Sari-Leena Himanen

AS03 Adjuvanted AH1N1 Vaccine Associated with an Abrupt Increase in the Incidence of Childhood Narcolepsy in Finland

Background Narcolepsy is a chronic sleep disorder with strong genetic predisposition causing excessive daytime sleepiness and cataplexy. A sudden increase in childhood narcolepsy was observed in Finland soon after pandemic influenza epidemic and vaccination with ASO3-adjuvanted Pandemrix. No increase was observed in other age groups. Methods Retrospective cohort study. From January 1, 2009 to December 31, 2010 we retrospectively followed the cohort of all children living in Finland and born from January 1991 through December 2005. Vaccination data of the whole population was obtained from primary health care databases. All new cases with assigned ICD-10 code of narcolepsy were identified and the medical records reviewed by two experts to classify the diagnosis of narcolepsy according to the Brighton collaboration criteria. Onset of narcolepsy was defined as the first documented contact to health care because of excessive daytime sleepiness. The primary follow-up period was restricted to August 15, 2010, the day before media attention on post-vaccination narcolepsy started. Findings Vaccination coverage in the cohort was 75%. Of the 67 confirmed cases of narcolepsy, 46 vaccinated and 7 unvaccinated were included in the primary analysis. The incidence of narcolepsy was 9.0 in the vaccinated as compared to 0.7/100,000 person years in the unvaccinated individuals, the rate ratio being 12.7 (95% confidence interval 6.1–30.8). The vaccine-attributable risk of developing narcolepsy was 1∶16,000 vaccinated 4 to 19-year-olds (95% confidence interval 1∶13,000–1∶21,000). Conclusions Pandemrix vaccine contributed to the onset of narcolepsy among those 4 to 19 years old during the pandemic influenza in 2009–2010 in Finland. Further studies are needed to determine whether this observation exists in other populations and to elucidate potential underlying immunological mechanism. The role of the adjuvant in particular warrants further research before drawing conclusions about the use of adjuvanted pandemic vaccines in the future.

The SIESTA project polygraphic and clinical database

The SIESTA project had two major goals: developing new tools for analyzing computer-based sleep recordings and creating a reference database for sleep-related features. Basically, both goals have been reached, although validation and fine tuning of the sleep analyzer is still on-going. Investigations on the Web interface will be finished soon and a documentation of the database (including a CD-ROM with all test forms and all clinical, psychometric and actigraphic data as well as all R&K-scorings) will be published. Besides its scientific impact, the SIESTA project also emphasizes two other important aspects: the need of national and international cooperation between different experts and disciplines and the importance of standardized methods in scientific and clinical research.

Interrater reliability between scorers from eight European sleep laboratories in subjects with different sleep disorders.

Interrater variability of sleep stage scorings is a well‐known phenomenon. The SIESTA project offered the opportunity to analyse interrater reliability (IRR) between experienced scorers from eight European sleep laboratories within a large sample of patients with different (sleep) disorders: depression, general anxiety disorder with and without non‐organic insomnia, Parkinsons disease, period limb movements in sleep and sleep apnoea. The results were based on 196 recordings from 98 patients (73 males: 52.3 ± 12.1 years and 25 females: 49.5 ± 11.9 years) for which two independent expert scorings from two different laboratories were available. Cohens κ was used to evaluate the IRR on the basis of epochs and intraclass correlation was used to analyse the agreement on quantitative sleep parameters. The overall level of agreement when five different stages were distinguished was κ = 0.6816 (76.8%), which in terms of κ reflects a ‘substantial’ agreement ( Landis and Koch, 1977 ). For different groups of patients κ values varied from 0.6138 (Parkinsons disease) to 0.8176 (generalized anxiety disorder). With regard to (sleep) stages, the IRR was highest for rapid eye movement (REM), followed by Wake, slow‐wave sleep (SWS), non‐rapid eye movement 2 (NREM2) and NREM1. The results of regression analysis showed that age and sex only had a statistically significant effect on κ when the (sleep) stages are considered separately. For NREM2 and SWS a statistically significant decrease of IRR with age has been observed and the IRR for SWS was lower for males than for females. These variations of IRR most probably reflect changes of the sleep electroencephalography (EEG) with age and gender.

Automatic sleep stage classification using two-channel electro-oculography.

An automatic method for the classification of wakefulness and sleep stages SREM, S1, S2 and SWS was developed based on our two previous studies. The method is based on a two-channel electro-oculography (EOG) referenced to the left mastoid (M1). Synchronous electroencephalographic (EEG) activity in S2 and SWS was detected by calculating cross-correlation and peak-to-peak amplitude difference in the 0.5-6 Hz band between the two EOG channels. An automatic slow eye-movement (SEM) estimation was used to indicate wakefulness, SREM and S1. Beta power 18-30 Hz and alpha power 8-12 Hz was also used for wakefulness detection. Synchronous 1.5-6 Hz EEG activity and absence of large eye movements was used for S1 separation from SREM. Simple smoothing rules were also applied. Sleep EEG, EOG and EMG were recorded from 265 subjects. The system was tuned using data from 132 training subjects and then applied to data from 131 validation subjects that were different to the training subjects. Cohens Kappa between the visual and the developed new automatic scoring in separating 30s wakefulness, SREM, S1, S2 and SWS epochs was substantial 0.62 with epoch by epoch agreement of 72%. With automatic subject specific alpha thresholds for offline applications results improved to 0.63 and 73%. The automatic method can be further developed and applied for ambulatory sleep recordings by using only four disposable, self-adhesive and self-applicable electrodes.

Development and comparison of four sleep spindle detection methods

OBJECTIVE The objective of the present work was to develop and compare methods for automatic detection of bilateral sleep spindles. METHODS AND MATERIALS All-night sleep electroencephalographic (EEG) recordings of 12 healthy subjects with a median age of 40 years were studied. The data contained 6043 visually scored bilateral spindles occurring in frontopolar or central brain location. In the present work a new sigma index for spindle detection was developed, based on the fast Fourier transform (FFT) spectrum, aiming at approximating our previous fuzzy spindle detector. The sigma index was complemented with spindle amplitude analysis, based on finite impulse response (FIR) filtering, to form of a combination detector of bilateral spindles. In this combination detector, the spindle amplitude distribution of each recording was estimated and used to tune two different amplitude thresholds. This combination detector was compared to bilaterally extracted sigma indexes and fuzzy detections, which aim to be independent of absolute spindle amplitudes. As a fourth method a fixed spindle amplitude detector was included. RESULTS The combination detector provided the best overall performance; in S2 sleep a 70% true positive rate was reached with a specificity of 98.6%, and a false-positive rate of 32%. The bilateral sigma indexes provided the second best results, followed by fuzzy detector, while the fixed amplitude detector provided the poorest results so that in S2 sleep a 70% true positive rate was reached with a specificity of 97.7% and false-positive rate of 46%. The spindle amplitude distributions automatically determined for each recording by the combination detector were compared to amplitudes of visually scored spindles and they proved to correspond well. Inter-hemispheric amplitude variation of visually scored bilateral spindles is also presented. CONCLUSION Flexibility is beneficial in the detection of bilateral spindles. The present work advances automated spindle detection and increases the knowledge of bilateral sleep spindle characteristics.

Spindle frequencies in sleep EEG show U-shape within first four NREM sleep episodes.

It has been shown in previous studies on sleep electroencephalogram (EEG) that spindles are slower in the beginning of the night fastening towards the end of the night. Corresponding findings have been obtained by spectral analysis. The present study was based on our preliminary observation that slower spindles are found in the middle of the nonrapid eye movement (NREM) sleep episodes as compared with the beginning or the end of the episodes. Eight healthy female and six male subjects were studied. Sleep spindles were visually selected and spindle frequencies calculated for 11 analysis points in each NREM sleep episode. The median spindle frequencies formed a clear U‐shape within NREM sleep episodes with an initial decrease and final increase. The decrease was statistically significant within the first four NREM sleep episodes. It is possible that the spindle frequency pattern could be used to reveal variations in sleep depth within sleep stage 2. In animal studies the spindle frequency has been found to be associated to the duration of the hyperpolarization‐rebound sequences of the thalamocortical cells. If it is assumed that the same cellular mechanisms are responsible for spindle frequencies in humans then the study of variations in spindle frequency could be used to examine the NREM sleep process in humans.

Optimization of sigma amplitude threshold in sleep spindle detection

Sleep spindles are transient EEG waveforms of non‐rapid eye movement sleep. There is considerable intersubject variability in spindle amplitudes. The problem in automatic spindle detection has been that, despite this fact, a fixed amplitude threshold has been used. Selection of the spindle detection threshold value is critical with respect to the sensitivity of spindle detection. In this study a method was developed to estimate the optimal recording‐specific threshold value for each all‐night recording without any visual scorings. The performance of the proposed method was validated using four test recordings each having a very different number of visually scored spindles. The optimal threshold values for the test recordings could be estimated well. The presented method seems very promising in providing information about sleep spindle amplitudes of individual all‐night recordings.

Sleep and the menopause - do postmenopausal women experience worse sleep than premenopausal women?

Objective To examine the sleep characteristics in three cross-sectional populations: young, premenopausal and postmenopausal women, and the associations between sleep, menopause, mood and cognitive performance. Study design Twenty-one premenopausal (45–51 years), 29 postmenopausal (59–71 years) and 11 young (20–26 years, using oral contraceptives) women were recruited. Polysomnography was used to measure objective sleep quality. Subjective sleep quality, sleepiness and mood were assessed using questionnaires. Cognitive performance was investigated by means of three attentional tests. Results Total sleep time in pre- and postmenopausal women was similar (404.9 and 384.7 minutes), but shorter than in young women (448.2 minutes, P = 0.030 and <0.003, respectively). Sleep efficiency followed the same pattern, being 84.3% in premenopausal (P = 0.027), 80.2% in postmenopausal (P < 0.003) and 93.4% in young women. Pre- and postmenopausal women had less slow wave sleep (duration or activity) and more wake time after sleep onset (duration or frequency). Insomnia complaints were more frequent after the menopause (P = 0.023). Sleepiness and mood scores were similar in all groups. Reaction speeds slowed with increasing age. After the menopause, better cognitive performance was associated with more rapid eye movement sleep. Conclusion Objective sleep measures differed significantly between the young and postmenopausal groups. These differences may be more because of the physiology of ageing than the rapid changes across the menopause, since similar sleep characteristics were already present in the premenopausal women. The increase in sleep complaints after menopause was not associated with sleepiness or disturbances in objective sleep quality, mood or cognitive performance.

Spindle frequency remains slow in sleep apnea patientsthroughout the night

BACKGROUND Our previous data suggested that in normal sleep the frequency of individual sleep spindles would be related to sleep depth and possibly to sleep pressure. Thus far spindle frequency patterns in patients with sleep disorders have not been studied. It would be expected that the spindle frequencies might be affected by sleep fragmentation disturbing the sleep process. METHODS Twelve apnea patients with age- and sex-matched control subjects were studied with whole-night sleep recordings. Sleep spindles were visually selected and their frequency was determined by spectral analysis. RESULTS Sleep spindles of the patients were in general slower than in the control subjects. As in our previous study, the frequency of the spindles in the middle-part of the non-rapid eye movement (NREM) sleep episodes increased towards the end of the night in the control group, whereas in the patient group no such increase was found. CONCLUSIONS The slow spindle frequencies in apnea patients could indicate disturbed sleep and altered neural mechanisms in the structures regulating sleep spindle activity.

Executive dysfunction in patients with obstructive sleep apnea syndrome

Aims: To clarify whether patients with obstructive sleep apnea syndrome (OSAS) have executive dysfunction, to identify the domains of executive function affected and to establish the severity of any dysfunction. Methods: A full-night polysomnography and a comprehensive neuropsychological assessment focusing on executive functions were conducted on 40 newly diagnosed OSAS patients and 20 healthy controls. The severity of dysfunction was analyzed using norm-referenced data. Results: All patients and controls were men. The groups did not differ statistically significantly in terms of age, education or intelligence quotient. Patients showed poorer performance than controls on the copy of the Rey-Osterrieth Complex Figure test, the Block Design, the Trails B of the Trail Making Test and the Intra-Extra Dimensional Set Shifting test. Based on the normative data, most OSAS patients performed at a normal level, but a few patients had either mild dysfunction (2.5–12.5%) or moderate to severe dysfunction (5–15%). Conclusions: OSAS patients have lower set-shifting and analysis/synthesis performance than healthy controls. According to the normative data, most patients in the present study had normal performance, but there were also a few patients with more serious deficits.