Hypocretin-1 Levels Research Articles

Teaching NeuroImage: Hypothalamic Involvement in Neuromyelitis Optica Spectrum Disorder in a Child.

A 10-year-old girl presented with a 15-day history of excessive daytime sleepiness and sudden sleep onset, hypnagogic hallucinations, hyporexia, and behavioral changes. An MRI examination of the brain revealed a bilateral hypothalamic lesion (Figure). We found positive AQP4 -IgG antibodies in serum and low hypocretin levels (93 pg/mL) in the CSF. A diagnosis of narcolepsy secondary to neuromyelitis optica spectrum disorder was made. She improved after glucocorticoid administration. After 10 months of immunosuppressive maintenance therapy with azathioprine, she remains asymptomatic without new lesions in the follow-up neuroimages. Any diencephalic clinical syndrome, such as narcolepsy, with hypothalamic involvement, should prompt a serum test for AQP4 -IgG.1,2

Narcolepsy.

This article addresses the clinical presentation, diagnosis, pathophysiology and management of narcolepsy type 1 and 2, with a focus on recent findings. A low level of hypocretin-1/orexin-A in the cerebrospinal fluid is sufficient to diagnose narcolepsy type 1, being a highly specific and sensitive biomarker, and the irreversible loss of hypocretin neurons is responsible for the main symptoms of the disease: sleepiness, cataplexy, sleep-related hallucinations and paralysis, and disrupted nocturnal sleep. The process responsible for the destruction of hypocretin neurons is highly suspected to be autoimmune, or dysimmune. Over the last two decades, remarkable progress has been made for the understanding of these mechanisms that were made possible with the development of new techniques. Conversely, narcolepsy type 2 is a less well-defined disorder, with a variable phenotype and evolution, andfew reliable biomarkers discovered so far. There is a dearth of knowledge about this disorder, and its aetiology remains unclear and needs to be further explored. Treatment of narcolepsy is still nowadays only symptomatic, targeting sleepiness, cataplexy and disrupted nocturnal sleep. However, new psychostimulants have been recently developed, and the upcoming arrival of non-peptide hypocretin receptor-2 agonists should be a revolution in the management of this rare sleep disease, and maybe also for disorders beyond narcolepsy.

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.

Neuroanatomical and Etiological Approaches to Secondary Narcolepsy

Narcolepsy is one among the disorders of central hypersomnolence characterized by excessive daytime sleepiness not related to disturbances in nocturnal sleep or misalignment in circadian rhythms. The cardinal symptom of this group of disorders is disabling daytime sleepiness, characterized by the repeated episodes of irresistible daytime sleepiness or lapses into sleep in monotonous situations, but also under unusual conditions such as eating. Narcolepsy is defined as type 1 and type 2 on the basis of the presence of cataplexy. The most pathognomonic feature of narcolepsy type 1 is cataplexy, which is characterized by sudden episodes of brief loss of muscle tone-sparing consciousness, usually triggered by strong emotions. Other nonspecific symptoms associated with rapid eye movement sleep dissociation include fragmentation of nocturnal sleep, hypnagogic or hypnopompic hallucinations, and sleep paralysis. The pathophysiology of narcolepsy type 1 is well established as the deficiency of hypocretin (orexin) signaling in the lateral hypothalamus. In narcolepsy type 2, on the other hand, hypocretin levels are not decreased, and it has been suggested that there is probably a partial deficiency in hypocretin signaling system to cause excessive daytime sleepiness but not severe enough to cause cataplexy. Instead of types 1 and 2, primary (idiopathic) narcolepsy, familial narcolepsy, secondary (symptomatic) narcolepsy, and narcolepsy plus (hereditary forms with additional neurological symptoms) forms were suggested to better classify the clinical entities. In this paper, the diagnosis of symptomatic or secondary narcolepsy is reviewed and classified based on the underlying pathophysiologic mechanisms.

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.

Increased Hypocretin (Orexin) Plasma Level in Depression, Bipolar Disorder Patients.

As hypocretin can markedly affect neurophysiological and behavioural processes in mood disorders. However, few studies have measured changes in hypocretin levels in patients with mood disorders. We estimated the hypocretin-1 plasma levels in mood disorder patients and controls (CON) using an enzyme-linked immunosorbent assay. Results: (i) The hypocretin-1 plasma level was significantly higher in major depressive disorder (MDD) patients [59.04 (35.78–80.12) pg/ml, P < 0.001] and bipolar disorder (BD) patients [65.50 (58.46–74.57) pg/ml, P < 0.001] patients than in CON [49.25 (28.51–80.40) pg/ml]. Moreover, the plasma hypocretin-1 levels in the BD group were significantly higher than those in the MDD group (P < 0.001). (ii). In the MDD group, patients with higher suicidal ideation had higher hypocretin-1 levels [62.09 (38.23–80.12) pg/ml] than those with lower suicidal ideation [59.63 (35.79–77.37) pg/ml), P = 0.032]. (iii). Plasma hypocretin-1 levels were increased in both female and male mood disorder patients compared to CON [male: MDD 60.51 (35.79–80.12) pg/ml; BD 65.40 (58.76–74.14) pg/ml; CON 45.63 (28.51–62.05) pg/ml; all P < 0.016; female: MDD 57.37 (34.59–80.40) pg/ml; BD 65.61 (58.46–74.57) pg/ml; CON 52.92 (38.23–78.89) pg/ml; all P < 0.015]. (iv). In CON, we found a significant negative correlation between plasma hypocretin-1 levels and age (rho = −0.251, P = 0.032), while this negative correlation was absent in the MDD and BD groups. Limitations may partly arise from the relatively small sample size and the medication history of patients participating in our research. We concluded that the clear changes found in plasma hypocretin-1 levels might be applied in the diagnosis of depression and the differential diagnosis of MDD and BD. The clear suicidal-ideation-related change found in hypocretin-1 levels in depression might be taken into account in the prevention of suicidal behaviour and further study of hypocretin-targeted therapies.

The Relationship between Plasma Hypocretin Levels and Sleep Disorders in Patients with Parkinson's Disease

Introduction: There are many areas of brain degeneration in people with Parkinson's disease. The dopaminergic degeneration process in the midbrain causes early symptoms of sleep disturbances. Hypocretin produced by the hypothalamus is involved in the pathophysiology of Parkinson's disease. Some research results regarding the relationship between plasma hypocretin levels and sleep disorders in patients with Parkinson's disease are still controversial.&#x0D; Method: This research is a cross sectional study in Neurology Polyclinic Dr. M. Djamil Padang and Network Hospital. All research subjects measured hypocretin levels and sleep disorders using the Epworth Sleepiness Scale. Statistical analysis was performed on a computerized basis using IBM SPSS statistics version 23.0 for windows.&#x0D; Result: A total of 60 patients with Parkinson's disease were included in this study, 30 subjects experienced sleep disorders and 30 others had no sleep disorders. There was a significant difference in lower plasma hypocretin levels in the Parkinson's group with sleep disorders, namely 81.817 ± 22.770 and in the group without sleep disorders, plasma hypocretin levels were found to be 255.416 ± 226.590 (p = 0.000). There was no statistical difference in clinical degree, age, duration of illness between the Parkinson's group with sleep disorders and the group without sleep disorders p &gt; 0.05.&#x0D; Conclusion: There is a significant difference in hypocretin levels against the sleep disorder group in people with Parkinson's disease. In this study, there was no association between age, clinical degree of Parkinson's disease, and duration of Parkinson's disease and sleep disturbances. Degeneration in the olfactory bulb area, hypothalamus, and brainstem can precede dopaminergic degeneration in the midbrain and cause sleep disturbance symptoms.

The Relationship between Plasma Hypocretin Levels and Sleep Disorders in Patients with Parkinson's Disease

Introduction: There are many areas of brain degeneration in people with Parkinson's disease. The dopaminergic degeneration process in the midbrain causes early symptoms of sleep disturbances. Hypocretin produced by the hypothalamus is involved in the pathophysiology of Parkinson's disease. Some research results regarding the relationship between plasma hypocretin levels and sleep disorders in patients with Parkinson's disease are still controversial.&#x0D; Method: This research is a cross sectional study in Neurology Polyclinic Dr. M. Djamil Padang and Network Hospital. All research subjects measured hypocretin levels and sleep disorders using the Epworth Sleepiness Scale. Statistical analysis was performed on a computerized basis using IBM SPSS statistics version 23.0 for windows.&#x0D; Result: A total of 60 patients with Parkinson's disease were included in this study, 30 subjects experienced sleep disorders and 30 others had no sleep disorders. There was a significant difference in lower plasma hypocretin levels in the Parkinson's group with sleep disorders, namely 81.817 ± 22.770 and in the group without sleep disorders, plasma hypocretin levels were found to be 255.416 ± 226.590 (p = 0.000). There was no statistical difference in clinical degree, age, duration of illness between the Parkinson's group with sleep disorders and the group without sleep disorders p &gt; 0.05.&#x0D; Conclusion: There is a significant difference in hypocretin levels against the sleep disorder group in people with Parkinson's disease. In this study, there was no association between age, clinical degree of Parkinson's disease, and duration of Parkinson's disease and sleep disturbances. Degeneration in the olfactory bulb area, hypothalamus, and brainstem can precede dopaminergic degeneration in the midbrain and cause sleep disturbance symptoms.

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.

2018 worldwide survey of health-care providers caring for patients with narcolepsy: WSS narcolepsy task force

BackgroundThere are limited data available on regional differences in the diagnosis and management of narcolepsy. In order to better understand worldwide trends in clinical assessment and management of narcolepsy, a survey of health-care providers was conducted by the World Sleep Society Narcolepsy task force. MethodsA total of 146 surveys that included items on the diagnosis and management of narcolepsy were completed by practitioners representing 37 countries. ResultsMost of the participants were from Europe, North America, Oceania, Asia and Latin America. A consistent approach to applying the diagnostic criteria of Narcolepsy was documented with the exception of measurement of CSF hypocretin-1, which has limited availability. While the majority of practitioners (58%) reported not using the test, 1% indicated always evaluating CSF hypocretin-1 levels. There was much variability in the availability of currently recommended medications such as sodium oxybate and pitolisant; modafinil and antidepressants were the most commonly used medications. Amphetamines were unavailable in some countries. ConclusionThe results of the study highlight clinical and therapeutic realities confronted by worldwide physicians in the management of narcolepsy. While the diagnostic criteria of narcolepsy rely in part on the quantification of CSF hypocretin-1, few physicians reported having incorporated this test into their routine assessment of the condition. Regional differences in the management of narcolepsy appeared to be related to geographic availability and expense of the therapeutic agents.

Cerebrospinal Fluid Hypocretin and Nightmares in Dementia Syndromes

Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia. Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments. Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming. Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.

Growing Ignorance of COVID-19 Preventive Measures in Ethiopia: Experts' Perspective on the Need of Effective Health Communication Strategies.

Despite the recent surge of COVID-19 infections in Ethiopia, we are observing a profound ignorance of preventive measures by the general public and leaders at different levels. This is presenting considerable challenges in the effort to contain and control the pandemic. We believe that the current health communication approach implemented by the health authorities and media outlets need to be redesigned to bring a sustainable COVID-19 preventive behavior. The purpose of this perspective paper, therefore, is to stimulate discussions on effective health communication strategy to help the public persistently practice COVID-19 preventive measures over the long term. We undertook a series of discussions amongst the authors in order to synthesize individual viewpoints into 'experts' perspective' driven by our daily observations and our expertise in the health service research. In light of this, we suggested that an effective health communication strategy need to address context specific situations to avoid temptation to ignore the ramifications of this very serious pandemic. This strategy includes trying to make sense of daily reported COVID-19 cases, being highly selective regarding sources of information, and being sensitive and responsive to religious and cultural factors. The media, health professionals, and leaders need to teach us how to live with the pandemic informed by robust scientific sources.

Single center analysis of patients with H1N1 vaccine-related narcolepsy and sporadic narcolepsy presenting over the same time period.

We aimed to describe the clinical features of narcolepsy in patients referred to our sleep center between 2009 and 2016, and to compare these features across age groups and between sporadic vs AS03-adjuvanted H1N1 influenza vaccine-related patients. This is a retrospective, consecutive study of adult and pediatric narcolepsy patients in the Republic of Ireland. All participants underwent structured assessments, including polysomnography and the Multiple Sleep Latency Test. Brain magnetic resonance imaging, hypocretin levels, and human leukocyte antigen typing were also carried out on the majority of patients. Patients were compared across age groups as well as etiology. The conditions of 40 (74%) patients were vaccine-related. The median age was 13.5 years and time from symptom onset to diagnosis was 112 weeks. Median time from vaccination to symptom onset was 26 weeks. In children, hypnogogic hallucinations and sleep paralysis were less frequent than in adults (17% vs 67%, P = .018 and 0% vs 75%, P < .0005). Sleep latency determined by the Multiple Sleep Latency Test was shorter in children than adults (median 1.75 vs 4 minutes, P = .011). Patients with vaccine-related and sporadic narcolepsies had typical clinical presentations. Vaccine-related patients had longer polysomnography latency (median 10.5 vs 5 minutes, P = .043), longer stage N2 sleep (209.6 ± 44.6 vs 182.3 ± 34.2 minutes, P = .042), and a trend toward longer total sleep times (P = .09). No differences were noted in relation to Multiple Sleep Latency Test, hypocretin, human leukocyte antigen typing, and magnetic resonance imaging. Results show that vaccine-related patients greatly outnumbered sporadic patients during the study period and suggest that sporadic and vaccine-related narcolepsy are clinically similar entities.

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.

Lipocalin-type prostaglandin D synthase levels increase in patients with narcolepsy and idiopathic hypersomnia.

Excessive daytime sleepiness (EDS) is a frequent cause for consultation and a defining symptom of narcolepsy and idiopathic hypersomnia (IH). The associated mechanisms remain unclear. Lipocalin-type prostaglandin D synthase (LPGDS) is a plausible sleep-inducing candidate. This study is to compare cerebral spinal fluid (CSF) and serum LPGDS levels in patients group with hypersomnia of central origin, including those with narcolepsy type 1 (NT1) and type 2 (NT2) and IH, to those in healthy controls (Con). Serum LPGDS, CSF LPGDS, and CSF hypocretin-1(Hcrt-1) levels were measured by ELISA in 122 narcolepsy patients (106 NT1 and 16 NT2), 27 IH, and 51Con. LPGDS levels in CSF (p = 0.02) and serum (p < 0.001) were 22%-25% lower in control subjects than in patients with EDS complaints, including NT1, NT2, and IH. In contrast to significant differences in CSF Hcrt-1 levels, CSF L-PGDS levels and serum L-PGDS were comparable among NT1, NT2, and IH (p > 0.05), except for slightly lower serum LPGDS in IH than in NT1 (p = 0.01). Serum L-PGDS correlated modestly and negatively to sleep latency on MSLT (r = -0.227, p = 0.007) in hypersomnia subjects. As a somnogen-producing enzyme, CSF/serum LPGDS may serve as a new biomarker for EDS of central origin and imply a common pathogenetic association, but would complement rather than replaces orexin markers.

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.

Linking peripheral IL-6, IL-1β and hypocretin-1 with cognitive impairment from major depression

BackgroundCognitive impairment has long challenged the patients with major depressive disorder (MDD), hypocretins and inflammation have recently been implicated in cognitive function. However, limited studies have compressively assessed their associations with cognitive impairment in MDD. MethodsA total of 100 MDD patients and 100 healthy controls (HC) were recruited for this study. They were tested with HAMD, HAMA, and MCCB scales. The plasma level of selected inflammatory factors (IL-1β, IL-6, and TNF-α) and hypocretin-1 were determined using enzyme-linked immunosorbent assay (ELISA). Correlation analysis was performed to explore the relationship between the plasma level of the factors and clinical performances. ResultsPatients with MDD showed cognitive impairment in each MCCB subdomain except working memory compared with HC. The levels of IL-6, IL-1β and hypocretin-1 in MDD patients were higher than HC. Besides, IL-1β levels was negatively correlated with overall cognitive function in the combined group. Hypocretin-1 was positively correlated with socially cognitive impairment in MDD patients. A negative correlation between plasma hypocretin-1 levels and HAMA scales was also observed in MDD patients. LimitationThe study was cross-sectional, thereby limiting causal inference, and had a relatively small sample size. There are no subcategories for MDD based on characteristics. ConclusionIL-1β, IL-6 and Hypocretin-1 were reported as potential factors involved in MDD pathology. Hypocretin-1 could contribute to the biological mechanisms of anxiety relief. Hypocretin-1, therefore, may be important in exploring the pathological mechanisms of social cognitive impairment in MDD patients. Conclusively, this study provides new insights for exploring cognitive impairment in depression.

High prevalence of ADHD symptoms in unmedicated youths with post-H1N1 narcolepsy type 1

ObjectivesTo characterize attention deficit-hyperactivity disorder (ADHD) symptoms in unmedicated post-H1N1 narcolepsy type 1 (NT1) youths, and explore associations between ADHD symptoms and the narcolepsy phenotype. MethodsA total of 50 consecutively enrolled post-H1N1 NT1 youths (7–20 years, 62% females, 98% HLA-DQB1∗06:02-positive, 98% CSF hypocretin-1 deficient, 88% vaccinated) were assessed after two weeks off medication for ADHD (ADHD diagnosis pre/post-narcolepsy, parent-rated ADHD symptoms) and narcolepsy-phenotyped (semi-structured interview, Stanford Sleep Questionnaire, Epworth Sleepiness Scale, polysomnography (PSG), Multiple Sleep Latency Test (MSLT)). ResultsIn sum, 26 (52%) and 15 (30%) of participants had ADHD symptoms above and below the clinical significant cut-off, respectively, while 9 (18%) had no ADHD symptoms. High values were found for ADHD total score (mean (SD), 17.9 (9.5)) and ADHD subscores (inattentive score, 11.0 (6.3); hyperactive/impulsivity score, 6.9 (4.7)). These were significantly higher than previously reported in a mainly medicated narcolepsy cohort (p < 0.0001). Age, gender and disease duration did not influence scores. Two participants (4%) had ADHD diagnosis prior to narcolepsy onset. ADHD symptoms were correlated with parent-rated, but not with patient rated ESS scores, objective sleepiness (mean sleep latency), sleep fragmentation (sleep stage shift index, awakening index), or CSF hypocretin-1 level. ConclusionComorbid ADHD symptoms were more prevalent in unmedicated post-H1N1 NT1 youths than previously reported in mainly medicated pediatric narcolepsy cohorts. The high prevalence was not due to pre-existing ADHD and generally not correlated with core narcolepsy sleep/wake phenotype characteristics, indicating that the ADHD symptoms were not a direct consequence of disturbed sleep or daytime sleepiness.

1261 The Long Term Exhaustion of a Viral Infection

Abstract Introduction Narcolepsy is a rare condition affecting only 0.02% to 0.18% of United States and Euro-pean populations. Throughout the years, hypersomnolence in the form of narcolepsy or idiopathic hypersomnia has been identified as a post infectious syndrome in rare instances. In this case, we observe a child with excessive daytime sleepiness after an infectious rash. Report of Case A 4 year old male presented to clinic for evaluation of excessive daytime sleepiness for the past 10 months. At that time, he developed a full body rash that lasted for about 1 week, and was treated with diphenhydramine and prednisone. No imminent cause was identified. For the preced-ing weeks, he was taking frequent and longer naps, and complained of difficulty with keeping his head up and his eyes open. He was evaluated for possible seizures via EEG with no seizure activity seen. Blood work was unremarkable, and a lumbar puncture showed highly elevated IgG for EBV, and low IgM for EBV, indicating a prior infection. His excessive somnolence persistent, and he was referred to undergo actigraphy, poly-somnography (PSG), and a multiple sleep latency test (MSLT). Actigraphy demonstrated disrupt-ed nocturnal sleep, PSG showed an elevated periodic leg movement index of 8.6/hr, and MSLT showed reduced sleep onset latency and sleep onset REM on 2 of 4 naps. During his physical exam, he had drooping eyelids and tongue protrusion, concerning for cataplectic facies, highly suspicious for Narcolepsy Type 1. Further confirmatory testing is pend-ing, including HLA subtype testing and hypocretin levels in CSF. Conclusion This case shows a strong association with a subacute EBV infection and the development of nar-colepsy. There are multiple cases involving the development of hypersomnolence conditions as a consequence of viral infections. Further cases would be beneficial to form additional associations.