Mammalian NREM and REM sleep: Why, when and how.

This report proposes that fish use the spinal-rhombencephalic regions of their brain to support their activities while awake. Instead, the brainstem-diencephalic regions support the wakefulness in amphibians and reptiles. Lastly, mammals developed the telencephalic cortex to attain the highest degree of wakefulness, the cortical wakefulness. However, a paralyzed form of spinal-rhombencephalic wakefulness remains in mammals in the form of REMS, whose phasic signs are highly efficient in promoting maternal care to mammalian litter. Therefore, the phasic REMS is highly adaptive. However, their importance is low for singletons, in which it is a neutral trait, devoid of adaptive value for adults, and is mal-adaptive for marine mammals. Therefore, they lost it. The spinal-rhombencephalic and cortical wakeful states disregard the homeostasis: animals only attend their most immediate needs: foraging defense and reproduction. However, these activities generate allostatic loads that must be recovered during NREMS, that is a paralyzed form of the amphibian-reptilian subcortical wakefulness. Regarding the regulation of tonic REMS, it depends on a hypothalamic switch. Instead, the phasic REMS depends on an independent proportional pontine control.

The Birth of the Mammalian Sleep.

Mammals evolved from small-sized reptiles that developed endothermic metabolism. This allowed filling the nocturnal niche. They traded-off visual acuity for sensitivity but became defenseless against the dangerous daylight. To avoid such danger, they rested with closed eyes in lightproof burrows during light-time. This was the birth of the mammalian sleep, the main finding of this report. Improved audition and olfaction counterweighed the visual impairments and facilitated the cortical development. This process is called "The Nocturnal Evolutionary Bottleneck". Pre-mammals were nocturnal until the Cretacic-Paleogene extinction of dinosaurs. Some early mammals returned to diurnal activity, and this allowed the high variability in sleeping patterns observed today. The traits of Waking Idleness are almost identical to those of behavioral sleep, including homeostatic regulation. This is another important finding of this report. In summary, behavioral sleep seems to be an upgrade of Waking Idleness Indeed, the trait that never fails to show is quiescence. We conclude that the main function of sleep consists in guaranteeing it during a part of the daily cycle.

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.

The conserved ASTN2/BRINP1 locus at 9q33.1-33.2 is associated with major psychiatric disorders in a large pedigree from Southern Spain.

We investigated the genetic causes of major mental disorders (MMDs) including schizophrenia, bipolar disorder I, major depressive disorder and attention deficit hyperactive disorder, in a large family pedigree from Alpujarras, South of Spain, a region with high prevalence of psychotic disorders. We applied a systematic genomic approach based on karyotyping (n = 4), genotyping by genome-wide SNP array (n = 34) and whole-genome sequencing (n = 12). We performed genome-wide linkage analysis, family-based association analysis and polygenic risk score estimates. Significant linkage was obtained at chromosome 9 (9q33.1-33.2, LOD score = 4.11), a suggestive region that contains five candidate genes ASTN2, BRINP1, C5, TLR4 and TRIM32, previously associated with MMDs. Comprehensive analysis associated the MMD phenotype with genes of the immune system with dual brain functions. Moreover, the psychotic phenotype was enriched for genes involved in synapsis. These results should be considered once studying the genetics of psychiatric disorders in other families, especially the ones from the same region, since founder effects may be related to the high prevalence.

[Positive effect of bright light therapy on mood and sleep quality in institutionalized older people]. / Efecto positivo de la terapia de luz brillante sobre el estado de ánimo y la calidad del sueño en las personas mayores institucionalizadas.

INTRODUCTION: Bright light exposure during the day has a positive effect on health and its deficit can cause multiple physiological and cognitive disorders, including depression. The aim of this study was to evaluate the effect of bright light therapy (BLT) on the quality of sleep and mood emotional state; cognitive status, global deterioration and quality of life in institutionalized elderly. MATERIAL AND METHODS: This is a study with repeated measures design. Thirty-seven older people admitted to a nursing home. The study lasted 3 weeks. The first week, the reference values were established with the Oviedo Sleep Questionnaire, Yesavage Depression Scale, Mini-Mental, Global Scale of Impairment and European Quality of Life Questionnaire. During the second week, they were exposed to BLT (7,000-10,000lx at eye level) between 9:30 a.m. and 11:00 a.m. During the third week, all the data were re-evaluated. RESULTS: All variables improved significantly after the application of light therapy. Sleep (COS) pre-test 4.1±1.49, post-test 4.9±1.46, p: 0.01), mood (pre-test 3.65±2.78, post-test 2.65±2.9, p: 0.01), cognitive state (pre-test 22.72±6.53, post-test 24±5.92, p: 0.001), state of global deterioration (pre-test 3.10±1.26, post-test 2.72±5.92, p: 0.001) and health-related quality of life (pre-test 6.93±1.86, post-test 7.82±1.62, p: 0.001). CONCLUSIONS: Sleep quality, mood, cognitive status, global deterioration status and quality of life significantly improved after the application of light bright therapy.

Familial Psychosis Associated With a Missense Mutation at MACF1 Gene Combined With the Rare Duplications DUP3p26.3 and DUP16q23.3, Affecting the CNTN6 and CDH13 Genes.

Psychosis is a highly heritable and heterogeneous psychiatric condition. Its genetic architecture is thought to be the result of the joint effect of common and rare variants. Families with high prevalence are an interesting approach to shed light on the rare variant's contribution without the need of collecting large cohorts. To unravel the genomic architecture of a family enriched for psychosis, with four affected individuals, we applied a system genomic approach based on karyotyping, genotyping by whole-exome sequencing to search for rare single nucleotide variants (SNVs) and SNP array to search for copy-number variants (CNVs). We identified a rare non-synonymous variant, g.39914279 C > G, in the MACF1 gene, segregating with psychosis. Rare variants in the MACF1 gene have been previously detected in SCZ patients. Besides, two rare CNVs, DUP3p26.3 and DUP16q23.3, were also identified in the family affecting relevant genes (CNTN6 and CDH13, respectively). We hypothesize that the co-segregation of these duplications with the rare variant g.39914279 C > G of MACF1 gene precipitated with schizophrenia and schizoaffective disorder.

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.

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.

Substance use during pregnancy and personality dimensions. / Consumo de substancias durante el embarazo y dimensiones de personalidad.

Our aim was to assess personality traits associated with substance use during pregnancy in a population-based, multicentre study of 1804 pregnant women. On day 2-3 postpartum, participants completed a semi-structured interview, including self-reported drug use (alcohol, tobacco, caffeine, cannabis, cocaine, opioids) during pregnancy, and socio-demographic, reproductive and obstetric variables, personal and family psychiatric history, social support, and the Eysenck personality questionnaire, short version (EPQ-RS). Logistic regression models were conducted. Fifty per cent of women reported substance use during pregnancy: 40% caffeine, 21% tobacco, 3.5% alcohol, and 0.3 % cannabis. Mean T-scores (SD) for personality dimensions were 51.1 (9.6) for extraversion, 48 (8.9) for psychoticism, and 43.6 (8.5) for neuroticism. Extroversion (p = .029) and psychoticism (p = .009) were identified as risk factors after adjustment by age, level of education, employment status during pregnancy, low social support, and previous psychiatric history. For each increment of 10 units in their scores, the odds of substance use increased by 12% and 16% respectively. Low education, being on leave during pregnancy, and previous psychiatric history were independent factors (p < .05) associated with substance use during pregnancy. Primiparity was a protective factor (p = .001). The final models showed a good fit (p = .26). The screening of substance use during pregnancy should include personality dimensions apart from psychosocial variables and history of psychiatric disorders. It is important to identify the associated risk factors for substance use during pregnancy to prevent and improve foetal/neonatal and maternal health during perinatal period.

Este estudio evalúa los patrones de consumo de substancias durante el embarazo y las dimensiones de personalidad asociadas, en una muestra multicéntrica de 1804 mujeres de población general. En el 2-3 día posparto, completaron una entrevista auto-administrada sobre el consumo de alcohol, tabaco, cafeína, cannabis, cocaína, opiáceos, drogas de diseño, además de variables socio-demográficas, obstétricas/reproductivas, historia psiquiátrica previa, apoyo social durante el embarazo y el cuestionario de personalidad de Eysenck (EPQ-RS). Se generaron modelos de regresión logística múltiple. La prevalencia del consumo fue del 50% (N=909): 40% cafeína, 21% tabaco, 3,5% alcohol, y 0,3 cannabis. Las puntuaciones T medias (DE) de personalidad fueron: extraversión 51,1 (9,6), psicoticismo 48 (8,9) y neuroticismo 43,6 (8,5). Las dimensiones de extraversión (p=0,029) y psicoticismo (p=0,009), fueron identificadas como factores de riesgo tras ajustar por edad, nivel educación, estatus laboral durante el embarazo, bajo apoyo social, e historia psiquiátrica previa. Para cada incremento de 10 unidades en sus puntuaciones, el odds de consumo de substancias durante el embarazo se incrementó un 12% y un 16% respectivamente. Menor educación, estar de baja, y antecedentes psiquiátricos fueron también factores independientes (p<0,05) asociados al consumo. Ser primípara fue factor protector (p=0,001). El modelo final mostró un ajuste satisfactorio (p=0,26). El cribaje de las mujeres con riesgo de consumo de substancias durante el embarazo debería incluir la personalidad además de variables psicosociales y antecedentes psiquiátricos. Identificar los factores de riesgo asociados es importante para prevenir y mejorar la salud materna y fetal/neonatal durante el embarazo y posparto.

Bright Light Therapy and Circadian Cycles in Institutionalized Elders.

BACKGROUND: Bright light therapy has been found to be an efficient method to improve the main parameters of circadian rhythms. However, institutionalized elders may suffer reduced exposure to diurnal light, which may impair their circadian rhythms, cognitive performance, and general health status. OBJECTIVES: To analyze the effects of 5 days of morning exposure for 90 min to bright light therapy (BLT) applied to institutionalized elderly subjects with mild/moderate cognitive impairment. SUBJECTS: Thirty-seven institutionalized subjects of both sexes, aged 70-93 years. METHODS: The study lasted three consecutive weeks. During the second week the subjects were submitted to BLT (7000-10,000 lux at eye level) on a daily basis. Cognition, attention, and sleep quality were evaluated at the beginning of the first and third week. Circadian variables were recorded continuously throughout the 3 weeks. Non-invasive holders and validated tests were used to analyze the variables studied. RESULTS: After BLT we have found significant improvements in general cognitive capabilities, sleep quality and in the main parameters of the subject's circadian rhythms. The results show that merely 90 min of BLT for five days seems to achieve a significant improvement in a constellation of circadian, sleep, health, and cognitive factors. CONCLUSION: Bright light therapy is an affordable, effective, fast-acting therapy for age-related disturbances, with many advantages over pharmacological alternatives. We hypothesize these effects were the result of activating the residual activity of their presumably weakened circadian system.

Factor Structure of the Spanish Version of the Edinburgh Postnatal Depression Scale.

INTRODUCTION: The Edinburgh Postnatal Depression Scale (EPDS) is considered the gold standard in screening for postpartum depression. Although the Spanish version has been widely used, its factorial structure has not yet been studied . METHODS: A total of 1,204 women completed the EPDS 32 weeks after delivery. To avoid multiple testing, we split the sample into two halves, randomly drawing two subsamples of 602 participants each. We conducted exploratory factor analysis (EFA), followed by an oblimin rotation with the first sub-sample. Confirmatory factor analysis (CFA) was conducted using a Weighted Least Squares Means and Variance (WLSMV) estimation of the data. We explored different solutions between two and four factors. We compared the factors between two groups with depression and non-depression (evaluated with the Diagnostic Interview for Genetic Studies (DIGS) for the DSM-IV). RESULTS: The EFA indicated a three-factor model consisting of anxiety, depression and anhedonia. The results of the CFA confirmed the three-factor model (χ2=99.203, p<0.001; RMSEA=0.06, 90% CI=0.04/0.07, CFI=0.87 and TLI=0.82). Women with depression in the first 32 weeks obtained higher scores for anxiety, depression and anhedonia dimensions (p<0.001). CONCLUSIONS: This is the first study of confirmatory analysis with the Spanish version of EPDS in a large sample of women without psychiatric care during pregnancy. A three-factor model consisting of anxiety, depression and anhedonia was used. Women with depression had a higher score in the three dimensions of the EPDS.

Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European Narcolepsy Network database with machine learning.

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

Effects of differences in the availability of light upon the circadian rhythms of institutionalized elderly.

The aim of this study was to compare the availability of diurnal and nocturnal light in two residences for aged persons (R1 and R2, Palma de Mallorca, Illes Balears, Spain). We found that the R1 inmates were exposed to lower amounts of light during waking time and higher amounts during sleeping time. The main traits of the circadian rhythms and the quality of sleep in the inmates of the two residences were found to be positively related to the availability of light during waking time and negatively to the increased light exposure during bed time. In addition, the sleep of R1 inmates suffered higher disturbances as a consequence of the different policy for nocturnal diapers check and change. Altogether, these two factors may explain the differences observed in the two residences regarding the circadian rhythms, health status and quality of life. Two conclusions stem from these results: (1) the circadian rhythms of aged people are particularly sensitive to the contrast between diurnal and nocturnal light and (2) the nursing staff of institutions for aged people must receive specific formation on the best practices for maintaining the circadian health of aged people.

Neuronal surface antibodies in HIV-infected patients with isolated psychosis.

Neuronal surface antibodies (NSA) involved in autoimmune encephalitis (AE) have been related to relapses in HVS encephalitis. Their role in non-encephalitic psychosis is controversial. We previously reported an HIV-infected patient, NSA-positive, only presenting psychosis. Therefore, we determined the NSA prevalence in a prospective cohort of 22 HIV-positive patients with psychosis and we analyzed the frequency of HIV infection among NSA tested patients due to AE suspicion. We found no NSA in the prospective cohort. In the retrospective analysis, 22% of NSA-positive versus 4.6% of negative patients were HIV-positive. Wider studies are required to clarify the relationship between NSA and HIV infection.

Anti-NMDAR antibodies in new-onset psychosis. Positive results in an HIV-infected patient.

The role of neuronal surface autoantibodies (NSAs) in non-encephalitic psychosis is of recent and controversial interest. Most of the studies relating NSAs with psychosis are retrospective and only focused on the N-methyl-d-aspartate glutamate receptor (NMDAR). Our goal was to evaluate the prevalence of IgG antibodies against the NMDAR NR1 subunit (NMDAR-Abs) along with five additional NSAs in 61 first psychotic episode patients and 47 matched controls. We found two patients positive for NMDAR-Abs (3.3%). One of them was eventually considered to have been misdiagnosed and reclassified as encephalitis. The other met the criteria for bipolar I disorder, presented no neurological symptoms and had a comorbid HIV infection of vertical transmission. This is the first reported case of an HIV-infected patient with psychosis associated with NSAs. This study shows that patients presenting with clinically incomplete forms of anti-NMDAR encephalitis, with predominant or isolated psychiatric symptoms, can remain undetected if no ancillary tests are performed. To improve patient diagnosis and treatment of individuals with a first psychotic episode, more detailed neurological examinations might be needed. Further studies are required to better clarify the role of NSAs in the neuropsychiatric effects of HIV infection.

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.

Increased daylight availability reduces length of hospitalisation in depressive patients.

In a retrospective study, hospital stay in two hospitals was compared for depressive patients. The mean amount of accumulated light impinging the patient's area was 86,145 lux/light period in Hospital Universitari Son Dureta and 258,909 lux/light period in Hospital Universitari Son Espases (~300 % increase). The median stay was 14 days (1q-3q 8-19, n = 101) and 11 (1q-3q 6-15, n = 106) days, respectively. The reduction was significant only for the entire group, though not for subgroups (p < 0.007). Although the light received was not individually measured, results point to a significant effect of light in the recovery time of depressive patients. Prospective studies are needed.

Coping strategies for postpartum depression: a multi-centric study of 1626 women.

The transition to motherhood is stressful as it requires several important changes in family dynamics, finances, and working life, along with physical and psychological adjustments. This study aimed at determining whether some forms of coping might predict postpartum depressive symptomatology. A total of 1626 pregnant women participated in a multi-centric longitudinal study. Different evaluations were performed 8 and 32 weeks after delivery. Depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS) and the structured Diagnostic Interview for Genetic Studies (DIGS). The brief Coping Orientation for Problem Experiences (COPE) scale was used to measure coping strategies 2-3 days postpartum. Some coping strategies differentiate between women with and without postpartum depression. A logistic regression analysis was used to explore the relationships between the predictors of coping strategies and major depression (according to DSM-IV criteria). In this model, the predictor variables during the first 32 weeks were self-distraction (OR 1.18, 95 % CI 1.04-1.33), substance use (OR 0.58, 95 % CI 0.35-0.97), and self-blame (OR 1.18, 95 % CI 1.04-1.34). In healthy women with no psychiatric history, some passive coping strategies, both cognitive and behavioral, are predictors of depressive symptoms and postpartum depression and help differentiate between patients with and without depression.

Dual cases of type 1 narcolepsy with schizophrenia and other psychotic disorders.

OBJECTIVE: Cases of narcolepsy in association with psychotic features have been reported but never fully characterized. These patients present diagnostic and treatment challenges and may shed new light on immune associations in schizophrenia. METHOD: Our case series was gathered at two narcolepsy specialty centers over a 9-year period. A questionnaire was created to improve diagnosis of schizophrenia or another psychotic disorder in patients with narcolepsy. Pathophysiological investigations included full HLA Class I and II typing, testing for known systemic and intracellular/synaptic neuronal antibodies, recently described neuronal surface antibodies, and immunocytochemistry on brain sections to detect new antigens. RESULTS: Ten cases were identified, one with schizoaffective disorder, one with delusional disorder, two with schizophreniform disorder, and 6 with schizophrenia. In all cases, narcolepsy manifested first in childhood or adolescence, followed by psychotic symptoms after a variable interval. These patients had auditory hallucinations, which was the most differentiating clinical feature in comparison to narcolepsy patients without psychosis. Narcolepsy therapy may have played a role in triggering psychotic symptoms but these did not reverse with changes in narcolepsy medications. Response to antipsychotic treatment was variable. Pathophysiological studies did not reveal any known autoantibodies or unusual brain immunostaining pattern. No strong HLA association outside of HLA DQB1*06:02 was found, although increased DRB3*03 and DPA1*02:01 was notable. CONCLUSION: Narcolepsy can occur in association with schizophrenia, with significant diagnostic and therapeutic challenges. Dual cases maybe under diagnosed, as onset is unusually early, often in childhood. Narcolepsy and psychosis may share an autoimmune pathology; thus, further investigations in larger samples are warranted.

DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.

STUDY OBJECTIVE: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. DESIGN: Retrospective case-control study. SETTING: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. PATIENTS AND PARTICIPANTS: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included. MEASUREMENTS AND RESULTS: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified. CONCLUSION: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.