Franco Ferrillo

Hypersomnia in the Prader Willi syndrome: clinical-electrophysiological features and underlying factors

OBJECTIVE Excessive daytime sleepiness is a common symptom in Prader Willi syndrome (PWs). Sleep disordered breathing (SDB) and narcoleptic traits such as REM sleep onsets (SOREMPs) have been reported in these subjects. We evaluated nighttime and daytime sleep patterns in patients with PWs in order to clarify the nature of their hypersomnia. DESIGN AND METHODS We performed overnight continuous EEG-polysomnographic studies (with breathing monitoring included) in 14 subjects (6 M,8 F; mean age 17 years, range 8-37) affected by PWs unselected for sleep disturbances. Ten patients underwent a Multiple Sleep Latency Test (MSLT) the day following the nocturnal sleep studies. Patients assessment was completed by means of immunogenetic characterization. RESULTS Nocturnal polysomnographic investigation documented sleep related breathing abnormalities such as central apneas, hypopneas or hypoventilation which mainly occurred during REM sleep in 8 subjects and did not cause sleep disruption. Only 4 subjects presented an increase in the Respiratory Disorder Index (RDI) slightly above the normal limits. In 8 subjects out of 10, with and without SDB, the mean daytime sleep latency could be considered abnormal according to the Tanner staging of pubertal development. Five patients showed at least two SOREMPs at MSLT. Subjects with and without SOREMPs had, respectively, a mean age of 18.6 SD 7.9 (4 M, 1 F) and 14.5 SD 2.9 (4 F, 1 M). The paternal deletion:uniparental dysomy ratio at genotypic characterization was 4:1 and 3.5:1 in subjects with and without SOREMPs, respectively. No patient presented DR-15 nor Dq-6. CONCLUSIONS Excessive sleepiness is a frequent disturbance in PWs. Subgroups of PW patients show hypersomnolence and SOREMPs. Sleep disordered breathing appears to have a limited role in the genesis of hypersomnia which not seems on the other hand attributable to the coexistence of narcolepsy phenotype. Hypersomnia in PW syndrome is likely to mainly be attributable to a primary hypothalamic dysfunction. The potential interacting role of other factors such as subjects age, sex and genetic pattern is suggested and deserve further investigation.

Sleep-wake cycle abnormalities in fatal familial insomnia. Evidence of the role of the thalamus in sleep regulation

Alterations in sleep organization were longitudinally studied in 6 new cases of fatal familial insomnia (FFI) by 24 h polygraphic recording. All patients showed an early reduction in sleep spindles and K complexes, and a drastic reduction in total sleep time and disruption of the cyclic sleep organization. Complete abolition of NREM sleep and persistence of only brief residual periods of REM sleep without atonia were features characteristic of the 3 patients with a short (less than 1 year) clinical course, and lacking in the 3 cases with a longer (more than 2 years) disease course. In the latter, sudden transitions from waking to NREM or REM sleep occurred, sometimes recurring periodically. Our findings confirm that impairment of sleep-wake regulation is a consistent distinctive feature of FFI.

Prevalence of patent foramen ovale in subjects with obstructive sleep apnea: a transcranial Doppler ultrasound study

BACKGROUND Under particular conditions a patent foramen ovale (PFO) can potentially give rise to ischemic stroke by means of paradoxic embolization. In obstructive sleep apnea syndrome (OSAS) right to left shunting (RLSh) can occur through PFO during periods of nocturnal apnea. Our study aimed to evaluate the prevalence of PFO diagnosed by means of transcranial Doppler (TcD) in subjects with OSAS. METHODS Seventy-eight consecutive subjects with OSAS (mean age 53+/-12 years) and 89 normal controls (mean age 48+/-9 years) underwent TcD with intravenous application of agitated physiological saline solution. The test was performed on patients at rest and during Valsalva maneuver. RESULTS PFO was present in 21 out of 78 patients with OSA (27%) and in 13 out of 89 control patients (15%). Seventeen out of 21 patients with OSA showed PFO only during Valsalva maneuver (85%) with respect to 12 out of 13 subjects of the control group (92%). Prevalence of PFO in OSAS was statistically different with respect to the control group (P<0.05). However, no statistically significant differences could be found for the prevalence of provocative-only shunting PFO with respect to already at rest shunting PFO in patients with OSAS with respect to the control group. CONCLUSIONS Prevalence of PFO in subjects with OSA is significantly higher than in normal controls. The shunt is frequently present only during Valsalva maneuver.

Quantitative analysis of sleep EEG microstructure in the time-frequency domain.

A number of phasic events influence sleep quality and sleep macrostructure. The detection of arousals and the analysis of cyclic alternating patterns (CAP) support the evaluation of sleep fragmentation and instability. Sixteen polygraphic overnight recordings were visually inspected for conventional Rechtscaffen and Kales scoring, while arousals were detected following the criteria of the American Sleep Disorders Association (ASDA). Three electroencephalograph (EEG) segments were associated to each event, corresponding to background activity, pre-arousal period and arousal. The study was supplemented by the analysis of time-frequency distribution of EEG within each subtype of phase A in the CAP. The arousals were characterized by the increase of alpha and beta power with regard to background. Within NREM sleep most of the arousals were preceded by a transient increase of delta power. The time-frequency evolution of the phase A of the CAP sequence showed a strong prevalence of delta activity during the whole A1, but high amplitude delta waves were found also in the first 2/3 s of A2 and A3, followed by desynchronization. Our results underline the strict relationship between the ASDA arousals, and the subtype A2 and A3 within the CAP: in both the association between a short sequence of transient slow waves and the successive increase of frequency and decrease of amplitude characterizes the arousal response.

CAP and arousals are involved in the homeostatic and ultradian sleep processes

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.

Relationship of sleep interictal epileptiform discharges to sigma activity (12–16 Hz) in benign epilepsy of childhood with rolandic spikes

OBJECTIVE The activation of interictal epileptic discharges (IEDs) by NREM sleep is a well-known phenomenon in benign epilepsy of childhood with rolandic spikes (BECRS). The activating properties of NREM sleep on IEDs have been attributed to increased synchronization within thalamocortical neurons. During NREM sleep two synchronizing mechanisms lead to the appearance of spindles and delta waves on the EEG. Spectral analysis technique is a suitable method that can be used to quantitatively describe the dynamics of delta (slow wave activity (SWA) 0.5-4.0 Hz) and sigma activity (12.0-16.0 Hz) during sleep. METHODS In order to define more accurately the relationship between synchronizing mechanisms (spindles and delta activities) and IEDs during sleep in BECRS, we have performed overnight continuous EEG polysomnography studies in 9 patients (mean age 7.4 +/- 2.5 years). The temporal series of SWA and sigma values, derived from spectral analysis, have been obtained from a spike-free derivation lead. The IEDs count has been performed on the most active lead. Relationships between sigma and SWA and time series of IEDs were tested by means of correlation techniques after data normalization. RESULTS Our results revealed a significant higher correlation between IEDs and sigma activity with respect to SWA in all the subjects, in total sleep time. The same analysis limited to NREM sleep highlights the better correlation between sigma and IEDs. CONCLUSIONS Data suggest that during sleep of BECRS patients, IEDs are more sensitive to the promoting action of the spindle-generating mechanism than to the SWA-producing one.

Comparison Between Visual Scoring of Cyclic Alternating Pattern (CAP) and Computerized Assessment of Slow EEG Oscillations in the Transition from Light to Deep Non-REM Sleep

Ten healthy volunteers (six men and four women) aged between 20 and 30 years underwent a nocturnal polygraphic recording on paper and on tape. Spectral analysis was accomplished and EEG sleep scored according to standard criteria and to the guidelines for the identification of cyclic alternating pattern (CAP). The initial 25 min of sleep, starting from the first clear-cut k-complex and ending within stage 4, was subdivided into five consecutive blocks of 5 min each. Using a zero-crossing technique, we evaluated the number of total power oscillations in each block and we tested the hypothesis of significant modifications of the number of total power oscillations and of their periodicity in the successive sessions. In addition, we measured the gap between the maximum and minimum values, respectively, of two successive half-waves making up each oscillation. The hypothesis of time-related trends of the values of the gaps was tested by means of linear regression techniques. Within the 25-min time span, the number of periodic oscillations and the number of CAP cycles showed significant increases. The amplitude gaps underwent a decreasing trend. The present data suggest that slow rhythmic oscillations expressed by CAP can be detected by means of spectral analysis. Their dynamics suggests a close relationship with the EEG synchronization processes.

Modulation of sleep interictal epileptiform discharges in partial epilepsy of childhood

OBJECTIVE NREM sleep increases the Interictal Epileptic Discharges (IEDs) in the majority of children affected by partial epilepsy (both symptomatic or cryptogenetic). Experimental data revealed that the normal sleep oscillations, leading to the appearance of spindles and delta waves on the surface EEG during NREM sleep, might develop into paroxysmal synchronization. Spectral analysis enables the quantitative description of the dynamics of delta (slow wave activity, SWA, 0,5-4,5 Hz) and sigma activity (SA, 12.0-16.0 Hz) and can be used to assess the relationship between SA, SWA and IEDs during sleep. DESIGN AND METHODS We have performed overnight continuous EEG-polysomnographic studies in 7 patients (mean age 7.2+/-1.3). The temporal series of SWA and SA were obtained from a spike-free derivation lead. The IEDs count was performed on the most active lead. Relationships between sigma and SWA and time series of IEDs were tested by means of correlation techniques after data normalization. RESULTS Our results revealed a significant higher correlation between IEDs and SA with respect to SWA in all the subjects, in total sleep time. The same analysis limited to NREM sleep highlights the better correlation between SA and IEDs. CONCLUSIONS Our data suggest that the neural mechanisms involved in the generation of sleep spindles facilitate the IEDs production in childhood partial epilepsies at least in those strongly activated by sleep.

Sleep EEG synchronization mechanisms and activation of interictal epileptic spikes

OBJECTIVE The temporal course of sleep interictal epileptic discharges (IEDs) has been studied focusing their relationship with the temporal course of the main sleep-EEG frequency bands that is thought to reflect the action of different synchronization neural mechanisms. The existence of a mutually exclusive mechanism between spindles and delta waves should be reflected in a mutually exclusive facilitation of IEDs activation by slow wave activity (SWA) and sigma activity (SA) during synchronized NREM sleep. METHODS We reanalyzed data from 19 children and 15 adult patients affected by different partial epileptic syndromes. The temporal series of SWA, SA and theta band (TB), derived from spectral analysis, were obtained from a spike-free and pathologic alteration-free derivation, controlateral to the most active lead, where the IEDs count was performed. Relationships between SA, SWA and TB and time series of IEDs were tested by means of correlation techniques after data normalization. RESULTS A positive correlation of spike distribution with SWA time course has been found in the majority of adults. Only a few adult patients showed IEDs that were correlated with SA or TB. Conversely SA was shown to be positively correlated with spiking in many different epileptic syndromes of childhood. Moreover, in the contest of the NREM sleep cycle an inverse relationship between the SWA and SA mode of spike activation has been detected. CONCLUSIONS Overall results give evidence that 3 main rhythmic spectral components that characterize sleep EEG can exert positive influences on IEDs production. Our studies demonstrate that within NREM sleep the facilitating influences on IEDs production exerted separately by either spindle activity or delta synchronization mechanisms can be detected. Moreover, a mutually exclusive mechanism between SA and SWA oscillations is detectable in the opposite relationship of the correlation between IEDs and the two bands in the central part of the NREM cycle.

Sleep-EEG modulation of interictal epileptiform discharges in adult partial epilepsy: a spectral analysis study

INTRODUCTION In order to define accurately the relationship between EEG components (spindles, delta and theta frequencies) and the occurrence of interictal epileptiform discharges (IED) during sleep in partial epilepsy, a correlation study between spike overnight distribution and EEG spectral power time series was performed. METHODS Eighteen patients (mean age: 24.7+/-5.5 years) affected by partial epilepsy underwent continuous EEG-polysomnography. The temporal series of Slow Wave Activity (SWA), Sigma Activity (SA) and Theta Band (TB), derived from spectral analysis, were obtained from a spike-free and pathologic alteration-free derivation, contralateral to the most active lead, where the IED count was performed. Relationships between SA, SWA and TB and time series of IED were tested by means of correlation techniques after data normalization. RESULTS Our results revealed a significantly higher correlation between IED and SWA in 12 subjects; a significantly higher correlation between IED and SA in three subjects and a significant correlation with TB in three cases. CONCLUSIONS Data suggest that in most adult patients with partial epilepsy IED production during sleep is facilitated by the action of synchronizing mechanisms which are active during NREM sleep and lead to the appearance of EEG delta waves. Nevertheless evidence is given of two smaller groups of patients. In one of them IED are more sensitive to the promoting action of the spindle generating mechanism, active during stage 2 of NREM sleep. In the other one the promoting action of TB, characterizing EEG during stage 1 and REM sleep, is evident.