Cerebrospinal Fluid Hypocretin-1 Levels Research Articles

CSF-profile and hypocretin levels in children with narcolepsy type 1 and 2

BackgroundNarcolepsy is a rare neurological disease caused by dysfunction of hypocretin-producing neurons. Hypocretin concentrations in the cerebrospinal fluid (CSF) of less than 110 pg/ml are considered pathological in adults. ObjectivesTo compare hypocretin levels of children with narcolepsy type 1, type 2 and disease control groups, in addition to a detailed CSF analysis, clinical and polysomnographic parameters. MethodsIn a retrospective, cross-sectional study, children diagnosed with narcolepsy based on clinical and polysomnographic parameters, who received a CSF analysis and hypocretin measurement, in addition to controls, were included. CSF was analyzed for the presence of cells, total protein, lactate, intrathecal synthesis of antibodies against measles, rubella and/or varicella zoster, and oligoclonal bands. All children had a complete sleep study including a multiple sleep latency test (MSLT). Results49 children with narcolepsy type 1, 15 children with type 2 and 37 children with other (suspected) neurological diseases were included. CSF routine analysis did not reveal any differences between the three groups. All children with narcolepsy type 1 had hypocretin levels of less than 110 pg/ml (range: 10 - 101 pg/ml). Hypocretin levels in type 2 patients ranged from 43 to 436 pg/ml (median 157 pg/ml). The median hypocretin level in the control cohort was 365 pg/ml (range: 153 - 583 pg/ml). In 4 children with narcolepsy type 2 the diagnosis was changed to narcolepsy level 1 because of a CSF hypocretin level of less than 110 pg/ml according to the recently proposed criteria, which consider the measurement of hypocretin in CSF. ConclusionChildren with narcolepsy type 1 showed significantly lower CSF hypocretin levels than children with narcolepsy type 2 and controls. As suggested by the recently published narcolepsy criteria, hypocretin levels of less than 110 pg/ml should be used as an additional criterion for the presence of narcolepsy type 1 in children.

Narcolepsy in a 4-Year-Old

Narcolepsy is a disabling neurodegenerative condition that is characterized by the hallmark of excessive daytime sleepiness. Diagnosis of narcolepsy can be difficult in all aged patients, but especially so in children less than 5 years old. We present a unique case of a 4-year-old girl who presented with slurred speech, behavioral changes, and hypersomnolence. After a thorough evaluation, she was diagnosed with narcolepsy type 1. We provide a literature review about this diagnosis and discuss the signs, symptoms, and workup, with a focus on the challenges associated with determining the definitive diagnosis. The role of obtaining cerebrospinal fluid hypocretin-1 levels in the diagnostic evaluation of patient with suspected narcolepsy is emphasized.

Repeated polysomnography and multiple sleep latency test in narcolepsy type 1 and other hypersomnolence disorders

BackgroundThe diagnosis of narcolepsy is based on clinical information, combined with polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). PSG and the MSLT are moderately reliable at diagnosing narcolepsy type 1 (NT1) but unreliable for diagnosing narcolepsy type 2 (NT2). This is a problem, especially given the increased risk of a false-positive MSLT in the context of circadian misalignment or sleep deprivation, both of which commonly occur in the general population. AimWe aimed to clarify the accuracy of PSG/MSLT testing in diagnosing NT1 versus controls without sleep disorders. Repeatability and reliability of PSG/MSLT testing and temporal changes in clinical findings of patients with NT1 versus patients with hypersomnolence with normal hypocretin-1 were compared. Method84 patients with NT1 and 100 patients with non-NT1-hypersomnolence disorders, all with congruent cerebrospinal fluid hypocretin-1 (CSF-hcrt-1) levels, were included. Twenty-five of the 84 NT1 patients and all the hypersomnolence disorder patients underwent a follow-up evaluation consisting of clinical assessment, PSG, and a modified MSLT. An additional 68 controls with no sleep disorders were assessed at baseline. ConclusionConfirming results from previous studies, we found that PSG and our modified MSLT accurately and reliably diagnosed hypocretin-deficient NT1 (accuracy = 0.88, reliability = 0.80). Patients with NT1 had stable clinical and electrophysiological presentations over time that suggested a stable phenotype. In contrast, the PSG/MSLT results of patients with hypersomnolence, and normal CSF-hcrt-1 had poor reliability (0.32) and low repeatability.

Associations between psychiatric comorbid disorders and executive dysfunctions in hypocretin-1 deficient pediatric narcolepsy type1

Objective/BackgroundPsychiatric symptoms and cognitive deficits add significantly to impairment in academic achievement and quality of life in patients with narcolepsy. The primary aim of this study was to evaluate the prevalence of psychiatric disorders and executive dysfunctions, secondly to explore the association between psychiatric comorbidity, executive dysfunctions, subjective and objective sleep measures, and severity of cerebrospinal fluid (CSF) hypocretin-1 deficiency in pediatric narcolepsy type 1 (PNT1). Patients/MethodsCross-sectional study of 59 consecutively included PNT1 patients (age: 6-20 years; 34:25 girls: boys; 54/59 H1N1 (Pandemrix®)-vaccinated). Core narcolepsy symptoms including subjective sleepiness, polysomnography and multiple sleep latency test results, CSF hypocretin-1 levels, psychiatric disorders (by semistructured diagnostic interview Kaufmann Schedule for Affective Disorders and Schizophrenia Present and Lifetime version (KSADS)), and executive dysfunction (by Behavior Rating of Executive Function (BRIEF)) were assessed. Results52.5% of the patients had one or more psychiatric comorbid disorder, and 64.7% had executive dysfunction in a clinically relevant range, with no sex difference in prevalence, while older age was associated with poorer executive function (p=0.013). Having any psychiatric comorbid disorder was associated with poorer executive functions (p=0.001). CSF hypocretin-1 deficiency severity was significantly associated with presence of psychiatric comorbidity (p=0.022) and poorer executive functions (p=0.030), and poorer executive functions was associated with subjective sleepiness (p=0.009). ConclusionsThe high occurrence of, and association between, psychiatric comorbidity and executive dysfunction underlines the importance of close attention to both these comorbidities in clinical care of NT1.

Intermediate hypocretin-1 cerebrospinal fluid levels and typical cataplexy: their significance in the diagnosis of narcolepsy type 1.

Study ObjectivesThe diagnosis of narcolepsy type 1 (NT1) is based upon the presence of cataplexy and/or a cerebrospinal fluid (CSF) hypocretin-1/orexin-A level ≤ 110 pg/mL. We determined the clinical and diagnostic characteristics of patients with intermediate hypocretin-1 levels (111–200 pg/mL) and the diagnostic value of cataplexy characteristics in individuals with central disorders of hypersomnolence.MethodsRetrospective cross-sectional study of 355 people with known CSF hypocretin-1 levels who visited specialized Sleep-Wake Centers in the Netherlands. For n = 271, we had full data on cataplexy type (“typical” or “atypical” cataplexy).ResultsCompared to those with normal hypocretin-1 levels (>200 pg/mL), a higher percentage of individuals with intermediate hypocretin-1 levels had typical cataplexy (75% or 12/16 vs 9% or 8/88, p < .05), and/or met the diagnostic polysomnographic (PSG) and Multiple Sleep Latency Test (MSLT) criteria for narcolepsy (50 vs 6%, p < .001). Of those with typical cataplexy, 88% had low, 7% intermediate, and 5% normal hypocretin-1 levels (p < .001). Atypical cataplexy was also associated with hypocretin deficiency but to a lesser extent. A hypocretin-1 cutoff of 150 pg/mL best predicted the presence of typical cataplexy and/or positive PSG and MSLT findings.ConclusionIndividuals with intermediate hypocretin-1 levels or typical cataplexy more often have outcomes fitting the PSG and MSLT criteria for narcolepsy than those with normal levels or atypical cataplexy. In addition, typical cataplexy has a much stronger association with hypocretin-1 deficiency than atypical cataplexy. We suggest increasing the NT1 diagnostic hypocretin-1 cutoff and adding the presence of clearly defined typical cataplexy to the diagnostic criteria of NT1. Clinical trial information: This study is not registered in a clinical trial register, as it has a retrospective database design.

Narcolepsy with intermediate cerebrospinal level of hypocretin-1

To describe the phenotype of narcolepsy with intermediate cerebrospinal fluid hypocretin-1 levels (CSF hcrt-1). From 1600 consecutive patients with narcolepsy from Bologna and Montpellier sleep centers, we selected patients with intermediate CSF hcrt-1 levels (110-200 pg/mL). Clinical, neurophysiological, and biological data were contrasted for the presence of cataplexy, human leukocyte haplotype (HLA)-DQB1*06:02, and median CSF hcrt-1 levels (149.34 pg/mL). Forty-five (55% males, aged 35 ± 17 years) patients (2.8% of all cases) were included. Thirty-three (73%) were HLA-DQB1*06:02, 29 (64%) reported cataplexy (21, 72.4% with typical features), and 5 (11%) had presumed secondary etiology. Cataplexy was associated with other core narcolepsy symptoms, increased sleep onset rapid eye movement periods, and nocturnal sleep disruption. Cataplexy and irrepressible daytime sleep were more frequent in HLA-DQB1*06:02 positive patients. Lower CSF hcrt-1 levels were associated with hallucinations. Narcolepsy with intermediate CSF hcrt-1 level is a rare condition with heterogeneous phenotype. HLA-DQB1*06:02 and lower CSF hcrt-1 were associated with typical narcolepsy features, calling for future research to distinguish incomplete from secondary narcolepsy forms.

Changes of Hypocretin (Orexin) System in Schizophrenia: From Plasma to Brain

Hypocretin (also called orexin) regulates various functions, such as sleep-wake rhythms, attention, cognition, and energy balance, which show significant changes in schizophrenia (SCZ). We aimed to identify alterations in the hypocretin system in SCZ patients. We measured plasma hypocretin-1 levels in SCZ patients and healthy controls and found significantly decreased plasma hypocretin-1 levels in SCZ patients, which was mainly due to a significant decrease in female SCZ patients compared with female controls. In addition, we measured postmortem hypothalamic hypocretin-1-immunoreactivity (ir), ventricular cerebrospinal fluid (CSF) hypocretin-1 levels, and hypocretin receptor (Hcrt-R) mRNA expression in the superior frontal gyrus (SFG) in SCZ patients and controls We observed a significant decrease in the amount of hypothalamic hypocretin-1 ir in SCZ patients, which was due to decreased amounts in female but not male patients. Moreover, Hcrt-R2 mRNA in the SFG was decreased in female SCZ patients compared with female controls, while male SCZ patients showed a trend of increased Hcrt-R1 mRNA and Hcrt-R2 mRNA expression compared with male controls. We conclude that central hypocretin neurotransmission is decreased in SCZ patients, especially female patients, and this is reflected in the plasma.

In Vitro Treg Immunosuppression Assay of GITR Proteins Could Elucidate the Autoimmune-mediated Mechanism Underlying Type 1 Narcolepsy

Abstract: Type 1 narcolepsy is a hypersomnia sleep disorder characterized by excessive daytime sleep and shallow NREM nighttime sleep. Deficiency of hypocretin-1 secreting neurons in the lateral hypothalamus is the primary cause of the disorder and studies demonstrated that these neurons were solely diminished in a brain region of remarkable heterogeneous neuronal population. Specific destruction of targeted neurons could be achieved via antigen presentation to immune cells, a characteristic of cell-mediated response in the adaptive immune system. Given that hypocretin-1 neurons were exclusively targeted, this cultivated significant interest in searching for an autoimmune-mediated mechanism but studies currently lack adequate knowledge and consistent results. In this research proposal, it is hypothesized that enhanced glucocorticoid-induced TNFR-related (GITR) protein expression in T regulatory (Treg) cells results in defective suppression capacity of CD4+CD25+ T helper cells and defective self-tolerance thereby promoting destruction of hypocretin-1 secreting-neurons in the lateral hypothalamus of narcoleptics. The proposal devises a correlational study to measure cerebrospinal fluid (CSF) hypocretin-1 levels that were inversely proportional to GITR expression levels in Treg cells to assess the autoimmune nature of the disorder. This study is aimed at investigating how defective T regulatory cells respond in type 1 narcolepsy patients via CSF hypocretin-1 measurement and in vitro human T regulatory cell suppression assay.

Cortical arousal frequency is increased in narcolepsy type 1.

Hypocretin deficient narcolepsy (type 1, NT1) presents with multiple sleep abnormalities including sleep-onset rapid eye movement (REM) periods (SOREMPs) and sleep fragmentation. We hypothesized that cortical arousals, as scored by an automatic detector, are elevated in NT1 and narcolepsy type 2 (NT2) patients as compared to control subjects. We analyzed nocturnal polysomnography (PSG) recordings from 25 NT1 patients, 20 NT2 patients, 18 clinical control subjects (CC, suspected central hypersomnia but with normal cerebrospinal (CSF) fluid hypocretin-1 (hcrt-1) levels and normal results on the multiple sleep latency test), and 37 healthy control (HC) subjects. Arousals were automatically scored using Multimodal Arousal Detector (MAD), a previously validated automatic wakefulness and arousal detector. Multiple linear regressions were used to compare arousal index (ArI) distributions across groups. Comparisons were corrected for age, sex, body-mass index, medication, apnea-hypopnea index, periodic leg movement index, and comorbid rapid eye movement sleep behavior disorder. NT1 was associated with an average increase in ArI of 4.02 events/h (p = 0.0246) compared to HC and CC, while no difference was found between NT2 and control groups. Additionally, a low CSF hcrt-1 level was predictive of increased ArI in all the CC, NT2, and NT1 groups. The results further support the hypothesis that a loss of hypocretin neurons causes fragmented sleep, which can be measured as an increased ArI as scored by the MAD.

Multiple Sleep Latency Test/Maintenance of Wakefulness Test and Central Hypersomnias: Evolving Diagnostic and Therapeutic Approaches.

Central disorders of hypersomnolence include a spectrum of conditions, such as narcolepsy, idiopathic hypersomnia, and Kleine-Levin syndrome, in which excessive daytime sleepiness is the primary feature. Subjective testing with tools, such as sleep logs and sleepiness scales, are often helpful in the evaluation of these disorders but do not necessarily correlate well with objective testing, such as polysomnography and multiple sleep latency test and maintenance of wakefulness test. The most recent International Classification of Sleep Disorders-Third Edition has incorporated biomarkers, such as cerebrospinal fluid hypocretin level, into the diagnostic criteria and have restructured the classification of conditions based on our evolved understanding of their underlying pathophysiologic mechanisms. Therapeutic approaches largely consist of behavioral therapy, with a focus on optimizing sleep hygiene, optimizing opportunity for sleep, and strategic napping, along with judicious use of analeptic and anticataleptic agents when necessary. Emerging therapy has revolved around hypocretin-replacement therapy, immunotherapy, and nonhypocretin agents, with the goal of better targeting the underlying pathophysiology of these disorders rather than addressing symptoms. The most novel treatments have targeted the histaminergic system (pitolisant), dopamine reuptake transmission (solriamfetol), and gamma-aminobutyric acid modulation (flumazenil and clarithromycin) to promote wakefulness. Continued research is required for a more solid understanding of the biology of these conditions to develop a more robust armamentarium of therapeutic options.

Utility of measuring CSF hypocretin-1 level in patients with suspected narcolepsy

ObjectivesThe patho-aetiology of narcolepsy Type I (NT1) is the loss of hypocretin-1 secreting neurons in the hypothalamus. Diagnostic criteria for NT1 include excessive daytime sleepiness (EDS) for at least three months not explained by any other condition, cataplexy and cerebrospinal fluid (CSF) hypocretin-1 concentrations lower than 110 pg/ml. In this study we evaluated the utility of measuring CSF hypocretin-1 levels in patients with suspected narcolepsy (N). MethodsThe study included 29 consecutively recruited patients at a tertiary sleep centre presenting with EDS for exclusion of N. All patients were examined using an extensive clinical interview followed by two weeks of actigraphy and sleep diary recordings, polysomnography (PSG) and multiple sleep latency testing (MSLT). Additionally, HLA-typing, urinary screening for substances of abuse and a lumbar puncture to measure CSF hypocretin-1 expression using radioimmunoassay were carried out. ResultsIn sum, 19 patients (66%) had a CSF hypocretin-1 level <110 pg/ml, of whom two had current severe depression without any features of narcolepsy except EDS. The predictive potential of hypocretin-1 measurement in diagnosing narcolepsy revealed a positive predictive value (PPV) of 89%, a specificity of 83%, with both negative predictive value (NPV) and sensitivity equal to 100%. ConclusionsDespite a high sensitivity and specificity, the MSLT is not always a reliable diagnostic test for narcolepsy and where this uncertainty exits, CSF hypocretin-1 concentrations <110 pg/ml can be useful. However, due to a lower PPV and specificity at this cut-off, it may also not be entirely reliable as a stand-alone diagnostic test, particularly in the context of severe depression.

Predictive value of typical cataplexy+ DQB1*0602 positive to hypocretin-1 reduction in cerebrospinal fluid in patients with narcolepsy

Objective: To discusses the predictive value of typical cataplexy+ HLA-DQB1*0602 positive to hypocretin-1 (HCRT-1) reduction in cerebrospinal fluid (CSF) in patients with narcolepsy. Methods: A total of 165 narcoleptic patients, who were diagnosed at the Sleep Center of Peking University People's Hospital and Peking University International Hospital from March 2003 to March 2017, were recruited. The CSF HCRT-1 level and DQB1*0602 were measured in all the subjects. The narcoleptic patients were divided into two groups: typical cataplexy+ DQB1*0602 positive were CH group, and others who were not typical cataplexy and DQB1*0602 positive simultaneously were NCH group. The HCRT-1 level in CSF was declared to have a serious reduction when HCRT-1≤110 ng/L. According to this standard, the CH group and NCH group were subdivided into sub-groups and the data was analyzed to investigate the predictive value of typical cataplexy+ HLA-DQB1*0602 positive to HCRT-1 reduction. Results: There were 142 patients in CH group, including 137 patients with HCRT-1 reduction and 5 patients without. There were 23 patients in NCH group, including 15 patients with HCRT-1 reduction and 8 patients without. The positive predictive value of typical cataplexy+ DQB1*0602 positive for the reduction of HCRT-1 in CSF was 96.5%. Typical cataplexy+ DQB1*0602 positive had a good consistency with the HCRT-1 reduction in CSF (χ(2)=26.7, P<0.001). Conclusion: Typical cataplexy+ DQB1*0602 positive has a good predictive value to the HCRT-1 reduction in CSF in patients with narcolepsy.

Impaired histaminergic neurotransmission in children with narcolepsy type 1.

Narcolepsy is a sleep disorder characterized in humans by excessive daytime sleepiness and cataplexy. Greater than fifty percent of narcoleptic patients have an onset of symptoms prior to the age of 18. Current general agreement considers the loss of hypothalamic hypocretin (orexin) neurons as the direct cause of narcolepsy notably cataplexy. To assess whether brain histamine (HA) is also involved, we quantified the cerebrospinal fluid (CSF) levels of HA and tele-methylhistamine (t-MeHA), the direct metabolite of HA between children with orexin-deficient narcolepsy type 1 (NT1) and controls. We included 24 children with NT1 (12.3±3.6years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2±4.2years, 10 boys). CSF HA and t-MeHA were measured in all subjects using a highly sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay. CSF hypocretin-1 values were determined in the narcoleptic patients. Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234pmol/L, P<0.001), lower t-MeHA levels (879 vs 1924pmol/L, P<0.001), and lower t-MeHA/HA ratios (1.1 vs 8.2, P<0.001). NT1 patients had higher BMI z-scores (2.7±1.6 vs 1.0±2.3, P=0.006) and were more often obese (58% vs 29%, P=0.05) than the controls. Multivariable analyses including age, gender, and BMI z-score showed a significant decrease in CSF HA levels when the BMI z-score increased in patients (P=0.007) but not in the controls. No association was found between CSF HA, t-MeHA, disease duration, age at disease onset, the presence of cataplexy, lumbar puncture timing, and CSF hypocretin levels. Narcolepsy type 1 children had a higher CSF HA level together with a lower t-MeHA level leading to a significant decrease in the t-MeHA/HA ratios. These results suggest a decreased HA turnover and an impairment of histaminergic neurotransmission in narcoleptic children and support the use of a histaminergic therapy in the treatment against narcolepsy.

Narcolepsy Features in Young Patients

Narcolepsy is a lifelong central hypersomnia characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep. Behavioral and psychiatric comorbidities are often associated clinical features. It is divided into two subtypes, narcolepsy type-1, and narcolepsy type-2, depending on the presence of cataplexy and the cerebrospinal fluid hypocretin-1 levels. An autoimmune process, along with environmental factors, has been hypothesized to cause the disease. Among children and adolescents, incidence in Europe falls between 0.14 and 0.3 in 100,000, with a reported increase in the incidence after the 2009 H1N1 pandemic influence and vaccination. Currently, specific pediatric diagnostic criteria and cut-off instrumental values are lacking. Clinical presentation of the disease may differ between children and adults, and misdiagnoses or diagnostic delays are still an issue. The treatment is based on behavioral and pharmacological therapy, but drugs in children are prescribed off-label. Overall, pathogenic mechanism of narcolepsy and data on drug efficacy in children are still limited: more research is needed to develop new drugs and to reach approval of current treatments in the pediatric population.

Sleep spindle density in narcolepsy

BackgroundPatients 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). MethodsAll-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. ResultsBetween-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. ConclusionsSS 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.

Sleep–wake stability in narcolepsy patients with normal, low and unmeasurable hypocretin levels

ObjectiveTo compare diurnal and nocturnal electrophysiological data from narcolepsy patients with undetectable (<20 pg/mL), low (20–110 pg/mL) and normal (>110 pg/mL) cerebrospinal fluid (CSF) hypocretin-1 levels. Patients/MethodsA total of 109 narcolepsy patients and 37 controls were studied; all had available CSF hypocretin-1 measurements. The sleep laboratory studies were conducted between 2008 and 2014. The study retrospectively examined measurements of sleep stage transitions in diurnal and nocturnal continuous polysomnography. The percentage distribution of time awake and rapid eye movement (REM) sleep, and the occurrence of sleep onset REM (SOREM) in the nocturnal polysomnography were also measured. ResultsParticipants with undetectable hypocretin-1 levels had significantly higher frequencies of transitions than controls and those with normal hypocretin-1 levels. Participants with low hypocretin-1 levels showed more transitions than controls and, in some cases, also more than those with normal hypocretin-1. Participants with normal hypocretin-1 failed to show any significant difference from the controls, except in the overall diurnal transitions. ConclusionUndetectable hypocretin-1 levels in particular, but also low hypocretin-1 levels, were associated with a less stable phenotype featuring more sleep state transitions and SOREM episodes. In addition, there was a distinction between nocturnal and diurnal REM sleep in hypocretin-deficient participants, expressed as increased diurnal REM sleep, which was not reflected in nocturnal sleep.

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.

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.

Low cerebrospinal fluid hypocretin levels during sudden infant death syndrome (SIDS) risk period

ObjectivesThe temporal association between sudden infant death syndrome (SIDS) and sleep suggests that the arousability from sleep provides a protective mechanism for survival. Recently, the hypocretin system, which promotes wakefulness, has been implicated in SIDS, since it has been reported that SIDS victims have fewer hypocretin neurons than infants who have died from other causes. To understand the role of hypocretin in SIDS, it is essential to better understand how this system matures. The present study compared cerebrospinal fluid (CSF) hypocretin in children aged 2–6 months, which is the age of peak incidence for SIDS, to both younger and older children. MethodHypocretin levels were measured in CSF samples from 101 children who underwent a clinically relevant lumbar puncture. Children were separated into five age groups: 0–2 months, 2–6 months, 1–5 years, 5–10 years, and 10–18 years. ResultsHypocretin levels were not significantly different between 1–5 years, 5–10 years, and 10–18 years. Therefore, these three groups were pooled into a single one (1–18 years) for further analysis. Between the 0–2 month, 2–6 month, and 1–18 year groups, a significant difference in CSF hypocretin levels existed (p = 0.001). Simple comparisons showed that CSF hypocretin levels in the 2–6 month age group were significantly lower than hypocretin levels in both the 0–2 month and 1–18 year group (p < 0.001 and p = 0.008, respectively), but not significantly between 0–2 month and 1–18 year children. ConclusionsThe CSF hypocretin levels were lower at the age of peak incidence for SIDS. This could underlie an increased vulnerability to SIDS at this specific age.

Evaluation of the potential effects of AS03-adjuvanted A(H1N1)pdm09 vaccine administration on the central nervous system of non-primed and A(H1N1)pdm09-primed cotton rats

ABSTRACTAn increased risk of narcolepsy following administration of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine (Pandemrix™) was described in children and adolescents in certain European countries. We investigated the potential effects of administration of the AS03-adjuvanted vaccine, non-adjuvanted vaccine antigen and AS03 Adjuvant System alone, on the central nervous system (CNS) in one-month-old cotton rats. Naïve or A(H1N1)pdm09 virus-primed animals received 2 or 3 intramuscular injections, respectively, of test article or saline at 2-week intervals. Parameters related to systemic inflammation (hematology, serum IL-6/IFN-γ/TNF-α) were assessed. Potential effects on the CNS were investigated by histopathological evaluation of brain sections stained with hematoxylin-and-eosin, or by immunohistochemical staining of microglia, using Iba1 and CD68 as markers for microglia identification/activation, albumin as indicator of vascular leakage, and hypocretin. We also determined cerebrospinal fluid (CSF) hypocretin levels and hemagglutination-inhibiting antibody titers. Immunogenicity of the AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine was confirmed by the induction of hemagglutination-inhibiting antibodies. Both AS03-adjuvanted vaccine and AS03 alone activated transient innate (neutrophils/eosinophils) immune responses. No serum cytokines were detected. CNS analyses revealed neither microglia activation nor inflammatory cellular infiltrates in the brain. No differences between treatment groups were detected for albumin extravascular leakage, CSF hypocretin levels, numbers of hypocretin-positive neuronal bodies or distributions of hypocretin-positive axonal/dendritic projections. Consequently, there was no evidence that intramuscular administration of the test articles promoted inflammation or damage in the CNS, or blood-brain barrier disruption, in this model.

Treatment Options for Narcolepsy.

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.