young adults received zolpidem, a new imidazopyridine hypnotic. During the noise perturbed nights, zolpidem clearly demonstrated a protective effect on CAPR (mainly during slow wave sleep) and on sleep quality. CAPR appears to be a sensitive indicator of sleep quality, and the cumulative distribution of CAPR throughout the night represents a new method to evaluate the effects of an hypnotic in sleep.

SYNOPSIS A 12-year-old girl presented three distinct attacks of classic migraine. In all attacks, an occipital seizure with impairment of consciousness was intercalated between the visual prodrome and the headache. A right occipital epileptogenic focus was detected by the EEG. Neurologic examination was normal. CT-scan and laboratory work were unremarkable. Flunarizine treatment controlled both the migraine and seizure components. Periodic migraine episodes with visual phenomena occurred in three other female components of the same family. However, the attacks were never associated with epileptic manifestations. Only the 10-year-old sister, who suffered from common migraine, showed sporadic interictal EEG abnormalities in the right posterior leads. The possible neurophysiologic interplay between classic migraine and epilepsy in intercalated attacks may be explained on the basis of the “spreading depression” mechanism. The intense neuronal excitation preceding the migraine aura might play a “triggering” role on the occipital epileptogenic focus. Similarities and differences between this benign though unusual syndrome and other forms of epilepsy in childhood, are also discussed.

We observed acute confusional migraine (ACM) attacks in two adolescents, and in both cases the episodes ended when the patients fell asleep spontaneously. Laboratory and neuroradiologic examinations were unremarkable. The post-ictal polysomnograms displayed a regular quality and duration of the physiologic components of sleep. Random posterior slow waves occurred only during the nocturnal awakenings and REM periods. The observation that sleep may resolve migraine attacks is emphasized. ACM is characterized by peculiar and relatively quickly reversible clinical manifestations and EEG abnormalities. The lack of significant abnormalities in post-ictal polysomnograms corresponds to a functional integrity of the brainstem structures involved in the global organization of sleep and may represent a useful laboratory feature in the diagnosis of ACM.

The cyclic alternating pattern (CAP) is a physiological component of normal NREM sleep, functionally correlated with long-lasting arousal oscillations. This EEG periodic activity, organized in sequences of two or more decasecond cycles, is detectable also in coma and in other neurologic disorders, appearing as a general modality of arousal organization. Within NREM sleep, the fluctuations of CAP alternate with sustained homogeneous EEG patterns, characterized by a greater stability of arousal and called non-CAP (NCAP). In 20 sleep records of 10 healthy young adults we analysed the chronological relationship between CAP and 3 fundamental states of arousal: wakefulness, NREM sleep, REM sleep. Sleep onset and sleep recoveries after nocturnal awakenings were closely linked to CAP sequences, indicating a functional linkage between cyclic fluctuations of arousal and the beginning of any sleep behavioural state. On the basis of their temporal relationship with CAP sequences, the waking to sleep and the waking transitions appeared a symmetrical events in the organization of arousal, whereas the NREM to REM transitions and the REM to NREM transitions occurred as asymmetrical events. Moreover, almost 50% of all NREM stage changes were accompanied by CAP sequences. The EEG and dynamic features of CAP sequences show morphological and behavioural analogies with some phasic phenomena (i.e., phase d'activation transitoire or micro-arousals) and EEG patterns reported in the literature (e.g., trace alternant; phase transitionnelles; trace intermittent). Our data suggest a functional correlation between the control mechanisms of CAP and the organization of sleep.

• A patient had seizures triggered by spontaneous blinking associated with the act of beginning to speak. Diffuse paroxysmal discharges in the EEG appeared when the patient was blinking in darkness or in bright light. Closing the eyes voluntarily, on command, or as a reflex reaction produced this response very infrequently. During intermittent photic stimulation the epileptic discharges were accompanied by myoclonic jerks. The act of beginning to speak was linked with spontaneous blinking and EEG changes and was accompanied consistently by seizures. These were characterized by a peculiar stuttering and an absencelike impairment of consciousness. Seizures have been controlled well using clonazepam and valproic acid.