Narcolepsy Type 1 Patients Research Articles

Predicting Depression Among Chinese Patients with Narcolepsy Type 1: A Machine-Learning Approach.

Depression is a common psychiatric issue among patients with narcolepsy type 1 (NT1). Effective management requires accurate screening and prediction of depression in NT1 patients. This study aims to identify relevant factors for predicting depression in Chinese NT1 patients using machine learning (ML) approaches. A total of 203 drug-free NT1 patients (aged 5-61), diagnosed based on the ICSD-3 criteria, were consecutively recruited from the Sleep Medicine Center at Peking University People's Hospital between September 2019 and April 2023. Depression, daytime sleepiness, and impulsivity were assessed using the Center for Epidemiologic Studies Depression Scale for Children (CES-DC) or the Self-Rating Depression Scale (SDS), the Epworth Sleepiness Scale for adult or children and adolescents (ESS or ESS-CHAD), and the Barratt Impulse Scale (BIS-11). Demographic characteristics and objective sleep parameters were also analyzed. Three ML models-Logistic Regression (LR), Random Forest (RF), and Support Vector Machine (SVM)-were used to predict depression. Model performance was evaluated using receiver operating curve (AUC), accuracy, precision, recall, F1 score, and decision curve analysis (DCA). The LR model identified hallucinations (OR 2.21, 95% CI 1.01-4.90, p = 0.048) and motor impulsivity (OR 1.10, 95% CI 1.02-1.18, p = 0.015) as predictors of depression. Among the ML models, SVM showed the best performance with an AUC of 0.653, accuracy of 0.659, sensitivity of 0.727, and F1 score of 0.696, reflecting its effectiveness in integrating sleep-related and psychosocial factors. This study highlights the potential of ML models for predicting depression in NT1 patients. The SVM model shows promise in identifying patients at high risk of depression, offering a foundation for developing a data-driven, personalized decision-making tool. Further research should validate these findings in diverse populations and include additional psychological variables to enhance model accuracy.

Clinical features and mechanisms of neck myoclonus in narcolepsy

Study objectivesThe purpose of this study was to investigate the effects of neck myoclonus (NM) on sleep quality and daytime sleepiness in patients with narcolepsy (NT) and to further explore possible underlying mechanisms. MethodsWe included 72 patients with narcolepsy type 1 (NT1), 34 patients with narcolepsy type 2 (NT2) and 33 healthy controls. Patients underwent questionnaires, lumbar puncture procedure, polysomnography, and multiple sleep latency test (MSLT). Healthy controls underwent polysomnography and questionnaires. Orexin-A levels in the cerebrospinal fluid (CSF) were analyzed by radioimmunoassay. Three catecholamines, including dopamine, norepinephrine and epinephrine, in the CSF were measured by high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). ResultsBoth the NT1 and NT2 groups displayed a higher level of NM incidence rate and index compared to the control group in PSG. NT1 displayed greater MSLT REM–-NM incidence rate and index than NT2. NM were often associated with arousal or awakening and body movements, which had a prominent influence on sleep quality in both narcoleptic patients and controls. There was a positive correlation between the NM index and the Pittsburgh Sleep Quality Index (PSQI), Stanford Sleepiness Scale (SSS) and Ullanlinna Narcolepsy Scale (UNS) scores in NT1 patients. In MSLT of NT1 patients, REM–NM index were positively correlated with the CSF dopamine levels, and there were elevated dopamine levels but reduced orexin-A levels in patients with REM–NM. ConclusionNM incidence rate and index were high in patients with narcolepsy, which had a huge effect on sleep quality and aggravated daytime sleepiness. NM should be considered pathological and viewed as a new sleep-related movement disorder. Orexin-A and dopamine may be involved in the development of NM.

Major alteration of motor control during rapid eye movements sleep in mice models of sleep disorders.

Alteration of motor control during rapid eye movements (REM) sleep has been extensively described in sleep disorders, in particular in isolated REM sleep behavior disorder (iRBD) and narcolepsy type 1 (NT1). NT1 is caused by the loss of orexin/hypocretin (ORX) neurons. Unlike in iRBD, the RBD comorbid symptoms of NT1 are not associated with alpha-synucleinopathies. To determine whether the chronic absence of ORX neuropeptides is sufficient to induce RBD symptoms, we analyzed during REM sleep the EMG signal of the prepro-hypocretin knockout mice (ORX-/-), a recognized mouse model of NT1. Then, we evaluated the severity of motor alterations by comparing the EMG data of ORX-/- mice to those of mice with a targeted suppression of the sublaterodorsal glutamatergic neurotransmission, a recognized rodent model of iRBD. We found a significant alteration of tonic and phasic components of EMG during REM sleep in ORX-/- mice, with more phasic events and more REM sleep episodes without atonia compared to the control wild-type mice. However, these phasic events were fewer, shorter, and less complex in ORX-/- mice compared to the RBD-like ORX-/- mice. We thus show that ORX deficiency, as seen in NT1, is sufficient to impair muscle atonia during REM sleep with a moderate severity of alteration as compared to isolated RBD mice. As described in NT1 patients, we report a major interindividual variability in the severity and frequency of RBD symptoms in ORX-deficient mice.

Serum N-Glycan Profiling of Patients with Narcolepsy Type 1 Using LC-MS/MS.

The neurological condition known as narcolepsy type 1 (NT1) is an uncommon condition marked by extreme daytime sleepiness, cataplexy, sleep paralysis, hallucinations, disrupted nocturnal sleep, and low or undetectable levels of orexin in the CSF fluid. NT1 has been hypothesized to be an immunological disorder; its treatment is currently only symptomatic, and misdiagnosis is not uncommon. This study compares the N-glycome of NT1 patients with healthy controls in search of potential glycan biomarkers using LC-MS/MS. A total of 121 candidate N-glycans were identified, 55 of which were isomeric N-glycan structures and 65 were not. Seventeen N-glycan biomarker candidates showed significant differences between the NT1 and control cohorts. All of the candidate glycan biomarkers were isomeric except HexNAc6Hex7Fuc0NeuAc1 (6701) and HexNAc6Hex7Fuc1NeuAc2 (6712). Therefore, with isomeric and nonisomeric structures, a total of 20 candidate N-glycan biomarkers are reported in this study, and interestingly, all are either sialylated or sialylated-fucosylated and upregulated in NT1 relative to the control. The distribution levels of all the identified N-glycans show that the sialylated glycan type is the most abundant in NT1 and is majorly disialylated, although the trisialylated subtype is three-fold higher in NT1 compared to the healthy control. The first isomers of HexNAc5Hex6Fuc0NeuAc3 (5603), HexNAc6Hex7Fuc0NeuAc2 (6702), and HexNAc6Hex7Fuc1NeuAc4 (6714) expressed a high level of fold changes (FC) of 1.62, 2.19, and 2.98, respectively. These results suggest a different N-glycome profile of NT1 and a relationship between sialylated glycan isomers in NT1 disease development or progression. The revelation of N-glycan expression alterations in this study may improve NT1 diagnostic methods, understanding of NT1 pathology, and the development of new targeted therapeutics.

Evaluating routine blood and cerebrospinal fluid samples in narcolepsy patients

Cerebrospinal fluid hypocretin-1 is proven to be a precise diagnostic marker of narcolepsy Type 1 (NT1). However other characteristics of cerebrospinal fluid and blood parameters have not yet been described. The objective of this study was to evaluate the differences in routine blood and cerebrospinal fluid analyses between NT1 patients and patients suspected of hypersomnia. We collected retrospectively all measures of cerebrospinal fluid hypocretin-1 between 2019 and 2022. This yielded 612 patients out of which 146 were diagnosed with NT1 and the rest (466 patients) were used as a control group. We selected the most relevant routine samples from both blood, plasma and cerebrospinal fluid and compared the two groups. The only significantly different analytes were plasma lactate dehydrogenase and cerebrospinal fluid hypocretin-1. No other differences were found between the groups including thyroid markers, markers of neuroendocrine function, inflammatory markers in blood or cerebrospinal fluid, markers of permeability of the blood brain barrier or metabolic markers in blood samples. We found no significant differences in routine blood or cerebrospinal fluid components, neuroendocrine function, neuroinflammation and metabolic markers. The results reflect that the hypocretin system does not seem to play a chronic major role in regulation of these markers. None of the parameters routinely measured in blood in these patients could differentiate between NT1 and non-NT1 disorders besides CSF-hcrt-1.

Development and validation of a machine learning model for prediction of comorbid major depression disorder among narcolepsy type 1

BackgroundMajor depression disorder (MDD) forms a common psychiatric comorbidity among patients with narcolepsy type 1 (NT1), yet its impact on patients with NT1 is often overlooked by neurologists. Currently, there is a lack of effective methods for accurately predicting MDD in patients with NT1. ObjectiveThis study utilized machine learning (ML) algorithms to identify critical variables and developed the prediction model for predicting MDD in patients with NT1. MethodsThe study included 267 NT1 patients from four sleep centers. The diagnosis of comorbid MDD was based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5). ML models, including six full models and six compact models, were developed using a training set. The performance of these models was compared in the testing set, and the optimal model was evaluated in the testing set. Various evaluation metrics, such as Area under the receiver operating curve (AUC), precision-recall (PR) curve and calibration curve were employed to assess and compare the performance of the ML models. Model interpretability was demonstrated using SHAP. ResultIn the testing set, the logistic regression (LG) model demonstrated superior performance compared to other ML models based on evaluation metrics such as AUC, PR curve, and calibration curve. The top eight features used in the LG model, ranked by feature importance, included social impact scale (SIS) score, narcolepsy severity scale (NSS) score, total sleep time, body mass index (BMI), education years, age of onset, sleep efficiency, sleep latency. ConclusionThe study yielded a straightforward and practical ML model for the early identification of MDD in patients with NT1. A web-based tool for clinical applications was developed, which deserves further verification in diverse clinical settings.

Executive function performance in children and adolescent patients with narcolepsy type 1

ObjectiveThe executive function profile in patients with narcolepsy type 1 (NT1) has been mentioned; however, limited research exists on children and adolescent patients with NT1.This study aims to assess executive function in children and adolescent patients with NT1 in China, examine potential influencing factors and evaluate the short-term treatment effect on executive function. Methods53 NT1 patients (36 males, age 12.2 ± 3.4 years) and 37 healthy controls (23 males, age 12.2 ± 2.5 years) underwent self-reported measures assessing subjective sleepiness, depression, anxiety and sleep quality. A comprehensive neuropsychological test was administered to assess executive function domains, including processing speed, inhibitory control, cognitive flexibility and working memory. These assessments were repeated in NT1 patients after three-day regular drug treatment. ResultsNT1 patients exhibited higher levels of excessive daytime sleepiness, depression, anxiety, and poor sleep quality compared to healthy controls. Patients showed impaired processing speed, inhibitory control and cognitive flexibility (p < 0.05), whereas working memory was unaffected (p > 0.05). Regression analysis revealed that parameters from sleep monitoring, such as sleep efficiency and sleep latency, were correlated with executive function performance after controlling for age, gender, and education years. The short-term treatment led to improvements in inhibitory control, cognitive flexibility, and working memory. ConclusionThe findings showed that executive function was impaired among children and adolescent patients with NT1, which was associated with objective sleep parameters. Furthermore, this study emphasizes the necessity of neuropsychological assessments and early interventions among children and adolescent NT1 patients.

The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study: feasibility of long-term monitoring with Fitbit smartwatches in central disorders of hypersomnolence and extraction of digital biomarkers in narcolepsy.

The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a multicenter research initiative to identify new biomarkers in central disorders of hypersomnolence (CDH). Whereas narcolepsy type 1 (NT1) is well characterized, other CDH disorders lack precise biomarkers. In SPHYNCS, we utilized Fitbit smartwatches to monitor physical activity, heart rate, and sleep parameters over 1 year. We examined the feasibility of long-term ambulatory monitoring using the wearable device. We then explored digital biomarkers differentiating patients with NT1 from healthy controls (HC). A total of 115 participants received a Fitbit smartwatch. Using a adherence metric to evaluate the usability of the wearable device, we found an overall adherence rate of 80% over 1 year. We calculated daily physical activity, heart rate, and sleep parameters from 2 weeks of greatest adherence to compare NT1 (n = 20) and HC (n = 9) participants. Compared to controls, NT1 patients demonstrated findings consistent with increased sleep fragmentation, including significantly greater wake-after-sleep onset (p = .007) and awakening index (p = .025), as well as standard deviation of time in bed (p = .044). Moreover, NT1 patients exhibited a significantly shorter REM latency (p = .019), and sleep latency (p = .001), as well as a lower peak heart rate (p = .008), heart rate standard deviation (p = .039) and high-intensity activity (p = .009) compared to HC. This ongoing study demonstrates the feasibility of long-term monitoring with wearable technology in patients with CDH and potentially identifies a digital biomarker profile for NT1. While further validation is needed in larger datasets, these data suggest that long-term wearable technology may play a future role in diagnosing and managing narcolepsy.

Absence of specific autoantibodies in patients with narcolepsy type 1 as indicated by an unbiased random peptide-displayed phage screening.

Narcolepsy type 1 (NT1) is an enigmatic sleep disorder characterized by the selective loss of neurons producing orexin (also named hypocretin) in the lateral hypothalamus. Although NT1 is believed to be an autoimmune disease, the orexinergic neuron-specific antigens targeted by the pathogenic immune response remain elusive. In this study, we evaluated the differential binding capacity of various peptides to serum immunoglobin G from patients with NT1 and other hypersomnolence complaints (OHCs). These peptides were selected using an unbiased phage display technology or based on their significant presence in the serum of NT1 patients as identified from previous studies. Although the subtractive biopanning strategy successfully enriched phage clones with high reactivity against NT1 serum IgG, the 101 randomly selected individual phage clones could not differentiate the sera from NT1 and OHC. Compared to the OHC control group, serum from several NT1 patients exhibited increased reactivity to the 12-mer peptides derived from TRBV7, BCL-6, NRXN1, RXRG, HCRT, and RTN4 proteins, although not statistically significant. Collectively, employing both unbiased and targeted methodologies, we were unable to detect the presence of specific autoantibodies in our NT1 patient cohort. This further supports the hypothesis that the autoimmune response in NT1 patients likely stems primarily from T cell-mediated immunity rather than humoral immunity.

Effectiveness of an intervention program on physical activity in children with narcolepsy type 1

ObjectivesPhysical activity (PA) is recommended as part of the management of narcolepsy type 1 (NT1). This study aimed at 1) characterizing PA in children and adolescents treated for NT1 using objective and subjective measurements, 2) evaluating how PA is associated with NT1 symptoms and comorbidities, and 3) evaluating the effects of an Adapted Physical Activity (APA) program on PA and clinical characteristics. Patients/methodsPatients with NT1 from the National Reference Center of Narcolepsy (Lyon, France) were consecutively included in an APA intervention protocol. Narcolepsy symptoms and comorbidities were collected using standardized questionnaires and sustained attention was evaluated using the Bron-Lyon Attention Stability Test before and after the four-week APA intervention. PA was measured objectively using actigraphy throughout the study. ResultsTwenty-seven NT1 patients were included (median age 14.7 years [8.3–18.4], cataplexy 88.9%, obesity 37.0%). At baseline, 52.4% of the patients had satisfactory PA levels according to international recommendations. Patients with leisure-time PA (LTPA) showed higher quality of life than patients without. 45% of the patients increased PA during the intervention compared to baseline. These responsive patients had more depressive feelings and tended to have lower objective PA than non-responsive patients at baseline. No significant correlation was found between PA levels before and during the intervention and other clinical data. ConclusionsMost children with NT1 showed satisfying PA levels despite their daytime sleepiness. LTPA engagement was associated with higher quality of life. An APA intervention could be effective in children with narcolepsy, especially for those with depressive feelings.

Cortical thickness and sub-cortical volumes in post-H1N1 narcolepsy type 1: A brain-wide MRI case-control study

ObjectiveThere was more than a 10-fold increase in the incidence of narcolepsy type 1 (NT1) after the H1N1 mass vaccination in 2009/2010 in several countries. NT1 is associated with loss and increase of cell groups in the hypothalamus which may be associated with secondary affected sub-cortical and cortical gray matter. We performed a case-control comparison of MRI-based global and sub-cortical volume and cortical thickness in post-H1N1 NT1 patients compared with controls. MethodsWe included 54 post-H1N1 NT1 patients (51 with confirmed hypocretin-deficiency; 48 H1N1-vaccinated with Pandemrix®; 39 females, mean age 21.8 ± 11.0 years) and 114 healthy controls (77 females, mean age 23.2 ± 9.0 years). 3T MRI brain scans were obtained, and the T1-weighted MRI data were processed using FreeSurfer. Group differences among three global, 10 sub-cortical volume measures and 34 cortical thickness measures for bilateral brain regions were tested using general linear models with permutation testing. ResultsPatients had significantly thinner brain cortex bilaterally in the temporal poles (Cohen's d = 0.68, p = 0.00080), entorhinal cortex (d = 0.60, p = 0.0018) and superior temporal gyrus (d = 0.60, p = 0.0020) compared to healthy controls. The analysis revealed no significant group differences for sub-cortical volumes. ConclusionsPost-H1N1(largely Pandemrix®-vaccinated) NT1 patients have significantly thinner cortex in temporal brain regions compared to controls. We speculate that this effect can be partly attributed to the hypothalamic neuronal change in NT1, including loss of function of the widely projecting hypocretin-producing neurons and secondary effects of the abnormal sleep-wake pattern in NT1 or could be specific for post-H1N1 (largely Pandemrix®-vaccinated) NT1 patients.

The Changed Nocturnal Sleep Structure and Higher Anxiety, Depression, and Fatigue in Patients with Narcolepsy Type 1.

This study aimed to evaluate nocturnal sleep structure and anxiety, depression, and fatigue in patients with narcolepsy type 1 (NT1). Thirty NT1 patients and thirty-five healthy controls were enrolled and evaluated using the Epworth sleepiness scale (ESS), Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, Fatigue Severity Scale (FSS), polysomnography, multiple sleep latency test, and brain function state monitoring. Statistical analyses were performed using SPSS Statistics for Windows, version 23.0. Benjamini-Hochberg correction was performed to control the false discovery rate. Apart from typical clinical manifestations, patients with NT1 are prone to comorbidities such as nocturnal sleep disorders, anxiety, depression, and fatigue. Compared with the control group, patients with NT1 exhibited abnormal sleep structure, including increased total sleep time (P adj=0.007), decreased sleep efficiency (P adj=0.002), shortening of sleep onset latency (P adj<0.001), elevated wake after sleep onset (P adj=0.002), increased N1% (P adj=0.006), and reduced N2%, N3%, and REM% (P adj=0.007, P adj<0.001, P adj=0.013). Thirty-seven percent of patients had moderate to severe obstructive sleep apnea-hypopnea syndrome. And sixty percent of patients were complicated with REM sleep without atonia. Patients with NT1 displayed increased anxiety propensity (P adj<0.001), and increased brain fatigue (P adj=0.020) in brain function state monitoring. FSS scores were positively correlated with brain fatigue (P adj<0.001) and mean sleep latency was inversely correlated with FSS scores and brain fatigue (P adj=0.013, P adj=0.029). Additionally, ESS scores and brain fatigue decreased after 3 months of therapy (P=0.012, P=0.030). NT1 patients had abnormal nocturnal sleep structures, who showed increased anxiety, depression, and fatigue. Excessive daytime sleepiness and fatigue improved after 3 months of treatment with methylphenidate hydrochloride prolonged-release tablets in combination with venlafaxine.

SPHYNCS: The Use of the Swiss Narcolepsy Scale in a New Cohort of Patients with Narcolepsy and Its Borderland and Review of the Literature

Introduction and aims: Narcolepsy type 1 (NT1) is a central disorder of hypersomnolence (CDH) characterized by excessive daytime sleepiness and cataplexy. The Swiss Narcolepsy Scale (SNS), which includes the updated and short (sSNS) versions, has recently been introduced as a reliable diagnostic tool for identifying NT1. This study aims to assess the validity of the SNS scales in a new cohort of patients with CDH, while also introducing the French and Italian versions of the SNS and providing a summary of the existing literature on SNS. Materials and methods: The current study is based on the international Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (iSPHYNCS) which aims to identify new biomarkers for CDH. Diagnostic accuracy of the SNS was assessed by calculating sensitivity, specificity, positive predictive value, and negative predictive value. Results: In our population, 108 participants with suspected CDH (including 28 NT1 patients) and 14 healthy controls completed the scale. Original SNS, updated SNS and sSNS scores showed a high sensitivity (86%, 89% and 79%, respectively) and high specificity (96%, 90% and 95%, respectively) for diagnosing NT1 compared to other CDH. The French version was completed by 5 participants, and the Italian version by 8 participants. Regarding previous studies, the SNS has now been assessed in six different populations, involving a total of 1247 subjects (including 326 with narcolepsy with cataplexy/NT1), suggesting high sensitivity (85–100%) and specificity (86–100%) of the SNS for the diagnosis of NT1. Conclusion: The SNS is a simple screening tool validated in seven languages (German, English, French, Italian, Dutch, Turkish and Japanese), demonstrating high sensitivity and specificity for the diagnosis of NT1.

Quality of life in adolescents with narcolepsy type 1– a transversal study in a tertiary hospital

Purpose– Narcolepsy type 1 (NT1) is a rare chronic sleep disorder, usually arising by adolescence that negatively impacts quality of life. It is characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis and sleep fragmentation. The goals of this work were to characterize NT1 adolescents regarding sleep characteristics, health-related quality of life (HRQoL) and future life perspectives and later to compare this group with a control group of healthy adolescents (HA). Methods– Transversal descriptive/analytical study including NT1 patients followed in a sleep center of a tertiary hospital and 23 HA. Data were collected through an online survey, fulfilled by the participants, including four sections: demographics; questionnaire evaluating sleep and EDS; questionnaire evaluating HRQoL; inquiry regarding future perspectives. An extra section for the NT1 group only, comprising questions about the characterization of narcolepsy, was included. Results22 NT1 adolescents were included, with a median age of 15.0 years-old. Beyond EDS, all had presented cataplexy - 19 still reported it. Twenty patients took psychostimulants regularly for EDS, while 13 patients took venlafaxine or fluoxetine for cataplexy. Nineteen adolescents took regular naps and 19 maintained psychological appointments. Self-reported sleep quality was similar between groups (p = 0.112). EDS was identified in seven NT1 patients and none in the control group. HRQOL was significantly lower in NT1 patients only for the physical well-being domain (p = 0.001). Regarding future perspectives, results were similar, except for a lower probability of getting a driver's license in NT1 patients, despite no statistical significance (p = 0.104). DiscussionDaytime sleepiness is difficult to control in NT1, despite specialized treatment. HRQoL was similar between groups in all domains except for the physical well-being. Despite good adherence to pharmacological and non-pharmacological treatments (namely psychological therapy) that account for these good results, the physical well-being domain is difficult to manage.

LC-MS/MS Quantitation of HILIC-Enriched N-glycopeptides Derived from Low-Abundance Serum Glycoproteins in Patients with Narcolepsy Type 1.

Glycoproteomic analysis is always challenging because of low abundance and complex site-specific heterogeneity. Glycoproteins are involved in various biological processes such as cell signaling, adhesion, and cell-cell communication and may serve as potential biomarkers when analyzing different diseases. Here, we investigate glycoproteins in narcolepsy type 1 (NT1) disease, a form of narcolepsy characterized by cataplexy-the sudden onset of muscle paralysis that is typically triggered by intense emotions. In this study, 27 human blood serum samples were analyzed, 16 from NT1 patients and 11 from healthy individuals serving as controls. We quantified hydrophilic interaction liquid chromatography (HILIC)-enriched glycopeptides from low-abundance serum samples of controls and NT1 patients via LC-MS/MS. Twenty-eight unique N-glycopeptides showed significant changes between the two studied groups. The sialylated N-glycopeptide structures LPTQNITFQTESSVAEQEAEFQSPK HexNAc6, Hex3, Neu5Ac2 (derived from the ITIH4 protein) and the structure IVLDPSGSMNIYLVLDGSDSIGASNFTGAK HexNAc5, Hex4, Fuc1 (derived from the CFB protein), with p values of 0.008 and 0.01, respectively, were elevated in NT1 samples compared with controls. In addition, the N-glycopeptide protein sources Ceruloplasmin, Complement factor B, and ITH4 were observed to play an important role in the complement activation and acute-phase response signaling pathways. This may explain the possible association between the biomarkers and pathophysiological effects.

Exploring the emotional and behavioural profile in paediatric narcolepsy type 1: A case-control study.

Narcolepsy type 1 (NT1) is a central disorder of hypersomnolence often arising in childhood and adolescence. NT1 has a significant, but poorly defined, psychological impact. We aimed to investigate the psycho-social functioning of children and adolescents with NT1. We performed a cross-sectional, child and parent-reported questionnaire survey in 37 children and adolescents (6-17 years) with NT1, compared with age- and sex-matched controls. Questionnaires (SSHS, ESS-CHAD, CDI, MASC, CBCL, CRS-R, and SNAP-IV) evaluated various aspects of behavioural and emotional profiles, sleep habits, and daytime sleepiness. Subsequently, NT1 intra-group analysis was performed to investigate the effect of sex (males vs females) and pharmacological treatment (treated vs non-treated) on psychological features. The NT1 questionnaires total scores were then correlated with the clinical characteristics (age, body mass index [BMI], ESS-CHAD score, cerebrospinal hypocretin-1 [Hcrt-1] levels, and diagnostic delay). Patients with NT1 showed a higher tendency to depressive symptoms, anxiety, somatisation, inattention, hyperactivity, oppositional/defiant problems, and other maladaptive behaviours compared with controls. Among NT1 patients, females showed a higher propensity to anxiety, and non-treated patients displayed higher depressive symptoms. Psychological symptoms increased with age, BMI, and daytime sleepiness in patients with NT1, while a younger age was associated with more frequent somatisation symptoms. Lower cerebrospinal Hcrt-1 levels correlated with poorer social competencies, daily activities, and inattention. Diagnostic delay was associated with a higher impact of depressive symptoms and behavioural problems. NT1 in children and adolescents is associated with poorer functioning in multiple psychological domains calling for a multidisciplinary approach and monitoring to reduce disease burden and to prevent psychiatric consequences.

A preliminary study investigating the clinical potential of measuring cerebrospinal-fluid lactate levels in patients with narcolepsy type 1 and 2

Study objectivesBesides the quantification of orexin-A/hypocretin-1 cerebrospinal fluid (CSF) levels in narcolepsy for diagnostic purposes, several other CSF biomarkers have been evaluated, although with controversial results. Since CSF lactate concentrations fluctuate according to the sleep-wake cycle with higher levels during wakefulness and lower levels during sleep, as documented in animal model studies, the present study aimed at quantifying the CSF lactate levels in patients with narcolepsy type 1 (NT1) and 2 (NT2), which are two sleep disorders featured by excessive daytime sleepiness (EDS). MethodsPatients with NT1 and NT2 were enrolled in this study and compared to a control group of similar age and sex. All the subjects included in the study underwent a polysomnographic study followed by lumbar puncture for the quantification of CSF lactate levels at awakening. Results23 NT1 (43.5 % male; 36.43 ± 11.89 years) and 15 NT2 patients (46.7 % male; 37.8 ± 14.1 years) were compared to 17 controls (58.8 % male; 32.3 ± 8.4 years). CSF lactate concentrations were reduced in patients with NT1 and NT2 compared to controls but no differences were found between the two groups of patients. ROC curves analysis showed that CSF lactate ≤1.3 mmol/l had a sensitivity of 96.49 and a specificity of 82.35 % for discriminating patients with narcolepsy from controls. ConclusionsThe present study showed a decrease in CSF lactate levels in patients with narcolepsy. Notably, the reduction of lactate levels was present in both NT1 and NT2 patients, independently of CSF orexin levels. Narcolepsy patients present EDS with daytime napping and REM-related episodes, possibly substantiating the CSF lactate levels reduction related to the impaired daytime wakefulness which was demonstrated in animal studies. Moreover, CSF lactate levels present a good sensitivity and adequate specificity for differentiating narcolepsy from controls. Further studies are needed to understand the role of CSF lactate and its usefulness for monitoring daytime vigilance in patients with narcolepsy.

Serum metabolomics study of narcolepsy type 1 based on ultra-performance liquid chromatography–tandem mass spectrometry

Narcolepsy is a chronic and underrecognized sleep disorder characterized by excessive daytime sleepiness and cataplexy. Furthermore, narcolepsy type 1 (NT1) has serious negative impacts on an individual's health, society, and the economy. Currently, many sleep centers lack the means to measure orexin levels in the cerebrospinal fluid. We aimed to analyze the characteristics of metabolite changes in patients with NT1, measured by ultra-performance liquid chromatography–tandem mass spectrometry. A principal component analysis (PCA), an orthogonal partial least square discriminant analysis (OPLS-DA), t tests, and volcano plots were used to construct a model of abnormal metabolic pathways in narcolepsy. We identified molecular changes in serum specimens from narcolepsy patients and compared them with control groups, including dehydroepiandrosterone, epinephrine, N-methyl-D-aspartic acid, and other metabolites, based on an OPLS-loading plot analysis. Nine metabolites yielded an area under the receiver operating curve > 0.75. Meanwhile, seven abnormal metabolic pathways were correlated with differential metabolites, such as metabolic pathways; neuroactive ligand‒receptor interaction; and glycine, serine, and threonine metabolism. To our knowledge, this is the first study to reveal the characteristic metabolite changes in sera from NT1 patients for the selection of potential blood biomarkers and the elucidation of NT1 pathogenesis.

Phenomenology and psychiatric correlates of pseudocataplexy.

Pseudocataplexy is a rare functional neurological disorder that mimics cataplexy, pathognomonic for narcolepsy type 1 (NT1). We describe the psychiatric comorbidity and personality traits of patients with pseudocataplexy versus NT1 cases. The case-control observational study enrolled consecutive patients with pseudocataplexy and a control group of age-matched consecutive NT1 patients. The diagnostic work-up included a structured interview, 48-hour polysomnography, multiple sleep latency test, cataplexy provoking test, and hypocretin-1 measurement in cerebrospinal fluid.All participants were administered Beck Depression Inventory, State-Trait Anxiety Inventory, Patient Health Questionnaire-15 (PHQ-15), Personality Inventory for DSM-5 brief form, and quality of life (QoL) measurement by 36-item Short Form health survey (SF-36). Fifteen patients with pseudocataplexy and 30 with NT1 were included. Despite the suspicion of possible cataplexy, none of the pseudocataplexy participants fulfilled international diagnostic criteria for NT1. Pseudocataplexy patients presented higher rates of moderate state anxiety (40% vs. 10%, p=0.018), medium level of somatic symptoms, defined by PHQ-15 score >10 (66.7% vs. 16.7%, p=0.003), and a trend towards moderate-to-severe depressive symptoms (33.3% vs. 10%, p=0.054) compared to NT1. No significant differences in personality traits emerged. Pseudocataplexy patients had worse QoL profile in almost all SF-36 domains including physical (mean±SD: 37.7±9.88 vs. 51.13±7.81, p<0.001) and mental (mean±SD: 33.36±12.69 vs.42.76±11.34, p=0.02) summary scores. Patients with pseudocataplexy present more severe psychiatric symptoms and a lower QoL profile in comparison with patients with NT1. The severe somatoform and affection impairment in pseudocataplexy may explain the poorer QoL and should require a tailored therapeutic approach.

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.