Turkka Kirjavainen

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.

Antigenic Differences between AS03 Adjuvanted Influenza A (H1N1) Pandemic Vaccines: Implications for Pandemrix-Associated Narcolepsy Risk

Background Narcolepsy results from immune-mediated destruction of hypocretin secreting neurons in hypothalamus, however the triggers and disease mechanisms are poorly understood. Vaccine-attributable risk of narcolepsy reported so far with the AS03 adjuvanted H1N1 vaccination Pandemrix has been manifold compared to the AS03 adjuvanted Arepanrix, which contained differently produced H1N1 viral antigen preparation. Hence, antigenic differences and antibody response to these vaccines were investigated. Methods and Findings Increased circulating IgG-antibody levels to Pandemrix H1N1 antigen were found in 47 children with Pandemrix-associated narcolepsy when compared to 57 healthy children vaccinated with Pandemrix. H1N1 antigen of Arepanrix inhibited poorly these antibodies indicating antigenic difference between Arepanrix and Pandemrix. High-resolution gel electrophoresis quantitation and mass spectrometry identification analyses revealed higher amounts of structurally altered viral nucleoprotein (NP) in Pandemrix. Increased antibody levels to hemagglutinin (HA) and NP, particularly to detergent treated NP, was seen in narcolepsy. Higher levels of antibodies to NP were found in children with DQB1*06∶02 risk allele and in DQB1*06∶02 transgenic mice immunized with Pandemrix when compared to controls. Conclusions This work identified 1) higher amounts of structurally altered viral NP in Pandemrix than in Arepanrix, 2) detergent-induced antigenic changes of viral NP, that are recognized by antibodies from children with narcolepsy, and 3) increased antibody response to NP in association of DQB1*06∶02 risk allele of narcolepsy. These findings provide a link between Pandemrix and narcolepsy. Although detailed mechanisms of Pandemrix in narcolepsy remain elusive, our results move the focus from adjuvant(s) onto the H1N1 viral proteins.

Hemodynamic responses to obstructive respiratory events during sleep are augmented in women with preeclampsia.

Preeclampsia is the most common disease of pregnancy, occurring in up to 10% of the pregnant population. The cause of the disease is as yet undetermined; however, most of the clinical effects are commonly attributed to damage to the endothelial layer, leading to increased pressor activity of all the maternal blood vessels. Therefore, we suspected that if obstructive sleep apnea (OSA) coexisted with preeclampsia in pregnancy, the hemodynamic effects of the OSA would be markedly potentiated. To test this hypothesis, we performed full sleep studies and overnight beat-to-beat blood pressure (BP) monitoring. The control patient group included 10 pregnant women with OSA and no evidence of hypertensive disease either before or during their current pregnancy. The test group included 10 women with preeclampsia and coexisting OSA. The pressor responses to obstructive respiratory events during sleep were enhanced in preeclamptic patients compared with control OSA patients (21+/-2/12+/-1 mm Hg and 38+/-5/25+/-4 mm Hg above baseline in control OSA and preeclamptic OSA patients, respectively, P = .005/.005). In contrast, there was no difference in heart rate responses between the two groups of subjects (34+/-5 beats/min and 49+/-13 beats/min above baseline in control and preeclamptic patient groups, respectively, P = .326). We suggest that the augmented pressor responses in preeclamptic women occur as a result of maternal endothelial damage induced by the preeclampsia disease process. These findings may have important implications in the management of preeclamptic patients.

Sleep problems and daytime tiredness in Finnish preschool-aged children-a community survey.

BACKGROUND Sleep is important to the well-being and development of children. Specially, small children are vulnerable to the effects of inadequate sleep. However, not much is known about the frequency of all types of sleep problems and daytime tiredness in preschool-aged children. OBJECTIVE To evaluate the prevalence of a wide spectrum of sleep problems, daytime tiredness and associations between these in 3- to 6-year-old Finnish children. METHODS A population-based study where parents of 3- to 6-year-old children (n= 904) living in Helsinki filled in the Sleep Disturbance Scale for Children (SDSC). RESULTS Of the children, 45% had at least one sleep-related problem occurring at least three times a week: 14.1% were unwilling to go to bed, 10.2% had difficulties in falling asleep, 10.2% had bruxism, 6.4% sleep talking, 2.1% sleep terrors, 8.2% had sleep-related breathing problem, 11.2% had excessive sweating while falling asleep and 12.9% excessive sweating during sleep. Age and gender were related to phenotype of the sleeping problems. In multiple regression analysis, the difficulties in initiating and maintaining sleep were most strongly associated with tiredness in the morning and during the day. CONCLUSIONS Different types of sleep problems are frequent in preschool-aged children. Poor sleep quality is associated with morning and daytime tiredness. In screening for sleep problems in children, attention should be paid not only to sleep amount but also to sleep quality.

Mood is associated with snoring in preschool-aged children.

Objective: To study emotional and behavioral problems and sleep and cognitive performance in snoring and nonsnoring 3- to 6-year-old children. Methods: As part of an epidemiological study of sleep disordered breathing (SDB) in preschool-aged children, 43 snorers and 46 nonsnorers participated in a clinical study. Their parents completed the Child Behavior Checklist (CBCL). The children were assessed with Wechsler Preschool and Primary Scale of Intelligence, Revised and subtests of the Developmental Neuropsychological Assessment (NEPSY-A) representing aspects of attention, language skills, sensorimotor functions, memory, and learning. Results: On the CBCL snoring children had significantly more parent reported internalizing symptoms (p < .05) than the nonsnoring children, especially symptoms of anxious/depressed mood (p < .01) and emotional reactivity (p < .05). More children from the snoring group than from the nonsnoring group (22 vs 11%) scored in the subclinical or clinical range on the internalizing scale. Interestingly, no significant difference between the groups was found in the amount of externalizing symptoms. The amount of sleep problems other than snoring was higher in the snoring than in the nonsnoring group (p < .01). On tests measuring auditory attention (p < .01) and language skills (verbal IQ, p < .05), the snoring group performed worse than the nonsnoring group. Conclusions: Our results support the view that SDB should be considered a possible risk factor for mood disorder symptoms and impaired cognitive performance in children.

Sleep of Excessively Crying Infants: A 24-Hour Ambulatory Sleep Polygraphy Study

Objective. Parents’ reports suggest that excessively crying or colicky infants sleep less compared with control subjects. The aim of this study was to determine the sleep-wake structure of excessively crying infants throughout a 24-hour cycle. Methods. A 24-hour sleep polygraphy study was conducted at home for 24 excessively crying infants and 23 control subjects at the age of 6 weeks. In addition, parental diaries were kept for 4 days. Results. In sleep polygraphy recordings, no major differences between study groups were observed in either the duration or the structure of the 24-hour sleep. In the diaries, the parents overestimated the amount of sleep in both study groups. The parents of the control infants overestimated the amount of sleep more than the parents of excessively crying infants (69.8 minutes [standard deviation: 79.3] compared with 27.1 minutes [standard deviation: 65.4], respectively). In excessively crying infants, the proportion of rapid eye movement sleep was higher during the 3-hour period from the beginning of the first long sleep in the evening and lower during the preceding 3-hour period compared with the control group. Conclusions. The results of this study suggest that diary-based studies are prone to be biased as the parents of the control infants are more likely to overestimate the amount of infant’s sleep and, therefore, report more sleep than the parents of the crying infants. Although no differences in the total amount of sleep or proportions of sleep stages were observed, excessively crying infants may be characterized by a disturbance that affects rapid eye movement and non–rapid eye movement sleep stage proportion during evening hours.

Sleep wake cycling in early preterm infants: Comparison of polysomnographic recordings with a novel EEG-based index

OBJECTIVE To document the occurrence of genuine sleep stages in the early preterm babies, and to develop an EEG-based index for following sleep wake cyclicity. METHODS Twelve preterm babies were recruited from a study that assessed ventilator strategies. We used altogether 18 polysomnography recordings that were collected at mean conceptional age of 29.3 (25.9-32.7) weeks. Spontaneous activity transients (SAT) were detected automatically and their cumulative coverage in each 20s interval was computed from the EEG derivations C3-A2 and O2-A1. Mean SAT% values between sleep stages were compared. RESULTS All babies exhibited all sleep stages, however the sleep was remarkably fragmentary in infants due to their respiratory issues. The EEG index, SAT% showed temporal behavior that strikingly well compared with the sleep stage fluctuations in the hypnogram. In the statistical analysis we found significant differences in all recordings between the deep (quiet) sleep and the REM sleep. CONCLUSION Genuine sleep states exist in the early preterm babies, and changes in sleep stages are reflected in the EEG activity in a way that can be readily measured by assessing fluctuation of the automatically detected, EEG based index, the SAT%. SIGNIFICANCE The findings open a possibility to construct automated analysis or monitoring of sleep wake cyclicity into brain monitors in neonatal intensive care unit.

The balance of the autonomic nervous system is normal in colicky infants.

Excessively crying, hard‐to‐soothe infants are described as colicky. The self‐limiting course of infantile colic during early infancy suggests an etiology of transient developmental dysmaturation. It has been proposed that emotional characteristics such as temperament and self‐soothing ability are correlated with the balance of the autonomic nervous system. Heart rate variability (HRV) analysis was used for evaluating the balance of the autonomic nervous system in colicky and control infants during and after the colicky period. HRV analysis was carried out on 12 colicky infants and 14 control infants at the age of 2 mo, and repeated on 10 colicky and 11 normal infants at the age of 7 mo. Measurements were performed during polygraphically confirmed slow‐wave sleep (sleep stages 3 and 4). Three HRV frequency bands were defined, including a high (0.2–1.0 Hz), middle (0.12–0.2 Hz) and low (0.025–0.12 Hz) frequency variability. There were no differences between the study groups in any of the three HRV frequency bands analyzed. The high frequency variability increased significantly with age in both study groups (p= 0.009).

Sleep disturbances in a community sample from preschool to school age.

OBJECTIVE To study the prevalence of various sleep problems at school age in a Finnish community sample and to evaluate the persistence of the sleep problems from the preschool age to school age in a 4-year follow-up. METHODS Parents completed the Sleep Disturbance Scale for Children questionnaire on their childs sleep during the preschool years (3-6 years) and again during the school years (7-11 years). At follow-up the parents also completed a questionnaire on family structure and socio-economic status. RESULTS The parents of 481 children completed the questionnaires during both the first study and the follow-up (girls 49%, boys 51%; mean age 9, range 7-11). At the population level, sleep problems slightly declined from preschool to school age (P < 0.05). However, sleep problems at preschool age showed a strong persistence to school age. At the follow-up, 35% of the children who were considered to have a sleep disorder at preschool age still suffered from it at school age. At the community level, this equates to 9% of the children. The children with no sleep problems at preschool age rarely developed sleep problems at school age. CONCLUSIONS This study showed that various types of sleep problems are common at school age. Sleep problems persisted from preschool to school age at the individual level. It is important to recognize all types of sleep problems, especially persistent ones. Persistent sleep problems in children may cause and exacerbate other somatic, cognitive and psychiatric problems. Therefore, more attention should be focused on sleep problems in paediatric health care with interventions aimed particularly at children with prolonged sleep problems.

Overnight Growth Hormone Secretion in Achondroplasia: Deconvolution Analysis, Correlation with Sleep State, and Changes after Treatment of Obstructive Sleep Apnea

The normal profile for overnight GH secretion in achondroplasia has not been previously studied. Factors that have been shown to influence GH secretion include age, obesity, sleep state, and the presence of obstructive sleep apnea (OSA). We assessed GH levels in a group of subjects with achondroplasia, during overnight polysomnography. Nineteen subjects with achondroplasia were studied at 11.3 y of age (median 6.7, range 1.8-30.9). Levels of GH were measured using time-resolved immunofluorometric assay(DELFIA, Pharmacia Biotech Inc.) and analyzed by a deconvolution method. Five subjects were restudied after treatment for OSA. Secretion rates of GH were greater in slow wave (SWS) and rapid eye movement (REM) sleep than in stage one and two (SI-II = light non-REM) sleep (p < 0.01). Total overnight GH secretion decreased with increasing age (r2 = 0.22 p < 0.04). Neither the frequency of arousals, frequency of sleep state transitions nor the severity of OSA correlated with measures of GH secretion. Levels of IGF-I correlated independently with age, body weight(percent ideal), and GH secretion rate (r2 = 0.76,p < 0.001). In a group of five subjects treated for OSA, improved respiratory distress index and reduced sleep state transitions were not associated with significant changes in GH secretion rate by sleep stage; SWS[from 0.62 ± 0.28 mIU/L/min to 1.02 ± 0.25 mIU/L/min (NS)] and SI-II sleep [from 0.26 ± 0.07 mIU/L/min to 0.60 ± 0.16 mIU/L/min(NS)]. However, in those five subjects, a GH secretion peak during the first 2 h of SWS was initially absent, appearing only after treatment of OSA (1.09± 0.38 mIU/L/min) compared with (2.40 ± 0.59 mIU/L/min(p = 0.01)). A profile of overnight GH secretion is presented for subjects with achondroplasia.