Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Is memory impaired in narcolepsy type 1?

Memory deficits in narcolepsy with cataplexy type 1 (NT1) have been poorly studied, and the results are controversial. Patients with NT1 usually report memory deficits, which are not seen in objective memory assessments. This study aimed to assess attention and memory processes in NT1 patients using standardised neuropsychological tests and to compare the results with a control group. Performance in memory and attention tests was studied in 12 NT1 patients (diagnosed according to ICSD-3 criteria) and the results compared with those of 14 control subjects. All participants completed questionnaires on sleepiness and depression symptoms. Significant differences were found in the depression symptoms questionnaire. Regarding neuropsychological assessment, NT1 patients performed worse in attention than the control group in that they processed fewer stimuli and achieved fewer correct stimuli. However, no significant differences were found in the memory test results, and the performance was similar between both groups. After application of the Holm-Bonferroni correction, the only differences that remained significant were those in the ESS and in BDI-II scores. Our results showed that memory processes are preserved in NT1 patients and that memory complaints may not be associated with an objective memory deficit. In addition, the significant difference observed for patients in the depression questionnaire could explain the subjective memory complaints.

Neuropsychological Alterations in Narcolepsy with Cataplexy and the Expression of Cognitive Deficits.

OBJECTIVES: The objective of our study was to assess attention processes and executive function in patients with narcolepsy with cataplexy (NT1). To do so, we compared the results with those of a control group from the general population using an extensive neuropsychological test battery. METHODS: We studied 28 patients with NT1 and 28 healthy control participants matched for age, gender, and educational level. They all completed questionnaires on sleepiness, anxiety, and depression symptoms. In addition, they underwent neuropsychological tests. The ability to maintain attention was assessed using three computer tasks with different levels of complexity. RESULTS: Patients had significantly more daytime sleepiness than controls. A significant negative correlation between depression and disease duration was found in NT1 patients. The results of the anxiety questionnaire correlated with the presence of sleep paralysis. There were significant differences in information processing speed subtasks. Patients made significantly more omissions and generally reacted slower and more variably than controls in computerized tasks. As for executive function, patients performed worse in phonologic fluency tasks than controls. However, when the influence of processing speed on fluency tasks was statistically controlled, part of this significant difference disappeared. CONCLUSIONS: Our results indicate that the negative correlation between depression and disease duration probably reflects progressive adaptation to the functional burden of the disease. Information processing speed plays a fundamental role in the expression of cognitive deficits. We emphasized the need to control the influence of processing speed and sustained attention in the neuropsychological assessment of NT1 patients.

Narcolepsy with cataplexy and pregnancy: a case-control study.

This was a retrospective case-control study in 25 patients with narcolepsy with cataplexy and 75 women in the control group. Patients completed the questionnaire by Maurovich-Horvat et al. (J. Sleep Res., 2013, 22: 496-512). We personally interviewed 25 patients with narcolepsy with cataplexy using the administered questionnaire regarding conception, pregnancy, delivery, perinatal and breastfeeding periods. Patients with narcolepsy with cataplexy reported 59 pregnancies versus 164 in the control group. In 16 cases (27.1%), a disease before pregnancy was present compared with eight cases (4.9%) in the control group (P < 0.001); among them, extrinsic asthma was reported 11 times in the narcolepsy with cataplexy group (P < 0.005). Patients with narcolepsy with cataplexy more often had a single pregnancy compared with controls (P < 0.05). Gestational diabetes was more frequent in patients with narcolepsy with cataplexy (P < 0.05). Induced deliveries were higher in controls (P < 0.009). No differences were found between the groups in terms of duration of pregnancies and complications during and after delivery, as during the puerperium. Neonates from patients had heavier birth weight (P < 0.015). The breastfeeding period was longer in patients (P < 0.01). Modafinil and methylphenidate were the drugs administered in six pregnancies. No significant differences in depression during pregnancy and during puerperium were found between patients and controls. This is the first case-control study in women with narcolepsy with cataplexy related to pregnancy, delivery, childbirth and puerperium. Data suggest that patients have pregnancy outcomes similar to controls. The prevalence of gestational diabetes was higher in women with narcolepsy with cataplexy. Caesarean sections, complications during delivery and normal perinatal period for infants were similar in both groups. Breastfeeding was longer in patients.

Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.

The European Narcolepsy Network (EU-NN) database.

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease-specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web-based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post-marketing medication side-effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials.

ImmunoChip study implicates antigen presentation to T cells in narcolepsy.

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy.

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score » 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].

Narcolepsy with cataplexy and comorbid immunopathological diseases.

Evidence suggests that autoimmune diseases tend to co-occur so that patients with an autoimmune disorder are at higher risk of a second autoimmune disease. The association between allergic and autoimmune diseases is also of considerable interest. There are no reports on the association between sporadic or familial narcolepsy with cataplexy and other non-neurological immune-mediated diseases. This study reported on the comorbid immunopathological diseases associated with narcolepsy. One-hundred and fifty six narcoleptic patients with a mean age at diagnosis of 39.1 ± 17.8 years (range, 6-70 years) were assessed using the clinical history, physical and neurological examinations, sleep questionnaires, neuroimaging and human leucocyte antigen typing. Diagnosis was confirmed by polysomnography followed by a multiple sleep latency test or by measuring hypocretin-1 levels. Patients with immunopathological diseases were matched for gender and age at the onset of narcoleptic symptoms with narcoleptic patients without immunopathological diseases. Twenty-six patients (16.6%; 50% women; one familial, 25 sporadic) had one or more immunopathological diseases associated: autoimmune diseases, such as idiopathic thrombocytopenic purpura, multiple sclerosis, systemic lupus erythematosus, psoriasis, Crohn's disease, ulcerative colitis, autoimmune thyroid disease, Peyronie's disease and idiopathic recurrent facial palsy; other immunopathological diseases, like atopic dermatitis, allergic asthma and allergic rhinitis. Although not significant, the age at diagnosis of narcolepsy was 9.3 years earlier in patients with narcolepsy + immunopathological diseases. The results demonstrate that the prevalence of comorbid immunopathological diseases is high in narcolepsy, and cataplexy is significantly more severe in patients with narcolepsy + immunopathological diseases.

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study.

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies.

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (n = 216) and without cataplexy (n = 33) completed a self-administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (P < 0.001) and had a higher body mass index (BMI) prior to pregnancy (P < 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (P < 0.01). More patients with narcolepsy-cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy-cataplexy group compared to the narcolepsy group (P < 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy-cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy-cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.

A unique association? A narcolepsy type 1 case comorbid with Primary Biliary Cholangitis.

The aim of the study was to present a woman affected of a narcolepsy with cataplexy (narcolepsy type 1) comorbid with an asymptomatic Primary Biliary Cholangitis (PBC). The HLA haplotype was DRB1*15:01, DQA1*01:02, DQB1*06:02. The allele DQB1*06:02 has been considered until now protective for PBC and dual pathology has not been published. We think the important clinical message of the Case would be of continuing to monitor adults with narcolepsy type 1 for late complications that may be associated with other autoimmune conditions. Clinicians should be aware of the relationship between Narcolepsy and PBC. This highlights the need for screening and management in these individuals.

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Sleep, Respiration and Nocturnal Paroxysmal Events in Joubert Syndrome: A Case Report.

Introduction: Joubert syndrome is a rare disorder, characterized by a complex midbrain malformation caused by defects in the structure and/or function of the primary cilium. Case Report: A 15-year-old boy with mild intellectual disability, hypotonia, mild ataxia, and abnormal eye movements diagnosed as having Joubert Syndrome since childhood, was referred to the Sleep Unit because spells of apnea while sleeping. He did not complain of snoring or daytime somnolence. The macro and microstructure of sleep and the comorbidities such respiratory abnormalities, periodic legs movements (PLM) and paroxysmal motor arousals (PA) and minimal motor events (MME) are described for the first time in Joubert syndrome. Results: EEG was normal. Video-polysomnography revealed a nocturnal disturbed sleep and periods of hyperpnea accompanied by body movements and followed by a periodic breathing lasting several minutes with no oxygen desaturation. The arousals provoked by apneas triggered paroxysmal motor events with dystonic movements in the hand and right foot accompanied by a spontaneous Babinski. Brain MRI showed the typical "molar tooth sign". Conclusion: Joubert syndrome is a heterogeneous disease. Epileptic seizures have been reported in some cases. Video-PSG is mandatory for the identification of nocturnal breathing abnormalities and sleep-related motor paroxysmal episodes.

Long-Term Outcome of a Series of Patients With Narcolepsy Type 1 and Comorbidity With Immunopathological and Autoimmune Diseases.

Background: The aim of this study was to evaluate the long-term outcome of our series of narcolepsy type 1 (NT1) patients with comorbid autoimmune diseases (ADs) and other immunopathological diseases (IDs), focusing on the incidence of new ADs and IDs in this sample. Methods: A longitudinal observational study was conducted over 6 years (2014 - 2020) in a series of 158 Caucasians NT1 patients (96 males; mean age: 50.1 ± 19.0 years) from the previous study. All but one case (familial case) were HLA-DQB1*06:02-positive. The diagnosis of narcolepsy was made according to the International Classification of Sleep Disorders (ICSD-3). Results: Twenty-one patients have been diagnosed with a new ID, 10 of them with an AD (autoimmune thyroid disease, psoriasis, rheumatoid arthritis, transverse myelitis, granuloma annulare, primary biliary cirrhosis, alopecia areata and antiphospholipid syndrome), and 11 with other IDs (allergic rhinitis, allergic asthma, atopic dermatitis, food allergy, contact dermatitis and drug allergy). One patient was diagnosed with two new ADs. We found IDs in 46 patients (24 females and 22 males) and the overall prevalence in this series is actually 29.11%; 22 of them (13.92%) had an AD, with a percentage higher than estimated in the general population. Conclusions: The prevalence of AD/ID is high in our series, suggesting that NT1 might arise on a background of generalized susceptibility to immune-mediated processes. The occurrence of an ID can in turn influence the development of others in genetically predisposed individuals, which explains the increased associations observed in this long-term study.

Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis.

Purpose: Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990-2018) and the factors associated with the delay in Europe. Patients and Methods: We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. Results: The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7-13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. Conclusion: Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.

Data-Driven Phenotyping of Central Disorders of Hypersomnolence With Unsupervised Clustering.

BACKGROUND AND OBJECTIVES: Recent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed, and the question arises of whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see whether data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers. METHODS: We used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups. RESULTS: We included 1,078 unmedicated adolescents and adults. Seven clusters were identified, of which 4 clusters included predominantly individuals with cataplexy. The 2 most distinct clusters consisted of 158 and 157 patients, were dominated by those without cataplexy, and among other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening, and weekend-week sleep length difference. Patients formally diagnosed as having narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these 2 clusters. DISCUSSION: Using a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of sleep-onset REM periods in diagnostic criteria for people without cataplexy and provide promising new variables for reliable diagnostic categories that better resemble different patient phenotypes. Cluster-guided classification will result in a more solid hypersomnolence classification system that is less vulnerable to instability of single features.

New 2013 incidence peak in childhood narcolepsy: more than vaccination?

Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009-2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009-2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy.

Development of NREM sleep instability-continuity (cyclic alternating pattern) in healthy term infants aged 1 to 4 months.

STUDY OBJECTIVES: To evaluate non-rapid eye movement (NREM) sleep instability, as measured by the cyclic alternating pattern (CAP), in the first months of life in a group of normal healthy infants, in order to obtain more information on the maturation of arousal mechanisms during NREM sleep and to set normative data of CAP parameters in this age range (from 1 to 4 months of life). DESIGN: Retrospective study. SETTING: Sleep unit of an academic centre. PARTICIPANTS: Twenty-three healthy newborns and infants with a mean conceptional age (gestational age plus postnatal age) of 47.6 + 3.8 weeks, age range 42 to 55 weeks, 10 boys (43.47%), were studied while they slept in the morning between feedings, by means of a 3-hour video-electroencephalographic (EEG)-polygraphic recording. Sleep was visually scored for sleep architecture and CAP in a blinded fashion, using standard criteria. MEASUREMENTS AND RESULTS: We found 3 different sleep EEG patterns in our infants, according to their age, and we subdivided the entire group into 3 subgroups. Group 1-Tracé alternant mixed with high-voltage slow activity included 9 subjects (3 boys), with a mean conceptional age of 43.9 +/- 1.3 weeks; Group 2 (high-voltage slow activity and rudimentary spindles) included 6 subjects (4 boys), with a mean conceptional age of 49.4 +/- 3.1 weeks; and Group 3 (slow-wave activity and spindles, scored as NREM sleep) included 8 subjects (3 boys), with a mean conceptional age of 50.4 +/- 2.9 weeks. CAP rate was 6.83 +/- 3.58 in infants belonging to Group 2 and increased to 12.91 +/- 2.21 in Group 3. We found a statistically significant higher A1 index in only Group 3. The relative percentages of the A1, A2, and A3 subtypes showed non significant changes with age. The duration of CAP events and the cortical and subcortical arousal indexes were not statistically different between Groups 2 and 3. CONCLUSIONS: With this study, we provide the first data on CAP analysis in infants from 1 to 4 months of life, and we found that there is a transitory period when trace alternant disappears and CAP events begin to occur. Furthermore, we suggest that the more appropriate time of life when CAP analysis can be first performed is related to the appearance of mature stage 2 NREM with spindles and slow delta waves mixed with theta waves, at approximately 3 months of life.

Prevalence of EEG paroxysmal activity in a population of children with obstructive sleep apnea syndrome.

STUDY OBJECTIVES: Sleep breathing disorders may trigger paroxysmal events during sleep such as parasomnias and may exacerbate preexisting seizures. We verified the hypothesis that the amount of EEG paroxysmal activity (PA) may be high in children with obstructive sleep apnea syndrome (OSAS). DESIGN: Prospective study. SETTINGS: Sleep unit of an academic center. PARTICIPANTS: Polysomnographic studies were performed in a population of children recruited prospectively, for suspected OSAS, from January to December 2007, with no previous history of epileptic seizures or any other medical conditions. All sleep studies included > or = 8 EEG channels, including centrotemporal leads. We collected data about clinical and respiratory parameters of children with OSAS and with primary snoring, then we performed sleep microstructure analysis in 2 OSAS subgroups, matched for age and sex, with and without paroxysmal activity. MEASUREMENTS AND RESULTS: We found 40 children who met the criteria for primary snoring, none of them showed PA, while 127 children met the criteria for OSAS and 18 of them (14.2%) showed PA. Children with PA were older, had a predominance of boys, a longer duration of OSAS, and a lower percentage of adenotonsillar hypertrophy than children without PA. Moreover, PA occurred over the centrotemporal regions in 9 cases, over temporal-occipital regions in 5, and over frontocentral regions in 4. Children with PA showed a lower percentage of REM sleep, a lower CAP rate and lower A1 index during slow wave sleep, and lower total A2 and arousal index than children without EEG abnormalities. CONCLUSIONS: We found a higher percentage of paroxysmal activity in children with OSAS, compared to children with primary snoring, who did not exhibit EEG abnormalities. The children with paroxysmal activity have peculiar clinical and sleep microstructure characteristics that may have implications in the neurocognitive outcome of OSAS.