Lucid Dreaming in Narcolepsy

PubMed Central

Dodet, Pauline; Chavez, Mario; Leu-Semenescu, Smaranda; Golmard, Jean-Louis; Arnulf, Isabelle

2015-01-01

Objective: To evaluate the frequency, determinants and sleep characteristics of lucid dreaming in narcolepsy Settings: University hospital sleep disorder unit Design: Case-control study Participants: Consecutive patients with narcolepsy and healthy controls Methods: Participants were interviewed regarding the frequency and determinants of lucid dreaming. Twelve narcolepsy patients and 5 controls who self-identified as frequent lucid dreamers underwent nighttime and daytime sleep monitoring after being given instructions regarding how to give an eye signal when lucid. Results: Compared to 53 healthy controls, the 53 narcolepsy patients reported more frequent dream recall, nightmares and recurrent dreams. Lucid dreaming was achieved by 77.4% of narcoleptic patients and 49.1% of controls (P < 0.05), with an average of 7.6 ± 11 vs. 0.3 ± 0.8 lucid dreams/month (P < 0.0001). The frequency of cataplexy, hallucinations, sleep paralysis, dyssomnia, HLA positivity, and the severity of sleepiness were similar in narcolepsy with and without lucid dreaming. Seven of 12 narcoleptic (and 0 non-narcoleptic) lucid dreamers achieved lucid REM sleep across a total of 33 naps, including 14 episodes with eye signal. The delta power in the electrode average, in delta, theta, and alpha powers in C4, and coherences between frontal electrodes were lower in lucid than non-lucid REM sleep in spectral EEG analysis. The duration of REM sleep was longer, the REM sleep onset latency tended to be shorter, and the percentage of atonia tended to be higher in lucid vs. non-lucid REM sleep; the arousal index and REM density and amplitude were unchanged. Conclusion: Narcoleptics have a high propensity for lucid dreaming without differing in REM sleep characteristics from people without narcolepsy. This suggests narcolepsy patients may provide useful information in future studies on the nature of lucid dreaming. Citation: Dodet P, Chavez M, Leu-Semenescu S, Golmard JL, Arnulf I. Lucid dreaming in

Narcolepsy in African Americans

PubMed Central

Kawai, Makoto; O'Hara, Ruth; Einen, Mali; Lin, Ling; Mignot, Emmanuel

2015-01-01

Study Objectives: Although narcolepsy affects 0.02–0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States. Design/Setting: Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level. Patients: 182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy. Results: Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%). Conclusions: Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy. Citation: Kawai M, O'Hara R, Einen M, Lin L

Measurement of narcolepsy symptoms: The Narcolepsy Severity Scale.

PubMed

Dauvilliers, Yves; Beziat, Severine; Pesenti, Carole; Lopez, Regis; Barateau, Lucie; Carlander, Bertrand; Luca, Gianina; Tafti, Mehdi; Morin, Charles M; Billiard, Michel; Jaussent, Isabelle

2017-04-04

To validate the Narcolepsy Severity Scale (NSS), a brief clinical instrument to evaluate the severity and consequences of symptoms in patients with narcolepsy type 1 (NT1). A 15-item scale to assess the frequency and severity of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nighttime sleep was developed and validated by sleep experts with patients' feedback. Seventy untreated and 146 treated adult patients with NT1 were evaluated and completed the NSS in a single reference sleep center. The NSS psychometric properties, score changes with treatment, and convergent validity with other clinical parameters were assessed. The NSS showed good psychometric properties with significant item-total score correlations. The factor analysis indicated a 3-factor solution with good reliability, expressed by satisfactory Cronbach α values. The NSS total score temporal stability was good. Significant NSS score differences were observed between untreated and treated patients (dependent sample, 41 patients before and after sleep therapy; independent sample, 29 drug-free and 105 treated patients). Scores were lower in the treated populations (10-point difference between groups), without ceiling effect. Significant correlations were found among NSS total score and daytime sleepiness (Epworth Sleepiness Scale, Mean Sleep Latency Test), depressive symptoms, and health-related quality of life. The NSS can be considered a reliable and valid clinical tool for the quantification of narcolepsy symptoms to monitor and optimize narcolepsy management. © 2017 American Academy of Neurology.

Genetic association, seasonal infections and autoimmune basis of narcolepsy

PubMed Central

Singh, Abinav Kumar; Mahlios, Josh; Mignot, Emmanuel

2014-01-01

In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky’s criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers. PMID:23497937

Multiple sleep latency test in narcolepsy type 1 and narcolepsy type 2: A 5-year follow-up study.

PubMed

Huang, Yu-Shu; Guilleminault, Christian; Lin, Cheng-Hui; Chen, Chia-Hsiang; Chin, Wei-Chih; Chen, Tzu-Shuang

2018-05-29

Excessively sleepy teenagers and young adults without sleep-disordered breathing are diagnosed with either narcolepsy type 1 or narcolepsy type 2, or hypersomnia, based on the presence/absence of cataplexy and the results of a multiple sleep latency test. However, there is controversy surrounding this nomenclature. We will try to find the differences between different diagnoses of hypersomnia from the results of the long-term follow-up evaluation of a sleep study. We diagnosed teenagers who had developed excessive daytime sleepiness based on the criteria of the International Classification of Sleep Disorders, 3rd edition. Each individual received the same clinical neurophysiologic testing every year for 5 years after the initial diagnosis of narcolepsy type 1 (n = 111) or type 2 (n = 46). The follow-up evaluation demonstrated that narcolepsy type 1 (narcolepsy-cataplexy) is a well-defined clinical entity, with very reproducible clinical neurophysiologic findings over time, whereas patients with narcolepsy type 2 presented clear clinical and test variability. By the fifth year of the follow-up evaluation, 17.6% of subjects did not meet the diagnostic criteria of narcolepsy type 2, and 23.9% didn't show any two sleep-onset rapid eye movement periods in multiple sleep latency during the 5-year follow-up. Therefore narcolepsy type 1 (narcolepsy-cataplexy) is a well-defined syndrome, with the presentation clearly related to the known consequences of destruction of hypocretin/orexin neurons. Narcolepsy type 2 covers patients with clinical and test variability over time, thus bringing into question the usage of the term "narcolepsy" to label these patients. © 2018 European Sleep Research Society.

Low-resolution brain electromagnetic tomography (LORETA) identifies brain regions linked to psychometric performance under modafinil in narcolepsy.

PubMed

Saletu, Michael; Anderer, Peter; Semlitsch, Heribert V; Saletu-Zyhlarz, Gerda Maria; Mandl, Magdalena; Zeitlhofer, Josef; Saletu, Bernd

2007-01-15

Low-resolution brain electromagnetic tomography (LORETA) showed a functional deterioration of the fronto-temporo-parietal network of the right hemispheric vigilance system in narcolepsy and a therapeutic effect of modafinil. The aim of this study was to determine the effects of modafinil on cognitive and thymopsychic variables in patients with narcolepsy and investigate whether neurophysiological vigilance changes correlate with cognitive and subjective vigilance alterations at the behavioral level. In a double-blind, placebo-controlled crossover design, EEG-LORETA and psychometric data were obtained during midmorning hours in 15 narcoleptics before and after 3 weeks of placebo or 400 mg modafinil. Cognitive investigations included the Pauli Test and complex reaction time. Thymopsychic/psychophysiological evaluation comprised drive, mood, affectivity, wakefulness, depression, anxiety, the Symptom Checklist 90 and critical flicker frequency. The Multiple Sleep Latency Test (MSLT) and the Epworth Sleepiness Scale (ESS) were performed too. Cognitive performance (Pauli Test) was significantly better after modafinil than after placebo. Concerning reaction time and thymopsychic variables, no significant differences were observed. Correlation analyses revealed that a decrease in prefrontal delta, theta and alpha-1 power correlated with an improvement in cognitive performance. Moreover, drowsiness was positively correlated with theta power in parietal and medial prefrontal regions and beta-1 and beta-2 power in occipital regions. A less significant correlation was observed between midmorning EEG LORETA and the MSLT; between EEG LORETA and the ESS, the correlation was even weaker. In conclusion, modafinil did not influence thymopsychic variables in narcolepsy, but it significantly improved cognitive performance, which may be related to medial prefrontal activity processes identified by LORETA.

Narcolepsy in African Americans.

PubMed

Kawai, Makoto; O'Hara, Ruth; Einen, Mali; Lin, Ling; Mignot, Emmanuel

2015-11-01

Although narcolepsy affects 0.02-0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States. Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level. 182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy. Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%). Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy. © 2015 Associated Professional Sleep Societies, LLC.

Treatment Options for Narcolepsy.

PubMed

Barateau, Lucie; Lopez, Régis; Dauvilliers, Yves

2016-05-01

Narcolepsy type 1 and narcolepsy type 2 are central disorders of hypersomnolence. Narcolepsy type 1 is characterized by excessive daytime sleepiness and cataplexy and is associated with hypocretin-1 deficiency. On the other hand, in narcolepsy type 2, cerebrospinal fluid hypocretin-1 levels are normal and cataplexy absent. Despite major advances in our understanding of narcolepsy mechanisms, its current management is only symptomatic. Treatment options may vary from a single drug that targets several symptoms, or multiple medications that each treats a specific symptom. In recent years, narcolepsy treatment has changed with the widespread use of modafinil/armodafinil for daytime sleepiness, antidepressants (selective serotonin and dual serotonin and noradrenalin reuptake inhibitors) for cataplexy, and sodium oxybate for both symptoms. Other psychostimulants can also be used, such as methylphenidate, pitolisant and rarely amphetamines, as third-line therapy. Importantly, clinically relevant subjective and objective measures of daytime sleepiness are required to monitor the treatment efficacy and to provide guidance on whether the treatment goals are met. Associated symptoms and comorbid conditions, such as hypnagogic/hypnopompic hallucinations, sleep paralysis, disturbed nighttime sleep, unpleasant dreams, REM- and non REM-related parasomnias, depressive symptoms, overweight/obesity, and obstructive sleep apnea, should also be taken into account and managed, if required. In the near future, the efficacy of new wake-promoting drugs, anticataplectic agents, hypocretin replacement therapy and immunotherapy at the early stages of the disease should also be evaluated.

Evidence for Metabolic Hypothalamo-Amygdala Dysfunction in Narcolepsy

PubMed Central

Poryazova, Rositsa; Schnepf, Betina; Werth, Esther; Khatami, Ramin; Dydak, Ulrike; Meier, Dieter; Boesiger, Peter; Bassetti, Claudio L.

2009-01-01

Study Objectives: Proton resonance spectroscopy (1H-MRS) allows noninvasive chemical tissue analysis in the living brain. As neuronal loss and gliosis have been described in narcolepsy, metabolites of primary interest are N-acetylaspartate (NAA), a marker of neuronal integrity and myo-Inositol (mI), a glial marker and second messenger involved in the regulation of intracellular calcium. One 1H-MRS study in narcolepsy found no metabolic changes in the pontomedullary junction. Another study showed a reduction in NAA/creatine-phosphocreatine (Cr) in the hypothalamus of narcolepsy patients with cataplexy. We aimed to test for metabolic changes in specific brain areas, “regions of interest,” thought to be involved in emotional processing, sleep regulation and pathophysiology of narcolepsy: hypothalamus, pontomesencephalic junction and both amygdalae. Design: We performed 1H-MRS using a 3T Philips Achieva whole body MR scanner. Single-voxel proton MR spectra were acquired and quantified with LCModel to determine metabolite concentration ratios. Setting: The participants in the study were recruited at the outpatient clinic for sleep medicine, Department of Neurology and magnetic resonance spectroscopy was performed at the MRI facility, University Hospital Zurich. Participants: 1H-MRS was performed in fourteen narcolepsy patients with cataplexy, CSF hypocretin deficiency (10/10) and HLA-DQB1*0602 positivity (14/14) and 14 age, gender and body mass index matched controls. Patients were treatment naïve or off therapy for at least 14 days before scanning. Measurements and Results: No differences were observed in the regions of interest for (total NAA)/Cr ratios. Myo-Inositol (mI)/Cr was significantly lower in the right amygdala of the patients, compared to controls (P < 0.042). Significant negative correlations only in the patients group were found between (total NAA)/Cr in hypothalamus and mI/Cr in the right amygdala (r = −0.89, P < 0.001), between mI/Cr in

A polymorphism in CCR1/CCR3 is associated with narcolepsy.

PubMed

Toyoda, Hiromi; Miyagawa, Taku; Koike, Asako; Kanbayashi, Takashi; Imanishi, Aya; Sagawa, Yohei; Kotorii, Nozomu; Kotorii, Tatayu; Hashizume, Yuji; Ogi, Kimihiro; Hiejima, Hiroshi; Kamei, Yuichi; Hida, Akiko; Miyamoto, Masayuki; Imai, Makoto; Fujimura, Yota; Tamura, Yoshiyuki; Ikegami, Azusa; Wada, Yamato; Moriya, Shunpei; Furuya, Hirokazu; Takeuchi, Masaki; Kirino, Yohei; Meguro, Akira; Remmers, Elaine F; Kawamura, Yoshiya; Otowa, Takeshi; Miyashita, Akinori; Kashiwase, Koichi; Khor, Seik-Soon; Yamasaki, Maria; Kuwano, Ryozo; Sasaki, Tsukasa; Ishigooka, Jun; Kuroda, Kenji; Kume, Kazuhiko; Chiba, Shigeru; Yamada, Naoto; Okawa, Masako; Hirata, Koichi; Mizuki, Nobuhisa; Uchimura, Naohisa; Shimizu, Tetsuo; Inoue, Yuichi; Honda, Yutaka; Mishima, Kazuo; Honda, Makoto; Tokunaga, Katsushi

2015-10-01

Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function. Copyright © 2015 Elsevier Inc. All rights reserved.

Lucid dreaming in narcolepsy.

PubMed

Dodet, Pauline; Chavez, Mario; Leu-Semenescu, Smaranda; Golmard, Jean-Louis; Arnulf, Isabelle

2015-03-01

To evaluate the frequency, determinants and sleep characteristics of lucid dreaming in narcolepsy. University hospital sleep disorder unit. Case-control study. Consecutive patients with narcolepsy and healthy controls. Participants were interviewed regarding the frequency and determinants of lucid dreaming. Twelve narcolepsy patients and 5 controls who self-identified as frequent lucid dreamers underwent nighttime and daytime sleep monitoring after being given instructions regarding how to give an eye signal when lucid. Compared to 53 healthy controls, the 53 narcolepsy patients reported more frequent dream recall, nightmares and recurrent dreams. Lucid dreaming was achieved by 77.4% of narcoleptic patients and 49.1% of controls (P < 0.05), with an average of 7.6±11 vs. 0.3±0.8 lucid dreams/ month (P < 0.0001). The frequency of cataplexy, hallucinations, sleep paralysis, dyssomnia, HLA positivity, and the severity of sleepiness were similar in narcolepsy with and without lucid dreaming. Seven of 12 narcoleptic (and 0 non-narcoleptic) lucid dreamers achieved lucid REM sleep across a total of 33 naps, including 14 episodes with eye signal. The delta power in the electrode average, in delta, theta, and alpha powers in C4, and coherences between frontal electrodes were lower in lucid than non-lucid REM sleep in spectral EEG analysis. The duration of REM sleep was longer, the REM sleep onset latency tended to be shorter, and the percentage of atonia tended to be higher in lucid vs. non-lucid REM sleep; the arousal index and REM density and amplitude were unchanged. Narcolepsy is a novel, easy model for studying lucid dreaming. © 2015 Associated Professional Sleep Societies, LLC.

The European Narcolepsy Network (EU-NN) database.

PubMed

Khatami, Ramin; Luca, Gianina; Baumann, Christian R; Bassetti, Claudio L; Bruni, Oliviero; Canellas, Francesca; Dauvilliers, Yves; Del Rio-Villegas, Rafael; Feketeova, Eva; Ferri, Raffaele; Geisler, Peter; Högl, Birgit; Jennum, Poul; Kornum, Birgitte R; Lecendreux, Michel; Martins-da-Silva, Antonio; Mathis, Johannes; Mayer, Geert; Paiva, Teresa; Partinen, Markku; Peraita-Adrados, Rosa; Plazzi, Guiseppe; Santamaria, Joan; Sonka, Karel; Riha, Renata; Tafti, Mehdi; Wierzbicka, Aleksandra; Young, Peter; Lammers, Gert Jan; Overeem, Sebastiaan

2016-06-01

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. © 2016 European Sleep Research Society.

Incidence of Narcolepsy in Germany.

PubMed

Oberle, Doris; Drechsel-Bäuerle, Ursula; Schmidtmann, Irene; Mayer, Geert; Keller-Stanislawski, Brigitte

2015-10-01

Following the 2009 pandemic, reports of an association between an AS03 adjuvanted H1N1 pandemic influenza vaccine and narcolepsy were published. Besides determining background incidence rates for narcolepsy in Germany this study aimed at investigating whether there was a change in incidence rates of narcolepsy between the pre-pandemic, pandemic, and the post-pandemic period on the population level. Retrospective epidemiological study on the incidence of narcolepsy with additional capture-recapture analysis. German sleep centers. Eligible were patients with an initial diagnosis of narcolepsy (ICD10 Code G47.4) within the period from January 1, 2007 to December 31, 2011. None; observational study. A total of 342 sleep centers were invited to participate in the study. Adequate and suitable data were provided by 233 sleep centers (68.1%). A total of 1,198 patients with an initial diagnosis of narcolepsy within the observed period were included, of whom 106 (8.8%) were children and adolescents under the age of 18 years and 1,092 (91.2%) were adults. In children and adolescents, the age-standardized adjusted incidence rate significantly increased from 0.14/100,000 person-years in the pre-pandemic period to 0.50/100,000 person-years in the post-pandemic period (incidence density ratio, IDR 3.57; 95% CI 1.94-7.00). In adults, no significant change was detectable. This increase started in spring 2009. For the years 2007-2011, valid estimates for the incidence of narcolepsy in Germany were provided. In individuals under 18, the incidence rates continuously increased from spring 2009. © 2015 Associated Professional Sleep Societies, LLC.

[Narcolepsy with cataplexy: an autoimmune disease?].

PubMed

Jacob, Louis; Dauvilliers, Yves

2014-12-01

Narcolepsy type 1 (also named narcolepsy-cataplexy or hypocretin deficiency syndrome) is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy, plus frequently hypnagogic hallucinations, sleep paralysis and nocturnal sleep disturbances. Narcolepsy type 1 is an immune system-associated disease linked with the destruction of 70.000-90.000 hypocretin neurons notably involved in wakefulness. Among narcoleptic patients, 98% are positive for HLA-DQB1*06:02, a HLA class II allele, against 20-25% in general population. Individuals carrying HLA-DQB1*06:02 have an extraordinary risk to develop narcolepsy (odd ratio: 251). Other genes involved in CD4+ T cells and immune system activation as T-cell receptor α are also associated with narcolepsy. The development of the disease is linked with environmental factors such as influenza and streptococcal infections. Narcolepsy type 1 incidence also increased in Europe following the use of Pandemrix, a 2009 H1N1 AS03-adjuvanted vaccine manufactured by GlaxoSmithKline. Interestingly, such increase was not observed with Arepanrix, another vaccine developed by GSK very similar to Pandemrix. © 2014 médecine/sciences – Inserm.

Cases of pediatric narcolepsy after misdiagnoses.

PubMed

Kauta, Shilpa R; Marcus, Carole L

2012-11-01

Narcolepsy is characterized by recurrent brief attacks of irresistible sleepiness. Signs can begin during childhood. However, diagnoses are frequently delayed by 10-15 years because of unfamiliarity with pediatric narcolepsy and variable presentations of its associated features (cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis). Therefore, patients may remain untreated during their formative years. Three children with narcolepsy who were initially misdiagnosed are described. Each child's signs were initially related to depression, hypothyroidism, jaw dysfunction, or conversion disorder. However, after a multiple sleep latency test, the diagnosis of narcolepsy was established. All three patients were treated appropriately with stimulant medications, selective serotonin reuptake inhibitors, or sodium oxybate, and demonstrated positive responses. Although no definitive cure exists for narcolepsy, early recognition and appropriate symptomatic treatment with medications can allow affected children to improve quality of life and achieve normality, both academically and socially. Copyright © 2012 Elsevier Inc. All rights reserved.

Update on therapy for narcolepsy.

PubMed

Thorpy, Michael J

2015-05-01

Narcolepsy is a severe, incurable, neurological disorder that is treated by pharmacological management of its symptoms. The main symptoms are excessive daytime sleepiness (EDS) and cataplexy, although addition symptoms that may require treatment include sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. Sodium oxybate and modafinil/armodafinil are the first-line treatments for EDS, and sodium oxybate for cataplexy. Sodium oxybate treats all the symptoms of narcolepsy, whereas modafinil is effective for EDS only. Alternative medications for EDS include methylphenidate or amphetamines such as dextroamphetamine, lisdexamfetamine, methamphetamine, or combination amphetamine salts. Non-FDA approved medications for cataplexy include norepinephrine reuptake inhibitors such as venlafaxine or atomoxetine. Combination therapy can be more effective for sleepiness such as sodium oxybate and modafinil/armodafinil. Medication for narcolepsy is generally well tolerated and usually required life-long although does not eliminate all symptoms of narcolepsy.

Narcolepsy and the hypocretins.

PubMed

Wurtman, Richard J

2006-10-01

Narcolepsy is a chronic neurologic disease characterized by excessive daytime sleepiness and one or more of three additional symptoms (cataplexy, or sudden loss of muscle tone; vivid hallucinations; and brief periods of total paralysis) related to the occurrence of rapid eye movement (REM) sleep at inappropriate times. The daytime sleepiness typically presents as a sudden overwhelming urge to sleep, followed by periods of sleep that last for seconds or minutes, or even longer. During daytime sleep episodes, patients may exhibit "automatic behavior," performing conventionalized functions (eg, taking notes), but not remembering having done so once they are awake. About 10% of narcoleptics are members of familial clusters; however, genetic factors alone are apparently insufficient to cause the disease, inasmuch as the most common genetic disorder, a mutation in chromosome 6 controlling the HLA antigen immune complex, although seen in 90% to 100% of patients, also occurs in as many as 50% of people without narcolepsy. A dog model of narcolepsy exhibits a mutation on chromosome 12 that disrupts the processing of the peptide neurotransmitter hypocretin. No such mutation characterizes human narcolepsy; however, cerebrospinal fluid (CSF) hypocretin levels are profoundly depressed in narcoleptic patients, and a specific reduction in hypocretin-containing neurons has been described. One hypothesis concerning the pathophysiology of narcolepsy proposes that the HLA subtype resulting from the mutation on chromosome 6 increases the susceptibility of hypocretin-containing brain neurons to immune attack. Because hypocretin may normally participate in the maintenance of wakefulness, the loss of neurons that release this peptide might allow REM sleep to occur at inappropriate times, ie, while the patient is awake, in contrast to its normal cyclic appearance after a period of slow-wave sleep. The cataplexy, hallucinations, and/or paralysis associated with REM episodes normally are

Narcolepsy in children: a diagnostic and management approach.

PubMed

Babiker, Mohamed O E; Prasad, Manish

2015-06-01

To provide a diagnostic and management approach for narcolepsy in children. Narcolepsy is a chronic disabling disorder characterized by excessive daytime sleepiness, cataplexy, hypnogogic and/or hypnopompic hallucinations, and sleep paralysis. All four features are present in only half of the cases. Excessive daytime sleepiness is the essential feature of narcolepsy at any age and is usually the first symptom to manifest. A combination of excessive daytime sleepiness and definite cataplexy is considered pathognomonic of narcolepsy syndrome. New treatment options have become available over the past few years. Early diagnosis and management can significantly improve the quality of life of patients with narcolepsy with cataplexy. This review summarizes the pathophysiology, clinical features, and management options for children with narcolepsy. Copyright © 2015 Elsevier Inc. All rights reserved.

Facing emotions in narcolepsy with cataplexy: haemodynamic and behavioural responses during emotional stimulation.

PubMed

de Zambotti, Massimiliano; Pizza, Fabio; Covassin, Naima; Vandi, Stefano; Cellini, Nicola; Stegagno, Luciano; Plazzi, Giuseppe

2014-08-01

Narcolepsy with cataplexy is a complex sleep disorder that affects the modulation of emotions: cataplexy, the key symptom of narcolepsy, is indeed strongly linked with emotions that usually trigger the episodes. Our study aimed to investigate haemodynamic and behavioural responses during emotional stimulation in narco-cataplexy. Twelve adult drug-naive narcoleptic patients (five males; age: 33.3 ± 9.4 years) and 12 healthy controls (five males; age: 30.9 ± 9.5 years) were exposed to emotional stimuli (pleasant, unpleasant and neutral pictures). Heart rate, arterial blood pressure and mean cerebral blood flow velocity of the middle cerebral arteries were continuously recorded using photoplethysmography and Doppler ultrasound. Ratings of valence and arousal and coping strategies were scored by the Self-Assessment Manikin and by questionnaires, respectively. Narcoleptic patients' haemodynamic responses to pictures overlapped with the data obtained from controls: decrease of heart rate and increase of mean cerebral blood flow velocity regardless of pictures' content, increase of systolic blood pressure during the pleasant condition, and relative reduction of heart rate during pleasant and unpleasant conditions. However, when compared with controls, narcoleptic patients reported lower arousal scores during the pleasant and neutral stimulation, and lower valence scores during the pleasant condition, respectively, and also a lower score at the 'focus on and venting of emotions' dimensions of coping. Our results suggested that adult narcoleptic patients, compared with healthy controls, inhibited their emotion-expressive behaviour to emotional stimulation, and that may be related to the development of adaptive cognitive strategies to face emotions avoiding cataplexy. © 2014 European Sleep Research Society.

Genome-wide analysis of CNV (copy number variation) and their associations with narcolepsy in a Japanese population.

PubMed

Yamasaki, Maria; Miyagawa, Taku; Toyoda, Hiromi; Khor, Seik-Soon; Koike, Asako; Nitta, Aino; Akiyama, Kumi; Sasaki, Tsukasa; Honda, Yutaka; Honda, Makoto; Tokunaga, Katsushi

2014-05-01

In humans, narcolepsy with cataplexy (narcolepsy) is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Narcolepsy is caused by a reduction in the number of neurons that produce hypocretin (orexin) neuropeptide. Both genetic and environmental factors contribute to the development of narcolepsy.Rare and large copy number variations (CNVs) reportedly play a role in the etiology of a number of neuropsychiatric disorders. Narcolepsy is considered a neurological disorder; therefore, we sought to investigate any possible association between rare and large CNVs and human narcolepsy. We used DNA microarray data and a CNV detection software application, PennCNV-Affy, to detect CNVs in 426 Japanese narcoleptic patients and 562 healthy individuals. Overall, we found a significant enrichment of rare and large CNVs (frequency ≤1%, size ≥100 kb) in the patients (case-control ratio of CNV count=1.54, P=5.00 × 10(-4)). Next, we extended a region-based association analysis by including CNVs with its size ≥30 kb. Rare and large CNVs in PARK2 region showed a significant association with narcolepsy. Four patients were assessed to carry duplications of the gene region, whereas no controls carried the duplication, which was further confirmed by quantitative PCR assay. This duplication was also found in 2 essential hypersomnia (EHS) patients out of 171 patients. Furthermore, a pathway analysis revealed enrichments of gene disruptions by rare and large CNVs in immune response, acetyltransferase activity, cell cycle regulation and regulation of cell development. This study constitutes the first report on the risk association between multiple rare and large CNVs and the pathogenesis of narcolepsy. In the future, replication studies are needed to confirm the associations.

HYPOCRETIN/OREXIN AND NARCOLEPSY NEW BASIC AND CLINICAL INSIGHTS

PubMed Central

NISHINO, Seiji; OKURO, Masashi; KOTORII, Nozomu; ANEGAWA, Emiko; ISHIMARU, Yuji; MATSUMURA, Mari; KANBAYASHI, Takashi

2009-01-01

Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans. The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin/orexin ligand and its receptor. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in a large majority of narcolepsy with cataplexy. Hypocretin ligand deficiency in human narcolepsy is likely due to the postnatal cell death of hypocretin neurons. Although tight association between human leukocyte antigen (HLA) association and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proven. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune-mediated neurological disorders, such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO) related disorder. These findings likely have significant clinical relevance and for understanding the mechanisms of hypocretin cell death and choice of treatment option. These series of discoveries in humans lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid [CSF] hypocretin-1 levels for narcolepsy with cataplexy and narcolepsy due to medical condition). Since a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress. PMID:19555382

Misleading hallucinations in unrecognized narcolepsy.

PubMed

Szucs, A; Janszky, J; Holló, A; Migléczi, G; Halász, P

2003-10-01

To describe psychosis-like hallucinatory states in unrecognized narcolepsy. Two patients with hypnagogic/hypnapompic hallucinations are presented. Both patients had realistic and complex - multi-modal and scenic-daytime sexual hallucinations leading, in the first case, to a legal procedure because of false accusation, and in the second, to serious workplace conflicts. Both patients were convinced of the reality of their hallucinatory experiences but later both were able to recognize their hallucinatory character. Clinical data, a multiple sleep latency test, polysomnography, and HLA typing revealed that both patients suffered from narcolepsy. We suggest that in unrecognized narcolepsy with daytime hypnagogic/hypnapompic hallucinations the diagnostic procedure may mistakenly incline towards delusional psychoses. Daytime realistic hypnagogic/hypnapompic hallucinations may also have forensic consequences and mislead legal evaluation. Useful clinical features in differentiating narcolepsy from psychoses are: the presence of other narcoleptic symptoms, features of hallucinations, and response to adequate medication.

Insufficient non-REM sleep intensity in narcolepsy-cataplexy.

PubMed

Khatami, Ramin; Landolt, Hans-Peter; Achermann, Peter; Rétey, Julia V; Werth, Esther; Mathis, Johannes; Bassetti, Claudio L

2007-08-01

To compare electroencephalogram (EEG) dynamics during nocturnal sleep in patients with narcolepsy-cataplexy and healthy controls. Fragmented nocturnal sleep is a prominent feature and contributes to excessive daytime sleepiness in narcolepsy-cataplexy. Only 3 studies have addressed changes in homeostatic sleep regulation as a possible mechanism underlying nocturnal sleep fragmentation in narcolepsy-cataplexy. Baseline sleep of 11 drug-naive patients with narcolepsy-cataplexy (19-37 years) and 11 matched controls (18-41 years) was polysomnographically recorded. The EEG was subjected to spectral analysis. None, baseline condition. All patients with narcolepsy-cataplexy but no control subjects showed a sleep-onset rapid eye movement (REM) episode. Non-REM (NREM)-REM sleep cycles were longer in patients with narcolepsy-cataplexy than in controls (P = 0.04). Mean slow-wave activity declined in both groups across the first 3 NREM sleep episodes (P<0.001). The rate of decline, however, appeared to be steeper in patients with narcolepsy-cataplexy (time constant: narcolepsy-cataplexy 51.1 +/- 23.8 minutes [mean +/- SEM], 95% confidence interval [CI]: 33.4-108.8 minutes) than in controls (169.4 +/- 81.5 minutes, 95% CI: 110.9-357.6 minutes) as concluded from nonoverlapping 95% confidence interval of the time constants. The steeper decline of SWA in narcolepsy-cataplexy compared to controls was related to an impaired build-up of slow-wave activity in the second cycle. Sleep in the second cycle was interrupted in patients with narcolepsy-cataplexy, when compared with controls, by an increased number (P = 0.01) and longer duration (P = 0.01) of short wake episodes. Insufficient NREM sleep intensity is associated with nonconsolidated nocturnal sleep in narcolepsy-cataplexy. The inability to consolidate sleep manifests itself when NREM sleep intensity has decayed below a certain level and is reflected in an altered time course of slow-wave activity across NREM sleep episodes.

Increase of histaminergic tuberomammillary neurons in narcolepsy.

PubMed

Valko, Philipp O; Gavrilov, Yury V; Yamamoto, Mihoko; Reddy, Hasini; Haybaeck, Johannes; Mignot, Emmanuel; Baumann, Christian R; Scammell, Thomas E

2013-12-01

Narcolepsy is caused by loss of the hypothalamic neurons producing the orexin/hypocretin neuropeptides. One key target of the orexin system is the histaminergic neurons of the tuberomammillary nucleus (TMN), an essential wake-promoting system. As cerebrospinal fluid histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in 2 mouse models of narcolepsy. We counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone, and histamine in 7 narcolepsy patients and 12 control subjects using stereological techniques. We identified histaminergic neurons using immunostaining for histidine decarboxylase. We also examined these systems in 6 wild-type mice, 6 orexin/ataxin-3 transgenic mice, and 5 orexin ligand knockout mice. Compared to controls, narcolepsy patients had 94% more histaminergic TMN neurons (233,572 ± 49,476 vs 120,455 ± 10,665, p < 0.001). This increase was higher in 5 narcolepsy patients with >90% orexin neuron loss than in 2 patients with ≤75% orexin neuron loss (252,279 ± 46,264 vs 186,804 ± 1,256, p = 0.03). Similarly, the number of histaminergic TMN neurons was increased 53% in orexin ligand knockout mice compared to wild-type mice, whereas orexin/ataxin-3 transgenic mice showed an intermediate 28% increase. This surprising increase in histaminergic neurons in narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons and may contribute to some of the symptoms of narcolepsy such as preserved consciousness during cataplexy and fragmented nighttime sleep. In addition, this finding may have therapeutic implications, as medications that enhance histamine signaling are now under development. © 2013 American Neurological Association.

Reward-Seeking Behavior in Human Narcolepsy

PubMed Central

Dimitrova, Alexandra; Fronczek, Rolf; Van der Ploeg, Janneke; Scammell, Thomas; Gautam, Shiva; Pascual-Leone, Alvaro; Lammers, Gert Jan

2011-01-01

Study Objectives: The hypocretin system enhances signaling in the mesolimbic pathways regulating reward processing and addiction. Because individuals with narcolepsy with cataplexy have low hypocretin levels, we hypothesized that they may be less prone to risk- and reward-seeking behaviors, including substance abuse. Design: Endpoints were performance on an array of psychometric tests (including the Eysenck Impulsiveness Scale, the Zuckerman Sensation Seeking Scale, the Gormally Binge Eating Scale, and the Beck Depression and Anxiety Inventory) and on the Balloon Analogue Risk Task (BART). Setting: Tertiary narcolepsy referral centers in Leiden (The Netherlands) and Boston (USA). Patients: Subjects with narcolepsy with cataplexy (n = 30), narcolepsy without cataplexy (n = 15), and controls (n = 32) matched for age, sex, and smoking behavior. Interventions: None. Measurements and Results: There was no difference in risk-taking behavior between narcolepsy with or without cataplexy and the control group, as measured using the BART and the array of questionnaires. However, subjects in the narcolepsy with cataplexy group had significantly higher scores on the Eysenck Impulsiveness Scale (p < 0.05), with 10.0% categorized as impulsive, compared to 6.7% of the narcolepsy without cataplexy group and none of the controls. Narcoleptics with cataplexy also scored significantly higher than controls on the Binge Eating Scale (p < 0.05), with moderate or severe binge eating in 23%. On the depression and anxiety scales, all narcolepsy patients, especially those with cataplexy, scored significantly higher than controls. Conclusions: We found that narcoleptics with or without cataplexy generally have normal risk-taking behavior, but narcoleptics with cataplexy were more impulsive and more prone to binge eating than patients without cataplexy and controls. Our findings shed new light on the relation between sleepiness and impulsiveness. Furthermore, rates of depression and anxiety

Altered Brain Microstate Dynamics in Adolescents with Narcolepsy

PubMed Central

Drissi, Natasha M.; Szakács, Attila; Witt, Suzanne T.; Wretman, Anna; Ulander, Martin; Ståhlbrandt, Henriettae; Darin, Niklas; Hallböök, Tove; Landtblom, Anne-Marie; Engström, Maria

2016-01-01

Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin-1 producing neurons in the hypothalamus. Previous neuroimaging studies have investigated brain function in narcolepsy during rest using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In addition to hypothalamic and thalamic dysfunction they showed aberrant prefrontal perfusion and glucose metabolism in narcolepsy. Given these findings in brain structure and metabolism in narcolepsy, we anticipated that changes in functional magnetic resonance imaging (fMRI) resting state network (RSN) dynamics might also be apparent in patients with narcolepsy. The objective of this study was to investigate and describe brain microstate activity in adolescents with narcolepsy and correlate these to RSNs using simultaneous fMRI and electroencephalography (EEG). Sixteen adolescents (ages 13–20) with a confirmed diagnosis of narcolepsy were recruited and compared to age-matched healthy controls. Simultaneous EEG and fMRI data were collected during 10 min of wakeful rest. EEG data were analyzed for microstates, which are discrete epochs of stable global brain states obtained from topographical EEG analysis. Functional MRI data were analyzed for RSNs. Data showed that narcolepsy patients were less likely than controls to spend time in a microstate which we found to be related to the default mode network and may suggest a disruption of this network that is disease specific. We concluded that adolescents with narcolepsy have altered resting state brain dynamics. PMID:27536225

Challenges in diagnosing narcolepsy without cataplexy: a consensus statement.

PubMed

Baumann, Christian R; Mignot, Emmanuel; Lammers, Gert Jan; Overeem, Sebastiaan; Arnulf, Isabelle; Rye, David; Dauvilliers, Yves; Honda, Makoto; Owens, Judith A; Plazzi, Giuseppe; Scammell, Thomas E

2014-06-01

Diagnosing narcolepsy without cataplexy is often a challenge as the symptoms are nonspecific, current diagnostic tests are limited, and there are no useful biomarkers. In this report, we review the clinical and physiological aspects of narcolepsy without cataplexy, the limitations of available diagnostic procedures, and the differential diagnoses, and we propose an approach for more accurate diagnosis of narcolepsy without cataplexy. A group of clinician-scientists experienced in narcolepsy reviewed the literature and convened to discuss current diagnostic tools, and to map out directions for research that should lead to a better understanding and more accurate diagnosis of narcolepsy without cataplexy. To aid in the identification of narcolepsy without cataplexy, we review key indicators of narcolepsy and present a diagnostic algorithm. A detailed clinical history is mainly helpful to rule out other possible causes of chronic sleepiness. The multiple sleep latency test remains the most important measure, and prior sleep deprivation, shift work, or circadian disorders should be excluded by actigraphy or sleep logs. A short REM sleep latency (≤ 15 minutes) on polysomnography can aid in the diagnosis of narcolepsy without cataplexy, although sensitivity is low. Finally, measurement of hypocretin levels can helpful, as levels are low to intermediate in 10% to 30% of narcolepsy without cataplexy patients.

Degenerative pontine lesions in patients with familial narcolepsy.

PubMed

Stepień, Adam; Staszewski, Jacek; Domzał, Teofan M; Tomczykiewicz, Kazimierz; Skrobowska, Ewa; Durka-Kesy, Marta

2010-01-01

Narcolepsy is characterized by chronic excessive daytime sleepiness with episodic sleep attacks. There are several associated symptoms of narcolepsy: cataplexy (bilateral muscle weakness without loss of consciousness provoked by an emotional trigger, e.g. laughter), sleep paralysis and hypnagogic-hypnopompic hallucinations. Most cases are sporadic; familial narcolepsy contributes to only 1-5% of all cases. While most cases of narcolepsy are idiopathic and are not associated with clinical or radiographic evidence of brain pathology, symptomatic or secondary narcolepsy may occur occasionally in association with lesions caused by tumours, demyelination or strokes of the diencephalon, midbrain, and pons. There are some examples of non-specific brainstem lesions found in magnetic resonance imaging (MRI) in patients with idiopathic narcolepsy. The authors present eleven patients from a five-generation family with many members who suffer from episodic excessive daytime sleepiness. Narcolepsy was diagnosed in 9 patients. Sleepiness was frequently associated with cataplexy, hypnagogic-hypnopompic hallucinations and sleep paralysis. Improvement in their clinical state was observed during the treatment with modafinil. All probands had MRI of the brain, routine blood tests, EEG, polysomnography, examination of the level of hypocretin in cerebrospinal fluid and evaluation by means of Epworth and Stanford Sleepiness Scales. In 9 patients with narcolepsy, decreased thickness of the substantia nigra was found and in six of them degenerative lesions in the pontine substantia nigra were also noticed. The significance of these changes remains unclear. No data have been published until now concerning the presence of any brain lesions in patients with familial narcolepsy.

Patient-Reported Measures of Narcolepsy: The Need for Better Assessment.

PubMed

Kallweit, Ulf; Schmidt, Markus; Bassetti, Claudio L

2017-05-15

Narcolepsy, a chronic disorder of the central nervous system, is clinically characterized by a symptom pentad that includes excessive daytime sleepiness, cataplexy, sleep paralysis, hypnopompic/hypnagogic hallucinations, and disrupted nighttime sleep. Ideally, screening and diagnosis instruments that assist physicians in evaluating a patient for type 1 or type 2 narcolepsy would be brief, easy for patients to understand and physicians to score, and would identify or rule out the need for electrophysiological testing. A search of the literature was conducted to review patient-reported measures used for the assessment of narcolepsy, mainly in clinical trials, with the goal of summarizing existing scales and identifying areas that may require additional screening questions and clinical practice scales. Of the seven scales reviewed, the Epworth Sleepiness Scale continues to be an important outcome measure to screen adults for excessive daytime sleepiness, which may be associated with narcolepsy. Several narcolepsy-specific scales have demonstrated utility, such as the Ullanlinna Narcolepsy Scale, Swiss Narcolepsy Scale, and Narcolepsy Symptom Assessment Questionnaire, but further validation is required. Although the narcolepsy-specific scales currently in use may identify type 1 narcolepsy, there are no validated questionnaires to identify type 2 narcolepsy. Thus, there remains a need for short, easily understood, and well-validated instruments that can be readily used in clinical practice to distinguish narcolepsy subtypes, as well as other hypersomnias, and for assessing symptoms of these conditions during treatment. © 2017 American Academy of Sleep Medicine

Challenges in the development of therapeutics for narcolepsy

PubMed Central

Black, Sarah Wurts; Yamanaka, Akihiro; Kilduff, Thomas S.

2016-01-01

Narcolepsy is a neurological disorder that afflicts 1 in 2000 individuals and is characterized by excessive daytime sleepiness and cataplexy—a sudden loss of muscle tone triggered by positive emotions. Features of narcolepsy include dysregulation of arousal state boundaries as well as autonomic and metabolic disturbances. Disruption of neurotransmission through the hypocretin/orexin (Hcrt) system, usually by degeneration of the HCRT-producing neurons in the posterior hypothalamus, results in narcolepsy. The cause of Hcrt neurodegeneration is unknown but thought to be related to autoimmune processes. Current treatments for narcolepsy are symptomatic, including wake-promoting therapeutics that increase presynaptic dopamine release and anticataplectic agents that activate monoaminergic neurotransmission. Sodium oxybate is the only medication approved by the US Food and Drug Administration that alleviates both sleep/wake disturbances and cataplexy. Development of therapeutics for narcolepsy has been challenged by historical misunderstanding of the disease, its many disparate symptoms and, until recently, its unknown etiology. Animal models have been essential to elucidating the neuropathology underlying narcolepsy. These models have also aided understanding the neurobiology of the Hcrt system, mechanisms of cataplexy, and the pharmacology of narcolepsy medications. Transgenic rodent models will be critical in the development of novel therapeutics for the treatment of narcolepsy, particularly efforts directed to overcome challenges in the development of hypocretin replacement therapy. PMID:26721620

Challenges in the development of therapeutics for narcolepsy.

PubMed

Black, Sarah Wurts; Yamanaka, Akihiro; Kilduff, Thomas S

2017-05-01

Narcolepsy is a neurological disorder that afflicts 1 in 2000 individuals and is characterized by excessive daytime sleepiness and cataplexy-a sudden loss of muscle tone triggered by positive emotions. Features of narcolepsy include dysregulation of arousal state boundaries as well as autonomic and metabolic disturbances. Disruption of neurotransmission through the hypocretin/orexin (Hcrt) system, usually by degeneration of the HCRT-producing neurons in the posterior hypothalamus, results in narcolepsy. The cause of Hcrt neurodegeneration is unknown but thought to be related to autoimmune processes. Current treatments for narcolepsy are symptomatic, including wake-promoting therapeutics that increase presynaptic dopamine release and anticataplectic agents that activate monoaminergic neurotransmission. Sodium oxybate is the only medication approved by the US Food and Drug Administration that alleviates both sleep/wake disturbances and cataplexy. Development of therapeutics for narcolepsy has been challenged by historical misunderstanding of the disease, its many disparate symptoms and, until recently, its unknown etiology. Animal models have been essential to elucidating the neuropathology underlying narcolepsy. These models have also aided understanding the neurobiology of the Hcrt system, mechanisms of cataplexy, and the pharmacology of narcolepsy medications. Transgenic rodent models will be critical in the development of novel therapeutics for the treatment of narcolepsy, particularly efforts directed to overcome challenges in the development of hypocretin replacement therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

An overview of hypocretin based therapy in narcolepsy.

PubMed

Takenoshita, Shinichi; Sakai, Noriaki; Chiba, Yuhei; Matsumura, Mari; Yamaguchi, Mai; Nishino, Seiji

2018-04-01

Narcolepsy with cataplexy is most commonly caused by a loss of hypocretin/orexin peptide-producing neurons in the hypothalamus (i.e., Narcolepsy Type 1). Since hypocretin deficiency is assumed to be the main cause of narcoleptic symptoms, hypocretin replacement will be the most essential treatment for narcolepsy. Unfortunately, this option is still not available clinically. There are many potential approaches to replace hypocretin in the brain for narcolepsy such as intranasal administration of hypocretin peptides, developing small molecule hypocretin receptor agonists, hypocretin neuronal transplantation, transforming hypocretin stem cells into hypothalamic neurons, and hypocretin gene therapy. Together with these options, immunotherapy treatments to prevent hypocretin neuronal death should also be developed. Areas covered: In this review, we overview the pathophysiology of narcolepsy and the current and emerging treatments of narcolepsy especially focusing on hypocretin receptor based treatments. Expert opinion: Among hypocretin replacement strategies, developing non-peptide hypocretin receptor agonists is currently the most encouraging since systemic administration of a newly synthesized, selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in murine models. If this option is effective in humans, hypocretin cell transplants or gene therapy technology may become realistic in the future.

Neuroimaging of Narcolepsy and Kleine-Levin Syndrome.

PubMed

Hong, Seung Bong

2017-09-01

Narcolepsy is a chronic neurologic disorder with the abnormal regulation of the sleep-wake cycle, resulting in excessive daytime sleepiness, disturbed nocturnal sleep, and manifestations related to rapid eye movement sleep, such as cataplexy, sleep paralysis, and hypnagogic hallucination. Over the past decade, numerous neuroimaging studies have been performed to characterize the pathophysiology and various clinical features of narcolepsy. This article reviews structural and functional brain imaging findings in narcolepsy and Kleine-Levin syndrome. Based on the current state of research, brain imaging is a useful tool to investigate and understand the neuroanatomic correlates and brain abnormalities of narcolepsy and other hypersomnia. Copyright © 2017 Elsevier Inc. All rights reserved.

Patient-Reported Measures of Narcolepsy: The Need for Better Assessment

PubMed Central

Kallweit, Ulf; Schmidt, Markus; Bassetti, Claudio L.

2017-01-01

Study Objectives: Narcolepsy, a chronic disorder of the central nervous system, is clinically characterized by a symptom pentad that includes excessive daytime sleepiness, cataplexy, sleep paralysis, hypnopompic/hypnagogic hallucinations, and disrupted nighttime sleep. Ideally, screening and diagnosis instruments that assist physicians in evaluating a patient for type 1 or type 2 narcolepsy would be brief, easy for patients to understand and physicians to score, and would identify or rule out the need for electrophysiological testing. Methods: A search of the literature was conducted to review patient-reported measures used for the assessment of narcolepsy, mainly in clinical trials, with the goal of summarizing existing scales and identifying areas that may require additional screening questions and clinical practice scales. Results: Of the seven scales reviewed, the Epworth Sleepiness Scale continues to be an important outcome measure to screen adults for excessive daytime sleepiness, which may be associated with narcolepsy. Several narcolepsy-specific scales have demonstrated utility, such as the Ullanlinna Narcolepsy Scale, Swiss Narcolepsy Scale, and Narcolepsy Symptom Assessment Questionnaire, but further validation is required. Conclusions: Although the narcolepsy-specific scales currently in use may identify type 1 narcolepsy, there are no validated questionnaires to identify type 2 narcolepsy. Thus, there remains a need for short, easily understood, and well-validated instruments that can be readily used in clinical practice to distinguish narcolepsy subtypes, as well as other hypersomnias, and for assessing symptoms of these conditions during treatment. Citation: Kallweit U, Schmidt M, Bassetti CL. Patient-reported measures of narcolepsy: the need for better assessment. J Clin Sleep Med. 2017;13(5):737–744. PMID:28162143

Challenges in Diagnosing Narcolepsy without Cataplexy: A Consensus Statement

PubMed Central

Baumann, Christian R.; Mignot, Emmanuel; Lammers, Gert Jan; Overeem, Sebastiaan; Arnulf, Isabelle; Rye, David; Dauvilliers, Yves; Honda, Makoto; Owens, Judith A.; Plazzi, Giuseppe; Scammell, Thomas E.

2014-01-01

Background: Diagnosing narcolepsy without cataplexy is often a challenge as the symptoms are nonspecific, current diagnostic tests are limited, and there are no useful biomarkers. In this report, we review the clinical and physiological aspects of narcolepsy without cataplexy, the limitations of available diagnostic procedures, and the differential diagnoses, and we propose an approach for more accurate diagnosis of narcolepsy without cataplexy. Methods: A group of clinician-scientists experienced in narcolepsy reviewed the literature and convened to discuss current diagnostic tools, and to map out directions for research that should lead to a better understanding and more accurate diagnosis of narcolepsy without cataplexy. Recommendations: To aid in the identification of narcolepsy without cataplexy, we review key indicators of narcolepsy and present a diagnostic algorithm. A detailed clinical history is mainly helpful to rule out other possible causes of chronic sleepiness. The multiple sleep latency test remains the most important measure, and prior sleep deprivation, shift work, or circadian disorders should be excluded by actigraphy or sleep logs. A short REM sleep latency (≤ 15 minutes) on polysomnography can aid in the diagnosis of narcolepsy without cataplexy, although sensitivity is low. Finally, measurement of hypocretin levels can helpful, as levels are low to intermediate in 10% to 30% of narcolepsy without cataplexy patients. Citation: Baumann CR, Mignot E, Lammers GJ, Overeem S, Arnulf I, Rye D, Dauvilliers Y, Honda M, Owens JA, Plazzi G, Scammell TE. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. SLEEP 2014;37(6):1035-1042. PMID:24882898

Narcolepsy

PubMed Central

Mitler, Merrill M.; Hajdukovic, Roza; Erman, Milton; Koziol, James A.

2008-01-01

Summary Narcolepsy is a neurological condition with a prevalence of up to 1 per 1,000 that is characterized by irresistible bouts of sleep. Associated features include the pathological manifestations of rapid-eye-movement (REM) sleep: cataplexy, sleep paralysis, hypnagogic hallucinations, and abnormal sleep-onset REM periods and disturbed nocturnal sleep. The condition is strongly associated with the HLA-DR2 and DQw1 phenotype. The phenomenology of narcolepsy is discussed, and diagnostic procedures are reviewed. Treatment modalities involving central nervous system stimulants for somnolence and tricyclic drugs for REM-sleep abnormalities are discussed. Sleep laboratory studies on the treatment efficacy of methylphenidate, pemoline, dextroamphetamine, protriptyline, and viloxazine are presented. Data suggest that: (1) methylphenidate and dextro-amphetamine objectively improve somnolence; (2) pemoline, at doses up to 112.5 mg, is less effective in controlling somnolence but may improve certain aspects of performance; and (3) protriptyline and viloxazine are effective anticataplectic agents that produce little improvement in somnolence. PMID:1968069

Pharmacological management of narcolepsy with and without cataplexy.

PubMed

Kallweit, Ulf; Bassetti, Claudio L

2017-06-01

Narcolepsy is an orphan neurological disease and presents with sleep-wake, motoric, neuropsychiatric and metabolic symptoms. Narcolepsy with cataplexy is most commonly caused by an immune-mediated process including genetic and environmental factors, resulting in the selective loss of hypocretin-producing neurons. Narcolepsy has a major impact on workableness and quality of life. Areas covered: This review provides an overview of the temporal available treatment options for narcolepsy (type 1 and 2) in adults, including authorization status by regulatory agencies. First- and second-line options are discussed as well as combination therapies. In addition, treatment options for frequent coexisting co-morbidities and different phenotypes of narcolepsy are presented. Finally, this review considers potential future management strategies. Non-pharmacological approaches are important in the management of narcolepsy but will not be covered in this review. Expert opinion: Concise evaluation of symptoms and type of narcolepsy, coexisting co-morbidities and patients´ distinct needs is mandatory in order to identify a suitable, individual pharmacological treatment. First-line options include Modafinil/Armodafinil (for excessive daytime sleepiness, EDS), Sodium Oxybate (for EDS and/with cataplexy), Pitolisant (for EDS and cataplexy) and Venlafaxine (for cataplexy (off-label) and co-morbid depression). New symptomatic and causal treatment most probably will be completed by hypocretin-replacement and immune-modifying strategies.

ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy

PubMed Central

Kornum, Birgitte Rahbek; Kenny, Eimear E.; Trynka, Gosia; Einen, Mali; Rico, Tom J.; Lichtner, Peter; Dauvilliers, Yves; Arnulf, Isabelle; Lecendreux, Michel; Javidi, Sirous; Geisler, Peter; Mayer, Geert; Pizza, Fabio; Poli, Francesca; Plazzi, Giuseppe; Overeem, Sebastiaan; Lammers, Gert Jan; Kemlink, David; Sonka, Karel; Nevsimalova, Sona; Rouleau, Guy; Desautels, Alex; Montplaisir, Jacques; Frauscher, Birgit; Ehrmann, Laura; Högl, Birgit; Jennum, Poul; Bourgin, Patrice; Peraita-Adrados, Rosa; Iranzo, Alex; Bassetti, Claudio; Chen, Wei-Min; Concannon, Patrick; Thompson, Susan D.; Damotte, Vincent; Fontaine, Bertrand; Breban, Maxime; Gieger, Christian; Klopp, Norman; Deloukas, Panos; Wijmenga, Cisca; Hallmayer, Joachim; Onengut-Gumuscu, Suna; Rich, Stephen S.; Winkelmann, Juliane; Mignot, Emmanuel

2013-01-01

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. PMID:23459209

IgG abnormality in narcolepsy and idiopathic hypersomnia.

PubMed

Tanaka, Susumu; Honda, Makoto

2010-03-05

A close association between narcolepsy and the Human Leukocyte Antigen (HLA)-DQB1*0602 allele suggests the involvement of the immune system, or possibly an autoimmune process. We investigated serum IgG levels in narcolepsy. We measured the serum total IgG levels in 159 Japanese narcolepsy-cataplexy patients positive for the HLA-DQB1*0602 allele, 28 idiopathic hypersomnia patients with long sleep time, and 123 healthy controls (the HLA-DQB1*0602 allele present in 45 subjects). The serum levels of each IgG subclass were subsequently measured. The distribution of serum IgG was significantly different among healthy controls negative for the HLA-DQB1*0602 allele (11.66+/-3.55 mg/ml), healthy controls positive for the HLA-DQB1*0602 allele (11.45+/-3.43), narcolepsy patients (9.67+/-3.38), and idiopathic hypersomnia patients (13.81+/-3.80). None of the following clinical variables, age, disease duration, Epworth Sleepiness Scale, smoking habit and BMI at the time of blood sampling, were associated with IgG levels in narcolepsy or idiopathic hypersomnia. Furthermore we found the decrease in IgG1 and IgG2 levels, stable expression of IgG3, and the increase in the proportion of IgG4 in narcolepsy patients with abnormally low IgG levels. The increase in the proportion of IgG4 levels was also found in narcolepsy patients with normal serum total IgG levels. Idiopathic hypersomnia patients showed a different pattern of IgG subclass distribution with high IgG3 and IgG4 level, low IgG2 level, and IgG1/IgG2 imbalance. Our study is the first to determine IgG abnormalities in narcolepsy and idiopathic hypersomnia by measuring the serum IgG levels in a large number of hypersomnia patients. The observed IgG abnormalities indicate humoral immune alterations in narcolepsy and idiopathic hypersomnia. Different IgG profiles suggest immunological differences between narcolepsy and idiopathic hypersomnia.

Psychotic symptoms in narcolepsy: phenomenology and a comparison with schizophrenia.

PubMed

Fortuyn, Hal A Droogleever; Lappenschaar, G A; Nienhuis, Fokko J; Furer, Joop W; Hodiamont, Paul P; Rijnders, Cees A; Lammers, Gert Jan; Renier, Willy O; Buitelaar, Jan K; Overeem, Sebastiaan

2009-01-01

Patients with narcolepsy often experience pervasive hypnagogic hallucinations, sometimes even leading to confusion with schizophrenia. We aimed to provide a detailed qualitative description of hypnagogic hallucinations and other "psychotic" symptoms in patients with narcolepsy and contrast these with schizophrenia patients and healthy controls. We also compared the prevalence of formal psychotic disorders between narcolepsy patients and controls. We used SCAN 2.1 interviews to compare psychotic symptoms between 60 patients with narcolepsy, 102 with schizophrenia and 120 matched population controls. In addition, qualitative data was collected to enable a detailed description of hypnagogic hallucinations in narcolepsy. There were clear differences in the pattern of hallucinatory experiences in narcolepsy vs. schizophrenia patients. Narcoleptics reported multisensory "holistic" hallucinations rather than the predominantly verbal-auditory sensory mode of schizophrenia patients. Psychotic symptoms such as delusions were not more frequent in narcolepsy compared to population controls. In addition, the prevalence of formal psychotic disorders was not increased in patients with narcolepsy. Almost half of narcoleptics reported moderate interference with functioning due to hypnagogic hallucinations, mostly due to related anxiety. Hypnagogic hallucinations in narcolepsy can be differentiated on a phenomenological basis from hallucinations in schizophrenia which is useful in differential diagnostic dilemmas.

Circadian Rest-Activity Rhythm in Pediatric Type 1 Narcolepsy

PubMed Central

Filardi, Marco; Pizza, Fabio; Bruni, Oliviero; Natale, Vincenzo; Plazzi, Giuseppe

2016-01-01

Study Objectives: Pediatric type 1 narcolepsy is often challenging to diagnose and remains largely undiagnosed. Excessive daytime sleepiness, disrupted nocturnal sleep, and a peculiar phenotype of cataplexy are the prominent features. The knowledge available about the regulation of circadian rhythms in affected children is scarce. This study compared circadian rest-activity rhythm and actigraphic estimated sleep measures of children with type 1 narcolepsy versus healthy controls. Methods: Twenty-two drug-naïve type 1 narcolepsy children and 21 age- and sex- matched controls were monitored for seven days during the school week by actigraphy. Circadian activity rhythms were analyzed through functional linear modeling; nocturnal and diurnal sleep measures were estimated from activity using a validated algorithm. Results: Children with type 1 narcolepsy presented an altered rest-activity rhythm characterized by enhanced motor activity throughout the night and blunted activity in the first afternoon. No difference was found between children with type 1 narcolepsy and controls in the timing of the circadian phase. Actigraphic sleep measures showed good discriminant capabilities in assessing type 1 narcolepsy nycthemeral disruption. Conclusions: Actigraphy reliably renders the nycthemeral disruption typical of narcolepsy type 1 in drug-naïve children with recent disease onset, indicating the sensibility of actigraphic assessment in the diagnostic work-up of childhood narcolepsy type 1. Citation: Filardi M, Pizza F, Bruni O, Natale V, Plazzi G. Circadian rest-activity rhythm in pediatric type 1 narcolepsy. SLEEP 2016;39(6):1241–1247. PMID:27091539

Cerebellar malformations alter regional cerebral development.

PubMed

Bolduc, Marie-Eve; Du Plessis, Adre J; Evans, Alan; Guizard, Nicolas; Zhang, Xun; Robertson, Richard L; Limperopoulos, Catherine

2011-12-01

The aim of this study was to compare total and regional cerebral volumes in children with isolated cerebellar malformations (CBMs) with those in typically developing children, and to examine the extent to which cerebellar volumetric reductions are associated with total and regional cerebral volumes. This is a case-control study of children diagnosed with isolated CBMs. Each child was matched on age and sex to two typically developing children. Using advanced three-dimensional volumetric magnetic resonance imaging, the cerebrum was segmented into tissue classes and partitioned into eight regions. Analysis of variance was used to compare cerebral volumes between children with CBMs and control children, and linear regressions to examine the impact of cerebellar volume reduction on cerebral volumes. Magnetic resonance imaging was performed at a mean age of 27 months in 20 children (10 males, 10 females) with CBMs and 40 typically developing children. Children with CBMs showed significantly smaller deep grey matter nuclei (p < 0.001), subgenual white matter (p = 0.03), midtemporal white matter (p = 0.02), and inferior occipital grey matter (p = 0.03) volumes than typically developing children. Greater cerebellar volumetric reduction in children with CBMs was associated with decreased total cerebral volume and deep grey matter nuclei (p = 0.02), subgenual white/grey matter (p = 0.001), midtemporal white (p = 0.02) and grey matter (p = 0.01), and parieto-occipital grey matter (p = 0.004). CBMs are associated with impaired regional cerebral growth, suggesting deactivation of principal cerebello-cerebral pathways. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

Narcolepsy in Adolescence—A Missed Diagnosis: A Case Report

PubMed Central

Gupta, Anoop K.; Sahoo, Swapnajeet

2017-01-01

ABSTRACT: Narcolepsy is an uncommon sleep cycle disorder with a usual onset in adolescence, but it is often misdiagnosed and underdiagnosed. Rarely is the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis seen in patients. The clinical characteristics of narcolepsy are often confused with many psychiatric and neurologic disorders. Lack of clinical awareness about narcolepsy leads to frequent prescriptions of antiepileptics and psychotropics, which can adversely affect the quality of life of children and adolescents. We report a case of an adolescent male who presented with all four cardinal symptoms of narcolepsy and had been misdiagnosed with epilepsy, psychosis, and depression. We discuss various issues regarding narcolepsy in children and adolescents. PMID:29616151

Status Cataplecticus as Initial Presentation of Late Onset Narcolepsy

PubMed Central

Panda, Samhita

2014-01-01

Narcolepsy, one of the important causes of hypersomnia, is an under diagnosed sleep disorder. It has a bimodal age of onset around 15 and 35 years. It is characterized by the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic/ hypnopompic hallucinations, and sleep paralysis. Cataplexy is by far the most predictive feature of narcolepsy. Status cataplecticus is the occurrence of cataplexy repeatedly for hours or days, a rare presentation of narcolepsy. This report describes an elderly gentleman with late onset narcolepsy in the sixth decade of life presenting with initial and chief symptom of status cataplecticus. Citation: Panda S. Status cataplecticus as initial presentation of late onset narcolepsy. J Clin Sleep Med 2014;10(2):207-209. PMID:24533005

Narcolepsy in Adolescence-A Missed Diagnosis: A Case Report.

PubMed

Gupta, Anoop K; Sahoo, Swapnajeet; Grover, Sandeep

2017-01-01

Narcolepsy is an uncommon sleep cycle disorder with a usual onset in adolescence, but it is often misdiagnosed and underdiagnosed. Rarely is the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis seen in patients. The clinical characteristics of narcolepsy are often confused with many psychiatric and neurologic disorders. Lack of clinical awareness about narcolepsy leads to frequent prescriptions of antiepileptics and psychotropics, which can adversely affect the quality of life of children and adolescents. We report a case of an adolescent male who presented with all four cardinal symptoms of narcolepsy and had been misdiagnosed with epilepsy, psychosis, and depression. We discuss various issues regarding narcolepsy in children and adolescents.

Circadian Rest-Activity Rhythm in Pediatric Type 1 Narcolepsy.

PubMed

Filardi, Marco; Pizza, Fabio; Bruni, Oliviero; Natale, Vincenzo; Plazzi, Giuseppe

2016-06-01

Pediatric type 1 narcolepsy is often challenging to diagnose and remains largely undiagnosed. Excessive daytime sleepiness, disrupted nocturnal sleep, and a peculiar phenotype of cataplexy are the prominent features. The knowledge available about the regulation of circadian rhythms in affected children is scarce. This study compared circadian rest-activity rhythm and actigraphic estimated sleep measures of children with type 1 narcolepsy versus healthy controls. Twenty-two drug-naïve type 1 narcolepsy children and 21 age- and sex- matched controls were monitored for seven days during the school week by actigraphy. Circadian activity rhythms were analyzed through functional linear modeling; nocturnal and diurnal sleep measures were estimated from activity using a validated algorithm. Children with type 1 narcolepsy presented an altered rest-activity rhythm characterized by enhanced motor activity throughout the night and blunted activity in the first afternoon. No difference was found between children with type 1 narcolepsy and controls in the timing of the circadian phase. Actigraphic sleep measures showed good discriminant capabilities in assessing type 1 narcolepsy nycthemeral disruption. Actigraphy reliably renders the nycthemeral disruption typical of narcolepsy type 1 in drug-naïve children with recent disease onset, indicating the sensibility of actigraphic assessment in the diagnostic work-up of childhood narcolepsy type 1. © 2016 Associated Professional Sleep Societies, LLC.

Narcolepsy and disorders of excessive somnolence.

PubMed

Dyken, Mark E; Yamada, Thoru

2005-06-01

Recent studies provide valid criteria that help differentiate idiopathic narcolepsy from other disorders of excessive daytime somnolence [3]. Research to date suggests that idiopathic narcolepsy might properly be considered a disorder of excessive sleepiness with dysfunctional REM-sleep mechanisms, clinically evidenced as cataplexy and electrophysiologically recognized as SOREMPs. Given these criteria, a diagnosis can generally be made using a combination of history, PSG, and MSLT. Traditionally, the medical treatment of idiopathic narcolepsy has centered on a two-drug regimen (stimulants for sleepiness and TCAs for cataplexy and auxiliary symptoms). Some newer medications are proving efficacious for sleepiness with minimal adverse effects, whereas others may provide a single-drug regimen that simultaneously addresses sleepiness and cataplexy [18]. New research has allowed some experts to hypothesize that idiopathic narcolepsy may be the result of a genetic predisposition to autoimmune disease [176]. It is possible that aberrant genetic coding of elements in the hypocretin/orexin systems allows a sensitivity to inducible and possibly virally mediated changes, which leave cells in the lateral hypothalamus susceptible to autoimmune attack [96]. As such, genetic screening of high-risk individuals might eventually rationalize the prophylactic use of immunosuppressants in some instances. In the future, for atypical cases(poorly responsive to therapy), genetic, CSF, and brain imaging studies, and possibly even neuronal transplantation may prove beneficial in the assessment and treatment of idiopathic narcolepsy.

Autoantibody targets in vaccine-associated narcolepsy.

PubMed

Häggmark-Månberg, Anna; Zandian, Arash; Forsström, Björn; Khademi, Mohsen; Lima Bomfim, Izaura; Hellström, Cecilia; Arnheim-Dahlström, Lisen; Hallböök, Tove; Darin, Niklas; Lundberg, Ingrid E; Uhlén, Mathias; Partinen, Markku; Schwenk, Jochen M; Olsson, Tomas; Nilsson, Peter

2016-09-01

Narcolepsy is a chronic sleep disorder with a yet unknown cause, but the specific loss of hypocretin-producing neurons together with a strong human leukocyte antigen (HLA) association has led to the hypothesis that autoimmune mechanisms might be involved. Here, we describe an extensive effort to profile autoimmunity repertoires in serum with the aim to find disease-related autoantigens. Initially, 57 serum samples from vaccine-associated and sporadic narcolepsy patients and controls were screened for IgG reactivity towards 10 846 fragments of human proteins using planar microarrays. The discovered differential reactivities were verified on suspension bead arrays in the same sample collection followed by further investigation of 14 antigens in 176 independent samples, including 57 narcolepsy patients. Among these 14 antigens, methyltransferase-like 22 (METTL22) and 5'-nucleotidase cytosolic IA (NT5C1A) were recognized at a higher frequency in narcolepsy patients of both sample sets. Upon sequence analysis of the 14 proteins, polymerase family, member 3 (PARP3), acyl-CoA-binding domain containing 7 (ARID4B), glutaminase 2 (GLS2) and cyclin-dependent kinase-like 1 (CDKL1) were found to contain amino acid sequences with homology to proteins found in the H1N1 vaccine. These findings could become useful elements of further clinical assays that aim towards a better phenotypic understanding of narcolepsy and its triggers.

Anti-Tribbles Homolog 2 Autoantibodies in Japanese Patients with Narcolepsy

PubMed Central

Toyoda, Hiromi; Tanaka, Susumu; Miyagawa, Taku; Honda, Yutaka; Tokunaga, Katsushi; Honda, Makoto

2010-01-01

Study Objectives: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy. The association with human leukocyte antigen (HLA)-DQB1*0602 and T-cell receptor alpha locus suggests that autoimmunity plays a role in narcolepsy. A recent study reported an increased prevalence of autoantibodies against Tribbles homolog 2 (TRIB2) in patients with narcolepsy. To replicate this finding, we examined anti-TRIB2 autoantibodies in Japanese patients with narcolepsy. Design: We examined anti-TRIB2 autoantibodies against a full-length [35S]-labeled TRIB2 antigen in Japanese patients with narcolepsy-cataplexy (n = 88), narcolepsy without cataplexy (n = 18), and idiopathic hypersomnia with long sleep time (n = 11). The results were compared to Japanese healthy controls (n = 87). Thirty-seven healthy control subjects were positive for HLA-DRB1*1501-DQB1*0602. We also examined autoantibodies against another Tribbles homolog, TRIB3, as an experimental control. Measurements and Results: Autoantibodies against TRIB2 were found in 26.1% of patients with narcolepsy-cataplexy, a significantly higher prevalence than the 2.3% in healthy controls. We found that anti-TRIB3 autoantibodies were rare in patients with narcolepsy and showed no association with anti-TRIB2 indices. No significant correlation was found between anti-TRIB2 positivity and clinical information. Conclusions: We confirmed the higher prevalence and specificity of anti-TRIB2 autoantibodies in Japanese patients with narcolepsy-cataplexy. This suggests a subgroup within narcolepsy-cataplexy might be affected by an anti-TRIB2 autoantibody-mediated autoimmune mechanism. Citation: Toyoda H; Tanaka S; Miyagawa T; Honda Y; Tokunaga K; Honda M. Anti-Tribbles homolog 2 autoantibodies in Japanese patients with narcolepsy. SLEEP 2010;33(7):875-878. PMID:20614847

The Humanistic and Economic Burden of Narcolepsy

PubMed Central

Flores, Natalia M.; Villa, Kathleen F.; Black, Jed; Chervin, Ronald D.; Witt, Edward A.

2016-01-01

Study Objectives: To evaluate the burden of narcolepsy--with respect to psychiatric comorbidities, Health-Related Quality of Life (HRQoL), direct costs for healthcare resource utilization, and indirect costs for reported work loss–through comparison of patients to matched controls. Methods: This analysis was conducted on data from the 2011, 2012, and 2013 US National Health and Wellness Survey (NHWS; 2011 NHWS n = 75,000, 2012 NHWS n = 71,157, and 2013 NHWS n = 75,000). Patients who reported a narcolepsy diagnosis (n = 437) were matched 1:2 with controls (n = 874) on age, sex, race/ethnicity, marital status, education, household income, body mass index, smoking status, alcohol use, exercise, and physical comorbidity. Chi-square tests and one-way analyses of variance were used to assess whether the narcolepsy and control groups differed on psychiatric comorbidities, HRQoL, labor force participation, work productivity, and healthcare resource utilization. Results: Patients with narcolepsy, in comparison to matched controls, reported substantially (two to four times) greater psychiatric comorbidity, HRQoL impairment, prevalence of long-term disability, absenteeism, and presenteeism, and greater resource use in the past 6 mo as indicated by higher mean number of hospitalizations, emergency department visits, traditional healthcare professional visits, neurologist visits, and psychiatrist visits (each p < 0.05). Conclusions: These population-based data suggest that a narcolepsy diagnosis is associated with substantial adverse impact on mental health, HRQoL, and key economic burdens that include work impairment, resource use, and both direct and indirect costs. Although this study is cross-sectional, the results highlight the magnitude of the potential opportunity to improve mental health, lower costs, and augment work-related productivity through effective assessment and treatment of narcolepsy. Citation: Flores NM, Villa KF, Black J, Chervin RD, Witt EA. The

Status cataplecticus as initial presentation of late onset narcolepsy.

PubMed

Panda, Samhita

2014-02-15

Narcolepsy, one of the important causes of hypersomnia, is an under diagnosed sleep disorder. It has a bimodal age of onset around 15 and 35 years. It is characterized by the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic/ hypnopompic hallucinations, and sleep paralysis. Cataplexy is by far the most predictive feature of narcolepsy. Status cataplecticus is the occurrence of cataplexy repeatedly for hours or days, a rare presentation of narcolepsy. This report describes an elderly gentleman with late onset narcolepsy in the sixth decade of life presenting with initial and chief symptom of status cataplecticus.

Complex Diagnostic and Treatment Issues in Psychotic Symptoms Associated with Narcolepsy

PubMed Central

Ivanenko, Anna

2009-01-01

Narcolepsy is an uncommon chronic, neurological disorder characterized by abnormal manifestations of rapid eye movement sleep and perturbations in the sleep-wake cycle. Accurate diagnosis of psychotic symptoms in a person with narcolepsy could be difficult due to side effects of stimulant treatment (e.g., hallucinations) as well as primary symptoms of narcolepsy (e.g., sleep paralysis and hypnagogic and/or hypnapompic hallucinations). Pertinent articles from peer-reviewed journals were identified to help understand the complex phenomenology of psychotic symptoms in patients with narcolepsy. In this ensuing review and discussion, we present an overview of narcolepsy and outline diagnostic and management approaches for psychotic symptoms in patients with narcolepsy. PMID:19724760

Delusional Confusion of Dreaming and Reality in Narcolepsy

PubMed Central

Wamsley, Erin; Donjacour, Claire E.H.M.; Scammell, Thomas E.; Lammers, Gert Jan; Stickgold, Robert

2014-01-01

Study Objectives: We investigated a generally unappreciated feature of the sleep disorder narcolepsy, in which patients mistake the memory of a dream for a real experience and form sustained delusions about significant events. Design: We interviewed patients with narcolepsy and healthy controls to establish the prevalence of this complaint and identify its predictors. Setting: Academic medical centers in Boston, Massachusetts and Leiden, The Netherlands. Participants: Patients (n = 46) with a diagnosis of narcolepsy with cataplexy, and age-matched healthy healthy controls (n = 41). Interventions: N/A. Measurements and Results: “Dream delusions” were surprisingly common in narcolepsy and were often striking in their severity. As opposed to fleeting hypnagogic and hypnopompic hallucinations of the sleep/wake transition, dream delusions were false memories induced by the experience of a vivid dream, which led to false beliefs that could persist for days or weeks. Conclusions: The delusional confusion of dreamed events with reality is a prominent feature of narcolepsy, and suggests the possibility of source memory deficits in this disorder that have not yet been fully characterized. Citation: Wamsley E; Donjacour CE; Scammell TE; Lammers GJ; Stickgold R. Delusional confusion of dreaming and reality in narcolepsy. SLEEP 2014;37(2):419-422. PMID:24501437

Narcolepsy: Let the Patient’s Voice Awaken Us!

PubMed Central

Flygare, Julie; Parthasarathy, Sairam

2014-01-01

This is a “patient-centered” review about narcolepsy that aims to awaken the reader to the narcolepsy condition and to the trials and tribulations of patients with sleep problems in general. Narcolepsy is a neurological disorder with a classic tetrad of symptoms consisting of excessive daytime sleepiness, cataplexy, sleep onset hallucinations, and sleep paralysis. The diagnosis of narcolepsy and other sleep disorders are often overlooked and could be attributed to other medical or even psychiatric conditions with years of missed diagnosis. Implementation of “two sleep-related questions” to the review of systems in the primary care physicians’ office visit may help address the issue of missed diagnosis and allow patients to seek prompt medical attention. Definitive diagnosis can be made by overnight sleep study followed by a nap test, “multiple sleep latency test” (MSLT). There is currently no cure for narcolepsy with the treatments addressing symptoms of excessive daytime sleepiness, cataplexy, and nighttime sleep disruption with stimulants (modafinil, methylphenidate, and amphetamines), anti-cataplexy medications (Serotonin-specific reuptake inhibitors and tricyclic antidepressants) and sedative-hypnotics including sodium oxybate. Narcolepsy, like other sleep disorders, can lead to marked reductions of health-related quality of life and affect patients’ social and work lives deleteriously. While traditional healthcare approaches are focused more on hard biomedical outcomes, a patient-centered approach with novel methods for better sleep assessment of patients, that can bypass the “impossibly crammed” physician office visit, would allow healthcare providers to better detect, diagnose and treat narcolepsy and other such sleep problems. PMID:24931392

Hypocretin Receptor Expression in Canine and Murine Narcolepsy Models and in Hypocretin-Ligand Deficient Human Narcolepsy

PubMed Central

Mishima, Kazuo; Fujiki, Nobuhiro; Yoshida, Yasushi; Sakurai, Takeshi; Honda, Makoto; Mignot, Emmanuel; Nishino, Seiji

2008-01-01

Study Objective: To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy. Design: Animal and human study. We measured hcrtR1 and hcrtR2 expression in the frontal cortex and pons using the RT-PCR method in murine models (8-week-old and 27-week-old orexin/ataxin-3 transgenic (TG) hypocretin cell ablated mice and wild-type mice from the same litter, 10 mice for each group), in canine models (8 genetically narcoleptic Dobermans with null mutations in the hcrtR2, 9 control Dobermans, 3 sporadic ligand-deficient narcoleptics, and 4 small breed controls), and in humans (5 narcolepsy-cataplexy patients with hypocretin deficiency (average age 77.0 years) and 5 control subjects (72.6 years). Measurement and Results: 27-week-old (but not 8-week-old) TG mice showed significant decreases in hcrtR1 expression, suggesting the influence of the long-term ligand loss on the receptor expression. Both sporadic narcoleptic dogs and human narcolepsy-cataplexy subjects showed a significant decrease in hcrtR1 expression, while declines in hcrtR2 expression were not significant in these cases. HcrtR2-mutated narcoleptic Dobermans (with normal ligand production) showed no alteration in hcrtR1 expression. Conclusions: Moderate declines in hcrtR expressions, possibly due to long-term postnatal loss of ligand production, were observed in hypocretin-ligand deficient narcoleptic subjects. These declines are not likely to be progressive and complete. The relative preservation of hcrtR2 expression also suggests that hypocretin based therapies are likely to be a viable therapeutic options in human narcolepsy-cataplexy. Citation: Mishima K; Fujiki N; Yoshida Y; Sakurai T; Honda M; Mignot E; Nishino S. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. SLEEP 2008;31(8):1119-1126. PMID:18714784

Facial expression recognition and emotional regulation in narcolepsy with cataplexy.

PubMed

Bayard, Sophie; Croisier Langenier, Muriel; Dauvilliers, Yves

2013-04-01

Cataplexy is pathognomonic of narcolepsy with cataplexy, and defined by a transient loss of muscle tone triggered by strong emotions. Recent researches suggest abnormal amygdala function in narcolepsy with cataplexy. Emotion treatment and emotional regulation strategies are complex functions involving cortical and limbic structures, like the amygdala. As the amygdala has been shown to play a role in facial emotion recognition, we tested the hypothesis that patients with narcolepsy with cataplexy would have impaired recognition of facial emotional expressions compared with patients affected with central hypersomnia without cataplexy and healthy controls. We also aimed to determine whether cataplexy modulates emotional regulation strategies. Emotional intensity, arousal and valence ratings on Ekman faces displaying happiness, surprise, fear, anger, disgust, sadness and neutral expressions of 21 drug-free patients with narcolepsy with cataplexy were compared with 23 drug-free sex-, age- and intellectual level-matched adult patients with hypersomnia without cataplexy and 21 healthy controls. All participants underwent polysomnography recording and multiple sleep latency tests, and completed depression, anxiety and emotional regulation questionnaires. Performance of patients with narcolepsy with cataplexy did not differ from patients with hypersomnia without cataplexy or healthy controls on both intensity rating of each emotion on its prototypical label and mean ratings for valence and arousal. Moreover, patients with narcolepsy with cataplexy did not use different emotional regulation strategies. The level of depressive and anxious symptoms in narcolepsy with cataplexy did not differ from the other groups. Our results demonstrate that narcolepsy with cataplexy accurately perceives and discriminates facial emotions, and regulates emotions normally. The absence of alteration of perceived affective valence remains a major clinical interest in narcolepsy with cataplexy

Investigational therapies for the treatment of narcolepsy.

PubMed

de Biase, Stefano; Nilo, Annacarmen; Gigli, Gian Luigi; Valente, Mariarosaria

2017-08-01

Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. While non-pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy. Expert opinion: Currently there is no cure for narcolepsy, with treatment focusing on symptoms control. However, these symptomatic treatments are often unsatisfactory. The research is leading to a better understanding of narcolepsy and its symptoms. New classes of compounds with possible applications in the development of novel stimulant/anticataplectic medications are described. H3 receptor antagonists represent a new therapeutic option for EDS in narcolepsy. JZP-110, with its distinct mechanism of action, would be a new therapeutic option for the treatment of EDS in the coming years. In the future, hypocretin-based therapies and immune-based therapies, could modify the clinical course of the disease. However, more information would be necessary to completely understand the autoimmune process and also how this process can be altered for therapeutic benefits.

Update on the treatment of narcolepsy: clinical efficacy of pitolisant

PubMed Central

Calik, Michael W

2017-01-01

Narcolepsy is a neurological disease that affects 1 in 2,000 individuals and is characterized by excessive daytime sleepiness (EDS). In 60–70% of individuals with narcolepsy, it is also characterized by cataplexy or a sudden loss of muscle tone that is triggered by positive or negative emotions. Narcolepsy decreases the quality of life of the afflicted individuals. Currently used drugs treat EDS alone (modafinil/armodafinil, methylphenidate, and amphetamine), cataplexy alone (“off-label” use of antidepressants), or both EDS and cataplexy (sodium oxybate). These drugs have abuse, tolerability, and adherence issues. A greater diversity of drug options is needed to treat narcolepsy. The small molecule drug, pitolisant, acts as an inverse agonist/antagonist at the H3 receptor, thus increasing histaminergic tone in the wake promoting system of the brain. Pitolisant has been studied in animal models of narcolepsy and used in clinical trials as a treatment for narcolepsy. A comprehensive search of online databases (eg, Medline, PubMed, EMBASE, the Cochrane Library Database, Ovid MEDLINE, Europe PubMed Central, EBSCOhost CINAHL, ProQuest Research Library, Google Scholar, and ClinicalTrials.gov) was performed. Nonrandomized and randomized studies were included. This review focuses on the outcomes of four clinical trials of pitolisant to treat narcolepsy. These four trials show that pitolisant is an effective drug to treat EDS and cataplexy in narcolepsy. PMID:28490912

A Global View on Narcolepsy - A Review Study.

PubMed

Klimova, Blanka; Maresova, Petra; Novotny, Michal; Kuca, Kamil

2018-02-14

Narcolepsy is an incurable neurological disorder when the brain is not able to regulate a sleep and wakefulness cycle correctly. The affected person suddenly falls asleep during the day or he/she suffers from excessive day sleepiness. In addition, people may also suffer from cataplexy, hypnagogic hallucinations, sleep paralysis, and disturbed nighttime sleep. The purpose of this review study is to provide the latest information on both clinical and socioeconomic issues in the field of narcolepsy treatment and emphasize its benefits and limitations. The methodological approaches include a method of literature review of available sources exploring the issue of narcolepsy, both from a global and specific perspective point of view. On the basis of evaluation of these literature sources, the researched issue is examined. The main benefits (e.g., new drugs are being tested or non-invasive cognitive behavioral therapies are being applied) and limitations (e.g., late diagnosis of the disease or lifelong and costly treatment) of the treatment of narcolepsy are highlighted. The findings call for more research in the field of the development of novel drugs reflecting understanding of the neurological basis of narcolepsy and early diagnosis in order to eliminate the symptoms of narcolepsy and prevent the development of this disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Allergies and Disease Severity in Childhood Narcolepsy: Preliminary Findings.

PubMed

Aydinoz, Secil; Huang, Yu-Shu; Gozal, David; Inocente, Clara O; Franco, Patricia; Kheirandish-Gozal, Leila

2015-12-01

Narcolepsy frequently begins in childhood, and is characterized by excessive daytime sleepiness, with the presence of cataplexy reflecting a more severe phenotype. Narcolepsy may result from genetic predisposition involving deregulation of immune pathways, particularly involving T helper 2 cells (Th2). Increased activation of Th2 cells is usually manifested as allergic conditions such as rhinitis, atopic dermatitis, and asthma. We hypothesized that the presence of allergic conditions indicative of increased Th2 balance may dampen the severity of the phenotype in children with narcolepsy. A retrospective chart review of childhood narcolepsy patients was conducted at three major pediatric sleep centers. Patients were divided into those with narcolepsy without cataplexy (NC-) and narcolepsy with cataplexy (NC+). Demographics, polysomnographic and multiple sleep latency test data, and extraction of information on the presence of allergic diseases such allergic rhinitis, atopic dermatitis, and asthma was performed. There were 468 children identified, with 193 children in NC- group and 275 patients in the NC+ group. Overall, NC+ children were significantly younger, had higher body mass index, and had shorter mean sleep latencies and increased sleep onset rapid eye movement events. The frequency of allergic conditions, particularly asthma and allergic rhinitis, was markedly lower in NC+ (58/275) compared to NC- patients (94/193; P < 0.0001). Involvement of the immune system plays an important role in the pathophysiology of narcolepsy. Current findings further suggest that an increased shift toward T helper 2 cells, as indicated by the presence of allergic conditions, may modulate the severity of the phenotype in childhood narcolepsy, and reduce the prevalence of cataplexy in these patients. © 2015 Associated Professional Sleep Societies, LLC.

The Medical and Economic Burden of Narcolepsy: Implications for Managed Care

PubMed Central

Thorpy, Michael J.; Hiller, George

2017-01-01

Background The neurologic disorder narcolepsy results from dysregulation of the sleep-wake cycle and is primarily characterized by chronic, severely excessive daytime sleepiness and cataplexy, an emotionally induced muscle weakness. The prevalence of narcolepsy is approximately 0.05%, and onset generally occurs during the first 2 decades of life. Narcolepsy is believed to be an autoimmune disorder with destruction of hypocretin-producing neurons in the lateral hypothalamus. Objectives To provide an enhanced understanding of narcolepsy and establish the need for early diagnosis and rapid initiation of effective treatment for patients with narcolepsy. Discussion Narcolepsy reduces daily functioning and is associated with a substantial medical and economic burden, with many patients being on full disability. The annual direct medical costs are approximately 2-fold higher in patients with narcolepsy than in matched controls without this condition ($11,702 vs $5261, respectively; P <.0001). Further contributing to the overall burden is a lack of recognition of the signs and symptoms of narcolepsy and an absence of easily measurable biomarkers, resulting in a diagnostic delay that often exceeds 10 years and may be associated with misdiagnosis and inappropriate resource utilization. Because narcolepsy generally has an onset in childhood or in adolescence, is often misdiagnosed, has no known cure, and requires lifelong treatment, it is an important disease from a managed care perspective. Clinical features, as well as objective testing, should be used to ensure the timely diagnosis and treatment of patients with narcolepsy. Conclusion Policies for the diagnosis and treatment of narcolepsy should be based on the current treatment guidelines, but they should also encourage shared decisions between clinicians and patients to allow for individualized diagnostic and treatment choices, as suggested in best practice recommendations. PMID:28975007

A Consensus Definition of Cataplexy in Mouse Models of Narcolepsy

PubMed Central

Scammell, Thomas E.; Willie, Jon T.; Guilleminault, Christian; Siegel, Jerome M.

2009-01-01

People with narcolepsy often have episodes of cataplexy, brief periods of muscle weakness triggered by strong emotions. Many researchers are now studying mouse models of narcolepsy, but definitions of cataplexy-like behavior in mice differ across labs. To establish a common language, the International Working Group on Rodent Models of Narcolepsy reviewed the literature on cataplexy in people with narcolepsy and in dog and mouse models of narcolepsy and then developed a consensus definition of murine cataplexy. The group concluded that murine cataplexy is an abrupt episode of nuchal atonia lasting at least 10 seconds. In addition, theta activity dominates the EEG during the episode, and video recordings document immobility. To distinguish a cataplexy episode from REM sleep after a brief awakening, at least 40 seconds of wakefulness must precede the episode. Bouts of cataplexy fitting this definition are common in mice with disrupted orexin/hypocretin signaling, but these events almost never occur in wild type mice. It remains unclear whether murine cataplexy is triggered by strong emotions or whether mice remain conscious during the episodes as in people with narcolepsy. This working definition provides helpful insights into murine cataplexy and should allow objective and accurate comparisons of cataplexy in future studies using mouse models of narcolepsy. Citation: Scammell TE; Willie JT; Guilleminault C; Siegel JM. A consensus definition of cataplexy in mouse models of narcolepsy. SLEEP 2009;32(1):111-116. PMID:19189786

Concomitant loss of dynorphin, NARP, and orexin in narcolepsy

PubMed Central

Crocker, Amanda; España, Rodrigo A.; Papadopoulou, Maria; Saper, Clifford B.; Faraco, Juliette; Sakurai, Takeshi; Honda, Makoto; Mignot, Emmanuel; Scammell, Thomas E.

2008-01-01

Background Narcolepsy with cataplexy is associated with a loss of orexin/hypocretin. It is speculated that an autoimmune process kills the orexin-producing neurons, but these cells may survive yet fail to produce orexin. Objective To examine whether other markers of the orexin neurons are lost in narcolepsy with cataplexy. Methods We used immunohistochemistry and in situ hybridization to examine the expression of orexin, neuronal activity-regulated pentraxin (NARP), and prodynorphin in hypothalami from five control and two narcoleptic individuals. Results In the control hypothalami, at least 80% of the orexin-producing neurons also contained prodynorphin mRNA and NARP. In the patients with narcolepsy, the number of cells producing these markers was reduced to about 5–10% of normal. Conclusions Narcolepsy with cataplexy is likely caused by a loss of the orexin-producing neurons. In addition, loss of dynorphin and NARP may contribute to the symptoms of narcolepsy. PMID:16247044

Narcolepsy: current treatment options and future approaches

PubMed Central

Billiard, Michel

2008-01-01

The management of narcolepsy is presently at a turning point. Three main avenues are considered in this review: 1) Two tendencies characterize the conventional treatment of narcolepsy. Modafinil has replaced methylphenidate and amphetamine as the first-line treatment of excessive daytime sleepiness (EDS) and sleep attacks, based on randomized, double blind, placebo-controlled clinical trials of modafinil, but on no direct comparison of modafinil versus traditional stimulants. For cataplexy, sleep paralysis, and hypnagogic hallucinations, new antidepressants tend to replace tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) in spite of a lack of randomized, double blind, placebo-controlled clinical trials of these compounds; 2) The conventional treatment of narcolepsy is now challenged by sodium oxybate, the sodium salt of gammahydroxybutyrate, based on a series of randomized, double-blind, placebo-controlled clinical trials and a long-term open label study. This treatment has a fairly good efficacy and is active on all symptoms of narcolepsy. Careful titration up to an adequate level is essential both to obtain positive results and avoid adverse effects; 3) A series of new treatments are currently being tested, either in animal models or in humans, They include novel stimulant and anticataplectic drugs, endocrine therapy, and, more attractively, totally new approaches based on the present state of knowledge of the pathophysiology of narcolepsy with cataplexy, hypocretine-based therapies, and immunotherapy. PMID:18830438

A consensus definition of cataplexy in mouse models of narcolepsy.

PubMed

Scammell, Thomas E; Willie, Jon T; Guilleminault, Christian; Siegel, Jerome M

2009-01-01

People with narcolepsy often have episodes of cataplexy, brief periods of muscle weakness triggered by strong emotions. Many researchers are now studying mouse models of narcolepsy, but definitions of cataplexy-like behavior in mice differ across labs. To establish a common language, the International Working Group on Rodent Models of Narcolepsy reviewed the literature on cataplexy in people with narcolepsy and in dog and mouse models of narcolepsy and then developed a consensus definition of murine cataplexy. The group concluded that murine cataplexy is an abrupt episode of nuchal atonia lasting at least 10 seconds. In addition, theta activity dominates the EEG during the episode, and video recordings document immobility. To distinguish a cataplexy episode from REM sleep after a brief awakening, at least 40 seconds of wakefulness must precede the episode. Bouts of cataplexy fitting this definition are common in mice with disrupted orexin/hypocretin signaling, but these events almost never occur in wild type mice. It remains unclear whether murine cataplexy is triggered by strong emotions or whether mice remain conscious during the episodes as in people with narcolepsy. This working definition provides helpful insights into murine cataplexy and should allow objective and accurate comparisons of cataplexy in future studies using mouse models of narcolepsy.

The Familial Risk and HLA Susceptibility among Narcolepsy Patients in Hong Kong Chinese

PubMed Central

Chen, Lei; Fong, S.Y.Y.; Lam, Ching W.; Tang, Nelson L.S.; Ng, Margaret H. L.; Li, Albert M.; Ho, C.K.W.; Cheng, Suk-Hang; Lau, Kin-Mang; Wing, Yun Kwok

2007-01-01

Study Objectives: To explore the familial aggregation and HLA susceptibility of narcolepsy in Hong Kong Chinese by objective sleep measurements and HLA typing. Design: Case control design Participants: Twelve narcoleptic probands, 34 first-degree relatives, and 30 healthy controls. Interventions: N/A Measurements and Results: Each subject underwent a standardized nocturnal polysomnogram (PSG), followed by a daytime multiple sleep latency test (MSLT). HLA typing was performed for all subjects. One relative (2.9%) was diagnosed as suffering from narcolepsy with cataplexy. Nearly 30% of the relatives fulfilled the criteria of narcolepsy spectrum disorder (shortened mean sleep latency [MSL] and/or the presence of sleep onset REM periods [SOREMPs]). When using the population data for comparison, the relative risk of narcolepsy in first-degree relatives was 85.3. The odds ratio of narcolepsy spectrum disorder in first-degree relatives was 5.8 (95% CI: 1.2 – 29.3) when compared to healthy controls. There existed 6 multiplex families, in which all 10 relatives with narcolepsy spectrum disorders, including all 3 relatives with multiple SOREMPs, were positive for HLA DQB1*0602. Conclusions: Our study demonstrated a definitive familial aggregation of narcolepsy, narcolepsy spectrum disorders, and possibly cataplexy in Hong Kong Chinese. This familial aggregation supported an inherited basis for narcolepsy spectrum. The tight co-segregation of HLA DQB1*0602 and narcolepsy spectrum disorders might suggest that HLA typing, especially DQB1*0602, at least partly confer the familial risk of narcolepsy. In addition, our study suggested that the subjective questionnaire measurements including Ullanlinna Narcolepsy Scale and Epworth Sleepiness Scale were unable to detect the presence of narcolepsy spectrum disorders among the relatives. A stringent objective measurement-based design for family studies is suggested for future study. Further studies are indicated for the determination

The Humanistic and Economic Burden of Narcolepsy.

PubMed

Flores, Natalia M; Villa, Kathleen F; Black, Jed; Chervin, Ronald D; Witt, Edward A

2016-03-01

To evaluate the burden of narcolepsy--with respect to psychiatric comorbidities, Health-Related Quality of Life (HRQoL), direct costs for healthcare resource utilization, and indirect costs for reported work loss-through comparison of patients to matched controls. This analysis was conducted on data from the 2011, 2012, and 2013 US National Health and Wellness Survey (NHWS; 2011 NHWS n = 75,000, 2012 NHWS n = 71,157, and 2013 NHWS n = 75,000). Patients who reported a narcolepsy diagnosis (n = 437) were matched 1:2 with controls (n = 874) on age, sex, race/ethnicity, marital status, education, household income, body mass index, smoking status, alcohol use, exercise, and physical comorbidity. Chi-square tests and one-way analyses of variance were used to assess whether the narcolepsy and control groups differed on psychiatric comorbidities, HRQoL, labor force participation, work productivity, and healthcare resource utilization. Patients with narcolepsy, in comparison to matched controls, reported substantially (two to four times) greater psychiatric comorbidity, HRQoL impairment, prevalence of long-term disability, absenteeism, and presenteeism, and greater resource use in the past 6 mo as indicated by higher mean number of hospitalizations, emergency department visits, traditional healthcare professional visits, neurologist visits, and psychiatrist visits (each p < 0.05). These population-based data suggest that a narcolepsy diagnosis is associated with substantial adverse impact on mental health, HRQoL, and key economic burdens that include work impairment, resource use, and both direct and indirect costs. Although this study is cross-sectional, the results highlight the magnitude of the potential opportunity to improve mental health, lower costs, and augment work-related productivity through effective assessment and treatment of narcolepsy. © 2016 American Academy of Sleep Medicine.

Narcolepsy and Orexins: An Example of Progress in Sleep Research

PubMed Central

De la Herrán-Arita, Alberto K.; Guerra-Crespo, Magdalena; Drucker-Colín, René

2011-01-01

Narcolepsy is a chronic neurodegenerative disease caused by a deficiency of orexin-producing neurons in the lateral hypothalamus. It is clinically characterized by excessive daytime sleepiness and by intrusions into wakefulness of physiological aspects of rapid eye movement sleep such as cataplexy, sleep paralysis, and hypnagogic hallucinations. The major pathophysiology of narcolepsy has been recently described on the bases of the discovery of the neuropeptides named orexins (hypocretins) in 1998; considerable evidence, summarized below, demonstrates that narcolepsy is the result of alterations in the genes involved in the pathology of the orexin ligand or its receptor. Deficient orexin transmission is sufficient to produce narcolepsy, as we describe here, animal models with dysregulated orexin signaling exhibit a narcolepsy-like phenotype. Remarkably, these narcoleptic models have different alterations of the orexinergic circuit, this diversity provide us with the means for making comparison, and have a better understanding of orexin-cell physiology. It is of particular interest that the most remarkable findings regarding this sleep disorder were fortuitous and due to keen observations. Sleep is a highly intricate and regulated state, and narcolepsy is a disorder that still remains as one of the unsolved mysteries in science. Nevertheless, advances and development of technology in neuroscience will provide us with the necessary tools to unravel the narcolepsy puzzle in the near future. Through an evaluation of the scientific literature we traced an updated picture of narcolepsy and orexins in order to provide insight into the means by which neurobiological knowledge is constructed. PMID:21541306

Parkinson's disease and narcolepsy-like symptoms.

PubMed

Ylikoski, Ari; Martikainen, Kirsti; Sarkanen, Tomi; Partinen, Markku

2015-04-01

Various sleep-related problems, for example, insomnia and symptoms of rapid eye movement behavior disorder (RBD), are common in patients with Parkinson's disease (PD). We studied the prevalence of symptoms of narcolepsy (NARC), hallucinations, and RBD and their association with other symptoms. Altogether, 1447 randomly selected patients with PD, aged 43-89 years, participated in a questionnaire study. A structured questionnaire with 207 items was based on the Basic Nordic Sleep Questionnaire. Questions on demographics, PD, RBD, and other issues were included. The response rate was 59.0%; of these patients, 73% had answered to all questions that were used in the analyses (N = 623). The occurrence of suspected narcolepsy (Ullanlinna Narcolepsy Scale ≥ 14 and Epworth Sleepiness Scale ≥ 11) was observed in 9.3% of the subjects (PD with NARC), RBD (REM Sleep Behavior Disorder Screening Questionnaire ≥ 6) in 39.2% of all patients with PD, and in 62.1% of those with PD and NARC. In patients with PD, hallucinations before going to bed in the evening occurred in 5.8%, hypnagogic hallucinations in 4.0%, hallucinations during night 8.3%, and hypnopompic hallucinations in 3.2%. Cataplexy symptoms occurred in 43.1% of subjects with PD and NARC. In a logistic regression analysis, PD with NARC was associated with RBD, all types of hallucinations, daytime sleepiness, fatigue, insomnia, and intense dreaming also when adjusted for age, sex, disease duration, and levodopa. Narcolepsy-like symptoms may be present in patients with PD. Symptoms of RBD were associated with symptoms of narcolepsy including symptoms of cataplexy. Copyright © 2014 Elsevier B.V. All rights reserved.

Cerebrospinal Fluid Biomarkers of Neurodegeneration Are Decreased or Normal in Narcolepsy.

PubMed

Jørgen Jennum, Poul; Østergaard Pedersen, Lars; Czarna Bahl, Justyna Maria; Modvig, Signe; Fog, Karina; Holm, Anja; Rahbek Kornum, Birgitte; Gammeltoft, Steen

2017-01-01

To investigate whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration are altered in narcolepsy in order to evaluate whether the hypocretin deficiency and abnormal sleep-wake pattern in narcolepsy leads to neurodegeneration. Twenty-one patients with central hypersomnia (10 type 1 narcolepsy, 5 type 2 narcolepsy, and 6 idiopathic hypersomnia cases), aged 33 years on average and with a disease duration of 2-29 years, and 12 healthy controls underwent CSF analyses of the levels of β-amyloid, total tau protein (T-tau), phosphorylated tau protein (P-tau181), α-synuclein, neurofilament light chain (NF-L), and chitinase 3-like protein-1 (CHI3L1). Levels of β-amyloid were lower in patients with type 1 narcolepsy (375.4 ± 143.5 pg/mL) and type 2 narcolepsy (455.9 ± 65.0 pg/mL) compared to controls (697.9 ± 167.3 pg/mL, p < .05). Furthermore, in patients with type 1 narcolepsy, levels of T-tau (79.0 ± 27.5 pg/mL) and P-tau181 (19.1 ± 4.3 pg/mL) were lower than in controls (162.2 ± 49.9 pg/mL and 33.8 ± 9.2 pg/mL, p < .05). Levels of α-synuclein, NF-L, and CHI3L1 in CSF from narcolepsy patients were similar to those of healthy individuals. Six CSF biomarkers of neurodegeneration were decreased or normal in narcolepsy indicating that taupathy, synucleinopathy, and immunopathy are not prevalent in narcolepsy patients with a disease duration of 2-29 years. Lower CSF levels of β-amyloid, T-tau protein, and P-tau181 in narcolepsy may indicate that hypocretin deficiency and an abnormal sleep-wake pattern alter the turnover of these proteins in the central nervous system. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Narcolepsy and cataplexy: a pediatric case report.

PubMed

Savaş, Tülin; Erol, Ilknur; Saygı, Semra; Habeşoğlu, Mehmet Ali

2016-12-01

Narcolepsy is characterized by excessive sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis during the rapid eye movement period of sleep. Herein, we present a boy aged eight years who was diagnosed as having narcolepsy and cataplexy about thirteen months after his first presentation. He was admitted with symptoms of daytime sleepiness. In the follow-up, cataplexy in the form of head dropping attacks developed seven months after the first admission. The patient was investigated for different prediagnoses and was eventually diagnosed as having narcolepsy and cataplexy through polysomnography and multiple sleep latency tests thirteen months after the first presentation. He is being followed up and is under drug therapy; his symptoms have improved substantially.

Central Disorders of Hypersomnolence: Focus on the Narcolepsies and Idiopathic Hypersomnia.

PubMed

Khan, Zeeshan; Trotti, Lynn Marie

2015-07-01

The central disorders of hypersomnolence are characterized by severe daytime sleepiness, which is present despite normal quality and timing of nocturnal sleep. Recent reclassification distinguishes three main subtypes: narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia (IH), which are the focus of this review. Narcolepsy type 1 results from loss of hypothalamic hypocretin neurons, while the pathophysiology underlying narcolepsy type 2 and IH remains to be fully elucidated. Treatment of all three disorders focuses on the management of sleepiness, with additional treatment of cataplexy in those patients with narcolepsy type 1. Sleepiness can be treated with modafinil/armodafinil or sympathomimetic CNS stimulants, which have been shown to be beneficial in randomized controlled trials of narcolepsy and, quite recently, IH. In those patients with narcolepsy type 1, sodium oxybate is effective for the treatment of both sleepiness and cataplexy. Despite these treatments, there remains a subset of hypersomnolent patients with persistent sleepiness, in whom alternate therapies are needed. Emerging treatments for sleepiness include histamine H3 antagonists (eg, pitolisant) and possibly negative allosteric modulators of the gamma-aminobutyric acid-A receptor (eg, clarithromycin and flumazenil).

Mechanistic insights into influenza vaccine-associated narcolepsy.

PubMed

Ahmed, S Sohail; Steinman, Lawrence

2016-12-01

We previously reported an increased frequency of antibodies to hypocretin (HCRT) receptor 2 in sera obtained from narcoleptic patients who received the European AS03-adjuvanted vaccine Pandemrix (GlaxoSmithKline Biologicals, s.a.) for the global influenza A H1N1 pandemic in 2009 [A(H1N1)pdm09]. These antibodies cross-reacted with a particular fragment of influenza nucleoprotein (NP) - one of the proteins naturally contained in the virus used to make seasonal influenza vaccine and pandemic influenza vaccines. The purpose of this commentary is to provide additional insights and interpretations of the findings and share additional data not presented in the original paper to help the reader appreciate the key messages of that publication. First, a brief background to narcolepsy and vaccine-induced narcolepsy will be provided. Then, additional insights and clarification will be provided on the following topics: 1) the critical difference identified in the adjuvanted A(H1N1)pdm09 vaccines, 2) the contributing factor likely for the discordant association of narcolepsy between the AS03-adjuvanted pandemic vaccines Pandemrix and Arepanrix (GlaxoSmithKline Biologicals, s.a.), 3) the significance of detecting HCRT receptor 2 (HCRTr2) antibodies in some Finnish control subjects, 4) the approach used for the detection of HCRTr2 antibodies in vaccine-associated narcolepsy, and 5) the plausibility of the proposed mechanism involving HCRTr2 modulation in vaccine-associated narcolepsy.

Sleeping Beauty in the Classroom: What Do Teachers Know about Narcolepsy?

ERIC Educational Resources Information Center

Cosgrove, Maryellen S.

2002-01-01

Investigated teachers' awareness of narcolepsy and the accuracy of their knowledge. Found educators uninformed about narcolepsy and how to accommodate narcoleptic students. Recommended that teachers be aware of narcolepsy's symptoms, plan variety and movement into students' lessons, and allow students to redo assignments if a sleep attack…

High-dimensional single-cell analysis reveals the immune signature of narcolepsy.

PubMed

Hartmann, Felix J; Bernard-Valnet, Raphaël; Quériault, Clémence; Mrdjen, Dunja; Weber, Lukas M; Galli, Edoardo; Krieg, Carsten; Robinson, Mark D; Nguyen, Xuan-Hung; Dauvilliers, Yves; Liblau, Roland S; Becher, Burkhard

2016-11-14

Narcolepsy type 1 is a devastating neurological sleep disorder resulting from the destruction of orexin-producing neurons in the central nervous system (CNS). Despite its striking association with the HLA-DQB1*06:02 allele, the autoimmune etiology of narcolepsy has remained largely hypothetical. Here, we compared peripheral mononucleated cells from narcolepsy patients with HLA-DQB1*06:02-matched healthy controls using high-dimensional mass cytometry in combination with algorithm-guided data analysis. Narcolepsy patients displayed multifaceted immune activation in CD4 + and CD8 + T cells dominated by elevated levels of B cell-supporting cytokines. Additionally, T cells from narcolepsy patients showed increased production of the proinflammatory cytokines IL-2 and TNF. Although it remains to be established whether these changes are primary to an autoimmune process in narcolepsy or secondary to orexin deficiency, these findings are indicative of inflammatory processes in the pathogenesis of this enigmatic disease. © 2016 Hartmann et al.

High-dimensional single-cell analysis reveals the immune signature of narcolepsy

PubMed Central

Quériault, Clémence; Krieg, Carsten; Nguyen, Xuan-Hung

2016-01-01

Narcolepsy type 1 is a devastating neurological sleep disorder resulting from the destruction of orexin-producing neurons in the central nervous system (CNS). Despite its striking association with the HLA-DQB1*06:02 allele, the autoimmune etiology of narcolepsy has remained largely hypothetical. Here, we compared peripheral mononucleated cells from narcolepsy patients with HLA-DQB1*06:02-matched healthy controls using high-dimensional mass cytometry in combination with algorithm-guided data analysis. Narcolepsy patients displayed multifaceted immune activation in CD4+ and CD8+ T cells dominated by elevated levels of B cell–supporting cytokines. Additionally, T cells from narcolepsy patients showed increased production of the proinflammatory cytokines IL-2 and TNF. Although it remains to be established whether these changes are primary to an autoimmune process in narcolepsy or secondary to orexin deficiency, these findings are indicative of inflammatory processes in the pathogenesis of this enigmatic disease. PMID:27821550

Health-related stigma as a determinant of functioning in young adults with narcolepsy.

PubMed

Kapella, Mary C; Berger, Barbara E; Vern, Boris A; Vispute, Sachin; Prasad, Bharati; Carley, David W

2015-01-01

Symptoms of narcolepsy tend to arise during adolescence or young adulthood, a formative time in human development during which people are usually completing their education and launching a career. Little is known about the impact of narcolepsy on the social aspects of health-related quality of life in young adults. The purpose of this study was to examine relationships between health-related stigma, mood (anxiety and depression) and daytime functioning in young adults with narcolepsy compared to those without narcolepsy. Young adults (age 18-35) with narcolepsy (N = 122) and without narcolepsy (N = 93) were mailed a packet that included questionnaires and a self-addressed postage paid envelope. The questionnaire included demographic information and a composite of instruments including the SF 36, Functional Outcomes of Sleep Questionnaire (FOSQ), Fife Stigma Scale (FSS), Epworth Sleepiness Scale (ESS) and Hospital Anxiety and Depression Scale (HADS). Variable associations were assessed using descriptive statistics, ANOVA, Mann-Whitney U Test, correlations, stepwise multiple regression and path analysis. Young adults with narcolepsy perceived significantly more stigma and lower mood and health-related quality of life than young adults without narcolepsy (p<0.01). Health-related stigma was directly and indirectly associated with lower functioning through depressed mood. Fifty-two percent of the variance in functioning was explained by the final model in the young adults with narcolepsy. Health-related stigma in young adults with narcolepsy is at a level consistent with other chronic medical illnesses. Health-related stigma may be an important determinant of functioning in young adults with narcolepsy. Future work is indicated toward further characterizing stigma and developing interventions that address various domains of stigma in people with narcolepsy.

Health-Related Stigma as a Determinant of Functioning in Young Adults with Narcolepsy

PubMed Central

Kapella, Mary C.; Berger, Barbara E.; Vern, Boris A.; Vispute, Sachin; Prasad, Bharati; Carley, David W.

2015-01-01

Symptoms of narcolepsy tend to arise during adolescence or young adulthood, a formative time in human development during which people are usually completing their education and launching a career. Little is known about the impact of narcolepsy on the social aspects of health-related quality of life in young adults. The purpose of this study was to examine relationships between health-related stigma, mood (anxiety and depression) and daytime functioning in young adults with narcolepsy compared to those without narcolepsy. Young adults (age 18–35) with narcolepsy (N = 122) and without narcolepsy (N = 93) were mailed a packet that included questionnaires and a self-addressed postage paid envelope. The questionnaire included demographic information and a composite of instruments including the SF 36, Functional Outcomes of Sleep Questionnaire (FOSQ), Fife Stigma Scale (FSS), Epworth Sleepiness Scale (ESS) and Hospital Anxiety and Depression Scale (HADS). Variable associations were assessed using descriptive statistics, ANOVA, Mann-Whitney U Test, correlations, stepwise multiple regression and path analysis. Young adults with narcolepsy perceived significantly more stigma and lower mood and health-related quality of life than young adults without narcolepsy (p<0.01). Health-related stigma was directly and indirectly associated with lower functioning through depressed mood. Fifty-two percent of the variance in functioning was explained by the final model in the young adults with narcolepsy. Health-related stigma in young adults with narcolepsy is at a level consistent with other chronic medical illnesses. Health-related stigma may be an important determinant of functioning in young adults with narcolepsy. Future work is indicated toward further characterizing stigma and developing interventions that address various domains of stigma in people with narcolepsy. PMID:25898361

Migraine and risk of narcolepsy in children: A nationwide longitudinal study.

PubMed

Yang, Chun-Pai; Hsieh, Meng-Lun; Chiang, Jen-Huai; Chang, Hsing-Yi; Hsieh, Vivian Chia-Rong

2017-01-01

The association between migraine and narcolepsy remains controversial. We aim to investigate whether migraine is associated with an increased risk of developing narcolepsy in children. In this longitudinal study, nationwide medical-claims data of pediatric patients (0-17y) with migraine are identified using the National Health Insurance Research Database (NHIRD) between 1997 and 2010 in Taiwan. Two cohorts are selected: migraine cases (n = 8,923) and propensity score-matched non-migraine controls (n = 35,692). Children with previous history of narcolepsy or headache before the index date are excluded. Cohorts are followed until the end of 2012, their withdrawal from the NHI program, or incidence of narcolepsy (ICD-9-CM: 347). Cox proportional hazards regression models are used to estimate hazard ratios (HRs) and 95% confidence intervals of developing narcolepsy in children with migraine compared to their non-migraine controls. A total of 13 incident cases with narcolepsy are observed during follow-up, with incidence rates of 0.1915 and 0.0278 per 1,000 person-years in migraine and non-migraine children, respectively. After a mean follow-up period of 4.68 and 5.04 years in the case and control cohort, respectively, the former exhibited a greater risk of developing narcolepsy compared to the latter (adjusted hazard ratio (aHR) = 5.30, 95% confidence interval (CI): 1.61, 17.4; p = 0.006). This finding persisted after controlling for potential confounders like baseline comorbidities and concurrent medication uptake, and in our analyses with migraine subtypes. Migraine is an independent risk factor for narcolepsy development in children. Further studies are needed to validate our findings and to explore the exact pathophysiological mechanisms linking migraine and narcolepsy.

Evaluation of polygenic risks for narcolepsy and essential hypersomnia.

PubMed

Yamasaki, Maria; Miyagawa, Taku; Toyoda, Hiromi; Khor, Seik-Soon; Liu, Xiaoxi; Kuwabara, Hitoshi; Kano, Yukiko; Shimada, Takafumi; Sugiyama, Toshiro; Nishida, Hisami; Sugaya, Nagisa; Tochigi, Mamoru; Otowa, Takeshi; Okazaki, Yuji; Kaiya, Hisanobu; Kawamura, Yoshiya; Miyashita, Akinori; Kuwano, Ryozo; Kasai, Kiyoto; Tanii, Hisashi; Sasaki, Tsukasa; Honda, Yutaka; Honda, Makoto; Tokunaga, Katsushi

2016-10-01

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (P HLA-DQB1*06:02 =2.30 × 10 -48 , P whole genome without HLA-DQB1*06:02 =6.73 × 10 -2 ) including HLA-DQB1*06:02 effects and 1.3% (P whole genome without HLA-DQB1*06:02 =2.43 × 10 -2 ) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (P whole genome without HLA-DQB1*06:02 =9.74 × 10 -2 ). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA

Cognitive behavioral treatment for narcolepsy: can it complement pharmacotherapy?

PubMed Central

Marín Agudelo, Hernán Andrés; Jiménez Correa, Ulises; Carlos Sierra, Juan; Pandi-Perumal, Seithikurippu R.; Schenck, Carlos H.

2014-01-01

Sleep medicine in general and psychology in particular have recently developed cognitive behavioral treatment for narcolepsy (CBT-N). Despite a growing interest in this topic, most studies since 2007 have reviewed CBT applications for other sleep disorders. Currently, 6 reviews have been published on narcolepsy, with an expert consensus being reached that CBT represented an important adjunctive treatment for the disease. The current paper reviews the need for CBT applications for narcolepsy by generalizing the application of multicomponent treatments and performing studies that extrapolate the results obtained from multicenter studies. Nineteen studies were found in which the need-for-treatment guidelines identified the use of CBT for narcolepsy. Three additional studies were identified that evaluated the effectiveness of cognitive behavioral measures and multicomponent treatments for which treatment protocols have been proposed. PMID:26483898

Narcolepsy in a three-year-old girl: A case report.

PubMed

Park, Eu Gene; Lee, Jiwon; Joo, Eun Yeon; Lee, Munhyang; Lee, Jeehun

2016-01-01

Narcolepsy is characterized by excessive daytime somnolence associated with sleep paralysis, hallucinations when falling asleep or awakening, and cataplexy. Early recognition of pediatric narcolepsy is essential for growth and development. We experienced a case of narcolepsy in a three-year-old girl. The patient underwent brain MRI and 24h video-electroencephalogram (EEG) monitoring. Polysomnography (PSG) with multiple sleep latency test (MSLT) and human leukocyte antigen (HLA) DQ typing was performed. The brain MRI was normal. 24h video-EEG monitoring revealed no abnormal slow or epileptiform discharge on interictal EEG, and no EEG change during tongue thrusting, dropping head with laughter, or flopping down, which was consistent with cataplexy associated with narcolepsy. A mean sleep latency of 2.5 min and four episodes of sleep-onset REM periods in five naps were observed in PSG with MSLT. She was positive in HLA-DQB1*0602. Based on these findings, she was diagnosed as narcoleptic with cataplexy. The history, combined with PSG and MSLT, was helpful in the diagnosis of narcolepsy. We report a case of early-onset narcolepsy presenting with excessive sleepiness and cataplexy. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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

PubMed

Canellas, Francesca; Lin, Ling; Julià, Maria Rosa; Clemente, Antonio; Vives-Bauza, Cristofol; Ollila, Hanna M; Hong, Seung Chul; Arboleya, Susana M; Einen, Mali A; Faraco, Juliette; Fernandez-Vina, Marcelo; Mignot, Emmanuel

2014-09-15

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. 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. 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. 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. © 2014 American Academy of Sleep Medicine.

Orexin neurons suppress narcolepsy via 2 distinct efferent pathways

PubMed Central

Hasegawa, Emi; Yanagisawa, Masashi; Sakurai, Takeshi; Mieda, Michihiro

2014-01-01

The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron–dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy. PMID:24382351

Psychosis in Patients with Narcolepsy as an Adverse Effect of Sodium Oxybate

PubMed Central

Sarkanen, Tomi; Niemelä, Valter; Landtblom, Anne-Marie; Partinen, Markku

2014-01-01

Aim: Hypnagogic and hypnopompic hallucinations are characteristic symptoms of narcolepsy, as are excessive daytime sleepiness, cataplexy, and sleep paralysis. Narcolepsy patients may also experience daytime hallucinations unrelated to sleep–wake transitions. The effect of medication on hallucinations is of interest since treatment of narcolepsy may provoke psychotic symptoms. We aim to analyze the relation between sodium oxybate (SXB) treatment and psychotic symptoms in narcolepsy patients. Furthermore, we analyze the characteristics of hallucinations to determine their nature as mainly psychotic or hypnagogic and raise a discussion about whether SXB causes psychosis or if psychosis occurs as an endogenous complication in narcolepsy. Method: We present altogether four patients with narcolepsy who experienced psychotic symptoms during treatment with SXB. In addition, we searched the literature for descriptions of hallucinations in narcolepsy and similarities and differences with psychotic symptoms in schizophrenia. Results: Three out of four patients had hallucinations typical for psychosis and one had symptoms that resembled aggravated hypnagogic hallucinations. Two patients also had delusional symptoms primarily associated with mental disorders. Tapering down SXB was tried and helped in two out of four cases. Adding antipsychotic treatment (risperidone) alleviated psychotic symptoms in two cases. Conclusion: Psychotic symptoms in narcolepsy may appear during SXB treatment. Hallucinations resemble those seen in schizophrenia; however, the insight that symptoms are delusional is usually preserved. In case of SXB-induced psychotic symptoms or hallucinations, reducing SXB dose or adding antipsychotic medication can be tried. PMID:25191304

Psychosis in patients with narcolepsy as an adverse effect of sodium oxybate.

PubMed

Sarkanen, Tomi; Niemelä, Valter; Landtblom, Anne-Marie; Partinen, Markku

2014-01-01

Hypnagogic and hypnopompic hallucinations are characteristic symptoms of narcolepsy, as are excessive daytime sleepiness, cataplexy, and sleep paralysis. Narcolepsy patients may also experience daytime hallucinations unrelated to sleep-wake transitions. The effect of medication on hallucinations is of interest since treatment of narcolepsy may provoke psychotic symptoms. We aim to analyze the relation between sodium oxybate (SXB) treatment and psychotic symptoms in narcolepsy patients. Furthermore, we analyze the characteristics of hallucinations to determine their nature as mainly psychotic or hypnagogic and raise a discussion about whether SXB causes psychosis or if psychosis occurs as an endogenous complication in narcolepsy. We present altogether four patients with narcolepsy who experienced psychotic symptoms during treatment with SXB. In addition, we searched the literature for descriptions of hallucinations in narcolepsy and similarities and differences with psychotic symptoms in schizophrenia. Three out of four patients had hallucinations typical for psychosis and one had symptoms that resembled aggravated hypnagogic hallucinations. Two patients also had delusional symptoms primarily associated with mental disorders. Tapering down SXB was tried and helped in two out of four cases. Adding antipsychotic treatment (risperidone) alleviated psychotic symptoms in two cases. Psychotic symptoms in narcolepsy may appear during SXB treatment. Hallucinations resemble those seen in schizophrenia; however, the insight that symptoms are delusional is usually preserved. In case of SXB-induced psychotic symptoms or hallucinations, reducing SXB dose or adding antipsychotic medication can be tried.

Altered Regional Cerebral Blood Flow in Idiopathic Hypersomnia.

PubMed

Boucetta, Soufiane; Montplaisir, Jacques; Zadra, Antonio; Lachapelle, Francis; Soucy, Jean-Paul; Gravel, Paul; Dang-Vu, Thien Thanh

2017-10-01

Idiopathic hypersomnia is characterized by excessive daytime sleepiness, despite normal or long sleep time. Its pathophysiological mechanisms remain unclear. This pilot study aims at characterizing the neural correlates of idiopathic hypersomnia using single photon emission computed tomography. Thirteen participants with idiopathic hypersomnia and 16 healthy controls were scanned during resting wakefulness using a high-resolution single photon emission computed tomography scanner with 99mTc-ethyl cysteinate dimer to assess cerebral blood flow. The main analysis compared regional cerebral blood flow distribution between the two groups. Exploratory correlations between regional cerebral blood flow and clinical characteristics evaluated the functional correlates of those brain perfusion patterns. Significance was set at p < .05 after correction for multiple comparisons. Participants with idiopathic hypersomnia showed regional cerebral blood flow decreases in medial prefrontal cortex and posterior cingulate cortex and putamen, as well as increases in amygdala and temporo-occipital cortices. Lower regional cerebral blood flow in the medial prefrontal cortex was associated with higher daytime sleepiness. These preliminary findings suggest that idiopathic hypersomnia is characterized by functional alterations in brain areas involved in the modulation of vigilance states, which may contribute to the daytime symptoms of this condition. The distribution of regional cerebral blood flow changes was reminiscent of the patterns associated with normal non-rapid-eye-movement sleep, suggesting the possible presence of incomplete sleep-wake transitions. These abnormalities were strikingly distinct from those induced by acute sleep deprivation, suggesting that the patterns seen here might reflect a trait associated with idiopathic hypersomnia rather than a non-specific state of sleepiness. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep

Frequencies and Associations of Narcolepsy-Related Symptoms: A Cross-Sectional Study

PubMed Central

Kim, Lenise Jihe; Coelho, Fernando Morgadinho; Hirotsu, Camila; Araujo, Paula; Bittencourt, Lia; Tufik, Sergio; Andersen, Monica Levy

2015-01-01

Objectives: Narcolepsy is a disabling disease with a delayed diagnosis. At least 3 years before the disorder identification, several comorbidities can be observed in patients with narcolepsy. The early recognition of narcolepsy symptoms may improve long-term prognosis of the patients. Thus, we aimed to investigate the prevalence of the symptoms associated with narcolepsy and its social and psychological association in a sample of Sao Paulo city inhabitants. Methods: We performed a cross-sectional evaluation with 1,008 individuals from the Sao Paulo Epidemiologic Sleep Study (EPISONO). Excessive daytime sleepiness (EDS) was assessed by the Epworth Sleepiness Scale. Volunteers were also asked about the occurrence of cataplectic-like, hypnagogic or hypnopompic hallucinations, and sleep paralysis symptoms. The participants underwent a full-night polysomnography and completed questionnaires about psychological, demographic, and quality of life parameters. Results: We observed a prevalence of 39.2% of EDS, 15.0% of cataplectic-like symptom, 9.2% of hypnagogic or hypnopompic hallucinations, and 14.9% of sleep paralysis in Sao Paulo city inhabitants. A frequency of 6.9% was observed when EDS and cataplectic-like symptoms were grouped. The other associations were EDS + hallucinations (4.7%) and EDS + sleep paralysis (7.5%). Symptomatic participants were predominantly women and younger compared with patients without any narcolepsy symptom (n = 451). Narcolepsy symptomatology was also associated with a poor quality of life and symptoms of depression, anxiety, and fatigue. Conclusions: Narcolepsy-related symptoms are associated with poor quality of life and worse psychological parameters. Citation: Kim LJ, Coelho FM, Hirotsu C, Araujo P, Bittencourt L, Tufik S, Andersen ML. Frequencies and associations of narcolepsy-related symptoms: a cross-sectional study. J Clin Sleep Med 2015;11(12):1377–1384. PMID:26235160

Treatment of Narcolepsy and other Hypersomnias of Central Origin

PubMed Central

Wise, Merrill S.; Arand, Donna L.; Auger, R. Robert; Brooks, Stephen N.; Watson, Nathaniel F.

2007-01-01

Objective: The purpose of this paper is to summarize current knowledge about treatment of narcolepsy and other hypersomnias of central origin. Methods: The task force performed a systematic and comprehensive review of the relevant literature and graded the evidence using the Oxford grading system. This paper discusses the strengths and limitations of the available evidence regarding treatment of these conditions, and summarizes key information about safety of these medications. Our findings provide the foundation for development of evidence-based practice parameters on this topic by the Standards of Practice Committee of the American Academy of Sleep Medicine. Results: The majority of recent papers in this field provide information about use of modafinil or sodium oxybate for treatment of sleepiness associated with narcolepsy. Several large randomized, placebo-controlled studies indicate that modafinil and sodium oxybate are effective for treatment of hypersomnia due to narcolepsy. We identified no studies that report direct comparison of these newer medications versus traditional stimulants, or that indicate what proportion of patients treated initially with these medications require transition to traditional stimulants or to combination therapy to achieve adequate alertness. As with the traditional stimulants, modafinil and sodium oxybate provide, at best, only moderate improvement in alertness rather than full restoration of alertness in patients with narcolepsy. Several large randomized placebo-controlled studies demonstrate that sodium oxybate is effective for treatment of cataplexy associated with narcolepsy, and earlier studies provide limited data to support the effectiveness of fluoxetine and tricyclic antidepressants for treatment of cataplexy. Our findings indicate that very few reports provide information regarding treatment of special populations such as children, older adults, and pregnant or breastfeeding women. The available literature provides a

Juvenile myoclonic epilepsy and narcolepsy: A series of three cases.

PubMed

Joshi, Puja Aggarwal; Poduri, Annapurna; Kothare, Sanjeev V

2015-10-01

This paper sets out to demonstrate the coexistence of juvenile myoclonic epilepsy (JME) and narcolepsy that raises the possibility of a shared genetic predisposition to both conditions. The electronic medical records (EMRs) were searched for narcolepsy and JME over 10years. We identified three young adult women diagnosed with JME in their teenage years, with myoclonic, generalized tonic-clonic, and absence seizure semiologies, along with psychiatric comorbidity, well managed on lamotrigine and/or levetiracetam. Our patients were also found to have disturbed sleep preceding the diagnosis of JME by many years, including excessive daytime sleepiness (EDS), fragmented nocturnal sleep, hypnagogic vivid hallucinations, and REM behavior disorder along with daytime cataplexy. They were ultimately diagnosed with coexisting narcolepsy, confirmed by sleep studies and multiple sleep latency testing, along with positive genetic testing for HLA-DQB1*0602 in all three patients. Stimulants, selective serotonin receptor inhibitors, and/or sodium oxybate were used to successfully treat their narcolepsy. The coexistence of JME and narcolepsy has not been well recognized and may be clinically relevant. In addition, it raises the possibility of a shared genetic predisposition to both conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

Listening to the Patient Voice in Narcolepsy: Diagnostic Delay, Disease Burden, and Treatment Efficacy.

PubMed

Maski, Kiran; Steinhart, Erin; Williams, David; Scammell, Thomas; Flygare, Julie; McCleary, Kimberly; Gow, Monica

2017-03-15

Describe common symptoms, comorbidities, functional limitations, and treatment responsiveness among patients with narcolepsy. Investigate the effect of pediatric onset of narcolepsy symptoms on time to diagnosis of narcolepsy and presence of comorbid depression. Cross-sectional survey of 1,699 people in the United States with self-reported diagnosis of narcolepsy. We utilized mixed-methods data analyses to report study findings. Most participants reported receiving a diagnosis of narcolepsy more than 1 y after symptom onset. We found that the strongest predictor of this delayed diagnosis was pediatric onset of symptoms (odds ratio = 2.4, p < 0.0005). Depression was the most common comorbidity but we detected no association with pediatric onset of narcolepsy symptoms. Overall, participants reported that fatigue and cognitive difficulties were their most burdensome symptoms in addition to sleepiness and cataplexy. The majority of participants reported residual daytime fatigue and/or sleepiness despite treatment. Most participants reported they could not perform at work or school as well as they would like because of narcolepsy symptoms. This study provides unique insight into the narcolepsy disease experience. The study quantifies the problem of diagnostic delay for narcolepsy patients in the United States and highlights that symptoms are more likely to be missed if they develop before 18 y of age. These results suggest that narcolepsy awareness efforts should be aimed at parents, pediatric health care providers, school professionals, and children/adolescents themselves. Disease burden is high because of problems with fatigue, cognition, and persistence of residual symptoms despite treatment. © 2017 American Academy of Sleep Medicine

Listening to the Patient Voice in Narcolepsy: Diagnostic Delay, Disease Burden, and Treatment Efficacy

PubMed Central

Maski, Kiran; Steinhart, Erin; Williams, David; Scammell, Thomas; Flygare, Julie; McCleary, Kimberly; Gow, Monica

2017-01-01

Study Objectives: Describe common symptoms, comorbidities, functional limitations, and treatment responsiveness among patients with narcolepsy. Investigate the effect of pediatric onset of narcolepsy symptoms on time to diagnosis of narcolepsy and presence of comorbid depression. Methods: Cross-sectional survey of 1,699 people in the United States with self-reported diagnosis of narcolepsy. We utilized mixed-methods data analyses to report study findings. Results: Most participants reported receiving a diagnosis of narcolepsy more than 1 y after symptom onset. We found that the strongest predictor of this delayed diagnosis was pediatric onset of symptoms (odds ratio = 2.4, p < 0.0005). Depression was the most common comorbidity but we detected no association with pediatric onset of narcolepsy symptoms. Overall, participants reported that fatigue and cognitive difficulties were their most burdensome symptoms in addition to sleepiness and cataplexy. The majority of participants reported residual daytime fatigue and/or sleepiness despite treatment. Most participants reported they could not perform at work or school as well as they would like because of narcolepsy symptoms. Conclusions: This study provides unique insight into the narcolepsy disease experience. The study quantifies the problem of diagnostic delay for narcolepsy patients in the United States and highlights that symptoms are more likely to be missed if they develop before 18 y of age. These results suggest that narcolepsy awareness efforts should be aimed at parents, pediatric health care providers, school professionals, and children/adolescents themselves. Disease burden is high because of problems with fatigue, cognition, and persistence of residual symptoms despite treatment. Citation: Maski K, Steinhart E, Williams D, Scammell T, Flygare J, McCleary K, Gow M. Listening to the patient voice in narcolepsy: diagnostic delay, disease burden and treatment efficacy. J Clin Sleep Med. 2017;13(3):419–425

Quality Measures for the Care of Patients with Narcolepsy

PubMed Central

Krahn, Lois E.; Hershner, Shelley; Loeding, Lauren D.; Maski, Kiran P.; Rifkin, Daniel I.; Selim, Bernardo; Watson, Nathaniel F.

2015-01-01

The American Academy of Sleep Medicine (AASM) commissioned a Workgroup to develop quality measures for the care of patients with narcolepsy. Following a comprehensive literature search, 306 publications were found addressing quality care or measures. Strength of association was graded between proposed process measures and desired outcomes. Following the AASM process for quality measure development, we identified three outcomes (including one outcome measure) and seven process measures. The first desired outcome was to reduce excessive daytime sleepiness by employing two process measures: quantifying sleepiness and initiating treatment. The second outcome was to improve the accuracy of diagnosis by employing the two process measures: completing both a comprehensive sleep history and an objective sleep assessment. The third outcome was to reduce adverse events through three steps: ensuring treatment follow-up, documenting medical comorbidities, and documenting safety measures counseling. All narcolepsy measures described in this report were developed by the Narcolepsy Quality Measures Work-group and approved by the AASM Quality Measures Task Force and the AASM Board of Directors. The AASM recommends the use of these measures as part of quality improvement programs that will enhance the ability to improve care for patients with narcolepsy. Citation: Krahn LE, Hershner S, Loeding LD, Maski KP, Rifkin DI, Selim B, Watson NF. Quality measures for the care of patients with narcolepsy. J Clin Sleep Med 2015;11(3):335–355. PMID:25700880

Frequencies and Associations of Narcolepsy-Related Symptoms: A Cross-Sectional Study.

PubMed

Kim, Lenise Jihe; Coelho, Fernando Morgadinho; Hirotsu, Camila; Araujo, Paula; Bittencourt, Lia; Tufik, Sergio; Andersen, Monica Levy

2015-12-15

Narcolepsy is a disabling disease with a delayed diagnosis. At least 3 years before the disorder identification, several comorbidities can be observed in patients with narcolepsy. The early recognition of narcolepsy symptoms may improve long-term prognosis of the patients. Thus, we aimed to investigate the prevalence of the symptoms associated with narcolepsy and its social and psychological association in a sample of Sao Paulo city inhabitants. We performed a cross-sectional evaluation with 1,008 individuals from the Sao Paulo Epidemiologic Sleep Study (EPISONO). Excessive daytime sleepiness (EDS) was assessed by the Epworth Sleepiness Scale. Volunteers were also asked about the occurrence of cataplectic-like, hypnagogic or hypnopompic hallucinations, and sleep paralysis symptoms. The participants underwent a full-night polysomnography and completed questionnaires about psychological, demographic, and quality of life parameters. We observed a prevalence of 39.2% of EDS, 15.0% of cataplectic-like symptom, 9.2% of hypnagogic or hypnopompic hallucinations, and 14.9% of sleep paralysis in Sao Paulo city inhabitants. A frequency of 6.9% was observed when EDS and cataplectic-like symptoms were grouped. The other associations were EDS + hallucinations (4.7%) and EDS + sleep paralysis (7.5%). Symptomatic participants were predominantly women and younger compared with patients without any narcolepsy symptom (n = 451). Narcolepsy symptomatology was also associated with a poor quality of life and symptoms of depression, anxiety, and fatigue. Narcolepsy-related symptoms are associated with poor quality of life and worse psychological parameters. © 2015 American Academy of Sleep Medicine.

Narcolepsy patients' blood-based miRNA expression profiling: miRNA expression differences with Pandemrix vaccination.

PubMed

Mosakhani, N; Sarhadi, V; Panula, P; Partinen, M; Knuutila, S

2017-11-01

Narcolepsy is a neurological sleep disorder characterized by excessive daytime sleepiness and nighttime sleep disturbance. Among children and adolescents vaccinated with Pandemrix vaccine in Finland and Sweden, the number of narcolepsy cases increased. Our aim was to identify miRNAs involved in narcolepsy and their association with Pandemrix vaccination. We performed global miRNA proofing by miRNA microarrays followed by RT-PCR verification on 20 narcolepsy patients (Pandemrix-associated and Pandemrix-non-associated) and 17 controls (vaccinated and non-vaccinated). Between all narcolepsy patients and controls, 11 miRNAs were differentially expressed; 17 miRNAs showed significantly differential expression between Pandemrix-non-associated narcolepsy patients and non-vaccinated healthy controls. MiR-188-5p and miR-4499 were over-expressed in narcolepsy patients vs healthy controls. Two miRNAs, miR-1470 and miR-4455, were under-expressed in Pandemrix-associated narcolepsy patients vs Pandemrix-non-associated narcolepsy patients. We identified miRNA expression patterns in narcolepsy patients that linked them to mRNA targets known to be involved in brain-related pathways or brain disorders. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Comorbidity of narcolepsy and depressive disorders: a nationwide population-based study in Taiwan.

PubMed

Lee, Min-Jing; Lee, Sheng-Yu; Yuan, Shin-Sheng; Yang, Chun-Ju; Yang, Kang-Chung; Lee, Tung-Liang; Sun, Chi-Chin; Shyu, Yu-Chiau; Wang, Liang-Jen

2017-11-01

Narcolepsy is a chronic sleep disorder that is likely to have neuropsychiatric comorbidities. Depression is a serious mood disorder that affects individuals' daily activities and functions. The current study aimed to investigate the relationship between narcolepsy and depressive disorders. The study consisted of patients diagnosed with narcolepsy between January 2002, and December 2011 (n = 258), and age-matched and gender-matched controls (n = 2580) from Taiwan's National Health Insurance database. Both the patients and the controls were monitored through December 31, 2011, to identify the occurrence of a depressive disorder. A multivariate logistic regression model was used to assess the narcolepsy's potential influence on the comorbidity of a depressive disorder. During the study period, 32.7%, 24.8%, and 10.9% of the narcoleptic patients were comorbid with any depressive disorder, dysthymic disorder, and major depressive disorder, respectively. When compared to the control subjects, the patients with narcolepsy were at greater risks of having any depressive disorder (aOR 6.77; 95% CI 4.90-9.37), dysthymic disorder (aOR 6.62; 95% CI 4.61-9.57), and major depressive disorder (aOR 6.83; 95% CI 4.06-11.48). Of the narcoleptic patients that were comorbid with depression, >50% had been diagnosed with depression prior to being diagnosed with narcolepsy. This nationwide data study revealed that narcolepsy and depression commonly co-occurred. Since some symptoms of narcolepsy overlapped with those of depressive disorders, the findings serve as a reminder that clinicians must pay attention to the comorbidity of narcolepsy and depression. Copyright © 2017 Elsevier B.V. All rights reserved.

Antibodies Against Hypocretin Receptor 2 Are Rare in Narcolepsy.

PubMed

Giannoccaro, Maria Pia; Waters, Patrick; Pizza, Fabio; Liguori, Rocco; Plazzi, Giuseppe; Vincent, Angela

2017-02-01

Recently, antibodies to the hypocretin receptor 2 (HCRTR2-Abs) were reported in a high proportion of narcolepsy patients who developed the disease following Pandemrix® vaccination. We tested a group of narcolepsy patients for the HCRTR2-Abs using a newly established cell-based assay. Sera from 50 narcolepsy type 1 (NT1) and 11 narcolepsy type 2 (NT2) patients, 22 patients with other sleep disorders, 15 healthy controls, and 93 disease controls were studied. Cerebrospinal fluid (CSFs) from three narcoleptic patients were subsequently included. Human embryonic kidney cells were transiently transfected with human HCRTR2, incubated with patients' sera for 1 hr at 1:20 dilution and then fixed. Binding of antibodies was detected by fluorescently labeled secondary antibodies to human immunoglobulin G (IgG) and the different IgG subclasses. A nonlinear visual scoring system was used from 0 to 4; samples scoring ≥1 were considered positive. Only 3 (5%) of 61 patients showed a score ≥1, one with IgG1- and two with IgG3-antibodies, but titers were low (1:40-1:100). CSFs from these patients were negative. The three positive patients included one NT1 case with associated psychotic features, one NT2 patient, and an NT1 patient with normal hypocretin CSF levels. Low levels of IgG1 or IgG3 antibodies against HCRTR2 were found in 3 of 61 patients with narcolepsy, although only 1 presented with full-blown NT1. HCRTR2-Abs are not common in narcolepsy unrelated to vaccination. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Clarifying the association of genes within the major histocompatibility complex with narcolepsy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Acton, R.T.; Watson, B.; Rivers, C.

1994-09-01

HLA-DR2 and DQwl has been reported to be strongly associated with narcolepsy. The particular phenotype and strength of these associations varies between races. For example DQB*0601 has been reported associated with some African American (AA) narcoleptics while some Caucasian American (CA) narcoleptics do not possess DR2 or DQw1. We have sought to clarify the relationship of MHC genes with narcolepsy in the local CA and AA population. There was no significant difference in the frequency of DR phenotypes in CA or AA narcoleptics compared to race, age, sex and geographic region-matched controls. DR2 was increased in CA cataplexy positive (Cat+)more » narcoleptics compared to controls (p=0.028, odds ratio (OR)=2.4) and to Cat- narcoleptics (p=<0.001, OR=8.8). DR11 was increased in AA Cat+ narcoleptics compared to controls (p=0.004, OR=11.2) and to Cat- narcoleptics (p=0.002). DQB1*0601 was not significantly associated with narcolepsy in our AA population. We have assessed the frequency of the TNFa (13 alleles, 1.1Mb telomeric to DQ{alpha}), D6S105 (13 alleles, 1kb telomeric of HLA-A), and GLP-1R (19 alleles, 18.5 Mb centromeric of DQ{alpha}), dinucleotide repeats in narcoleptics compared to controls. The TNFa allele 117 was increased in CA Cat+ vs. controls (p=0.003). The GLP-1R allele 144 was increased in CA Cat- vs. controls (p=0.02). In AA narcoleptics, the TNFa allele 109 was significantly increased (p=0.04) along with the D6S105 allele 130 (p=0.02) compared to controls. The D6S105 allele 130 was increased in AA Cat- vs. controls (p=0.03). The GLP-1R allele 154 was significantly decreased in AA Cat+ vs. Cat- (p=0.04). These data suggest that DR and/or DQ genes are not responsible for narcolepsy and that cataplexy is associated with different regions around the MHC in various racial groups.« less

Complex movement disorders at disease onset in childhood narcolepsy with cataplexy

PubMed Central

Pizza, Fabio; Palaia, Vincenzo; Franceschini, Christian; Poli, Francesca; Moghadam, Keivan K.; Cortelli, Pietro; Nobili, Lino; Bruni, Oliviero; Dauvilliers, Yves; Lin, Ling; Edwards, Mark J.; Mignot, Emmanuel; Bhatia, Kailash P.

2011-01-01

Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of hypocretin-producing neurons in the hypothalamus of likely autoimmune aetiology. Noting that children with narcolepsy often display complex abnormal motor behaviours close to disease onset that do not meet the classical definition of cataplexy, we systematically analysed motor features in 39 children with narcolepsy with cataplexy in comparison with 25 age- and sex-matched healthy controls. We found that patients with narcolepsy with cataplexy displayed a complex array of ‘negative’ (hypotonia) and ‘active’ (ranging from perioral movements to dyskinetic–dystonic movements or stereotypies) motor disturbances. ‘Active’ and ‘negative’ motor scores correlated positively with the presence of hypotonic features at neurological examination and negatively with disease duration, whereas ‘negative’ motor scores also correlated negatively with age at disease onset. These observations suggest that paediatric narcolepsy with cataplexy often co-occurs with a complex movement disorder at disease onset, a phenomenon that may vanish later in the course of the disease. Further studies are warranted to assess clinical course and whether the associated movement disorder is also caused by hypocretin deficiency or by additional neurochemical abnormalities. PMID:21930661

Does Narcolepsy Symptom Severity Vary According to HLA-DQB1*0602 Allele Status?

PubMed Central

Watson, Nathaniel F.; Ton, Thanh G.N.; Koepsell, Thomas D.; Gersuk, Vivian H.; Longstreth, W.T.

2010-01-01

Study Objectives: To investigate associations between HLA-DQB1*0602 allele status and measures of narcolepsy symptom severity. Design: Cross-sectional study of population-based narcolepsy patients. Setting: King County, Washington. Participants: All prevalent cases (n = 279) of physician-diagnosed narcolepsy ascertained from 2001-2005. Interventions: N/A Measurements: Narcolepsy diagnosis was based on cataplexy status, diagnostic sleep study results, and chart review. The number of HLA-DQB1 alleles was determined from buccal genomic DNA. Symptom severity instruments included the Epworth Sleepiness Scale (ESS), the Ullanlinna Narcolepsy Scale (UNS), age of symptom onset, subjective sleep latency and duration, and various clinical sleep parameters. We used linear regression adjusted for African American race and an extended chi-square test of trend to assess relationships across ordered groups defined by allele number (0, 1, or 2). Results: Narcolepsy patients were 63% female and 82% Caucasian, with a mean age of 47.6 years (SD = 17.1). One hundred forty-one (51%) patients had no DQB1*0602 alleles; 117 (42%) had one; and 21 (7%) had two. In the complete narcolepsy sample after adjustment for African American race, we observed a linear relationship between HLA-DQB1*0602 frequency and sleepiness as defined by the ESS (P < 0.01), narcolepsy severity as defined by UNS (P < 0.001), age of symptom onset (P < 0.05), and sleep latency (P < 0.001). In univariate analyses, HLA-DQB1*0602 frequency was also associated with napping (P < 0.05) and increased car and work accidents or near accidents (both P < 0.01). Habitual sleep duration was not associated with HLA status. These race-adjusted associations remained for the ESS (P < 0.05), UNS (P < 0.01), and sleep latency (P < 0.001) when restricting to narcolepsy with cataplexy. Conclusions: Narcolepsy symptom severity varies in a linear manner according to HLA-DQB1*0602 allele status. These findings support the notion that HLA

Adenotonsillectomy outcomes in children with sleep apnea and narcolepsy.

PubMed

Biyani, Sneh; Cunningham, Tina D; Baldassari, Cristina M

2017-09-01

To identify improvements in daytime sleepiness following adenotonsillectomy in children with non-severe obstructive sleep apnea and narcolepsy. Case series with chart review over 15 years. Tertiary Children's Hospital. Children between 6 and 17 years of age with narcolepsy that underwent adenotonsillectomy for non-severe obstructive sleep apnea (OSA) were included. Narcolepsy was diagnosed based on clinical assessment and the Multiple Sleep Latency Test (MSLT) results. A standardized instrument, the pediatric Epworth Sleepiness Scale (ESS), was used to assess daytime sleepiness before and after adenotonsillectomy. Nine children with a mean age of 12.1 years were included. The majority of the subjects (78%, n = 7) were African American and six children (66.7%) were obese. Four children (44%) were treated with wake promoting agents during the study. The mean preoperative apnea hypopnea index on polysomnography was 4.89 (SD 1.86), while the mean sleep latency on MSLT was 6.32 min (SD 3.14). The mean preoperative ESS was 16.10 and the postoperative ESS was 10.80 (SD 3.96). There was significant improvement (p = 0.02) in the ESS following adenotonsillectomy with seven children (78%) reporting diminished daytime sleepiness. Children with non-severe OSA and narcolepsy experience significant improvement in daytime sleepiness following adenotonsillectomy. Future studies are needed to determine the incidence and clinical significance of non-severe OSA in children with narcolepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

Altered Sleep Stage Transitions of REM Sleep: A Novel and Stable Biomarker of Narcolepsy

PubMed Central

Liu, Yaping; Zhang, Jihui; Lam, Venny; Ho, Crover Kwok Wah; Zhou, Junying; Li, Shirley Xin; Lam, Siu Ping; Yu, Mandy Wai Man; Tang, Xiangdong; Wing, Yun-Kwok

2015-01-01

Objectives: To determine the diagnostic values, longitudinal stability, and HLA association of the sleep stage transitions in narcolepsy. Methods: To compare the baseline differences in the sleep stage transition to REM sleep among 35 patients with type 1 narcolepsy, 39 patients with type 2 narcolepsy, 26 unaffected relatives, and 159 non-narcoleptic sleep patient controls, followed by a reassessment at a mean duration of 37.4 months. Results: The highest prevalence of altered transition from stage non-N2/N3 to stage R in multiple sleep latency test (MSLT) and nocturnal polysomnography (NPSG) was found in patients with type 1 narcolepsy (92.0% and 57.1%), followed by patients with type 2 narcolepsy (69.4% and 12.8%), unaffected relatives (46.2% and 0%), and controls (39.3% and 1.3%). Individual sleep variables had varied sensitivity and specificity in diagnosing narcolepsy. By incorporating a combination of sleep variables, the decision tree analysis improved the sensitivity to 94.3% and 82.1% and enhanced specificity to 82.4% and 83% for the diagnosis of type 1 and type 2 narcolepsy, respectively. There was a significant association of DBQ1*0602 with the altered sleep stage transition (OR = 16.0, 95% CI: 1.7–149.8, p = 0.015). The persistence of the altered sleep stage transition in both MSLT and NPSG was high for both type 1 (90.5% and 64.7%) and type 2 narcolepsy (92.3% and 100%), respectively. Conclusions: Altered sleep stage transition is a significant and stable marker of narcolepsy, which suggests a vulnerable wake-sleep dysregulation trait in narcolepsy. Altered sleep stage transition has a significant diagnostic value in the differential diagnosis of hypersomnias, especially when combined with other diagnostic sleep variables in decision tree analysis. Citation: Liu Y, Zhang J, Lam V, Ho CK, Zhou J, Li SX, Lam SP, Yu MW, Tang X, Wing YK. Altered sleep stage transitions of REM sleep: a novel and stable biomarker of narcolepsy. J Clin Sleep Med 2015

Altered Sleep Stage Transitions of REM Sleep: A Novel and Stable Biomarker of Narcolepsy.

PubMed

Liu, Yaping; Zhang, Jihui; Lam, Venny; Ho, Crover Kwok Wah; Zhou, Junying; Li, Shirley Xin; Lam, Siu Ping; Yu, Mandy Wai Man; Tang, Xiangdong; Wing, Yun-Kwok

2015-08-15

To determine the diagnostic values, longitudinal stability, and HLA association of the sleep stage transitions in narcolepsy. To compare the baseline differences in the sleep stage transition to REM sleep among 35 patients with type 1 narcolepsy, 39 patients with type 2 narcolepsy, 26 unaffected relatives, and 159 non-narcoleptic sleep patient controls, followed by a reassessment at a mean duration of 37.4 months. The highest prevalence of altered transition from stage non-N2/N3 to stage R in multiple sleep latency test (MSLT) and nocturnal polysomnography (NPSG) was found in patients with type 1 narcolepsy (92.0% and 57.1%), followed by patients with type 2 narcolepsy (69.4% and 12.8%), unaffected relatives (46.2% and 0%), and controls (39.3% and 1.3%). Individual sleep variables had varied sensitivity and specificity in diagnosing narcolepsy. By incorporating a combination of sleep variables, the decision tree analysis improved the sensitivity to 94.3% and 82.1% and enhanced specificity to 82.4% and 83% for the diagnosis of type 1 and type 2 narcolepsy, respectively. There was a significant association of DBQ1*0602 with the altered sleep stage transition (OR = 16.0, 95% CI: 1.7-149.8, p = 0.015). The persistence of the altered sleep stage transition in both MSLT and NPSG was high for both type 1 (90.5% and 64.7%) and type 2 narcolepsy (92.3% and 100%), respectively. Altered sleep stage transition is a significant and stable marker of narcolepsy, which suggests a vulnerable wake-sleep dysregulation trait in narcolepsy. Altered sleep stage transition has a significant diagnostic value in the differential diagnosis of hypersomnias, especially when combined with other diagnostic sleep variables in decision tree analysis. © 2015 American Academy of Sleep Medicine.

CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome.

PubMed

Kanbayashi, Takashi; Kodama, Tohru; Kondo, Hideaki; Satoh, Shinsuke; Inoue, Yuichi; Chiba, Shigeru; Shimizu, Tetsuo; Nishino, Seiji

2009-02-01

To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency. Cross sectional studies. Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2. We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean +/- SEM; 176.0 +/- 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 +/- 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 +/- 16.4 pg/mL), and idiopathic hypersomnia (161.0 +/- 29.3 pg/ mL); the levels in OSAS (259.3 +/- 46.6 pg/mL) did not statistically differ from those in the controls (333.8 +/- 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 +/- 16.3 pg/ mL) and idiopathic hypersomnia (143.3 +/- 28.8 pg/mL), while the levels in the medicated patients were in the normal range. The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin.

Body Mass Index-Independent Metabolic Alterations in Narcolepsy with Cataplexy

PubMed Central

Poli, Francesca; Plazzi, Giuseppe; Di Dalmazi, Guido; Ribichini, Danilo; Vicennati, Valentina; Pizza, Fabio; Mignot, Emmanuel; Montagna, Pasquale; Pasquali, Renato; Pagotto, Uberto

2009-01-01

Study Objectives: To contribute to the anthropometric and metabolic phenotyping of orexin-A–deficient narcoleptic patients, and to explore a possible risk of their developing a metabolic syndrome. Design: We performed a cross-sectional study comparing metabolic alterations in patients with narcolepsy with cataplexy (NC) and patients with idiopathic hypersomnia without long sleep time. Setting: University hospital. Patients: Fourteen patients with narcolepsy with cataplexy and 14 sex and age-matched patients with idiopathic hypersomnia without long sleep time. Interventions: N/A. Measurements and results: Metabolic parameters were evaluated by measuring body mass index (BMI), waist circumference (also with abdominal computed tomography), blood pressure, and daily calorie intake (3-day diary). Chronotypes were assessed through the morningness-eveningness questionnaire. Lumbar puncture for cerebrospinal fluid orexin-A determination and HLA typing were performed. Patients with narcolepsy with cataplexy (all HLA DQB1*0602 positive and with cerebrospinal fluid orexin-A levels < 110 pg/mL) had a higher BMI and BMI-independent metabolic alterations, namely waist circumference, high-density lipoprotein cholesterol, and glucose/insulin ratio (an insulin resistance index), with respect to patients with idiopathic hypersomnia without long sleep time (cerebrospinal fluid orexin-A levels > 300 pg/mL). Despite lower daily food intake, patients with narcolepsy with cataplexy displayed significant alterations in metabolic parameters resulting in a diagnosis of metabolic syndrome in more than half the cases. Conclusions: BMI-independent metabolic alterations and the relative hypophagia of patients with narcolepsy with cataplexy, as compared with patients with idiopathic hypersomnia without long sleep time, suggest that orexin-A influences the etiology of this phenotype. Moreover, considering that these dysmetabolic alterations are present from a young age, a careful metabolic

An Interesting Case of Late Age at Onset of Narcolepsy with Cataplexy

PubMed Central

Krishnamurthy, Venkatesh B.; Nallamothu, Vijaya; Singareddy, Ravi

2014-01-01

The usual age at onset of narcolepsy with cataplexy is in the second or third decade. In cases with late onset narcolepsy with cataplexy, symptoms are usually mild with relatively less severe daytime sleepiness and less frequent cataplexy. Here we present a case of narcolepsy with cataplexy with onset of symptoms around sixty years of age. This case is unique, with severe daytime sleepiness both by subjective report as well as on objective Multiple Sleep Latency Test and having multiple cataplexy episodes in a day. Citation: Krishnamurthy VB; Nallamothu V; Singareddy R. An interesting case of late age at onset of narcolepsy with cataplexy. J Clin Sleep Med 2014;10(2):203-205. PMID:24533004

Narcolepsy in Southern Chinese patients: clinical characteristics, HLA typing and seasonality of birth.

PubMed

Wing, Y K; Chen, L; Fong, S Y Y; Ng, M H L; Ho, C K W; Cheng, S H; Tang, N L S; Li, A M

2008-11-01

To report clinical characteristics, human leukocyte antigen (HLA) typing and seasonality of birth of a series of 54 Southern Chinese patients suffering from narcolepsy. All subjects underwent detailed medical and psychiatric interviews and a standardised nocturnal polysomnogram followed by a daytime Multiple Sleep Latency Test. Each subject also completed a set of sleep questionnaires. HLA typing was performed in 91% of subjects. A total of 78% and 22% of patients were diagnosed with suffering from cataplectic and non-cataplectic narcolepsy, respectively. The majority (n = 47, 87%) of patients were referred to our sleep clinic for excessive daytime sleepiness (EDS). The cataplectic narcolepsy differed from non-cataplectic narcolepsy by having more rapid eye movement (REM)-related clinical symptoms (more sleep paralysis and sleep-related hallucination) and sleep disturbances (shorter REM latency), as well as tighter association with HLA DQB1*0602. A bi-modal peak pattern was observed at 11 and 39 years old. A similar bi-modal pattern also occurred for EDS and cataplexy. Excess winter births were observed for this series of patients. 81% of patients with cataplectic narcolepsy were DQB1*0602-positive. There were no differences between early- and late-onset cases in the association with positive DQB1*0602 (71.4% vs 60%). Narcolepsy had prominent pernicious effects on various social, academic, family and mental aspects in our patients. In our Southern Chinese narcolepsy series, bi-modal peak pattern of age of onset, excess winter birth and tight association of HLA DQB1*0602 with cataplectic narcolepsy were found.

Narcolepsy with cataplexy in a child with Charcot-Marie-Tooth disease. Case Report.

PubMed

Zheng, Feixia; Wang, Shuang

2016-09-01

We report an 8-year-old boy diagnosed with both CMT1 and narcolepsy, which were not reported simultaneously presenting in one person. The boy presented with a history of increased suddenly falling frequency and excessive daytime sleepiness for 3 months. CMT1 was diagnosed by electrophysiology and genetic testing. Narcolepsy had not been diagnosed until the frequently falling caused by sudden and transient episodes of legs weakness triggered by emotion was found. Multiple sleep latency test showed multiple sleep onset REM periods with reduced sleep latency. When CMT1 and narcolepsy were coexist in an individual, the latter might be overlooked. Cataplexy caused by narcolepsy might be disregard as distal muscle weakness of CMT1. The daytime sleepiness might also be ignored. Therefore, we recommend that patients with sleep disorders should be queried about the symptoms of narcolepsy.

Identification of Differentially Expressed Genes in Blood Cells of Narcolepsy Patients

PubMed Central

Tanaka, Susumu; Honda, Yutaka; Honda, Makoto

2007-01-01

Study Objective: A close association between the human leukocyte antigen (HLA)-DRB1*1501/DQB1*0602 and abnormalities in some inflammatory cytokines have been demonstrated in narcolepsy. Specific alterations in the immune system have been suggested to occur in this disorder. We attempted to identify alterations in gene expression underlying the abnormalities in the blood cells of narcoleptic patients. Designs: Total RNA from 12 narcolepsy-cataplexy patients and from 12 age- and sex-matched healthy controls were pooled. The pooled samples were initially screened for candidate genes for narcolepsy by differential display analysis using annealing control primers (ACP). The second screening of the samples was carried out by semiquantitative PCR using gene-specific primers. Finally, the expression levels of the candidate genes were further confirmed by quantitative real-time PCR using a new set of samples (20 narcolepsy-cataplexy patients and 20 healthy controls). Results: The second screening revealed differential expression of 4 candidate genes. Among them, MX2 was confirmed as a significantly down-regulated gene in the white blood cells of narcoleptic patients by quantitative real-time PCR. Conclusion: We found the MX2 gene to be significantly less expressed in comparison with normal subjects in the white blood cells of narcoleptic patients. This gene is relevant to the immune system. Although differential display analysis using ACP technology has a limitation in that it does not help in determining the functional mechanism underlying sleep/wakefulness dysregulation, it is useful for identifying novel genetic factors related to narcolepsy, such as HLA molecules. Further studies are required to explore the functional relationship between the MX2 gene and narcolepsy pathophysiology. Citation: Tanaka S; Honda Y; Honda M. Identification of differentially expressed genes in blood cells of narcolepsy patients. SLEEP 2007;30(8):974-979. PMID:17702266

Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system.

PubMed

Nishino, Seiji; Kanbayashi, Takashi

2005-08-01

Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases

A population-based epidemiologic study of adult-onset narcolepsy incidence and associated risk factors, 2004-2013.

PubMed

Lee, Rachel U; Radin, Jennifer M

2016-11-15

An increase in narcolepsy incidence was noted after the novel pandemic influenza of 2009, leading to further interest in risk factors associated with this disease. However, there is limited data on the epidemiology of narcolepsy, particularly in the adult population. Therefore, we sought to examine narcolepsy incidence rates in the United States and describe associated characteristics. We performed a population based epidemiologic study of active duty military personnel. All outpatient clinics in the continental United States providing care for active duty military between 2004 through 2013 were included utilizing existing databases. Narcolepsy was defined in 3 ways: (1) 2 diagnoses of narcolepsy within 6months of each other, one made by a sleep expert; (2) 2 diagnoses by any provider followed by a narcolepsy prescription within 14days of last visit; and (3) procedure code for a sleep study followed by a narcolepsy diagnosis by a sleep expert within 6months. There were 1675 narcolepsy cases. Overall incidence of narcolepsy trended from 14.6 to 27.3 cases per 100,000 person-years, with an increase starting after 2005-2006 and peaking during the 2011-2012 influenza season. Higher frequencies were seen among females, non-Hispanic blacks, and members living in the south. Narcolepsy incidence rates among active duty military members are higher than previously described. The reason for the steady rise of incidence from 2005 to 2006 through 2011-2012 is unknown; however, these findings require further exploration. We detected risk factors associated with the development of narcolepsy which may aid in future study efforts. Published by Elsevier B.V.

The diagnosis and treatment of pediatric narcolepsy.

PubMed

Nevsimalova, Sona

2014-08-01

Narcolepsy in children is a serious disorder marked by a chronic course and lifelong handicap in school performance and choice of employment, by free time activity limitation, and by behavior and personality changes, all of which constitute a major influence on the quality of life. Increased daytime sleepiness may be the only sign at the disease onset, with attacks of sleep becoming longer and lasting up to hours. Also present may be confusional arousals with features of sleep drunkenness. Paradoxically, preschool and young children may show inattentiveness, emotional lability, and hyperactive behavior. Cataplexy may develop after onset of sleepiness and affect mainly muscles of the face. Hypnagogic hallucinations and sleep paralysis are seldom present. Multiple Sleep Latency Test criteria are not available for children younger than 6 years. The haplotype (HLA-DQB1:0602) can be associated with the disorder; however, the best predictor of narcolepsy-cataplexy is hypocretin deficiency. The treatment generally used in adults is regarded as off-label in childhood, which is why the management of pediatric narcolepsy is difficult.

Narcolepsy with Long Sleep Time: A Specific Entity?

PubMed Central

Vernet, Cyrille; Arnulf, Isabelle

2009-01-01

Background: The classical narcolepsy patient reports intense feelings of sleepiness (with/out cataplexy), normal or disrupted nighttime sleep, and takes short and restorative naps. However, with long-term monitoring, we identified some narcoleptics resembling patients with idiopathic hypersomnia. Objective: To isolate and describe a new subtype of narcolepsy with long sleep time). Setting: University Hospital Design: Controlled, prospective cohort Participants: Out of 160 narcoleptics newly diagnosed within the past 3 years, 29 (18%) had a long sleep time (more than 11 h/24 h). We compared narcoleptics with (n = 23) and without (n = 29) long sleep time to 25 hypersomniacs with long sleep time and 20 healthy subjects. Intervention: Patients and controls underwent face-to face interviews, questionnaires, human leukocyte antigen (HLA) genotype, an overnight polysomnography, multiple sleep latency tests, and 24-h ad libitum sleep monitoring. Results: Narcoleptics with long sleep time had a similar disease course and similar frequencies of cataplexy, sleep paralysis, hallucinations, multiple sleep onset in REM periods, short mean sleep latencies, and HLA DQB1*0602 positivity as narcoleptics with normal sleep time did. However, they had longer sleep time during 24 h, and higher sleep efficiency, lower Epworth Sleepiness Scale scores, and reported their naps were more often unrefreshing. Only 3/23 had core narcolepsy (HLA and cataplexy positive). Conclusions: The subgroup of narcoleptics with a long sleep time comprises 18% of narcoleptics. Their symptoms combine the disabilities of both narcolepsy (severe sleepiness) and idiopathic hypersomnia (long sleep time and unrefreshing naps). Thus, they may constitute a group with multiple arousal system dysfunctions. Citation: Vernet C; Arnulf I. Narcolepsy with long sleep time: a specific entity? SLEEP 2009;32(9):1229-1235. PMID:19750928

Comparison of Polysomnography and Multiple Sleep Latency Test Findings in Subjects with Narcolepsy and İdiopathic Hypersomnia.

PubMed

Erdem, Murat; Bolu, Abdullah; Ünlü, A Gazi; Alper, Mustafa; Yetkin, Sinan

2013-09-01

Both narcolepsy and idiopathic hypersomnia are the main causes of excessive daytime sleepiness. In this study, we aimed to compare polysomnography (PSG) and multiple sleep latency test (MSLT) findings in narcolepsy and idiopathic hypersomnia patients. The files of patients with narcolepsy and hypersomnia who were admitted between 1995 and 2009 were reviewed. We evaluated data from 94 patients with narcolepsy with cataplexy, 49 with narcolepsy without cataplexy and 140 patients with idiopathic hypersomnia. Sleep latency and REM latency were longer in idiopathic hypersomnia group than in narcolepsy with and without cataplexy group. Mean sleep latency in MSLT was the shortest in narcolepsy with cataplexy group. There was no difference in sleep efficiency, percentage of sleep stage and number of awakenings in PSG between three groups. The findings of the study indicated that narcolepsy patients differ from idiopathic hypersomnia patients in terms of sleep latency and REM latency in PSG.

CSF Histamine Contents in Narcolepsy, Idiopathic Hypersomnia and Obstructive Sleep Apnea Syndrome

PubMed Central

Kanbayashi, Takashi; Kodama, Tohru; Kondo, Hideaki; Satoh, Shinsuke; Inoue, Yuichi; Chiba, Shigeru; Shimizu, Tetsuo; Nishino, Seiji

2009-01-01

Study Objective: To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency. Design: Cross sectional studies. Setting and Patients: Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2. Results: We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean ± SEM; 176.0 ± 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 ± 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 ± 16.4 pg/mL), and idiopathic hypersomnia (161.0 ± 29.3 pg/mL); the levels in OSAS (259.3 ± 46.6 pg/mL) did not statistically differ from those in the controls (333.8 ± 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 ± 16.3 pg/mL) and idiopathic hypersomnia (143.3 ± 28.8 pg/mL), while the levels in the medicated patients were in the normal range. Conclusion: The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin. Citation: Kanbayashi T; Kodama T; Kondo H; Satoh S; Inoue Y; Chiba S; Shimizu T; Nishino S. CSF

Narcolepsy induced by chronic heavy alcohol consumption: a case report

PubMed Central

Wang, Xinyuan

2012-01-01

Summary Narcolepsy is a chronic neurological disorder, characterized by uncontrollable excessive daytime sleepiness, cataplectic episodes, sleep paralysis, hypnagogic hallucinations, and night time sleep disruption. The paper reviewed the related literature and reported a case of long-term drinking induced narcolepsy which was significantly improved after treatment with paroxetine and dexzopiclone. PMID:25328357

The neurobiology, diagnosis, and treatment of narcolepsy.

PubMed

Scammell, Thomas E

2003-02-01

Narcolepsy is a common cause of chronic sleepiness distinguished by intrusions into wakefulness of physiological aspects of rapid eye movement sleep such as cataplexy and hallucinations. Recent advances provide compelling evidence that narcolepsy may be a neurodegenerative or autoimmune disorder resulting in a loss of hypothalamic neurons containing the neuropeptide orexin (also known as hypocretin). Because orexin promotes wakefulness and inhibits rapid eye movement sleep, its absence may permit inappropriate transitions between wakefulness and sleep. These discoveries have considerably improved our understanding of the neurobiology of sleep and should foster the development of rational treatments for a variety of sleep disorders.

Impact of extracranial contamination on regional cerebral oxygen saturation: a comparison of three cerebral oximetry technologies.

PubMed

Davie, Sophie N; Grocott, Hilary P

2012-04-01

Cerebral oximetry is a noninvasive technology using near-infrared spectroscopy (NIRS) to estimate regional cerebral oxygen saturation. Although NIRS cerebral oximetry is being increasingly used in many clinical settings, interdevice technologic differences suggest potential variation in the ability to accurately acquire brain oxygenation signals. The primary objective of this study was to determine if NIRS-derived regional cerebral oxygen saturation measurements accurately account for oxygen saturation contamination from extracranial tissue. Twelve healthy volunteers had each of three NIRS devices (FORE-SIGHT [CAS Medical Systems Inc; Brandford, CT], INVOS 5100C-PB [Covidien; Boulder, CO], and EQUANOX Classic 7600 [Nonin Medical Inc; Plymouth, MN]) randomly applied to the forehead. After this, a circumferential pneumatic head cuff was positioned such that when inflated, hypoxia-ischemia would be produced in the extracranial scalp tissue beneath the NIRS cerebral oximeters. Comparisons among the three devices were made of the NIRS measurements before and following hypoxia-ischemia produced in the scalp tissue with inflation of the head cuff. The induction of extracranial hypoxia-ischemia resulted in a significant reduction in regional cerebral oxygen saturation measurements in all three NIRS devices studied. At 5 min postinflation of the pneumatic head cuff, the INVOS demonstrated a 16.6 ± 9.6% (mean ± SD) decrease from its baseline (P = 0.0001), the FORE-SIGHT an 11.8 ± 5.3% decrease from its baseline (P < 0.0001), and the EQUANOX a 6.8 ± 6.0% reduction from baseline (P = 0.0025). Extracranial contamination appears to significantly affect NIRS measurements of cerebral oxygen saturation. Although the clinical implications of these apparent inaccuracies require further study, they suggest that the oxygen saturation measurements provided by cerebral oximetry do not solely reflect that of the brain alone.

Positive effects of massage therapy on a patient with narcolepsy.

PubMed

Hill, Robyn; Baskwill, Amanda

2013-01-01

The purpose of this case report was to investigate the effects of massage therapy on the sleep patterns of a woman with narcolepsy. The 23-year-old woman's primary symptoms included excessive daytime sleepiness and periodic leg movements (PLM), which were associated with her diagnoses of both narcolepsy and cataplexy. Five 45-minute massage therapy treatments were administered over a five-week period. The patient's sleep patterns were recorded each week before the treatment. A final measurement was recorded in the sixth week. The sleep patterns were monitored using the Leeds Sleep Evaluation Questionnaire, which included ten visual analogue scales. The results of this case report included an improvement in getting to sleep by 148%, an improvement in quality of sleep by 1100%, an improvement in awake following sleep by 121%, and an improvement in behaviour following wakening by 28% using the Leeds Sleep Evaluation Questionnaire. This case report suggests that massage therapy had a positive effect on this patient with narcolepsy. Further research is needed to investigate the effects of massage therapy on narcolepsy and sleep patterns.

Effective treatment of narcolepsy-like symptoms with high-frequency repetitive transcranial magnetic stimulation

PubMed Central

Lai, Jian-bo; Han, Mao-mao; Xu, Yi; Hu, Shao-hua

2017-01-01

Abstract Rationale: Narcolepsy is a rare sleep disorder with disrupted sleep-architecture. Clinical management of narcolepsy lies dominantly on symptom-driven pharmacotherapy. The treatment role of repetitive transcranial magnetic stimulation (rTMS) for narcolepsy remains unexplored. Patient concerns: In this paper, we present a case of a 14-year-old young girl with excessive daytime sleepiness (EDS), cataplexy and hypnagogic hallucinations. Diagnoses: After excluding other possible medical conditions, this patient was primarily diagnosed with narcolepsy. Interventions: The patient received 25 sessions of high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC). Outcomes: The symptoms of EDS and cataplexy significantly improved after rTMS treatment. Meanwhile, her score in the Epworth sleep scale (ESS) also remarkably decreased. Lessons: This case indicates that rTMS may be selected as a safe and effective alternative strategy for treating narcolepsy-like symptoms. Well-designed researches are warranted in future investigations on this topic. PMID:29145290

Clinical and practical considerations in the pharmacologic management of narcolepsy.

PubMed

Thorpy, Michael J; Dauvilliers, Yves

2015-01-01

Despite published treatment recommendations and the availability of approved and off-label pharmacologic therapies for narcolepsy, the clinical management of this incurable, chronic neurologic disorder remains challenging. While treatment is generally symptomatically driven, decisions regarding which drug(s) to use need to take into account a variety of factors that may affect adherence, efficacy, and tolerability. Type 1 narcolepsy (predominantly excessive daytime sleepiness with cataplexy) or type 2 narcolepsy (excessive daytime sleepiness without cataplexy) may drive treatment decisions, with consideration given either to a single drug that targets multiple symptoms or to multiple drugs that each treat a specific symptom. Other drug-related characteristics that affect drug choice are dosing regimens, tolerability, and potential drug-drug interactions. Additionally, the patient should be an active participant in treatment decisions, and the main symptomatic complaints, treatment goals, psychosocial setting, and use of lifestyle substances (ie, alcohol, nicotine, caffeine, and cannabis) need to be discussed with respect to treatment decisions. Although there is a lack of narcolepsy-specific instruments for monitoring therapeutic effects, clinically relevant subjective and objective measures of daytime sleepiness (eg, Epworth Sleepiness Scale and Maintenance of Wakefulness Test) can be used to provide guidance on whether treatment goals are being met. These considerations are discussed with the objective of providing clinically relevant recommendations for making treatment decisions that can enhance the effective management of patients with narcolepsy. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Complex Movement Disorders at Disease Onset in Childhood Narcolepsy with Cataplexy

ERIC Educational Resources Information Center

Plazzi, Giuseppe; Pizza, Fabio; Palaia, Vincenzo; Franceschini, Christian; Poli, Francesca; Moghadam, Keivan K.; Cortelli, Pietro; Nobili, Lino; Bruni, Oliviero; Dauvilliers, Yves; Lin, Ling; Edwards, Mark J.; Mignot, Emmanuel; Bhatia, Kailash P.

2011-01-01

Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of…

Rare missense mutations in P2RY11 in narcolepsy with cataplexy.

PubMed

Degn, Matilda; Dauvilliers, Yves; Dreisig, Karin; Lopez, Régis; Pfister, Corinne; Pradervand, Sylvain; Rahbek Kornum, Birgitte; Tafti, Mehdi

2017-06-01

The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients. No mutations were found in healthy controls. Six of the eight narcolepsy-associated P2Y11 mutations resulted in significant functional deficits in P2Y11 signalling through both Ca2+ and cAMP signalling pathways. In conclusion, our data show that decreased P2Y11 signalling plays an important role in the development of narcolepsy with cataplexy. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Impact of cytokine in type 1 narcolepsy: Role of pandemic H1N1 vaccination ?

PubMed

Lecendreux, Michel; Libri, Valentina; Jaussent, Isabelle; Mottez, Estelle; Lopez, Régis; Lavault, Sophie; Regnault, Armelle; Arnulf, Isabelle; Dauvilliers, Yves

2015-06-01

Recent advances in the identification of susceptibility genes and environmental exposures (pandemic influenza 2009 vaccination) provide strong support that narcolepsy type 1 is an immune-mediated disease. Considering the limited knowledge regarding the immune mechanisms involved in narcolepsy whether related to flu vaccination or not and the recent progresses in cytokine measurement technology, we assessed 30 cytokines, chemokines and growth factors using the Luminex technology in either peripheral (serum) or central (CSF) compartments in a large population of 90 children and adult patients with narcolepsy type 1 in comparison to 58 non-hypocretin deficient hypersomniacs and 41 healthy controls. Furthermore, we compared their levels in patients with narcolepsy whether exposed to pandemic flu vaccine or not, and analyzed the effect of age, duration of disease and symptom severity. Comparison for sera biomarkers between narcolepsy (n = 84, 54 males, median age: 15.5 years old) and healthy controls (n = 41, 13 males, median age: 20 years old) revealed an increased stimulation of the immune system with high release of several pro- and anti-inflammatory serum cytokines and growth factors with interferon-γ, CCL11, epidermal growth factor, and interleukin-2 receptor being independently associated with narcolepsy. Increased levels of interferon-γ, CCL11, and interleukin-12 were found when close to narcolepsy onset. After several adjustments, only one CSF biomarker differed between narcolepsy (n = 44, 26 males, median age: 15 years old) and non-hypocretin deficient hypersomnias (n = 57, 24 males, median age: 36 years old) with higher CCL 3 levels found in narcolepsy. Comparison for sera biomarkers between patients with narcolepsy who developed the disease post-pandemic flu vaccination (n = 36) to those without vaccination (n = 48) revealed an increased stimulation of the immune system with high release of three cytokines, regulated upon activation normal T-cell expressed

Beta-amyloid and phosphorylated tau metabolism changes in narcolepsy over time.

PubMed

Liguori, Claudio; Placidi, Fabio; Izzi, Francesca; Nuccetelli, Marzia; Bernardini, Sergio; Sarpa, Maria Giovanna; Cum, Fabrizio; Marciani, Maria Grazia; Mercuri, Nicola Biagio; Romigi, Andrea

2016-03-01

The aim od this study is to test whether metabolism of beta-amyloid and tau proteins changes in narcolepsy along with the disease course. We analyzed a population of narcoleptic drug-naïve patients compared to a sample of healthy controls. Patients and controls underwent lumbar puncture for assessment of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels. Moreover, based on the median disease duration of the whole narcolepsy group, the patients were divided into two subgroups: patients with a short disease duration (SdN, <5 years) and patients with a long disease duration (LdN, >5 years). We found significantly lower CSF Aβ42 levels in the whole narcolepsy group with respect to controls. Taking into account the patient subgroups, we documented reduced CSF Aβ42 levels in SdN compared to both LdN and controls. Even LdN patients showed lower CSF Aβ42 levels with respect to controls. Moreover, we documented higher CSF p-tau levels in LdN patients compared to both SdN and controls. Finally, a significant positive correlation between CSF Aβ42 levels and disease duration was evident. We hypothesize that beta-amyloid metabolism and cascade may be impaired in narcolepsy not only at the onset but also along with the disease course, although they show a compensatory profile over time. Concurrently, also CSF biomarkers indicative of neural structure (p-tau) appear to be altered in narcolepsy patients with a long disease duration. However, the mechanism underlying beta-amyloid and tau metabolism impairment in narcolepsy remains still unclear and deserves to be better elucidated.

[Workplace accomodations for two workers with narcolepsy].

PubMed

Vico Garcerán, Belén; Monzó Salas, Monserrat; Cuenca Esteve, Francisco; Luis Domingo, José

2013-01-01

We describe the case of two workers evaluated in our occupational health unit. The first worker was a kitchen aide; the second was a primary care physician. Both had been diagnosed with narcolepsy and had obvious disability.We assessed occupational hazards related to their jobs, analysed their tasks, and performed medical examinations. Afterwards, we offered recommendations to the patients, consisting of avoidance of situations involving a risk of work accidents and improving their sleep habits. Narcolepsy is a rare disorder, but it has important social and occupational consequences. A better understanding of the disease and some work accommodations can help improve the quality of life of affected workers.

Disrupted Sleep in Narcolepsy: Exploring the Integrity of Galanin Neurons in the Ventrolateral Preoptic Area.

PubMed

Gavrilov, Yury V; Ellison, Brian A; Yamamoto, Mihoko; Reddy, Hasini; Haybaeck, Johannes; Mignot, Emmanuel; Baumann, Christian R; Scammell, Thomas E; Valko, Philipp O

2016-05-01

To examine the integrity of sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO) in postmortem brains of narcolepsy type 1 patients. Postmortem examination of five narcolepsy and eight control brains. VLPO galanin neuron count did not differ between narcolepsy patients (11,151 ± 3,656) and controls (13,526 ± 9,544). A normal number of galanin-immunoreactive VLPO neurons in narcolepsy type 1 brains at autopsy suggests that VLPO cell loss is an unlikely explanation for the sleep fragmentation that often accompanies the disease. © 2016 Associated Professional Sleep Societies, LLC.

Positive Effects of Massage Therapy on a Patient with Narcolepsy

PubMed Central

Hill, Robyn; Baskwill, Amanda

2013-01-01

Purpose The purpose of this case report was to investigate the effects of massage therapy on the sleep patterns of a woman with narcolepsy. Participant The 23-year-old woman’s primary symptoms included excessive daytime sleepiness and periodic leg movements (PLM), which were associated with her diagnoses of both narcolepsy and cataplexy. Intervention Five 45-minute massage therapy treatments were administered over a five-week period. The patient’s sleep patterns were recorded each week before the treatment. A final measurement was recorded in the sixth week. The sleep patterns were monitored using the Leeds Sleep Evaluation Questionnaire, which included ten visual analogue scales. Results The results of this case report included an improvement in getting to sleep by 148%, an improvement in quality of sleep by 1100%, an improvement in awake following sleep by 121%, and an improvement in behaviour following wakening by 28% using the Leeds Sleep Evaluation Questionnaire. Conclusion This case report suggests that massage therapy had a positive effect on this patient with narcolepsy. Further research is needed to investigate the effects of massage therapy on narcolepsy and sleep patterns. PMID:23730398

CSF Hypocretin-1 Levels and Clinical Profiles in Narcolepsy and Idiopathic CNS Hypersomnia in Norway

PubMed Central

Heier, Mona Skard; Evsiukova, Tatiana; Vilming, Steinar; Gjerstad, Michaela D.; Schrader, Harald; Gautvik, Kaare

2007-01-01

Objective: To evaluate the relationship between CSF hypocretin-1 levels and clinical profiles in narcolepsy and CNS hypersomnia in Norwegian patients. Method: CSF hypocretin-1 was measured by a sensitive radioimmunoassay in 47 patients with narcolepsy with cataplexy, 7 with narcolepsy without cataplexy, 10 with idiopathic CNS hypersomnia, and a control group. Results: Low hypocretin-1 values were found in 72% of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy. Patients with low CSF hypocretin-1 levels reported more extensive muscular involvement during cataplectic attacks than patients with normal levels. Hypnagogic hallucinations and sleep paralysis occurred more frequently in patients with cataplexy than in the other patient groups, but with no correlation to hypocretin-1 levels. Conclusion: About three quarters of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy had low CSF hypocretin-1 values, and appear to form a distinct clinical entity. Narcolepsy without cataplexy could not be distinguished from idiopathic CNS hypersomnia by clinical symptoms or biochemical findings. Citation: Heier MS; Evsiukova T; Vilming S; Gjerstad MD; Schrader H; Gautvik K. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in norway. SLEEP 2007;30(8):969-973. PMID:17702265

Fused cerebral organoids model interactions between brain regions.

PubMed

Bagley, Joshua A; Reumann, Daniel; Bian, Shan; Lévi-Strauss, Julie; Knoblich, Juergen A

2017-07-01

Human brain development involves complex interactions between different regions, including long-distance neuronal migration or formation of major axonal tracts. Different brain regions can be cultured in vitro within 3D cerebral organoids, but the random arrangement of regional identities limits the reliable analysis of complex phenotypes. Here, we describe a coculture method combining brain regions of choice within one organoid tissue. By fusing organoids of dorsal and ventral forebrain identities, we generate a dorsal-ventral axis. Using fluorescent reporters, we demonstrate CXCR4-dependent GABAergic interneuron migration from ventral to dorsal forebrain and describe methodology for time-lapse imaging of human interneuron migration. Our results demonstrate that cerebral organoid fusion cultures can model complex interactions between different brain regions. Combined with reprogramming technology, fusions should offer researchers the possibility to analyze complex neurodevelopmental defects using cells from neurological disease patients and to test potential therapeutic compounds.

Disrupted Sleep in Narcolepsy: Exploring the Integrity of Galanin Neurons in the Ventrolateral Preoptic Area

PubMed Central

Gavrilov, Yury V.; Ellison, Brian A.; Yamamoto, Mihoko; Reddy, Hasini; Haybaeck, Johannes; Mignot, Emmanuel; Baumann, Christian R.; Scammell, Thomas E.; Valko, Philipp O.

2016-01-01

Study Objectives: To examine the integrity of sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO) in postmortem brains of narcolepsy type 1 patients. Methods: Postmortem examination of five narcolepsy and eight control brains. Results: VLPO galanin neuron count did not differ between narcolepsy patients (11,151 ± 3,656) and controls (13,526 ± 9,544). Conclusions: A normal number of galanin-immunoreactive VLPO neurons in narcolepsy type 1 brains at autopsy suggests that VLPO cell loss is an unlikely explanation for the sleep fragmentation that often accompanies the disease. Citation: Gavrilov YV, Ellison BA, Yamamoto M, Reddy H, Haybaeck J, Mignot E, Baumann CR, Scammell TE, Valko PO. Disrupted sleep in narcolepsy: exploring the integrity of galanin neurons in the ventrolateral preoptic area. SLEEP 2016;39(5):1059–1062. PMID:26951397

Tolerance and Efficacy of Sodium Oxybate in Childhood Narcolepsy with Cataplexy: A Retrospective Study

PubMed Central

Lecendreux, Michel; Poli, Francesca; Oudiette, Delphine; Benazzouz, Fatima; Donjacour, Claire E.H.M; Franceschini, Christian; Finotti, Elena; Pizza, Fabio; Bruni, Oliviero; Plazzi, Giuseppe

2012-01-01

Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness, irresistible sleep episodes, and sudden loss of muscle tone (cataplexy) mostly triggered by emotions. Narcolepsy with cataplexy is a disabling lifelong disorder frequently arising during childhood. Pediatric narcolepsy often results in severe learning and social impairment. Improving awareness about this condition increases early diagnosis and may allow patients to rapidly access adequate treatments, including pharmacotherapy and/or non-medication-based approaches. Even though children currently undergo pharmacotherapy, data about safety and efficacy in the pediatric population are scarce. Lacking international guidelines as well as drugs registered for childhood narcolepsy with cataplexy, physicians have no other alternative but to prescribe in an off-label manner medications identical to those recommended for adults. We retrospectively evaluated 27 children ranging from 6 to 16 years old, suffering from narcolepsy with cataplexy, who had been treated with off-label sodium oxybate and had been followed in a clinical setting. Throughout a semi-structured interview, we documented the good efficacy and tolerability of sodium oxybate in the majority of the patients. This study constitutes a preliminary step towards a further randomized controlled trial in childhood narcolepsy with cataplexy. Citation: Lecendreux M; Poli F; Oudiette D; Benazzouz F; Donjacour CEHM; Franceschini C; Finotti E; Pizza F; Bruni O; Plazzi G. Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a retrospective study. SLEEP 2012;35(5):709-711. PMID:22547897

Levothyroxine Improves Subjective Sleepiness in a Euthyroid Patient with Narcolepsy without Cataplexy

PubMed Central

Sobol, Danielle L.; Spector, Andrew R.

2014-01-01

Objective: We discuss the use of levothyroxine for excessive daytime sleepiness (EDS) and prolonged nocturnal sleep time in a euthyroid patient with narcolepsy. Methods: After failure of first-line narcolepsy treatments, a 48-year-old female began levothyroxine (25 mcg/day). After 12 weeks of treatment, the patient was evaluated for improvement in total sleep time and subjective daytime sleepiness assessed by Epworth Sleepiness Scale (ESS). Results: At baseline, ESS score was 16 and total sleep time averaged 16 h/day. After 12 weeks, ESS was 13 and reported total sleep time was 13 h/day. Conclusions: Levothyroxine improved EDS and total sleep time in a euthyroid patient with narcolepsy without cataplexy after 12 weeks without side effects. Citation: Sobol DL, Spector AR. Levothyroxine improves subjective sleepiness in a euthyroid patient with narcolepsy without cataplexy. J Clin Sleep Med 2014;10(11):1231-1232. PMID:25325591

Cerebral oxygenation in the beach chair position for shoulder surgery in regional anesthesia: impact on cerebral blood flow and neurobehavioral outcome.

PubMed

Aguirre, José A; Märzendorfer, Olivia; Brada, Muriel; Saporito, Andrea; Borgeat, Alain; Bühler, Philipp

2016-12-01

Beach chair position is considered a potential risk factor for central neurological events particularly if combined with low blood pressure. The aim of this study was to assess the impact of regional anesthesia on cerebral blood flow and neurobehavioral outcome. This is a prospective, assessor-blinded observational study evaluating patients in the beach chair position undergoing shoulder surgery under regional anesthesia. University hospital operating room. Forty patients with American Society of Anesthesiologists classes I-II physical status scheduled for elective shoulder surgery. Cerebral saturation and blood flow of the middle cerebral artery were measured prior to anesthesia and continued after beach chair positioning until discharge to the postanesthesia care unit. The anesthesiologist was blinded for these values. Controlled hypotension with systolic blood pressure≤100mm Hg was maintained during surgery. Neurobehavioral tests and values of regional cerebral saturation, bispectral index, the mean maximal blood flow of the middle cerebral artery, and invasive blood pressure were measured prior to regional anesthesia, and measurements were repeated after placement of the patient on the beach chair position and every 20 minutes thereafter until discharge to postanesthesia care unit. The neurobehavioral tests were repeated the day after surgery. The incidence of cerebral desaturation events was 5%. All patients had a significant blood pressure drop 5 minutes after beach chair positioning, measured at the heart as well as the acoustic meatus levels, when compared with baseline values (P<.05). There was no decrease in either the regional cerebral saturation (P=.136) or the maximal blood flow of the middle cerebral artery (P=.212) at the same time points. Some neurocognitive tests showed an impairment 24 hours after surgery (P<.001 for 2 of 3 tests). Beach chair position in patients undergoing regional anesthesia for shoulder surgery had no major impact on

Differences in Brain Morphological Findings between Narcolepsy with and without Cataplexy

PubMed Central

Nakamura, Masaki; Nishida, Shingo; Hayashida, Kenichi; Ueki, Yoichiro; Dauvilliers, Yves; Inoue, Yuichi

2013-01-01

Objective Maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) obtained by diffusion tensor imaging (DTI) can detect microscopic axonal changes by estimating the diffusivity of water molecules using magnetic resonance imaging (MRI). We applied an MRI voxel-based statistical approach to FA and ADC maps to evaluate microstructural abnormalities in the brain in narcolepsy and to investigate differences between patients having narcolepsy with and without cataplexy. Methods Twelve patients with drug-naive narcolepsy with cataplexy (NA/CA), 12 with drug-naive narcolepsy without cataplexy (NA w/o CA) and 12 age-matched healthy normal controls (NC) were enrolled. FA and ADC maps for these 3 groups were statistically compared by using voxel-based one-way ANOVA. In addition, we investigated the correlation between FA and ADC values and clinical variables in the patient groups. Results Compared to the NC group, the NA/CA group showed higher ADC values in the left inferior frontal gyrus and left amygdala, and a lower ADC value in the left postcentral gyrus. The ADC value in the right inferior frontal gyrus and FA value in the right precuneus were higher for NA/CA group than for the NA w/o CA group. However, no significant differences were observed in FA and ADC values between the NA w/o CA and NC groups in any of the areas investigated. In addition, no correlation was found between the clinical variables and ADC and FA values of any brain areas in these patient groups. Conclusions Several microstructural changes were noted in the inferior frontal gyrus and amygdala in the NA/CA but not in the NA w/o CA group. These findings suggest that these 2 narcolepsy conditions have different pathological mechanisms: narcolepsy without cataplexy form appears to be a potentially broader condition without any significant brain imaging differences from normal controls. PMID:24312261

DQB1 Locus Alone Explains Most of the Risk and Protection in Narcolepsy with Cataplexy in Europe

PubMed Central

Tafti, Mehdi; Hor, Hyun; Dauvilliers, Yves; Lammers, Gert J.; Overeem, Sebastiaan; Mayer, Geert; Javidi, Sirous; Iranzo, Alex; Santamaria, Joan; Peraita-Adrados, Rosa; Vicario, José L.; Arnulf, Isabelle; Plazzi, Giuseppe; Bayard, Sophie; Poli, Francesca; Pizza, Fabio; Geisler, Peter; Wierzbicka, Aleksandra; Bassetti, Claudio L.; Mathis, Johannes; Lecendreux, Michel; Donjacour, Claire E.H.M.; van der Heide, Astrid; Heinzer, Raphaël; Haba-Rubio, José; Feketeova, Eva; Högl, Birgit; Frauscher, Birgit; Benetó, Antonio; Khatami, Ramin; Cañellas, Francesca; Pfister, Corinne; Scholz, Sabine; Billiard, Michel; Baumann, Christian R.; Ercilla, Guadalupe; Verduijn, Willem; Claas, Frans H.J.; Dubois, Valérie; Nowak, Jacek; Eberhard, Hans-Peter; Pradervand, Sylvain; Hor, Charlotte N.; Testi, Manuela; Tiercy, Jean-Marie; Kutalik, Zoltán

2014-01-01

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. Citation: Tafti M; Hor H; Dauvilliers Y; Lammers GJ; Overeem S; Mayer G; Javidi S; Iranzo A; Santamaria J; Peraita-Adrados R; Vicario JL; Arnulf I; Plazzi G; Bayard S; Poli F; Pizza F; Geisler P; Wierzbicka A; Bassetti CL

Cerebral edema, mass effects, and regional blood volume in man.

PubMed

Penn, R D; Kurtz, D

1977-03-01

The authors conducted quantitative analysis of computerized tomography (CT) scans to measure tumor size, cerebral edema, and regional blood volume in man. Mass lesions without edema caused a local reduction in blood volume. Cerebral edema also reduced blood volume in proportion to its severity. Consideration of the electrolyte changes and water shifts in white-matter edema suggested that the decrease in absorption coefficient seen in CT scans was due to the increase in water content. Thus, in cerebral edema separation of blood vessels as well as increased interstitial pressure decrease blood volume, and the regional differences in turn reflect pressure gradients within the brain.

Transcranial Doppler of the middle cerebral artery indicates regional gray matter cerebral perfusion.

PubMed

Pasha, Evan P; Tarumi, Takashi; Haley, Andreana P; Tanaka, Hirofumi

2017-11-30

We determined if transcranial color-coded Doppler derived hemodynamics are associated with MRI-based cerebral blood flow (CBF) in regions clinically important to dementia in healthy middle-aged adults. In 30 subjects (18m/12f; age  =  52  ±  1 years), blood flow velocity (BFV) and cerebrovascular conductance (CVC) were measured with transcranial color-coded Doppler (TCCD) at the middle cerebral artery (MCA) and cerebral blood flow (CBF) was assessed with arterial spin labeled perfusion MRI. BFV and CVC were associated with hippocampus (r  =  0.58 and r  =  0.61, both p  <  0.01) and occipitoparietal (r  =  0.50 and r  =  0.58, both p  <  0.01) CBF. CVC was further associated with posterior cingulate CBF (r  =  0.58 p  <  0.01). Independent of age and sex, BFV and CVC were associated with hippocampus (r  =  0.59 and r  =  0.55, both p  <  0.003) and occipitoparietal (r  =  0.50 and r  =  0.57, both p  <  0.01) CBF. CVC was independently associated with posterior cingulate CBF (r  =  0.38, p  =  0.049). TCCD-measured BFV and CVC of the MCA are indicators of cerebral perfusion to clinically valuable brain regions in healthy middle-aged adults. TCCD may not be a good indicator of blood flow to cerebral white matter.

Narcolepsy

PubMed Central

Murray, T. J.; Foley, Anita

1974-01-01

Narcolepsy is a disorder of sleep control characterized by a tetrad of symptoms: sleep attacks, cataplexy, sleep paralysis and hypnagogic hallucinations. A diagnosis is made from a careful history. The incidence is estimated as high as 0.3% of the population. Unfortunately patients go for many years before the diagnosis is made and often have experienced disruption of their employment, social and family life, and may have experienced a number of car accidents because of falling asleep at the wheel. An unknown number of narcoleptics kill themselves on the highways before the diagnosis is ever made. Sleep attacks can usually be controlled by methylphenidate, and if the other symptoms persist they can often be effectively managed by imipramine. PMID:4809449

Sleep spindle density in narcolepsy.

PubMed

Christensen, Julie Anja Engelhard; Nikolic, Miki; Hvidtfelt, Mathias; Kornum, Birgitte Rahbek; Jennum, Poul

2017-06-01

Patients with narcolepsy type 1 (NT1) show alterations in sleep stage transitions, rapid-eye-movement (REM) and non-REM sleep due to the loss of hypocretinergic signaling. However, the sleep microstructure has not yet been evaluated in these patients. We aimed to evaluate whether the sleep spindle (SS) density is altered in patients with NT1 compared to controls and patients with narcolepsy type 2 (NT2). All-night polysomnographic recordings from 28 NT1 patients, 19 NT2 patients, 20 controls (C) with narcolepsy-like symptoms, but with normal cerebrospinal fluid hypocretin levels and multiple sleep latency tests, and 18 healthy controls (HC) were included. Unspecified, slow, and fast SS were automatically detected, and SS densities were defined as number per minute and were computed across sleep stages and sleep cycles. The between-cycle trends of SS densities in N2 and NREM sleep were evaluated within and between groups. Between-group comparisons in sleep stages revealed no significant differences in any type of SS. Within-group analyses of the SS trends revealed significant decreasing trends for NT1, HC, and C between first and last sleep cycle. Between-group analyses of SS trends between first and last sleep cycle revealed that NT2 differ from NT1 patients in the unspecified SS density in NREM sleep, and from HC in the slow SS density in N2 sleep. SS activity is preserved in NT1, suggesting that the ascending neurons to thalamic activation of SS are not significantly affected by the hypocretinergic system. NT2 patients show an abnormal pattern of SS distribution. Copyright © 2017 Elsevier B.V. All rights reserved.

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice.

PubMed

Bernard-Valnet, Raphaël; Yshii, Lidia; Quériault, Clémence; Nguyen, Xuan-Hung; Arthaud, Sébastien; Rodrigues, Magda; Canivet, Astrid; Morel, Anne-Laure; Matthys, Arthur; Bauer, Jan; Pignolet, Béatrice; Dauvilliers, Yves; Peyron, Christelle; Liblau, Roland S

2016-09-27

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin(+) neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin(+) neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin(+) neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin(+) neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin(+) neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

PubMed Central

Bernard-Valnet, Raphaël; Yshii, Lidia; Quériault, Clémence; Nguyen, Xuan-Hung; Arthaud, Sébastien; Rodrigues, Magda; Canivet, Astrid; Morel, Anne-Laure; Matthys, Arthur; Bauer, Jan; Pignolet, Béatrice; Dauvilliers, Yves; Peyron, Christelle; Liblau, Roland S.

2016-01-01

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin+ neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a “neo-self-antigen” specifically in hypothalamic orexin+ neurons (called Orex-HA), which were transferred with effector neo-self-antigen–specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin+ neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin+ neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin+ neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy. PMID:27621438

Cataplexy in anxious patients: is subclinical narcolepsy underrecognized in anxiety disorders?

PubMed

Flosnik, Dawn L; Cortese, Bernadette M; Uhde, Thomas W

2009-06-01

Excessive daytime sleepiness, hypnagogic-hypnopompic hallucinations, sleep paralysis, and cataplexy are symptoms associated with narcolepsy. Recent findings indicate that anxiety disorders also are associated with excessive daytime sleepiness, hypnagogic-hypnopompic hallucinations, and sleep paralysis. These observations suggest a possible relationship between anxiety disorders and narcolepsy. Cataplexy is considered the most specific symptom of narcolepsy, but its association with anxiety disorders is unknown. This preliminary investigation examined the prevalence and types of cataplexy in patients with primary anxiety disorders. Sex- and age-matched patients with anxiety disorders (N = 33) and healthy volunteers (N = 33) were assessed on standardized and validated measures of subjective sleep quality (Pittsburgh Sleep Quality Index) and subclinical narcoleptic events in the form of cataplexy (Stanford Center for Narcolepsy Revised Sleep Inventory). Patients were recruited from October 2006 to January 2007 from 2 programs of the Penn State Behavioral Health Clinic. Anxiety disorder patients as a group reported poorer sleep quality and endorsed a larger number of different types of situations (e.g., surprise, embarrassment) associated with cataplectic events. Among anxious patients, 33.3% (11 of 33) endorsed events specific for classic cataplexy, as opposed to 9.1% (3 of 33) of healthy volunteers (chi(2) = 5.80, p = .016). Our preliminary findings suggest that anxiety disorders are associated with increased rates of cataplexy. Future research is indicated to elucidate the relationship between anxiety and narcolepsy, with a particular focus on panic and generalized anxiety disorders. Copyright 2009 Physicians Postgraduate Press, Inc.

Abnormal activity in reward brain circuits in human narcolepsy with cataplexy.

PubMed

Ponz, Aurélie; Khatami, Ramin; Poryazova, Rositsa; Werth, Esther; Boesiger, Peter; Bassetti, Claudio L; Schwartz, Sophie

2010-02-01

Hypothalamic hypocretins (or orexins) regulate energy metabolism and arousal maintenance. Recent animal research suggests that hypocretins may also influence reward-related behaviors. In humans, the loss of hypocretin-containing neurons results in a major sleep-wake disorder called narcolepsy-cataplexy, which is associated with emotional disturbances. Here, we aim to test whether narcoleptic patients show an abnormal pattern of brain activity during reward processing. We used functional magnetic resonance imaging in 12 unmedicated patients with narcolepsy-cataplexy to measure the neural responses to expectancy and experience of monetary gains and losses. We statistically compared the patients' data with those obtained in a group of 12 healthy matched controls. Our results reveal that activity in the dopaminergic ventral midbrain (ventral tegmental area) was not modulated in narcolepsy-cataplexy patients during high reward expectancy (unlike controls), and that ventral striatum activity was reduced during winning. By contrast, the patients showed abnormal activity increases in the amygdala and in dorsal striatum for positive outcomes. In addition, we found that activity in the nucleus accumbens and the ventral-medial prefrontal cortex correlated with disease duration, suggesting that an alternate neural circuit could be privileged over the years to control affective responses to emotional challenges and compensate for the lack of influence from ventral midbrain regions. Our study offers a detailed picture of the distributed brain network involved during distinct stages of reward processing and shows for the first time, to our knowledge, how this network is affected in hypocretin-deficient narcoleptic patients.

Association Study of HLA-DQB1*0602 Allele in Iranian Patients with Narcolepsy.

PubMed

Geremew, Demeke; Rahimi-Golkhandan, Ania; Sadeghniiat-Haghighi, Khosro; Shakiba, Yadollah; Khajeh-Mehrizi, Ahmad; Ansaripour, Bita; Izad, Maryam

2017-10-01

Narcolepsy is a rare, disabling disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. Several studies demonstrated its association with HLA-DQB1*0602 in various ethnic groups. Our study aimed to determine the prevalence of HLA-DQB1*0602 allele in Iranian patients with narcolepsy and assess its predictive parameters for diagnosing narcolepsy. In addition, car accidents and job problems were assessed among narcoleptic patients. We studied 44 narcoleptic patients, 30 patients with other types of excessive daytime sleepiness (EDS)  and 50 healthy age and sex matched individuals in this case-control study. Patients and controls filled out a questionnaire including items about car accidents due to sleepiness and job problems. International classification of sleep disorders-2 criteria was used as the gold standard for diagnosis of narcolepsy. The DNAs isolated from whole blood samples were collected from the patients and controls to assess the presence of HLA-DQB1*0602. The results showed that HLA DQB1*0602 was present in 4 (8%) individual of controls and 20 (45.5%) patients with higher prevalence in patients with cataplexy (78.9%) than patients without cataplexy (p<0.001). The sensitivities of the DQB1*0602 for diagnosing narcolepsy with cataplexy and narcolepsy without cataplexy were 78.9 and 20; specificities were 88 and 72.4, respectively. 18.2% of patients had car accidents due to sleepiness and 68.2% suffered from job problems. Our study shows that evaluation of DQB1*0602 in patients suspected to narcolepsy could be helpful especially in complex cases with atypical cataplexy and indistinguishable multiple sleep latency test MSLT results. Moreover, high rates of car accidents and job problems are found among narcoleptic patients.

Diagnosis of narcolepsy and idiopathic hypersomnia. An update based on the International classification of sleep disorders, 2nd edition.

PubMed

Billiard, Michel

2007-10-01

Defining the precise nosological limits of narcolepsy and idiopathic hypersomnia is an ongoing process dating back to the first description of the two conditions. The most recent step forward has been done within the preparation of the second edition of the "International classification of sleep disorders" published in June 2005. Appointed by Dr Emmanuel Mignot, the Task Force on "Hypersomnias of central origin, not due to a circadian rhythm sleep disorder, sleep related breathing disorder, or other causes of disturbed nocturnal sleep" thoroughly revisited the nosology of narcolepsy and of idiopathic hypersomnia. Narcolepsy is now distinguished into three different entities, narcolepsy with cataplexy, narcolepsy without cataplexy and narcolepsy due to medical condition, and idiopathic hypersomnia into two entities, idiopathic hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time. Nevertheless there are still a number of pending issues. What are the limits of narcolepsy without cataplexy? Is there a continuum in the pathophysiology of narcolepsy with and without cataplexy? Should sporadic and familial forms of narcolepsy with cataplexy appear as subgroups in the classification? Are idiopathic hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time, two forms of the same condition or two different conditions? Is there a pathophysiological relationship between narcolepsy without cataplexy and idiopathic hypersomnia without long sleep time?

Parental Fitness Questioned on the Grounds of Narcolepsy: Presentation of Two Cases

PubMed Central

Barbero, Laura; Govi, Annamaria; Pizza, Fabio; Plazzi, Giuseppe; Ingravallo, Francesca

2017-01-01

We report two cases of fathers whose parental fitness was questioned during divorce and custody litigation because of narcolepsy type 2 and type 1, respectively. These cases highlighted both the existence of a narcolepsy-related stigma and the need to involve sleep experts in custody assessments when concerns about the parental fitness are related to a sleep disorder, expanding the field of interest of the growing “sleep forensics.” Citation: Barbero L, Govi A, Pizza F, Plazzi G, Ingravallo F. Parental fitness questioned on the grounds of narcolepsy: presentation of two cases. J Clin Sleep Med. 2017;13(8):1017–1018. PMID:28728625

Absence of anti-hypocretin receptor 2 autoantibodies in post pandemrix narcolepsy cases.

PubMed

Luo, Guo; Lin, Ling; Jacob, Louis; Bonvalet, Mélodie; Ambati, Aditya; Plazzi, Giuseppe; Pizza, Fabio; Leib, Ryan; Adams, Christopher M; Partinen, Markku; Mignot, Emmanuel Jean-Marie

2017-01-01

A recent publication suggested molecular mimicry of a nucleoprotein (NP) sequence from A/Puerto Rico/8/1934 (PR8) strain, the backbone used in the construction of the reassortant strain X-179A that was used in Pandemrix® vaccine, and reported on anti-hypocretin (HCRT) receptor 2 (anti-HCRTR2) autoantibodies in narcolepsy, mostly in post Pandemrix® narcolepsy cases (17 of 20 sera). In this study, we re-examined this hypothesis through mass spectrometry (MS) characterization of Pandemrix®, and two other pandemic H1N1 (pH1N1)-2009 vaccines, Arepanrix® and Focetria®, and analyzed anti-HCRTR2 autoantibodies in narcolepsy patients and controls using three independent strategies. MS characterization of Pandemrix® (2 batches), Arepanrix® (4 batches) and Focetria® (1 batch) was conducted with mapping of NP 116I or 116M spectrogram. Two sets of narcolepsy cases and controls were used: 40 post Pandemrix® narcolepsy (PP-N) cases and 18 age-matched post Pandemrix® controls (PP-C), and 48 recent (≤6 months) early onset narcolepsy (EO-N) cases and 70 age-matched other controls (O-C). Anti-HCRTR2 autoantibodies were detected using three strategies: (1) Human embryonic kidney (HEK) 293T cells with transient expression of HCRTR2 were stained with human sera and then analyzed by flow cytometer; (2) In vitro translation of [35S]-radiolabelled HCRTR2 was incubated with human sera and immune complexes of autoantibody and [35S]-radiolabelled HCRTR2 were quantified using a radioligand-binding assay; (3) Optical density (OD) at 450 nm (OD450) of human serum immunoglobulin G (IgG) binding to HCRTR2 stably expressed in Chinese hamster ovary (CHO)-K1 cell line was measured using an in-cell enzyme-linked immunosorbent assay (ELISA). NP 116M mutations were predominantly present in all batches of Pandemrix®, Arepanrix® and Focetria®. The wild-type NP109-123 (ILYDKEEIRRIWRQA), a mimic to HCRTR234-45 (YDDEEFLRYLWR), was not found to bind to DQ0602. Three or four subjects were found

Absence of anti-hypocretin receptor 2 autoantibodies in post pandemrix narcolepsy cases

PubMed Central

Lin, Ling; Jacob, Louis; Bonvalet, Mélodie; Ambati, Aditya; Plazzi, Giuseppe; Pizza, Fabio; Leib, Ryan; Adams, Christopher M.; Partinen, Markku; Mignot, Emmanuel Jean-Marie

2017-01-01

Background A recent publication suggested molecular mimicry of a nucleoprotein (NP) sequence from A/Puerto Rico/8/1934 (PR8) strain, the backbone used in the construction of the reassortant strain X-179A that was used in Pandemrix® vaccine, and reported on anti-hypocretin (HCRT) receptor 2 (anti-HCRTR2) autoantibodies in narcolepsy, mostly in post Pandemrix® narcolepsy cases (17 of 20 sera). In this study, we re-examined this hypothesis through mass spectrometry (MS) characterization of Pandemrix®, and two other pandemic H1N1 (pH1N1)-2009 vaccines, Arepanrix® and Focetria®, and analyzed anti-HCRTR2 autoantibodies in narcolepsy patients and controls using three independent strategies. Methods MS characterization of Pandemrix® (2 batches), Arepanrix® (4 batches) and Focetria® (1 batch) was conducted with mapping of NP 116I or 116M spectrogram. Two sets of narcolepsy cases and controls were used: 40 post Pandemrix® narcolepsy (PP-N) cases and 18 age-matched post Pandemrix® controls (PP-C), and 48 recent (≤6 months) early onset narcolepsy (EO-N) cases and 70 age-matched other controls (O-C). Anti-HCRTR2 autoantibodies were detected using three strategies: (1) Human embryonic kidney (HEK) 293T cells with transient expression of HCRTR2 were stained with human sera and then analyzed by flow cytometer; (2) In vitro translation of [35S]-radiolabelled HCRTR2 was incubated with human sera and immune complexes of autoantibody and [35S]-radiolabelled HCRTR2 were quantified using a radioligand-binding assay; (3) Optical density (OD) at 450 nm (OD450) of human serum immunoglobulin G (IgG) binding to HCRTR2 stably expressed in Chinese hamster ovary (CHO)-K1 cell line was measured using an in-cell enzyme-linked immunosorbent assay (ELISA). Results NP 116M mutations were predominantly present in all batches of Pandemrix®, Arepanrix® and Focetria®. The wild-type NP109-123 (ILYDKEEIRRIWRQA), a mimic to HCRTR234-45 (YDDEEFLRYLWR), was not found to bind to DQ0602. Three

Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms in Pediatric Narcolepsy: A Cross-Sectional Study

PubMed Central

Lecendreux, Michel; Lavault, Sophie; Lopez, Régis; Inocente, Clara Odilia; Konofal, Eric; Cortese, Samuele; Franco, Patricia; Arnulf, Isabelle; Dauvilliers, Yves

2015-01-01

Study Objectives: To evaluate the frequency, severity, and associations of symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with narcolepsy with and without cataplexy. Design: Cross-sectional survey. Setting: Four French national reference centers for narcolepsy. Patients: One hundred eight consecutively referred children aged younger than 18 y with narcolepsy, with (NwC, n = 86) or without cataplexy (NwoC, n = 22), and 67 healthy controls. Interventions: The participants, their families, and sleep specialists completed a structured interview and questionnaires about sleep, daytime sleepiness, fatigue, and ADHD symptoms (ADHD-rating scale based upon Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] symptoms), and use of psychostimulants for the treatment of narcolepsy (administered in 68.2%). Polysomnographic measures were collected. Measurements and Results: Clinically significant levels of ADHD symptoms were found in 4.8% of controls compared with 35.3% in patients with NwoC (P < 0.001) and 19.7% in patients with NwC (P < 0.01). Total ADHD scores were 6.4 (95% confidence interval [CI]: 4.5, 9.0) in controls compared with 14.2 (95% CI: 10.6, 18.9; P < 0.001), in patients with NwoC and 12.2 (95% CI: 9.8, 15.3; P < 0.01) in patients with NwC; subscores of inattention and hyperactivity/impulsivity were also significantly higher in both narcolepsy groups compared with controls. No difference was found between the NwC and NwoC groups for any ADHD measure. ADHD symptom severity was associated with increased levels of sleepiness, fatigue, and insomnia. Compared with the 34 untreated patients, the 73 patients treated with psychostimulants (modafinil in 91%) showed a trend toward lower narcolepsy symptoms but not lower ADHD symptoms. Conclusions: Pediatric patients with narcolepsy have high levels of treatment-resistant attention-deficit/hyperactivity disorder (ADHD) symptoms. The optimal treatment for

miRNA Profiles in Plasma from Patients with Sleep Disorders Reveal Dysregulation of miRNAs in Narcolepsy and Other Central Hypersomnias

PubMed Central

Holm, Anja; Bang-Berthelsen, Claus Heiner; Knudsen, Stine; Kornum, Birgitte R.; Modvig, Signe; Jennum, Poul; Gammeltoft, Steen

2014-01-01

Study Objectives: MicroRNAs (miRNAs) have been implicated in the pathogenesis of human diseases including neurological disorders. The aim is to address the involvement of miRNAs in the pathophysiology of central hypersomnias including autoimmune narcolepsy with cataplexy and hypocretin deficiency (type 1 narcolepsy), narcolepsy without cataplexy (type 2 narcolepsy), and idiopathic hypersomnia. Design: We conducted high-throughput analysis of miRNA in plasma from three groups of patients—with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively—in comparison with healthy controls using quantitative real-time polymerase chain reaction (qPCR) panels. Setting: University hospital based sleep clinic and research laboratories. Patients: Twelve patients with type 1 narcolepsy, 12 patients with type 2 narcolepsy, 12 patients with idiopathic hypersomnia, and 12 healthy controls. Measurements and Results: By analyzing miRNA in plasma with qPCR we identified 50, 24, and 6 miRNAs that were different in patients with type 1 narcolepsy, type 2 narcolepsy, and idiopathic hypersomnia, respectively, compared with healthy controls. Twenty miRNA candidates who fulfilled the criteria of at least two-fold difference and p-value < 0.05 were selected to validate the miRNA changes in an independent cohort of patients. Four miRNAs differed significantly between type 1 narcolepsy patients and healthy controls. Levels of miR-30c, let-7f, and miR-26a were higher, whereas the level of miR-130a was lower in type 1 narcolepsy than healthy controls. The miRNA differences were not specific for type 1 narcolepsy, since the levels of the four miRNAs were also altered in patients with type 2 narcolepsy and idiopathic hypersomnia compared with healthy controls. Conclusion: The levels of four miRNAs differed in plasma from patients with type 1 narcolepsy, type 2 narcolepsy and idiopathic hypersomnia suggesting that alterations of miRNAs may be involved in the

Comparable Cerebral Blood Flow in Both Hemispheres During Regional Cerebral Perfusion in Infant Aortic Arch Surgery.

PubMed

Rüffer, André; Tischer, Philip; Münch, Frank; Purbojo, Ariawan; Toka, Okan; Rascher, Wolfgang; Cesnjevar, Robert Anton; Jüngert, Jörg

2017-01-01

Cerebral protection during aortic arch repair can be provided by regional cerebral perfusion (RCP) through the innominate artery. This study addresses the question of an adequate bilateral blood flow in both hemispheres during RCP. Fourteen infants (median age 11 days [range, 3 to 108]; median weight, 3.6 kg [range, 2.8 to 6.0 kg]) undergoing RCP (flow rate 54 to 60 mL · kg -1 · min -1 ) were prospectively included. Using combined transfontanellar/transtemporal two- and three-dimensional power/color Doppler sonography, cerebral blood flow intensity in the main cerebral vessels was displayed. Mean time average velocities were measured with combined pulse-wave Doppler in the basilar artery, and both sides of the internal carotid, anterior, and medial cerebral arteries. In addition, bifrontal regional cerebral oximetry (rSO 2 ) was assessed. Comparing both hemispheres, measurements were performed at target temperature (28°C) during full-flow total body perfusion (TBP) and RCP. A regular circle of Willis with near-symmetric blood flow intensity to both hemispheres was visualized in all infants during both RCP and TBP. In the left internal carotid artery, blood flow direction was mixed (retrograde, n = 5; antegrade, n = 8) during TBP and retrograde during RCP. Comparison between sides showed comparable cerebral time average velocities and rSO 2 , except for higher time average velocities in the right internal carotid artery (TBP p = 0.019, RCP p = 0.09). Unilateral comparison between perfusion methods revealed significantly higher rSO 2 in the right hemisphere during TBP (82% ± 9%) compared with RCP (74% ± 11%, p = 0.036). Bilateral assessment of cerebral rSO 2 and time average velocity in the main great cerebral vessels suggests that RCP is associated with near-symmetric blood flow intensity to both hemispheres. Further neurodevelopmental studies are necessary to verify RCP for neuroprotection during aortic arch repair. Copyright © 2017 The Society of

Is there a relationship between narcolepsy, multiple sclerosis and HLA-DQB1*06:02?

PubMed

Lorenzoni, Paulo José; Werneck, Lineu Cesar; Crippa, Ana Christina de Souza; Zanatta, Alessandra; Kay, Cláudia S Kamoi; Silvado, Carlos Eduardo S; Scola, Rosana Herminia

2017-06-01

We studied multiple sclerosis (MS) patients with the HLA-DQB1*06:02 allele and compared them with MS patients who did not carry the HLA-DQB1*06:02 allele. We analyzed clinical and neurophysiological criteria for narcolepsy in six MS patients with HLA-DQB1*06:02, compared with 12 MS patients who were HLA-DQB1*06:02 non-carriers. Only two patients with HLA-DQB1*06:02 allele scored higher than 10 on the Epworth Sleepiness Scale. Polysomnography recording parameters and the multiple sleep latency test showed an absence of narcolepsy in the study group. Our study suggested no significant correlation between narcolepsy, MS and HLA-DQB1*06:02. The HLA-DQB1*06:02 allele alone was not sufficient to cause MS patients to develop narcolepsy.

Effective treatment of narcolepsy-like symptoms with high-frequency repetitive transcranial magnetic stimulation: A case report.

PubMed

Lai, Jian-Bo; Han, Mao-Mao; Xu, Yi; Hu, Shao-Hua

2017-11-01

Narcolepsy is a rare sleep disorder with disrupted sleep-architecture. Clinical management of narcolepsy lies dominantly on symptom-driven pharmacotherapy. The treatment role of repetitive transcranial magnetic stimulation (rTMS) for narcolepsy remains unexplored. In this paper, we present a case of a 14-year-old young girl with excessive daytime sleepiness (EDS), cataplexy and hypnagogic hallucinations. After excluding other possible medical conditions, this patient was primarily diagnosed with narcolepsy. The patient received 25 sessions of high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC). The symptoms of EDS and cataplexy significantly improved after rTMS treatment. Meanwhile, her score in the Epworth sleep scale (ESS) also remarkably decreased. This case indicates that rTMS may be selected as a safe and effective alternative strategy for treating narcolepsy-like symptoms. Well-designed researches are warranted in future investigations on this topic.

Increased GABA Levels in Medial Prefrontal Cortex of Young Adults with Narcolepsy

PubMed Central

Kim, Seog Ju; Lyoo, In Kyoon; Lee, Yujin S.; Sung, Young Hoon; Kim, Hengjun J.; Kim, Jihyun H.; Kim, Kye Hyun; Jeong, Do-Un

2008-01-01

Study Objectives: To explore absolute concentrations of brain metabolites including gamma amino-butyric acid (GABA) in the medial prefrontal cortex and basal ganglia of young adults with narcolepsy. Design: Proton magnetic resonance (MR) spectroscopy centered on the medial prefrontal cortex and the basal ganglia was acquired. The absolute concentrations of brain metabolites including GABA and glutamate were assessed and compared between narcoleptic patients and healthy comparison subjects. Setting: Sleep and Chronobiology Center at Seoul National University Hospital; A high strength 3.0 Tesla MR scanner in the Department of Radiology at Seoul National University Hospital. Patients or Participants: Seventeen young adults with a sole diagnosis of HLA DQB1 0602 positive narcolepsy with cataplexy (25.1 ± 4.6 years old) and 17 healthy comparison subjects (26.8 ± 4.8 years old). Interventions: N/A. Measurements and Results: Relative to comparison subjects, narcoleptic patients had higher GABA concentration in the medial prefrontal cortex (t = 4.10, P <0.001). Narcoleptic patients with nocturnal sleep disturbance had higher GABA concentration in the medial prefrontal cortex than those without nocturnal sleep disturbance (t = 2.45, P= 0.03), but had lower GABA concentration than comparison subjects (t = 2.30, P = 0.03). Conclusions: The current study reports that young adults with narcolepsy had a higher GABA concentration in the medial prefrontal cortex, which was more prominent in patients without nocturnal sleep disturbance. Our findings suggest that the medial prefrontal GABA level may be increased in narcolepsy, and the increased medial prefrontal GABA might be a compensatory mechanism to reduce nocturnal sleep disturbances in narcolepsy. Citation: Kim SJ; Lyoo IK; Lee YS; Sung YH; Kim HJ; Kim JH; Kim KH; Jeong DU. Increased GABA levels in medial prefrontal cortex of young adults with narcolepsy. SLEEP 2008;31(3):342-347. PMID:18363310

Aberrant Food Choices after Satiation in Human Orexin-Deficient Narcolepsy Type 1

PubMed Central

van Holst, Ruth Janke; van der Cruijsen, Lisa; van Mierlo, Petra; Lammers, Gert Jan; Cools, Roshan; Overeem, Sebastiaan; Aarts, Esther

2016-01-01

Study Objectives: Besides influencing vigilance, orexin neurotransmission serves a variety of functions, including reward, motivation, and appetite regulation. As obesity is an important symptom in orexin-deficient narcolepsy, we explored the effects of satiety on food-related choices and spontaneous snack intake in patients with narcolepsy type 1 (n = 24) compared with healthy matched controls (n = 19). In additional analyses, we also included patients with idiopathic hypersomnia (n = 14) to assess sleepiness-related influences. Methods: Participants were first trained on a choice task to earn salty and sweet snacks. Next, one of the snack outcomes was devalued by having participants consume it until satiation (i.e., sensory-specific satiety). We then measured the selective reduction in choices for the devalued snack outcome. Finally, we assessed the number of calories that participants consumed spontaneously from ad libitum available snacks afterwards. Results: After satiety, all participants reported reduced hunger and less wanting for the devalued snack. However, while controls and idiopathic hypersomnia patients chose the devalued snack less often in the choice task, patients with narcolepsy still chose the devalued snack as often as before satiety. Subsequently, narcolepsy patients spontaneously consumed almost 4 times more calories during ad libitum snack intake. Conclusions: We show that the manipulation of food-specific satiety has reduced effects on food choices and caloric intake in narcolepsy type 1 patients. These mechanisms may contribute to their obesity, and suggest an important functional role for orexin in human eating behavior. Clinical Trials Registration: Study registered at Netherlands Trial Register. URL: www.trialregister.nl. Trial ID: NTR4508. Citation: van Holst RJ, van der Cruijsen L, van Mierlo P, Lammers GJ, Cools R, Overeem S, Aarts E. Aberrant food choices after satiation in human orexindeficient narcolepsy type 1. SLEEP 2016

New developments in the management of narcolepsy.

PubMed

Abad, Vivien C; Guilleminault, Christian

2017-01-01

Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%-0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy's strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss. Current treatment modalities alleviate the main symptoms of excessive daytime somnolence (EDS) and cataplexy and, to a lesser extent, reduce nocturnal sleep disruption, hypnagogic hallucinations, and sleep paralysis. Sodium oxybate (SXB), a sodium salt of γ hydroxybutyric acid, is a first-line agent for cataplexy and EDS and may help sleep disruption, hypnagogic hallucinations, and sleep paralysis. Various antidepressant medications including norepinephrine serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants are second-line agents for treating cataplexy. In addition to SXB, modafinil and armodafinil are first-line agents to treat EDS. Second-line agents for EDS are stimulants such as methylphenidate and extended-release amphetamines. Emerging therapies include non-hypocretin-based therapy, hypocretin-based treatments, and immunotherapy to prevent hypocretin neuronal death. Non-hypocretin-based novel treatments for narcolepsy include pitolisant (BF2.649, tiprolisant); JZP-110 (ADX-N05) for EDS in adults; JZP 13-005 for children; JZP-386, a deuterated sodium oxybate oral suspension; FT 218 an extended-release formulation of SXB; and JNJ-17216498, a new formulation of modafinil. Clinical trials are investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA) modulation with GABA A receptor agonists clarithromycin and flumazenil may help daytime somnolence

Transient Impact of Rituximab in H1N1 Vaccination-associated Narcolepsy With Severe Psychiatric Symptoms.

PubMed

Sarkanen, Tomi; Alén, Reija; Partinen, Markku

2016-09-01

Narcolepsy type 1 is an organic sleep disorder caused by the destruction of hypocretin producing neurons in hypothalamus. In addition to daytime sleepiness, the spectrum and severity of symptoms are very variable. Psychiatric comorbidity and phenomena resembling psychotic symptoms are also common. Current treatment options for narcolepsy are symptomatic but there are few case reports of positive effect of immunotherapy. We report a very severely affected young boy treated with rituximab (RXB). A 12-year-old boy developed narcolepsy after Pandemrix H1N1 vaccination in 2010. He started to express severe psychiatric symptoms shortly after the onset. Cataplexy and sleepiness were devastatingly disabling. Conventional treatments did not have any effect on symptoms so we decided to try RXB, chimeric human monoclonal antibody against CD20 expressed in B lymphocytes. After the first treatment his condition ameliorated dramatically. Unfortunately, the effect lasted only for 2 months. Following attempts did not show any effect. Effect of RXB on narcolepsy has not been reported before. Remarkable but short-lasting effect of RXB in narcolepsy is intriguing as it could imply that there is still ongoing B cell-mediated autoimmune response possible contributing to symptoms in narcolepsy.

Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms in Pediatric Narcolepsy: A Cross-Sectional Study.

PubMed

Lecendreux, Michel; Lavault, Sophie; Lopez, Régis; Inocente, Clara Odilia; Konofal, Eric; Cortese, Samuele; Franco, Patricia; Arnulf, Isabelle; Dauvilliers, Yves

2015-08-01

To evaluate the frequency, severity, and associations of symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with narcolepsy with and without cataplexy. Cross-sectional survey. Four French national reference centers for narcolepsy. One hundred eight consecutively referred children aged younger than 18 y with narcolepsy, with (NwC, n = 86) or without cataplexy (NwoC, n = 22), and 67 healthy controls. The participants, their families, and sleep specialists completed a structured interview and questionnaires about sleep, daytime sleepiness, fatigue, and ADHD symptoms (ADHD-rating scale based upon Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] symptoms), and use of psychostimulants for the treatment of narcolepsy (administered in 68.2%). Polysomnographic measures were collected. Clinically significant levels of ADHD symptoms were found in 4.8% of controls compared with 35.3% in patients with NwoC (P < 0.001) and 19.7% in patients with NwC (P < 0.01). Total ADHD scores were 6.4 (95% confidence interval [CI]: 4.5, 9.0) in controls compared with 14.2 (95% CI: 10.6, 18.9; P < 0.001), in patients with NwoC and 12.2 (95% CI: 9.8, 15.3; P < 0.01) in patients with NwC; subscores of inattention and hyperactivity/impulsivity were also significantly higher in both narcolepsy groups compared with controls. No difference was found between the NwC and NwoC groups for any ADHD measure. ADHD symptom severity was associated with increased levels of sleepiness, fatigue, and insomnia. Compared with the 34 untreated patients, the 73 patients treated with psychostimulants (modafinil in 91%) showed a trend toward lower narcolepsy symptoms but not lower ADHD symptoms. Pediatric patients with narcolepsy have high levels of treatment-resistant attention-deficit/hyperactivity disorder (ADHD) symptoms. The optimal treatment for ADHD symptoms in these patients warrants further evaluation in longitudinal intervention studies. �

Clinical and polysomnographic course of childhood narcolepsy with cataplexy.

PubMed

Pizza, Fabio; Franceschini, Christian; Peltola, Hanna; Vandi, Stefano; Finotti, Elena; Ingravallo, Francesca; Nobili, Lino; Bruni, Oliviero; Lin, Ling; Edwards, Mark J; Partinen, Markku; Dauvilliers, Yves; Mignot, Emmanuel; Bhatia, Kailash P; Plazzi, Giuseppe

2013-12-01

Our aim was to investigate the natural evolution of cataplexy and polysomnographic features in untreated children with narcolepsy with cataplexy. To this end, clinical, polysomnographic, and cataplexy-video assessments were performed at diagnosis (mean age of 10 ± 3 and disease duration of 1 ± 1 years) and after a median follow-up of 3 years from symptom onset (mean age of 12 ± 4 years) in 21 children with narcolepsy with cataplexy and hypocretin 1 deficiency (tested in 19 subjects). Video assessment was also performed in two control groups matched for age and sex at first evaluation and follow-up and was blindly scored for presence of hypotonic (negative) and active movements. Patients' data at diagnosis and at follow-up were contrasted, compared with controls, and related with age and disease duration. At diagnosis children with narcolepsy with cataplexy showed an increase of sleep time during the 24 h; at follow-up sleep time and nocturnal sleep latency shortened, in the absence of other polysomnographic or clinical (including body mass index) changes. Hypotonic phenomena and selected facial movements decreased over time and, tested against disease duration and age, appeared as age-dependent. At onset, childhood narcolepsy with cataplexy is characterized by an abrupt increase of total sleep over the 24 h, generalized hypotonia and motor overactivity. With time, the picture of cataplexy evolves into classic presentation (i.e., brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases, returning to more age-appropriate levels.

Clinical and polysomnographic course of childhood narcolepsy with cataplexy

PubMed Central

Pizza, Fabio; Franceschini, Christian; Peltola, Hanna; Vandi, Stefano; Finotti, Elena; Ingravallo, Francesca; Nobili, Lino; Bruni, Oliviero; Lin, Ling; Edwards, Mark J.; Partinen, Markku; Dauvilliers, Yves; Mignot, Emmanuel; Bhatia, Kailash P.

2013-01-01

Our aim was to investigate the natural evolution of cataplexy and polysomnographic features in untreated children with narcolepsy with cataplexy. To this end, clinical, polysomnographic, and cataplexy-video assessments were performed at diagnosis (mean age of 10 ± 3 and disease duration of 1 ± 1 years) and after a median follow-up of 3 years from symptom onset (mean age of 12 ± 4 years) in 21 children with narcolepsy with cataplexy and hypocretin 1 deficiency (tested in 19 subjects). Video assessment was also performed in two control groups matched for age and sex at first evaluation and follow-up and was blindly scored for presence of hypotonic (negative) and active movements. Patients’ data at diagnosis and at follow-up were contrasted, compared with controls, and related with age and disease duration. At diagnosis children with narcolepsy with cataplexy showed an increase of sleep time during the 24 h; at follow-up sleep time and nocturnal sleep latency shortened, in the absence of other polysomnographic or clinical (including body mass index) changes. Hypotonic phenomena and selected facial movements decreased over time and, tested against disease duration and age, appeared as age-dependent. At onset, childhood narcolepsy with cataplexy is characterized by an abrupt increase of total sleep over the 24 h, generalized hypotonia and motor overactivity. With time, the picture of cataplexy evolves into classic presentation (i.e. brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases, returning to more age-appropriate levels. PMID:24142146

Morbidity of childhood onset narcolepsy: a controlled national study.

PubMed

Jennum, Poul; Pickering, Line; Thorstensen, Eva Wiberg; Ibsen, Rikke; Kjellberg, Jakob

2017-01-01

Narcolepsy is associated with significant morbidities. We evaluated the morbidities and mortality in a national group of child and adolescent patients after a first diagnosis of narcolepsy. Identified from the Danish National Patient Registry (NPR), 243 patients (128 boys) aged 0-19 years diagnosed with narcolepsy between 1998 and 2012 with follow-up until 2014 were compared with 970 controls who were randomly chosen from the Danish Civil Registration System Statistics and matched by age, gender and geography. Comorbidities were calculated three years before and after diagnoses. In addition to the more frequent health contacts due to neurological diseases, patients showed elevated odds ratios before and after diagnosis of endocrine and metabolic conditions (4.4 (95% CI, 1.9-10.4); 3.8 (1.7-8.4)), nervous disorders (16.6 (8.0-34.4); 198 (49.0-804)), psychiatric illnesses (4.5 (2.3-9.1)/5.8 (2.8-12.1)), pulmonary diseases, and other diseases (3.1 (2.0-4.9); 3.1 (2.0-4.9)). Congenital abnormalities (2.5 (1.1-5.5)), respiratory (2.9 (1.5-5-5)) and eye (5.7 (2.2-15.0)) diseases were more common before diagnosis. Injuries were also more common after diagnosis (1.5 (1.0-2.1)). Narcoleptic children presented significantly more diagnoses of multiple comorbidities than controls before and after diagnosis. Before and after a diagnosis of narcolepsy in children, morbidity is more frequent in several domains, including metabolic, psychiatric, neurological and other diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Benefit and risk of modafinil in idiopathic hypersomnia vs. narcolepsy with cataplexy.

PubMed

Lavault, Sophie; Dauvilliers, Yves; Drouot, Xavier; Leu-Semenescu, Smaranda; Golmard, Jean-Louis; Lecendreux, Michel; Franco, Patricia; Arnulf, Isabelle

2011-06-01

The benefit/risk ratio of modafinil was recently re-evaluated by the European Medicines Agency and was shown to be negative for idiopathic hypersomnia (IH) because of insufficient data. To evaluate the benefit/risk ratio of modafinil in idiopathic hypersomnia (with and without long sleep time) vs. narcolepsy/cataplexy. The benefit (Epworth sleepiness score, ESS; visual analog scale, patient and clinician opinions) and risks (habituation, adverse effects) of modafinil were studied in a consecutive clinical cohort of 104 IH patients (59 with long sleep time) and 126 patients with narcolepsy/cataplexy. Modafinil was the first line treatment in 96-99% of patients. It produced a similar ESS change in IH patients and in narcolepsy patients (-2.6±5.1 vs. -3±5.1) and a similar benefit as estimated by the patients (6.9±2.7 vs. 6.5±2.5 on a visual analog scale) and clinicians. The ESS change was lower in IH patients with long sleep time than in those without. Sudden loss of efficacy and habituation were rare in both groups. Patients with IH reported similar but more frequent adverse effects with modafinil than narcolepsy patients: nervousness (14%), palpitations (13%), and headache (11%). Modafinil has an excellent benefit/risk ratio in idiopathic hypersomnia, with or without long sleep time, similar to its effect on narcolepsy/cataplexy. Copyright © 2011 Elsevier B.V. All rights reserved.

Regional microstructural organization of the cerebral cortex is affected by preterm birth.

PubMed

Bouyssi-Kobar, Marine; Brossard-Racine, Marie; Jacobs, Marni; Murnick, Jonathan; Chang, Taeun; Limperopoulos, Catherine

2018-01-01

To compare regional cerebral cortical microstructural organization between preterm infants at term-equivalent age (TEA) and healthy full-term newborns, and to examine the impact of clinical risk factors on cerebral cortical micro-organization in the preterm cohort. We prospectively enrolled very preterm infants (gestational age (GA) at birth<32 weeks; birthweight<1500 g) and healthy full-term controls. Using non-invasive 3T diffusion tensor imaging (DTI) metrics, we quantified regional micro-organization in ten cerebral cortical areas: medial/dorsolateral prefrontal cortex, anterior/posterior cingulate cortex, insula, posterior parietal cortex, motor/somatosensory/auditory/visual cortex. ANCOVA analyses were performed controlling for sex and postmenstrual age at MRI. We studied 91 preterm infants at TEA and 69 full-term controls. Preterm infants demonstrated significantly higher diffusivity in the prefrontal, parietal, motor, somatosensory, and visual cortices suggesting delayed maturation of these cortical areas. Additionally, postnatal hydrocortisone treatment was related to accelerated microstructural organization in the prefrontal and somatosensory cortices. Preterm birth alters regional microstructural organization of the cerebral cortex in both neurocognitive brain regions and areas with primary sensory/motor functions. We also report for the first time a potential protective effect of postnatal hydrocortisone administration on cerebral cortical development in preterm infants.

Narcolepsy susceptibility gene CCR3 modulates sleep-wake patterns in mice.

PubMed

Toyoda, Hiromi; Honda, Yoshiko; Tanaka, Susumu; Miyagawa, Taku; Honda, Makoto; Honda, Kazuki; Tokunaga, Katsushi; Kodama, Tohru

2017-01-01

Narcolepsy is caused by the loss of hypocretin (Hcrt) neurons and is associated with multiple genetic and environmental factors. Although abnormalities in immunity are suggested to be involved in the etiology of narcolepsy, no decisive mechanism has been established. We previously reported chemokine (C-C motif) receptor 3 (CCR3) as a novel susceptibility gene for narcolepsy. To understand the role of CCR3 in the development of narcolepsy, we investigated sleep-wake patterns of Ccr3 knockout (KO) mice. Ccr3 KO mice exhibited fragmented sleep patterns in the light phase, whereas the overall sleep structure in the dark phase did not differ between Ccr3 KO mice and wild-type (WT) littermates. Intraperitoneal injection of lipopolysaccharide (LPS) promoted wakefulness and suppressed both REM and NREM sleep in the light phase in both Ccr3 KO and WT mice. Conversely, LPS suppressed wakefulness and promoted NREM sleep in the dark phase in both genotypes. After LPS administration, the proportion of time spent in wakefulness was higher, and the proportion of time spent in NREM sleep was lower in Ccr3 KO compared to WT mice only in the light phase. LPS-induced changes in sleep patterns were larger in Ccr3 KO compared to WT mice. Furthermore, we quantified the number of Hcrt neurons and found that Ccr3 KO mice had fewer Hcrt neurons in the lateral hypothalamus compared to WT mice. We found abnormalities in sleep patterns in the resting phase and in the number of Hcrt neurons in Ccr3 KO mice. These observations suggest a role for CCR3 in sleep-wake regulation in narcolepsy patients.

Subjective deficits of attention, cognition and depression in patients with narcolepsy.

PubMed

Zamarian, Laura; Högl, Birgit; Delazer, Margarete; Hingerl, Katharina; Gabelia, David; Mitterling, Thomas; Brandauer, Elisabeth; Frauscher, Birgit

2015-01-01

Patients with narcolepsy often complain about attention deficits in everyday situations. In comparison with these subjective complaints, deficits in objective testing are subtler. The present study assessed the relationships between subjective complaints, objectively measured cognitive performance, disease-related variables, and mood. A total of 51 patients with narcolepsy and 35 healthy controls responded to questionnaires regarding subjectively perceived attention deficits, sleepiness, anxiety and depression. Moreover, they performed an extensive neuropsychological assessment tapping into attention, executive functions, and memory. Patients rated their level of attention in everyday situations to be relatively poor. In an objective assessment of cognitive functioning, they showed only slight attention and executive function deficits. The subjective ratings of attention deficits significantly correlated with ratings of momentary sleepiness, anxiety, and depression, but not with objectively measured cognitive performance. Momentary sleepiness and depression predicted almost 39% of the variance in the ratings of subjectively perceived attention deficits. The present study showed that sleepiness and depression, more than objective cognitive deficits, might play a role in the subjectively perceived attention deficits of patients with narcolepsy. The results suggested that when counselling and treating patients with narcolepsy, clinicians should pay attention to potential depression because subjective cognitive complaints may not relate to objective cognitive impairments. Copyright © 2014 Elsevier B.V. All rights reserved.

Intravenous Immunoglobulin Therapy in Pediatric Narcolepsy: A Nonrandomized, Open-Label, Controlled, Longitudinal Observational Study

PubMed Central

Lecendreux, Michel; Berthier, Johanna; Corny, Jennifer; Bourdon, Olivier; Dossier, Claire; Delclaux, Christophe

2017-01-01

Study Objectives: Previous case reports of intravenous immunoglobulins (IVIg) in pediatric narcolepsy have shown contradictory results. Methods: This was a nonrandomized, open-label, controlled, longitudinal observational study of IVIg use in pediatric narcolepsy with retrospective data collection from medical files obtained from a single pediatric national reference center for the treatment of narcolepsy in France. Of 56 consecutively referred patients with narcolepsy, 24 received IVIg (3 infusions administered at 1-mo intervals) in addition to standard care (psychostimulants and/or anticataplectic agents), and 32 continued on standard care alone (controls). Results: For two patients in each group, medical files were unavailable. Of the 22 IVIg patients, all had cerebrospinal fluid (CSF) hypocretin ≤ 110 pg/mL and were HLA-DQB1*06:02 positive. Of the 30 control patients, 29 were HLA-DQB1*06:02 positive and of those with available CSF measurements, all 12 had hypocretin ≤ 110 pg/mL. Compared with control patients, IVIg patients had shorter disease duration, shorter latency to sleep onset, and more had received H1N1 vaccination. Mean (standard deviation) follow-up length was 2.4 (1.1) y in the IVIg group and 3.9 (1.7) y in controls. In multivariate-adjusted linear mixed-effects analyses of change from baseline in Ullanlinna Narcolepsy Scale (UNS) scores, high baseline UNS, but not IVIg treatment, was associated with a reduction in narcolepsy symptoms. On time-to-event analysis, among patients with high baseline UNS scores, control patients achieved a UNS score < 14 (indicating remission) less rapidly than IVIg patients (adjusted hazard ratio 0.18; 95% confidence interval: 95% confidence interval: 0.03, 0.95; p = 0.043). Shorter or longer disease duration did not influence treatment response in any analysis. Conclusions: Overall, narcolepsy symptoms were not significantly reduced by IVIg. However, in patients with high baseline symptoms, a subset of IVIg

Mechanism of action of narcolepsy medications.

PubMed

Gowda, Chandan R; Lundt, Leslie P

2014-12-01

The medications used to treat narcolepsy are targeted toward alleviating symptoms such as excessive sleepiness and cataplexy. The cause of this neurological sleep disorder is still not completely clear, though a destruction of hypocretin/orexin neurons has been implicated. The destruction of these neurons is linked to inactivity of neurotransmitters including histamine, norepinephrine, acetylcholine, and serotonin, causing a disturbance in the sleep/wake cycles of narcoleptic patients. Stimulants and MAOIs have traditionally been used to counteract excessive daytime sleepiness and sleep attacks by inhibiting the breakdown of catecholamines. Newer drugs, called wake-promoting agents, have recently become first-line agents due to their better side-effect profile, efficacy, and lesser potential for abuse. These agents similarly inhibit reuptake of dopamine, but have a novel mechanism of action, as they have been found to increase neuronal activity in the tuberomamillary nucleus and in orexin neurons. Sodium oxybate, a sodium salt of gamma-hydroxybutyrate (GHB), is another class that is used to treat many symptoms of narcolepsy, and is the only U.S. Food and Drug Administration (FDA)-approved medication for cataplexy. It has a different mechanism of action than either stimulants or wake-promoting agents, as it binds to its own unique receptor. Antidepressants, like selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), have also been used, as similar to stimulants, they inhibit reuptake of specific catecholamines. In this article, we seek to review the mechanisms behind these classes of drugs in relation to the proposed pathophysiology of narcolepsy. Appropriate clinical strategies will be discussed, including specific combinations of medications that have been shown to be effective.

Aberrant Food Choices after Satiation in Human Orexin-Deficient Narcolepsy Type 1.

PubMed

van Holst, Ruth Janke; van der Cruijsen, Lisa; van Mierlo, Petra; Lammers, Gert Jan; Cools, Roshan; Overeem, Sebastiaan; Aarts, Esther

2016-11-01

Besides influencing vigilance, orexin neurotransmission serves a variety of functions, including reward, motivation, and appetite regulation. As obesity is an important symptom in orexin-deficient narcolepsy, we explored the effects of satiety on food-related choices and spontaneous snack intake in patients with narcolepsy type 1 (n = 24) compared with healthy matched controls (n = 19). In additional analyses, we also included patients with idiopathic hypersomnia (n = 14) to assess sleepiness-related influences. Participants were first trained on a choice task to earn salty and sweet snacks. Next, one of the snack outcomes was devalued by having participants consume it until satiation (i.e., sensory-specific satiety). We then measured the selective reduction in choices for the devalued snack outcome. Finally, we assessed the number of calories that participants consumed spontaneously from ad libitum available snacks afterwards. After satiety, all participants reported reduced hunger and less wanting for the devalued snack. However, while controls and idiopathic hypersomnia patients chose the devalued snack less often in the choice task, patients with narcolepsy still chose the devalued snack as often as before satiety. Subsequently, narcolepsy patients spontaneously consumed almost 4 times more calories during ad libitum snack intake. We show that the manipulation of food-specific satiety has reduced effects on food choices and caloric intake in narcolepsy type 1 patients. These mechanisms may contribute to their obesity, and suggest an important functional role for orexin in human eating behavior. Study registered at Netherlands Trial Register. URL: www.trialregister.nl. Trial ID: NTR4508. © 2016 Associated Professional Sleep Societies, LLC.

Body weight and basal metabolic rate in childhood narcolepsy: a longitudinal study.

PubMed

Wang, Zongwen; Wu, Huijuan; Stone, William S; Zhuang, Jianhua; Qiu, Linli; Xu, Xing; Wang, Yan; Zhao, Zhengqing; Han, Fang; Zhao, Zhongxin

2016-09-01

The aims of this study were to document the trajectory of weight gain and body mass index (BMI) in children with type 1 narcolepsy, and to analyze basal metabolic rate (BMR). A total of 65 Chinese children with type 1 narcolepsy with a disease duration ≤12 months were included. In addition, 79 healthy age-matched students were enrolled as controls. Height and body weight were measured every six months for up to 36 months to calculate BMI growth. BMR was measured using COSMED K4b2 indirect calorimetry in 34 patients and 30 healthy controls at six months. At the end of 36 months, the BMR was compared among 18 patients and 16 healthy controls. The children with type 1 narcolepsy showed higher BMIs at follow-up assessments. At the end of the study, 38.46% of the patients were obese and an additional 26.15% were overweight. The patients' BMI growth at six, 12, 18, 24 and 30 months of follow-up was significantly higher, but not at month 36. The patients' basal energy expenditure was significantly lower than that of the controls at six months but not at 36 months. BMI increased rapidly in children with type 1 narcolepsy after disease onset, but BMI growth decreased gradually with prolonged disease. Decreased BMR is an important cause underlying rapid weight gain. The gradual restoration of BMI growth and BMR in narcolepsy emphasizes the importance of compensatory metabolic mechanisms in this disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Two cases of childhood narcolepsy mimicking epileptic seizures in video-EEG/EMG.

PubMed

Yanagishita, Tomoe; Ito, Susumu; Ohtani, Yui; Eto, Kaoru; Kanbayashi, Takashi; Oguni, Hirokazu; Nagata, Satoru

2018-06-06

Narcolepsy is characterized by excessive sleepiness, hypnagogic hallucinations, and sleep paralysis, and can occur with or without cataplexy. Here, we report two children with narcolepsy presenting with cataplexy mimicking epileptic seizures as determined by long-term video-electroencephalography (EEG) and electromyography (EMG) monitoring. Case 1 was a 15-year-old girl presenting with recurrent episodes of "convulsions" and loss of consciousness, who was referred to our hospital with a diagnosis of epilepsy showing "convulsions" and "complex partial seizures". The long-term video-polygraph showed a clonic attack lasting for 15 s, which corresponded to 1-2 Hz with interruption of mentalis EMG discharges lasting for 70-300 ms without any EEG changes. Narcolepsy was suspected due to the attack induced by hearty laughs and the presence of sleep attacks, and confirmed by low orexin levels in cerebrospinal fluid (CSF). Case 2 was an 11-year-old girl presenting with recurrent episodes of myoclonic attacks simultaneously with dropping objects immediately after hearty laughs, in addition to sleep attacks, hypnagogic hallucinations, and sleep paralysis. The long-term video-polygraph showed a subtle attack, characterized by dropping chopsticks from her hand, which corresponded to an interruption of ongoing deltoid EMG discharges lasting 140 ms without any EEG changes. A diagnosis of narcolepsy was confirmed by the low orexin levels in CSF. These cases demonstrate that children with narcolepsy may have attacks of cataplexy that resemble clonic or myoclonic seizures. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Narcolepsy and Predictors of Positive MSLTs in the Wisconsin Sleep Cohort

PubMed Central

Goldbart, Aviv; Peppard, Paul; Finn, Laurel; Ruoff, Chad M.; Barnet, Jodi; Young, Terry; Mignot, Emmanuel

2014-01-01

Study Objectives: To study whether positive multiple sleep latency tests (MSLTs, mean sleep latency [MSL] ≤ 8 minutes, ≥ 2 sleep onset REM sleep periods [SOREMPs]) and/or nocturnal SOREMP (REM sleep latency ≤ 15 minutes during nocturnal polysomonography [NPSG]) are stable traits and can reflect incipient narcolepsy. Design and Setting: Cross-sectional and longitudinal investigation of the Wisconsin Sleep Cohort Study. Participants: Adults (44% females, 30-81 years) underwent NPSG (n = 4,866 in 1,518 subjects), and clinical MSLT (n = 1,135), with 823 having a repeat NPSG-MSLT at 4-year intervals, totaling 1725 NPSG with MSLT studies. Data were analyzed using linear mixed-effects models, and the stability of positive MSLTs was explored using κ statistics. Measurements and Results: Prevalence of a nocturnal SOREMP on a NPSG, of ≥ 2 SOREMPs on the MSLT, of MSL ≤ 8 minutes on the MSLT, and of a positive MSLT (MSL ≤ 8 minutes plus ≥ 2 SOREMPs) were 0.35%, 7.0%, 22%, and 3.4%, respectively. Correlates of a positive MSLT were shift work (OR = 7.8, P = 0.0001) and short sleep (OR = 1.51/h, P = 0.04). Test-retest for these parameters was poor, with κ < 0.2 (n.s.) after excluding shift workers and short sleepers. Excluding shift-work, short sleep, and subjects with negative MSLTs, we found one undiagnosed subject with possible cataplexy (≥ 1/month) and a NPSG SOREMPs; one subject previously diagnosed with narcolepsy without cataplexy with 2 NPSG SOREMPs and a positive MSLT, and two subjects with 2 independently positive MSLTs (66% human leukocyte antigen [HLA] positive). The proportions for narcolepsy with and without cataplexy were 0.07% (95% CI: 0.02-0.37%) and 0.20% (95% CI: 0.07-0.58%), respectively. Conclusions: The diagnostic value of multiple sleep latency tests is strongly altered by shift work and to a lesser extent by chronic sleep deprivation. The prevalence of narcolepsy without cataplexy may be 3-fold higher than that of narcolepsy

Reduced deep regional cerebral venous oxygen saturation in hemodialysis patients using quantitative susceptibility mapping.

PubMed

Chai, Chao; Liu, Saifeng; Fan, Linlin; Liu, Lei; Li, Jinping; Zuo, Chao; Qian, Tianyi; Haacke, E Mark; Shen, Wen; Xia, Shuang

2018-02-01

Cerebral venous oxygen saturation (SvO 2 ) is an important indicator of brain function. There was debate about lower cerebral oxygen metabolism in hemodialysis patients and there were no reports about the changes of deep regional cerebral SvO 2 in hemodialysis patients. In this study, we aim to explore the deep regional cerebral SvO 2 from straight sinus using quantitative susceptibility mapping (QSM) and the correlation with clinical risk factors and neuropsychiatric testing . 52 hemodialysis patients and 54 age-and gender-matched healthy controls were enrolled. QSM reconstructed from original phase data of 3.0 T susceptibility-weighted imaging was used to measure the susceptibility of straight sinus. The susceptibility was used to calculate the deep regional cerebral SvO 2 and compare with healthy individuals. Correlation analysis was performed to investigate the correlation between deep regional cerebral SvO 2 , clinical risk factors and neuropsychiatric testing. The deep regional cerebral SvO 2 of hemodialysis patients (72.5 ± 3.7%) was significantly lower than healthy controls (76.0 ± 2.1%) (P < 0.001). There was no significant difference in the measured volume of interests of straight sinus between hemodialysis patients (250.92 ± 46.65) and healthy controls (249.68 ± 49.68) (P = 0.859). There were no significant correlations between the measured susceptibility and volume of interests in hemodialysis patients (P = 0.204) and healthy controls (P = 0.562), respectively. Hematocrit (r = 0.480, P < 0.001, FDR corrected), hemoglobin (r = 0.440, P < 0.001, FDR corrected), red blood cell (r = 0.446, P = 0.003, FDR corrected), dialysis duration (r = 0.505, P = 0.002, FDR corrected) and parathyroid hormone (r = -0.451, P = 0.007, FDR corrected) were risk factors for decreased deep regional cerebral SvO 2 in patients. The Mini-Mental State Examination (MMSE) scores of hemodialysis patients were

Comparison of driving simulator performance and neuropsychological testing in narcolepsy.

PubMed

Kotterba, Sylvia; Mueller, Nicole; Leidag, Markus; Widdig, Walter; Rasche, Kurt; Malin, Jean-Pierre; Schultze-Werninghaus, Gerhard; Orth, Maritta

2004-09-01

Daytime sleepiness and cataplexy can increase automobile accident rates in narcolepsy. Several countries have produced guidelines for issuing a driving license. The aim of the study was to compare driving simulator performance and neuropsychological test results in narcolepsy in order to evaluate their predictive value regarding driving ability. Thirteen patients with narcolepsy (age: 41.5+/-12.9 years) and 10 healthy control patients (age: 55.1+/-7.8 years) were investigated. By computer-assisted neuropsychological testing, vigilance, alertness and divided attention were assessed. In a driving simulator patients and controls had to drive on a highway for 60 min (mean speed of 100 km/h). Different weather and daytime conditions and obstacles were presented. Epworth Sleepiness Scale-Scores were significantly raised (narcolepsy patients: 16.7+/-5.1, controls: 6.6+/-3.6, P < or = 0.001). The accident rate of the control patients increased (3.2+/-1.8 versus 1.3+/-1.5, P < or = 0.01). Significant differences in concentration lapses (e.g. tracking errors and deviation from speed limit) could not be revealed (9.8+/-3.5 versus 7.1+/-3.2, pns). Follow-up investigation in five patients after an optimising therapy could demonstrate the decrease in accidents due to concentration lapses (P < or = 0.05). Neuropsychological testing (expressed as percentage compared to a standardised control population) revealed deficits in alertness (32.3+/-28.6). Mean percentage scores of divided attention (56.9+/-25.4) and vigilance (58.7+/-26.8) were in a normal range. There was, however, a high inter-individual difference. There was no correlation between driving performance and neuropsychological test results or ESS Score. Neuropsychological test results did not significantly change in the follow-up. The difficulties encountered by the narcolepsy patient in remaining alert may account for sleep-related motor vehicle accidents. Driving simulator investigations are closely related to real

Novel method for evaluation of eye movements in patients with narcolepsy.

PubMed

Christensen, Julie A E; Kempfner, Lykke; Leonthin, Helle L; Hvidtfelt, Mathias; Nikolic, Miki; Kornum, Birgitte Rahbek; Jennum, Poul

2017-05-01

Narcolepsy causes abnormalities in the control of wake-sleep, non-rapid-eye-movement (non-REM) sleep and REM sleep, which includes specific eye movements (EMs). In this study, we aim to evaluate EM characteristics in narcolepsy as compared to controls using an automated detector. We developed a data-driven method to detect EMs during sleep based on two EOG signals recorded as part of a polysomnography (PSG). The method was optimized using the manually scored hypnograms from 36 control subjects. The detector was applied on a clinical sample with subjects suspected for central hypersomnias. Based on PSG, multiple sleep latency test and cerebrospinal fluid hypocretin-1 measures, they were divided into clinical controls (N = 20), narcolepsy type 2 (NT2, N = 19), and narcolepsy type 1 (NT1, N = 28). We investigated the distribution of EMs across sleep stages and cycles. NT1 patients had significantly less EMs during wake, N1, and N2 sleep and more EMs during REM sleep compared to clinical controls, and significantly less EMs during wake and N1 sleep compared to NT2 patients. Furthermore, NT1 patients showed less EMs during NREM sleep in the first sleep cycle and more EMs during NREM sleep in the second sleep cycle compared to clinical controls and NT2 patients. NT1 patients show an altered distribution of EMs across sleep stages and cycles compared to NT2 patients and clinical controls, suggesting that EMs are directly or indirectly controlled by the hypocretinergic system. A data-driven EM detector may contribute to the evaluation of narcolepsy and other disorders involving the control of EMs. Copyright © 2016 Elsevier B.V. All rights reserved.

Incidence of narcolepsy before and after MF59-adjuvanted influenza A(H1N1)pdm09 vaccination in South Korean soldiers.

PubMed

Kim, Woo Jung; Lee, Sang Don; Lee, Eun; Namkoong, Kee; Choe, Kang-Won; Song, Joon Young; Cheong, Hee Jin; Jeong, Hye Won; Heo, Jung Yeon

2015-09-11

Previous reports mostly from Europe suggested an association between an occurrence of narcolepsy and an influenza A(H1N1)pdm09 vaccine adjuvanted with AS03 (Pandemrix(®)). During the 2009 H1N1 pandemic vaccination campaign, the Korean military performed a vaccination campaign with one type of influenza vaccine containing MF59-adjuvants. This study was conducted to investigate the background incidence rate of narcolepsy in South Korean soldiers and the association of the MF59-adjuvanted vaccine with the occurrence of narcolepsy in a young adult group. To assess the incidence of narcolepsy, we retrospectively reviewed medical records of suspicious cases of narcolepsy in 2007-2013 in the whole 20 military hospitals of the Korean military. The screened cases were classified according to the Brighton Collaboration case definition of narcolepsy. After obtaining the number of confirmed cases of narcolepsy per 3 months in 2007-2013, we compared the crude incidence rate of narcolepsy before and after the vaccination campaign. We included 218 narcolepsy suspicious cases in the initial review, which were screened by the diagnostic code on the computerized disease registry in 2007-2013. Forty-one cases were finally diagnosed with narcolepsy in 2007-2013 (male sex, 95%; median age, 21 years). The average background incidence rate of narcolepsy in Korean soldiers was 0.91 cases per 100,000 persons per year. During the 9 months before vaccination implementation (April to December 2009), 6 narcolepsy cases occurred, whereas during the next 9 months (January to September 2010) including the 3-month vaccination campaign, 5 cases occurred. The incidence of narcolepsy in South Korean soldiers was not increased after the pandemic vaccination campaign using the MF59-adjuvanted vaccine. Our results suggest that the MF59-adjuvanted H1N1 vaccine did not contribute to the occurrence of narcolepsy in this young adult group. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cardiovascular fitness in narcolepsy is inversely related to sleepiness and the number of cataplexy episodes.

PubMed

Matoulek, Martin; Tuka, Vladimír; Fialová, Magdalena; Nevšímalová, Soňa; Šonka, Karel

2017-06-01

Cardiopulmonary fitness depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy spent more time being sleepy or asleep than controls; thus we may speculate that they have a lower quantity and quality of physical activity. The aim of the present study was thus to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness. The cross-sectional study included 32 patients with narcolepsy with cataplexy, 10 patients with narcolepsy without cataplexy, and 36 age- and gender-matched control subjects, in whom a symptom-limited exercise stress test with expired gas analysis was performed. A linear regression analysis with multivariate models was used with stepwise variable selection. In narcolepsy patients, maximal oxygen uptake (VO 2peak ) was 30.1 ± 7.5 mL/kg/min, which was lower than 36.0 ± 7.8 mL/kg/min, p = 0.001, in controls and corresponded to 86.4% ± 20.0% of the population norm (VO 2peak %) and to a standard deviation (VO 2peak SD) of -1.08 ± 1.63 mL/kg/min of the population norm. VO 2peak depended primarily on gender (p = 0.007) and on sleepiness (p = 0.046). VO 2peak % depended on sleepiness (p = 0.028) and on age (p = 0.039). VO 2peak SD depended on the number of cataplexy episodes per month (p = 0.015) and on age (p = 0.030). Cardiopulmonary fitness in narcolepsy and in narcolepsy without cataplexy is inversely related to the degree of sleepiness and cataplexy episode frequency. Copyright © 2017 Elsevier B.V. All rights reserved.

Intravenous Immunoglobulin Therapy in Pediatric Narcolepsy: A Nonrandomized, Open-Label, Controlled, Longitudinal Observational Study.

PubMed

Lecendreux, Michel; Berthier, Johanna; Corny, Jennifer; Bourdon, Olivier; Dossier, Claire; Delclaux, Christophe

2017-03-15

Previous case reports of intravenous immunoglobulins (IVIg) in pediatric narcolepsy have shown contradictory results. This was a nonrandomized, open-label, controlled, longitudinal observational study of IVIg use in pediatric narcolepsy with retrospective data collection from medical files obtained from a single pediatric national reference center for the treatment of narcolepsy in France. Of 56 consecutively referred patients with narcolepsy, 24 received IVIg (3 infusions administered at 1-mo intervals) in addition to standard care (psychostimulants and/or anticataplectic agents), and 32 continued on standard care alone (controls). For two patients in each group, medical files were unavailable. Of the 22 IVIg patients, all had cerebrospinal fluid (CSF) hypocretin ≤ 110 pg/mL and were HLA-DQB1*06:02 positive. Of the 30 control patients, 29 were HLA-DQB1*06:02 positive and of those with available CSF measurements, all 12 had hypocretin ≤ 110 pg/mL. Compared with control patients, IVIg patients had shorter disease duration, shorter latency to sleep onset, and more had received H1N1 vaccination. Mean (standard deviation) follow-up length was 2.4 (1.1) y in the IVIg group and 3.9 (1.7) y in controls. In multivariate-adjusted linear mixed-effects analyses of change from baseline in Ullanlinna Narcolepsy Scale (UNS) scores, high baseline UNS, but not IVIg treatment, was associated with a reduction in narcolepsy symptoms. On time-to-event analysis, among patients with high baseline UNS scores, control patients achieved a UNS score < 14 (indicating remission) less rapidly than IVIg patients (adjusted hazard ratio 0.18; 95% confidence interval: 95% confidence interval: 0.03, 0.95; p = 0.043). Shorter or longer disease duration did not influence treatment response in any analysis. Overall, narcolepsy symptoms were not significantly reduced by IVIg. However, in patients with high baseline symptoms, a subset of IVIg-treated patients achieved remission more rapidly than

Nocturnal Sleep Dynamics Identify Narcolepsy Type 1

PubMed Central

Pizza, Fabio; Vandi, Stefano; Iloti, Martina; Franceschini, Christian; Liguori, Rocco; Mignot, Emmanuel; Plazzi, Giuseppe

2015-01-01

Study Objectives: To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence. Design: Cross-sectional. Setting: Sleep laboratory. Patients: One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and “subjective” hypersomnolence (sHS, n = 52). Interventions: None. Methods: Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1. Results: Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients showed the highest number of awakenings, sleep stage transitions, and more time spent in N1 sleep, as well as most SOREMPs at daytime PSG and at multiple sleep latency test (MSLT) than all other groups. ROC curve analysis showed that nocturnal SOREMP (area under the curve of 0.724 ± 0.041, P < 0.0001), percent of total sleep time spent in N1 (0.896 ± 0.023, P < 0.0001), and the wakefulness-sleep transition index (0.796 ± 0.034, P < 0.0001) had a good sensitivity and specificity profile to identify NT1 sleep, especially when used in combination (0.903 ± 0.023, P < 0.0001), similarly to SOREMP number at continuous daytime PSG (0.899 ± 0.026, P < 0.0001) and at MSLT (0.956 ± 0.015, P < 0.0001). Conclusions: Sleep macrostructure (i.e. SOREMP, N1 timing) including stage transitions reliably identifies hypocretin-deficient narcolepsy type 1 among central disorders of hypersomnolence. Citation: Pizza F, Vandi S

Nocturnal Dynamics of Sleep-Wake Transitions in Patients With Narcolepsy.

PubMed

Zhang, Xiaozhe; Kantelhardt, Jan W; Dong, Xiao Song; Krefting, Dagmar; Li, Jing; Yan, Han; Pillmann, Frank; Fietze, Ingo; Penzel, Thomas; Zhao, Long; Han, Fang

2017-02-01

We investigate how characteristics of sleep-wake dynamics in humans are modified by narcolepsy, a clinical condition that is supposed to destabilize sleep-wake regulation. Subjects with and without cataplexy are considered separately. Differences in sleep scoring habits as a possible confounder have been examined. Four groups of subjects are considered: narcolepsy patients from China with (n = 88) and without (n = 15) cataplexy, healthy controls from China (n = 110) and from Europe (n = 187, 2 nights each). After sleep-stage scoring and calculation of sleep characteristic parameters, the distributions of wake-episode durations and sleep-episode durations are determined for each group and fitted by power laws (exponent α) and by exponentials (decay time τ). We find that wake duration distributions are consistent with power laws for healthy subjects (China: α = 0.88, Europe: α = 1.02). Wake durations in all groups of narcolepsy patients, however, follow the exponential law (τ = 6.2-8.1 min). All sleep duration distributions are best fitted by exponentials on long time scales (τ = 34-82 min). We conclude that narcolepsy mainly alters the control of wake-episode durations but not sleep-episode durations, irrespective of cataplexy. Observed distributions of shortest wake and sleep durations suggest that differences in scoring habits regarding the scoring of short-term sleep stages may notably influence the fitting parameters but do not affect the main conclusion. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Narcolepsy with and without cataplexy, idiopathic hypersomnia with and without long sleep time: a cluster analysis.

PubMed

Šonka, Karel; Šusta, Marek; Billiard, Michel

2015-02-01

The successive editions of the International Classification of Sleep Disorders (ICSD) reflect the evolution of the concepts of various sleep disorders. This is particularly the case for central disorders of hypersomnolence, with continuous changes in terminology and divisions of narcolepsy, idiopathic hypersomnia, and recurrent hypersomnia. According to the ICSD 2nd Edition (ICSD-2), narcolepsy with cataplexy (NwithC), narcolepsy without cataplexy (Nw/oC), idiopathic hypersomnia with long sleep time (IHwithLST), and idiopathic hypersomnia without long sleep time (IHw/oLST) are four, well-defined hypersomnias of central origin. However, in the absence of biological markers, doubts have been raised as to the relevance of a division of idiopathic hypersomnia into two forms, and it is not yet clear whether Nw/oC and IHw/oLST are two distinct entities. With this in mind, it was decided to empirically review the ICSD-2 classification by using a hierarchical cluster analysis to see whether this division has some relevance, even though the terms "with long sleep time" and "without long sleep time" are inappropriate. The cluster analysis differentiated three main clusters: Cluster 1, "combined monosymptomatic hypersomnia/narcolepsy type 2" (people initially diagnosed with IHw/oLST and Nw/oC); Cluster 2 "polysymptomatic hypersomnia" (people initially diagnosed with IHwithLST); and Cluster 3, narcolepsy type 1 (people initially diagnosed with NwithC). Cluster analysis confirmed that narcolepsy type 1 and polysymptomatic hypersomnia are independent sleep disorders. People who were initially diagnosed with Nw/oC and IHw/oLST formed a single cluster, referred to as "combined monosymptomatic hypersomnia/narcolepsy type 2." Copyright © 2014 Elsevier B.V. All rights reserved.

White matter alterations in narcolepsy patients with cataplexy: tract-based spatial statistics.

PubMed

Park, Yun K; Kwon, Oh-Hun; Joo, Eun Yeon; Kim, Jae-Hun; Lee, Jong M; Kim, Sung T; Hong, Seung B

2016-04-01

Functional imaging studies and voxel-based morphometry analysis of brain magnetic resonance imaging showed abnormalities in the hypothalamus-thalamus-orbitofrontal pathway, demonstrating altered hypocretin pathway in narcolepsy. Those distinct morphometric changes account for problems in wake-sleep control, attention and memory. It also raised the necessity to evaluate white matter changes. To investigate brain white matter alterations in drug-naïve narcolepsy patients with cataplexy and to explore relationships between white matter changes and patient clinical characteristics, drug-naïve narcolepsy patients with cataplexy (n = 22) and healthy age- and gender-matched controls (n = 26) were studied. Fractional anisotropy and mean diffusivity images were obtained from whole-brain diffusion tensor imaging, and tract-based spatial statistics were used to localize white matter abnormalities. Compared with controls, patients showed significant decreases in fractional anisotropy of white matter of the bilateral anterior cingulate, fronto-orbital area, frontal lobe, anterior limb of the internal capsule and corpus callosum, as well as the left anterior and medial thalamus. Patients and controls showed no differences in mean diffusivity. Among patients, mean diffusivity values of white matter in the bilateral superior frontal gyri, bilateral fronto-orbital gyri and right superior parietal gyrus were positively correlated with depressive mood. This tract-based spatial statistics study demonstrated that drug-naïve patients with narcolepsy had reduced fractional anisotropy of white matter in multiple brain areas and significant relationship between increased mean diffusivity of white matter in frontal/cingulate and depression. It suggests the widespread disruption of white matter integrity and prevalent brain degeneration of frontal lobes according to a depressive symptom in narcolepsy. © 2015 European Sleep Research Society.

Executive Control of Attention in Narcolepsy

PubMed Central

Bayard, Sophie; Croisier Langenier, Muriel; Cochen De Cock, Valérie; Scholz, Sabine; Dauvilliers, Yves

2012-01-01

Background Narcolepsy with cataplexy (NC) is a disabling sleep disorder characterized by early loss of hypocretin neurons that project to areas involved in the attention network. We characterized the executive control of attention in drug-free patients with NC to determine whether the executive deficits observed in patients with NC are specific to the disease itself or whether they reflect performance changes due to the severity of excessive daytime sleepiness. Methodology Twenty-two patients with NC compared to 22 patients with narcolepsy without cataplexy (NwC) matched for age, gender, intellectual level, objective daytime sleepiness and number of sleep onset REM periods (SOREMPs) were studied. Thirty-two matched healthy controls were included. All participants underwent a standardized interview, completed questionnaires, and neuropsychological tests. All patients underwent a polysomnography followed by multiple sleep latency tests (MSLT), with neuropsychological evaluation performed the same day between MSLT sessions. Principal Findings Irrespective of diagnosis, patients reported higher self-reported attentional complaints associated with the intensity of depressive symptoms. Patients with NC performed slower and more variably on simple reaction time tasks than patients with NwC, who did not differ from controls. Patients with NC and NwC generally performed slower, reacted more variably, and made more errors than controls on executive functioning tests. Individual profile analyses showed a clear heterogeneity of the severity of executive deficit. This severity was related to objective sleepiness, higher number of SOREMPs on the MSLT, and lower intelligence quotient. The nature and severity of the executive deficits were unrelated to NC and NwC diagnosis. Conclusions We demonstrated that drug-free patients with NC and NwC complained of attention deficit, with altered executive control of attention being explained by the severity of objective sleepiness and

[Narcolepsy in childhood and adolescence: symptoms, diagnosis, and therapy. A case report].

PubMed

Gehrmann, Jochen; Siegler, Dominik; Ignacy, Evelin; Reimer, Inga

2017-03-01

Narcolepsy is a rare, multifactorial disease of the hypothalamus characterized by its leading symptoms of excessive daytime sleepiness and cataplexy. Sleep-EEG and a HLA-DR-genotype serve to secure the diagnosis. We report here on a 14-year-old girl suffering from anxieties, depression, school refusal, social withdrawal as well as very frequent attacks of sleep during the day and cataplexy. Currently, there is no approved drug for children and adolescents suffering from narcolepsy. Our patient benefited significantly and quickly from an off-label treatment with methylphenidate in combination with psychoeducation, cognitive behavioral therapy, and family therapy. Narcolepsy is a very rare but probably underestimated differential diagnosis applied to unclear daytime sleepiness, anxieties, or depression in childhood and adolescence. Both the key symptoms and the comorbid symptoms improve significantly under treatment with stimulants, albeit at a higher dosage.

Management of cerebral palsy varies by healthcare region.

PubMed

Rackauskaite, Gija; Uldall, Peter W; Bech, Bodil H; Østergaard, John R

2015-11-01

Cerebral palsy (CP) is the most common type of motor disability in childhood. The aim of the present paper was to describe regional differences in the management of CP in school-aged children in Denmark. This was a cross-sectional study based on the Danish Cerebral Palsy Registry. The parents of 462 children answered a questionnaire about their child's treatment and the family's characteristics. Descriptive and logistic regression analyses were performed for every treatment modality, stratified by the Gross Motor Function Classification System (GMFCS) level and adjusted for family and child characteristics. Significant regional differences were found regarding the provision of occupational therapy at all GMFCS levels, speech therapy at GMFCS levels II-V and orthopaedic surgery at GMFCS levels I and III-V. No regional differences were observed in the frequency of physiotherapy. We found no regional differences in the severity of disability. Regional differences in the management of CP cannot be explained by social differences or differences in the severity of the disability. This study was funded by the Research Foundation from the Central Denmark Region and the Department of Clinical Medicine at Aarhus University Hospital, the Augustinus Foundation, the Bevica Foundation, the Dagmar Marshalls Foundation, the Ludvig and Sara Elsass Foundation, and the Civil Engineer Frode V. Nyegaard's and his Wife's Foundation. not relevant.

Regional cerebral metabolic correlates of WASO during NREM sleep in insomnia.

PubMed

Nofzinger, Eric A; Nissen, Christoph; Germain, Anne; Moul, Douglas; Hall, Martica; Price, Julie C; Miewald, Jean M; Buysse, Daniel J

2006-07-15

To investigate the non-rapid eye movement (NREM) sleep-related regional cerebral metabolic correlates of wakefulness after sleep onset (WASO) in patients with primary insomnia. Fifteen patients who met DSM-IV criteria for primary insomnia completed 1-week sleep diary (subjective) and polysomnographic (objective) assessments of WASO and regional cerebral glucose metabolic assessments during NREM sleep using [18F] fluoro-2-deoxy-D-glucose positron emission tomography. Whole-brain voxel-by-voxel correlations, as well as region of interest analyses, were performed between subjective and objective WASO and relative regional cerebral metabolism using the statistical software SPM2. Subjective WASO was significantly greater than objective WASO, but the 2 measures were positively correlated. Objective WASO correlated positively with the percentage of stage 2 sleep and negatively with the percentage of stages 3 and 4 sleep. Both subjective and objective WASO positively correlated with NREM sleep-related cerebral glucose metabolism in the pontine tegmentum and in thalamocortical networks in a frontal, anterior temporal, and anterior cingulate distribution. Increased relative metabolism in these brain regions during NREM sleep in patients with insomnia is associated with increased WASO measured either subjectively or objectively. These effects are related to the lighter sleep stages of patients with more WASO and may result from increased activity in arousal systems during sleep and or to activity in higher-order cognitive processes related to goal-directed behavior, conflict monitoring, emotional awareness, anxiety, and fear. Such changes may decrease arousal thresholds and/or increase perceptions of wakefulness in insomnia.

An autoantibody in narcolepsy disrupts colonic migrating motor complexes.

PubMed

Jackson, Michael W; Reed, Joanne H; Smith, Anthony J F; Gordon, Tom P

2008-12-03

Despite strong circumstantial evidence for the autoimmune hypothesis of narcolepsy, conventional immunological methods have failed to detect an autoantibody. This study investigated the real-time effects of narcoleptic immunoglobulins on a spontaneous colonic migrating motor complex (CMMC) preparation. IgG from patients with narcolepsy with cataplexy or healthy controls was added directly to isolated mouse colons undergoing CMMC activity to test for autoantibodies that disrupt colonic motility. The effect of immunoglobulins prepared for clinical intravenous treatment (IVIg) on autoantibody-mediated colonic disruption was also assessed. Narcoleptic IgGs markedly reduced the frequency of CMMCs or irreversibly abolished them. Abrogation of CMMCs was followed by an increase in the resting tension of the colon preparation and appearance of atropine-sensitive phasic smooth muscle contractions. IVIg partially neutralized the inhibitory effect of narcoleptic IgG on the CMMCs. The dramatic effect of narcoleptic IgG on CMMC generation is consistent with an autoantibody-mediated disruption of enteric neural pathways. The ex vivo whole-organ approach allows real-time examination of the physiological effects of the narcoleptic autoantibody and offers a new avenue for exploring the autoimmune basis of narcolepsy. The neutralizing effect of IVIg on the autoantibody provides a rationale for the reported clinical improvement in cataplexy when IVIg are given at disease onset.

Narcolepsy Type 1 and Idiopathic Generalized Epilepsy: Diagnostic and Therapeutic Challenges in Dual Cases

PubMed Central

Baiardi, Simone; Vandi, Stefano; Pizza, Fabio; Alvisi, Lara; Toscani, Lucia; Zambrelli, Elena; Tinuper, Paolo; Mayer, Geert; Plazzi, Giuseppe

2015-01-01

Study Objectives: The aim of this study is to describe the possible co-occurrence of narcolepsy type 1 and generalized epilepsy, focusing on diagnostic challenge and safety of dual treatments. Methods and Results: Four patients with comorbidity for narcolepsy type 1 and idiopathic generalized epilepsy are reported: in three cases the onset of epilepsy preceded narcolepsy type 1 appearance, whereas in one case epileptic spells onset was subsequent. Patients presented with absences, myoclonic and tonic-clonic seizure type: in the patient with tonic-clonic seizures the dual pathology was easily recognized, in the other cases the first diagnosis caused the comorbid disease to be overlooked, independent of the time-course sequence. All four patients underwent neurological examination, video-electroencephalogram during which ictal and interictal epileptic discharges were recorded, and sleep polysomnographic studies. Repeated sleep onset rapid eye movement periods (SOREMPs) were documented with the multiple sleep latency test (MLST) in all the four cases. All patients had unremarkable brain magnetic resonance imaging studies and cerebrospinal hypocretin-1 was assessed in two patients, revealing undetectable levels. The association of antiepileptic drugs and substances currently used to treat narcolepsy type 1, including sodium oxybate, was effective in improving seizures, sleep disturbance, and cataplexy. Conclusions: Narcolepsy type 1 may occur in association with idiopathic generalized epilepsy, leading to remarkable diagnostic and therapeutic challenges. Electrophysiological studies as well as a comprehensive somnologic interview can help confirm the diagnosis in patients with ambiguous neurological history. Sodium oxybate in combination with antiepileptic drugs is safe and effective in treating cataplexy and excessive daytime sleepiness. Citation: Baiardi S, Vandi S, Pizza F, Alvisi L, Toscani L, Zambrelli E, Tinuper P, Mayer G, Plazzi G. Narcolepsy type 1 and

Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis.

PubMed

Sarkanen, Tomi O; Alakuijala, Anniina P E; Dauvilliers, Yves A; Partinen, Markku M

2018-04-01

An increased incidence of narcolepsy was seen in many countries after the pandemic H1N1 influenza vaccination campaign in 2009-2010. The H1N1 vaccine - narcolepsy connection is based on observational studies that are prone to various biases, e.g., confounding by H1N1 infection, and ascertainment, recall and selection biases. A direct pathogenic link has, however, remained elusive. We conducted a systematic review and meta-analysis to analyze the magnitude of H1N1 vaccination related risk and to examine if there was any association with H1N1 infection itself. We searched all articles from PubMed, Web of Science and Scopus, and other relevant sources reporting the incidence and risk of post-vaccine narcolepsy. In our paper, we show that the risk appears to be limited to only one vaccine (Pandemrix ® ). During the first year after vaccination, the relative risk of narcolepsy was increased 5 to 14-fold in children and adolescents and 2 to 7-fold in adults. The vaccine attributable risk in children and adolescents was around 1 per 18,400 vaccine doses. Studies from Finland and Sweden also appear to demonstrate an extended risk of narcolepsy into the second year following vaccination, but such conclusions should be interpreted with a word of caution due to possible biases. Benefits of immunization outweigh the risk of vaccination-associated narcolepsy, which remains a rare disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

Case report of narcolepsy in a six-year-old child initially misdiagnosed as atypical epilepsy.

PubMed

Zhou, Jinquan; Zhang, Xi; Dong, Zaiwen

2014-08-01

This report describes a case of first-onset narcolepsy in a six-year-old female that was misdiagnosed as atypical epilepsy and other diagnoses at eight different hospitals over a period of 10 months before the correct diagnosis was made. The diagnosis of narcolepsy is more difficult in children because very few of them experience all four cardinal symptoms of narcolepsy - paroxysmal sleep, cataplexy, hypnagogic hallucination, and sleep paralysis - and they often have a more prolonged onset and diverse symptoms. To decrease the time lag between initial presentation and accurate diagnosis, we recommend that in all cases in which children report excessive sleep of unknown etiology - regardless of the associated symptoms - that sleep monitoring and sleep latency tests be conducted to rule out the possibility of narcolepsy. The case highlights the wide variety of presentations of uncommon psychiatric conditions, particularly in children, and the need for clinicians to be aware of the atypical presentations of these conditions when collecting medical histories.

Effect of sensor location on regional cerebral oxygen saturation measured by INVOS 5100 in on-pump cardiac surgery.

PubMed

Cho, Ah-Reum; Kwon, Jae-Young; Kim, Choongrak; Hong, Jung-Min; Kang, Christine

2017-04-01

Near-infrared spectroscopy sensors often cannot be attached at the commercially recommended locations because combined use of neurological monitoring systems is common during on-pump cardiac surgery. The primary purpose of this study was to compare the incidence of regional cerebral oxygen desaturation and regional cerebral oxygen saturation values detected using near-infrared spectroscopy between the upper and lower forehead during on-pump cardiac surgery. A prospective observational study was conducted with 25 adult patients scheduled for elective on-pump cardiac surgery. Regional cerebral oxygen saturations at the left upper and lower forehead and other clinical measurements were monitored intraoperatively. McNemar's test was used to analyze differences in the incidence of cerebral regional oxygen desaturation between the left upper and lower forehead. Two-way repeated measures ANOVA with post hoc Bonferroni correction was used to compare the regional cerebral oxygen saturation at each time point. There was a significantly higher incidence of regional cerebral oxygen desaturation at the upper than lower forehead only at 1 h after initiation of aortic cross-clamping. There were significant differences between the left upper and lower regional cerebral oxygen saturation values throughout the observation period. Regional cerebral oxygen saturation was significantly lower at the upper than lower forehead during on-pump cardiac surgery. However, disagreements in detection of cerebral regional oxygen desaturation were only significant at 1 h after initiation of aortic cross-clamping. WHO-ICTRP, Clinical Research Information Service (CRiS). ID: KCT0000971. URL: https://cris.nih.go.kr/cris/search/search_result_st01_en.jsp?seq=3678&type=my .

Rehabilitation with dental prosthesis can increase cerebral regional blood volume.

PubMed

Miyamoto, Ikuya; Yoshida, Kazuya; Tsuboi, Yoichi; Iizuka, Tadahiko

2005-12-01

Treatment with denture for edentulous people is highly important for maintaining quality of life. However, its effect on the brain is unknown. In this experimental study, we hypothesized that dental prosthesis can recover not only the physical condition of mastication system but also the regional brain activity. We evaluated functional brain imaging of edentulous subjects fixed by dental implant prosthesis with clenching tasks by multi-channel near-infrared optical topography. Results revealed a significantly (P<0.001; paired t-test) increased cerebral regional blood volume during maximum voluntary clenching task by implant-retained prosthesis. There were no statistically significant differences between patients with and without prosthesis in the latency to the maximum regional blood volume after the task. Conclusively, clenching can be effective for increasing cerebral blood volume; accordingly maintenance of normal chewing might prevent the brain from degenerating.

Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France.

PubMed

Dauvilliers, Yves; Arnulf, Isabelle; Lecendreux, Michel; Monaca Charley, Christelle; Franco, Patricia; Drouot, Xavier; d'Ortho, Marie-Pia; Launois, Sandrine; Lignot, Séverine; Bourgin, Patrice; Nogues, Béatrice; Rey, Marc; Bayard, Sophie; Scholz, Sabine; Lavault, Sophie; Tubert-Bitter, Pascale; Saussier, Cristel; Pariente, Antoine

2013-08-01

An increased incidence of narcolepsy in children was detected in Scandinavian countries where pandemic H1N1 influenza ASO3-adjuvanted vaccine was used. A campaign of vaccination against pandemic H1N1 influenza was implemented in France using both ASO3-adjuvanted and non-adjuvanted vaccines. As part of a study considering all-type narcolepsy, we investigated the association between H1N1 vaccination and narcolepsy with cataplexy in children and adults compared with matched controls; and compared the phenotype of narcolepsy with cataplexy according to exposure to the H1N1 vaccination. Patients with narcolepsy-cataplexy were included from 14 expert centres in France. Date of diagnosis constituted the index date. Validation of cases was performed by independent experts using the Brighton collaboration criteria. Up to four controls were individually matched to cases according to age, gender and geographic location. A structured telephone interview was performed to collect information on medical history, past infections and vaccinations. Eighty-five cases with narcolepsy-cataplexy were included; 23 being further excluded regarding eligibility criteria. Of the 62 eligible cases, 59 (64% males, 57.6% children) could be matched with 135 control subjects. H1N1 vaccination was associated with narcolepsy-cataplexy with an odds ratio of 6.5 (2.1-19.9) in subjects aged<18 years, and 4.7 (1.6-13.9) in those aged 18 and over. Sensitivity analyses considering date of referral for diagnosis or the date of onset of symptoms as the index date gave similar results, as did analyses focusing only on exposure to ASO3-adjuvanted vaccine. Slight differences were found when comparing cases with narcolepsy-cataplexy exposed to H1N1 vaccination (n=32; mostly AS03-adjuvanted vaccine, n=28) to non-exposed cases (n=30), including shorter delay of diagnosis and a higher number of sleep onset rapid eye movement periods for exposed cases. No difference was found regarding history of infections. In

Case report of narcolepsy in a six-year-old child initially misdiagnosed as atypical epilepsy

PubMed Central

ZHOU, Jinquan; ZHANG, Xi; DONG, Zaiwen

2014-01-01

Summary This report describes a case of first-onset narcolepsy in a six-year-old female that was misdiagnosed as atypical epilepsy and other diagnoses at eight different hospitals over a period of 10 months before the correct diagnosis was made. The diagnosis of narcolepsy is more difficult in children because very few of them experience all four cardinal symptoms of narcolepsy – paroxysmal sleep, cataplexy, hypnagogic hallucination, and sleep paralysis – and they often have a more prolonged onset and diverse symptoms. To decrease the time lag between initial presentation and accurate diagnosis, we recommend that in all cases in which children report excessive sleep of unknown etiology – regardless of the associated symptoms – that sleep monitoring and sleep latency tests be conducted to rule out the possibility of narcolepsy. The case highlights the wide variety of presentations of uncommon psychiatric conditions, particularly in children, and the need for clinicians to be aware of the atypical presentations of these conditions when collecting medical histories. PMID:25317010

Narcolepsy Type 1 and Idiopathic Generalized Epilepsy: Diagnostic and Therapeutic Challenges in Dual Cases.

PubMed

Baiardi, Simone; Vandi, Stefano; Pizza, Fabio; Alvisi, Lara; Toscani, Lucia; Zambrelli, Elena; Tinuper, Paolo; Mayer, Geert; Plazzi, Giuseppe

2015-11-15

The aim of this study is to describe the possible co-occurrence of narcolepsy type 1 and generalized epilepsy, focusing on diagnostic challenge and safety of dual treatments. Four patients with comorbidity for narcolepsy type 1 and idiopathic generalized epilepsy are reported: in three cases the onset of epilepsy preceded narcolepsy type 1 appearance, whereas in one case epileptic spells onset was subsequent. Patients presented with absences, myoclonic and tonic-clonic seizure type: in the patient with tonic-clonic seizures the dual pathology was easily recognized, in the other cases the first diagnosis caused the comorbid disease to be overlooked, independent of the time-course sequence. All four patients underwent neurological examination, video-electroencephalogram during which ictal and interictal epileptic discharges were recorded, and sleep polysomnographic studies. Repeated sleep onset rapid eye movement periods (SOREMPs) were documented with the multiple sleep latency test (MLST) in all the four cases. All patients had unremarkable brain magnetic resonance imaging studies and cerebrospinal hypocretin-1 was assessed in two patients, revealing undetectable levels. The association of antiepileptic drugs and substances currently used to treat narcolepsy type 1, including sodium oxybate, was effective in improving seizures, sleep disturbance, and cataplexy. Narcolepsy type 1 may occur in association with idiopathic generalized epilepsy, leading to remarkable diagnostic and therapeutic challenges. Electrophysiological studies as well as a comprehensive somnologic interview can help confirm the diagnosis in patients with ambiguous neurological history. Sodium oxybate in combination with antiepileptic drugs is safe and effective in treating cataplexy and excessive daytime sleepiness. © 2015 American Academy of Sleep Medicine.

Predictors of Hypocretin (Orexin) Deficiency in Narcolepsy Without Cataplexy

PubMed Central

Andlauer, Olivier; Moore, Hyatt; Hong, Seung-Chul; Dauvilliers, Yves; Kanbayashi, Takashi; Nishino, Seiji; Han, Fang; Silber, Michael H.; Rico, Tom; Einen, Mali; Kornum, Birgitte R.; Jennum, Poul; Knudsen, Stine; Nevsimalova, Sona; Poli, Francesca; Plazzi, Giuseppe; Mignot, Emmanuel

2012-01-01

Study Objectives: To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (≤ 110 pg/ml), intermediate (110–200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) hypocretin-1. Setting: University-based sleep clinics and laboratories. Patients: Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF hypocretin-1. Design and interventions: Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis. Measurements and Results: The optimal cutoff of CSF hypocretin-1 for narcolepsy without cataplexy diagnosis was 200 pg/ml rather than 110 pg/ml (sensitivity 33%, specificity 99%). Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (≤ 110 pg/ml) of CSF hypocretin-1. Patients with low concentrations of hypocretin-1 only differed subjectively from other groups by a higher Epworth Sleepiness Scale score and more frequent sleep paralysis. Compared with patients with normal hypocretin-1 concentration (n = 117, 68%), those with low hypocretin-1 concentration had higher HLA DQB1*06:02 frequencies, were more frequently non-Caucasians (notably African Americans), with lower age of onset, and longer duration of illness. They also had more frequently short rapid-eye movement (REM) sleep latency (≤ 15 min) during polysomnography (64% versus 23%), and shorter sleep latencies (2.7 ± 0.3 versus 4.4 ± 0.2 min) and more sleep-onset REM periods (3.6 ± 0.1 versus 2.9 ± 0.1 min) during the Multiple Sleep Latency Test (MSLT). Patients with intermediate concentrations of CSF hypocretin-1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. Of the 127 patients we were able to recontact, survival analysis showed that almost half (48%) with low concentration of CSF hypocretin-1 had developed

Neuronal Antibodies in Children with or without Narcolepsy following H1N1-AS03 Vaccination

PubMed Central

Thebault, Simon; Waters, Patrick; Snape, Matthew D.; Cottrell, Dominic; Darin, Niklas; Hallböök, Tove; Huutoniemi, Anne; Partinen, Markku; Pollard, Andrew J.; Vincent, Angela

2015-01-01

Type 1 narcolepsy is caused by deficiency of hypothalamic orexin/hypocretin. An autoimmune basis is suspected, but no specific antibodies, either causative or as biomarkers, have been identified. However, the AS03 adjuvanted split virion H1N1 (H1N1-AS03) vaccine, created to protect against the 2009 Pandemic, has been implicated as a trigger of narcolepsy particularly in children. Sera and CSFs from 13 H1N1-AS03-vaccinated patients (12 children, 1 young adult) with type 1 narcolepsy were tested for autoantibodies to known neuronal antigens including the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein 2 (CASPR2), both associated with encephalopathies that include disordered sleep, to rodent brain tissue including the lateral hypothalamus, and to live hippocampal neurons in culture. When sufficient sample was available, CSF levels of melanin-concentrating hormone (MCH) were measured. Sera from 44 H1N1-ASO3-vaccinated children without narcolepsy were also examined. None of these patients’ CSFs or sera was positive for NMDAR or CASPR2 antibodies or binding to neurons; 4/13 sera bound to orexin-neurons in rat brain tissue, but also to other neurons. MCH levels were a marginally raised (n = 8; p = 0.054) in orexin-deficient narcolepsy patients compared with orexin-normal children (n = 6). In the 44 H1N1-AS03-vaccinated healthy children, there was no rise in total IgG levels or in CASPR2 or NMDAR antibodies three weeks following vaccination. In conclusion, there were no narcolepsy-specific autoantibodies identified in type 1 narcolepsy sera or CSFs, and no evidence for a general increase in immune reactivity following H1N1-AS03 vaccination in the healthy children. Antibodies to other neuronal specific membrane targets, with their potential for directing use of immunotherapies, are still an important goal for future research. PMID:26090827

Neuronal Antibodies in Children with or without Narcolepsy following H1N1-AS03 Vaccination.

PubMed

Thebault, Simon; Waters, Patrick; Snape, Matthew D; Cottrell, Dominic; Darin, Niklas; Hallböök, Tove; Huutoniemi, Anne; Partinen, Markku; Pollard, Andrew J; Vincent, Angela

2015-01-01

Type 1 narcolepsy is caused by deficiency of hypothalamic orexin/hypocretin. An autoimmune basis is suspected, but no specific antibodies, either causative or as biomarkers, have been identified. However, the AS03 adjuvanted split virion H1N1 (H1N1-AS03) vaccine, created to protect against the 2009 Pandemic, has been implicated as a trigger of narcolepsy particularly in children. Sera and CSFs from 13 H1N1-AS03-vaccinated patients (12 children, 1 young adult) with type 1 narcolepsy were tested for autoantibodies to known neuronal antigens including the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein 2 (CASPR2), both associated with encephalopathies that include disordered sleep, to rodent brain tissue including the lateral hypothalamus, and to live hippocampal neurons in culture. When sufficient sample was available, CSF levels of melanin-concentrating hormone (MCH) were measured. Sera from 44 H1N1-ASO3-vaccinated children without narcolepsy were also examined. None of these patients' CSFs or sera was positive for NMDAR or CASPR2 antibodies or binding to neurons; 4/13 sera bound to orexin-neurons in rat brain tissue, but also to other neurons. MCH levels were a marginally raised (n = 8; p = 0.054) in orexin-deficient narcolepsy patients compared with orexin-normal children (n = 6). In the 44 H1N1-AS03-vaccinated healthy children, there was no rise in total IgG levels or in CASPR2 or NMDAR antibodies three weeks following vaccination. In conclusion, there were no narcolepsy-specific autoantibodies identified in type 1 narcolepsy sera or CSFs, and no evidence for a general increase in immune reactivity following H1N1-AS03 vaccination in the healthy children. Antibodies to other neuronal specific membrane targets, with their potential for directing use of immunotherapies, are still an important goal for future research.

Health-Related Quality of Life Among Drug-Naïve Patients with Narcolepsy with Cataplexy, Narcolepsy Without Cataplexy, and Idiopathic Hypersomnia Without Long Sleep Time

PubMed Central

Ozaki, Akiko; Inoue, Yuichi; Nakajima, Toru; Hayashida, Kenichi; Honda, Makoto; Komada, Yoko; Takahashi, Kiyohisa

2008-01-01

Objective: To evaluate the health-related quality life (HRQOL) of drugnaïve patients with narcolepsy with cataplexy (NA with CA), narcolepsy without cataplexy (NA without CA) and idiopathic hypersomnia without long sleep time (IHS without LST), and to explore the factors influencing the HRQOL. Factors associated with the occurrence of automobile accidents are also discussed. Methods: A total of 137 consecutive drug naïve patients who met the criteria of the 2nd edition of the International Classification of Sleep Disorders (NA with CA, n = 28; NA without CA, n = 27; IHS without LST, n = 82) were enrolled. The patients were asked to fill out questionnaires, including the SF-36, Epworth Sleepiness Scale (ESS), sociodemographic variables, and items regarding driving habits and the experiences related to automobile accidents. Results: All 3 diagnostic groups had significantly lower scores in most SF-36 domains compared with Japanese normative data. Significant differences among the 3 diagnostic groups were not observed. Specific factors in SF-36 domains were not found with multiple linear regression analyses, while disease duration was positively correlated with mental health among all subjects. Among the patients reporting driving habits, ESS score (≥16) was positively associated with the experience of automobile accidents. Conclusions: Our results indicated that HRQOL decreases in drugnaïve patients with hypersomnia, but neither disease category nor severity of the disorder appears as an associated factor. Increased severity of hypersomnia, however, was thought to play an important role in the occurrence of automobile accidents. Citation: Ozaki A; Inoue Y; Nakajima T; Hayashida K; Honda M; Komada Y; Takahashi K. Health-related quality of life among drug-naïve patients with narcolepsy with cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia without long sleep time. J Clin Sleep Med 2008;4(6):572-578. PMID:19110887

Narcolepsy and syndromes of primary excessive daytime somnolence.

PubMed

Black, Jed E; Brooks, Stephen N; Nishino, Seiji

2004-09-01

Excessive daytime sleepiness (EDS) or somnolence is common in our patients and in society in general. The most common cause of EDS is "voluntary" sleep restriction. Other common causes include sleep-fragmenting disorders such as the obstructive sleep apnea syndrome. Somewhat less familiar to the clinician are EDS conditions arising from central nervous system dysfunction. Of these so-called primary disorders of somnolence, narcolepsy is the most well known and extensively studied, yet often misunderstood and misdiagnosed. Idiopathic hypersomnia, the recurrent hypersomnias, and EDS associated with nervous system disorders also must be well-understood to provide appropriate evaluation and management of the patient with EDS. This review summarizes the distinguishing features of these clinical syndromes of primary EDS. A brief overview of the pharmacological management of primary EDS is included. Finally, in view of the tremendous advances that have occurred in the past few years in our understanding of the pathophysiology of canine and human narcolepsy, we also highlight these discoveries.

Cataplectic facies: clinical marker in the diagnosis of childhood narcolepsy-report of two cases.

PubMed

Prasad, Manish; Setty, Gururaj; Ponnusamy, Athi; Hussain, Nahin; Desurkar, Archana

2014-05-01

Narcolepsy is a chronic disease and is commonly diagnosed in adulthood. However, more than half of the patients have onset of symptoms in childhood and/or adolescence. The full spectrum of clinical manifestations, namely excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis, is usually not present at disease onset, delaying diagnosis during childhood. Mean delay in diagnosis since symptom onset is known to be several years. Initial manifestations can sometimes be as subtle as only partial drooping of eyelids leading to confusion with a myasthenic condition. We present two children who presented with "cataplectic facies," an unusual facial feature only recently described in children with narcolepsy with cataplexy. The diagnosis of narcolepsy was confirmed by multiple sleep latency test along with human leukocyte antigen typing and cerebrospinal fluid hypocretin assay. The diagnosis of narcolepsy with cataplexy at onset can be challenging in young children. With more awareness of subtle signs such as cataplectic facies, earlier diagnosis is possible. To date, only 11 children between 6 and 18 years of age presenting with typical cataplectic facies have been reported in the literature. We present two patients, one of whom is the youngest individual (4 years old) yet described with the typical cataplectic facies. Copyright © 2014 Elsevier Inc. All rights reserved.

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

PubMed Central

Vaarala, Outi; Vuorela, Arja; Partinen, Markku; Baumann, Marc; Freitag, Tobias L.; Meri, Seppo; Saavalainen, Päivi; Jauhiainen, Matti; Soliymani, Rabah; Kirjavainen, Turkka; Olsen, Päivi; Saarenpää-Heikkilä, Outi; Rouvinen, Juha; Roivainen, Merja; Nohynek, Hanna; Jokinen, Jukka; Julkunen, Ilkka; Kilpi, Terhi

2014-01-01

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. PMID:25501681

Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients.

PubMed

Wirth, Miranka; Pichet Binette, Alexa; Brunecker, Peter; Köbe, Theresa; Witte, A Veronica; Flöel, Agnes

2017-03-01

Reductions of cerebral blood flow and gray matter structure have been implicated in early pathogenesis of Alzheimer's disease, potentially providing complementary information. The present study evaluated regional patterns of cerebral hypoperfusion and atrophy in patients with mild cognitive impairment and healthy older adults. In each participant, cerebral perfusion and gray matter structure were extracted within selected brain regions vulnerable to Alzheimer's disease using magnetic resonance imaging. Measures were compared between diagnostic groups with/without adjustment for covariates. In mild cognitive impairment patients, cerebral blood flow was significantly reduced in comparison with healthy controls in temporo-parietal regions and the basal ganglia in the absence of local gray matter atrophy. By contrast, gray matter structure was significantly reduced in the hippocampus in the absence of local hypoperfusion. Both, cerebral perfusion and gray matter structure were significantly reduced in the entorhinal and isthmus cingulate cortex in mild cognitive impairment patients compared with healthy older adults. Our results demonstrated partly divergent patterns of temporo-parietal hypoperfusion and medial-temporal atrophy in mild cognitive impairment patients, potentially indicating biomarker sensitivity to dissociable pathological mechanisms. The findings support applicability of cerebral perfusion and gray matter structure as complementary magnetic resonance imaging-based biomarkers in early Alzheimer's disease detection, a hypothesis to be further evaluated in longitudinal studies.

Sodium Oxybate treatment in pediatric type 1 narcolepsy.

PubMed

Moresco, Monica; Pizza, Fabio; Antelmi, Elena; Plazzi, Giuseppe

2018-03-05

Narcolepsy type 1 (NT1) is a rare chronic neurologic disorder characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations and disrupted nocturnal sleep, usually with onset during childhood/adolescence. Pediatric NT1 is associated with limitations on children's activities and achievements, especially poor performance at school, difficulty with peers due to disease symptoms and comorbidities including depression, obesity, and precocious puberty. NT1 disease is caused by the selective loss of hypocretin-producing neurons in the lateral hypothalamus, most probably related to an autoimmune pathophysiology. Indeed a strong genetic predisposition including the HLA system and other associations in genes involved in immune responses has been found together with the triggering role of environmental agents such as H1N1 influenza infections and vaccinations. Sodium Oxybate (SO) is a sodium salt of γ-hydroxybutyric (GHB) acid that is synthetized by neurons in the brain and functions as neurotransmitter. GHB is a central nervous system depressant and produces dose-dependent sedation. SO is a first line medication for cataplexy and excessive daytime sleepiness in adults with NT1, but can be helpful also for sleep disruption, hypnagogic hallucination and sleep paralysis in these patients. Although in the majority of patients narcolepsy develops before 15 years of age, there are no approved treatments for pediatric NT1. However, SO has been widely used off-label to treat narcolepsy symptoms in children and adolescents with NT1 in non-controlled studies, showing a similar safety profile and therapeutic response to adult patients. Current therapy is based only on empirical data shared among expert sleep disorders clinicians. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Changes in Medical Services and Drug Utilization and Associated Costs After Narcolepsy Diagnosis in the United States

PubMed Central

Villa, Kathleen F.; Reaven, Nancy L.; Funk, Susan E.; McGaughey, Karen; Black, Jed

2018-01-01

Background Healthcare utilization and the cost implications associated with undiagnosed and/or misdiagnosed narcolepsy have not been evaluated, and there is scant literature characterizing the newly diagnosed population with narcolepsy with respect to treatment patterns and resource utilization. Objective To analyze the changes in medication use, healthcare utilization, and the associated costs after a new diagnosis of narcolepsy. Methods In this retrospective cohort study, we used data from the Truven Health Analytics MarketScan Research Databases, between January 2006 and March 2013, to identify patients who had a probable new diagnosis of narcolepsy—defined as a de novo medical claim for a multiple sleep latency test—which was preceded by ≥6 months of continuous insurance and was followed by a de novo diagnosis of narcolepsy. The utilization and cost of medical services and the percentage of patients filling prescriptions for narcolepsy-related medications were evaluated in 3 consecutive 1-year periods from the date of a positive multiple sleep latency test result (ie, index date), and each year's findings were compared with the annualized results from the 6-month preindex period. Results A total of 3757 patients who met the definition of a new diagnosis of narcolepsy were identified. The total medical service utilization decreased each year from a preindex average of 28.2 visits per patient per year (PPPY) to 26.9 visits (P <.05), 23.1 visits (P <.0001), and 22.5 visits (P <.0001) PPPY in years 1, 2, and 3 postdiagnosis, respectively. In each outpatient service category, the medical services utilization decreased from preindex to year 3 postdiagnosis, including hospital outpatient and physician visits (P <.0001), and other outpatient and emergency department visits (P <.05). The percentage of patients receiving narcolepsy-related medications increased from 54.0% preindex to 77.4%, 70.0%, and 66.9% for years 1, 2, and 3 postindex (all P <.0001 vs preindex

Clinical course of H1N1-vaccine-related narcolepsy.

PubMed

Sarkanen, Tomi; Alakuijala, Anniina; Partinen, Markku

2016-03-01

To follow and analyze the clinical course and quality of life of Pandemrix H1N1-vaccine-related narcolepsy (pNT1). Twenty-six drug-naïve confirmed pNT1 subjects completed Epworth Sleepiness Scale (ESS), Ullanlinna Narcolepsy Scale (UNS), Swiss Narcolepsy Scale (SNS), Rimon's Brief Depression scale (RDS), and WHO-5 Well-being index questionnaires near the disease onset and in a follow-up a minimum of two years later. The number of cataplexies and body mass index (BMI) were recorded. The effects of hypocretin-1 levels and sleep recording results were analyzed. The findings at the follow-up visit were compared with 25 non-vaccine-related type 1 narcolepsy (NT1) subjects. In pNT1, RDS score decreased significantly (mean 10.2, SD 4.7 vs mean 6.7, SD 4.5, p = 0.003). Median of BMI increased from 20.8 kg m(-2) to 23.4 kg m(-2), p <0.001. There were no significant differences in other sleep scores. However, deviation and range in questionnaire scores at the follow-up were wide. Subjects with very low or undetectable hypocretin-1 levels had worse scores in UNS (mean 26.4, SD 6.95 vs mean 19.1, SD 3.83, p = 0.006) and ESS (mean 17.9, SD = 4.29 vs mean 14.1, SD = 3.70, p = 0.047) than those with hypocretin-1 levels of 20-110 pg/mL. Most disabling symptoms were excessive daytime sleepiness and disturbed sleep. There were no significant differences between the scores in pNT1 and NT1. Clinical course of pNT1 is heterogeneous but the evolution of pNT1 seems similar to NT1. Lower hypocretin levels in pNT1 are associated with a more severe phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

Delayed Diagnosis, Range of Severity, and Multiple Sleep Comorbidities: A Clinical and Polysomnographic Analysis of 100 Patients of the Innsbruck Narcolepsy Cohort

PubMed Central

Frauscher, Birgit; Ehrmann, Laura; Mitterling, Thomas; Gabelia, David; Gschliesser, Viola; Brandauer, Elisabeth; Poewe, Werner; Högl, Birgit

2013-01-01

Study Objectives: Narcolepsy is reported to affect 26-56/100,000 in the general population. We aimed to describe clinical and polysomnographic features of a large narcolepsy cohort in order to comprehensively characterize the narcoleptic spectrum. Methods: We performed a chart- and polysomnographybased review of all narcolepsy patients of the Innsbruck narcolepsy cohort. Results: A total of 100 consecutive narcolepsy patients (87 with cataplexy [NC], 13 without cataplexy [N]) were included in the analysis. All subjects had either excessive daytime sleepiness or cataplexy as their initial presenting clinical feature. Age at symptom onset was 20 (6-69) years. Diagnostic delay was 6.5 (0-39) years. The complete narcolepsy tetrad was present in 36/100 patients; 28/100 patients had three cardinal symptoms; 29/100 had two; and 7/100 had only excessive daytime sleepiness. Severity varied broadly with respect to excessive daytime sleepiness (median Epworth Sleepiness Scale score: 18, range 10-24), cataplexy (8-point Likert scale: median 4.5, range 1-8), hypnagogic hallucinations (median 4.5, range 1-7), and sleep paralysis (median 3, range 1-7). Sleep comorbidity was highly prevalent and ranged from sleeprelated movement disorders (n = 55/100), parasomnias (n = 34/100), and sleeprelated breathing disorders (n = 24/100), to insomnia (n = 28/100). REM sleep without atonia or a periodic limb movement in sleep index > 5/h were present in most patients (90/100 and 75/100). A high percentage of narcoleptic patients in the present study had high frequency leg movements (35%) and excessive fragmentary myoclonus (22%). Of the narcolepsy patients with clinical features of REM sleep behavior disorder (RBD), 76.5% had EMG evidence for RBD on the multiple sleep latency test (MSLT), based on a standard cutoff of a minimum of 18% of 3-sec miniepochs. Conclusion: This study is one of the largest monocentric polysomnographic studies to date of patients with narcolepsy and confirms the

Associations Between Neuropsychological, Neurobehavioral and Emotional Functioning and Either Narcolepsy or Idiopathic Hypersomnia in Children and Adolescents.

PubMed

Ludwig, Beris; Smith, Simon; Heussler, Helen

2018-04-15

Narcolepsy and idiopathic hypersomnia are chronic neurological sleep disorders characterized by hypersomnolence or excessive daytime sleepiness. This review aims to systematically examine the scientific literature on the associations between narcolepsy and idiopathic hypersomnia and their effect on intellectual functioning, academic achievement, behavior, and emotion. Published studies that examined those associations in children and adolescents were included. Studies in which children or adolescents received a clinical diagnosis, and in which the associated function was measured with at least one objective instrument were included. Twenty studies published between 1968 and 2017 were eligible for inclusion in this review. There does not appear to be a clear association between intellectual functioning and narcolepsy or idiopathic hypersomnia; however, limited research is an obstacle to obtaining generalizability. The variability in results from studies investigating associations between academic achievement and these two hypersomnolence disorders suggests that further research using standardized and validated assessment instruments is required to determine if there is an association. Behavior and emotion appear to be significantly affected by narcolepsy. Only two studies included populations of children and adolescents with idiopathic hypersomnia. Further research using larger populations of children and adolescents with narcolepsy or idiopathic hypersomnia while utilizing standardized and validated instruments is required, because the effect of these conditions of hypersomnolence varies and is significant for each individual. © 2018 American Academy of Sleep Medicine.

The Prevalence and Characteristics of Primary Headache and Dream-Enacting Behaviour in Japanese Patients with Narcolepsy or Idiopathic Hypersomnia: A Multi-Centre Cross-Sectional Study.

PubMed

Suzuki, Keisuke; Miyamoto, Masayuki; Miyamoto, Tomoyuki; Inoue, Yuichi; Matsui, Kentaro; Nishida, Shingo; Hayashida, Kenichi; Usui, Akira; Ueki, Yoichiro; Nakamura, Masaki; Murata, Momoyo; Numao, Ayaka; Watanabe, Yuji; Suzuki, Shiho; Hirata, Koichi

2015-01-01

Because the prevalence and characteristics of primary headache have yet to be thoroughly studied in patients with hypersomnia disorders, including narcolepsy and idiopathic hypersomnia, we examined these parameters in the Japanese population. In a multicentre cross-sectional survey, among 576 consecutive outpatients with sleep disorders, 68 narcolepsy patients and 35 idiopathic hypersomnia patients were included. Additionally, 61 healthy control subjects participated. Semi-structured headache questionnaires were administered to all participants. The patients with narcolepsy (52.9%) and idiopathic hypersomnia (77.1%) more frequently experienced headache than the healthy controls (24.6%; p<0.0001). The prevalence rates were 23.5%, 41.2% and 4.9% for migraine (p<0.0001) and 16.2%, 23.5% and 14.8% (p = 0.58) for tension-type headache among the narcolepsy patients, the idiopathic hypersomnia patients and the control subjects, respectively. Those who experienced migraine more frequently experienced excessive daytime sleepiness, defined as an Epworth Sleepiness Scale score of ≥10, than those who did not experience headache among the patients with narcolepsy (93.8% vs. 65.6%, p = 0.040) and idiopathic hypersomnia (86.7% vs. 37.5%, p = 0.026). Dream-enacting behaviour (DEB), as evaluated by the rapid eye movement sleep disorders questionnaire, was more frequently observed in the narcolepsy patients than in the idiopathic hypersomnia patients and the control subjects. An increased DEB frequency was observed in the narcolepsy patients with migraines compared to those without headache. Migraines were frequently observed in patients with narcolepsy and idiopathic hypersomnia. DEB is a characteristic of narcolepsy patients. Further studies are required to assess the factors that contribute to migraines in narcolepsy and idiopathic hypersomnia patients.

HLA DQB1*06:02 Negative Narcolepsy with Hypocretin/Orexin Deficiency

PubMed Central

Han, Fang; Lin, Ling; Schormair, Barbara; Pizza, Fabio; Plazzi, Giuseppe; Ollila, Hanna M.; Nevsimalova, Sona; Jennum, Poul; Knudsen, Stine; Winkelmann, Juliane; Coquillard, Cristin; Babrzadeh, Farbod; Strom, Tim M.; Wang, Chunlin; Mindrinos, Michael; Vina, Marcelo Fernandez; Mignot, Emmanuel

2014-01-01

Study Objectives: To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02. Settings: China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University). Design: CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes. Measurements and Results: Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing. Conclusions: Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1

The effectiveness of high-flow regional cerebral perfusion in Norwood stage I palliation.

PubMed

Miyaji, Kagami; Miyamoto, Takashi; Kohira, Satoshi; Yoshii, Takeshi; Itatani, Kei-Ichi; Sato, Hajime; Inoue, Nobuyuki

2011-11-01

Regional cerebral perfusion (RCP) has been shown to provide cerebral circulatory support during Norwood procedure. In our institution, high-flow RCP (HFRCP) from the right innominate artery has been induced to keep sufficient cerebral and somatic oxygen delivery via collateral vessels. We studied the effectiveness of HFRCP to regional cerebral and somatic tissue oxygenation in Norwood stage I palliation. Seventeen patients, who underwent the Norwood procedure, were separated into two groups: group C (n=6) using low-flow RCP and group H (n=11) using HFRCP (mean flow: 54 vs 92mlkg(-1)min(-1), P<0.0001). The mean duration of RCP was 64±10min (range, 49-86min) under the moderate hypothermia. Chlorpromazine (3.0mgkg(-1)) was given to group H patients before and during RCP to increase RCP flow. The mean radial arterial pressure was kept <50mmHg during RCP. To clarify the effectiveness of HFRCP for cerebral and somatic tissue oxygenation, cerebral regional oxygen saturation (rSO(2)) and systemic venous oxygenation (SvO(2)) during RCP were compared between the two groups. Changes in the lactate level before and after RCP, and changes in the blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), and creatinine kinase (CK) levels before and after surgery, were also compared between the groups. Mean rSO(2) was 82.9±9.0% in group H and 65.9±10.7% in group C (P<0.05). Mean SvO(2) during RCP was 98.2±4.3% in group H and 85.4±9.7% in group C (P<0.01). During RCP, lactate concentration significantly increased in group C compared with that in group H (P<0.001). After surgery, the LDH and CK levels significantly increased in group C compared with that in group H (P<0.05). Our study revealed that HFRCP preserved sufficient cerebral and somatic tissue oxygenation during the Norwood procedure. The reduction of vascular resistance of collateral vessels increased both cerebral and somatic blood flow, resulting in improved tissue oxygen delivery. Copyright © 2011

Nocturnal Sleep Dynamics Identify Narcolepsy Type 1.

PubMed

Pizza, Fabio; Vandi, Stefano; Iloti, Martina; Franceschini, Christian; Liguori, Rocco; Mignot, Emmanuel; Plazzi, Giuseppe

2015-08-01

To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence. Cross-sectional. Sleep laboratory. One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and "subjective" hypersomnolence (sHS, n = 52). None. Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1. Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients showed the highest number of awakenings, sleep stage transitions, and more time spent in N1 sleep, as well as most SOREMPs at daytime PSG and at multiple sleep latency test (MSLT) than all other groups. ROC curve analysis showed that nocturnal SOREMP (area under the curve of 0.724 ± 0.041, P < 0.0001), percent of total sleep time spent in N1 (0.896 ± 0.023, P < 0.0001), and the wakefulness-sleep transition index (0.796 ± 0.034, P < 0.0001) had a good sensitivity and specificity profile to identify NT1 sleep, especially when used in combination (0.903 ± 0.023, P < 0.0001), similarly to SOREMP number at continuous daytime PSG (0.899 ± 0.026, P < 0.0001) and at MSLT (0.956 ± 0.015, P < 0.0001). Sleep macrostructure (i.e. SOREMP, N1 timing) including stage transitions reliably identifies hypocretin-deficient narcolepsy type 1 among central disorders of hypersomnolence. © 2015 Associated Professional Sleep Societies, LLC.

New developments in the management of narcolepsy

PubMed Central

Abad, Vivien C; Guilleminault, Christian

2017-01-01

Narcolepsy is a life-long, underrecognized sleep disorder that affects 0.02%–0.18% of the US and Western European populations. Genetic predisposition is suspected because of narcolepsy’s strong association with HLA DQB1*06-02, and genome-wide association studies have identified polymorphisms in T-cell receptor loci. Narcolepsy pathophysiology is linked to loss of signaling by hypocretin-producing neurons; an autoimmune etiology possibly triggered by some environmental agent may precipitate hypocretin neuronal loss. Current treatment modalities alleviate the main symptoms of excessive daytime somnolence (EDS) and cataplexy and, to a lesser extent, reduce nocturnal sleep disruption, hypnagogic hallucinations, and sleep paralysis. Sodium oxybate (SXB), a sodium salt of γ hydroxybutyric acid, is a first-line agent for cataplexy and EDS and may help sleep disruption, hypnagogic hallucinations, and sleep paralysis. Various antidepressant medications including norepinephrine serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants are second-line agents for treating cataplexy. In addition to SXB, modafinil and armodafinil are first-line agents to treat EDS. Second-line agents for EDS are stimulants such as methylphenidate and extended-release amphetamines. Emerging therapies include non-hypocretin-based therapy, hypocretin-based treatments, and immunotherapy to prevent hypocretin neuronal death. Non-hypocretin-based novel treatments for narcolepsy include pitolisant (BF2.649, tiprolisant); JZP-110 (ADX-N05) for EDS in adults; JZP 13-005 for children; JZP-386, a deuterated sodium oxybate oral suspension; FT 218 an extended-release formulation of SXB; and JNJ-17216498, a new formulation of modafinil. Clinical trials are investigating efficacy and safety of SXB, modafinil, and armodafinil in children. γ-amino butyric acid (GABA) modulation with GABAA receptor agonists clarithromycin and flumazenil may help daytime somnolence

Regional cerebral glucose metabolism in systemic lupus erythematosus patients with major depressive disorder.

PubMed

Saito, Tomoyuki; Tamura, Maasa; Chiba, Yuhei; Katsuse, Omi; Suda, Akira; Kamada, Ayuko; Ikura, Takahiro; Abe, Kie; Ogawa, Matsuyoshi; Minegishi, Kaoru; Yoshimi, Ryusuke; Kirino, Yohei; Ihata, Atsushi; Hirayasu, Yoshio

2017-08-15

Depression is frequently observed in patients with systemic lupus erythematosus (SLE). Neuropsychiatric SLE (NPSLE) patients often exhibit cerebral hypometabolism, but the association between cerebral metabolism and depression remains unclear. To elucidate the features of cerebral metabolism in SLE patients with depression, we performed brain 18F-fluoro-d-glucose positron emission tomography (FDG-PET) on SLE patients with and without major depressive disorder. We performed brain FDG-PET on 20 SLE subjects (5 male, 15 female). The subjects were divided into two groups: subjects with major depressive disorder (DSLE) and subjects without major depressive disorder (non-DSLE). Cerebral glucose metabolism was analyzed using the three-dimensional stereotactic surface projection (3D-SSP) program. Regional metabolism was evaluated by stereotactic extraction estimation (SEE), in which the whole brain was divided into segments. Every SLE subject exhibited cerebral hypometabolism, in contrast to the normal healthy subjects. Regional analysis revealed a significantly lower ER in the left medial frontal gyrus (p=0.0055) and the right medial frontal gyrus (p=0.0022) in the DSLE group than in the non-DSLE group. Hypometabolism in the medial frontal gyrus may be related to major depressive disorder in SLE. Larger studies are needed to clarify this relationship. Copyright © 2017 Elsevier B.V. All rights reserved.

Dynamic alteration of regional cerebral blood flow during carotid compression and proof of reversibility.

PubMed

Asahi, Kouichi; Hori, M; Hamasaki, N; Sato, S; Nakanishi, H; Kuwatsuru, R; Sasai, K; Aoki, S

2012-01-01

It is difficult to non-invasively visualize changes in regional cerebral blood flow caused by manual compression of the carotid artery. To visualize dynamic changes in regional cerebral blood flow during and after manual compression of the carotid artery. Two healthy volunteers were recruited. Anatomic features and flow directions in the circle of Willis were evaluated with time-of-flight magnetic resonance angiography (MRA) and two-dimensional phase-contrast (2DPC) MRA, respectively. Regional cerebral blood flow was visualized with territorial arterial spin-labeling magnetic resonance imaging (TASL-MRI). TASL-MRI and 2DPC-MRA were performed in three states: at rest, during manual compression of the right carotid artery, and after decompression. In one volunteer, time-space labeling inversion pulse (Time-SLIP) MRA was performed to confirm collateral flow. During manual carotid compression, in one volunteer, the right thalamus changed to be fed only by the vertebrobasilar system, and the right basal ganglia changed to be fed by the left internal carotid artery. In the other volunteer, the right basal ganglia changed to be fed by the vertebrobasilar system. 2DPC-MRA showed that the flow direction changed in the right A1 segment of the anterior cerebral artery and the right posterior communicating artery. Perfusion patterns and flow directions recovered after decompression. Time-SLIP MRA showed pial vessels and dural collateral circulation when the right carotid artery was manually compressed. Use of TASL-MRI and 2DPC-MRA was successful for non-invasive visualization of the dynamic changes in regional cerebral blood flow during and after manual carotid compression.

Hypocretin-1 Levels Associate with Fragmented Sleep in Patients with Narcolepsy Type 1.

PubMed

Alakuijala, Anniina; Sarkanen, Tomi; Partinen, Markku

2016-05-01

We aimed to analyze nocturnal sleep characteristics of patients with narcolepsy type 1 (narcolepsy with cataplexy) measured by actigraphy in respect to cerebrospinal fluid hypocretin-1 levels of the same patients. Actigraphy recording of 1-2 w and hypocretin-1 concentration analysis were done to thirty-six unmedicated patients, aged 7 to 63 y, 50% female. Twenty-six of them had hypocretin-1 levels under 30 pg/mL and the rest had levels of 31-79 pg/mL. According to actigraphy, patients with very low hypocretin levels had statistically significantly longer sleep latency (P = 0.033) and more fragmented sleep, indicated by both the number of immobile phases of 1 min (P = 0.020) and movement + fragmentation index (P = 0.049). There were no statistically significant differences in the actual sleep time or circadian rhythm parameters measured by actigraphy. Actigraphy gives additional information about the stabilization of sleep in patients with narcolepsy type 1. Very low hypocretin levels associate with more wake intruding into sleep. © 2016 Associated Professional Sleep Societies, LLC.

Increased Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1 Pandemic Vaccination Campaign in Finland

PubMed Central

Partinen, Markku; Saarenpää-Heikkilä, Outi; Ilveskoski, Ismo; Hublin, Christer; Linna, Miika; Olsén, Päivi; Nokelainen, Pekka; Alén, Reija; Wallden, Tiina; Espo, Merimaaria; Rusanen, Harri; Olme, Jan; Sätilä, Heli; Arikka, Harri; Kaipainen, Pekka; Julkunen, Ilkka; Kirjavainen, Turkka

2012-01-01

Background Narcolepsy is a rare neurological sleep disorder especially in children who are younger than 10 years. In the beginning of 2010, an exceptionally large number of Finnish children suffered from an abrupt onset of excessive daytime sleepiness (EDS) and cataplexy. Therefore, we carried out a systematic analysis of the incidence of narcolepsy in Finland between the years 2002–2010. Methods All Finnish hospitals and sleep clinics were contacted to find out the incidence of narcolepsy in 2010. The national hospital discharge register from 2002 to 2009 was used as a reference. Findings Altogether 335 cases (all ages) of narcolepsy were diagnosed in Finland during 2002–2009 giving an annual incidence of 0.79 per 100 000 inhabitants (95% confidence interval 0.62–0.96). The average annual incidence among subjects under 17 years of age was 0.31 (0.12–0.51) per 100 000 inhabitants. In 2010, 54 children under age 17 were diagnosed with narcolepsy (5.3/100 000; 17-fold increase). Among adults ≥20 years of age the incidence rate in 2010 was 0.87/100 000, which equals that in 2002–2009. Thirty-four of the 54 children were HLA-typed, and they were all positive for narcolepsy risk allele DQB1*0602/DRB1*15. 50/54 children had received Pandemrix vaccination 0 to 242 days (median 42) before onset. All 50 had EDS with abnormal multiple sleep latency test (sleep latency <8 min and ≥2 sleep onset REM periods). The symptoms started abruptly. Forty-seven (94%) had cataplexy, which started at the same time or soon after the onset of EDS. Psychiatric symptoms were common. Otherwise the clinical picture was similar to that described in childhood narcolepsy. Interpretation A sudden increase in the incidence of abrupt childhood narcolepsy was observed in Finland in 2010. We consider it likely that Pandemrix vaccination contributed, perhaps together with other environmental factors, to this increase in genetically susceptible children. PMID:22470463

The Prevalence and Characteristics of Primary Headache and Dream-Enacting Behaviour in Japanese Patients with Narcolepsy or Idiopathic Hypersomnia: A Multi-Centre Cross-Sectional Study

PubMed Central

Suzuki, Keisuke; Miyamoto, Masayuki; Miyamoto, Tomoyuki; Inoue, Yuichi; Matsui, Kentaro; Nishida, Shingo; Hayashida, Kenichi; Usui, Akira; Ueki, Yoichiro; Nakamura, Masaki; Murata, Momoyo; Numao, Ayaka; Watanabe, Yuji; Suzuki, Shiho; Hirata, Koichi

2015-01-01

Background Because the prevalence and characteristics of primary headache have yet to be thoroughly studied in patients with hypersomnia disorders, including narcolepsy and idiopathic hypersomnia, we examined these parameters in the Japanese population. Methods In a multicentre cross-sectional survey, among 576 consecutive outpatients with sleep disorders, 68 narcolepsy patients and 35 idiopathic hypersomnia patients were included. Additionally, 61 healthy control subjects participated. Semi-structured headache questionnaires were administered to all participants. Results The patients with narcolepsy (52.9%) and idiopathic hypersomnia (77.1%) more frequently experienced headache than the healthy controls (24.6%; p<0.0001). The prevalence rates were 23.5%, 41.2% and 4.9% for migraine (p<0.0001) and 16.2%, 23.5% and 14.8% (p = 0.58) for tension-type headache among the narcolepsy patients, the idiopathic hypersomnia patients and the control subjects, respectively. Those who experienced migraine more frequently experienced excessive daytime sleepiness, defined as an Epworth Sleepiness Scale score of ≥10, than those who did not experience headache among the patients with narcolepsy (93.8% vs. 65.6%, p = 0.040) and idiopathic hypersomnia (86.7% vs. 37.5%, p = 0.026). Dream-enacting behaviour (DEB), as evaluated by the rapid eye movement sleep disorders questionnaire, was more frequently observed in the narcolepsy patients than in the idiopathic hypersomnia patients and the control subjects. An increased DEB frequency was observed in the narcolepsy patients with migraines compared to those without headache. Conclusions Migraines were frequently observed in patients with narcolepsy and idiopathic hypersomnia. DEB is a characteristic of narcolepsy patients. Further studies are required to assess the factors that contribute to migraines in narcolepsy and idiopathic hypersomnia patients. PMID:26418536

The Safety of Adjuvanted Vaccines Revisited: Vaccine-Induced Narcolepsy.

PubMed

Ahmed, S Sohail; Montomoli, Emanuele; Pasini, Franco Laghi; Steinman, Lawrence

2016-01-01

Despite the very high benefit-to-risk ratio of vaccines, the fear of negative side effects has discouraged many people from getting vaccinated, resulting in the reemergence of previously controlled diseases such as measles, pertussis and diphtheria. This fear has been amplified more recently by multiple epidemiologic studies that confirmed the link of an AS03-adjuvanted pandemic influenza vaccine (Pandemrix, GlaxoSmithKline Biologicals, Germany) used in Europe during the 2009 H1N1 influenza pandemic [A(H1N1) pdm09] with the development of narcolepsy, a chronic sleep disorder, in children and adolescents. However, public misperceptions of what adjuvants are and why they are used in vaccines has created in some individuals a closed "black box" attitude towards all vaccines. The focus of this review article is to revisit this "black box" using the example of narcolepsy associated with the European AS03-adjuvanted pandemic influenza vaccine.

AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery.

PubMed

Subudhi, Andrew W; Fan, Jui-Lin; Evero, Oghenero; Bourdillon, Nicolas; Kayser, Bengt; Julian, Colleen G; Lovering, Andrew T; Roach, Robert C

2014-05-01

Cerebral hypoxaemia associated with rapid ascent to high altitude can be life threatening; yet, with proper acclimatization, cerebral function can be maintained well enough for humans to thrive. We investigated adjustments in global and regional cerebral oxygen delivery (DO2) as 21 healthy volunteers rapidly ascended and acclimatized to 5260 m. Ultrasound indices of cerebral blood flow in internal carotid and vertebral arteries were measured at sea level, upon arrival at 5260 m (ALT1; atmospheric pressure 409 mmHg) and after 16 days of acclimatization (ALT16). Cerebral DO2 was calculated as the product of arterial oxygen content and flow in each respective artery and summed to estimate global cerebral blood flow. Vascular resistances were calculated as the quotient of mean arterial pressure and respective flows. Global cerebral blood flow increased by ∼70% upon arrival at ALT1 (P < 0.001) and returned to sea-level values at ALT16 as a result of changes in cerebral vascular resistance. A reciprocal pattern in arterial oxygen content maintained global cerebral DO2 throughout acclimatization, although DO2 to the posterior cerebral circulation was increased by ∼25% at ALT1 (P = 0.032). We conclude that cerebral DO2 is well maintained upon acute exposure and acclimatization to hypoxia, particularly in the posterior and inferior regions of the brain associated with vital homeostatic functions. This tight regulation of cerebral DO2 was achieved through integrated adjustments in local vascular resistances to alter cerebral perfusion during both acute and chronic exposure to hypoxia. © 2013 The Authors. Experimental Physiology © 2013 The Physiological Society.

CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1.

PubMed

Ramberger, Melanie; Högl, Birgit; Stefani, Ambra; Mitterling, Thomas; Reindl, Markus; Lutterotti, Andreas

2017-03-01

Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease. We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte-macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3+CD4+ T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools. Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4+ T-cell proliferation (p = .2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope. A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4+ T cells and possible target antigens in narcolepsy type 1 patients. © Sleep Research Society 2016. Published by Oxford University Press [on behalf of the Sleep Research Society].

Medical exposures in youth and the frequency of narcolepsy with cataplexy: a population-based case-control study in genetically predisposed people

PubMed Central

Koepsell, Thomas D.; Longstreth, William T.; Ton, Thanh G. N.

2012-01-01

SUMMARY Epidemiological observations suggest that exposures in youth may trigger narcolepsy in genetically predisposed individuals. In this population-based case–control study, we sought to identify all prevalent cases of narcolepsy with cataplexy aged 18–50 years as of 1 July 2001, in King County, Washington. The 45 eligible cases who were DQB1*0602-positive were compared with 95 controls with this allele, identified through random-digit dialing and buccal smears. Cases and controls were interviewed in person about physician-diagnosed infectious and non-infectious illnesses, immunizations, head trauma and parasomnias or psychiatric problems during youth. Narcolepsy with cataplexy was more frequent in African-Americans and in poorer households. Adjusting for these factors, the condition was 5.4-fold more common [95% confidence interval (CI) = 1.5–19.1] among people reporting a physician-diagnosed strep throat before the age of 21 years. No other significant associations with childhood diseases, immunizations or head trauma were found. However, prevalence was increased 16.3-fold (95% CI = 6.1–44.1) in subjects who reported having had ‘night terrors’. Strep throat may be related to narcolepsy with cataplexy in genetically susceptible individuals. The association with night terrors could simply reflect early symptoms of narcolepsy, or they could be a prodromal sign of disturbed sleep physiology. keywords epidemiology, head injuries, immunization, narcolepsy, night terrors, streptococcal infections PMID:19732319

Paraneoplastic limbic encephalitis and possible narcolepsy in a patient with testicular cancer: case study.

PubMed Central

Landolfi, Joseph C.; Nadkarni, Mangala

2003-01-01

We describe a patient who presented with a clinical syndrome of limbic encephalitis, narcolepsy, and cataplexy. The anti-Ma2 antibody was positive. Although there was no mass on imaging, orchiectomy was performed in this patient, and testicular carcinoma was found. This is the first known case of limbic encephalitis and anti-Ma2 antibody to be associated with cataplexy and possible narcolepsy. Neurological symptoms precede the diagnosis of cancer in 50% of patients with paraneoplastic syndromes, and clinicians are therefore strongly advised to evaluate patients with neurological symptoms for this condition. PMID:12816728

Usefulness of a Nocturnal SOREMP for Diagnosing Narcolepsy with Cataplexy in a Pediatric Population

PubMed Central

Reiter, Joel; Katz, Eliot; Scammell, Thomas E.; Maski, Kiran

2015-01-01

Study Objectives: We investigated the diagnostic accuracy of a nocturnal sleep onset rapid eye movement sleep period (nSOREMP) for the identification of narcolepsy with cataplexy (N+C) among children and adolescents referred to the sleep laboratory for an overnight polysomnography (PSG) and multiple sleep latency test (MSLT). Design: Retrospective chart review of sleep clinic notes and PSG and MSLT reports. Setting: Boston Children's Hospital sleep laboratory and outpatient clinics. Patients: All patients 6–18 y old, referred for consecutive PSG and MSLT for the evaluation of central hypersomnias, between January 2005 and January 2014. Measurements and Results: We analyzed the records of 148 patients and established diagnostic categories using the International Classification of Sleep Disorders, 2nd Edition. Patient diagnoses included narcolepsy with cataplexy (28.4%), narcolepsy without cataplexy (8.1%), other hypersomnia conditions (9.5%), delayed sleep phase syndrome (12.2%), behaviorally induced insufficient sleep syndrome (4.1%), other sleep disorders (obstructive sleep apnea, periodic limb movements of sleep; 6.8%), isolated cataplexy (2%), and various diagnoses (29.1%). There were 54.8% of the N+C patients who had an nSOREMP, but only 2.4% of all other patients had an nSOREMP. The specificity of an nSOREMP for detection of N+C was high at 97.3% (95% confidence interval [CI]: 92.2–99.4%), but the sensitivity was moderate at 54.8% (95% CI: 38.7–70.2%). Overall, the positive predictive value of an nSOREMP for the diagnosis of N+C was 88.5% (95% CI: 69.8–97.4%). Conclusions: In children, the presence of an nocturnal sleep onset rapid eye movement sleep period is highly suggestive of narcolepsy with cataplexy and provides further evidence of rapid eye movement sleep dysregulation in this condition. Citation: Reiter J, Katz E, Scammell TE, Maski K. Usefulness of a nocturnal SOREMP for diagnosing narcolepsy with cataplexy in a pediatric population. SLEEP

The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality.

PubMed

Ruoff, Chad; Rye, David

2016-07-20

Narcolepsy is a chronic neurological disease manifesting as difficulty with maintaining continuous wake and sleep. Clinical presentation varies but requires excessive daytime sleepiness (EDS) occurring alone or together with features of rapid-eye movement (REM) sleep dissociation (e.g., cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis), and disrupted nighttime sleep. Narcolepsy with cataplexy is associated with reductions of cerebrospinal fluid (CSF) hypocretin due to destruction of hypocretin peptide-producing neurons in the hypothalamus in individuals with a specific genetic predisposition. Updated diagnostic criteria include the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) and International Classification of Sleep Disorders Third Edition (ICSD-3). DSM-5 criteria require EDS in association with any one of the following: (1) cataplexy; (2) CSF hypocretin deficiency; (3) REM sleep latency ≤15 minutes on nocturnal polysomnography (PSG); or (4) mean sleep latency ≤8 minutes on multiple sleep latency testing (MSLT) with ≥2 sleep-onset REM-sleep periods (SOREMPs). ICSD-3 relies more upon objective data in addition to EDS, somewhat complicating the diagnostic criteria: 1) cataplexy and either positive MSLT/PSG findings or CSF hypocretin deficiency; (2) MSLT criteria similar to DSM-5 except that a SOREMP on PSG may count as one of the SOREMPs required on MSLT; and (3) distinct division of narcolepsy into type 1, which requires the presence of cataplexy or documented CSF hypocretin deficiency, and type 2, where cataplexy is absent, and CSF hypocretin levels are either normal or undocumented. We discuss limitations of these criteria such as variability in clinical presentation of cataplexy, particularly when cataplexy may be ambiguous, as well as by age; multiple and/or invasive CSF diagnostic test requirements; and lack of normative diagnostic test data (e.g., MSLT) in certain populations. While ICSD-3 criteria

Use of PCR with Sequence-specific Primers for High-Resolution Human Leukocyte Antigen Typing of Patients with Narcolepsy

PubMed Central

Woo, Hye In; Joo, Eun Yeon; Lee, Kyung Wha

2012-01-01

Background Narcolepsy is a neurologic disorder characterized by excessive daytime sleepiness, symptoms of abnormal rapid eye movement (REM) sleep, and a strong association with HLA-DRB1*1501, -DQA1*0102, and -DQB1*0602. Here, we investigated the clinico-physical characteristics of Korean patients with narcolepsy, their HLA types, and the clinical utility of high-resolution PCR with sequence-specific primers (PCR-SSP) as a simple typing method for identifying DRB1*15/16, DQA1, and DQB1 alleles. Methods The study population consisted of 67 consecutively enrolled patients having unexplained daytime sleepiness and diagnosed narcolepsy based on clinical and neurological findings. Clinical data and the results of the multiple sleep latency test and polysomnography were reviewed, and HLA typing was performed using both high-resolution PCR-SSP and sequence-based typing (SBT). Results The 44 narcolepsy patients with cataplexy displayed significantly higher frequencies of DRB1*1501 (Pc= 0.003), DQA1*0102 (Pc=0.001), and DQB1*0602 (Pc=0.014) than the patients without cataplexy. Among patients carrying DRB1*1501-DQB1*0602 or DQA1*0102, the frequencies of a mean REM sleep latency of less than 20 min in nocturnal polysomnography and clinical findings, including sleep paralysis and hypnagogic hallucination were significantly higher. SBT and PCR-SSP showed 100% concordance for high-resolution typing of DRB1*15/16 alleles and DQA1 and DQB1 loci. Conclusions The clinical characteristics and somnographic findings of narcolepsy patients were associated with specific HLA alleles, including DRB1*1501, DQA1*0102, and DQB1*0602. Application of high-resolution PCR-SSP, a reliable and simple method, for both allele- and locus-specific HLA typing of DRB1*15/16, DQA1, and DQB1 would be useful for characterizing clinical status among subjects with narcolepsy. PMID:22259780

Chronic Stress Modulates Regional Cerebral Glucose Transporter Expression in an Age-Specific and Sexually-Dimorphic Manner

PubMed Central

Kelly, Sean D.; Harrell, Constance S.; Neigh, Gretchen N.

2014-01-01

Facilitative glucose transporters (GLUT) mediate glucose uptake across the blood-brain-barrier into neurons and glia. Deficits in specific cerebral GLUT isoforms are linked to developmental and neurological dysfunction, but less is known about the range of variation in cerebral GLUT expression in normal conditions and the effects of environmental influences on cerebral GLUT expression. Knowing that puberty is a time of increased cerebral plasticity, metabolic demand, and shifts in hormonal balance for males and females, we first assessed gene expression of five GLUT subtypes in four brain regions in male and female adolescent and adult Wistar rats. The data indicated that sex differences in GLUT expression were most profound in the hypothalamus, and the transition from adolescence to adulthood had the most profound effect on GLUT expression in the hippocampus. Next, given the substantial energetic demands during adolescence and prior demonstrations of the adverse effects of adolescent stress, we determined the extent to which chronic stress altered GLUT expression in males and females in both adolescence and adulthood. Chronic stress significantly altered cerebral GLUT expression in males and females throughout both developmental stages but in a sexually dimorphic and brain region-specific manner. Collectively, our data demonstrate that cerebral GLUTs are expressed differentially based on brain region, sex, age, and stress exposure. These results suggest that developmental and environmental factors influence GLUT expression in multiple brain regions. Given the importance of appropriate metabolic balance within the brain, further assessment of the functional implications of life stage and environmentally-induced changes in GLUTs are warranted. PMID:24382486

Low regional cerebral blood flow in burning mouth syndrome patients with depression.

PubMed

Liu, B-L; Yao, H; Zheng, X-J; Du, G-H; Shen, X-M; Zhou, Y-M; Tang, G-Y

2015-07-01

The main aims of this study were to (i) investigate the emotional disorder status of patients with burning mouth syndrome (BMS) and (ii) detect regional cerebral blood flow in BMS patients with the application of combined single-photon emission computed tomography and computed tomography (SPECT/CT). The degree of pain was measured using the visual analysis scale, and emotional disorder with the self-rating anxiety scale, self-rating depression scale, and Hamilton depression rating scale in 29 patients with BMS and 10 healthy controls. SPECT/CT was performed in 29 patients with BMS and 10 healthy controls, and statistical parametric mapping method was used for between-group analyses. The incidence rate of depression in patients with BMS was 31.0%. Compared to the control group, patients with BMS displayed significantly different depression and anxiety scales (P < 0.05). Significantly lower regional cerebral blood flow in the left parietal and left temporal lobes was recorded for BMS patients with depression (P < 0.05). Patients with BMS experience more depression and anxious emotion. Moreover, depression in patients with BMS may be associated with lower regional cerebral blood flow in the left temporal and left parietal lobes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of Oral L-Carnitine Administration in Narcolepsy Patients: A Randomized, Double-Blind, Cross-Over and Placebo-Controlled Trial

PubMed Central

Miyagawa, Taku; Kawamura, Hiromi; Obuchi, Mariko; Ikesaki, Asuka; Ozaki, Akiko; Tokunaga, Katsushi; Inoue, Yuichi; Honda, Makoto

2013-01-01

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in β-oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral l-carnitine for the treatment of narcolepsy, we performed a clinical trial administering l-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). l-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. l-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality and mental health subscales did not reach statistical significance between l-carnitine and placebo. This study suggests that oral l-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients. Trial Registration University hospital Medical Information Network (UMIN) UMIN000003760 PMID:23349733

Decreased Regional Cerebral Perfusion in Moderate-Severe Obstructive Sleep Apnoea during Wakefulness.

PubMed

Innes, Carrie R H; Kelly, Paul T; Hlavac, Michael; Melzer, Tracy R; Jones, Richard D

2015-05-01

To investigate gray matter volume and concentration and cerebral perfusion in people with untreated obstructive sleep apnea (OSA) while awake. Voxel-based morphometry to quantify gray matter concentration and volume. Arterial spin labeling perfusion imaging to quantify cerebral perfusion. Lying supine in a 3-T magnetic resonance imaging scanner in the early afternoon. 19 people with OSA (6 females, 13 males; mean age 56.7 y, range 41-70; mean AHI 18.5, range 5.2-52.8) and 19 controls (13 females, 6 males; mean age: 50.0 y, range 41-81). N/A. There were no differences in regional gray matter concentration or volume between participants with OSA and controls. Neither was there any difference in regional perfusion between controls and people with mild OSA (n = 11). However, compared to controls, participants with moderate-severe OSA (n = 8) had decreased perfusion (while awake) in three clusters. The largest cluster incorporated, bilaterally, the paracingulate gyrus, anterior cingulate gyrus, and subcallosal cortex, and the left putamen and left frontal orbital cortex. The second cluster was right-lateralized, incorporating the posterior temporal fusiform cortex, parahippocampal gyrus, and hippocampus. The third cluster was located in the right thalamus. There is decreased regional perfusion during wakefulness in participants with moderate-severe obstructive sleep apnea, and these are in brain regions which have shown decreased regional gray matter volume in previous studies in people with severe OSA. Thus, we hypothesize that cerebral perfusion changes are evident before (and possibly underlie) future structural changes. © 2015 Associated Professional Sleep Societies, LLC.

Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up.

PubMed

Persson, I; Granath, F; Askling, J; Ludvigsson, J F; Olsson, T; Feltelius, N

2014-02-01

To investigate the association between vaccination with Pandemrix and risk of selected neurological and immune-related diseases including narcolepsy. Population-based prospective cohort study using data from regional vaccination registries and national health registries. Seven healthcare regions in Sweden comprising 61% of the Swedish population. Study population of 3,347,467 vaccinated and 2,497,572 nonvaccinated individuals (vaccination coverage ≈ 60%) followed between 2009 and 2011 for 6.9 million person-years after exposure and 6.0 million person-years without exposure. First recorded diagnosis of neurological and immune-related diseases. Relative risks [hazard ratios (HRs) with 95% confidence intervals (CIs)] assessed using Cox regression, adjusted for covariates. For all selected neurological and immune-related outcomes under study, other than allergic vaccine reactions (for which we verified an expected increase in risk) and narcolepsy, HRs were close to 1.0 and always below 1.3. We observed a three-fold increased risk of a diagnosis of narcolepsy (HR: 2.92, 95% CI: 1.78-4.79; that is, four additional cases per 100,000 person-years) in individuals ≤ 20 years of age at vaccination and a two-fold increase (HR: 2.18, 95% CI: 1.00-4.75) amongst young adults between 21 and 30 years of age. The excess risk declined successively with increasing age at vaccination; no increase in risk was seen after 40 years of age. For a large number of selected neurological and immune-related diseases, we could neither confirm any causal association with Pandemrix nor refute entirely a small excess risk. We confirmed an increased risk for a diagnosis of narcolepsy in individuals ≤ 20 years of age and observed a trend towards an increased risk also amongst young adults between 21 and 30 years. © 2013 The Association for the Publication of the Journal of Internal Medicine.

Potentiation of a functional autoantibody in narcolepsy by a cholinesterase inhibitor.

PubMed

Jackson, Michael W; Spencer, Nicolas J; Reed, Joanne H; Smith, Anthony J F; Gordon, Tom P

2009-12-01

We have recently reported the presence of an immunoglobulin G (IgG) autoantibody (Ab) in patients with narcolepsy with cataplexy that abolishes spontaneous colonic migrating motor complexes (CMMCs) and increases smooth muscle tension and atropine-sensitive phasic contractions in a physiological assay of an isolated colon. In this study, we used the cholinesterase inhibitor, neostigmine, to explore the mechanism of the narcoleptic IgG-mediated disruption of enteric motor function in four patients with narcolepsy with cataplexy and to identify a pharmacological mimic of the Ab. Neostigmine potentiated the narcoleptic IgG-mediated increase in smooth muscle resting tension and phasic smooth muscle contractions by an atropine-sensitive mechanism but exerted no effect on resting tension in the presence of control IgG. Decreased frequency of CMMCs mediated by IgG with anti-M3R activity was reversed by neostigmine. Therefore, a challenge with a cholinesterase inhibitor improves the specificity of the CMMC assay for narcoleptic IgG. Tetrodotoxin (TTX), a neuronal sodium channel blocker, also abolished CMMCs and increased resting tone, and a similar potentiation was observed with neostigmine; thus, TTX is a mimic of the functional effects of the narcoleptic IgG in this bioassay. These findings provide a link to pharmacological studies of canine narcolepsy and are consistent with a functional blockade of both excitatory and inhibitory motor neurons by the narcoleptic Ab, similar to the TTX mimic, presumably by binding to an autoantigenic target expressed in both populations of neurons.

Determinants of inclusive education of 8-12 year-old children with cerebral palsy in 9 European regions.

PubMed

Sentenac, Mariane; Ehlinger, Virginie; Michelsen, Susan Ishoy; Marcelli, Marco; Dickinson, Heather Olivia; Arnaud, Catherine

2013-01-01

The principle of inclusive education has been increasingly recognised over recent decades and most countries officially support schooling of children with disabilities in mainstream settings. The SPARCLE study offers the opportunity to report on the schooling practices for children with cerebral palsy according to the nature and severity of their impairments and the schooling policy in European regions. The aim of this paper is to describe the type of schooling of children with cerebral palsy in various European regions after controlling for relevant individual factors. Children aged 8-12 years with cerebral palsy from 9 European regions and their families were interviewed. Our findings support the hypothesis that between-region variations in the type of schooling are still significant after adjustment for individual factors; and that motor function and intellectual ability have different effects on inclusion in mainstream school, depending on the region. Copyright © 2012 Elsevier Ltd. All rights reserved.

Environmental factors in the development of narcolepsy with cataplexy. A case-control study.

PubMed

Peraita-Adrados, R; del Rio-Villegas, R; Vela-Bueno, A

2015-06-16

Epidemiological studies suggest the importance of environmental factors in the etiology of narcolepsy-cataplexy in genetically predisposed subjects. To assess the role of environmental factors in the development of narcolepsy-cataplexy, using a case-control design with control subjects being matched for ethnicity and age. All patients were recruited through two outpatient clinics at the community of Madrid, ant the diagnosis of narcolepsy fulfilled the criteria of the International Classification on Sleep Disorders-2005. A questionnaire, including 54 environmental psychological stressor life events and 42 infectious diseases items, was administered to 54 patients. We specifically assessed the stressful factors and infectious diseases that occurred in the year preceding the onset of the first symptom of narcolepsy (excessive daytime sleepiness and/or cataplexy). The same questionnaire was administered to 84 control subjects recruited from non-related family members of the same community. Fifty four patients (55.6% males) answered the questionnaire, The mean age at onset of the first symptom was 21.6 ± 9.3 years, and the mean age at diagnosis was 36.5 ± 12.4 years. The main finding in narcoleptic patients as compared to control subjects was major changes in the 'number of arguments with partner, family, or friends' (odds ratio: 5.2; 95% confidence interval: 1.8-14.5). This can be interpreted as having a protective function and it suggests that psychological mechanisms are present since the beginning of the disease. As for the infectious factors, chickenpox was the most frequently reported. No significant differences were found in terms of total numbers of stress-related and infectious factors between cases and controls. Prospective studies regarding the interaction between environmental and genetic factors are warranted.

Diagnostic delay in narcolepsy type 1: combining the patients' and the doctors' perspectives.

PubMed

Taddei, Raquel N; Werth, Esther; Poryazova, Rositsa; Baumann, Christian R; Valko, Philipp O

2016-12-01

Narcolepsy type 1 is a neurological disorder characterized by a unique syndrome, including the pathognomonic symptom of cataplexy. The diagnosis can be confirmed by objective measures, such as typical findings in the multiple sleep latency test, reduced or undetectable levels of orexin (hypocretin) in the cerebrospinal fluid, and linkage to a specific HLA haplotype. Nevertheless, the mean time that elapses from symptom onset to the correct diagnosis ranges between 10 and 20 years, and the causes and correlates of this delay are poorly understood. Diagnostic delay was assessed on 52 well-defined patients with narcolepsy type 1, evaluating clinical, electrophysiological and neurochemical parameters and the results of a 41-item questionnaire developed to obtain the patients' perspective on various aspects of the diagnostic process. The mean time gap between disease onset and first medical consultation was 3.2 ± 5.1 years; the mean diagnostic delay was 8.9 ± 11.0 years. Prior to correct diagnosis, patients received a wide variety of misdiagnoses. The self-ratings of the patients revealed that the undiagnosed symptoms caused high levels of anxiety and unjustified criticism by family, friends and employers. Multiple regression analysis identified higher cerebrospinal fluid orexin levels (β = 0.311, P = 0.01), and a longer interval between the onset of excessive daytime sleepiness and cataplexy (β = 0.368, P = 0.002) as independent associates of longer diagnostic delay. The diagnostic delay decreased over the last decades (β = -0.672, P < 0.001). In conclusion, delayed diagnosis of narcolepsy type 1 is very common, associated with many adverse consequences, and requires educational efforts to improve awareness on narcolepsy among healthcare providers and the general population. © 2016 European Sleep Research Society.

Effects of blockade of cerebral lymphatic drainage on regional cerebral blood flow and brain edema after subarachnoid hemorrhage.

PubMed

Sun, Bao-Liang; Xia, Zuo-Li; Wang, Jing-Ru; Yuan, Hui; Li, Wen-Xia; Chen, Yu-She; Yang, Ming-Feng; Zhang, Su-Ming

2006-01-01

The study was designed to observe the influence of blockade of cerebral lymphatic drainage on the regional cerebral blood flow (rCBF) and brain edema after experimental subarachnoid hemorrhage (SAH). Wistar rats were divided into non-SAH, SAH, and SAH plus cervical lymphatic blockade (SAH + CLB) groups. Autologous arterial hemolysate was injected into rat's cisterna magna to induce SAH. The rCBF was recorded continuously by a laser Doppler flowmeter. Intracranial pressure (ICP) was also monitored. After 24 hours and 72 hours of SAH, the rats were sacrificed and the brain was harvested for water content detection. It was found that there was no obvious change of rCBF and brain water content during the experiment in non-SAH group. An immediate and persistent drop in rCBF was found in SAH group. The drop in rCBF was more obvious in SAH + CLB group. CLB also worsened the SAH-induced increase in ICP. The brain water content 24 hours and 72 hours after induction of SAH in SAH group increased significantly. CLB led to a further increase of brain water content. In conclusion, blockade of cerebral lymphatic drainage pathway deteriorates the secondary cerebral ischemia and brain edema after SAH.

Narcolepsy (with and without cataplexy) and commercial motor vehicle driver safety.

DOT National Transportation Integrated Search

2009-10-01

The purpose of this evidence report is to address several questions posed by FMCSA regarding the topic of narcolepsy and commercial motor vehicle (CMV) driver safety. In the early scope development work conducted by the Agency and the Medical Review ...

Identification of the variations in the CPT1B and CHKB genes along with the HLA-DQB1*06:02 allele in Turkish narcolepsy patients and healthy persons.

PubMed

Cingoz, Sultan; Agilkaya, Sinem; Oztura, Ibrahim; Eroglu, Secil; Karadeniz, Derya; Evlice, Ahmet; Altungoz, Oguz; Yilmaz, Hikmet; Baklan, Baris

2014-04-01

The HLA-DQB1*06:02 allele across all ethnic groups and the rs5770917 variation between CPT1B and CHKB genes in Japanese and Koreans are common genetic susceptibility factors for narcolepsy. This comprehensive genetic study sought to assess variations in CHKB and CPT1B susceptibility genes and HLA-DQB1*06:02 allele status in Turkish patients with narcolepsy and healthy persons. CHKB/CPT1B genes were sequenced in patients with narcolepsy (n=37) and healthy persons (n=100) to detect variations. The HLA-DQB1*06:02 allele status was determined by sequence specific polymerase chain reaction. The HLA-DQB1*06:02 allele was significantly more frequent in narcoleptic patients than in healthy persons (p=2×10(-7)) and in patients with narcolepsy and cataplexy than in those without (p=0.018). The mean of the multiple sleep latency test, sleep-onset rapid eye movement periods, and frequency of sleep paralysis significantly differed in the HLA-DQB1*06:02-positive patients. rs5770917, rs5770911, rs2269381, and rs2269382 were detected together as a haplotype in three patients and 11 healthy persons. In addition to this haplotype, the indel variation (rs144647670) was detected in the 5' upstream region of the human CHKB gene in the patients and healthy persons carrying four variants together. This study identified a novel haplotype consisting of the indel variation, which had not been detected in previous studies in Japanese and Korean populations, and observed four single-nucleotide polymorphisms in CHKB/CPT1B. The study confirmed the association of the HLA-DQB1*06:02 allele with narcolepsy and cataplexy susceptibility. The findings suggest that the presence of HLA-DQB1*06:02 may be a predictor of cataplexy in narcoleptic patients and could therefore be used as an additional diagnostic marker alongside hypocretin.

Impact of Methamphetamine on Regional Metabolism and Cerebral Blood Flow after Traumatic Brain Injury

PubMed Central

O'Phelan, Kristine; Ernst, Thomas; Park, Dalnam; Stenger, Andrew; Denny, Katherine; Green, Deborah; Chang, Cherylee; Chang, Linda

2014-01-01

Substance abuse is a frequent comorbid condition among patients with Traumatic Brain Injury (TBI), but little is known about its potential additive or interactive effects on tissue injury or recovery from TBI. This study aims to evaluate changes in regional metabolism and cerebral perfusion in subjects who used methamphetamine(METH) prior to sustaining a TBI. We hypothesized that METH use would decrease pericontusional cerebral perfusion and markers of neuronal metabolism, in TBI patients compared to those without METH use. Methods This is a single center prospective observational study. Adults with moderate and severe TBI were included. MRI scanning was performed on a 3 Tesla scanner. MP-RAGE and FLAIR sequences as well as Metabolite spectra of NAA and lactate in pericontusional and contralateral voxels identified on the MP-RAGE scans. A spiral-based FAIR sequence was used for the acquisition of cerebral blood flow (CBF) maps. Regional CBF images were analyzed using Image J open source software. Pericontusional and contralateral CBF, NAA and lactate were assessed in the entire cohort and in the METH and non-METH groups. Results 17 subjects completed the MR studies. Analysis of entire cohort: Pericontusional NAA concentrations (5.81 ± 2.0 mM/kg) were 12% lower compared to the contralateral NAA (6.98 ± 1.2 mM/kg; p=0.03). Lactate concentrations and CBF were not significantly different between the two regions, however, regional cerebral blood flow was equally reduced in the two regions. Subgroup analysis: 41% of subjects tested positive for METH. The mean age, Glasgow Coma Scale and time to scan did not differ between groups. The two subject groups also had similar regional NAA and lactate. Pericontusional CBF was 60% lower in the METH users than the non-users, p=0.04; contralateral CBF did not differ between the groups. Conclusion This small study demonstrates that tissue metabolism is regionally heterogeneous after TBI and pericontusional perfusion was

Retrospective multicenter matched case-control study on the risk factors for narcolepsy with special focus on vaccinations (including pandemic influenza vaccination) and infections in Germany.

PubMed

Oberle, Doris; Pavel, Jutta; Mayer, Geert; Geisler, Peter; Keller-Stanislawski, Brigitte

2017-06-01

Studies associate pandemic influenza vaccination with narcolepsy. In Germany, a retrospective, multicenter, matched case-control study was performed to identify risk factors for narcolepsy, particularly regarding vaccinations (seasonal and pandemic influenza vaccination) and infections (seasonal and pandemic influenza) and to quantify the detected risks. Patients with excessive daytime sleepiness who had been referred to a sleep center between April 2009 and December 2012 for multiple sleep latency test (MSLT) were eligible. Case report forms were validated according to the criteria for narcolepsy defined by the Brighton Collaboration (BC). Confirmed cases of narcolepsy (BC level of diagnostic certainty 1-4a) were matched with population-based controls by year of birth, gender, and place of residence. A second control group was established including patients in whom narcolepsy was definitely excluded (test-negative controls). A total of 103 validated cases of narcolepsy were matched with 264 population-based controls. The second control group included 29 test-negative controls. A significantly increased odd ratio (OR) to develop narcolepsy (crude OR [cOR] = 3.9, 95% confidence interval [CI] = 1.8-8.5; adjusted OR [aOR] = 4.5, 95% CI = 2.0-9.9) was detected in individuals immunized with pandemic influenza A/H1N1/v vaccine prior to symptoms onset as compared to nonvaccinated individuals. Using test-negative controls, in individuals immunized with pandemic influenza A/H1N1/v vaccine prior to symptoms onset, a nonsignificantly increased OR of narcolepsy was detected when compared to nonvaccinated individuals (whole study population, BC levels 1-4a: cOR = 1.9, 95% CI = 0.5-6.9; aOR = 1.8, 95% CI = 0.3-10.1). The findings of this study support an increased risk for narcolepsy after immunization with pandemic influenza A/H1N1/v vaccine. Copyright © 2017 Elsevier B.V. All rights reserved.

[Clinical effect of atomoxetine hydrochloride in 66 children with narcolepsy].

PubMed

Zhang, Shen; Ding, Changhong; Wu, Husheng; Fang, Fang; Wang, Xiaohui; Ren, Xiaotun

2015-10-01

To observe the efficacy and safety of atomoxetine hydrochloride in children with narcolepsy. Totally 66 patients with narcolepsy who were conformed international classification of sleep disturbances (ICSD-2) diagnostic criteria treated with atomoxetine hydrochloride seen from November 2010 to December 2014 were enrolled into this study, 42 of them were male and 24 female, mean age of onset was 7.5 years (3.75-13.00 years), mean duration before diagnosis was 1.75 years (0.25-5.00 years). Complete blood count, liver and kidney function, multiple sleep latency test (MSLT), polysomnography (PGS), neuroimaging and electroencephalography (EEG) were performed for each patient. For some of the children HLA-DR2 gene and serum markers of infection were tested. The 66 cases were followed up from 2 to 49 months (average 18 months) to observe the clinical efficacy and adverse reactions. In 62 cases excessive daytime sleepiness was improved, in 11 cases (16.7%) it was controlled (16.7%), in 29 cases (43.9%) the treatment was obviously effective and in 22 (33.3%) it was effective; cataplexy occurred in 54 cases, in 18 (33.3%) it was controlled, in 19 (35.2%) the treatment was obviously effective and in 10 (18.5%) effective; night sleep disorders existed in 55 cases, in 47 cases it was improved, in 14 (25.5%) it was controlled, in 20 (36.4%) the treatment was obviously effective and in 13 (23.6%) effective; hypnagogic or hypnopompic hallucination was present in 13 cases, in only 4 these symptoms were controlled. Sleep paralysis existed in 4 cases, it was controlled in only 1 case. In 18 cases attention and learning efficiency improved.Anorexia occurred in 18 cases, mood disorder in 5 cases, depression in 2 cases, nocturia, muscle tremors, involuntary tongue movement each occurred in 1 case. P-R interval prolongation and atrial premature contraction were found in 1 case. Atomoxetine hydrochloride showed good effects in patients with narcolepsy on excessive daytime sleepiness

Reducing the Clinical and Socioeconomic Burden of Narcolepsy by Earlier Diagnosis and Effective Treatment.

PubMed

Thorpy, Michael; Morse, Anne Marie

2017-03-01

The burden of narcolepsy is likely the result of 2 main aspects: the clinical difficulties and disability incurred as a direct effect of the disorder and the socioeconomic burden. The clinical burden includes the symptoms, diagnosis, comorbidities, treatment, and even mortality that can be associated with narcolepsy. Lifelong therapy is necessary for these patients. Effective treatment results in long-term benefits from both patient and societal perspectives by improving clinical outcomes, potentially enabling improved education and increased employment and work productivity, and quality of life. Thus, reducing the time to appropriate management results in improved outcomes in these patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Multichannel near infrared spectroscopy indicates regional variations in cerebral autoregulation in infants supported on extracorporeal membrane oxygenation

NASA Astrophysics Data System (ADS)

Papademetriou, Maria D.; Tachtsidis, Ilias; Elliot, Martin J.; Hoskote, Aparna; Elwell, Clare E.

2012-06-01

Assessing noninvasively cerebral autoregulation, the protective mechanism of the brain to maintain constant cerebral blood flow despite changes in blood pressure, is challenging. Infants on life support system (ECMO) for cardiorespiratory failure are at risk of cerebral autoregulation impairment and consequent neurological problems. We measured oxyhaemoglobin concentration (HbO2) by multichannel (12 channels) near-infrared spectroscopy (NIRS) in six infants during sequential changes in ECMO flow. Wavelet cross-correlation (WCC) between mean arterial pressure (MAP) and HbO2 was used to construct a time-frequency representation of the concordance between the two signals to assess the nonstationary aspect of cerebral autoregulation and investigate regional variations. Group data showed that WCC increases with decreasing ECMO flow indicating higher concordance between MAP and HbO2 and demonstrating loss of cerebral autoregulation at low ECMO flows. Statistically significant differences in WCC were observed between channels placed on the right and left scalp with channels on the right exhibiting higher values of WCC suggesting that the right hemisphere was more susceptible to disruption of cerebral autoregulation. Multichannel NIRS in conjunction with wavelet analysis methods can be used to assess regional variations in dynamic cerebral autoregulation with important clinical application in the management of critically ill children on life support systems.

Improved vigilance after sodium oxybate treatment in narcolepsy: a comparison between in-field and in-laboratory measurements.

PubMed

van Schie, Mojca K M; Werth, Esther; Lammers, Gert Jan; Overeem, Sebastiaan; Baumann, Christian R; Fronczek, Rolf

2016-08-01

This two-centre observational study of vigilance measurements assessed the feasibility of vigilance measurements on multiple days using the Sustained Attention to Response Task and the Psychomotor Vigilance Test with portable task equipment, and subsequently assessed the effect of sodium oxybate treatment on vigilance in patients with narcolepsy. Twenty-six patients with narcolepsy and 15 healthy controls were included. The study comprised two in-laboratory days for the Maintenance of Wakefulness Test and the Oxford Sleep Resistance test, followed by 7-day portable vigilance battery measurements. This procedure was repeated for patients with narcolepsy after at least 3 months of stable treatment with sodium oxybate. Patients with narcolepsy had a higher Sustained Attention to Response Task error count, lower Psychomotor Vigilance Test reciprocal reaction time, higher Oxford Sleep Resistance test omission error count adjusted for test duration (Oxford Sleep Resistance testOMIS / MIN ), and lower Oxford Sleep Resistance test and Maintenance of Wakefulness Test sleep latency compared with controls (all P < 0.01). Treatment with sodium oxybate was associated with a longer Maintenance of Wakefulness Test sleep latency (P < 0.01), lower Oxford Sleep Resistance testOMIS / MIN (P = 0.01) and a lower Sustained Attention to Response Task error count (P = 0.01) in patients with narcolepsy, but not with absolute changes in Oxford Sleep Resistance test sleep latency or Psychomotor Vigilance Test reciprocal reaction time. It was concluded that portable measurements of sustained attention as well as in-laboratory Oxford Sleep Resistance test and Maintenance of Wakefulness Test measurements revealed worse performance for narcoleptic patients compared with controls, and that sodium oxybate was associated with an improvement of sustained attention and a better resistance to sleep. © 2016 European Sleep Research Society.

Sleep-stage sequencing of sleep-onset REM periods in MSLT predicts treatment response in patients with narcolepsy.

PubMed

Drakatos, Panagis; Patel, Kishankumar; Thakrar, Chiraag; Williams, Adrian J; Kent, Brian D; Leschziner, Guy D

2016-04-01

Current treatment recommendations for narcolepsy suggest that modafinil should be used as a first-line treatment ahead of conventional stimulants or sodium oxybate. In this study, performed in a tertiary sleep disorders centre, treatment responses were examined following these recommendations, and the ability of sleep-stage sequencing of sleep-onset rapid eye movement periods in the multiple sleep latency test to predict treatment response. Over a 3.5-year period, 255 patients were retrospectively identified in the authors' database as patients diagnosed with narcolepsy, type 1 (with cataplexy) or type 2 (without) using clinical and polysomnographic criteria. Eligible patients were examined in detail, sleep study data were abstracted and sleep-stage sequencing of sleep-onset rapid eye movement periods were analysed. Response to treatment was graded utilizing an internally developed scale. Seventy-five patients were included (39% males). Forty (53%) were diagnosed with type 1 narcolepsy with a mean follow-up of 2.37 ± 1.35 years. Ninety-seven percent of the patients were initially started on modafinil, and overall 59% reported complete response on the last follow-up. Twenty-nine patients (39%) had the sequence of sleep stage 1 or wake to rapid eye movement in all of their sleep-onset rapid eye movement periods, with most of these diagnosed as narcolepsy type 1 (72%). The presence of this specific sleep-stage sequence in all sleep-onset rapid eye movement periods was associated with worse treatment response (P = 0.0023). Sleep-stage sequence analysis of sleep-onset rapid eye movement periods in the multiple sleep latency test may aid the prediction of treatment response in narcoleptics and provide a useful prognostic tool in clinical practice, above and beyond their classification as narcolepsy type 1 or 2. © 2015 European Sleep Research Society.

Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin An American Academy of Sleep Medicine Report

PubMed Central

Morgenthaler, Timothy I.; Kapur, Vishesh K.; Brown, Terry; Swick, Todd J.; Alessi, Cathy; Aurora, R. Nisha; Boehlecke, Brian; Chesson, Andrew L.; Friedman, Leah; Maganti, Rama; Owens, Judith; Pancer, Jeffrey; Zak, Rochelle

2007-01-01

These practice parameters pertain to the treatment of hypersomnias of central origin. They serve as both an update of previous practice parameters for the therapy of narcolepsy and as the first practice parameters to address treatment of other hypersomnias of central origin. They are based on evidence analyzed in the accompanying review paper. The specific disorders addressed by these parameters are narcolepsy (with cataplexy, without cataplexy, due to medical condition and unspecified), idiopathic hypersomnia (with long sleep time and without long sleep time), recurrent hypersomnia and hypersomnia due to medical condition. Successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce the fullest possible return of normal function, and regular follow-up to monitor response to treatment. Modafinil, sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for excessive sleepiness associated with narcolepsy, while tricyclic antidepressants and fluoxetine are effective treatments for cataplexy, sleep paralysis, and hypnagogic hallucinations; but the quality of published clinical evidence supporting them varies. Scheduled naps can be beneficial to combat sleepiness in narcolepsy patients. Based on available evidence, modafinil is an effective therapy for sleepiness due to idiopathic hypersomnia, Parkinson's disease, myotonic dystrophy, and multiple sclerosis. Based on evidence and/or long history of use in the therapy of narcolepsy committee consensus was that modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate are reasonable options for the therapy of hypersomnias of central origin. Citation: Morgenthaler TI; Kapur VK; Brown T; Swick TJ; Alessi C; Aurora RN; Boehlecke B; Chesson AL; Friedman L; Maganti R; Owens J; Pancer J; Zak R; Standards of Practice Committee of the AASM. Practice parameters for the treatment

Comorbidity of Narcolepsy Type 1 With Autoimmune Diseases and Other Immunopathological Disorders: A Case-Control Study

PubMed Central

Martinez-Orozco, Francisco Javier; Vicario, Jose Luis; De Andres, Clara; Fernandez-Arquero, Miguel; Peraita-Adrados, Rosa

2016-01-01

Background Several evidences suggest that autoimmune diseases (ADs) tend to co-occur in an individual and within the same family. Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a selective loss of hypocretin-producing neurons due to a mechanism of neural destruction that indicates an autoimmune pathogenesis, although no evidence is available. We report on the comorbidity of ADs and other immunopathological diseases (including allergy diseases) in narcolepsy. Methods We studied 158 Caucasian NT1 patients (60.7% male; mean age 49.4 ± 19.7 years), in whom the diagnosis was confirmed by polysomnography followed by a multiple sleep latency test, or by hypocretin-1 levels measurements. Results Thirty out of 158 patients (18.99%; 53.3% female; 29 sporadic and one familial cases) had one or more immunopathological diseases associated. A control group of 151 subjects were matched by gender and age with the narcolepsy patients. Results demonstrated that there was a higher frequency of ADs in our series of narcolepsy patients compared to the sample of general population (odds ratio: 3.17; 95% confidence interval: 1.01 - 10.07; P = 0.040). A temporal relationship with the age at onset of the diseases was found. Conclusions Cataplexy was significantly more severe in NT1 patients with immunopathological diseases, and immunopathological diseases are a risk factor for severe forms of cataplexy in our series (odds ratio: 23.6; 95% confidence interval: 5.5 - 100.1). PMID:27298657

Sleep-wake patterns, non-rapid eye movement, and rapid eye movement sleep cycles in teenage narcolepsy.

PubMed

Xu, Xing; Wu, Huijuan; Zhuang, Jianhua; Chen, Kun; Huang, Bei; Zhao, Zhengqing; Zhao, Zhongxin

2017-05-01

To further characterize sleep disorders associated with narcolepsy, we assessed the sleep-wake patterns, rapid eye movement (REM), and non-REM (NREM) sleep cycles in Chinese teenagers with narcolepsy. A total of 14 Chinese type 1 narcoleptic patients (13.4 ± 2.6 years of age) and 14 healthy age- and sex-matched control subjects (13.6 ± 1.8 years of age) were recruited. Ambulatory 24-h polysomnography was recorded for two days, with test subjects adapting to the instruments on day one and the study data collection performed on day two. Compared with the controls, the narcoleptic patients showed a 1.5-fold increase in total sleep time over 24 h, characterized by enhanced slow-wave sleep and REM sleep. Frequent sleep-wake transitions were identified in nocturnal sleep with all sleep stages switching to wakefulness, with more awakenings and time spent in wakefulness after sleep onset. Despite eight cases of narcolepsy with sleep onset REM periods at night, the mean duration of NREM-REM sleep cycle episode and the ratio of REM/NREM sleep between patients and controls were not significantly different. Our study identified hypersomnia in teenage narcolepsy despite excessive daytime sleepiness. Sleep fragmentation extended to all sleep stages, indicating impaired sleep-wake cycles and instability of sleep stages. The limited effects on NREM-REM sleep cycles suggest the relative conservation of ultradian regulation of sleep. Copyright © 2016 Elsevier B.V. All rights reserved.

78 FR 43209 - Narcolepsy Public Meeting on Patient-Focused Drug Development

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-19

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0815] Narcolepsy Public Meeting on Patient-Focused Drug Development AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public meeting; request for comments. SUMMARY: The Food and Drug Administration (FDA...

Dual role of cerebral blood flow in regional brain temperature control in the healthy newborn infant.

PubMed

Iwata, Sachiko; Tachtsidis, Ilias; Takashima, Sachio; Matsuishi, Toyojiro; Robertson, Nicola J; Iwata, Osuke

2014-10-01

Small shifts in brain temperature after hypoxia-ischaemia affect cell viability. The main determinants of brain temperature are cerebral metabolism, which contributes to local heat production, and brain perfusion, which removes heat. However, few studies have addressed the effect of cerebral metabolism and perfusion on regional brain temperature in human neonates because of the lack of non-invasive cot-side monitors. This study aimed (i) to determine non-invasive monitoring tools of cerebral metabolism and perfusion by combining near-infrared spectroscopy and echocardiography, and (ii) to investigate the dependence of brain temperature on cerebral metabolism and perfusion in unsedated newborn infants. Thirty-two healthy newborn infants were recruited. They were studied with cerebral near-infrared spectroscopy, echocardiography, and a zero-heat flux tissue thermometer. A surrogate of cerebral blood flow (CBF) was measured using superior vena cava flow adjusted for cerebral volume (rSVC flow). The tissue oxygenation index, fractional oxygen extraction (FOE), and the cerebral metabolic rate of oxygen relative to rSVC flow (CMRO₂ index) were also estimated. A greater rSVC flow was positively associated with higher brain temperatures, particularly for superficial structures. The CMRO₂ index and rSVC flow were positively coupled. However, brain temperature was independent of FOE and the CMRO₂ index. A cooler ambient temperature was associated with a greater temperature gradient between the scalp surface and the body core. Cerebral oxygen metabolism and perfusion were monitored in newborn infants without using tracers. In these healthy newborn infants, cerebral perfusion and ambient temperature were significant independent variables of brain temperature. CBF has primarily been associated with heat removal from the brain. However, our results suggest that CBF is likely to deliver heat specifically to the superficial brain. Further studies are required to assess the

Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy.

PubMed

Kaushik, Mahesh K; Aritake, Kosuke; Imanishi, Aya; Kanbayashi, Takashi; Ichikawa, Tadashi; Shimizu, Tetsuo; Urade, Yoshihiro; Yanagisawa, Masashi

2018-06-05

Narcolepsy-cataplexy is a chronic neurological disorder caused by loss of orexin (hypocretin)-producing neurons, associated with excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations, and fragmentation of nighttime sleep. Currently, human narcolepsy is treated by providing symptomatic therapies, which can be associated with an array of side effects. Although peripherally administered orexin does not efficiently penetrate the blood-brain barrier, centrally delivered orexin can effectively alleviate narcoleptic symptoms in animal models. Chronic intrathecal drug infusion through an implantable pump is a clinically available strategy to treat a number of neurological diseases. Here we demonstrate that the narcoleptic symptoms of orexin knockout mice can be reversed by lumbar-level intrathecal orexin delivery. Orexin was delivered via a chronically implanted intrathecal catheter at the upper lumbar level. The computed tomographic scan confirmed that intrathecally administered contrast agent rapidly moved from the spinal cord to the brain. Intrathecally delivered orexin was detected in the brain by radioimmunoassay at levels comparable to endogenous orexin levels. Cataplexy and sleep-onset REM sleep were significantly decreased in orexin knockout mice during and long after slow infusion of orexin (1 nmol/1 µL/h). Sleep/wake states remained unchanged both quantitatively as well as qualitatively. Intrathecal orexin failed to induce any changes in double orexin receptor-1 and -2 knockout mice. This study supports the concept of intrathecal orexin delivery as a potential therapy for narcolepsy-cataplexy to improve the well-being of patients.

Narcolepsy type 1 and hypersomnia associated with a psychiatric disorder show different slow wave activity dynamics.

PubMed

Walacik-Ufnal, Ewa; Piotrowska, Anna Justyna; Wołyńczyk-Gmaj, Dorota; Januszko, Piotr; Gmaj, Bartłomiej; Ufnal, Marcin; Kabat, Marek; Wojnar, Marcin

2017-01-01

The aim of the study was to compare electrophysiological parameters of night sleep in narcolepsy type 1 and hypersomnia associated with a psychiatric disorder. Fortyfour patients: 15 with narcolepsy type 1, 14 with hypersomnia associated with a psychiatric disorder and 15 age- and sex-matched controls participated in the study. The study subjects filled in the Athens Insomnia Scale (AIS) and the Beck Depression Inventory (BDI). The severity of daytime sleepiness was quantified subjectively using the Epworth Sleepiness Scale (ESS) and the Stanford Sleepiness Scale (SSS), and objectively using the Multiple Sleep Latency Test (MSLT). All subjects underwent polysomnography (PSG) on the two consecutive nights. The data from the second night was analysed. The slow wave activity (SWA, 1-4 Hz) was calculated for the three consecutive sleep cycles, and topographic delta power maps were plotted. In contrast to narcoleptics, psychiatric hypersomniacs had undisturbed nocturnal sleep, high sleep efficiency, normal non-rapid eye movement (NREM) and rapid eye movement (REM) sleep proportions, normal REM latency and sleep latencies on MSLT and PSG. The subjective and objective sleepiness was significantly higher in narcolepsy group than in psychiatric hypersomnia group. In all the study groups SWA was the most prominent in frontal areas, while the greatest between-group differences were found in the central areas. There were significant differences between the groups in SWA in the second NREM episode. The highest SWA was observed in the hypersomnia group, while the lowest in the narcolepsy group. Psychiatric hypersomniacs and controls did not differ in the SWA exponential decline over consecutive NREM episodes, whereas narcoleptics exhibited a steeper dissipation of sleep pressure from the first to the second NREM episode. In conclusion, narcolepsy type1 and hypersomnia associated with psychiatric disorder differ in the SWA dynamics. Narcoleptics presented with the altered

Clinical utility of the Chinese version of the Pediatric Daytime Sleepiness Scale in children with obstructive sleep apnea syndrome and narcolepsy.

PubMed

Yang, Chien-Ming; Huang, Yu-Shu; Song, Yu-Chen

2010-04-01

The present study examined the psychometric properties of the Chinese version of the Pediatric Daytime Sleepiness Scale (PDSS) and the utility of the PDSS as a screening tool for pathological daytime sleepiness in teenagers with obstructive sleep apnea (OSA) and narcolepsy. The PDSS was first administered to 238 middle and high school students to assess the reliability of the scale, and then administered to 28 teenagers with OSA, 31 teenagers with narcolepsy, and 34 normal controls to evaluate its clinical utility. Test-retest reliability and internal consistency were acceptable. The PDSS scores were significantly higher in narcoleptic subjects than in subjects with OSA, and higher in OSA syndrome (OSAS) subjects than normal controls. Furthermore, the scores decreased in narcoleptic subjects after medical treatment. Both reliability and validity were proven to be good. As a screening tool for narcolepsy, receiver operator characteristic (ROC) curve analysis showed that the PDSS, with a cut-off score of 16/17, had good sensitivity (87.1%) and fair specificity (74.3%) for identifying individuals with narcolepsy. When used for screening OSA, however, the differentiating power was not as good. The PDSS is a reliable and valid tool for the measurement of sleepiness in clinical youth populations. When used as a screening tool, it is useful for sleep disorders involving more severe pathological sleepiness, as in narcolepsy.

Narcolepsy with Cataplexy Mimicry: The Strange Case of Two Sisters

PubMed Central

Pizza, Fabio; Vandi, Stefano; Poli, Francesca; Moghadam, Keivan Kaveh; Franceschini, Christian; Bellucci, Claudia; Cipolli, Carlo; Ingravallo, Francesca; Natalini, Giuliana; Mignot, Emmanuel; Plazzi, Giuseppe

2013-01-01

We report on two sisters, 17 and 12 years of age, with clinical features suggesting narcolepsy with cataplexy (NC): daytime sleepiness, spontaneous and emotionally triggered sudden falls to the ground, and overweight/obesity. MSLT showed borderline sleep latency, with 1 and 0 sleep onset REM periods. HLA typing disclosed the DQB1*0602 allele. Video-polygraphy of the spells ruled out NC diagnosis by demonstrating their easy elicitation by suggestion, with wake EEG, electromyo-graphic persistence of muscle tone, and stable presence of tendon reflexes (i.e., pseudo-cataplexy), together with normal cerebrospinal hypocretin-1 levels. Our cases emphasize the need of a clear depiction of cataplexy pattern at the different ages, the usefulness of examining ictal neurophysiology, and collecting all available disease markers in ambiguous cases. Citation: Pizza F; Vandi S; Poli F; Moghadam KK; Fran-ceschini C; Bellucci C; Cipolli C; Ingravallo F; Natalini G; Mignot E; Plazzi G. Narcolepsy with cataplexy mimicry: the strange case of two sisters. J Clin Sleep Med 2013;9(6):611-612. PMID:23772196

Modafinil : A Review of its Pharmacology and Clinical Efficacy in the Management of Narcolepsy.

PubMed

McClellan, K J; Spencer, C M

1998-04-01

Modafinil promotes wakefulness through an as yet unknown mechanism of action. It significantly increases daytime sleep latency and reduces excessive daytime sleepiness (EDS) compared with placebo in patients with narcolepsy. However, the drug does not suppress cataplexy. Although direct comparative data are lacking, modafinil offers advantages over amphetamines and methylphenidate in patients with narcolepsy because of its lack of rebound phenomena after treatment withdrawal and its low abuse potential. Clinical trials have shown modafinil to be well tolerated in patients with narcolepsy. Except for headache, which was reported with a significantly greater frequency in modafinil recipients, the tolerability profile of modafinil 200 to 400 mg/day was similar to that of placebo in patients treated for 9 weeks. Preliminary data suggest that the tolerability of modafinil is maintained long term (40 weeks). Thus, modafinil is effective in the treatment of EDS in patients with narcolepsy, although it is not effective against cataplexy. Preliminary findings indicate that, unlike other psychostimulants, the drug is unlikely to be abused and is not associated with withdrawal phenomena. Therefore, modafinil is likely to be an effective therapeutic option for the treatment of EDS in patients with narcolepsy. The mechanism of action of modafinil has not been clearly established. However, it may indirectly increase wakefulness, at least in part, through inhibition of cortical γ-aminobutyric acid (GABA) release via serotonergic mechanisms. Modafinil induces wakefulness and increases locomotor activity in a variety of animal species without causing stereotyped behaviour. In rhesus monkeys, the effects of oral modafinil were not associated with changes in blood pressure or heart rate. In contrast to dexamphetamine 20mg, single night-time doses of modafinil 100 or 200mg had no significant effects on objective sleep variables or sleep structure in young or elderly healthy

Event-related-potential low-resolution brain electromagnetic tomography (ERP-LORETA) suggests decreased energetic resources for cognitive processing in narcolepsy.

PubMed

Saletu, Michael; Anderer, Peter; Saletu-Zyhlarz, Gerda Maria; Mandl, Magdalena; Zeitlhofer, Josef; Saletu, Bernd

2008-08-01

Event-related potentials (ERPs) are sensitive measures of both perceptual and cognitive processes. The aim of the present study was to identify brain regions involved in the processes of cognitive dysfunction in narcolepsy by means of ERP tomography. In 17 drug-free patients with narcolepsy and 17 controls, ERPs were recorded (auditory odd-ball paradigm). Latencies, amplitudes and LORETA sources were determined for standard (N1 and P2) and target (N2 and P300) ERP components. Psychometry included measures of mental performance, affect and critical flicker fusion frequency (CFF). In the ERPs patients demonstrated delayed cognitive N2 and P300 components and reduced amplitudes in midline regions, while N1 and P2 components did not differ from controls. LORETA suggested reduced P300 sources bilaterally in the precuneus, the anterior and posterior cingulate gyri, the ventrolateral prefrontal cortex and the parahippocampal gyrus. In psychometry, patients demonstrated deteriorated mood, increased trait anxiety, decreased CFF and a trend toward reduced general verbal memory and psychomotor activity. Narcoleptic patients showed prolonged information processing, as indexed by N2 and P300 latencies and decreased energetic resources for cognitive processing. Electrophysiological aberrations in brain areas related to the 'executive attention network' and the 'limbic system' may contribute to a deterioration in mental performance and mood at the behavioral level.

Narcolepsy: Autoimmunity, Effector T Cell Activation Due to Infection, or T Cell Independent, Major Histocompatibility Complex Class II Induced Neuronal Loss?

ERIC Educational Resources Information Center

Fontana, Adriano; Gast, Heidemarie; Reith, Walter; Recher, Mike; Birchler, Thomas; Bassetti, Claudio L.

2010-01-01

Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of…

Efficiency of a Combination of Pharmacological Treatment and Nondrug Interventions in Childhood Narcolepsy.

PubMed

Kacar Bayram, Ayşe; Per, Hüseyin; Ismailoğullari, Sevda; Canpolat, Mehmet; Gumus, Hakan; Aksu, Murat

2016-12-01

Objective  Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic and/or hypnopompic hallucinations, and sleep paralysis. It is one of the most important causes of excessive daytime sleepiness in the pediatric population. The aim of this study is to present the clinical and laboratory findings, and treatment results of pediatric patients with narcolepsy. Materials and Methods  We studied five unrelated consecutive children with narcolepsy, focusing on clinical and laboratory features, the therapy and outcome over the 33-month follow-up period. Results  The study subjects included two boys and three girls. The mean age at diagnosis was 11.8 ± 3.3 years (range: 8-16 years). Three patients had cataplexy. There were no hypnagogic hallucinations and/or sleep paralysis in any patients. All patients were educated about sleep hygiene, appropriate nutrition, and regular exercise. Three patients were treated with modafinil, while two patients received methylphenidate. Sodium oxybate was added to existing treatment in patients with cataplexy. Cataplexy attacks did not respond well to the treatment in one patient; therefore intravenous immunoglobulin therapy was given. Conclusions  Early diagnosis is important to help narcoleptic patients in improving their quality of life. A combination of pharmacological treatment and nondrug interventions can greatly improve children's clinical symptoms. Georg Thieme Verlag KG Stuttgart · New York.

Patterns of spontaneous reports on narcolepsy following administration of pandemic influenza vaccine; a case series of individual case safety reports in Eudravigilance.

PubMed

Gadroen, Kartini; Straus, Sabine M J M; Pacurariu, Alexandra; Weibel, Daniel; Kurz, Xavier; Sturkenboom, Miriam C J M

2016-09-22

This study aims to describe the frequency and quality of spontaneous narcolepsy case reports following administration of pandemic influenza vaccine as captured in the Eudravigilance database. We conducted a retrospective descriptive study of spontaneous Individual Case Safety Reports (ICSRs), reporting narcolepsy following administration of pandemic influenza vaccine as received by Eudravigilance until July 2014. De-duplication was carried out by Eudravigilance. Frequency of reporting is described as number of ICSRs received per month over time. The quality of the ICSRs was evaluated by completeness of information and diagnostic certainty using the Automated Brighton Collaboration case definition tool (ABC-tool) for narcolepsy. After de-duplication, a total of 1333 ICSRs of narcolepsy and/or cataplexy following pandemic influenza vaccine were identified, originating from 18 countries worldwide. Most of the ICSRs (61.9%) originated from the signaling countries, Sweden and Finland. Although de-duplication of case reports was carried out, it is suspected that many duplicates exist, in particular from Sweden. The majority of the ICSRs (95.3%), reported exposure to Pandemrix®. Only few reports were received for Arepanrix® (1.6%) or Focetria® (0.5%), and Celvapan® (0.1%). Of those ICSRs reporting age, 73.1% concerned persons below age of 20years. When using the ABC-tool, all ICSRs were classified as having insufficient information to meet the Brighton Collaboration case definition of narcolepsy. An increase in reporting of narcolepsy appeared in Eudravigilance only after awareness was raised by the national authorities. Most narcolepsy reports were received from countries where the signal initially occurred, and were related to Pandemrix® in children/adolescents. Basic information about the patient and the exposure was present in most of the ICSRs. The ICSRs captured by Eudravigilance however, do not collect enough information to assess the diagnostic certainty

The spectrum of REM sleep-related episodes in children with type 1 narcolepsy.

PubMed

Antelmi, Elena; Pizza, Fabio; Vandi, Stefano; Neccia, Giulia; Ferri, Raffaele; Bruni, Oliviero; Filardi, Marco; Cantalupo, Gaetano; Liguori, Rocco; Plazzi, Giuseppe

2017-06-01

Type 1 narcolepsy is a central hypersomnia due to the loss of hypocretin-producing neurons and characterized by cataplexy, excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. In children, close to the disease onset, type 1 narcolepsy has peculiar clinical features with severe cataplexy and a complex admixture of movement disorders occurring while awake. Motor dyscontrol during sleep has never been systematically investigated. Suspecting that abnormal motor control might affect also sleep, we systematically analysed motor events recorded by means of video polysomnography in 40 children with type 1 narcolepsy (20 females; mean age 11.8 ± 2.6 years) and compared these data with those recorded in 22 age- and sex-matched healthy controls. Motor events were classified as elementary movements, if brief and non-purposeful and complex behaviours, if simulating purposeful behaviours. Complex behaviours occurring during REM sleep were further classified as 'classically-defined' and 'pantomime-like' REM sleep behaviour disorder episodes, based on their duration and on their pattern (i.e. brief and vivid-energetic in the first case, longer and with subcontinuous gesturing mimicking daily life activity in the second case). Elementary movements emerging either from non-REM or REM sleep were present in both groups, even if those emerging from REM sleep were more numerous in the group of patients. Conversely, complex behaviours could be detected only in children with type 1 narcolepsy and were observed in 13 patients, with six having 'classically-defined' REM sleep behaviour disorder episodes and seven having 'pantomime-like' REM sleep behaviour disorder episodes. Complex behaviours during REM sleep tended to recur in a stereotyped fashion for several times during the night, up to be almost continuous. Patients displaying a more severe motor dyscontrol during REM sleep had also more severe motor disorder during daytime (i

Treatment with venlafaxine in six cases of children with narcolepsy and with cataplexy and hypnagogic hallucinations.

PubMed

Møller, Lene Ruge; Østergaard, John R

2009-04-01

Narcolepsy with cataplexy is a chronic neuropsychiatric disorder associated with inappropriate control of rapid eye movement (REM) sleep. The main symptoms are excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and disturbed nocturnal sleep. Cataplexy is marked by episodes of muscular weakness and may cause the patient to collapse to the ground. So far, pharmacotherapy of cataplexy and hypnagogic hallucinations has been predominantly based on tricyclic antidepressants. Recently, new drugs that block the reuptake of norepineprine and serotonin (e.g., venlafaxine) have been suggested as first-line treatment. These drugs have become our choice in treating children with cataplexy and nightmares as a symptom in narcolepsy. We describe clinical case reports of venlafaxine treatment in 6 children aged 7-12 years old when diagnosed with narcolepsy-cataplexy. In 2 cases with up to 50 daily cataplectic attacks, an initial effect of 37.5 mg of venlafaxine was initially observed. However, during the first year, the dose had to be increased to 112.5 mg daily to avoid cataplexy. A third patient with partial cataplexy was treated with 75 mg of venlafaxine daily. In 2 cases, hypnagogic hallucinations, described by the patients as nightmares, were the most troubling symptom and were successfully treated with only 37.5 mg of venlafaxine daily. Side effects included an increase of disturbed nocturnal sleep when venlafaxine was taken after 2:00 p.m. No major aggressive or suicidal thoughts and no raised blood pressure were recorded. Venlafaxine has proven to be an effective treatment of cataplexy and hypnagogic hallucinations in 6 children with narcolepsy. No severe side effects were observed.

English Translations Of The First Clinical Reports On Narcolepsy And Cataplexy By Westphal And Gélineau In The Late 19th Century, With Commentary

PubMed Central

Schenck, Carlos H.; Bassetti, Claudio L.; Arnulf, Isabelle; Mignot, Emmanuel

2007-01-01

Study Objectives: To publish the first English translations, with commentary, of the original reports describing narcolepsy and cataplexy by Westphal in German (1877) and by Gélineau in French (1880). Methods: A professional translation service translated the 2 reports from either German or French to English, with each translation then being slightly edited by one of the authors. All authors then provided commentary. Results: Both Westphal and Gélineau correctly identified and described the new clinical entities of cataplexy and narcolepsy, with recurrent, self-limited sleep attacks and/or cataplectic attacks affecting 2 otherwise healthy people. Narcolepsy was named by Gélineau (and cataplexy was named by Henneberg in 1916). The evidence in both cases is sufficiently convincing to conclude that they were likely each HLA-DQB1*0602 positive and hypocretin deficient. Conclusions: The original descriptions of narcolepsy and cataplexy are now available in English, allowing for extensive clinical and historical commentary. Citations: Schenck CH; Bassetti CL; Arnulf I et al. English translations of the first clinical reports on narcolepsy and cataplexy by Westphal and Gélineau in the late 19th century, with commentary. J Clin Sleep Med 2007;3(3):301–311 PMID:17561602

Cerebral oxygenation in patients undergoing shoulder surgery in beach chair position: comparing general to regional anesthesia and the impact on neurobehavioral outcome.

PubMed

Aguirre, J; Borgeat, A; Trachsel, T; Cobo Del Prado, I; De Andrés, J; Bühler, P

2014-02-01

Ischemic brain damage has been reported in healthy patients after beach chair position for surgery due to cerebral hypoperfusion. Near-infrared spectroscopy has been described as a non-invasive, continuous method to monitor cerebral oxygen saturation. However, its impact on neurobehavioral outcome comparing different anesthesia regimens has been poorly described. In this prospective, assessor-blinded study, 90 patients undergoing shoulder surgery in beach chair position following general (G-group, n=45) or regional anesthesia (R-group; n=45) were enrolled to assess the prevalence of cerebral desaturation events comparing anesthesia regimens and their impact on neurobehavioral and neurological outcome. Anesthesiologists were blinded to regional cerebral oxygen saturation values. Baseline data assessed the day before surgery included neurological and neurobehavioral tests, which were repeated the day after surgery. The baseline data for regional cerebral oxygen saturation/bispectral index and invasive blood pressure both at heart and auditory meatus levels were taken prior to anesthesia, 5 min after induction of anesthesia, 5 min after beach chair positioning, after skin incision and thereafter all 20 min until discharge. Patients in the R-group showed significantly less cerebral desaturation events (p<0.001), drops in regional cerebral oxygen saturation values (p<0.001), significantly better neurobehavioral test results the day after surgery (p<0.001) and showed a greater hemodynamic stability in the beach chair position compared to patients in the G-group. The incidence of regional cerebral oxygen desaturations seems to influence the neurobehavioral outcome. Regional anesthesia offers more stable cardiovascular conditions for shoulder surgery in beach chair position influencing neurobehavioral test results at 24h. Copyright © 2013 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Published by Elsevier España. All rights reserved.

Cerebral Hyperperfusion Syndrome After Revascularization Surgery in Moyamoya Disease: Region-Symptom Mapping and Estimating a Critical Threshold.

PubMed

Kazumata, Ken; Uchino, Haruto; Tokairin, Kikutaro; Ito, Masaki; Shiga, Tohru; Osanai, Toshiya; Kawabori, Masahito

2018-06-01

Cerebral hyperperfusion complicates the postoperative course of patients with moyamoya disease after direct revascularization surgery. There is no clear distinction between cerebral hyperperfusion syndrome and benign postoperative increase in regional cerebral blood flow (rCBF). The present study aimed to determine clinically relevant changes in rCBF, anatomical correlations, and factors associated with transient neurologic symptoms after revascularization surgery in moyamoya disease. Whole-brain voxel-based perfusion mapping was used to identify regions involved in cerebral hyperperfusion and quantify the changes in 105 hemispheric surgeries with the use of single-photon computed tomography acquired on postoperative day 7. The changes in rCBF were quantitatively analyzed, and associations with cerebral hyperperfusion syndrome were determined. Transient neurologic symptoms appeared with rCBF increase in 37.9% of adults. Speech impairments were associated with an increase in rCBF in the operculo-insula region. Cheiro-oral syndrome was associated with the posterior insula as well as the prefrontal region. A receiver operating curve analysis yielded transient neurologic symptoms with maximum accuracy at >15.5% increase from baseline. Age and preoperative rCBF were independently associated with transient neurologic symptoms (P < 0.001). Areas showing rCBF increase during the experience of transient neurologic symptoms were spatially compatible with the known functional anatomy of the brain. An increase of approximately 15% from baseline was found to be critical, which is a far lower threshold than what has been reported previously. Increasing age was significantly associated with the occurrence of symptomatic hyperperfusion. Furthermore, patients with preserved rCBF also showed symptomatic hyperperfusion. Copyright © 2018 Elsevier Inc. All rights reserved.

The Nightly Use of Sodium Oxybate Is Associated with a Reduction in Nocturnal Sleep Disruption: A Double-Blind, Placebo-Controlled Study in Patients with Narcolepsy

PubMed Central

Black, Jed; Pardi, Daniel; Hornfeldt, Carl S.; Inhaber, Neil

2010-01-01

Objective: To further explore the effects of sodium oxybate (SXB) administration on nocturnal sleep in narcolepsy patients during a double-blind, placebo-controlled, parallel group study conducted with 228 adult patients with narcolepsy/cataplexy in the United States, Canada, and Europe. Method: Patients were withdrawn from antidepressants and sedative/hypnotics, and then randomized to receive 4.5, 6, or 9 g SXB or placebo nightly for 8 weeks. Patients receiving 6 and 9 g/night doses were titrated to their final dose in weekly 1.5 g increments, while patients receiving placebo were randomized to undergo a similar mock dose titration. The use of stimulant therapy continued unchanged. Changes in sleep architecture were measured using centrally scored nocturnal polysomnograms. Daily diaries were used to record changes in narcolepsy symptoms and adverse events. Results: Following 8 weeks of SXB treatment, study patients demonstrated significant dose-related increases in the duration of stage 3 and 4 sleep, reaching a median increase of 52.5 minutes in patients receiving 9 g nightly. Compared to placebo-treated patients, delta power was significantly increased in all dose groups. Stage 1 sleep and the frequency of nocturnal awakenings were each significantly decreased at the 6 and 9 g/night doses. The changes in nocturnal sleep coincided with significant decreases in the severity and frequency of narcolepsy symptoms. Conclusions: The nightly administration of SXB to narcolepsy patients significantly impacts measures of slow wave sleep, wake after sleep onset, awakenings, total sleep time, and stage 1 sleep in a dose-related manner. The frequency and severity of narcolepsy symptoms decreased with treatment. Citation: Black J; Pardi D; Hornfeldt CS; Inhaber N. The nightly use of sodium oxybate is associated with a reduction in nocturnal sleep disruption: a double-blind, placebo-controlled study in patients with narcolepsy. J Clin Sleep Med 2010;6(6):596-602. PMID:21206549

In Vivo Theranostics at the Peri-Infarct Region in Cerebral Ischemia

PubMed Central

Agulla, Jesús; Brea, David; Campos, Francisco; Sobrino, Tomás; Argibay, Bárbara; Al-Soufi, Wajih; Blanco, Miguel; Castillo, José; Ramos-Cabrer, Pedro

2014-01-01

The use of theranostics in neurosciences has been rare to date because of the limitations imposed on the free delivery of substances to the brain by the blood-brain barrier. Here we report the development of a theranostic system for the treatment of stroke, a leading cause of death and disability in developed countries. We first performed a series of proteomic, immunoblotting and immunohistological studies to characterize the expression of molecular biomarkers for the so-called peri-infarct tissue, a key region of the brain for stroke treatment. We confirmed that the HSP72 protein is a suitable biomarker for the peri-infarct region, as it is selectively expressed by at-risk tissue for up to 7 days following cerebral ischemia. We also describe the development of anti-HSP72 vectorized stealth immunoliposomes containing imaging probes to make them traceable by conventional imaging techniques (fluorescence and MRI) that were used to encapsulate a therapeutic agent (citicoline) for the treatment of cerebral ischemia. We tested the molecular recognition capabilities of these nano-platforms in vitro together with their diagnostic and therapeutic properties in vivo, in an animal model of cerebral ischemia. Using MRI, we found that 80% of vectorized liposomes were located on the periphery of the ischemic lesion, and animals treated with citicoline encapsulated on these liposomes presented lesion volumes up to 30% smaller than animals treated with free (non-encapsulated) drugs. Our results show the potential of nanotechnology for the development of effective tools for the treatment of neurological diseases. PMID:24396517

Relations of Blood Pressure and Head Injury to Regional Cerebral Blood Flow

PubMed Central

Allen, Allyssa J.; Katzel, Leslie I.; Wendell, Carrington R.; Siegel, Eliot L.; Lefkowitz, David; Waldstein, Shari R.

2016-01-01

Hypertension confers increased risk for cognitive decline, dementia, and cerebrovascular disease. These associations have been attributed, in part, to cerebral hypoperfusion. Here we posit that relations of higher blood pressure to lower levels of cerebral perfusion may be potentiated by a prior head injury. Participants were 87 community-dwelling older adults -69% men, 90% white, mean age= 66.9 years, 27.6% with a history of mild traumatic brain injury (mTBI) defined as a loss of consciousness regions. Cerebellum served as the denominator. Sex-stratified multiple regression analyses, adjusted for age, education, race, alcohol consumption, smoking status, and depressive symptomatology, revealed significant interactions of blood pressure and head injury to cerebral blood flow in men only. Specifically, among men with a history of head injury, higher systolic blood pressure was associated with lower levels of perfusion in the left orbital (β=-3.21, p=.024) and left dorsolateral (β=-2.61, p=.042) prefrontal cortex, and left temporal cortex (β=-3.36, p=.014); higher diastolic blood pressure was marginally associated with lower levels of perfusion in the left dorsolateral prefrontal cortex (β=-2.79, p=.051). Results indicate that men with a history of head injury may be particularly vulnerable to the impact of higher blood pressure on cerebral perfusion in left anterior cortical regions, thus potentially enhancing risk for adverse brain and neurocognitive outcomes. PMID:27206865

Where are we in our understanding of the association between narcolepsy and one of the 2009 adjuvanted influenza A (H1N1) vaccines?

PubMed

Johansen, K; Brasseur, D; MacDonald, N; Nohynek, H; Vandeputte, J; Wood, D; Neels, P

2016-07-01

Evaluating new rare serious vaccine safety signals is difficult and complex work. To further assess the observed increase in narcolepsy cases seen in Europe with the 2009 pandemic H1N1 influenza vaccine, the International Alliance for Biological Standardization (IABS) invited a wide range of experts to a one day meeting in Geneva in October 2015 to present data and to discuss the implications. The presentations covered the following topics: clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaigns; epidemiological studies conducted to assess the risk of narcolepsy, other neurological and immune-related diseases following 2009 pandemic H1N1 influenza vaccine; potential biases influencing the different epidemiological study designs; potential genetic contribution to the development of narcolepsy; potential biological mechanisms for development of narcolepsy in this setting including the role of the virus itself, antigenic differences between the vaccines and differences in AS03-adjuvanted vaccines. The presentations were followed by fulsome roundtable discussions. Members from affected families also attended and made informal comments to round out the day's deliberations. This meeting emphasized the value added in bringing together in a neutral setting a wide range of experts and vaccine producers to discuss such a complex new serious adverse event following immunization. Copyright © 2016.

Cerebral Cortex Regions Selectively Vulnerable to Radiation Dose-Dependent Atrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seibert, Tyler M.; Karunamuni, Roshan; Kaifi, Samar

Purpose and Objectives: Neurologic deficits after brain radiation therapy (RT) typically involve decline in higher-order cognitive functions such as attention and memory rather than sensory defects or paralysis. We sought to determine whether areas of the cortex critical to cognition are selectively vulnerable to radiation dose-dependent atrophy. Methods and Materials: We measured change in cortical thickness in 54 primary brain tumor patients who underwent fractionated, partial brain RT. The study patients underwent high-resolution, volumetric magnetic resonance imaging (T1-weighted; T2 fluid-attenuated inversion recovery, FLAIR) before RT and 1 year afterward. Semiautomated software was used to segment anatomic regions of the cerebral cortex formore » each patient. Cortical thickness was measured for each region before RT and 1 year afterward. Two higher-order cortical regions of interest (ROIs) were tested for association between radiation dose and cortical thinning: entorhinal (memory) and inferior parietal (attention/memory). For comparison, 2 primary cortex ROIs were also tested: pericalcarine (vision) and paracentral lobule (somatosensory/motor). Linear mixed-effects analyses were used to test all other cortical regions for significant radiation dose-dependent thickness change. Statistical significance was set at α = 0.05 using 2-tailed tests. Results: Cortical atrophy was significantly associated with radiation dose in the entorhinal (P=.01) and inferior parietal ROIs (P=.02). By contrast, no significant radiation dose-dependent effect was found in the primary cortex ROIs (pericalcarine and paracentral lobule). In the whole-cortex analysis, 9 regions showed significant radiation dose-dependent atrophy, including areas responsible for memory, attention, and executive function (P≤.002). Conclusions: Areas of cerebral cortex important for higher-order cognition may be most vulnerable to radiation-related atrophy. This is consistent with clinical

Normal Morning Melanin-Concentrating Hormone Levels and No Association with Rapid Eye Movement or Non-Rapid Eye Movement Sleep Parameters in Narcolepsy Type 1 and Type 2

PubMed Central

Schrölkamp, Maren; Jennum, Poul J.; Gammeltoft, Steen; Holm, Anja; Kornum, Birgitte R.; Knudsen, Stine

2017-01-01

Study Objectives: Other than hypocretin-1 (HCRT-1) deficiency in narcolepsy type 1 (NT1), the neurochemical imbalance of NT1 and narcolepsy type 2 (NT2) with normal HCRT-1 levels is largely unknown. The neuropeptide melanin-concentrating hormone (MCH) is mainly secreted during sleep and is involved in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep regulation. Hypocretin neurons reciprocally interact with MCH neurons. We hypothesized that altered MCH secretion contributes to the symptoms and sleep abnormalities of narcolepsy and that this is reflected in morning cerebrospinal fluid (CSF) MCH levels, in contrast to previously reported normal evening/afternoon levels. Methods: Lumbar CSF and plasma were collected from 07:00 to 10:00 from 57 patients with narcolepsy (subtypes: 47 NT1; 10 NT2) diagnosed according to International Classification of Sleep Disorders, Third Edition (ICSD-3) and 20 healthy controls. HCRT-1 and MCH levels were quantified by radioimmunoassay and correlated with clinical symptoms, polysomnography (PSG), and Multiple Sleep Latency Test (MSLT) parameters. Results: CSF and plasma MCH levels were not significantly different between narcolepsy patients regardless of ICSD-3 subtype, HCRT-1 levels, or compared to controls. CSF MCH and HCRT-1 levels were not significantly correlated. Multivariate regression models of CSF MCH levels, age, sex, and body mass index predicting clinical, PSG, and MSLT parameters did not reveal any significant associations to CSF MCH levels. Conclusions: Our study shows that MCH levels in CSF collected in the morning are normal in narcolepsy and not associated with the clinical symptoms, REM sleep abnormalities, nor number of muscle movements during REM or NREM sleep of the patients. We conclude that morning lumbar CSF MCH measurement is not an informative diagnostic marker for narcolepsy. Citation: Schrölkamp M, Jennum PJ, Gammeltoft S, Holm A, Kornum BR, Knudsen S. Normal morning melanin

Risk of Narcolepsy after AS03 Adjuvanted Pandemic A/H1N1 2009 Influenza Vaccine in Adults: A Case-Coverage Study in England.

PubMed

Stowe, Julia; Andrews, Nicholas; Kosky, Christopher; Dennis, Gary; Eriksson, Sofia; Hall, Andrew; Leschziner, Guy; Reading, Paul; Shneerson, John M; Donegan, Katherine; Miller, Elizabeth

2016-05-01

An increased risk of narcolepsy has been observed in children following ASO3-adjuvanted pandemic A/H1N1 2009 (Pandemrix) vaccine. We investigated whether this risk extends to adults in England. Six adult sleep centers in England were visited between November 2012 and February 2014 and vaccination/clinical histories obtained from general practitioners. Suspected narcolepsy cases aged older than 17 y were selected. The risk of narcolepsy following Pandemrix was calculated using cases diagnosed by the time of the center visits and those with a diagnosis by November 30, 2011 after which there was increased awareness of the risk in children. The odds of vaccination in cases and in matched population data were compared using a case-coverage design. Of 1,446 possible cases identified, most had onset before 2009 or were clearly not narcolepsy. Of the 60 remaining cases, 20 were excluded after expert review, leaving 40 cases with narcolepsy; 5 had received Pandemrix between 3 and 18 mo before onset. All the vaccinated cases had cataplexy, two received a diagnosis by November 2011 and two were aged 40 y or older. The odds ratio for vaccination in cases compared to the population was 4.24 (95% confidence interval 1.45-12.38) using all cases and 9.06 (1.90-43.17) using cases with a diagnosis by November 2011, giving an attributable risk of 0.59 cases per 100,000 doses. We found a significantly increased risk of narcolepsy in adults following Pandemrix vaccination in England. The risk was lower than that seen in children using a similar study design. © 2016 Associated Professional Sleep Societies, LLC.

The relationship between orexin levels and blood pressure changes in patients with narcolepsy.

PubMed

Sieminski, Mariusz; Chwojnicki, Kamil; Sarkanen, Tomi; Partinen, Markku

2017-01-01

Narcolepsy type 1 (NT1) is caused by a deficiency or absence of the neurotransmitter orexin. NT1 is also associated with a reduced nocturnal "dipping" of blood pressure (BP). The study objective was to analyze whether nocturnal BP values differed in patients depleted of orexin, versus those in whom production was preserved. We performed a retrospective analysis of the polysomnographic recordings, orexin levels, and BP values of patients with NT1. Data was collected from a total of 21 patients, divided into two groups as follows: those with a complete depletion of orexin (n = 11) (Group1), and those with a remaining, limited presence of orexin (n = 10) (Group 2). The groups did not differ in terms of the clinical features of NT1 or sleep characteristics, with an exception of increased number of cataplexy episodes and increased percentage of sleep stage 2 in the Group 1. Daytime and nocturnal BP did not differ between the groups. Most patients, regardless of group, had a non-dipping blood pressure pattern, and no difference in dipping prevalence was observed between groups. The amplitude of the daytime to nighttime change in BP did not differ between the groups. Non-dipping BP patterns are frequent among patients with narcolepsy type 1, but we saw no evidence that they depended on whether orexin levels were above or below the assay detection threshold. Therefore, our results do not support the hypothesis that in patients with narcolepsy type 1 residual orexin levels play a role in the control of nocturnal BP dipping.

Narcolepsy-cataplexy and loss of sphincter control.

PubMed Central

Vgontzas, A. N.; Sollenberger, S. E.; Kales, A.; Bixler, E. O.; Vela-Bueno, A.

1996-01-01

We describe the case of a 34-year-old man who presented intermittent faecal incontinence as a manifestation of cataplexy. The patient's sleep history was positive for the full narcoleptic tetrad (sleep attacks, cataplexy, sleep paralysis and hypnagogic hallucinations) while extensive neuropsychiatric work up was negative for any neurologic or psychiatric illness. Repeat polysomnograms (including a polysomnogram with a full seizure montage) were positive for pathologic sleepiness, but there was no evidence of a seizure disorder. The course of the patient's symptomatology and the favourable response of his symptoms to stimulants and imipramine support the theory that his intermittent loss of sphincter control is part of his narcolepsy-cataplexy. PMID:8796217

No Evidence for Disease History as a Risk Factor for Narcolepsy after A(H1N1)pdm09 Vaccination.

PubMed

Lamb, Favelle; Ploner, Alexander; Fink, Katharina; Maeurer, Markus; Bergman, Peter; Piehl, Fredrik; Weibel, Daniel; Sparén, Pär; Dahlström, Lisen Arnheim

2016-01-01

To investigate disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy. Case-control study in Sweden. Cases included persons referred for a Multiple Sleep Latency Test between 2009 and 2010, identified through diagnostic sleep centres and confirmed through independent review of medical charts. Controls, selected from the total population register, were matched to cases on age, gender, MSLT-referral date and county of residence. Disease history (prescriptions and diagnoses) and vaccination history was collected through telephone interviews and population-based healthcare registers. Conditional logistic regression was used to investigate disease history before A(H1N1)pdm09 vaccination as a risk-factor for narcolepsy. In total, 72 narcolepsy cases and 251 controls were included (range 3-69 years mean19-years). Risk of narcolepsy was increased in individuals with a disease history of nervous system disorders (OR range = 3.6-8.8) and mental and behavioural disorders (OR = 3.8, 95% CI 1.6-8.8) before referral. In a second analysis of vaccinated individuals only, nearly all initial associations were no longer statistically significant and effect sizes were smaller (OR range = 1.3-2.6). A significant effect for antibiotics (OR = 0.4, 95% CI 0.2-0.8) and a marginally significant effect for nervous system disorders was observed. In a third case-only analysis, comparing cases referred before vaccination to those referred after; prescriptions for nervous system disorders (OR = 26.0 95% CI 4.0-170.2) and ADHD (OR = 35.3 95% CI 3.4-369.9) were statistically significant during the vaccination period, suggesting initial associations were due to confounding by indication. The findings of this study do not support disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy.

Regional cerebral blood flow changes associated with focal electrically administered seizure therapy (FEAST).

PubMed

Chahine, George; Short, Baron; Spicer, Ken; Schmidt, Matthew; Burns, Carol; Atoui, Mia; George, Mark S; Sackeim, Harold A; Nahas, Ziad

2014-01-01

Use of electroconvulsive therapy (ECT) is limited by cognitive disturbance. Focal electrically-administered seizure therapy (FEAST) is designed to initiate focal seizures in the prefrontal cortex. To date, no studies have documented the effects of FEAST on regional cerebral blood flow (rCBF). A 72 year old depressed man underwent three single photon emission computed tomography (SPECT) scans to capture the onset and resolution of seizures triggered with right unilateral FEAST. We used Bioimage Suite for within-subject statistical analyses of perfusion differences ictally and post-ictally compared with the baseline scan. Early ictal increases in regional cerebral blood flow (rCBF) were limited to the right prefrontal cortex. Post-ictally, perfusion was reduced in bilateral frontal and occipital cortices and increased in left motor and precuneus cortex. FEAST appears to triggers focal onsets of seizure activity in the right prefrontal cortex with subsequent generalization. Future studies are needed on a larger sample. Copyright © 2014 Elsevier Inc. All rights reserved.

Identifying clinically important difference on the Epworth Sleepiness Scale: results from a narcolepsy clinical trial of JZP-110.

PubMed

Scrima, Lawrence; Emsellem, Helene A; Becker, Philip M; Ruoff, Chad; Lankford, Alan; Bream, Gary; Khayrallah, Moise; Lu, Yuan; Black, Jed

2017-10-01

While scores ≤10 on the Epworth Sleepiness Scale (ESS) are within the normal range, the reduction in elevated ESS score that is clinically meaningful in patients with narcolepsy has not been established. This post hoc analysis of a clinical trial of patients with narcolepsy evaluated correlations between Patient Global Impression of Change (PGI-C) and ESS. Data of adult patients with narcolepsy from a double-blind, 12-week placebo-controlled study of JZP-110, a wake-promoting agent, were used in this analysis. Descriptive statistics and receiver operating characteristic (ROC) analysis compared PGI-C (anchor measure) to percent change from baseline in ESS to establish the responder criterion from patients taking either placebo or JZP-110 (treatments). At week 12, patients (n = 10) who reported being "very much improved" on the PGI-C had a mean 76.7% reduction in ESS score, and patients (n = 33) who reported being "much improved" on the PGI-C had a mean 49.1% reduction in ESS score. ROC analysis showed that patients who improved were almost exclusively from JZP-110 treatment group, with an area-under-the-curve of 0.9, and revealed that a 25% reduction in ESS (sensitivity, 81.4%; specificity, 80.9%) may be an appropriate threshold for defining a meaningful patient response to JZP-110 and placebo. A ≥25% reduction in patients' subjective ESS score may be useful as a threshold to identify patients with narcolepsy who respond to JZP-110 treatment. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Normal Morning Melanin-Concentrating Hormone Levels and No Association with Rapid Eye Movement or Non-Rapid Eye Movement Sleep Parameters in Narcolepsy Type 1 and Type 2.

PubMed

Schrölkamp, Maren; Jennum, Poul J; Gammeltoft, Steen; Holm, Anja; Kornum, Birgitte R; Knudsen, Stine

2017-02-15

Other than hypocretin-1 (HCRT-1) deficiency in narcolepsy type 1 (NT1), the neurochemical imbalance of NT1 and narcolepsy type 2 (NT2) with normal HCRT-1 levels is largely unknown. The neuropeptide melanin-concentrating hormone (MCH) is mainly secreted during sleep and is involved in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep regulation. Hypocretin neurons reciprocally interact with MCH neurons. We hypothesized that altered MCH secretion contributes to the symptoms and sleep abnormalities of narcolepsy and that this is reflected in morning cerebrospinal fluid (CSF) MCH levels, in contrast to previously reported normal evening/afternoon levels. Lumbar CSF and plasma were collected from 07:00 to 10:00 from 57 patients with narcolepsy (subtypes: 47 NT1; 10 NT2) diagnosed according to International Classification of Sleep Disorders, Third Edition (ICSD-3) and 20 healthy controls. HCRT-1 and MCH levels were quantified by radioimmunoassay and correlated with clinical symptoms, polysomnography (PSG), and Multiple Sleep Latency Test (MSLT) parameters. CSF and plasma MCH levels were not significantly different between narcolepsy patients regardless of ICSD-3 subtype, HCRT-1 levels, or compared to controls. CSF MCH and HCRT-1 levels were not significantly correlated. Multivariate regression models of CSF MCH levels, age, sex, and body mass index predicting clinical, PSG, and MSLT parameters did not reveal any significant associations to CSF MCH levels. Our study shows that MCH levels in CSF collected in the morning are normal in narcolepsy and not associated with the clinical symptoms, REM sleep abnormalities, nor number of muscle movements during REM or NREM sleep of the patients. We conclude that morning lumbar CSF MCH measurement is not an informative diagnostic marker for narcolepsy. © 2017 American Academy of Sleep Medicine

A Mobile Device for Measuring Regional Cerebral Circulation

PubMed Central

Howard, George; Griffith, David W.; Stump, David A.; Hinschelwood, Laura

1980-01-01

Immobility and costs of currently available regional cerebral blood flow (rCBF) equipment usually require having a single fixed blood flow lab, which cannot be used to study non-ambulatory patients who are often the most interesting to study. After careful study of the information flow between the steps involved in the collection, analysis and display of data, a new rCBF machine has been developed with a mobile satellite and a host processor. The satellite is equipped with a Z-80 microprocessor which controls the data collection, screen formating, data display and communications with the host. The host provides the processing power necessary for moderately complex curve fitting and data storage.

Prevalence of the HLA-DQB1*0602 allele in narcolepsy and idiopathic hypersomnia patients seen at a sleep disorders outpatient unit in São Paulo.

PubMed

Coelho, Fernando Morgadinho Santos; Pradella-Hallinan, Márcia; Predazzoli Neto, Mario; Bittencourt, Lia Rita Azeredo; Tufik, Sérgio

2009-03-01

Narcolepsy (with and without cataplexy) and idiopathic hypersomnia, are disorders with common features but with different HLA-DQB1*0602 allele prevalence. The present study describes the prevalence of HLA-DQB1*0602 allele in narcoleptics with and without cataplexy and in patients with idiopathic hypersomnia. Subjects comprised 68 patients who were diagnosed for narcolepsy or idiopathic hypersomnia and 23 healthy controls according to the International Classification of Sleep Disorders-2. Subjects comprised 43 patients with narcolepsy and cataplexy, 11 patients with narcolepsy but without cataplexy, 14 patients with idiopathic hypersomnia and 23 healthy controls. Genotyping of HLA-DQB1*0602 allele was performed for all subjects. The prevalence of the HLA-DQB1*0602 allele was increased in idiopathic hypersomnia and in narcoleptic patients with and without cataplexy when compared to healthy subjects (p = 0.04; p = 0.03 and p < 0.0001, respectively). This finding is in accordance with those of previous studies. The gold standard exam of narcolepsy with cataplexy is Hypocretin-1 dosage, but in patients without cataplexy and idiopathic hypersomnia, there are no specific diagnostic lab findings. The presence of the HLA-DQB1* 0602 allele may be important for the differential diagnosis of situations that resemble those sleep disorders such as secondary changes in sleep structure due to drugs' consumption.

Psychiatric comorbidity and cognitive profile in children with narcolepsy with or without association to the H1N1 influenza vaccination.

PubMed

Szakács, Attila; Hallböök, Tove; Tideman, Pontus; Darin, Niklas; Wentz, Elisabet

2015-04-01

To evaluate psychiatric comorbidity and the cognitive profile in children and adolescents with narcolepsy in western Sweden and the relationship of these problems to H1N1 vaccination. Thirty-eight patients were included in the study. We performed a population-based, cross-sectional study to investigate psychiatric comorbidity using a test battery of semistructured interviews generating Diagnostic and Statistical Manual of Mental Disorders, 4th Edition diagnoses, including the Development and Well-Being Assessment and the attention deficit hyperactivity disorder rating scale. The Autism Spectrum Screening Questionnaire and the Positive and Negative Syndrome Scale were used to screen for autistic traits and psychotic symptoms, respectively. The cognitive assessments were made by a clinical psychologist using the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, the Wechsler Intelligence Scale for Children, Fourth Edition, or the Wechsler Adult Intelligence Scale, Fourth Edition. In the post-H1N1 vaccination (PHV) narcolepsy group (n = 31), 43% of patients had psychiatric comorbidity, 29% had attention deficit hyperactivity disorder (ADHD) inattentive type, 20% had major depression, 10% had general anxiety disorder, 7% had oppositional defiant disorder (ODD), 3% had pervasive developmental disorder not otherwise specified (i.e., atypical autism), and 3% had eating disorder not otherwise specified (anorectic type). In the non-post-H1N1 vaccination (nPHV) narcolepsy group, one of seven patients had ADHD, inattentive type and ODD. The most frequent psychiatric symptom was temper tantrums, which occurred in 94% of the patients in the PHV group and 71% of the patients in the nPHV narcolepsy group. The cognitive assessment profile was similar in both groups and showed normal results for mean full-scale IQ and perceptual speed but decreased verbal comprehension and working memory. Patients with psychiatric comorbidity had a significantly lower full

Quality of life and trust among young people with narcolepsy and their families, after the Pandemrix® vaccination: protocol for a case-control study.

PubMed

Blomberg, Karin; Carlsson, Agneta Anderzén; Hagberg, Lars; Jonsson, Östen; Leissner, Lena; Eriksson, Mats H

2017-08-23

The extensive vaccination programme against swine flu resulted in an increased incidence of narcolepsy among children and adolescents. There is a need to explore if these young persons' experiences have affected their trust in healthcare, their willingness to participate in future prevention programmes, and their contacts with the healthcare system. The overall aim is to identify factors important for the life-situation of children and adolescents with narcolepsy and their families, and factors that correlate with trust in healthcare. Data will be collected via questionnaires from all available children with narcolepsy following the vaccination and their families, as well as a control group of children with diabetes and their families. Longitudinal descriptive interviews will also be conducted with a selection of 20-25 children and their families. Techniques from media research will be used for Internet-based data collection and analysis of information relating to narcolepsy from social media. This project will use the situation of young persons with narcolepsy after the swine flu vaccination as a case to build a model that can be used in situations where trust in healthcare is essential. This model will be based on findings from the included studies on how trust is influenced by support, quality of life, burden of disease, impact on family, and use of social media. The model developed in this project will be beneficial in future situations where trust in healthcare is essential, such as new pandemic outbreaks but also for "everyday" adherence to health advice.

Differential diagnosis of regional cerebral hyperfixation of TC-99m HMPAO on SPECT imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shirazi, P.; Konopka, L.; Crayton, J.W.

1994-05-01

Accurate diagnostic evaluation of patients with neurologic and neuropsychiatric disease is important because early treatment may halt disease progression and prevent impairment or disability. Cerebral hyperfixation of HMPAO has been ascribed to luxury perfusion following ischemic infarction. The present study sought to identify other conditions that also display radiotracer hyperfixation in order to develop a differential diagnosis of this finding on SPECT imaging. Two hundred fifty (n=250) successive cerebral SPECT images were reviewed for evidence of HMPAO hyperfixation. Hyperfixation was defined as enhanced focal perfusion surrounded by a zone of diminished or normal cerebral perfusion. All patients were scanned aftermore » intravenous injection of 25 mCi Tc-99m HMPAO. Volume-rendered and oblique images were obtained with a Trionix triple-head SPECT system using ultra high resolution fan beam collimators. Thirteen (13/250; 5%) of the patients exhibited regions of HMPAO hyperfixation. CT or MRI abnormalities were detected in 6/13 cases. Clinical diagnoses in these patients included intractable psychosis, post-traumatic stress disorder, alcohol and narcotic dependence, major depression, acute closed-head trauma, hypothyroidism, as well as subacute ischemic infarction. A wide variety of conditions may be associated with cerebral hyperfixation of HMPAO. These conditions include neurologic and psychiatric diagnoses, and extend the consideration of hyperfixation beyond ischemic infarction. Consequently, a differential diagnosis of HMPAO hyperfixation may be broader than originally considered, and this may suggest a fundamental role for local cerebral hyperperfusion. Elucidation of the fundamental mechanism(s) for cerebral hyperperfusion requires further investigation.« less

Assessing narcolepsy with cataplexy in children and adolescents: development of a cataplexy diary and the ESS-CHAD

PubMed Central

Wang, Y Grace; Benmedjahed, Khadra; Lambert, Jérémy; Evans, Christopher J; Hwang, Steve; Black, Jed; Johns, Murray W

2017-01-01

Objective The aim of this study was to qualitatively evaluate concepts for incorporation into a daily diary to capture cataplexy frequency and to assess the content validity of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) in pediatric patients with narcolepsy. Patients and methods Face-to-face concept elicitation and cognitive interviews were conducted with children (7–9 years; n=13) and adolescents (10–17 years; n=16) who have narcolepsy with cataplexy, and their parents/caregivers. Results Similarities and differences were noted between narcolepsy concepts described by children and their parents/caregivers, suggesting some different but complementary perspectives; parents may not recognize cataplexy symptoms/triggers as well as children, but parents have greater recognition of the circumstances of falling asleep. Cataplexy diary modifications included changes in definitions and examples of cataplexy, using child-friendly terminology, adding a quantitative question to determine daily frequency, and standardizing the questionnaire for evening administration with self-completion by the child. Modifications were made to ESS-CHAD for child-friendly wording and to ensure that items reflect activities (eating, watching TV/video) and environments (school, bus/car transport) in which children are likely to participate. Two ESS-CHAD versions were proposed: one with a 1-month recall period, for general use, and the other with a recall period of “since your last study visit,” for research, which could be shorter or longer than 1 month (as short as 1 week). Conclusion The cataplexy diary and ESS-CHAD were modified for the assessment of children and adolescents. Further psychometric validation is recommended. These measures are being used in a Phase III, placebo-controlled clinical trial of sodium oxybate in children and adolescents with narcolepsy. PMID:28860883

Increased β-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases.

PubMed

Ambati, A; Poiret, T; Svahn, B-M; Valentini, D; Khademi, M; Kockum, I; Lima, I; Arnheim-Dahlström, L; Lamb, F; Fink, K; Meng, Q; Kumar, A; Rane, L; Olsson, T; Maeurer, M

2015-09-01

Type 1 narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy associated with the HLA allele DQB1*06:02. Genetic predisposition along with external triggering factors may drive autoimmune responses, ultimately leading to the selective loss of hypocretin-positive neurons. The aim of this study was to investigate potential aetiological factors in Swedish cases of postvaccination (Pandemrix) narcolepsy defined by interferon-gamma (IFNγ) production from immune cells in response to molecularly defined targets. Cellular reactivity defined by IFNγ production was examined in blood from 38 (HLA-DQB1*06:02(+) ) Pandemrix-vaccinated narcolepsy cases and 76 (23 HLA-DQB1*06:02(+) and 53 HLA-DQB1*06:02(-) ) control subjects, matched for age, sex and exposure, using a variety of different antigens: β-haemolytic group A streptococcal (GAS) antigens (M5, M6 and streptodornase B), influenza (the pandemic A/H1N1/California/7/09 NYMC X-179A and A/H1N1/California/7/09 NYMC X-181 vaccine antigens, previous Flu-A and -B vaccine targets, A/H1N1/Brisbane/59/2007, A/H1N1/Solomon Islands/3/2006, A/H3N2/Uruguay/716/2007, A/H3N2/Wisconsin/67/2005, A/H5N1/Vietnam/1203/2004 and B/Malaysia/2506/2004), noninfluenza viral targets (CMVpp65, EBNA-1 and EBNA-3) and auto-antigens (hypocretin peptide, Tribbles homolog 2 peptide cocktail and extract from rat hypothalamus tissue). IFN-γ production was significantly increased in whole blood from narcolepsy cases in response to streptococcus serotype M6 (P = 0.0065) and streptodornase B protein (P = 0.0050). T-cell recognition of M6 and streptodornase B was confirmed at the single-cell level by intracellular cytokine (IL-2, IFNγ, tumour necrosis factor-alpha and IL-17) production after stimulation with synthetic M6 or streptodornase B peptides. Significantly, higher (P = 0.02) titres of serum antistreptolysin O were observed in narcolepsy cases, compared to vaccinated controls. β-haemolytic GAS may be

Characterization of REM sleep without atonia in patients with narcolepsy and idiopathic hypersomnia using AASM scoring manual criteria.

PubMed

DelRosso, Lourdes M; Chesson, Andrew L; Hoque, Romy

2013-07-15

The AASM Manual for the Scoring of Sleep and Associated Events (Manual) has provided standardized definitions for tonic and phasic REM sleep without atonia (RSWA). This study used Manual criteria to characterize REM sleep in patients with narcolepsy and idiopathic hypersomnia (IH). A retrospective review of PSG data from ICSD-2 defined patients with narcolepsy or IH, performed by two board certified sleep medicine physicians. Data compiled included REM sleep epochs and the presence in REM sleep of epochs scored as sustained muscle activity (tonic), and excessive transient muscle activity (phasic) as defined by Manual criteria. PSG data from 8 narcolepsy patients (mean age: 27.5 years; age range: 11-55) showed mean ± standard deviation values for: total REM sleep epochs 205 ± 46.1; RSWA/ phasic epochs 56.1 ± 25.4; and RSWA/tonic epochs 15.0 ± 10.7. PSG data from 8 IH patients (mean age: 33.1 years; age range: 20-57) showed mean ± standard deviation values of total REM sleep epochs 163.8 ± 67.9; RSWA/phasic epochs 6.2 ± 3.5; and RSWA/tonic epochs 0.2 ± 0.4. Comparison revealed intergroup differences in phasic REM sleep (p < 0.01) and tonic REM sleep (p < 0.01) were significantly increased in narcoleptics compared to IH. Our retrospective analysis showed that RSWA phasic activity and RSWA tonic activity are significantly increased in patients meeting ICSD-2 criteria for narcolepsy compared to patients meeting ICSD-2 criteria for IH. This robust difference, with further validation, could be useful as electrophysiological criteria differentiating the two disorders and understanding the physiological differences.

Diagnostic value of sleep stage dissociation as visualized on a 2-dimensional sleep state space in human narcolepsy.

PubMed

Olsen, Anders Vinther; Stephansen, Jens; Leary, Eileen; Peppard, Paul E; Sheungshul, Hong; Jennum, Poul Jørgen; Sorensen, Helge; Mignot, Emmanuel

2017-04-15

Type 1 narcolepsy (NT1) is characterized by symptoms believed to represent Rapid Eye Movement (REM) sleep stage dissociations, occurrences where features of wake and REM sleep are intermingled, resulting in a mixed state. We hypothesized that sleep stage dissociations can be objectively detected through the analysis of nocturnal Polysomnography (PSG) data, and that those affecting REM sleep can be used as a diagnostic feature for narcolepsy. A Linear Discriminant Analysis (LDA) model using 38 features extracted from EOG, EMG and EEG was used in control subjects to select features differentiating wake, stage N1, N2, N3 and REM sleep. Sleep stage differentiation was next represented in a 2D projection. Features characteristic of sleep stage differences were estimated from the residual sleep stage probability in the 2D space. Using this model we evaluated PSG data from NT1 and non-narcoleptic subjects. An LDA classifier was used to determine the best separation plane. This method replicates the specificity/sensitivity from the training set to the validation set better than many other methods. Eight prominent features could differentiate narcolepsy and controls in the validation dataset. Using a composite measure and a specificity cut off 95% in the training dataset, sensitivity was 43%. Specificity/sensitivity was 94%/38% in the validation set. Using hypersomnia subjects, specificity/sensitivity was 84%/15%. Analyzing treated narcoleptics the specificity/sensitivity was 94%/10%. Sleep stage dissociation can be used for the diagnosis of narcolepsy. However the use of some medications and presence of undiagnosed hypersomnolence patients impacts the result. Copyright © 2017 Elsevier B.V. All rights reserved.

Regional gray matter growth, sexual dimorphism, and cerebral asymmetry in the neonatal brain.

PubMed

Gilmore, John H; Lin, Weili; Prastawa, Marcel W; Looney, Christopher B; Vetsa, Y Sampath K; Knickmeyer, Rebecca C; Evans, Dianne D; Smith, J Keith; Hamer, Robert M; Lieberman, Jeffrey A; Gerig, Guido

2007-02-07

Although there has been recent interest in the study of childhood and adolescent brain development, very little is known about normal brain development in the first few months of life. In older children, there are regional differences in cortical gray matter development, whereas cortical gray and white matter growth after birth has not been studied to a great extent. The adult human brain is also characterized by cerebral asymmetries and sexual dimorphisms, although very little is known about how these asymmetries and dimorphisms develop. We used magnetic resonance imaging and an automatic segmentation methodology to study brain structure in 74 neonates in the first few weeks after birth. We found robust cortical gray matter growth compared with white matter growth, with occipital regions growing much faster than prefrontal regions. Sexual dimorphism is present at birth, with males having larger total brain cortical gray and white matter volumes than females. In contrast to adults and older children, the left hemisphere is larger than the right hemisphere, and the normal pattern of fronto-occipital asymmetry described in older children and adults is not present. Regional differences in cortical gray matter growth are likely related to differential maturation of sensory and motor systems compared with prefrontal executive function after birth. These findings also indicate that whereas some adult patterns of sexual dimorphism and cerebral asymmetries are present at birth, others develop after birth.

Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats.

PubMed

Cauli, Omar; López-Larrubia, Pilar; Rodrigo, Regina; Agusti, Ana; Boix, Jordi; Nieto-Charques, Laura; Cerdán, Sebastián; Felipo, Vicente

2011-02-01

Patients with acute liver failure (ALF) often die of intracranial pressure (IP) and cerebral herniation. Main contributors to increased IP are ammonia, glutamine, edema, and blood flow. The sequence of events and underlying mechanisms, as well as the temporal pattern, regional distribution, and contribution of each parameter to the progression of neurologic deterioration and IP, are unclear. We studied rats with ALF to follow the progression of changes in ammonia, glutamine, grade and type (vasogenic or cytotoxic) of edema, blood-brain barrier permeability, cerebral blood flow, and IP. We assessed whether the changes in these parameters were similar between frontal cortex and cerebellum and evaluated the presence, type, and progression of edema in 12 brain areas. ALF was induced by injection of galactosamine. The grade and type of edema was assessed by measuring the apparent diffusion coefficient by magnetic resonance imaging. Cerebral blood flow was measured by magnetic resonance and blood-brain barrier permeability by Evans blue-albumin extravasation. Increased IP arises from an early increase of blood-brain barrier permeability in certain areas (including cerebellum but not frontal cortex) followed by vasogenic edema. Ammonia and glutamine then increase progressively, leading to cytotoxic edema in many areas. Alterations in lactate and cerebral blood flow are later events that further increase IP. Different mechanisms in specific regions of the brain contribute, with different temporal patterns, to the progression of cerebral alterations and IP in ALF. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Meta-analyses of structural regional cerebral effects in type 1 and type 2 diabetes.

PubMed

Moulton, Calum D; Costafreda, Sergi G; Horton, Paul; Ismail, Khalida; Fu, Cynthia H Y

2015-12-01

Diabetes is associated with macrovascular and microvascular complications and is a major risk factor for neurological and psychiatric disorders, such as dementia and depression. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) have distinct etiologies and pathophysiological effects while sharing a common endpoint of persistent hyperglycemia. Neuroimaging studies in T1DM have revealed reductions in numerous regions, including the parahippocampal and occipital regions, while in T2DM there have been numerous reports of hippocampal atrophy. This meta-analysis aimed to identify consistent regional abnormalities in cerebral structures in T1DM and T2DM respectively, and also to examine the impact of potential confounds, including age, depression and vascular risk factors. Neuroimaging studies of both voxel-based morphometry (VBM) data and volumetric data were included. Ten T1DM studies (n = 613 patients) and 23 T2DM studies (n = 1364 patients) fulfilled inclusion criteria. The T1DM meta-analysis revealed reduced bilateral thalamus grey matter density in adults. The T2DM meta-analysis revealed reduced global brain volume and regional atrophy in the hippocampi, basal ganglia, and orbitofrontal and occipital lobes. Moreover, hippocampal atrophy in T2DM was not modified by hypertension, although there were more marked reductions in younger patients relative to healthy controls. In conclusion, T1DM and T2DM demonstrated distinct cerebral effects with generalised and specific target areas of grey matter reduction. Thalamic atrophy in T1DM may be a substrate of associated cognitive deficits. In T2DM, global cerebral atrophy may reflect atherosclerotic factors, while hippocampal atrophy was an independent effect providing a potential common neuropathological etiology for the comorbidity of T2DM with dementia and depression.

Regional cerebral blood flow in Parkinson disease with nonpsychotic visual hallucinations.

PubMed

Oishi, N; Udaka, F; Kameyama, M; Sawamoto, N; Hashikawa, K; Fukuyama, H

2005-12-13

Patients with Parkinson disease (PD) often experience visual hallucinations (VH) with retained insight (nonpsychotic) but the precise mechanism remains unclear. To clarify which neural substrates participate in nonpsychotic VH in PD, the authors evaluated regional cerebral blood flow (rCBF) changes in patients with PD and VH. The authors compared 24 patients with PD who had nonpsychotic VH (hallucinators) and 41 patients with PD who had never experienced VH (non-hallucinators) using SPECT images with N-isopropyl-p-[(123)I]iodoamphetamine. There were no significant differences in age, sex, duration of disease, doses of PD medications, Hoehn and Yahr scale, or Mini-Mental State Examination (MMSE) scores between the two groups. The rCBF data were analyzed using statistical parametric mapping (SPM). The rCBF in the right fusiform gyrus was lower in the hallucinators than in the non-hallucinators (corrected p < 0.05 at cluster levels). The hallucinators revealed higher rCBF in the right superior and middle temporal gyri than the non-hallucinators (uncorrected p < 0.001). These significant differences were demonstrated after MMSE scores and duration of disease, which are the relevant factors associated with VH, were covariated out. Nonpsychotic visual hallucinations in Parkinson disease (PD) may be associated with hypoperfusion in the right fusiform gyrus and hyperperfusion in the right superior and middle temporal gyri. These temporal regions are important for visual object recognition and these regional cerebral blood flow changes are associated with inappropriate visual processing and are responsible for nonpsychotic visual hallucinations in PD.

Main Effects of Diagnoses, Brain Regions, and their Interaction Effects for Cerebral Metabolites in Bipolar and Unipolar Depressive Disorders

NASA Astrophysics Data System (ADS)

Tan, Hai-Zhu; Li, Hui; Liu, Chen-Feng; Guan, Ji-Tian; Guo, Xiao-Bo; Wen, Can-Hong; Ou, Shao-Min; Zhang, Yin-Nan; Zhang, Jie; Xu, Chong-Tao; Shen, Zhi-Wei; Wu, Ren-Hua; Wang, Xue-Qin

2016-11-01

Previous studies suggested patients with bipolar depressive disorder (BDd) or unipolar depressive disorder (UDd) have cerebral metabolites abnormalities. These abnormalities may stem from multiple sub-regions of gray matter in brain regions. Thirteen BDd patients, 20 UDd patients and 20 healthy controls (HC) were enrolled to investigate these abnormalities. Absolute concentrations of 5 cerebral metabolites (glutamate-glutamine (Glx), N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), parietal cortex (PC)) were measured from 4 subregions (the medial frontal cortex (mPFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and parietal cortex (PC)) of gray matter. Main and interaction effects of cerebral metabolites across subregions of gray matter were evaluated. For example, the Glx was significantly higher in BDd compared with UDd, and so on. As the interaction analyses showed, some interaction effects existed. The concentrations of BDds’ Glx, Cho, Cr in the ACC and HCs’ mI and Cr in the PC were higher than that of other interaction effects. In addition, the concentrations of BDds’ Glx and Cr in the PC and HCs’ mI in the ACC were statistically significant lower than that of other interaction effects. These findings point to region-related abnormalities of cerebral metabolites across subjects with BDd and UDd.

Main Effects of Diagnoses, Brain Regions, and their Interaction Effects for Cerebral Metabolites in Bipolar and Unipolar Depressive Disorders.

PubMed

Tan, Hai-Zhu; Li, Hui; Liu, Chen-Feng; Guan, Ji-Tian; Guo, Xiao-Bo; Wen, Can-Hong; Ou, Shao-Min; Zhang, Yin-Nan; Zhang, Jie; Xu, Chong-Tao; Shen, Zhi-Wei; Wu, Ren-Hua; Wang, Xue-Qin

2016-11-21

Previous studies suggested patients with bipolar depressive disorder (BDd) or unipolar depressive disorder (UDd) have cerebral metabolites abnormalities. These abnormalities may stem from multiple sub-regions of gray matter in brain regions. Thirteen BDd patients, 20 UDd patients and 20 healthy controls (HC) were enrolled to investigate these abnormalities. Absolute concentrations of 5 cerebral metabolites (glutamate-glutamine (Glx), N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), parietal cortex (PC)) were measured from 4 subregions (the medial frontal cortex (mPFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and parietal cortex (PC)) of gray matter. Main and interaction effects of cerebral metabolites across subregions of gray matter were evaluated. For example, the Glx was significantly higher in BDd compared with UDd, and so on. As the interaction analyses showed, some interaction effects existed. The concentrations of BDds' Glx, Cho, Cr in the ACC and HCs' mI and Cr in the PC were higher than that of other interaction effects. In addition, the concentrations of BDds' Glx and Cr in the PC and HCs' mI in the ACC were statistically significant lower than that of other interaction effects. These findings point to region-related abnormalities of cerebral metabolites across subjects with BDd and UDd.

A broadband continuous-wave multichannel near-infrared system for measuring regional cerebral blood flow and oxygen consumption in newborn piglets.

PubMed

Diop, Mamadou; Elliott, Jonathan T; Tichauer, Kenneth M; Lee, Ting-Yim; St Lawrence, Keith

2009-05-01

Near-infrared spectroscopy (NIRS) is a promising technique for assessing brain function in newborns, particularly due to its portability and sensitivity to cerebral hemodynamics and oxygenation. Methods for measuring cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)) have been developed based on broadband continuous-wave NIRS. However, broadband NIRS apparatus typically have only one detection channel, which limits their applicability to measuring regional CBF and CMRO(2). In this study, a relatively simple multiplexing approach based on electronically controlled mechanical shutters is proposed to expand the detection capabilities from one to eight channels. The tradeoff is an increase in the sampling interval; however, this has negligible effects on CBF measurements for intervals less than or equal to 1 s. The ability of the system to detect focal brain injury was demonstrated in piglets by injecting endothelin-1 (ET-1) into the cerebral cortex. For validation, CBF was independently measured by computed tomography (CT) perfusion. The average reduction in CBF from the source-detector pair that interrogated the injured region was 51%+/-9%, which was in good agreement with the CBF reduction measured by CT perfusion (55%+/-5%). No significant changes in regional CMRO(2) were observed. The average regional differential pathlength prior to ET-1 injection was 8.4+/-0.2 cm (range of 7.1-9.6 cm) and did not significantly change after the injury.

Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice.

PubMed

Drakatos, Panagis; Lykouras, Dimosthenis; D'Ancona, Grainne; Higgins, Sean; Gildeh, Nadia; Macavei, Raluca; Rosenzweig, Ivana; Steier, Joerg; Williams, Adrian J; Muza, Rexford; Kent, Brian D; Leschziner, Guy

2017-07-01

Sodium oxybate is licensed in Europe for the treatment of narcolepsy with cataplexy in adults. The aim of this study was to assess the efficacy and safety of sodium oxybate in clinical practice in patients with narcolepsy and cataplexy refractory to other treatments. This was a retrospective single centre study including patients with severe narcolepsy with cataplexy refractory to other treatments, who were initiated on sodium oxybate between 2009 and 2015. Patients were allowed to be on other stimulants or/and anti-cataplectic agents. Epworth sleepiness scale (ESS) and weekly cataplexy events were recorded. Side effects (SEs) were recorded at every follow-up visit. 90 patients were prescribed sodium oxybate, with a total of 3116 patient-months of drug exposure. ESS and weekly cataplexy events were significantly reduced by sodium oxybate for all patients (ΔESS = 4.3 ± 4.4 and Δcataplexy = 21.8 ± 18.5 events/week; p < 0.0001, respectively). The required maintenance dose could not be predicted based upon gender, body mass index, or clinical factors. 60% of patients were able to reduce or come off other medications. Half of the patients experienced at least one SE, and 26.6% had to stop treatment due to limiting SEs. Nausea, mood swings and enuresis were the most commonly reported SEs. SEs that led to drug discontinuation, particularly psychosis, were associated with increasing age and were observed early after the initiation of the drug. Sodium oxybate provides a good clinical efficacy and acceptable safety profile in routine clinical practice for the treatment of patients suffering from narcolepsy with cataplexy. A quarter of patients experience SEs requiring withdrawal of the drug with older patients being more vulnerable to the more serious SEs. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Regional vulnerability of longitudinal cortical association connectivity: Associated with structural network topology alterations in preterm children with cerebral palsy.

PubMed

Ceschin, Rafael; Lee, Vince K; Schmithorst, Vince; Panigrahy, Ashok

2015-01-01

Preterm born children with spastic diplegia type of cerebral palsy and white matter injury or periventricular leukomalacia (PVL), are known to have motor, visual and cognitive impairments. Most diffusion tensor imaging (DTI) studies performed in this group have demonstrated widespread abnormalities using averaged deterministic tractography and voxel-based DTI measurements. Little is known about structural network correlates of white matter topography and reorganization in preterm cerebral palsy, despite the availability of new therapies and the need for brain imaging biomarkers. Here, we combined novel post-processing methodology of probabilistic tractography data in this preterm cohort to improve spatial and regional delineation of longitudinal cortical association tract abnormalities using an along-tract approach, and compared these data to structural DTI cortical network topology analysis. DTI images were acquired on 16 preterm children with cerebral palsy (mean age 5.6 ± 4) and 75 healthy controls (mean age 5.7 ± 3.4). Despite mean tract analysis, Tract-Based Spatial Statistics (TBSS) and voxel-based morphometry (VBM) demonstrating diffusely reduced fractional anisotropy (FA) reduction in all white matter tracts, the along-tract analysis improved the detection of regional tract vulnerability. The along-tract map-structural network topology correlates revealed two associations: (1) reduced regional posterior-anterior gradient in FA of the longitudinal visual cortical association tracts (inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, optic radiation, posterior thalamic radiation) correlated with reduced posterior-anterior gradient of intra-regional (nodal efficiency) metrics with relative sparing of frontal and temporal regions; and (2) reduced regional FA within frontal-thalamic-striatal white matter pathways (anterior limb/anterior thalamic radiation, superior longitudinal fasciculus and cortical spinal tract) correlated with

Core Body and Skin Temperature in Type 1 Narcolepsy in Daily Life; Effects of Sodium Oxybate and Prediction of Sleep Attacks

PubMed Central

van der Heide, Astrid; Werth, Esther; Donjacour, Claire E.H.M.; Reijntjes, Robert H.A.M.; Lammers, Gert Jan; Van Someren, Eus J.W.; Baumann, Christian R.; Fronczek, Rolf

2016-01-01

Study Objectives: Previous laboratory studies in narcolepsy patients showed altered core body and skin temperatures, which are hypothesised to be related to a disturbed sleep wake regulation. In this ambulatory study we assessed temperature profiles in normal daily life, and whether sleep attacks are heralded by changes in skin temperature. Furthermore, the effects of three months of treatment with sodium oxybate (SXB) were investigated. Methods: Twenty-five narcolepsy patients and 15 healthy controls were included. Core body, proximal and distal skin temperatures, and sleep-wake state were measured simultaneously for 24 hours in ambulatory patients. This procedure was repeated in 16 narcolepsy patients after at least 3 months of stable treatment with SXB. Results: Increases in distal skin temperature and distal-to-proximal temperature gradient (DPG) strongly predicted daytime sleep attacks (P < 0.001). As compared to controls, patients had a higher proximal and distal skin temperature in the morning, and a lower distal skin temperature during the night (all P < 0.05). Furthermore, they had a higher core body temperature during the first part of the night (P < 0.05), which SXB decreased (F = 4.99, df = 1, P = 0.03) to a level similar to controls. SXB did not affect skin temperature. Conclusions: This ambulatory study demonstrates that daytime sleep attacks were preceded by clear changes in distal skin temperature and DPG. Furthermore, changes in core body and skin temperature in narcolepsy, previously only studied in laboratory settings, were partially confirmed. Treatment with SXB resulted in a normalisation of the core body temperature profile. Future studies should explore whether predictive temperature changes can be used to signal or even prevent sleep attacks. Citation: van der Heide A, Werth E, Donjacour CE, Reijntjes RH, Lammers GJ, Van Someren EJ, Baumann CR, Fronczek R. Core body and skin temperature in type 1 narcolepsy in daily life; effects of sodium

Relationship between white matter lesions and regional cerebral blood flow changes during longitudinal follow up in Alzheimer's disease.

PubMed

Hanaoka, Takuya; Kimura, Noriyuki; Aso, Yasuhiro; Takemaru, Makoto; Kimura, Yuki; Ishibashi, Masato; Matsubara, Etsuro

2016-07-01

The aim of the present study was to evaluate the relationship between baseline white matter lesions (WML) and changes in regional cerebral blood flow during longitudinal follow up of patients with Alzheimer's disease (AD). A total of 38 patients with AD were included in the study (16 men, 22 women; mean age 77.8 years). All patients were evaluated using the Mini-Mental State Examination and brain perfusion single-photon emission computed tomography at baseline with an approximately 2-year follow up. The patients were divided into two subgroups according to the presence of WML on magnetic resonance imaging. Single-photon emission computed tomography data were analyzed using a voxel-by-voxel group analysis with Statistical Parametric Mapping 8 and region of interest analysis using FineSRT. Changes in Mini-Mental State Examination scores and regional cerebral blood flow were analyzed using the Wilcoxon signed-rank test. Mean Mini-Mental State Examination scores in AD patients with WML significantly decreased from 19.4 ± 4.8 to 15.5 ± 6.5 (P = 0.003). Statistical Parametric Mapping 8 and FineSRT analysis showed more severe and widespread regional cerebral blood flow reduction, mainly in the frontal and mesial temporal regions in AD patients with WML compared with those without WML. Baseline WML could predict a rapid progression of cognitive and brain functional impairment during longitudinal follow up in AD. Geriatr Gerontol Int 2016; 16: 836-842. © 2015 Japan Geriatrics Society.

Decreased sleep stage transition pattern complexity in narcolepsy type 1.

PubMed

Ferri, Raffaele; Pizza, Fabio; Vandi, Stefano; Iloti, Martina; Plazzi, Giuseppe

2016-08-01

To analyze the complexity of the nocturnal sleep stage sequence in central disorders of hypersomnolence (CDH), with the hypothesis that narcolepsy type 1 (NT1) might exhibit distinctive sleep stage sequence organization and complexity. Seventy-nine NT1 patients, 22 narcolepsy type 2 (NT2), 22 idiopathic hypersomnia (IH), and 52 patients with subjective hypersomnolence (sHS) were recruited and their nocturnal sleep was polysomnographically recorded and scored. Group between-stage transition probability matrices were obtained and compared. Patients with NT1 differed significantly from all the other patient groups, the latter, in turn, were not different between each other. The individual probability of the R-to-N2 transition was found to be the parameter showing the difference of highest significance between the groups (lowest in NT1) and classified patients with or without NT1 with an accuracy of 78.9% (sensitivity 78.5% and specificity 79.2%), by applying a cut-off value of 0.15. The main result of this study is that the structure of the sleep stage transition pattern of hypocretin-deficient NT1 patients is significantly different from that of other forms of CDH and sHS, with normal hypocretin levels. The lower probability of R-to-N2 transition occurrence in NT1 appears to be a reliable polysomnographic feature with potential application at the individual level, for supportive diagnostic purposes. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

A broadband continuous-wave multichannel near-infrared system for measuring regional cerebral blood flow and oxygen consumption in newborn piglets

NASA Astrophysics Data System (ADS)

Diop, Mamadou; Elliott, Jonathan T.; Tichauer, Kenneth M.; Lee, Ting-Yim; St. Lawrence, Keith

2009-05-01

Near-infrared spectroscopy (NIRS) is a promising technique for assessing brain function in newborns, particularly due to its portability and sensitivity to cerebral hemodynamics and oxygenation. Methods for measuring cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) have been developed based on broadband continuous-wave NIRS. However, broadband NIRS apparatus typically have only one detection channel, which limits their applicability to measuring regional CBF and CMRO2. In this study, a relatively simple multiplexing approach based on electronically controlled mechanical shutters is proposed to expand the detection capabilities from one to eight channels. The tradeoff is an increase in the sampling interval; however, this has negligible effects on CBF measurements for intervals less than or equal to 1 s. The ability of the system to detect focal brain injury was demonstrated in piglets by injecting endothelin-1 (ET-1) into the cerebral cortex. For validation, CBF was independently measured by computed tomography (CT) perfusion. The average reduction in CBF from the source-detector pair that interrogated the injured region was 51%±9%, which was in good agreement with the CBF reduction measured by CT perfusion (55%±5%). No significant changes in regional CMRO2 were observed. The average regional differential pathlength prior to ET-1 injection was 8.4±0.2 cm (range of 7.1-9.6 cm) and did not significantly change after the injury.

Health-related quality of life among drug-naïve patients with narcolepsy with cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia without long sleep time.

PubMed

Ozaki, Akiko; Inoue, Yuichi; Nakajima, Toru; Hayashida, Kenichi; Honda, Makoto; Komada, Yoko; Takahashi, Kiyohisa

2008-12-15

To evaluate the health-related quality life (HRQOL) of drug-naïve patients with narcolepsy with cataplexy (NAwith CA), narcolepsy without cataplexy (NA without CA) and idiopathic hypersomnia without long sleep time (IHS without LST), and to explore the factors influencing the HRQOL. Factors associated with the occurrence of automobile accidents are also discussed. A total of 137 consecutive drug naïve patients who met the criteria of the 2nd edition of the International Classification of Sleep Disorders (NA with CA, n = 28; NA without CA, n = 27; IHS without LST, n = 82) were enrolled. The patients were asked to fill out questionnaires, including the SF-36, Epworth Sleepiness Scale (ESS), sociodemographic variables, and items regarding driving habits and the experiences related to automobile accidents. All 3 diagnostic groups had significantly lower scores in most SF-36 domains compared with Japanese normative data. Significant differences among the 3 diagnostic groups were not observed. Specific factors in SF-36 domains were not found with multiple linear regression analyses, while disease duration was positively correlated with mental health among all subjects. Among the patients reporting driving habits, ESS score (> or =16) was positively associated with the experience of automobile accidents. Our results indicated that HRQOL decreases in drug-naïve patients with hypersomnia, but neither disease category nor severity of the disorder appears as an associated factor. Increased severity of hypersomnia, however, was thought to play an important role in the occurrence of automobile accidents.

Regional cerebral blood flow measurement with intravenous ( sup 15 O)water bolus and ( sup 18 F)fluoromethane inhalation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herholz, K.; Pietrzyk, U.; Wienhard, K.

1989-09-01

In 20 patients with ischemic cerebrovascular disease, classic migraine, or angiomas, we compared paired dynamic positron emission tomographic measurements of regional cerebral blood flow using both ({sup 15}O)water and ({sup 18}F)fluoromethane as tracers. Cerebral blood flow was also determined according to the autoradiographic technique with a bolus injection of ({sup 15}O)water. There were reasonable overall correlations between dynamic ({sup 15}O)water and ({sup 18}F)fluoromethane values for cerebral blood flow (r = 0.82) and between dynamic and autoradiographic ({sup 15}O)water values for cerebral blood flow (r = 0.83). We found a close correspondence between abnormal pathologic findings and visually evaluated cerebral bloodmore » flow tomograms obtained with the two tracers. On average, dynamic ({sup 15}O)water cerebral blood flow was 6% lower than that measured with ({sup 18}F)fluoromethane. There also was a general trend toward a greater underestimation with ({sup 15}O)water in high-flow areas, particularly in hyperemic areas, probably due to incomplete first-pass extraction of ({sup 15}O)water. Underestimation was not detected in low-flow areas or in the cerebellum. Absolute cerebral blood flow values were less closely correlated between tracers and techniques than cerebral blood flow patterns. The variability of the relation between absolute flow values was probably caused by confounding effects of the variation in the circulatory delay time. The autoradiographic technique was most sensitive to this type error.« less

A coordinated cross-disciplinary research initiative to address an increased incidence of narcolepsy following the 2009-2010 Pandemrix vaccination programme in Sweden.

PubMed

Feltelius, N; Persson, I; Ahlqvist-Rastad, J; Andersson, M; Arnheim-Dahlström, L; Bergman, P; Granath, F; Adori, C; Hökfelt, T; Kühlmann-Berenzon, S; Liljeström, P; Maeurer, M; Olsson, T; Örtqvist, Å; Partinen, M; Salmonson, T; Zethelius, B

2015-10-01

In response to the 2009-2010 influenza A(H1N1)pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferon-gamma production in response to streptococcus-associated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar

Increased regional cerebral glucose uptake in an APP/PS1 model of Alzheimer’s disease

PubMed Central

Poisnel, Géraldine; Hérard, Anne-Sophie; El Tannir El Tayara, Nadine; Bourrin, Emmanuel; Volk, Andreas; Kober, Frank; Delatour, Benoit; Delzescaux, Thierry; Debeir, Thomas; Rooney, Thomas; Benavides, Jésus; Hantraye, Philippe; Dhenain, Marc

2013-01-01

Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder, is characterized by the invariant cerebral accumulation of β-amyloid peptide. This event occurs early in the disease process. In humans, [18F]-Fluoro-2-deoxy-D-Glucose-Positron Emission Tomography ([18F]-FDG-PET) is largely used to follow-up in vivo cerebral glucose utilisation (CGU) and brain metabolism modifications associated to the AD pathology. Here, [18F]-FDG-PET was used to study age-related changes of CGU under resting conditions in 3, 6 and 12-month-old APPSweLon/PS1M146L, a mouse model of amyloidosis. We showed an age-dependent increase of glucose uptake in several brain regions of APP/PS1 mice but not in control animals and a higher [18F]-FDG uptake in the cortex and the hippocampus of 12-month-old APP/PS1 mice as compared to age-matched control mice. We then developed a method of 3D-microscopic autoradiography to evaluate glucose uptake at the level of amyloid plaques and showed an increased glucose uptake close to the plaques rather than in amyloid-free cerebral tissues. These data suggest a macroscopic and microscopic reorganisation of glucose uptake in relation to cerebral amyloidosis. PMID:22079157

A patient with coexisting narcolepsy and morbid jealousy showing favourable response to fluoxetine.

PubMed Central

Wing, Y. K.; Lee, S.; Chiu, H. F.; Ho, C. K.; Chen, C. N.

1994-01-01

A 37 year old Chinese man suffered from coexisting narcolepsy and morbid jealousy which were precipitated by head injury 5 years previously. Fluoxetine 20 mg/day reduced his narcoleptic symptoms and morbid jealousy but not his sleepiness. On defaulting treatment, the patient's symptoms and marital problem recurred. A common central serotonin disturbance might be involved in mediating the sleep disorder and associated psychopathology. PMID:8140016

Core Body and Skin Temperature in Type 1 Narcolepsy in Daily Life; Effects of Sodium Oxybate and Prediction of Sleep Attacks.

PubMed

van der Heide, Astrid; Werth, Esther; Donjacour, Claire E H M; Reijntjes, Robert H A M; Lammers, Gert Jan; Van Someren, Eus J W; Baumann, Christian R; Fronczek, Rolf

2016-11-01

Previous laboratory studies in narcolepsy patients showed altered core body and skin temperatures, which are hypothesised to be related to a disturbed sleep wake regulation. In this ambulatory study we assessed temperature profiles in normal daily life, and whether sleep attacks are heralded by changes in skin temperature. Furthermore, the effects of three months of treatment with sodium oxybate (SXB) were investigated. Twenty-five narcolepsy patients and 15 healthy controls were included. Core body, proximal and distal skin temperatures, and sleep-wake state were measured simultaneously for 24 hours in ambulatory patients. This procedure was repeated in 16 narcolepsy patients after at least 3 months of stable treatment with SXB. Increases in distal skin temperature and distal-to-proximal temperature gradient (DPG) strongly predicted daytime sleep attacks (P < 0.001). As compared to controls, patients had a higher proximal and distal skin temperature in the morning, and a lower distal skin temperature during the night (all P < 0.05). Furthermore, they had a higher core body temperature during the first part of the night (P < 0.05), which SXB decreased (F = 4.99, df = 1, P = 0.03) to a level similar to controls. SXB did not affect skin temperature. This ambulatory study demonstrates that daytime sleep attacks were preceded by clear changes in distal skin temperature and DPG. Furthermore, changes in core body and skin temperature in narcolepsy, previously only studied in laboratory settings, were partially confirmed. Treatment with SXB resulted in a normalisation of the core body temperature profile. Future studies should explore whether predictive temperature changes can be used to signal or even prevent sleep attacks. © 2016 Associated Professional Sleep Societies, LLC.

The Psychosocial Problems of Children with Narcolepsy and Those with Excessive Daytime Sleepiness of Uncertain Origin

ERIC Educational Resources Information Center

Stores, Gregory; Montgomery, Paul; Wiggs, Luci

2007-01-01

Background: Narcolepsy is a predominantly rapid eye movement sleep disorder with onset usually in the second decade but often in earlier childhood. Classically it is characterized by combinations of excessive sleepiness especially sleep attacks, cataplexy, hypnagogic hallucinations, and sleep paralysis. The psychosocial effects of this lifelong…

Disorders of Excessive Daytime Sleepiness Including Narcolepsy and Idiopathic Hypersomnia.

PubMed

Berkowski, Joseph Andrew; Shelgikar, Anita Valanju

2016-09-01

Central disorders of hypersomnolence are rare conditions with a poorly understood pathophysiology, making the identification and management challenging for sleep clinicians. Clinical history is essential for ruling out secondary causes of hypersomnolence and distinguishing among diagnoses. Current diagnostic criteria rely heavily on the polysomnogram and multiple sleep latency test. The current focus of treatment of hypersomnolence is on drugs that promote alertness. Additionally, in the case of narcolepsy type 1, medication management addresses control of cataplexy, the hallmark symptom of this disorder. Elucidation of pathophysiology of these disorders in the future will be essential to better categorization and management. Published by Elsevier Inc.

Comparing Treatment Effect Measurements in Narcolepsy: The Sustained Attention to Response Task, Epworth Sleepiness Scale and Maintenance of Wakefulness Test.

PubMed

van der Heide, Astrid; van Schie, Mojca K M; Lammers, Gert Jan; Dauvilliers, Yves; Arnulf, Isabelle; Mayer, Geert; Bassetti, Claudio L; Ding, Claire-Li; Lehert, Philippe; van Dijk, J Gert

2015-07-01

To validate the Sustained Attention to Response Task (SART) as a treatment effect measure in narcolepsy, and to compare the SART with the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS). Validation of treatment effect measurements within a randomized controlled trial (RCT). Ninety-five patients with narcolepsy with or without cataplexy. The RCT comprised a double-blind, parallel-group, multicenter trial comparing the effects of 8-w treatments with pitolisant (BF2.649), modafinil, or placebo (NCT01067222). MWT, ESS, and SART were administered at baseline and after an 8-w treatment period. The severity of excessive daytime sleepiness and cataplexy was also assessed using the Clinical Global Impression scale (CGI-C). The SART, MWT, and ESS all had good reliability, obtained for the SART and MWT using two to three sessions in 1 day. The ability to distinguish responders from nonresponders, classified using the CGI-C score, was high for all measures, with a high performance for the SART (r = 0.61) and the ESS (r = 0.54). The Sustained Attention to Response Task is a valid and easy-to-administer measure to assess treatment effects in narcolepsy, enhanced by combining it with the Epworth Sleepiness Scale. © 2015 Associated Professional Sleep Societies, LLC.

Test-Retest Reliability of the Multiple Sleep Latency Test in Narcolepsy without Cataplexy and Idiopathic Hypersomnia

PubMed Central

Trotti, Lynn Marie; Staab, Beth A.; Rye, David B.

2013-01-01

Study Objectives: Differentiation of narcolepsy without cataplexy from idiopathic hypersomnia relies entirely upon the multiple sleep latency test (MSLT). However, the test-retest reliability for these central nervous system hypersomnias has never been determined. Methods: Patients with narcolepsy without cataplexy, idiopathic hypersomnia, and physiologic hypersomnia who underwent two diagnostic multiple sleep latency tests were identified retrospectively. Correlations between the mean sleep latencies on the two studies were evaluated, and we probed for demographic and clinical features associated with reproducibility versus change in diagnosis. Results: Thirty-six patients (58% women, mean age 34 years) were included. Inter -test interval was 4.2 ± 3.8 years (range 2.5 months to 16.9 years). Mean sleep latencies on the first and second tests were 5.5 (± 3.7 SD) and 7.3 (± 3.9) minutes, respectively, with no significant correlation (r = 0.17, p = 0.31). A change in diagnosis occurred in 53% of patients, and was accounted for by a difference in the mean sleep latency (N = 15, 42%) or the number of sleep onset REM periods (N = 11, 31%). The only feature predictive of a diagnosis change was a history of hypnagogic or hypnopompic hallucinations. Conclusions: The multiple sleep latency test demonstrates poor test-retest reliability in a clinical population of patients with central nervous system hypersomnia evaluated in a tertiary referral center. Alternative diagnostic tools are needed. Citation: Trotti LM; Staab BA; Rye DB. Test- retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med 2013;9(8):789-795. PMID:23946709

The role of regional nerve block anesthesia for carotid endarterectomy: an experimental comparison with previous series with the use of general anesthesia and barbiturates for cerebral protection.

PubMed

Agrifoglio, G; Agus, G B; Bonalumi, F; Costantini, A; Carlesi, R

1987-01-01

A retrospective analysis was performed on a consecutive series of 60 cases divided into two groups given carotid endarterectomy (C.E.) for atherosclerotic disease. In the first group general anesthesia and barbiturate cerebral protection were employed; in group two, loco-regional anesthesia. Indications and risk factors were similar in the two groups; the surgical procedure was identical. The differences in the results are reported and factors contributing to cerebral protection or reduction in the risk of stroke are analyzed. The analysis indicates that loco-regional anesthesia for C.E. is a reliable method for detecting cerebral ischemia and guaranteeing cerebral protection by means of a temporary shunt when strictly necessary.

Increasing the Contrast-to-Noise Ratio of MRI Signals for Regional Assessment of Dynamic Cerebral Autoregulation.

PubMed

Jara, José L; Saeed, Nazia P; Panerai, Ronney B; Robinson, Thompson G

2018-01-01

To devise an appropriate measure of the quality of a magnetic resonance imaging (MRI) signal for the assessment of dynamic cerebral autoregulation, and propose simple strategies to improve its quality. Magnetic resonance images of 11 healthy subjects were scanned during a transient decrease in arterial blood pressure (BP). Mean signals were extracted from non-overlapping brain regions for each image. An ad-hoc contrast-to-noise ratio (CNR) was used to evaluate the quality of these regional signals. Global mean signals were obtained by averaging the set of regional signals resulting after applying a Hampel filter and discarding a proportion of the lower quality component signals. Significant improvements in CNR values of global mean signals were obtained, whilst maintaining significant correlation with the original ones. A Hampel filter with a small moving window and a low rejection threshold combined with a selection of the 50% component signals seems a recommendable option. This work has demonstrated the possibility of improving the quality of MRI signals acquired during transient drops in BP. This approach needs validation at a voxel level, which could help to consolidate MRI as a technological alternative to the standard techniques for the study of cerebral autoregulation.

Tolerability and efficacy of armodafinil in naïve patients with excessive sleepiness associated with obstructive sleep apnea, shift work disorder, or narcolepsy: a 12-month, open-label, flexible-dose study with an extension period.

PubMed

Schwartz, Jonathan R L; Khan, Arifulla; McCall, W Vaughn; Weintraub, James; Tiller, Jane

2010-10-15

This 12-month, open-label, flexible-dose study with an extension period evaluated the tolerability and efficacy of armodafinil in patients with excessive sleepiness associated with treated obstructive sleep apnea (OSA), shift work disorder (SWD), or narcolepsy. Armodafinil-naïve, adult patients with excessive sleepiness associated with treated OSA (n = 170), SWD (n = 108), or narcolepsy (n = 50) received armodafinil (100-250 mg) once daily (treated OSA or narcolepsy) or before night shifts (SWD). Patients with OSA were regular users of continuous positive airway pressure (CPAP) therapy. Efficacy measures included the Clinical Global Impression of Improvement (CGI-I) and the Epworth Sleepiness Scale (ESS). Across the diagnosis groups, the most commonly occurring adverse event was headache (14%-24%). Forty-three patients (13%) and 13 patients (4%) were withdrawn because of adverse events and insufficient efficacy, respectively. Armodafinil did not adversely affect CPAP therapy. At the final visit, 80% (95% CI: 74.1, 86.7) of patients with treated OSA and 84% (72.7, 94.8) of patients with narcolepsy were rated on the CGI-I as at least minimally improved with regard to overall clinical condition; 98% (95.2, 100.0) of patients with SWD were rated as improved with regard to sleepiness during night shifts, including the commute to and from work. Armodafinil improved ESS total scores in patients with treated OSA (mean [SD] [95% CI] change from baseline, -7.3 [5.6] [-8.39, -6.30]) and patients with narcolepsy (-4.7 [6.0] [-7.41, -1.93]). Armodafinil administered for 12 months or more was generally well tolerated and improved wakefulness in patients with excessive sleepiness associated with treated OSA, SWD, or narcolepsy. Armodafinil improved the overall clinical condition of patients with treated OSA or narcolepsy.

Multiple Transmitter Receptors in Regions and Layers of the Human Cerebral Cortex

PubMed Central

Zilles, Karl; Palomero-Gallagher, Nicola

2017-01-01

We measured the densities (fmol/mg protein) of 15 different receptors of various transmitter systems in the supragranular, granular and infragranular strata of 44 areas of visual, somatosensory, auditory and multimodal association systems of the human cerebral cortex. Receptor densities were obtained after labeling of the receptors using quantitative in vitro receptor autoradiography in human postmortem brains. The mean density of each receptor type over all cortical layers and of each of the three major strata varies between cortical regions. In a single cortical area, the multi-receptor fingerprints of its strata (i.e., polar plots, each visualizing the densities of multiple different receptor types in supragranular, granular or infragranular layers of the same cortical area) differ in shape and size indicating regional and laminar specific balances between the receptors. Furthermore, the three strata are clearly segregated into well definable clusters by their receptor fingerprints. Fingerprints of different cortical areas systematically vary between functional networks, and with the hierarchical levels within sensory systems. Primary sensory areas are clearly separated from all other cortical areas particularly by their very high muscarinic M2 and nicotinic α4β2 receptor densities, and to a lesser degree also by noradrenergic α2 and serotonergic 5-HT2 receptors. Early visual areas of the dorsal and ventral streams are segregated by their multi-receptor fingerprints. The results are discussed on the background of functional segregation, cortical hierarchies, microstructural types, and the horizontal (layers) and vertical (columns) organization in the cerebral cortex. We conclude that a cortical column is composed of segments, which can be assigned to the cortical strata. The segments differ by their patterns of multi-receptor balances, indicating different layer-specific signal processing mechanisms. Additionally, the differences between the strata-and area

Regional cerebral blood flow in childhood headache

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roach, E.S.; Stump, D.A.

1989-06-01

Regional cerebral blood flow (rCBF) was measured in 16 cranial regions in 23 children and adolescents with frequent headaches using the non-invasive Xenon-133 inhalation technique. Blood flow response to 5% carbon dioxide (CO2) was also determined in 21 patients, while response to 50% oxygen was measured in the two patients with hemoglobinopathy. Included were 10 patients with a clinical diagnosis of migraine, 4 with musculoskeletal headaches, and 3 with features of both types. Also studied were 2 patients with primary thrombocythemia, 2 patients with hemoglobinopathy and headaches, 1 patient with polycythemia, and 1 with headaches following trauma. With two exceptions,more » rCBF determinations were done during an asymptomatic period. Baseline rCBF values tended to be higher in these young patients than in young adults done in our laboratory. Localized reduction in the expected blood flow surge after CO2 inhalation, most often noted posteriorly, was seen in 8 of the 13 vascular headaches, but in none of the musculoskeletal headache group. Both patients with primary thrombocythemia had normal baseline flow values and altered responsiveness to CO2 similar to that seen in migraineurs; thus, the frequently reported headache and transient neurologic signs with primary thrombocythemia are probably not due to microvascular obstruction as previously suggested. These data support the concept of pediatric migraine as a disorder of vasomotor function and also add to our knowledge of normal rCBF values in younger patients. Demonstration of altered vasomotor reactivity to CO2 could prove helpful in children whose headache is atypical.« less

Reference ranges for regional cerebral tissue oxygen saturation and fractional oxygen extraction in neonates during immediate transition after birth.

PubMed

Pichler, Gerhard; Binder, Corinna; Avian, Alexander; Beckenbach, Elisabeth; Schmölzer, Georg M; Urlesberger, Berndt

2013-12-01

To define reference ranges for regional cerebral tissue oxygen saturation (crSO2) and regional cerebral fractional tissue oxygen extraction (cFTOE) during the first 15 minutes after birth in neonates requiring no medical support. The crSO2 was measured using near infrared spectroscopy (Invos 5100 cerebral/somatic oximeter monitor; Somanetics Corp, Troy, Michigan) during the first 15 minutes after birth for term and preterm neonates. The near infrared spectroscopy sensor was placed on the left forehead. Peripheral oxygen saturation and heart rate were continuously measured by pulse oximetry, and cFTOE was calculated. Neonates were excluded if they required any medical support. A total of 381 neonates were included: 82 term neonates after vaginal delivery, 272 term neonates after cesarean delivery, and 27 preterm neonates after cesarean delivery. In all neonates, median (10th-90th percentiles) crSO2 was 41% (23-64) at 2 minutes, 68% (45-85) at 5 minutes, 79% (65-90) at 10 minutes, and 77% (63-89) at 15 minutes of age. In all neonates, median (10th-90th percentiles) cFTOE was 33% (11-70) at 2 minutes, 21% (6-45) at 5 minutes, 15% (5-31) at 10 minutes, and 18% (7-34) at 15 minutes of age. We report reference ranges of crSO2 and cFTOE in neonates requiring no medical support during transition immediately after birth. The use of cerebral oxygenation monitoring and use of these reference ranges in neonates during transition may help to guide oxygen delivery and avoid cerebral hypo-oxygenation and hyperoxygenation. Copyright © 2013 Mosby, Inc. All rights reserved.

Regional Cerebral Oxygen Saturation Level Predicts 30-Day Mortality Rate After Left Ventricular Assist Device Surgery.

PubMed

Ghosal, Soutik; Trivedi, Jaimin; Chen, James; Rogers, Michael P; Cheng, Allen; Slaughter, Mark S; Kong, Maiying; Huang, Jiapeng

2018-06-01

Left ventricular assist device (LVAD) surgery is complex, high risk, and expensive. The authors' hypothesis is baseline regional cerebral oxygen saturation (rSO 2 ) might be a predictor of postoperative clinical outcomes. Retrospective review of 210 consecutive continuous flow LVAD patients between 2008 and 2014. The primary measure is 30-day mortality rate and secondary measures include modified major adverse cardiocerebral events (MACE), length of stay (LOS), and intensive care unit (ICU) stay. Multiple logistic regression models were applied to examine if a binary outcome variable, such as 30-day mortality and MACE, is associated with rSO 2 at baseline. Log-linear model was used to examine whether LOS or ICU stay hours is associated with rSO 2 at baseline. Single institution, academic hospital. Patients who received LVAD surgery ​at Jewish Hospital, Louisville, KY. All patients received LVAD surgery. Cerebral oximetry monitoring was used in both the preoperative and intraoperative periods. The authors found that higher rSO 2 at baseline is associated with lower 30-day mortality with an odds ratio of 0.94 and 95% confidence interval (0.888, 0.995) for every 1% increase of rSO 2 . For secondary outcomes, baseline rSO 2 was not significantly associated with MACE, requirement for postoperative renal failure/dialysis, reoperation for bleeding, and LOS or ICU hours. Regional cerebral oxygen saturation levels at baseline are significantly associated with 30-day mortality after LVAD surgeries. Copyright © 2017 Elsevier Inc. All rights reserved.

Growing Up with Type 1 Narcolepsy: Its Anthropometric and Endocrine Features

PubMed Central

Ponziani, Virginia; Gennari, Monia; Pizza, Fabio; Balsamo, Antonio; Bernardi, Filippo; Plazzi, Giuseppe

2016-01-01

Study Objectives: To evaluate the effect of type 1 narcolepsy (NT1) on anthropometric and endocrine features in childhood/adolescence, focusing on patterns and correlates of weight, pubertal development, and growth in treated and untreated patients. Methods: We collected anthropometric (height, weight, body mass index (BMI) z-scores), pubertal, metabolic, and endocrine data from 72 NT1 patients at diagnosis and all available premorbid anthropometric parameters of patients from their pediatric files (n = 30). New measurements at 1-y reassessment in patients undergoing different treatments were compared with baseline data. Results: We detected a high prevalence of overweight (29.2%), obesity (25%), metabolic syndrome (18.8%), and precocious puberty (16.1%), but no signs of linear growth alterations at diagnosis. According to anthropometric records, weight gain started soon after NT1 onset. At 1-y follow-up reassessment, sodium oxybate treatment was associated with a significant BMI z-score reduction (−1.29 ± 0.30, p < 0.0005) after adjusting for baseline age, sex, sleepiness, and BMI. Conclusions: NT1 onset in children/adolescents is associated with rapid weight gain up to overweight/obesity and precocious puberty without affecting growth. In our study, sodium oxybate treatment resulted in a significant weight reduction in NT1 overweight/obese patients at 1-y follow-up. Citation: Ponziani V, Gennari M, Pizza F, Balsamo A, Bernardi F, Plazzi G. Growing up with type 1 narcolepsy: its anthropometric and endocrine features. J Clin Sleep Med 2016;12(12):1649–1657. PMID:27707443

Effects of ischemic preconditioning on PDGF-BB expression in the gerbil hippocampal CA1 region following transient cerebral ischemia

PubMed Central

Lee, Jae-Chul; Kim, Yang Hee; Lee, Tae-Kyeong; Kim, In Hye; Cho, Jeong Hwi; Cho, Geum-Sil; Shin, Bich-Na; Park, Joon Ha; Ahn, Ji Hyeon; Shin, Myoung Cheol; Cho, Jun Hwi; Kang, Il Jun; Won, Moo-Ho; Seo, Jeong Yeol

2017-01-01

Ischemic preconditioning (IPC) is induced by exposure to brief durations of transient ischemia, which results in ischemic tolerance to a subsequent longer or lethal period of ischemia. In the present study, the effects of IPC (2 min of transient cerebral ischemia) were examined on immunoreactivity of platelet-derived growth factor (PDGF)-BB and on neuroprotection in the gerbil hippocampal CA1 region following lethal transient cerebral ischemia (LTCI; 5 min of transient cerebral ischemia). IPC was subjected to a 2-min sublethal ischemia and a LTCI was given 5-min transient ischemia. The animals in all of the groups were given recovery times of 1, 2 and 5 days and change in PDGF-BB immunoreactivity was examined as was the neuronal damage/death in the hippocampus induced by LTCI. LTCI induced a significant loss of pyramidal neurons in the hippocampal CA1 region 5 days after LTCI, and significantly decreased PDGF-BB immunoreactivity in the CA1 pyramidal neurons from day 1 after LTCI. Conversely, IPC effectively protected the CA1 pyramidal neurons from LTCI and increased PDGF-BB immunoreactivity in the CA1 pyramidal neurons post-LTCI. In conclusion, the results demonstrated that LTCI significantly altered PDGF-BB immunoreactivity in pyramidal neurons in the hippocampal CA1 region, whereas IPC increased the immunoreactivity. These findings indicated that PDGF-BB may be associated with IPC-mediated neuroprotection. PMID:28627606

Cerebral hematocrit decreases with hemodynamic compromise in carotid artery occlusion: a PET study.

PubMed

Yamauchi, H; Fukuyama, H; Nagahama, Y; Katsumi, Y; Okazawa, H

1998-01-01

This study investigated whether in patients with internal carotid artery occlusion the regional cerebral hematocrit correlates with cerebral hemodynamics or metabolic state and, if so, how the regional cerebral hematocrit changes in the hemodynamically compromised region. We used positron emission tomography to study seven patients with unilateral internal carotid artery occlusion and no cortical infarction in the chronic stage. The distributions of red blood cell and plasma volumes were assessed using oxygen-15-labeled carbon monoxide and copper-62-labeled human serum albumin-dithiosemicarbazone tracers, respectively. The calculated hematocrit value was compared with the hemodynamic and metabolic parameters measured with the oxygen-15 steady-state technique. In the cerebral cortex, the value of the cerebral hematocrit varied but was correlated with the hemodynamic and metabolic status. Stepwise regression analysis revealed that the large vessel hematocrit, the cerebral metabolic rate of oxygen, and the cerebral blood flow or the oxygen extraction fraction accounted for a significant proportion of variance of the cerebral hematocrit. The oxygen extraction fraction and the cerebral metabolic rate of oxygen negatively correlated with the cerebral hematocrit, whereas the cerebral blood flow correlated positively: patients with reduced blood supply relative to metabolic demand (decreased blood flow with increased oxygen extraction fraction) showed low hematocrit values. In carotid artery occlusion in the chronic stage, regional cerebral hematocrit may vary according to cerebral hemodynamics and metabolic status. Regional cerebral hematocrit may decrease with hemodynamic compromise unless oxygen metabolism concomitantly decreases.

Usefulness of Deep Hypothermic Circulatory Arrest and Regional Cerebral Perfusion in Children

PubMed Central

Guo, Zheng; Hu, Ren-Jie; Zhu, De-Ming; Zhu, Zhong-Qun; Zhang, Hai-Bo

2013-01-01

To compare the safety and usefulness of deep hypothermic circulatory arrest (DHCA) and regional cerebral perfusion (RCP) during pediatric open heart surgery. Between January 1, 2004 and September 30, 2012, 1250 children with congenital cardiac defect underwent corrective operation with the DHCA or RCP technique in the Shanghai Children's Medical Center. Of them, 947 cases underwent the operation with the aid of DHCA (DHCA group), and 303 cases with RCP (RCP group). The mean DHCA time was 30.64±15.81 (7–63) minutes and mean RCP time was 36.18±12.86 (10–82) minutes. The mortality rate was 7.18% (68/947) and 6.60% (20/30) in two groups, respectively. The postoperative incidences of temporary and permanent neurological dysfunction were 6.23% (59/947) in the DHCA group and 2.64% (8/303) in the RCP group (p<0.01). The incidence of other complications such as low cardiac output, renal dysfunction, and lung issues are similar in both groups. RCP is a reliable technique for cerebral protection and it facilitates time-consuming corrected procedures for complex congenital cardiac defect repair procedures. PMID:24066266

Cerebral Apolipoprotein-D Is Hypoglycosylated Compared to Peripheral Tissues and Is Variably Expressed in Mouse and Human Brain Regions.

PubMed

Li, Hongyun; Ruberu, Kalani; Karl, Tim; Garner, Brett

2016-01-01

Recent studies have shown that cerebral apoD levels increase with age and in Alzheimer's disease (AD). In addition, loss of cerebral apoD in the mouse increases sensitivity to lipid peroxidation and accelerates AD pathology. Very little data are available, however, regarding the expression of apoD protein levels in different brain regions. This is important as both brain lipid peroxidation and neurodegeneration occur in a region-specific manner. Here we addressed this using western blotting of seven different regions (olfactory bulb, hippocampus, frontal cortex, striatum, cerebellum, thalamus and brain stem) of the mouse brain. Our data indicate that compared to most brain regions, the hippocampus is deficient in apoD. In comparison to other major organs and tissues (liver, spleen, kidney, adrenal gland, heart and skeletal muscle), brain apoD was approximately 10-fold higher (corrected for total protein levels). Our analysis also revealed that brain apoD was present at a lower apparent molecular weight than tissue and plasma apoD. Utilising peptide N-glycosidase-F and neuraminidase to remove N-glycans and sialic acids, respectively, we found that N-glycan composition (but not sialylation alone) were responsible for this reduction in molecular weight. We extended the studies to an analysis of human brain regions (hippocampus, frontal cortex, temporal cortex and cerebellum) where we found that the hippocampus had the lowest levels of apoD. We also confirmed that human brain apoD was present at a lower molecular weight than in plasma. In conclusion, we demonstrate apoD protein levels are variable across different brain regions, that apoD levels are much higher in the brain compared to other tissues and organs, and that cerebral apoD has a lower molecular weight than peripheral apoD; a phenomenon that is due to the N-glycan content of the protein.

Cerebral Effect of Intratracheal Aerosolized Surfactant Versus Bolus Therapy in Preterm Lambs.

PubMed

Rey-Santano, Carmen; Mielgo, Victoria E; López-de-Heredia-y-Goya, Jon; Murgia, Xabier; Valls-i-Soler, Adolfo

2016-04-01

Aerosolization has been proposed as a useful alternative to rapid intratracheal instillation for the delivery of exogenous surfactant in neonatal respiratory distress syndrome. However, there is a lack of information regarding the likely safety of this new therapeutic approach for the neonatal brain. We aimed to compare the cerebral effects of aerosolized versus bolus surfactant administration in premature lambs with respiratory distress syndrome. Prospective randomized study. BioCruces Institute Animal Research Facility. Fourteen intensively monitored and mechanically ventilated preterm lambs. Preterm lambs were randomly assigned to receive intratracheal aerosolized surfactant or bolus surfactant. Brain hemodynamics (cerebral and regional cerebral blood flow) and cerebral oxygen metabolism (cerebral oxygen delivery, cerebral metabolic rate of oxygen, and oxygen extraction fraction) were measured every 30 minutes for 6 hours. We also performed cerebral biochemical and histological analysis. In preterm lambs with respiratory distress syndrome, cerebral blood flow, regional cerebral blood flow, cerebral oxygen delivery, and cerebral metabolic rate of oxygen increased significantly in the bolus surfactant group during the first 5 minutes, without changes in cerebral oxygen extraction fraction. By 60 minutes, all parameters had decreased in both groups, cerebral blood flow and regional cerebral blood flow (in inner and cerebellum brainstem regions) remaining higher in the bolus surfactant than in the aerosolized surfactant group. Overall, the impact of aerosol surfactant was not significantly different to that of bolus surfactant in terms of cerebral necrosis, edema, inflammation, hemorrhage, infarct, apoptosis, or oxidative stress. In preterm lambs with severe respiratory distress syndrome, aerosol surfactant administration seems to be as safe as bolus administration, showing more stable cerebral hemodynamics and cerebral oxygen metabolism to the same dose of

Narcolepsy with cataplexy and hyperthyroidism sudden appeared after H1N1 vaccination

PubMed Central

Leiva, Silvia; Madrazo, Jimena; Podesta, Claudio

2018-01-01

Narcolepsy type 1 (NT1) is a chronic sleep disorder, characterized by excessive daytime sleepiness, cataplexy and fragmented nocturnal sleep. It is caused by a hypocretin deficiency due to a significant reduction of the neurons producing it. In the last years, it has been postulated that an autoimmune mechanism would be responsible for the destruction of these neurons in those genetically predisposed patients. The increased incidence of narcolepsy after the pandemic H1N1 influenza vaccination campaign in 2009-2010 is known. We present below the case of an adult patient who, 10 days after receiving H1N1 vaccination, suffers a traffic accident after falling asleep. Subsequent studies revealed hyperthyroidism due to Graves disease. In spite of the treatment, the patient persisted with daily and disabling daytime sleepiness, sleep attacks and episodes of generalized muscle atony with preservation of consciousness. A nocturnal polysomnography and multiple sleep latency test (MSLT) were performed with a diagnosis of NT1. The particularity of this case is the presentation of 2 autoimmune diseases triggered by an H1N1 vaccine without adjuvant, so far there is only evidence of NT1 associated with vaccines with adjuvant and viral infection. The association of both entities has made us reflect on the autoimmune mechanism, reinforcing the theory of its role in the onset of the disease. PMID:29796199

Single-photon tomographic determination of regional cerebral blood flow in epilepsy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bonte, F.J.; Devous, M.D. Sr.; Stokely, E.M.

Using a single-photon emission computed tomographic scanner (SPECT) the authors determined regional cerebral blood flow (rCBF) with inhaled xenon-133, a noninvasive procedure. Studies were performed in 40 normal individuals, and these were compared with rCBF determinations in 51 patients with seizure disorders. Although positive results were obtained in 15 of 16 patients with mass lesions, the group of principal interest comprised 25 patients suffering from ''temporal lobe'' epilepsy. Only one of these had a positive x-ray computed tomogram, but 16 had positive findings on rCBF study. These findings included increased local blood flow in the ictal state and reduced flowmore » interictally.« less

[Regional cerebral oxygen saturation as a marker of hemodynamic state following cardiac surgery].

PubMed

García-Hernández, J A; Aldemira-Liz, A; Martínez-López, A I; Cayuela, A; Charlo-Molina, M T; Cano-Franco, J; Loscertales-Abril, M

2013-10-01

Regional cerebral oxygen saturation (rSO₂) is a measure of the general state of perfusion and oxygenation. We aim to analyze the relationship between this and various hemodynamic and respiratory parameters. Forty-three patients, operated on between October 2011 and July 2012, were included in this prospective observational descriptive study. The following parameters were measured: mean arterial pressure, both arterial and central venous oxygen saturation and partial pressures of oxygen and carbon dioxide, and lactate levels. From these parameters, the oxygenation index and the oxygen extraction ratio were calculated. These measurements were studied to evaluate whether rSO₂ correlated significantly with the other parameters. The average age and weight of the patients were 27.3 months and 9.2 kg, respectively. The rSO₂ correlated positively with both central venous oxygen saturation (r=0.73, P<.01) and mean arterial pressure (r=0.59, P<.01), and negatively with the oxygen extraction ratio (r=-0.7, P<.01). No correlation was found with the respiratory parameters. Concordance analysis established an acceptable Kappa index (> 0.4) between the rSO₂ and central venous oxygen saturation, and between the rSO₂ and oxygen extraction ratio. Regional cerebral oxygen saturation correlates well with hemodynamic parameters - mean arterial pressure, venous saturation, and the tissue oxygen extraction. However, it does not correlate with respiratory parameters. Copyright © 2012 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Verbal fluency and positron emission tomographic mapping of regional cerebral glucose metabolism.

PubMed

Boivin, M J; Giordani, B; Berent, S; Amato, D A; Lehtinen, S; Koeppe, R A; Buchtel, H A; Foster, N L; Kuhl, D E

1992-06-01

Impairment in verbal fluency (VF) has been a consistently reported clinical feature of focal cerebral deficits in frontal and temporal regions. More recent behavioral activation studies with healthy control subjects using positron emission tomography (PET), however, have noted a negative correlation between performance on verbal fluency tasks and regional cortical activity. To see if this negative relationship extends to steady-state non-activation PET measures, thirty-three healthy adults were given a VF task within a day of their 18F-2-fluoro-2-deoxy-D-glucose PET scan. VF was found to correlate positively with left temporal cortical region metabolic activity but to correlate negatively with right and left frontal activity. VF was not correlated significantly with right temporal cortical metabolic activity. Some previous studies with normals using behavioral activation paradigms and PET have reported negative correlations between metabolic activity and cognitive performance similar to that reported here. An explanation for the disparate relationships that were observed between frontal and temporal brain areas and VF might be found in the mediation of different task demands by these separate locations, i.e., task planning and/or initiation by frontal regions and verbal memory by the left temporal area.

Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions.

PubMed

Burns, Christine M; Chen, Kewei; Kaszniak, Alfred W; Lee, Wendy; Alexander, Gene E; Bandy, Daniel; Fleisher, Adam S; Caselli, Richard J; Reiman, Eric M

2013-04-23

To investigate whether higher fasting serum glucose levels in cognitively normal, nondiabetic adults were associated with lower regional cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer disease (AD). This is a cross-sectional study of 124 cognitively normal persons aged 64 ± 6 years with a first-degree family history of AD, including 61 APOEε4 noncarriers and 63 carriers. An automated brain mapping algorithm characterized and compared correlations between higher fasting serum glucose levels and lower [(18)F]-fluorodeoxyglucose-PET rCMRgl measurements. As predicted, higher fasting serum glucose levels were significantly correlated with lower rCMRgl and were confined to the vicinity of brain regions preferentially affected by AD. A similar pattern of regional correlations occurred in the APOEε4 noncarriers and carriers. Higher fasting serum glucose levels in cognitively normal, nondiabetic adults may be associated with AD pathophysiology. Findings suggest that the risk imparted by higher serum glucose levels may be independent of APOEε4 status. This study raises additional questions about the role of the metabolic process in the predisposition to AD and supports the possibility of targeting these processes in presymptomatic AD trials.

Cerebral and non-cerebral coenurosis: on the genotypic and phenotypic diversity of Taenia multiceps.

PubMed

Christodoulopoulos, Georgios; Dinkel, Anke; Romig, Thomas; Ebi, Dennis; Mackenstedt, Ute; Loos-Frank, Brigitte

2016-12-01

We characterised the causative agents of cerebral and non-cerebral coenurosis in livestock by determining the mitochondrial genotypes and morphological phenotypes of 52 Taenia multiceps isolates from a wide geographical range in Europe, Africa, and western Asia. Three studies were conducted: (1) a morphological comparison of the rostellar hooks of cerebral and non-cerebral cysts of sheep and goats, (2) a morphological comparison of adult worms experimentally produced in dogs, and (3) a molecular analysis of three partial mitochondrial genes (nad1, cox1, and 12S rRNA) of the same isolates. No significant morphological or genetic differences were associated with the species of the intermediate host. Adult parasites originating from cerebral and non-cerebral cysts differed morphologically, e.g. the shape of the small hooks and the distribution of the testes in the mature proglottids. The phylogenetic analysis of the mitochondrial haplotypes produced three distinct clusters: one cluster including both cerebral isolates from Greece and non-cerebral isolates from tropical and subtropical countries, and two clusters including cerebral isolates from Greece. The majority of the non-cerebral specimens clustered together but did not form a monophyletic group. No monophyletic groups were observed based on geography, although specimens from the same region tended to cluster. The clustering indicates high intraspecific diversity. The phylogenetic analysis suggests that all variants of T. multiceps can cause cerebral coenurosis in sheep (which may be the ancestral phenotype), and some variants, predominantly from one genetic cluster, acquired the additional capacity to produce non-cerebral forms in goats and more rarely in sheep.

Regional cerebral energy metabolism during intravenous anesthesia with etomidate, ketamine or thiopental

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davis, D.W.

1987-01-01

Regional brain glucose utilization (rCMRglc) was measured in rats during steady-state levels of intravenous anesthesia to determine if alterations in brain function due to anesthesia could provide information on the mechanisms of anesthesia. Intravenous anesthetics from three different chemical classes were studied: etomidate, ketamine and thiopental. All rCMRglc experiments were conducted in freely moving rats in isolation chambers, with the use of (6-/sup 14/C) glucose and guantitative autoradiography. Etomidate caused a rostral-to-caudal gradient of depression of rCMRglc. The four doses of etomidate did not differ in their effects on energy metabolism. Sub-anesthetic (5 mg kg/sup -1/) and anesthetic (30 mgmore » kg /sup -1/) doses of ketamine produced markedly different patterns of behavior. Brain energy metabolism during the sub-anesthetic dose was stimulated in most regions, while the anesthetic dose selectively stimulated the hippocampus, leaving most brain regions unaffected. Thiopental produced a dose-dependent reduction of rCMRglc in all gray matter regions. No brain region was selectively affected. Comparison of the drug-specific alterations of cerebral energy metabolism suggests these anesthetics do not act through a common mechanism. The hypothesis that each acts by binding to specific cell membrane receptors is consistent with these observations.« less

Regional cerebral (18)FDG uptake during subarachnoid hemorrhage induced vasospasm.

PubMed

Novak, Laszlo; Emri, Miklos; Molnar, Peter; Balkay, Laszlo; Szabo, Sandor; Rozsa, Laszlo; Lengyel, Zsolt; Tron, Lajos

2006-12-01

The aim was to elucidate whether aneurysmal subarachnoid hemorrhage (SAH)-induced vasospasm induces changes of regional glucose uptake in surgically treated, asymptomatic cases. (18)FDG uptake (standardized uptake value, SUV) was analysed with PET in eight surgically treated aneurismal patients with a mean middle cerebral artery flow velocity >120 cm/seconds measured with transcranial Doppler ultrasound. Data were compared with a healthy control group using Statistical Parametric Mapping (SPM99b). Six of the eight patients had no focal neurological signs. The inhomogeneous bilateral increase in SUV (p<0.0001) was asymmetrical, with an almost 70% larger volume on the operated side. Reduced glucose uptake was found in the frontal and temporobasal regions of the two patients with neurological deficits (p<0.0001); the affected volume was 40% larger on the operated side. SAH-induced vasospasm results in widespread increase of glucose uptake-probably reflecting increased glycolysis. This was earlier than neurological focal signs appear. Decreased glucose uptake can be detected in severe cases of vasospasm reflected by neurological deficit. Although the changes are more prominent where surgery had taken place our results suggest that not only the surgery, but also subarachnoid blood might have resulted in our findings.

Use of Electrical Impedance Tomography to Monitor Regional Cerebral Edema during Clinical Dehydration Treatment

PubMed Central

Hu, Shi-Jie; Li, Xia; Xu, Can-Hua; Wang, Bing; Yang, Bin; Tang, Meng-Xing; Dong, Xiu-Zhen; Fei, Zhou; Shi, Xue-Tao

2014-01-01

Objective Variations of conductive fluid content in brain tissue (e.g. cerebral edema) change tissue impedance and can potentially be measured by Electrical Impedance Tomography (EIT), an emerging medical imaging technique. The objective of this work is to establish the feasibility of using EIT as an imaging tool for monitoring brain fluid content. Design a prospective study. Setting In this study EIT was used, for the first time, to monitor variations in cerebral fluid content in a clinical model with patients undergoing clinical dehydration treatment. The EIT system was developed in house and its imaging sensitivity and spatial resolution were evaluated on a saline-filled tank. Patients 23 patients with brain edema. Interventions The patients were continuously imaged by EIT for two hours after initiation of dehydration treatment using 0.5 g/kg intravenous infusion of mannitol for 20 minutes. Measurement and Main Results Overall impedance across the brain increased significantly before and after mannitol dehydration treatment (p = 0.0027). Of the all 23 patients, 14 showed high-level impedance increase and maintained this around 4 hours after the dehydration treatment whereas the other 9 also showed great impedance gain during the treatment but it gradually decreased after the treatment. Further analysis of the regions of interest in the EIT images revealed that diseased regions, identified on corresponding CT images, showed significantly less impedance changes than normal regions during the monitoring period, indicating variations in different patients' responses to such treatment. Conclusions EIT shows potential promise as an imaging tool for real-time and non-invasive monitoring of brain edema patients. PMID:25474474

Environmental toxins and risk of narcolepsy among people with HLA DQB1*0602

PubMed Central

Ton, Thanh G.N.; Longstreth, WT; Koepsell, Thomas D.

2010-01-01

One etiologic model for narcolepsy suggests that some environmental toxin selectively and irreversibly destroys hypocretin-producing cells in individuals with human leukocyte antigen (HLA) DQB1*0602. Between 2001-2005, the authors conducted a population-based case-control study in King County, Washington to examine narcolepsy risk in relation to toxins found in jobs, hobbies and other non-vocational activities. Sixty-seven cases and 95 controls were enrolled; all were between ages 18-50 and positive for HLA DQB1*0602. All were administered in-person interviews about jobs, hobbies or other non-vocational activities before age 21. All analyses were adjusted for African American race and income. Risk increased significantly for jobs involving heavy metals (odds ratio [OR]=4.7; 95% confidence interval [CI]: 1.5, 14.5) and for highest levels of exposure to woodwork (OR: 3.0; 95% CI: 1.0, 8.9), fertilizer (OR=3.1; 95% CI: 1.1, 9.1), and bug or weed killer (OR=4.5; 95% CI: 1.5, 13.4). Associations were of borderline significance for activities involving ceramics, pesticides, and painting projects. Significant dose-response relationships were evident for jobs involving metals (p<0.03), paints (p<0.03), and bug or weed killer (p<0.02). Additional studies are needed to replicate these findings and continue the search for specific toxins that could damage hypocretin neurons in genetically susceptible people. PMID:20519130

Narcolepsy with cataplexy mimicry: the strange case of two sisters.

PubMed

Pizza, Fabio; Vandi, Stefano; Poli, Francesca; Moghadam, Keivan Kaveh; Franceschini, Christian; Bellucci, Claudia; Cipolli, Carlo; Ingravallo, Francesca; Natalini, Giuliana; Mignot, Emmanuel; Plazzi, Giuseppe

2013-06-15

We report on two sisters, 17 and 12 years of age, with clinical features suggesting narcolepsy with cataplexy (NC): daytime sleepiness, spontaneous and emotionally triggered sudden falls to the ground, and overweight/obesity. MSLT showed borderline sleep latency, with 1 and 0 sleep onset REM periods. HLA typing disclosed the DQB1*0602 allele. Video-polygraphy of the spells ruled out NC diagnosis by demonstrating their easy elicitation by suggestion, with wake EEG, electromyographic persistence of muscle tone, and stable presence of tendon reflexes (i.e., pseudo-cataplexy), together with normal cerebrospinal hypocretin-1 levels. Our cases emphasize the need of a clear depiction of cataplexy pattern at the different ages, the usefulness of examining ictal neurophysiology, and collecting all available disease markers in ambiguous cases.

Psychosocial Profile and Quality of Life in Children With Type 1 Narcolepsy: A Case-Control Study

PubMed Central

Rocca, Francesca Letizia; Finotti, Elena; Pizza, Fabio; Ingravallo, Francesca; Gatta, Michela; Bruni, Oliviero; Plazzi, Giuseppe

2016-01-01

Study Objectives: To investigate behavioral aspects and quality of life in children and adolescents with type 1 narcolepsy (NT1). Methods: We performed a case-control study comparing 29 patients with NT1 versus sex- and age-matched patients with idiopathic epilepsy (n = 39) and healthy controls (n = 39). Behavior and quality of life were evaluated by self-administered questionnaires (Child Behavior Checklist, Pediatric Quality of Life Inventory). Patient groups were contrasted and scale results were correlated with clinical and polysomnographic parameters, and cerebrospinal fluid hypocretin-1 levels. Results: Young patients with NT1 showed increased internalizing problems associated with aggressive behavior. Emotional profile in patients with NT1 positively correlated with age at onset, diagnostic delay, and subjective sleepiness, whereas treatment and disease duration were associated with fewer behavioral problems (attention problems, aggressive behavior, and attention deficit/hyperactivity disorder). Psychosocial health domains of pediatric NT1 were worse than in healthy controls, whereas the physical health domains were comparable. Conclusions: Young NT1 patients show a discrete pattern of altered behavioral, thought, and mood profile in comparison with healthy controls and with idiopathic epilepsy patients thus suggesting a direct link with sleepiness. Further studies investigating behavior in patients with idiopathic hypersomnia or type 2 narcolepsy are needed to disentangle the role of REM sleep dysfunction and hypocretin deficiency in psychiatric disorders. Symptoms of withdrawal, depression, somatic complaints, thought problems, and aggressiveness were common, NT1 children perceived lower school competencies than healthy children, and their parents also reported worse psychosocial health. Our data suggest that early effective treatment and disease self-awareness should be promoted in NT1 children for their positive effect on behavior and psychosocial health

Cerebral Microcirculation during Experimental Normovolaemic Anemia

PubMed Central

Bellapart, Judith; Cuthbertson, Kylie; Dunster, Kimble; Diab, Sara; Platts, David G.; Raffel, O. Christopher; Gabrielian, Levon; Barnett, Adrian; Paratz, Jenifer; Boots, Rob; Fraser, John F.

2016-01-01

Anemia is accepted among critically ill patients as an alternative to elective blood transfusion. This practice has been extrapolated to head injury patients with only one study comparing the effects of mild anemia on neurological outcome. There are no studies quantifying microcirculation during anemia. Experimental studies suggest that anemia leads to cerebral hypoxia and increased rates of infarction, but the lack of clinical equipoise, when testing the cerebral effects of transfusion among critically injured patients, supports the need of experimental studies. The aim of this study was to quantify cerebral microcirculation and the potential presence of axonal damage in an experimental model exposed to normovolaemic anemia, with the intention of describing possible limitations within management practices in critically ill patients. Under non-recovered anesthesia, six Merino sheep were instrumented using an intracardiac transeptal catheter to inject coded microspheres into the left atrium to ensure systemic and non-chaotic distribution. Cytometric analyses quantified cerebral microcirculation at specific regions of the brain. Amyloid precursor protein staining was used as an indicator of axonal damage. Animals were exposed to normovolaemic anemia by blood extractions from the indwelling arterial catheter with simultaneous fluid replacement through a venous central catheter. Simultaneous data recording from cerebral tissue oxygenation, intracranial pressure, and cardiac output was monitored. A regression model was used to examine the effects of anemia on microcirculation with a mixed model to control for repeated measures. Homogeneous and normal cerebral microcirculation with no evidence of axonal damage was present in all cerebral regions, with no temporal variability, concluding that acute normovolaemic anemia does not result in short-term effects on cerebral microcirculation in the ovine brain. PMID:26869986

Shortened dental arch and cerebral regional blood volume: an experimental pilot study with optical topography.

PubMed

Miyamoto, Ikuya; Yoshida, Kazuya; Bessho, Kazuhisa

2009-04-01

A shortened dental arch without posterior occlusal support has been thought to maintain sufficient oral function. The mechanism of occlusal adaptation with a shortened dental arch is unclear. For a better understanding of the effects of molar teeth on brain function, the authors combined experimentally-shortened dental arches and a neuro-imaging technique. Regional cerebral blood volume was measured using near-infrared optical topography during maximum voluntary clenching tasks from 10 subjects on individually fabricated oral appliances, which can create experimentally complete and shortened dental arches. Results suggested that clenching on the complete dental arch showed a significantly higher brain blood volume than that on the shortened dental arch. Moreover, there were no differences between the two splints in the latency to the maximum oxyhemoglobin concentration. These findings suggest that occlusal status is closely related to brain blood flow and lack of occlusal molar support rapidly reduces cerebral blood volume in the maximum voluntary clenching condition.

Regional cerebral perfusion for surgical correction of neonatal aortic arch obstruction.

PubMed

Zhang, Hui; Cheng, Pei; Hou, Jia; Li, Lei; Liu, Hu; Liu, Ruifang; Ji, Bingyang; Luo, Yi

2009-05-01

One-stage repair of aortic arch obstruction and associated cardiac anomalies is a surgical challenge in infants.The purpose of the present study is to review the current outcome using regional cerebral perfusion (RCP) during a procedure correcting interrupted aortic arch (IAA) and also isolated aortic coarctation (CoA) and CoA combined with hypoplastic aortic arch (CoA-HyAA) in our center. Between January 2007 and July 2008, 24 infant patients with interrupted aortic arch (IAA) (n=3), isolated aortic coarctation (iCoA) (n=9) and aortic coarctation with hypoplastic aortic arch (CoA-HyAA) (n=12) underwent one-stage surgical correction in our hospital. End-to-end anastomosis was employed in 12 infants (IAA n=3 and iCoA n=9); for the other 12 patients with CoA-HyAA, an end-to-end extended anastomosis was used in 8 cases, end-to-side anastomosis in 2 cases, and composite heterologous pericardial patch in 2 cases. RCP with 40 mL/kg/min through the innominate artery during aortic arch reconstruction was employed for all pediatric patients. One single-dose histidine-ketoglutarate-tryptophan (HTK) solution was used for myocardial protection during CPB. Cardiopulmonary bypass time and aortic cross-clamp time were 165.6+/-32.4 min and 81.7+/-30.0 min, respectively. The mean regional cerebral perfusion time was 31.0+/-10.6 min; lowest nasopharyngeal temperature was 19.1+/-1.1 degrees C. Operative mortality rate in both groups was 8.3%. Mean follow-up was 10.5+/-4.8 months. There was no late mortality or postoperative neurologic, renal or hepatic complications. All patients are asymptomatic and are developing normally. One-stage total arch repair using the RCP technique is an excellent method that may minimize neurologic and renal complications. Our surgical strategy for arch anomaly has a low rate of residual and recurrent coarctation when performed in these infants.

Autonomic Response to Periodic Leg Movements during Sleep in Narcolepsy-Cataplexy

PubMed Central

Dauvilliers, Yves; Pennestri, Marie-Hélène; Whittom, Shirley; Lanfranchi, Paola A.; Montplaisir, Jacques Y.

2011-01-01

Study Objectives: To test the hypothesis of autonomic nervous system dysfunction in patients with narcolepsy-cataplexy (NC) by assessing the physiologic activations associated with periodic limb movements during sleep (PLMS). Design: Sleep and heart rate (HR) were recorded during 1 night of polysomnography. Setting: Data were collected at the Sleep Disorders Center, Sacre-Coeur Hospital, Montreal, Canada. Participants: Data from 14 patients with NC (6 men, 8 women, mean age: 52.5 ± 11.9 years) were compared with data from 14 healthy control subjects matched for age and sex. Interventions: NA. Measurements and Results: Analyses included sleep stages, PLMS, microarousals, RR intervals converted into beats per minute on segments lasting 25 heartbeats (10 RR intervals before PLMS and 15 after), and cardiac-activation amplitudes. A Group-by-Heartbeat interaction was noted for PLMS without microarousals; the patients had a tachycardia of lower amplitude and a delayed and lower-amplitude bradycardia, compared with normal control subjects. Similar significant HR modifications were observed for PLMS with microarousals between patients with NC and control subjects. Patients with NC had a reduced magnitude of cardiac activation associated with PLMS with and without microarousals, as compared with control subjects. A negative correlation was noted between cardiac-activation amplitude and age in patients with NC, but no correlation with PLMS index was found in either patients with NC or control subjects. Conclusion: A significant reduction in the amplitude of PLMS-related HR responses in both tachycardia and bradycardia was found in patients with NC. These findings favor the physiologic relevance of the action of hypocretin on autonomic function that may be of clinical significance, i.e., increasing the risk of cardiovascular diseases. Citation: Dauvilliers Y; Pennestri MH; Whittom S; Lanfranchi PA; Montplaisir JY. Autonomic response to periodic leg movements during sleep in

Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia.

PubMed

Chi, O Z; Barsoum, S; Vega-Cotto, N M; Jacinto, E; Liu, X; Mellender, S J; Weiss, H R

2016-03-01

Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1h and reperfusion for 2h with and without rapamycin (20mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C(14)-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5±0.8% control vs. 21.5±0.9% rapamycin). We also found that ischemia-reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia-reperfusion. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Autistic Traits, ADHD Symptoms, Neurological Soft Signs and Regional Cerebral Blood Flow in Adults with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Manouilenko, Irina; Pagani, Marco; Stone-Elander, Sharon; Odh, Richard; Brolin, Fredrik; Hatherly, Robert; Jacobsson, Hans; Larsson, Stig A.; Bejerot, Susanne

2013-01-01

The resting regional cerebral blood flow (rCBF) patterns related to co-occurring symptoms such as inattention, hyperactivity, neurological soft signs and motor problems have not yet been disclosed in autism spectrum disorders (ASD). In this study thirteen adults with ASD and ten matched neurotypical controls underwent PET. The scores of rating…

[The cerebral hemodynamics in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy].

PubMed

Jin, De-xin; Chen, Xiu-yun; Huang, He; Zhang, Xu

2006-12-01

To investigate the cerebral hemodynamics in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The blood flow velocity of cerebral arteries was measured by using transcranial Doppler ultrasound (TCD) in 6 cases with CADASIL and a quite number of age and sex matched control subjects. All patients (4 were symptomatic and 2 asymptomatic), being an established CADASIL family with the diagnosis confirmed by clinical characteristics, neuroimaging, pathology and molecular genetics, had abnormal mark signals on MR imagining and no history of hypertension, diabetes, heart disease and migraine. A routinely TCD detection, including peak-systolic velocity (Vp), end-diastolic velocity (Vd), mean velocity (Vm) and pulsatility index (PI), was carried out on the bilateral middle cerebral arteries (MCA), anterior cerebral arteries (ACA), posterior cerebral arteries (PCA) and vertebral arteries (VA) as well as the basilar artery (BA). A comparison between the cases and controls was made. Then, the changes of flow velocity in middle cerebral arteries (MCA) of the patients with CADASIL were observed before and after breathholding tests. In addition, brain CT perfusion imaging (CTP) was carried out in all the cases by using 16-slice spiral CT. The appearances of frequency spectrum were nearly normal in all the cases and there was no abnormality between the two sides on velocity (P > 0.05). As compared with the controls, the bilateral Vp, Vd and Vm in ACA and PCA were decreased obviously (P < 0.05). The velocity parameters of MCA with the exception of left Vm and right PI showed changes (P < 0.05) and there were no changes of PI in the bilateral ACA, PCA and Left MCA (P > 0.05). Moreover, there were marked changes in MCA (including Vm, Vd and PI) of all the cases as compared with the controls after breathholding (P < 0.01). Brain perfusion imaging showing the regional cerebral blood flow and regional cerebral blood volume in frontal

Antibody Affinity Against 2009 A/H1N1 Influenza and Pandemrix Vaccine Nucleoproteins Differs Between Childhood Narcolepsy Patients and Controls.

PubMed

Lind, Alexander; Freyhult, Eva; Ramelius, Anita; Olsson, Tomas; Arnheim-Dahlström, Lisen; Lamb, Favelle; Khademi, Mohsen; Ambati, Aditya; Maeurer, Markus; Lima Bomfim, Izaura; Fink, Katharina; Fex, Malin; Törn, Carina; Elding Larsson, Helena; Lernmark, Åke

2017-10-01

Increased narcolepsy incidence was observed in Sweden following the 2009 influenza vaccination with Pandemrix ® . A substitution of the 2009 nucleoprotein for the 1934 variant has been implicated in narcolepsy development. The aims were to determine (a) antibody levels toward wild-type A/H1N1-2009[A/California/04/2009(H1N1)] (NP-CA2009) and Pandemrix-[A/Puerto Rico/8/1934(H1N1)] (NP-PR1934) nucleoproteins in 43 patients and 64 age-matched controls; (b) antibody affinity in reciprocal competitive assays in 11 childhood narcolepsy patients compared with 21 age-matched controls; and (c) antibody levels toward wild-type A/H1N1-2009[A/California/04/2009(H1N1)] (H1N1 NS1), not a component of the Pandemrix vaccine. In vitro transcribed and translated 35 S-methionine-labeled H1N1 influenza A virus proteins were used in radiobinding reciprocal competition assays to estimate antibody levels and affinity (Kd). Childhood patients had higher NP-CA2009 (p = 0.0339) and NP-PR1934 (p = 0.0246) antibody levels compared with age-matched controls. These childhood controls had lower NP-CA2009 (p = 0.0221) and NP-PR1934 (p = 0.00619) antibodies compared with controls 13 years or older. In contrast, in patients 13 years or older, the levels of NP-PR1934 (p = 0.279) and NP-CA2009 (p = 0.0644) antibodies did not differ from the older controls. Childhood antibody affinity (Kd) against NP-CA2009 was comparable between controls (68 ng/mL) and patients (74 ng/mL; p = 0.21) with NP-CA2009 and NP-PR1934 displacement (controls: 165 ng/mL; patients: 199 ng/mL; p = 0.48). In contrast, antibody affinity against NP-PR1934 was higher in controls with either NP-PR1934 (controls: 9 ng/mL; patients: 20 ng/mL; p = 0.0031) or NP-CA2009 (controls: 14 ng/mL; patients: 23 ng/mL; p = 0.0048). A/H1N1-NS1 antibodies were detected in 0/43 of the narcolepsy patients compared with 3/64 (4.7%) controls (p = 0.272). Similarly, none (0/11) of the childhood

Cerebellar asymmetry and its relation to cerebral asymmetry estimated by intrinsic functional connectivity

PubMed Central

Wang, Danhong; Buckner, Randy L.

2013-01-01

Asymmetry of the human cerebellum was investigated using intrinsic functional connectivity. Regions of functional asymmetry within the cerebellum were identified during resting-state functional MRI (n = 500 subjects) and replicated in an independent cohort (n = 500 subjects). The most strongly right lateralized cerebellar regions fell within the posterior lobe, including crus I and crus II, in regions estimated to link to the cerebral association cortex. The most strongly left lateralized cerebellar regions were located in lobules VI and VIII in regions linked to distinct cerebral association networks. Comparison of cerebellar asymmetry with independently estimated cerebral asymmetry revealed that the lateralized regions of the cerebellum belong to the same networks that are strongly lateralized in the cerebrum. The degree of functional asymmetry of the cerebellum across individuals was significantly correlated with cerebral asymmetry and varied with handedness. In addition, cerebellar asymmetry estimated at rest predicted cerebral lateralization during an active language task. These results demonstrate that functional lateralization is likely a unitary feature of large-scale cerebrocerebellar networks, consistent with the hypothesis that the cerebellum possesses a roughly homotopic map of the cerebral cortex including the prominent asymmetries of the association cortex. PMID:23076113

Shy-Drager syndrome. Effect of fludrocortisone and L-threo-3,4-dihydroxyphenylserine on the blood pressure and regional cerebral blood flow.

PubMed Central

Matsubara, S; Sawa, Y; Yokoji, H; Takamori, M

1990-01-01

In nine cases of Shy-Drager syndrome, the changes in blood pressure and cerebral blood flow on sitting up from a supine position were studied. The influence of fludrocortisone, a synthetic mineralocorticoid, and L-threo-3,4-dihydroxyphenylserine (DOPS), a precursor of norepinephrine, on these changes was examined. On sitting up, the regional cerebral blood flow (rCBF) measured by Xe133 inhalation showed a tendency to decrease. Fludrocortisone reduced the fall of the mean blood pressure significantly. DOPS reduced the fall of both the diastolic blood pressure and rCBF significantly. PMID:2283531

Different Alterations of Cerebral Regional Homogeneity in Early-Onset and Late-Onset Parkinson's Disease

PubMed Central

Sheng, Ke; Fang, Weidong; Zhu, Yingcheng; Shuai, Guangying; Zou, Dezhi; Su, Meilan; Han, Yu; Cheng, Oumei

2016-01-01

HIGHLIGHTS Eighteen EOPD, 21 LOPD and 37 age-matched normal control subjects participated in the resting state fMRI scans.Age at onset of PD modulates the distribution of cerebral regional homogeneity during resting state.Disproportionate putamen alterations are more prominent in PD patients with a younger age of onset. Objective: Early-onset Parkinson's disease (EOPD) is distinct from late-onset PD (LOPD) as it relates to the clinical profile and response to medication. The objective of current paper is to investigate whether characteristics of spontaneous brain activity in the resting state are associated with the age of disease onset. Methods: We assessed the correlation between neural activity and age-at-onset in a sample of 39 PD patients (18 EOPD and 21 LOPD) and 37 age-matched normal control subjects. Regional homogeneity (ReHo) approaches were employed using ANOVA with two factors: PD and age. Results: In the comparisons between LOPD and EOPD, EOPD revealed lower ReHo values in the right putamen and higher ReHo values in the left superior frontal gyrus. Compared with age-matched control subjects, EOPD exhibited lower ReHo values in the right putamen and higher ReHo values in the left inferior temporal gyrus; However, LOPD showed lower ReHo values in the right putamen and left insula. The ReHo values were negatively correlated with the UPDRS total scores in the right putamen in LOPD, but a correlation between the ReHo value and UPDRS score was not detected in EOPD. Conclusions: Our findings support the notion that age at onset is associated with the distribution of cerebral regional homogeneity in the resting state and suggest that disproportionate putamen alterations are more prominent in patients with a younger age of onset. PMID:27462265

Absence of NMDA receptor antibodies in the rare association between Type 1 Narcolepsy and Psychosis

PubMed Central

Dauvilliers, Y.; Gaig, C.; Barateau, L.; Graus, F.; Iranzo, A.; Lopez, R.; Santamaria, J.

2016-01-01

Frequency and mechanisms underlying the association between narcolepsy type 1 (NT1) and psychosis remain unclear with potential role for a common immune pathway. We estimated the frequency of psychosis and its characteristics in NT1 at two European sleep centers (France, n = 381; Spain, n = 161) and measured IgG autoantibodies that recognize the GluN1 subunit of the NMDAR in 9 patients with NT1 with psychosis, and 25 NT1 patients without psychosis. Ten NT1 patients (6 in France, 4 in Spain) were diagnosed with comorbid psychosis, a frequency of 1.8%. One patient reported psychotic symptoms few months before narcolepsy onset, two patients few months after onset, and one patient one year after onset but after modafinil introduction. The six remaining patients reported long delays between NT1 and psychosis onset. Half the patients, mostly male adults, reported onset or worsening of psychotic symptoms after medication. We found no IgG antibodies to NR1/NR2B heteromers of the NMDARs in patients with NT1 with or without psychosis. To conclude, psychosis is rare in NT1, with limited evidence for a key impact of stimulants, and no association with anti-NMDAR antibodies. However, dramatic NT1 and schizophrenia exists especially in early onset NT1, which may lead to inappropriate diagnosis and management. PMID:27143278

Selected sleep disorders: restless legs syndrome and periodic limb movement disorder, sleep apnea syndrome, and narcolepsy.

PubMed

Erman, Milton K

2006-12-01

Sleep disorders, including restless legs syndrome and periodic limb movement disorder, sleep apnea syndrome, and narcolepsy, are prevalent medical conditions, likely to be seen by practicing psychiatrists. Awareness of these conditions and their presentations, pathophysiology, and treatment allows psychiatrists to treat these conditions where appropriate, to minimize complications and health consequences associated with delayed diagnosis, and to reduce the burden of disease that these conditions may place on patients already experiencing primary psychiatric disorders.

Proteomic identification of altered cerebral proteins in the complex regional pain syndrome animal model.

PubMed

Nahm, Francis Sahngun; Park, Zee-Yong; Nahm, Sang-Soep; Kim, Yong Chul; Lee, Pyung Bok

2014-01-01

Complex regional pain syndrome (CRPS) is a rare but debilitating pain disorder. Although the exact pathophysiology of CRPS is not fully understood, central and peripheral mechanisms might be involved in the development of this disorder. To reveal the central mechanism of CRPS, we conducted a proteomic analysis of rat cerebrum using the chronic postischemia pain (CPIP) model, a novel experimental model of CRPS. After generating the CPIP animal model, we performed a proteomic analysis of the rat cerebrum using a multidimensional protein identification technology, and screened the proteins differentially expressed between the CPIP and control groups. Results. A total of 155 proteins were differentially expressed between the CPIP and control groups: 125 increased and 30 decreased; expressions of proteins related to cell signaling, synaptic plasticity, regulation of cell proliferation, and cytoskeletal formation were increased in the CPIP group. However, proenkephalin A, cereblon, and neuroserpin were decreased in CPIP group. Altered expression of cerebral proteins in the CPIP model indicates cerebral involvement in the pathogenesis of CRPS. Further study is required to elucidate the roles of these proteins in the development and maintenance of CRPS.

Estimation of regional cerebral blood flow distribution in infants by multichannel near-infrared spectroscopy with indocyanine green

NASA Astrophysics Data System (ADS)

Kusaka, Takashi; Isobe, Kenichi; Nagano, Keiko; Okubo, Kensuke; Yasuda, Saneyuki; Kawada, Kou; Itoh, Susumu; Onishi, Shoju; Oda, Ichiro; Wada, Yukihisa; Konishi, Ikuo; Tsunazawa, Yoshio

2001-06-01

This is the report on the use of multichannel near-infrared spectroscopy (MNIRS) with indocyanine green (ICG) to determine regional cerebral blood flow (rCBF) distribution disturbance in infants. We measured rCBF in an infant with subdural hemorrhage after surgical removal of a subdural hematoma. A probe consisting of 12 optical fibers, 6 for transmission and 6 for detection, was set on the right and then left temporal regions of the head of the infant, and 16 measuring points were determined. Changes in ICG concentration were recorded using MNIRS (near infrared optical imaging system, OMM-2000, Shimadzu Corp., Japan).

[Indicators of general, cerebral, and regional hemodynamics in myopic schoolchildren aged 13-15 years].

PubMed

Iastrebtseva, T A; Chuprov, A D; Plotnikova, Iu A

2002-01-01

110 schoolchildren aged 13-15 years were examined. 24 of them had pseudomyopia and 6 patients myopia of various forms. A control group consisted of 38 children. Central hemodynamics was estimated by average dynamic pressure, cerebral hemodynamics--by rheoencephalography, regional hemodynamics--by dopplerography of the internal carotid and suprapubic arteries. It was found that with myopia progression, the average dynamic pressure positively comes down with reduction of reographic waves amplitude in rheogram. The blood flow rate in internal carotid and suprapubic arteries has no substantial impact on myopia course. Predisposition to arterial hypotension is a risk factor for myopia development and progression.

Regional Cerebral Oximetry During Cardiopulmonary Resuscitation: Useful or Useless?

PubMed

Genbrugge, Cornelia; Dens, Jo; Meex, Ingrid; Boer, Willem; Eertmans, Ward; Sabbe, Marc; Jans, Frank; De Deyne, Cathy

2016-01-01

Approximately 375,000 people annually experience sudden cardiac arrest (CA) in Europe. Most patients who survive the initial hours and days after CA die of postanoxic brain damage. Current monitors, such as electrocardiography and end-tidal capnography, provide only indirect information about the condition of the brain during cardiopulmonary resuscitation (CPR). In contrast, cerebral near-infrared spectroscopy provides continuous, noninvasive, real-time information about brain oxygenation without the need for a pulsatile blood flow. It measures transcutaneous cerebral tissue oxygen saturation (rSO2). This information could supplement currently used monitors. Moreover, an evolution in rSO2 monitoring technology has made it easier to assess rSO2 in CA conditions. We give an overview of the literature regarding rSO2 measurements during CPR and the current commercially available devices. We highlight the feasibility of cerebral saturation measurement during CPR, its role as a quality parameter of CPR, predictor of return of spontaneous circulation (ROSC) and neurologic outcome, and its monitoring function during transport. rSO2 is feasible in the setting of CA and has the potential to measure the quality of CPR, predict ROSC and neurologic outcome, and monitor post-CA patients during transport. The literature shows that rSO2 has the potential to serve multiple roles as a neuromonitoring tool during CPR and also to guide neuroprotective therapeutic strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy.

PubMed

Black, Sarah Wurts; Morairty, Stephen R; Fisher, Simon P; Chen, Tsui-Ming; Warrier, Deepti R; Kilduff, Thomas S

2013-03-01

Humans with narcolepsy and orexin/ataxin-3 transgenic (TG) mice exhibit extensive, but incomplete, degeneration of hypo-cretin (Hcrt) neurons. Partial Hcrt cell loss also occurs in Parkinson disease and other neurologic conditions. Whether Hcrt antagonists such as almorexant (ALM) can exert an effect on the Hcrt that remains after Hcrt neurodegeneration has not yet been determined. The current study was designed to evaluate the hypnotic and cataplexy-inducing efficacy of a Hcrt antagonist in an animal model with low Hcrt tone and compare the ALM efficacy profile in the disease model to that produced in wild-type (WT) control animals. Counterbalanced crossover study. Home cage. Nine TG mice and 10 WT mice. ALM (30, 100, 300 mg/kg), vehicle and positive control injections, dark/active phase onset. During the 12-h dark period after dosing, ALM exacerbated cataplexy in TG mice and increased nonrapid eye movement sleep with heightened sleep/wake fragmentation in both genotypes. ALM showed greater hypnotic potency in WT mice than in TG mice. The 100 mg/kg dose conferred maximal promotion of cataplexy in TG mice and maximal promotion of REM sleep in WT mice. In TG mice, ALM (30 mg/ kg) paradoxically induced a transient increase in active wakefulness. Core body temperature (Tb) decreased after acute Hcrt receptor blockade, but the reduction in Tb that normally accompanies the wake-to-sleep transition was blunted in TG mice. These complex dose- and genotype-dependent interactions underscore the importance of effector mechanisms downstream from Hcrt receptors that regulate arousal state. Cataplexy promotion by ALM warrants cautious use of Hcrt antagonists in patient populations with Hcrt neurodegeneration, but may also facilitate the discovery of anticataplectic medications. Black SW; Morairty SR; Fisher SP; Chen TM; Warrier DR; Kilduff TS. Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. SLEEP 2013;36(3):325-336.

Pseudotumor cerebri syndrome in a patient with narcolepsy type 1.

PubMed

Rossor, Thomas; Lim, Ming; VanDenEshof, Kirandeep; Gringras, Paul

2018-01-01

Type 1 narcolepsy (NT1) is a chronic primary disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disrupted nocturnal sleep. NT1 is linked to hypothalamic hypocretin deficiency, strongly associated with Human Leukocyte Antigen (HLA) marker DQB1*06:02 and of probable autoimmune origin. NT1 is usually associated with increased rates of overweight and obesity, and sometimes with increases in overnight blood pressure and increased rates of hypoventilation with raised CO 2 levels overnight. Many of these are predisposing factors for pseudotumor cerebri syndrome (PTCS). We present a case of a young girl with both NT1 and PTCS that responded well to treatment with acetazolamide after early identification, with improvement of headache and resolution of hypoventilation. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Regional Cerebral Blood Flow during Wakeful Rest in Older Subjects with Mild to Severe Obstructive Sleep Apnea

PubMed Central

Baril, Andrée-Ann; Gagnon, Katia; Arbour, Caroline; Soucy, Jean-Paul; Montplaisir, Jacques; Gagnon, Jean-François; Gosselin, Nadia

2015-01-01

Objectives: To evaluate changes in regional cerebral blood flow (rCBF) during wakeful rest in older subjects with mild to severe obstructive sleep apnea (OSA) and healthy controls, and to identify markers of OSA severity that predict altered rCBF. Design: High-resolution 99mTc-HMPAO SPECT imaging during wakeful rest. Setting: Research sleep laboratory affiliated with a University hospital. Participants: Fifty untreated OSA patients aged between 55 and 85 years, divided into mild, moderate, and severe OSA, and 20 age-matched healthy controls. Interventions: N/A. Measurements: Using statistical parametric mapping, rCBF was compared between groups and correlated with clinical, respiratory, and sleep variables. Results: Whereas no rCBF change was observed in mild and moderate groups, participants with severe OSA had reduced rCBF compared to controls in the left parietal lobules, left precentral gyrus, bilateral postcentral gyri, and right precuneus. Reduced rCBF in these regions and in areas of the bilateral frontal and left temporal cortex was associated with more hypopneas, snoring, hypoxemia, and sleepiness. Higher apnea, microarousal, and body mass indexes were correlated to increased rCBF in the basal ganglia, insula, and limbic system. Conclusions: While older individuals with severe obstructive sleep apnea (OSA) had hypoperfusion in the sensorimotor and parietal areas, respiratory variables and subjective sleepiness were correlated with extended regions of hypoperfusion in the lateral cortex. Interestingly, OSA severity, sleep fragmentation, and obesity correlated with increased perfusion in subcortical and medial cortical regions. Anomalies with such a distribution could result in cognitive deficits and reflect impaired vascular regulation, altered neuronal integrity, and/or undergoing neurodegenerative processes. Citation: Baril AA, Gagnon K, Arbour C, Soucy JP, Montplaisir J, Gagnon JF, Gosselin N. Regional cerebral blood flow during wakeful rest in older

Smart catheter flow sensor for real-time continuous regional cerebral blood flow monitoring

NASA Astrophysics Data System (ADS)

Li, Chunyan; Wu, Pei-Ming; Hartings, Jed A.; Wu, Zhizhen; Ahn, Chong H.; LeDoux, David; Shutter, Lori A.; Narayan, Raj K.

2011-12-01

We present a smart catheter flow sensor for real-time, continuous, and quantitative measurement of regional cerebral blood flow using in situ temperature and thermal conductivity compensation. The flow sensor operates in a constant-temperature mode and employs a periodic heating and cooling technique. This approach ensures zero drift and provides highly reliable data with microelectromechanical system-based thin film sensors. The developed flow sensor has a sensitivity of 0.973 mV/ml/100 g/min in the range from 0 to 160 ml/100 g/min with a linear correlation coefficient of R2 = 0.9953. It achieves a resolution of 0.25 ml/100 g/min and an accuracy better than 5 ml/100 g/min.

HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

PubMed Central

Ollila, Hanna M.; Ravel, Jean-Marie; Han, Fang; Faraco, Juliette; Lin, Ling; Zheng, Xiuwen; Plazzi, Giuseppe; Dauvilliers, Yves; Pizza, Fabio; Hong, Seung-Chul; Jennum, Poul; Knudsen, Stine; Kornum, Birgitte R.; Dong, Xiao Song; Yan, Han; Hong, Heeseung; Coquillard, Cristin; Mahlios, Joshua; Jolanki, Otto; Einen, Mali; Lavault, Sophie; Högl, Birgit; Frauscher, Birgit; Crowe, Catherine; Partinen, Markku; Huang, Yu Shu; Bourgin, Patrice; Vaarala, Outi; Désautels, Alex; Montplaisir, Jacques; Mack, Steven J.; Mindrinos, Michael; Fernandez-Vina, Marcelo; Mignot, Emmanuel

2015-01-01

Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1∗01:02-DQB1∗06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1∗01:03-DPB1∗04:02 (DP0402; odds ratio [OR] = 0.51 [0.38–0.67], p = 1.01 × 10−6) and HLA-DPA1∗01:03-DPB1∗04:01 (DP0401; OR = 0.61 [0.47–0.80], p = 2.07 × 10−4) and predisposing effects of HLA-DPB1∗05:01 in Asians (OR = 1.76 [1.34–2.31], p = 4.71 × 10−05). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38–0.55] p = 8.99 × 10−17) and DP0501 (OR = 1.38 [1.18–1.61], p = 7.11 × 10−5). HLA-class-II-independent associations with HLA-A∗11:01 (OR = 1.32 [1.13–1.54], p = 4.92 × 10−4), HLA-B∗35:03 (OR = 1.96 [1.41–2.70], p = 5.14 × 10−5), and HLA-B∗51:01 (OR = 1.49 [1.25–1.78], p = 1.09 × 10−5) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza. PMID:25574827

Regional brain blood flow and cerebral hemispheric oxygen consumption during acute hypoxaemia in the llama fetus

PubMed Central

Llanos, Aníbal J; Riquelme, Raquel A; Sanhueza, Emilia M; Herrera, Emilio; Cabello, Gertrudis; Giussani, Dino A; Parer, Julian T

2002-01-01

Unlike fetal animals of lowland species, the llama fetus does not increase its cerebral blood flow during an episode of acute hypoxaemia. This study tested the hypothesis that the fetal llama brain maintains cerebral hemispheric O2 consumption by increasing cerebral O2 extraction rather than decreasing cerebral oxygen utilisation during acute hypoxaemia. Six llama fetuses were surgically instrumented under general anaesthesia at 217 days of gestation (term ca 350 days) with vascular and amniotic catheters in order to carry out cardiorespiratory studies. Following a control period of 1 h, the llama fetuses underwent 3 × 20 min episodes of progressive hypoxaemia, induced by maternal inhalational hypoxia. During basal conditions and during each of the 20 min of hypoxaemia, fetal cerebral blood flow was measured with radioactive microspheres, cerebral oxygen extraction was calculated, and fetal cerebral hemispheric O2 consumption was determined by the modified Fick principle. During hypoxaemia, fetal arterial O2 tension and fetal pH decreased progressively from 24 ± 1 to 20 ± 1 Torr and from 7.36 ± 0.01 to 7.33 ± 0.01, respectively, during the first 20 min episode, to 16 ± 1 Torr and 7.25 ± 0.05 during the second 20 min episode and to 14 ± 1 Torr and 7.21 ± 0.04 during the final 20 min episode. Fetal arterial partial pressure of CO2 (Pa,CO2, 42 ± 2 Torr) remained unaltered from baseline throughout the experiment. Fetal cerebral hemispheric blood flow and cerebral hemispheric oxygen extraction were unaltered from baseline during progressive hypoxaemia. In contrast, a progressive fall in fetal cerebral hemispheric oxygen consumption occurred during the hypoxaemic challenge. In conclusion, these data do not support the hypothesis that the fetal llama brain maintains cerebral hemispheric O2 consumption by increasing cerebral hemispheric O2 extraction. Rather, the data show that in the llama fetus, a reduction in cerebral hemispheric metabolism occurs during acute

Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers.

PubMed

London, Edythe D; Simon, Sara L; Berman, Steven M; Mandelkern, Mark A; Lichtman, Aaron M; Bramen, Jennifer; Shinn, Ann K; Miotto, Karen; Learn, Jennifer; Dong, Yun; Matochik, John A; Kurian, Varughese; Newton, Thomas; Woods, Roger; Rawson, Richard; Ling, Walter

2004-01-01

Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood. To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers. Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task. Participants were recruited from the general community to a research center. Seventeen abstaining (4-7 days) MA abusers (6 women) were compared with 18 control subjects (8 women). Self-reports of depressive symptoms and anxiety were measured, as were global and relative glucose metabolism in the orbitofrontal, cingulate, lateral prefrontal, and insular cortices and the amygdala, striatum, and cerebellum. Abusers of MA provided higher self-ratings of depression and anxiety than control subjects and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula and higher in the lateral orbitofrontal area, middle and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA abusers, self-reports of depressive symptoms covaried positively with relative glucose metabolism in limbic regions (eg, perigenual anterior cingulate gyrus and amygdala) and ratings of state and trait anxiety covaried negatively with relative activity in the anterior cingulate cortex and left insula. Trait anxiety also covaried negatively with relative activity in the orbitofrontal cortex and positively with amygdala activity. Abusers of MA have abnormalities in brain regions implicated in mood disorders. Relationships between relative glucose metabolism in limbic and paralimbic regions and self-reports of depression and anxiety in MA abusers suggest that these regions are involved in affective dysregulation and may be an important target of intervention for MA dependence.

[Effects of carbon dioxide insufflation on regional cerebral oxygenation during laparoscopic surgery in children: a prospective study].

PubMed

Tuna, Ayca Tas; Akkoyun, Ibrahim; Darcin, Sevtap; Palabiyik, Onur

2016-01-01

Laparoscopic surgery has become a popular surgical tool when compared to traditional open surgery. There are limited data on pediatric patients regarding whether pneumoperitoneum affects cerebral oxygenation although end-tidal CO2 concentration remains normal. Therefore, this study was designed to evaluate the changes of cerebral oxygen saturation using near-infrared spectroscope during laparoscopic surgery in children. The study comprised forty children who were scheduled for laparoscopic (Group L, n=20) or open (Group O, n=20) appendectomy. Hemodynamic variables, right and left regional cerebral oxygen saturation (RrSO2 and LrSO2), fraction of inspired oxygen, end-tidal carbon dioxide pressure (PETCO2), peak inspiratory pressure (Ppeak), respiratory minute volume, inspiratory and end-tidal concentrations of sevoflurane and body temperature were recorded. All parameters were recorded after anesthesia induction and before start of surgery (T0, baseline), 15min after start of surgery (T1), 30min after start of surgery (T2), 45min after start of surgery (T3), 60min after start of surgery (T4) and end of the surgery (T5). There were progressive decreases in both RrSO2 and LrSO2 levels in both groups, which were not statistically significant at T1, T2, T3, T4. The RrSO2 levels of Group L at T5 were significantly lower than that of Group O. One patient in Group L had an rSO2 value <80% of the baseline value. Carbon dioxide insufflation during pneumoperitoneum in pediatric patients may not affect cerebral oxygenation under laparoscopic surgery. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Effects of carbon dioxide insufflation on regional cerebral oxygenation during laparoscopic surgery in children: a prospective study.

PubMed

Tuna, Ayca Tas; Akkoyun, Ibrahim; Darcin, Sevtap; Palabiyik, Onur

2016-01-01

Laparoscopic surgery has become a popular surgical tool when compared to traditional open surgery. There are limited data on pediatric patients regarding whether pneumoperitoneum affects cerebral oxygenation although end-tidal CO2 concentration remains normal. Therefore, this study was designed to evaluate the changes of cerebral oxygen saturation using near-infrared spectroscope during laparoscopic surgery in children. The study comprised forty children who were scheduled for laparoscopic (Group L, n=20) or open (Group O, n=20) appendectomy. Hemodynamic variables, right and left regional cerebral oxygen saturation (RrSO2 and LrSO2), fraction of inspired oxygen, end-tidal carbon dioxide pressure (PETCO2), peak inspiratory pressure (Ppeak), respiratory minute volume, inspiratory and end-tidal concentrations of sevoflurane and body temperature were recorded. All parameters were recorded after anesthesia induction and before start of surgery (T0, baseline), 15min after start of surgery (T1), 30min after start of surgery (T2), 45min after start of surgery (T3), 60min after start of surgery (T4) and end of the surgery (T5). There were progressive decreases in both RrSO2 and LrSO2 levels in both groups, which were not statistically significant at T1, T2, T3, T4. The RrSO2 levels of Group L at T5 were significantly lower than that of Group O. One patient in Group L had an rSO2 value <80% of the baseline value. Carbon dioxide insufflation during pneumoperitoneum in pediatric patients may not affect cerebral oxygenation under laparoscopic surgery. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia.

PubMed

Trotti, Lynn Marie; Staab, Beth A; Rye, David B

2013-08-15

Differentiation of narcolepsy without cataplexy from idiopathic hypersomnia relies entirely upon the multiple sleep latency test (MSLT). However, the test-retest reliability for these central nervous system hypersomnias has never been determined. Patients with narcolepsy without cataplexy, idiopathic hypersomnia, and physiologic hypersomnia who underwent two diagnostic multiple sleep latency tests were identified retrospectively. Correlations between the mean sleep latencies on the two studies were evaluated, and we probed for demographic and clinical features associated with reproducibility versus change in diagnosis. Thirty-six patients (58% women, mean age 34 years) were included. Inter -test interval was 4.2 ± 3.8 years (range 2.5 months to 16.9 years). Mean sleep latencies on the first and second tests were 5.5 (± 3.7 SD) and 7.3 (± 3.9) minutes, respectively, with no significant correlation (r = 0.17, p = 0.31). A change in diagnosis occurred in 53% of patients, and was accounted for by a difference in the mean sleep latency (N = 15, 42%) or the number of sleep onset REM periods (N = 11, 31%). The only feature predictive of a diagnosis change was a history of hypnagogic or hypnopompic hallucinations. The multiple sleep latency test demonstrates poor test-retest reliability in a clinical population of patients with central nervous system hypersomnia evaluated in a tertiary referral center. Alternative diagnostic tools are needed.

Effect of Oral JZP-110 (ADX-N05) on Wakefulness and Sleepiness in Adults with Narcolepsy: A Phase 2b Study

PubMed Central

Ruoff, Chad; Swick, Todd J.; Doekel, Robert; Emsellem, Helene A.; Feldman, Neil T.; Rosenberg, Russell; Bream, Gary; Khayrallah, Moise A.; Lu, Yuan; Black, Jed

2016-01-01

Study Objectives: To evaluate the efficacy and safety of oral JZP-110, a second-generation wake-promoting agent with dopaminergic and noradrenergic activity, for treatment of impaired wakefulness and excessive sleepiness in adults with narcolepsy. Methods: This was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial conducted at 28 centers in the United States. Patients were adults with narcolepsy who had baseline scores ≥ 10 on the Epworth Sleepiness Scale (ESS) and baseline sleep latency ≤ 10 min on the Maintenance of Wakefulness Test (MWT). Patients received a daily placebo (n = 49) or JZP-110 (n = 44) 150 mg/day weeks 1–4 and 300 mg/day weeks 5–12. Primary efficacy endpoints were change from baseline in average MWT sleep latency, and the Clinical Global Impression-Change (CGI-C); secondary endpoints were change from baseline in ESS score and Patient Global Impression-Change. Results: Improvements were significantly greater with JZP-110 versus placebo on mean MWT sleep latency (4 w, 9.5 versus 1.4 min, P < 0.0001; 12 w, 12.8 versus 2.1 min, P < 0.0001), percentage of patients with CGI-C improvement (4 w, 80% versus 51%, P = 0.0066; 12 w, 86% versus 38%, P < 0.0001), and mean change in ESS (4 w, −5.6 versus −2.4, P = 0.0038; 12 w, −8.5 versus −2.5, P < 0.0001). Three JZP-110-treated patients (6.8%) discontinued due to adverse events (AEs). The most common AEs with JZP-110 versus placebo were insomnia (23% versus 8%), headache (16% versus 10%), nausea (14% versus 6%), diarrhea (11% versus 6%), decreased appetite (14% versus 0%), and anxiety (11% versus 0%). Conclusions: At doses of 150–300 mg/day, JZP-110 was well tolerated and significantly improved the ability to stay awake and subjective symptoms of excessive sleepiness in adults with narcolepsy. Clinical Trials Registration: Clinicaltrials.gov identifier NCT01681121. Citation: Ruoff C, Swick TJ, Doekel R, Emsellem HA, Feldman NT, Rosenberg R, Bream G, Khayrallah MA

Relationship between regional cerebral metabolism and consciousness disturbance in traumatic diffuse brain injury without large focal lesions: an FDG-PET study with statistical parametric mapping analysis.

PubMed

Nakayama, N; Okumura, A; Shinoda, J; Nakashima, T; Iwama, T

2006-07-01

The cerebral metabolism of patients in the chronic stage of traumatic diffuse brain injury (TDBI) has not been fully investigated. To study the relationship between regional cerebral metabolism (rCM) and consciousness disturbance in patients with TDBI. 52 patients with TDBI in the chronic stage without large focal lesions were enrolled, and rCM was evaluated by fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) with statistical parametric mapping (SPM). All the patients were found to have disturbed consciousness or cognitive function and were divided into the following three groups: group A (n = 22), patients in a state with higher brain dysfunction; group B (n = 13), patients in a minimally conscious state; and group C (n = 17), patients in a vegetative state. rCM patterns on FDG-PET among these groups were evaluated and compared with those of normal control subjects on statistical parametric maps. Hypometabolism was consistently indicated bilaterally in the medial prefrontal regions, the medial frontobasal regions, the cingulate gyrus and the thalamus. Hypometabolism in these regions was the most widespread and prominent in group C, and that in group B was more widespread and prominent than that in group A. Bilateral hypometabolism in the medial prefrontal regions, the medial frontobasal regions, the cingulate gyrus and the thalamus may reflect the clinical deterioration of TDBI, which is due to functional and structural disconnections of neural networks rather than due to direct cerebral focal contusion.

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain.

PubMed

Hawkes, Cheryl A; Gatherer, Maureen; Sharp, Matthew M; Dorr, Adrienne; Yuen, Ho Ming; Kalaria, Rajesh; Weller, Roy O; Carare, Roxana O

2013-04-01

Development of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-β (Aβ) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic APP mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Aβ contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Aβ into the hippocampus or thalamus showed an age-related reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Aβ in the brain in AD and may facilitate development of improved therapeutic strategies to remove Aβ from the brain in AD. © 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.

Regional cerebral blood flow for singers and nonsingers while speaking, singing, and humming a rote passage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Formby, C.; Thomas, R.G.; Halsey, J.H. Jr.

1989-05-01

Two groups of singers (n = 12,13) and a group of nonsingers (n = 12) each produced the national anthem by (1) speaking and (2) singing the words and by (3) humming the melody. Regional cerebral blood flow (rCBF) was measured at rest and during each phonation task from seven areas in each hemisphere by the {sup 133}Xe-inhalation method. Intrahemisphere, interhemisphere, and global rCBF were generally similar across phonation tasks and did not yield appreciable differences among the nonsingers and the singers.

Regional cerebral blood flow for singers and nonsingers while speaking, singing, and humming a rote passage.

PubMed

Formby, C; Thomas, R G; Halsey, J H

1989-05-01

Two groups of singers (n = 12,13) and a group of nonsingers (n = 12) each produced the national anthem by (1) speaking and (2) singing the words and by (3) humming the melody. Regional cerebral blood flow (rCBF) was measured at rest and during each phonation task from seven areas in each hemisphere by the 133Xe-inhalation method. Intrahemisphere, interhemisphere, and global rCBF were generally similar across phonation tasks and did not yield appreciable differences among the nonsingers and the singers.

Evaluation of cerebral ischemia using near-infrared spectroscopy with oxygen inhalation

NASA Astrophysics Data System (ADS)

Ebihara, Akira; Tanaka, Yuichi; Konno, Takehiko; Kawasaki, Shingo; Fujiwara, Michiyuki; Watanabe, Eiju

2012-09-01

Conventional methods presently used to evaluate cerebral hemodynamics are invasive, require physical restraint, and employ equipment that is not easily transportable. Therefore, it is difficult to take repeated measurements at the patient's bedside. An alternative method to evaluate cerebral hemodynamics was developed using near-infrared spectroscopy (NIRS) with oxygen inhalation. The bilateral fronto-temporal areas of 30 normal volunteers and 33 patients with cerebral ischemia were evaluated with the NIRS system. The subjects inhaled oxygen through a mask for 2 min at a flow rate of 8 L/min. Principal component analysis (PCA) was applied to the data, and a topogram was drawn using the calculated weights. NIRS findings were compared with those of single-photon-emission computed tomography (SPECT). In normal volunteers, no laterality of the PCA weights was observed in 25 of 30 cases (83%). In patients with cerebral ischemia, PCA weights in ischemic regions were lower than in normal regions. In 28 of 33 patients (85%) with cerebral ischemia, NIRS findings agreed with those of SPECT. The results suggest that transmission of the changes in systemic SpO2 were attenuated in ischemic regions. The method discussed here should be clinically useful because it can be used to measure cerebral ischemia easily, repeatedly, and noninvasively.

Healthcare Costs Among Patients with Excessive Sleepiness Associated with Obstructive Sleep Apnea, Shift Work Disorder, or Narcolepsy

PubMed Central

Carlton, Rashad; Lunacsek, Orsolya; Regan, Timothy; Carroll, Cathryn A.

2014-01-01

Background Excessive daytime sleepiness affects nearly 20% of the general population and is associated with many medical conditions, including shift work disorder (SWD), obstructive sleep apnea (OSA), and narcolepsy. Excessive sleepiness imposes a significant clinical, quality-of-life, safety, and economic burden on society. Objective To compare healthcare costs for patients receiving initial therapy with armodafinil or with modafinil for the treatment of excessive sleepiness associated with OSA, SWD, or narcolepsy. Methods A retrospective cohort analysis of medical and pharmacy claims was conducted using the IMS LifeLink Health Plan Claims Database. Patients aged ≥18 years who had a pharmacy claim for armodafinil or for modafinil between June 1, 2009, and February 28, 2012, and had 6 months of continuous eligibility before the index prescription date, as well as International Classification of Diseases, Ninth Revision diagnosis for either OSA (327.23), SWD (327.36), or narcolepsy (347.0x) were included in the study. Patients were placed into 1 of 2 treatment cohorts based on their index prescription and followed for 1 month minimum and 34 months maximum. The annualized all-cause costs were calculated by multiplying the average per-month medical and pharmacy costs for each patient by 12 months. The daily average consumption (DACON) for armodafinil or for modafinil was calculated by dividing the total units dispensed of either drug by the prescription days supply. Results A total of 5693 patients receiving armodafinil and 9212 patients receiving modafinil were included in this study. A lower DACON was observed for armodafinil (1.04) compared with modafinil (1.47). The postindex mean medical costs were significantly lower for the armodafinil cohort compared with the modafinil cohort after adjusting for baseline differences ($11,363 vs $13,775, respectively; P = .005). The mean monthly drug-specific pharmacy costs were lower for the armodafinil cohort compared with

Acute and chronic head-down tail suspension diminishes cerebral perfusion in rats

NASA Technical Reports Server (NTRS)

Wilkerson, M. Keith; Colleran, Patrick N.; Delp, Michael D.

2002-01-01

The purpose of this study was to test the hypothesis that regional brain blood flow and vascular resistance are altered by acute and chronic head-down tail suspension (HDT). Regional cerebral blood flow, arterial pressure, heart rate, and vascular resistance were measured in a group of control rats during normal standing and following 10 min of HDT and in two other groups of rats after 7 and 28 days of HDT. Heart rate was not different among conditions, whereas mean arterial pressure was elevated at 10 min of HDT relative to the other conditions. Total brain blood flow was reduced from that during standing by 48, 24, and 27% following 10 min and 7 and 28 days of HDT, respectively. Regional blood flows to all cerebral tissues and the eyes were reduced with 10 min of HDT and remained lower in the eye, olfactory bulbs, left and right cerebrum, thalamic region, and the midbrain with 7 and 28 days of HDT. Total brain vascular resistance was 116, 44, and 38% greater following 10 min and 7 and 28 days of HDT, respectively, relative to that during control standing. Vascular resistance was elevated in all cerebral regions with 10 min of HDT and remained higher than control levels in most brain regions. These results demonstrate that HDT results in chronic elevations in total and regional cerebral vascular resistance, and this may be the underlying stimulus for the HDT-induced smooth muscle hypertrophy of cerebral resistance arteries.

Higher cerebral oxygen saturation may provide higher urinary output during continuous regional cerebral perfusion.

PubMed

Miyamoto, Takashi; Miyaji, Kagami; Okamoto, Hirotsugu; Kohira, Satoshi; Tomoyasu, Takahiro; Inoue, Nobuyuki; Ohara, Kuniyoshi

2008-10-31

We examined the hypothesis that higher cerebral oxygen saturation (rSO2) during RCP is correlated with urinary output. Between December 2002 and August 2006, 12 patients aged 3 to 61 days and weighing 2.6 to 3.4 kg underwent aortic arch repair with RCP. Urinary output and rSO2 were analyzed retrospectively. Data were assigned to either of 2 groups according to their corresponding rSO2: Group A (rSO2 < or = 75%) and Group B (rSO2 < 75%). Seven and 5 patients were assigned to Group A and Group B, respectively.Group A was characterized by mean radial arterial pressure (37.9 +/- 9.6 vs 45.8 +/- 7.8 mmHg; P = 0.14) and femoral arterial pressure (6.7 +/- 6.1 vs 20.8 +/- 14.6 mmHg; P = 0.09) compared to Group B. However, higher urinary output during CPB (1.03 +/- 1.18 vs 0.10 +/- 0.15 ml.kg-1.h-1; P = 0.03). Furthermore our results indicate that a higher dose of Chlorpromazine was used in Group A (2.9 +/- 1.4 vs 1.7 +/- 1.0 mg/kg; P = 0.03). Higher cerebral oxygenation may provide higher urinary output due to higher renal blood flow through collateral circulation.

Absence of autoreactive CD4+ T-cells targeting HLA-DQA1*01:02/DQB1*06:02 restricted hypocretin/orexin epitopes in narcolepsy type 1 when detected by EliSpot.

PubMed

Kornum, Birgitte Rahbek; Burgdorf, Kristoffer Sølvsten; Holm, Anja; Ullum, Henrik; Jennum, Poul; Knudsen, Stine

2017-08-15

Narcolepsy type 1, a neurological sleep disorder strongly associated with Human Leukocyte Antigen (HLA-)DQB1*06:02, is caused by the loss of hypothalamic neurons producing the wake-promoting neuropeptide hypocretin (hcrt, also known as orexin). This loss is believed to be caused by an autoimmune reaction. To test whether hcrt itself could be a possible target in the autoimmune attack, CD4 + T-cell reactivity towards six different 15-mer peptides from prepro-hypocretin with high predicted affinity to the DQA1*01:02/DQB1*06:02 MHC class II dimer was tested using EliSpot in a cohort of 22 narcolepsy patients with low CSF hcrt levels, and 23 DQB1*06:02 positive healthy controls. Our ELISpot assay had a detection limit of 1:10,000 cells. We present data showing that autoreactive CD4 + T-cells targeting epitopes from the hcrt precursor in the context of MHC-DQA1*01:02/DQB1*06:02 are either not present or present in a frequency is <1:10,000 among peripheral CD4 + T-cells from narcolepsy type 1 patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Network architecture of the cerebral nuclei (basal ganglia) association and commissural connectome.

PubMed

Swanson, Larry W; Sporns, Olaf; Hahn, Joel D

2016-10-04

The cerebral nuclei form the ventral division of the cerebral hemisphere and are thought to play an important role in neural systems controlling somatic movement and motivation. Network analysis was used to define global architectural features of intrinsic cerebral nuclei circuitry in one hemisphere (association connections) and between hemispheres (commissural connections). The analysis was based on more than 4,000 reports of histologically defined axonal connections involving all 45 gray matter regions of the rat cerebral nuclei and revealed the existence of four asymmetrically interconnected modules. The modules form four topographically distinct longitudinal columns that only partly correspond to previous interpretations of cerebral nuclei structure-function organization. The network of connections within and between modules in one hemisphere or the other is quite dense (about 40% of all possible connections), whereas the network of connections between hemispheres is weak and sparse (only about 5% of all possible connections). Particularly highly interconnected regions (rich club and hubs within it) form a topologically continuous band extending through two of the modules. Connection path lengths among numerous pairs of regions, and among some of the network's modules, are relatively long, thus accounting for low global efficiency in network communication. These results provide a starting point for reexamining the connectional organization of the cerebral hemispheres as a whole (right and left cerebral cortex and cerebral nuclei together) and their relation to the rest of the nervous system.

Network architecture of the cerebral nuclei (basal ganglia) association and commissural connectome

PubMed Central

Swanson, Larry W.; Sporns, Olaf; Hahn, Joel D.

2016-01-01

The cerebral nuclei form the ventral division of the cerebral hemisphere and are thought to play an important role in neural systems controlling somatic movement and motivation. Network analysis was used to define global architectural features of intrinsic cerebral nuclei circuitry in one hemisphere (association connections) and between hemispheres (commissural connections). The analysis was based on more than 4,000 reports of histologically defined axonal connections involving all 45 gray matter regions of the rat cerebral nuclei and revealed the existence of four asymmetrically interconnected modules. The modules form four topographically distinct longitudinal columns that only partly correspond to previous interpretations of cerebral nuclei structure–function organization. The network of connections within and between modules in one hemisphere or the other is quite dense (about 40% of all possible connections), whereas the network of connections between hemispheres is weak and sparse (only about 5% of all possible connections). Particularly highly interconnected regions (rich club and hubs within it) form a topologically continuous band extending through two of the modules. Connection path lengths among numerous pairs of regions, and among some of the network’s modules, are relatively long, thus accounting for low global efficiency in network communication. These results provide a starting point for reexamining the connectional organization of the cerebral hemispheres as a whole (right and left cerebral cortex and cerebral nuclei together) and their relation to the rest of the nervous system. PMID:27647882

Enhanced contractility of intraparenchymal arterioles after global cerebral ischaemia in rat - new insights into the development of delayed cerebral hypoperfusion.

PubMed

Spray, S; Johansson, S E; Radziwon-Balicka, A; Haanes, K A; Warfvinge, K; Povlsen, G K; Kelly, P A T; Edvinsson, L

2017-08-01

Delayed cerebral hypoperfusion is a secondary complication found in the days after transient global cerebral ischaemia that worsens the ischaemic damage inflicted by the initial transient episode of global cerebral ischaemia. A recent study demonstrated increased cerebral vasoconstriction in the large arteries on the brain surface (pial arteries) after global cerebral ischaemia. However, smaller arterioles inside the brain (parenchymal arterioles) are equally important in the regulation of cerebral blood flow and yet their pathophysiology after global cerebral ischaemia is largely unknown. Therefore, we investigated whether increased contractility occurs in the intraparenchymal arterioles. Global cerebral ischaemia was induced in male Wistar rats by bilateral common carotid occlusion for 15 min combined with hypovolaemia. Regional cerebral blood flow was determined by quantitative autoradiography. Intraparenchymal arterioles were isolated and pressurized, and concentration-response curves to endothelin-1 with and without the endothelin B receptor-selective antagonist BQ788 was generated. Endothelin B receptor expression was investigated by quantitative flow cytometry and immunohistochemistry. We observed increased endothelin-1-mediated contractility of parenchymal arterioles correlating with reduced cerebral blood flow of the cortex, hippocampus and caudate nucleus 48 h after global cerebral ischaemia. The increased endothelin-1-mediated contractility was abolished by BQ788, and the vascular smooth muscle cell-specific expression of endothelin B receptors was significantly increased after global cerebral ischaemia. Increased endothelin-1-mediated contractility and expression of endothelin B receptors in the intraparenchymal vasculature contributes to the development of delayed cerebral hypoperfusion after global cerebral ischaemia in combination with vascular changes of the pial vasculature. © 2016 Scandinavian Physiological Society. Published by John Wiley

Temporal lobe interictal epileptic discharges affect cerebral activity in “default mode” brain regions

PubMed Central

Laufs, Helmut; Hamandi, Khalid; Salek-Haddadi, Afraim; Kleinschmidt, Andreas K; Duncan, John S; Lemieux, Louis

2007-01-01

A cerebral network comprising precuneus, medial frontal, and temporoparietal cortices is less active both during goal-directed behavior and states of reduced consciousness than during conscious rest. We tested the hypothesis that the interictal epileptic discharges affect activity in these brain regions in patients with temporal lobe epilepsy who have complex partial seizures. At the group level, using electroencephalography-correlated functional magnetic resonance imaging in 19 consecutive patients with focal epilepsy, we found common decreases of resting state activity in 9 patients with temporal lobe epilepsy (TLE) but not in 10 patients with extra-TLE. We infer that the functional consequences of TLE interictal epileptic discharges are different from those in extra-TLE and affect ongoing brain function. Activity increases were detected in the ipsilateral hippocampus in patients with TLE, and in subthalamic, bilateral superior temporal and medial frontal brain regions in patients with extra-TLE, possibly indicating effects of different interictal epileptic discharge propagation. PMID:17133385

The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow.

PubMed

Goker-Alpan, Ozlem; Masdeu, Joseph C; Kohn, Philip D; Ianni, Angela; Lopez, Grisel; Groden, Catherine; Chapman, Molly C; Cropp, Brett; Eisenberg, Daniel P; Maniwang, Emerson D; Davis, Joie; Wiggs, Edythe; Sidransky, Ellen; Berman, Karen F

2012-08-01

Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with (18)F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H(2)(15)O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion

Correlated regions of cerebral blood flow with clinical parameters in Parkinson's disease; comparison using 'Anatomy' and 'Talairach Daemon' software.

PubMed

Yoon, Hyun Jin; Cheon, Sang Myung; Jeong, Young Jin; Kang, Do-Young

2012-02-01

We assign the anatomical names of functional activation regions in the brain, based on the probabilistic cyto-architectonic atlas by Anatomy 1.7 from an analysis of correlations between regional cerebral blood flow (rCBF) and clinical parameters of the non-demented Parkinson's disease (PD) patients by SPM8. We evaluated Anatomy 1.7 of SPM toolbox compared to 'Talairach Daemon' (TD) Client 2.4.2 software. One hundred and thirty-six patients (mean age 60.0 ± 9.09 years; 73 women and 63 men) with non-demented PD were selected. Tc-99m-HMPAO brain single-photon emission computed tomography (SPECT) scans were performed on the patients using a two-head gamma-camera. We analyzed the brain image of PD patients by SPM8 and found the anatomical names of correlated regions of rCBF perfusion with the clinical parameters using TD Client 2.4.2 and Anatomy 1.7. The SPM8 provided a correlation coefficient between clinical parameters and cerebral hypoperfusion by a simple regression method. To the clinical parameters were added age, duration of disease, education period, Hoehn and Yahr (H&Y) stage and Korean mini-mental state examination (K-MMSE) score. Age was correlated with cerebral perfusion in the Brodmann area (BA) 6 and BA 3b assigned by Anatomy 1.7 and BA 6 and pyramis in gray matter by TD Client 2.4.2 with p < 0.001 uncorrected. Also, assigned significant correlated regions were found in the left and right lobules VI (Hem) with duration of disease, in left and right lobules VIIa crus I (Hem) with education, in left insula (Ig2), left and right lobules VI (Hem) with H&Y, and in BA 4a and 6 with K-MMSE score with p < 0.05 uncorrected by Anatomy 1.7, respectively. Most areas of correlation were overlapped by two different anatomical labeling methods, but some correlation areas were found with different names. Age was the most significantly correlated clinical parameter with rCBF. TD Client found the exact anatomical name by the peak intensity position of the cluster while

The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow

PubMed Central

Goker-Alpan, Ozlem; Masdeu, Joseph C.; Kohn, Philip D.; Ianni, Angela; Lopez, Grisel; Groden, Catherine; Chapman, Molly C.; Cropp, Brett; Eisenberg, Daniel P.; Maniwang, Emerson D.; Davis, Joie; Wiggs, Edythe; Berman, Karen F.

2012-01-01

Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with 18F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H215O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the

Smoking, Alcohol, Drug Use, Abuse and Dependence in Narcolepsy and Idiopathic Hypersomnia: A Case-Control Study

PubMed Central

Barateau, Lucie; Jaussent, Isabelle; Lopez, Régis; Boutrel, Benjamin; Leu-Semenescu, Smaranda; Arnulf, Isabelle; Dauvilliers, Yves

2016-01-01

Study Objectives: Basic experiments support the impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Our aim was to assess the frequencies of smoking, alcohol and drug use, abuse and dependence in narcolepsy type 1 (NT1, hypocretin-deficient), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) (non-hypocretin-deficient conditions), in comparison to controls. We hypothesized that NT1 patients would be less vulnerable to drug abuse and addiction compared to other hypersomniac patients and controls from general population. Methods: We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 450 adult patients (median age 35 years; 41.3% men) with NT1 (n = 243), NT2 (n = 116), IH (n = 91), and 710 adult controls. All participants were evaluated for alcohol consumption, smoking habits, and substance (alcohol and illicit drug) abuse and dependence diagnosis during the past year using the Mini International Neuropsychiatric Interview. Results: An increased proportion of both tobacco and heavy tobacco smokers was found in NT1 compared to controls and other hypersomniacs, despite adjustments for potential confounders. We reported an increased regular and frequent alcohol drinking habit in NT1 versus controls but not compared to other hypersomniacs in adjusted models. In contrast, heavy drinkers were significantly reduced in NT1 versus controls but not compared to other hypersomniacs. The proportion of patients with excessive drug use (codeine, cocaine, and cannabis), substance dependence, or abuse was low in all subgroups, without significant differences between either hypersomnia disorder categories or compared with controls. Conclusions: We first described a low frequency of illicit drug use, dependence, or abuse in patients with central hypersomnia, whether Hcrt-deficient or not, and whether drug-free or medicated, in the same range as in controls. Conversely, heavy drinkers were

Narcolepsy Treated with Racemic Amphetamine during Pregnancy and Breastfeeding.

PubMed

Öhman, Inger; Wikner, Birgitta Norstedt; Beck, Olof; Sarman, Ihsan

2015-08-01

This case report describes a woman with narcolepsy treated with racemic amphetamine (rac-amphetamine) during pregnancy and breastfeeding with follow-up on the infant's development up to 10 months of age. The pregnancy outcome and the pharmacokinetics of rac-amphetamine were studied during breastfeeding. The pregnancy and the delivery were uneventful. Concentrations of rac-amphetamine were determined in the plasma of the mother and infant, and in the breast milk with a liquid chromatography-mass spectrometry method. Samples were obtained at 2, 5, and 9 weeks postpartum. The transfer of rac-amphetamine to the breast milk was extensive (mean milk/maternal plasma concentration ratio approximately 3). The breastfed infant had a low plasma concentration of rac-amphetamine (about 9% of the maternal plasma level) and the calculated relative infant dose was low (2%). No adverse effects were observed in the breastfed infant. The infant's somatic and psychomotor development up to 10 months of age was normal. Further studies of amphetamine prescribed for medical reasons during pregnancy and lactation are needed. © The Author(s) 2015.

Cerebral hemodynamic and metabolic changes caused by brain retraction after aneurysmal subarachnoid hemorrhage.

PubMed

Yundt, K D; Grubb, R L; Diringer, M N; Powers, W J

1997-03-01

The cerebral hemodynamic and metabolic effects of aneurysmal subarachnoid hemorrhage are complex. To investigate the impact of surgical retraction, we analyzed position emission tomography (PET) studies that measured the regional cerebral metabolic rate for oxygen, regional oxygen extraction fraction, and regional cerebral blood flow in four patients before and after right frontotemporal craniotomies for clipping of ruptured anterior circulation aneurysms. Preoperative studies were conducted 1 day before surgery and postoperative studies 6 to 17 days after surgery. No patient had hydrocephalus or intracerebral hematoma. At the time of the second PET study, none of the patients had signs of clinical vasospasm. Regional measurements were obtained from the right ventrolateral frontal and anterior temporal regions corresponding to the area of retraction and compared to the same regions in the opposite hemisphere. To establish a quantitative means to differentiate between hemodynamic and metabolic changes related to arterial vasospasm and those caused by brain retraction, we studied a second group of preoperative patients, who had undergone PET during angiographic and clinical vasospasm. There was a 45% reduction in regional cerebral metabolic rate for oxygen (1.87 +/- 0.22 to 1.04 +/- 0.28 ml 100 g-1 min-1) and 32% reduction in regional oxygen extraction fraction (0.41 +/- 0.04 to 0.28 +/- 0.03) in the region of retraction but no change in the opposite hemisphere (paired t test; P = 0.042 and 0.003, respectively). There was no change in regional cerebral blood flow in any region. Brain retraction produced a focal area of tissue injury at the site of retractor blade placement, as compared to more diffuse vascular territory changes produced by vasospasm. This reduction in the cerebral metabolic rate of oxygen and the oxygen extraction fraction indicates a primary reduction in metabolism and uncoupling of flow and metabolism (luxury perfusion). Similar findings of luxury

Higher cerebral oxygen saturation may provide higher urinary output during continuous regional cerebral perfusion

PubMed Central

Miyamoto, Takashi; Miyaji, Kagami; Okamoto, Hirotsugu; Kohira, Satoshi; Tomoyasu, Takahiro; Inoue, Nobuyuki; Ohara, Kuniyoshi

2008-01-01

Objective We examined the hypothesis that higher cerebral oxygen saturation (rSO2) during RCP is correlated with urinary output. Methods Between December 2002 and August 2006, 12 patients aged 3 to 61 days and weighing 2.6 to 3.4 kg underwent aortic arch repair with RCP. Urinary output and rSO2 were analyzed retrospectively. Data were assigned to either of 2 groups according to their corresponding rSO2: Group A (rSO2 ≦ 75%) and Group B (rSO2 < 75%). Results Seven and 5 patients were assigned to Group A and Group B, respectively. Group A was characterized by mean radial arterial pressure (37.9 ± 9.6 vs 45.8 ± 7.8 mmHg; P = 0.14) and femoral arterial pressure (6.7 ± 6.1 vs 20.8 ± 14.6 mmHg; P = 0.09) compared to Group B. However, higher urinary output during CPB (1.03 ± 1.18 vs 0.10 ± 0.15 ml·kg-1·h-1; P = 0.03). Furthermore our results indicate that a higher dose of Chlorpromazine was used in Group A (2.9 ± 1.4 vs 1.7 ± 1.0 mg/kg; P = 0.03). Conclusion Higher cerebral oxygenation may provide higher urinary output due to higher renal blood flow through collateral circulation. PMID:18973699

High Prevalence of Precocious Puberty and Obesity in Childhood Narcolepsy with Cataplexy

PubMed Central

Poli, Francesca; Pizza, Fabio; Mignot, Emmanuel; Ferri, Raffaele; Pagotto, Uberto; Taheri, Shahrad; Finotti, Elena; Bernardi, Filippo; Pirazzoli, Piero; Cicognani, Alessandro; Balsamo, Antonio; Nobili, Lino; Bruni, Oliviero; Plazzi, Giuseppe

2013-01-01

Study Objectives: We analyzed the potential predictive factors for precocious puberty, observed in some cases of childhood narcolepsy with cataplexy (NC) and for obesity, a much more common feature of NC, through a systematic assessment of pubertal staging, body mass index (BMI), and metabolic/endocrine biochemical analyses. Design: Cross-sectional on consecutive recruitment. Setting: Hospital sleep center and pediatric unit. Patients: Forty-three children and adolescents with NC versus 52 age-matched obese children as controls. Interventions: N/A. Measurements and Results: Patients underwent clinical interview, polysomnographic recordings, cerebrospinal fluid hypocretin-1 measurement, and human leukocyte antigen typing. Height, weight, arterial blood pressure, and Tanner pubertal stage were evaluated. Plasma lipid and glucose profiles were analyzed. When an altered pubertal development was clinically suspected, plasma concentrations of hypothalamic-pituitary-gonadal axis hormones were determined. Children with NC showed a high prevalence of overweight/obesity (74%) and a higher occurrence of precocious puberty (17%) than obese controls (1.9%). Isolated signs of accelerated pubertal development (thelarche, pubic hair, advanced bone age) were also present (41%). Precocious puberty was significantly predicted by a younger age at first NC symptom onset but not by overweight/obesity or other factors. In addition, overweight/obesity was predicted by younger age at diagnosis; additional predictors were found for overweight/obesity (short disease duration, younger age at weight gain and lower high-density lipoprotein cholesterol), which did not include precocious puberty. NC symptoms, pubertal signs appearance, and body weight gain developed in close temporal sequence. Conclusions: NC occurring during prepubertal age is frequently accompanied by precocious puberty and overweight/obesity, suggesting an extended hypothalamic dysfunction. The severity of these comorbidities

Hemodilution increases cerebral blood flow in acute ischemic stroke

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vorstrup, S.; Andersen, A.; Juhler, M.

1989-07-01

We measured cerebral blood flow in 10 consecutive, but selected, patients with acute ischemic stroke (less than 48 hours after onset) before and after hemodilution. Cerebral blood flow was measured by xenon-133 inhalation and emission tomography, and only patients with focal hypoperfusion in clinically relevant areas were included. Hemodilution was done according to the hematocrit level: for a hematocrit greater than or equal to 42%, 500 ml whole blood was drawn and replaced by the same volume of dextran 40; for a hematocrit between 37% and 42%, only 250 ml whole blood was drawn and replaced by 500 cc ofmore » dextran 40. Mean hematocrit was reduced by 16%, from 46 +/- 5% (SD) to 39 +/- 5% (SD) (p less than 0.001). Cerebral blood flow increased in both hemispheres by an average of 20.9% (p less than 0.001). Regional cerebral blood flow increased in the ischemic areas in all cases, on an average of 21.4 +/- 12.0% (SD) (p less than 0.001). In three patients, a significant redistribution of flow in favor of the hypoperfused areas was observed, and in six patients, the fractional cerebral blood flow increase in the hypoperfused areas was of the same magnitude as in the remainder of the brain. In the last patient, cerebral blood flow increased relatively less in the ischemic areas. Our findings show that cerebral blood flow increases in the ischemic areas after hemodilution therapy in stroke patients. The marked regional cerebral blood flow increase seen in some patients could imply an improved oxygen delivery to the ischemic tissue.« less

Measurement of regional cerebral blood flow with copper-62-PTSM and a three-compartment model.

PubMed

Okazawa, H; Yonekura, Y; Fujibayashi, Y; Mukai, T; Nishizawa, S; Magata, Y; Ishizu, K; Tamaki, N; Konishi, J

1996-07-01

We evaluated quantitatively 62Cu-labeled pyruvaldehyde bis(N4-methylthiosemicarbazone) copper II (62Cu-PTSM) as a brain perfusion tracer for positron emission tomography (PET). For quantitative measurement, the octanol extraction method is needed to correct for arterial radioactivity in estimating the lipophilic input function, but the procedure is not practical for clinical studies. To measure regional cerebral blood flow (rCBF) by 62Cu-PTSM with simple arterial blood sampling, a standard curve of the octanol extraction ratio and a three-compartment model were applied. We performed both 15O-labeled water PET and 62 Cu-PTSM PET with dynamic data acquisition and arterial sampling in six subjects. Data obtained in 10 subjects studied previously were used for the standard octanol extraction curve. Arterial activity was measured and corrected to obtain the true input function using the standard curve. Graphical analysis (Gjedde-Patlak plot) with the data for each subject fitted by a straight regression line suggested that 62Cu-PTSM can be analyzed by the three-compartment model with negligible K4. Using this model, K1-K3 were estimated from curve fitting of the cerebral time-activity curve and the corrected input function. The fractional uptake of 62Cu-PTSM was corrected to rCBF with the individual extraction at steady state calculated from K1-K3. The influx rates (Ki) obtained from three-compartment model and graphical analyses were compared for the validation of the model. A comparison of rCBF values obtained from 62Cu-PTSM and 150-water studies demonstrated excellent correlation. The results suggest the potential feasibility of quantitation of cerebral perfusion with 62Cu-PTSM accompanied by dynamic PET and simple arterial sampling.

Regional cerebral blood flow and cerebrovascular reactivity in Alzheimer's disease and vascular dementia assessed by arterial spinlabeling magnetic resonance imaging.

PubMed

Gao, Yong-Zhe; Zhang, Jun-Jian; Liu, Hui; Wu, Guang-Yao; Xiong, Li; Shu, Min

2013-02-01

Hemodynamic disturbance in cerebral blood flow (CBF) is common in both Alzheimer's disease (AD) and vascular dementia (VaD).The aim of this study is to investigate the different patterns of regional cerebral blood flow (rCBF) change and cerebrovascular reactivity (CVR) in these two types of dementia. Mean flow velocity (MFV) of middle cerebral artery and rCBF were measured by Transcranial Doppler ultrasound (TCD) and arterial spin-labeling (ASL) magnetic resonance, separately. CVR was evaluated by MFV or rCBF change in response to 5% CO2 inhalation. The ASL results showed that, rCBF was significantly lower in both the bilateral frontal and temporal lobes in AD group and lower in left frontal and temporal white matter in patients with VaD. CVR calculated by rCBF was impaired more severely in bilateral frontal cortices in AD. Conversely, TCD tests failed to demonstrate significant difference in MFV and CVR between the two groups. It is concluded that the different patterns detected by ASL in resting rCBF change and cerebrovascular reactivity in response to carbogen inhalation may serve as a potential marker to distinguish AD and VaD.

An analysis of regional cerebral blood flow in impulsive murderers using single photon emission computed tomography.

PubMed

Amen, Daniel G; Hanks, Chris; Prunella, Jill R; Green, Aisa

2007-01-01

The authors explored differences in regional cerebral blood flow in 11 impulsive murderers and 11 healthy comparison subjects using single photon emission computed tomography. The authors assessed subjects at rest and during a computerized go/no-go concentration task. Using statistical parametric mapping software, the authors performed voxel-by-voxel t tests to assess significant differences, making family-wide error corrections for multiple comparisons. Murderers were found to have significantly lower relative rCBF during concentration, particularly in areas associated with concentration and impulse control. These results indicate that nonemotionally laden stimuli may result in frontotemporal dysregulation in people predisposed to impulsive violence.

Sleep-Wake Differences in Relative Regional Cerebral Metabolic Rate for Glucose among Patients with Insomnia Compared with Good Sleepers

PubMed Central

Kay, Daniel B.; Karim, Helmet T.; Soehner, Adriane M.; Hasler, Brant P.; Wilckens, Kristine A.; James, Jeffrey A.; Aizenstein, Howard J.; Price, Julie C.; Rosario, Bedda L.; Kupfer, David J.; Germain, Anne; Hall, Martica H.; Franzen, Peter L.; Nofzinger, Eric A.; Buysse, Daniel J.

2016-01-01

Study Objectives: The neurobiological mechanisms of insomnia may involve altered patterns of activation across sleep-wake states in brain regions associated with cognition, self-referential processes, affect, and sleep-wake promotion. The objective of this study was to compare relative regional cerebral metabolic rate for glucose (rCMRglc) in these brain regions across wake and nonrapid eye movement (NREM) sleep states in patients with primary insomnia (PI) and good sleeper controls (GS). Methods: Participants included 44 PI and 40 GS matched for age (mean = 37 y old, range 21–60), sex, and race. We conducted [18F]fluoro-2-deoxy-d-glucose positron emission tomography scans in PI and GS during both morning wakefulness and NREM sleep at night. Repeated measures analysis of variance was used to test for group (PI vs. GS) by state (wake vs. NREM sleep) interactions in relative rCMRglc. Results: Significant group-by-state interactions in relative rCMRglc were found in the precuneus/posterior cingulate cortex, left middle frontal gyrus, left inferior/superior parietal lobules, left lingual/fusiform/occipital gyri, and right lingual gyrus. All clusters were significant at Pcorrected < 0.05. Conclusions: Insomnia was characterized by regional alterations in relative glucose metabolism across NREM sleep and wakefulness. Significant group-by-state interactions in relative rCMRglc suggest that insomnia is associated with impaired disengagement of brain regions involved in cognition (left frontoparietal), self-referential processes (precuneus/posterior cingulate), and affect (left middle frontal, fusiform/lingual gyri) during NREM sleep, or alternatively, to impaired engagement of these regions during wakefulness. Citation: Kay DB, Karim HT, Soehner AM, Hasler BP, Wilckens KA, James JA, Aizenstein HJ, Price JC, Rosario BL, Kupfer DJ, Germain A, Hall MH, Franzen PL, Nofzinger EA, Buysse DJ. Sleep-wake differences in relative regional cerebral metabolic rate for glucose among

T2’-Imaging to Assess Cerebral Oxygen Extraction Fraction in Carotid Occlusive Disease: Influence of Cerebral Autoregulation and Cerebral Blood Volume

PubMed Central

Deichmann, Ralf; Pfeilschifter, Waltraud; Hattingen, Elke; Singer, Oliver C.; Wagner, Marlies

2016-01-01

Purpose Quantitative T2'-mapping detects regional changes of the relation of oxygenated and deoxygenated hemoglobin (Hb) by using their different magnetic properties in gradient echo imaging and might therefore be a surrogate marker of increased oxygen extraction fraction (OEF) in cerebral hypoperfusion. Since elevations of cerebral blood volume (CBV) with consecutive accumulation of Hb might also increase the fraction of deoxygenated Hb and, through this, decrease the T2’-values in these patients we evaluated the relationship between T2’-values and CBV in patients with unilateral high-grade large-artery stenosis. Materials and Methods Data from 16 patients (13 male, 3 female; mean age 53 years) with unilateral symptomatic or asymptomatic high-grade internal carotid artery (ICA) or middle cerebral artery (MCA) stenosis/occlusion were analyzed. MRI included perfusion-weighted imaging and high-resolution T2’-mapping. Representative relative (r)CBV-values were analyzed in areas of decreased T2’ with different degrees of perfusion delay and compared to corresponding contralateral areas. Results No significant elevations in cerebral rCBV were detected within areas with significantly decreased T2’-values. In contrast, rCBV was significantly decreased (p<0.05) in regions with severe perfusion delay and decreased T2’. Furthermore, no significant correlation between T2’- and rCBV-values was found. Conclusions rCBV is not significantly increased in areas of decreased T2’ and in areas of restricted perfusion in patients with unilateral high-grade stenosis. Therefore, T2’ should only be influenced by changes of oxygen metabolism, regarding our patient collective especially by an increase of the OEF. T2’-mapping is suitable to detect altered oxygen consumption in chronic cerebrovascular disease. PMID:27560515

The inappropriate occurrence of rapid eye movement sleep in narcolepsy is not due to a defect in homeostatic regulation of rapid eye movement sleep.

PubMed

Roman, Alexis; Meftah, Soraya; Arthaud, Sébastien; Luppi, Pierre-Hervé; Peyron, Christelle

2018-06-01

Narcolepsy type 1 is a disabling disorder with four primary symptoms: excessive-daytime-sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. The later three symptoms together with a short rapid eye movement (REM) sleep latency have suggested impairment in REM sleep homeostatic regulation with an enhanced propensity for (i.e. tendency to enter) REM sleep. To test this hypothesis, we challenged REM sleep homeostatic regulation in a recognized model of narcolepsy, the orexin knock-out (Orex-KO) mice and their wild-type (WT) littermates. We first performed 48 hr of REM sleep deprivation using the classic small-platforms-over-water method. We found that narcoleptic mice are similarly REM sleep deprived to WT mice. Although they had shorter sleep latency, Orex-KO mice recovered similarly to WT during the following 10 hr of recovery. Interestingly, Orex-KO mice also had cataplexy episodes immediately after REM sleep deprivation, anticipating REM sleep rebound, at a time of day when cataplexy does not occur in baseline condition. We then evaluated REM sleep propensity using our new automated method of deprivation that performs a specific and efficient REM sleep deprivation. We showed that REM sleep propensity is similar during light phase in Orex-KO and WT mice. However, during the dark phase, REM sleep propensity was not suppressed in Orex-KO mice when hypocretin/orexin neuropeptides are normally released. Altogether our data suggest that in addition to the well-known wake-promoting role of hypocretin/orexin, these neuropeptides would also suppress REM sleep. Therefore, hypocretin/orexin deficiency would facilitate the occurrence of REM sleep at any time of day in an opportunistic manner as seen in human narcolepsy.

The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daniel, D.G.; Weinberger, D.R.; Jones, D.W.

1991-07-01

To explore the role of monoamines on cerebral function during specific prefrontal cognitive activation, we conducted a double-blind placebo-controlled crossover study of the effects of 0.25 mg/kg oral dextroamphetamine on regional cerebral blood flow (rCBF) as determined by 133Xe dynamic single-photon emission-computed tomography (SPECT) during performance of the Wisconsin Card Sorting Test (WCST) and a sensorimotor control task. Ten patients with chronic schizophrenia who had been stabilized for at least 6 weeks on 0.4 mg/kg haloperidol participated. Amphetamine produced a modest, nonsignificant, task-independent, global reduction in rCBF. However, the effect of amphetamine on task-dependent activation of rCBF (i.e., WCST minusmore » control task) was striking. Whereas on placebo no significant activation of rCBF was seen during the WCST compared with the control task, on amphetamine significant activation of the left dorsolateral prefrontal cortex (DLPFC) occurred (p = 0.0006). Both the mean number of correct responses and the mean conceptual level increased (p less than 0.05) with amphetamine relative to placebo. In addition, with amphetamine, but not with placebo, a significant correlation (p = -0.71; p less than 0.05) emerged between activation of DLPFC rCBF and performance of the WCST task. These findings are consistent with animal models in which mesocortical catecholaminergic activity modulates and enhances the signal-to-noise ratio of evoked cortical activity.« less

Improved power for characterizing longitudinal amyloid-β PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region.

PubMed

Chen, Kewei; Roontiva, Auttawut; Thiyyagura, Pradeep; Lee, Wendy; Liu, Xiaofen; Ayutyanont, Napatkamon; Protas, Hillary; Luo, Ji Luo; Bauer, Robert; Reschke, Cole; Bandy, Daniel; Koeppe, Robert A; Fleisher, Adam S; Caselli, Richard J; Landau, Susan; Jagust, William J; Weiner, Michael W; Reiman, Eric M

2015-04-01

In this article, we describe an image analysis strategy with improved power for tracking longitudinal amyloid-β (Aβ) PET changes and evaluating Aβ-modifying treatments. Our aims were to compare the power of template-based cerebellar, pontine, and cerebral white matter reference regions to track 24-mo florbetapir standardized uptake value (SUV) ratio (SUVR) changes; to relate those changes to 24-mo clinical declines; and to evaluate Aβ-modifying treatments in Aβ-positive (Aβ+) and Aβ-negative (Aβ-) patients with probable Alzheimer dementia (pAD), in patients with mild cognitive impairment (MCI), in cognitively normal controls (NCs), and in cognitively normal apolipoprotein E4 (APOE4) carriers and noncarriers. We used baseline and follow-up (∼24 mo) florbetapir PET scans from 332 Aβ+ and Aβ- subjects participating in the multicenter Alzheimer's Disease Neuroimaging Initiative. Each of the proposed analyses included 31 pAD patients, 187 MCI patients, and 114 NCs. Cerebral-to-white matter, cerebellar, and pontine SUVRs were characterized in terms of their longitudinal variability; their power to track longitudinal fibrillar Aβ increases in Aβ+ and Aβ- subgroups and cognitively normal APOE4 carriers and noncarriers; the sample sizes needed to detect attenuated accumulation of or clearance of fibrillar Aβ accumulation in randomized clinical trials; and their ability to relate 24-mo fibrillar Aβ increases to clinical declines. As predicted, cerebral-to-white matter SUVR changes were significantly less variable and had significantly greater power to detect 24-mo fibrillar Aβ increases and evaluate Aβ-modifying treatment effects in Aβ+ pAD, MCI, and NC subjects and cognitively normal APOE4 carriers. They were also distinguished by the ability to detect significant associations between 24-mo Aβ increases and clinical declines. A cerebral white matter reference region may improve the power to track longitudinal fibrillar Aβ increases, to characterize

Anxiety and cerebral blood flow during behavioral challenge. Dissociation of central from peripheral and subjective measures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zohar, J.; Insel, T.R.; Berman, K.F.

1989-06-01

To investigate the relationship between anxiety and regional cerebral blood flow, we administered behavioral challenges to 10 patients with obsessive-compulsive disorder while measuring regional cerebral blood flow with the xenon 133 inhalation technique. Each patient was studied under three conditions: relaxation, imaginal flooding, and in vivo (actual) exposure to the phobic stimulus. Subjective anxiety, obsessive-compulsive ratings, and autonomic measures (heart rate, blood pressure) increased significantly, but respiratory rate and PCO/sub 2/ did not change across the three conditions. Regional cerebral blood flow increased slightly (in the temporal region) during imaginal flooding, but decreased markedly in several cortical regions during inmore » vivo exposure, when anxiety was highest by subjective and peripheral autonomic measures. These results demonstrate that intense anxiety can be associated with decreased rather than increased cortical perfusion and that ostensibly related states of anxiety (eg, anticipatory and obsessional anxiety) may be associated with opposite effects on regional cerebral blood flow.« less

Regional cerebral blood flow and abnormal eating behavior in Prader-Willi syndrome.

PubMed

Ogura, Kaeko; Fujii, Toshikatsu; Abe, Nobuhito; Hosokai, Yoshiyuki; Shinohara, Mayumi; Fukuda, Hiroshi; Mori, Etsuro

2013-05-01

Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder and is generally regarded as a genetic model of obesity. Individuals with PWS exhibit behavioral symptoms including temper tantrums, rigid thinking, and compulsive behavior. The most striking feature of PWS is abnormal eating behavior, including hyperphagia, intense preoccupation with food, and incessant food seeking. To explore brain regions associated with the behavioral symptoms of PWS, we investigated differences in resting-state regional cerebral blood flow (rCBF) between individuals with PWS and healthy controls. Correlation analyses were also performed to examine the relationship between rCBF and altered eating behavior in PWS individuals. Twelve adults with PWS and 13 age- and gender-matched controls underwent resting-state single photon emission computerized tomography (SPECT) with N-isopropyl-p-[(123)I] iodoamphetamine (IMP). The rCBF data were analyzed on a voxel-by-voxel basis using SPM5 software. The results demonstrated that compared with controls, individuals with PWS had significantly lower rCBF in the right thalamus, left insular cortex, bilateral lingual gyrus, and bilateral cerebellum. They had significantly higher rCBF in the right inferior frontal gyrus, left middle/inferior frontal gyrus (anterior and posterior clusters), and bilateral angular gyrus. Additionally, rCBF in the left insula, which was significantly lower in PWS individuals, was negatively correlated with the eating behavior severity score. These results suggest that specific brain regions, particularly the left insula, may be partly responsible for the behavioral symptoms in PWS. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Mechanisms of Acupuncture Therapy for Cerebral Ischemia: an Evidence-Based Review of Clinical and Animal Studies on Cerebral Ischemia.

PubMed

Zhu, Wen; Ye, Yang; Liu, Yi; Wang, Xue-Rui; Shi, Guang-Xia; Zhang, Shuai; Liu, Cun-Zhi

2017-12-01

Ischemic stroke is a major cause of mortality and disability worldwide. As a part of Traditional Chinese Medicine (TCM), acupuncture has been shown to be effective in promoting recovery after stroke. In this article, we review the clinical and experimental studies that demonstrated the mechanisms of acupuncture treatment for cerebral ischemia. Clinical studies indicated that acupuncture activated relevant brain regions, modulated cerebral blood flow and related molecules in stroke patients. Evidence from laboratory indicated that acupuncture regulates cerebral blood flow and metabolism after the interrupt of blood supply. Acupuncture regulates multiple molecules and signaling pathways that lead to excitoxicity, oxidative stress, inflammation, neurons death and survival. Acupuncture also promotes neurogenesis, angiogenesis as well as neuroplasticity after ischemic damage. The evidence provided from clinical and laboratory suggests that acupuncture induces multi-level regulation via complex mechanisms and a single factor may not be enough to explain the beneficial effects against cerebral ischemia.

Correlation of Changes in Patient-Reported Quality of Life With Physician-Rated Global Impression of Change in Patients With Narcolepsy Participating in a Clinical Trial of Sodium Oxybate: A Post Hoc Analysis.

PubMed

Bogan, Richard K; Black, Jed; Swick, Todd; Mamelak, Mortimer; Kovacevic-Ristanovic, Ruzica; Villa, Kathleen F; Mori, Fannie; Montplaisir, Jacques

2017-12-01

Narcolepsy patients report lower health-related quality of life (HRQoL) than the general population, as measured by the Short Form-36 Health Survey (SF-36). This analysis evaluated whether changes in SF-36 correlated with physician-rated Clinical Global Impression of Change (CGI-C). Data were from 209 of 228 narcolepsy patients participating in an 8-week clinical trial of sodium oxybate. Changes from baseline for SF-36 subscales (Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health) and the summary scores were evaluated for correlation with CGI-C overall and by treatment group. Correlations were calculated using the Pearson product-moment correlation coefficient (r). Correlations described an inverse relationship in scores, but a direct relationship in improvement; lower CGI-C scores (i.e., better) were associated with higher SF-36 subscale scores (i.e., improved HRQoL). Moderate and significant correlations were observed for Vitality (r = -0.464; P < 0.0001) and Role Physical (r = -0.310; P < 0.0001) subscales, but weak correlations were observed with other subscales including summary scores. Correlations were stronger at higher sodium oxybate doses for most SF-36 subscales. Some aspects of HRQoL, measured by the SF-36, may be associated with narcolepsy. In particular, Vitality (indicative of energy and tiredness) and Role Physical (impact of physical function on daily roles) moderately correlated with overall change in status observed by clinicians. However, lack of strong correlations between SF-36 and CGI-C indicates differences in patient and clinician perspectives of disease, and suggest a need for broader assessment of the impact of narcolepsy and its treatment on patients. Jazz Pharmaceuticals.

Opiates and cerebral functional activity in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trusk, T.C.

1986-01-01

Cerebral activity was measured using the free-fatty acid (1-/sup 14/C) octanoate as a fast functional tracer in conscious, unrestrained rats 5 minutes after intravenous injection of heroin, cocaine or saline vehicle. Regional changes of octanoate labeling density in the autoradiograms relative to saline-injected animals were used to determine the functional activity effects of each drug. Heroin and cocaine each produced a distinctive pattern of activity increases and suppression throughout the rat brain. Similar regional changes induced by both drugs were found in limbic brain regions implicated in drug reinforcement. Labeled octanoate autoradiography was used to measure the cerebral functional responsemore » to a tone that had previously been paired to heroin injections. Rats were trained in groups of three consisting of one heroin self-administration animal, and two animals receiving yoked infusion of heroin or saline. A tone was paired with each infusion during training. Behavioral experiments in similarly trained rats demonstrated that these training conditions impart secondary reinforcing properties to the tone in animals previously self-administering heroin, while the tone remains behaviorally neutral in yoked-infusion rats. Cerebral functional activity was measured during presentation of the tone without drug infusion. Octanoate labeling density changed in fifteen brain areas in response to the tone previously paired to heroin without response contingency. Labeling density was significantly modified in sixteen regions as a result of previously pairing the tone to response-contingent heroin infusions.« less

Narcolepsy in pediatric age – Experience of a tertiary pediatric hospital

PubMed Central

Dias Costa, Filipa; Barreto, Maria Inês; Clemente, Vanda; Vasconcelos, Mónica; Estêvão, Maria Helena; Madureira, Núria

2014-01-01

Narcolepsy, a chronic disorder of the sleep–wake cycle of multifactorial etiology, is characterized by excessive daytime sleepiness, often associated with cataplexy, hypnagogic/hypnopompic hallucinations and sleep paralysis. Both early clinical suspicion and therapeutic approach are essential for promotion of cognitive development and social integration of these children. The authors present a descriptive retrospective study of a series of eight children in whom symptoms first started between 6.8 and 10.5 years of age. Diagnostic delay ranged from 4 months to 2 years. One child had H1N1 flu vaccination eight months before the clinical onset. The first multiple sleep latency test was positive in 6 of 8 cases. All cases were treated with methylphenidate, and venlafaxine was associated in 4 of them. In one case the initial therapy was exclusively behavioral. In all cases, symptomatic improvement, better school performance and social integration were achieved after therapeutic adjustment. PMID:26483902

[Regional cerebral blood flow changes in Parkinson's disease: correlation with disease duration].

PubMed

Kapitán, M; Ferrando, R; Diéguez, E; de Medina, O; Aljanati, R; Ventura, R; Amorin, I; Salinas, D; Langhain, M; Gioia, A; Cardoso, A; Lago, G; Buzó, R

2009-01-01

Changes in regional cerebral blood flow (rCBF) have been reported in idiopathic Parkinson's disease (PD). Nonetheless, their typical pattern still remains controversial regarding some features, such as basal ganglia involvement and the main cortical regions affected. Functional neuroimaging makes it possible to identify the brain dysfunctions of the neural circuits underlying the disease. Voxel-based analysis methods make it possible to increase the reliability of the results. To assess the rCBF changes in patients with PD and their relation with disease duration. Thirty PD adult patients without dementia underwent evaluation with (99m)Tc-ECD SPECT. SPM5 was used for statistical comparison with 25 normal controls of similar ages. The disease course duration in years was added as a covariate. Additionally, patients with a 6-year evolution or less and those with more than 6 years were compared separately with normal controls. Significant hypoperfusion was detected in bilateral premotor and posterior parietal cortex and increase of perfusion was present in the cerebellum. These changes correlated with the years of evolution of the illness. Patients with longer evolution also presented thalamic, subthalamic and basal ganglia hypoperfusion. We describe rCBF changes in PD in neural circuits related with control of movements. These changes are more manifest in patients with a longer duration of the disease.

Regional cerebral blood flow changes in female to male gender identity disorder.

PubMed

Nawata, Hideyuki; Ogomori, Koji; Tanaka, Mariko; Nishimura, Ryoji; Urashima, Hajime; Yano, Rika; Takano, Koichi; Kuwabara, Yasuo

2010-04-01

Despite a range of research on gender identity disorder (GID), at present there is no scientific consensus on whether the etiology of GID is mental or physical. In particular recent advances in the technology of neuroimaging research have led to an increased understanding of the biological basis of various mental disorders. GID also should be evaluated from this perspective. The aim of the present study was therefore to do the first trial to examine the regional cerebral blood flow (rCBF) in GID. Persons considered biologically male fulfilling the GID criteria are termed male to female (MTF) and, conversely, persons considered biological female are termed female to male (FTM). We compared 11 FTM subjects and nine age- and handedness-matched female control subjects. None of the subjects was regularly taking medication and none had any kind of physical or psychiatric comorbidity. To evaluate rCBF in GID subjects and control subjects, statistical parametric mapping analysis of (99m)Tc-ethyl-cysteinate dimer single-photon emission computed tomography was used. GID subjects had a significant decrease in rCBF in the left anterior cingulate cortex (ACC) and a significant increase in the right insula compared to control subjects. The ACC and insula are regions that have been noted as being related to human sexual behavior and consciousness. From these findings, useful insights into the biological basis of GID were suggested.

Abnormal regional cerebral blood flow in childhood autism.

PubMed

Ohnishi, T; Matsuda, H; Hashimoto, T; Kunihiro, T; Nishikawa, M; Uema, T; Sasaki, M

2000-09-01

Neuroimaging studies of autism have shown abnormalities in the limbic system and cerebellar circuits and additional sites. These findings are not, however, specific or consistent enough to build up a coherent theory of the origin and nature of the brain abnormality in autistic patients. Twenty-three children with infantile autism and 26 non-autistic controls matched for IQ and age were examined using brain-perfusion single photon emission computed tomography with technetium-99m ethyl cysteinate dimer. In autistic subjects, we assessed the relationship between regional cerebral blood flow (rCBF) and symptom profiles. Images were anatomically normalized, and voxel-by-voxel analyses were performed. Decreases in rCBF in autistic patients compared with the control group were identified in the bilateral insula, superior temporal gyri and left prefrontal cortices. Analysis of the correlations between syndrome scores and rCBF revealed that each syndrome was associated with a specific pattern of perfusion in the limbic system and the medial prefrontal cortex. The results confirmed the associations of (i) impairments in communication and social interaction that are thought to be related to deficits in the theory of mind (ToM) with altered perfusion in the medial prefrontal cortex and anterior cingulate gyrus, and (ii) the obsessive desire for sameness with altered perfusion in the right medial temporal lobe. The perfusion abnormalities seem to be related to the cognitive dysfunction observed in autism, such as deficits in ToM, abnormal responses to sensory stimuli, and the obsessive desire for sameness. The perfusion patterns suggest possible locations of abnormalities of brain function underlying abnormal behaviour patterns in autistic individuals.

A feasibility study of cerebral oximetry during in-hospital mechanical and manual cardiopulmonary resuscitation*.

PubMed

Parnia, Sam; Nasir, Asad; Ahn, Anna; Malik, Hanan; Yang, Jie; Zhu, Jiawen; Dorazi, Francis; Richman, Paul

2014-04-01

A major hurdle limiting the ability to improve the quality of resuscitation has been the lack of a noninvasive real-time detection system capable of monitoring the quality of cerebral and other organ perfusion, as well as oxygen delivery during cardiopulmonary resuscitation. Here, we report on a novel system of cerebral perfusion targeted resuscitation. An observational study evaluating the role of cerebral oximetry (Equanox; Nonin, Plymouth, MI, and Invos; Covidien, Mansfield, MA) as a real-time marker of cerebral perfusion and oxygen delivery together with the impact of an automated mechanical chest compression system (Life Stat; Michigan Instruments, Grand Rapids, MI) on oxygen delivery and return of spontaneous circulation following in-hospital cardiac arrest. Tertiary medical center. In-hospital cardiac arrest patients (n = 34). Cerebral oximetry provided real-time information regarding the quality of perfusion and oxygen delivery. The use of automated mechanical chest compression device (n = 12) was associated with higher regional cerebral oxygen saturation compared with manual chest compression device (n = 22) (53.1% ± 23.4% vs 24% ± 25%, p = 0.002). There was a significant difference in mean regional cerebral oxygen saturation (median % ± interquartile range) in patients who achieved return of spontaneous circulation (n = 15) compared with those without return of spontaneous circulation (n = 19) (47.4% ± 21.4% vs 23% ± 18.42%, p < 0.001). After controlling for patients achieving return of spontaneous circulation or not, significantly higher mean regional cerebral oxygen saturation levels during cardiopulmonary resuscitation were observed in patients who were resuscitated using automated mechanical chest compression device (p < 0.001). The integration of cerebral oximetry into cardiac arrest resuscitation provides a novel noninvasive method to determine the quality of cerebral perfusion and oxygen delivery to the brain. The use of automated mechanical

Sex-dependent alterations in resting-state cerebral blood flow, amplitude of low-frequency fluctuations and their coupling relationship in schizophrenia.

PubMed

Ma, Xiaomei; Wang, Di; Zhou, Yujing; Zhuo, Chuanjun; Qin, Wen; Zhu, Jiajia; Yu, Chunshui

2016-04-01

We aimed to investigate sex-dependent alterations in resting-state relative cerebral blood flow, amplitude of low-frequency fluctuations and relative cerebral blood flow-amplitude of low-frequency fluctuations coupling in patients with schizophrenia. Resting-state functional magnetic resonance imaging and three-dimensional pseudo-continuous arterial spin labeling imaging were performed to obtain resting-state amplitude of low-frequency fluctuations and relative cerebral blood flow in 95 schizophrenia patients and 99 healthy controls. Sex differences in relative cerebral blood flow and amplitude of low-frequency fluctuations were compared in both groups. Diagnostic group differences in relative cerebral blood flow, amplitude of low-frequency fluctuations and relative cerebral blood flow-amplitude of low-frequency fluctuations coupling were compared in male and female subjects, respectively. In both healthy controls and schizophrenia patients, the males had higher relative cerebral blood flow in anterior brain regions and lower relative cerebral blood flow in posterior brain regions than did the females. Compared with multiple regions exhibiting sex differences in relative cerebral blood flow, only the left middle frontal gyrus had a significant sex difference in amplitude of low-frequency fluctuations. In the females, schizophrenia patients exhibited increased relative cerebral blood flow and amplitude of low-frequency fluctuations in the basal ganglia, thalamus and hippocampus and reduced relative cerebral blood flow and amplitude of low-frequency fluctuations in the frontal, parietal and occipital regions compared with those of healthy controls. However, there were fewer brain regions with diagnostic group differences in the males than in the females. Brain regions with diagnostic group differences in relative cerebral blood flow and amplitude of low-frequency fluctuations only partially overlapped. Only the female patients exhibited increased relative cerebral

Perisylvian sulcal morphology and cerebral asymmetry patterns in adults who stutter.

PubMed

Cykowski, Matthew D; Kochunov, Peter V; Ingham, Roger J; Ingham, Janis C; Mangin, Jean-François; Rivière, Denis; Lancaster, Jack L; Fox, Peter T

2008-03-01

Previous investigations of cerebral anatomy in persistent developmental stutterers have reported bilateral anomalies in the perisylvian region and atypical patterns of cerebral asymmetry. In this study, perisylvian sulcal patterns were analyzed to compare subjects with persistent developmental stuttering (PDS) and an age-, hand-, and gender-matched control group. This analysis was accomplished using software designed for 3-dimensional sulcal identification and extraction. Patterns of cerebral asymmetry were also investigated with standard planimetric measurements. PDS subjects showed a small but significant increase in both the number of sulci connecting with the second segment of the right Sylvian fissure and in the number of suprasylvian gyral banks (of sulci) along this segment. No differences were seen in the left perisylvian region for either sulcal number or gyral bank number. Measurements of asymmetry revealed typical patterns of cerebral asymmetry in both groups with no significant differences in frontal and occipital width asymmetry, frontal and occipital pole asymmetry, or planum temporale and Sylvian fissure asymmetries. The subtle difference in cortical folding of the right perisylvian region observed in PDS subjects may correlate with functional imaging studies that have reported increased right-hemisphere activity during stuttered speech.

Spatial transcriptomic survey of human embryonic cerebral cortex by single-cell RNA-seq analysis.

PubMed

Fan, Xiaoying; Dong, Ji; Zhong, Suijuan; Wei, Yuan; Wu, Qian; Yan, Liying; Yong, Jun; Sun, Le; Wang, Xiaoye; Zhao, Yangyu; Wang, Wei; Yan, Jie; Wang, Xiaoqun; Qiao, Jie; Tang, Fuchou

2018-06-04

The cellular complexity of human brain development has been intensively investigated, although a regional characterization of the entire human cerebral cortex based on single-cell transcriptome analysis has not been reported. Here, we performed RNA-seq on over 4,000 individual cells from 22 brain regions of human mid-gestation embryos. We identified 29 cell sub-clusters, which showed different proportions in each region and the pons showed especially high percentage of astrocytes. Embryonic neurons were not as diverse as adult neurons, although they possessed important features of their destinies in adults. Neuron development was unsynchronized in the cerebral cortex, as dorsal regions appeared to be more mature than ventral regions at this stage. Region-specific genes were comprehensively identified in each neuronal sub-cluster, and a large proportion of these genes were neural disease related. Our results present a systematic landscape of the regionalized gene expression and neuron maturation of the human cerebral cortex.

Altered regional and circuit resting-state activity in patients with occult spastic diplegic cerebral palsy.

PubMed

Mu, Xuetao; Wang, Zhiqun; Nie, Binbin; Duan, Shaofeng; Ma, Qiaozhi; Dai, Guanghui; Wu, Chunnan; Dong, Yuru; Shan, Baoci; Ma, Lin

2017-10-07

Very few studies have been made to investigate functional activity changes in occult spastic diplegic cerebral palsy (SDCP). The purpose of this study was to analyze whole-brain resting state regional brain activity and functional connectivity (FC) changes in patients with SDCP. We examined 12 occult SDCP and 14 healthy control subjects using resting-state functional magnetic resonance imaging. The data were analyzed using Resting-State fMRI Data Analysis Toolkit (REST) software. The regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF), and whole brain FC of the motor cortex and thalamus were analyzed and compared between the occult SDCP and control groups. Compared with the control group, the occult SDCP group showed decreased ReHo regions, including the bilateral frontal, parietal, and temporal lobes, the cerebellum, right cingulate gyrus, and right lenticular nucleus, whereas an increased ReHo value was observed in the left precuneus, calcarine, fusiform gyrus, and right precuneus. Compared with the control group, no significant differences in ALFF were noted in the occult SDCP group. With the motor cortex as the region of interest, the occult SDCP group showed decreased connectivity regions in the bilateral fusiform and lingual gyrus, but increased connectivity regions in the contralateral precentral and postcentral gyrus, supplementary motor area, and the ipsilateral postcentral gyrus. With the thalamus being regarded as the region of interest, the occult SDCP group showed decreased connectivity regions in the bilateral basal ganglia, cingulate, and prefrontal cortex, but increased connectivity regions in the bilateral precentral gyrus, the contralateral cerebellum, and inferior temporal gyrus. Resting-state regional brain activities and FC changes in the patients with occult SDCP exhibited a special distribution pattern, which is consistent with the pathology of the disease. Copyright © 2017. Published by Elsevier B.V.

Narcolepsy with Cataplexy Associated with Nocturnal Compulsive Behaviors: A Case-Control Study

PubMed Central

Palaia, Vincenzo; Poli, Francesca; Pizza, Fabio; Antelmi, Elena; Franceschini, Christian; Moghadam, Keivan Kaveh; Provini, Frederica; Pagotto, Uberto; Montagna, Pasquale; Schenck, Carlos H.; Mignot, Emmanuel; Plazzi, Giuseppe

2011-01-01

Study Objectives: To assess the prevalence of sleep related-eating disorder (SRED) and nocturnal smoking (NS) in patients with narcolepsy with cataplexy (NC). Design: Case-control study. Setting: University hospital. Patients or Participants: 65 consecutive adult NC patients (33 men; mean age 43.9 ± 19.2 years) and 65 age-, sex-, and geographical origin-matched controls. Interventions: Validated questionnaires were used to investigate SRED, NS, restless legs syndrome (RLS), and psychopathological traits (using Eating Disorder Inventory-2 [EDI-2]; Maudsley Obsessive-Compulsive Inventory [MOCI]; and Beck Depression Inventory [BDI]). Measurements and Results: NC patients showed a higher prevalence of SRED (32% vs 3%, P = 0.00001), NS (21% vs 0%, P = 0.00006), and RLS (18% vs 5%, P = 0.013) than controls. Moreover, NC patients presented more frequently with an eating-related pathological profile on the EDI-2 (80% vs 46%, P = 0.00006) and had a higher prevalence of depressed mood on the BDI (41% vs 18%, P = 0.004). In comparison to patients without SRED, NC patients with SRED were more frequently women (71% vs 39%, P = 0.013), had higher “bulimic” (29% vs 2%, P = 0.004) and “social insecurity” (48% vs 18%, P = 0.013) traits on the EDI-2, had higher obsessive-compulsiveness on the MOCI (29% vs 4%, P = 0.009), and were more depressed on the BDI (67% vs 29%, P = 0.005). NC patients with NS showed more frequent pathological profiles on the EDI-2 (100% vs 75%, P = 0.035), including the “bulimic” (29% vs 6%, P = 0.015), “perfectionism” (43% vs 14%, P = 0.016), and “social insecurity” (50% vs 22, P = 0.035) profiles. Conclusion: Our study shows a strong association of the compulsive nocturnal behaviors SRED and NS with adult NC. Citation: Palaia V; Poli F; Pizza F; Antelmi E; Franceschini C; Moghadam KK; Provini F; Pagotto U; Montagna P; Schenck CH; Mignot E; Plazzi G. Narcolepsy with cataplexy associated with nocturnal compulsive behaviors: a case

Brain regions associated with cognitive impairment in patients with Parkinson disease: quantitative analysis of cerebral blood flow using 123I iodoamphetamine SPECT.

PubMed

Hattori, Naoya; Yabe, Ichiro; Hirata, Kenji; Shiga, Tohru; Sakushima, Ken; Tsuji-Akimoto, Sachiko; Sasaki, Hidenao; Tamaki, Nagara

2013-05-01

Cognitive impairment is a representative neuropsychiatric presentation that accompanies Parkinson disease (PD). The purpose of this study was to localize the cerebral regions associated with cognitive impairment in patients with PD using quantitative SPECT. Thirty-two patients with PD (mean [SD] age, 75 [8] years; 25 women; Hoehn-Yahr scores from 2 to 5) underwent quantitative brain SPECT using 123I iodoamphetamine. Parametric images of regional cerebral blood flow (rCBF) were spatially normalized to the standard brain atlas. First, voxel-by-voxel comparison between patients with PD with versus without cognitive impairment was performed to visualize overall trend of regional differences. Next, the individual quantitative rCBF values were extracted in representative cortical regions using a standard region-of-interest template to compare the quantitative rCBF values. Patients with cognitive impairment showed trends of lower rCBF in the left frontal and temporal cortices as well as in the bilateral medial frontal and anterior cingulate cortices in the voxel-by-voxel analyses. Region-of-interest-based analysis demonstrated significantly lower rCBF in the bilateral anterior cingulate cortices (right, 25.8 [5.5] vs 28.9 [5.7] mL per 100 g/min, P < 0.05; left, 25.8 [5.8] vs 29.1 [5.7] mL per 100 g/min, P < 0.05) associated with cognitive impairment. Patients with cognitive impairment showed lower rCBF in the left frontal and temporal cortices as well as in the bilateral medial frontal and anterior cingulate cortices. The results suggested dysexecutive function as an underlining mechanism of cognitive impairment in patients with PD.

Arterial blood gas management in retrograde cerebral perfusion: the importance of carbon dioxide.

PubMed

Ueno, K; Takamoto, S; Miyairi, T; Morota, T; Shibata, K; Murakami, A; Kotsuka, Y

2001-11-01

Many interventional physiological assessments for retrograde cerebral perfusion (RCP) have been explored. However, the appropriate arterial gas management of carbon dioxide (CO2) remains controversial. The aim of this study is to determine whether alpha-stat or pH-stat could be used for effective brain protection under RCP in terms of cortical cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), and distribution of regional cerebral blood flow. Fifteen anesthetized dogs (25.1+/-1.1 kg) on cardiopulmonary bypass (CPB) were cooled to 18 degrees C under alpha-stat management and had RCP for 90 min under: (1), alpha-stat; (2), pH-stat; or (3), deep hypothermic (18 degrees C) antegrade CPB (antegrade). RCP flow was regulated for a sagittal sinus pressure of around 25 mmHg. CBF was monitored by a laser tissue flowmeter. Serial analyses of blood gas were made. The regional cerebral blood flow was measured with colored microspheres before discontinuation of RCP. CBF and CMRO2 were evaluated as the percentage of the baseline level (%CBF, %CMRO2). The oxygen content of arterial inflow and oxygen extraction was not significantly different between the RCP groups. The %CBF and %CMRO2 were significantly higher for pH-stat RCP than for alpha-stat RCP. The regional cerebral blood flow, measured with colored microspheres, tended to be higher for pH-stat RCP than for alpha-stat RCP, at every site in the brain. Irrespective of CO2 management, regional differences were not significant among any site in the brain. CO2 management is crucial for brain protection under deep hypothermic RCP. This study revealed that pH-stat was considered to be better than alpha-stat in terms of CBF and oxygen metabolism in the brain. The regional blood flow distribution was considered to be unchanged irrespective of CO2 management.

[Research on brain white matter network in cerebral palsy infant].

PubMed

Li, Jun; Yang, Cheng; Wang, Yuanjun; Nie, Shengdong

2017-10-01

Present study used diffusion tensor image and tractography to construct brain white matter networks of 15 cerebral palsy infants and 30 healthy infants that matched for age and gender. After white matter network analysis, we found that both cerebral palsy and healthy infants had a small-world topology in white matter network, but cerebral palsy infants exhibited abnormal topological organization: increased shortest path length but decreased normalize clustering coefficient, global efficiency and local efficiency. Furthermore, we also found that white matter network hub regions were located in the left cuneus, precuneus, and left posterior cingulate gyrus. However, some abnormal nodes existed in the frontal, temporal, occipital and parietal lobes of cerebral palsy infants. These results indicated that the white matter networks for cerebral palsy infants were disrupted, which was consistent with previous studies about the abnormal brain white matter areas. This work could help us further study the pathogenesis of cerebral palsy infants.

Time-on-task decrements in "steer clear" performance of patients with sleep apnea and narcolepsy

NASA Technical Reports Server (NTRS)

Findley, L. J.; Suratt, P. M.; Dinges, D. F.

1999-01-01

Loss of attention with time-on-task reflects the increasing instability of the waking state during performance in experimentally induced sleepiness. To determine whether patients with disorders of excessive sleepiness also displayed time-on-task decrements indicative of wake state instability, visual sustained attention performance on "Steer Clear," a computerized simple RT driving simulation task, was compared among 31 patients with untreated sleep apnea, 16 patients with narcolepsy, and 14 healthy control subjects. Vigilance decrement functions were generated by analyzing the number of collisions in each of six four-minute periods of Steer Clear task performance in a mixed-model analysis of variance and linear regression equations. As expected, patients had more Steer Clear collisions than control subjects (p=0.006). However, the inter-subject variability in errors among the narcoleptic patients was four-fold that of the apnea patients, and 100-fold that of the controls volunteers; the variance in errors among untreated apnea patients was 27-times that of controls. The results of transformed collision data revealed main effects for group (p=0.006), time-on-task (p=0.001), and a significant interaction (p=0.022). Control subjects showed no clear evidence of increasing collision errors with time-on-task (adjusted R2=0.22), while apnea patients showed a trend toward vigilance decrement (adjusted R2=0.42, p=0.097), and narcolepsy patients evidenced a robust linear vigilance decrement (adjusted R2=0.87, p=0.004). The association of disorders of excessive somnolence with escalating time-on-task decrements makes it imperative that when assessment of neurobehavioral performance is conducted in patients, it involves task durations and analyses that will evaluate the underlying vulnerability of potentially sleepy patients to decrements over time in tasks that require sustained attention and timely responses, both of which are key components in safe driving performance.

Quantifying regional cerebral blood flow by N-isopropyl-P-[I-123]iodoamphetamine (IMP) using a ring type single-photon emission computed tomography system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takahashi, N.; Odano, I.; Ohkubo, M.

1994-05-01

We developed a more accurate quantitative measurement of regional cerebral blood flow (rCBF) with the microsphere model using N-isopropyl-p-[I-123] iodoamphetamine (IMP) and a ring type single photon emission computed tomography (SPECT) system. SPECT studies were performed in 17 patients with brain diseases. A dose of 222 MBq (6 mCi) of [I-123]IMP was injected i.v., at the same time a 5 min period of arterial blood withdrawal was begun. SPECT data were acquired from 25 min to 60 min after tracer injection. For obtaining the brain activity concentration at 5 min after IMP injection, total brain counts collections and one minutemore » period short time SPECT studies were performed at 5, 20, and 60 min. Measurement of the values of rCBF was calculated using short time SPECT images at 5 min (rCBF), static SPECT images corrected with total cerebral counts (rCBF{sub Ct}.) and those corrected with reconstructed counts on short time SPECT images (rCBF{sub Cb}). There was a good relationship (r=0.69) between rCBF and rCBF{sub Ct}, however, rCBF{sub Ct} tends to be underestimated in high flow areas and overestimated in low flow areas. There was better relationship between rCBF and rCBF{sub Cb}(r=0.92). The overestimation and underestimation shown in rCBF{sub Ct} was considered to be due to the correction of reconstructed counts using a total cerebral time activity curve, because of the kinetic behavior of [I-123]IMP was different in each region. We concluded that more accurate rCBF values could be obtained using the regional time activity curves.« less

Cerebral blood flow asymmetries in headache-free migraineurs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levine, S.R.; Welch, K.M.; Ewing, J.R.

1987-11-01

Regional cerebral blood flow (rCBF) asymmetries were studied in controls and patients with common and classic/complicated migraine using /sup 133/Xe inhalation with 8 homologously situated external collimators over each cerebral hemisphere. Migraine patients as a group more frequently had posterior rCBF asymmetries than controls (p less than 0.03). Although there were no differences in the number of anterior rCBF asymmetries, migraine patients had 2 or more asymmetric probe pairs more often than controls (p less than 0.02). The posterior rCBF asymmetries, consistent with the site of activation of many migraine attacks, may be related to more labile control of themore » cerebral circulation.« less

Neuroimaging findings in children with retinopathy-confirmed cerebral malaria.

PubMed

Potchen, Michael J; Birbeck, Gretchen L; Demarco, J Kevin; Kampondeni, Sam D; Beare, Nicholas; Molyneux, Malcolm E; Taylor, Terrie E

2010-04-01