Narcolepsy: an interface among neurology, immunology, sleep, and genetics.

Narcolepsy is a primary disorder of the central nervous system resulting from genetic, environmental, and immunological interactions defined as excessive daytime sleepiness plus cataplexy, hallucinations, sleep paralysis, and sleep fragmentation. The pathophysiology is not entirely known, but the interaction among genetic predisposition, environmental exposition, and immune component with consequent hypocretin-1 deficiency is the model to explain narcolepsy type I. The mechanism of narcolepsy type II is less understood. There is a delay of over ten years for the diagnosis of narcolepsy around the world. Patients with narcolepsy have many comorbidities with a negative impact on quality of life. The treatment of narcolepsy must contain an educational approach for the family, coworkers, and patients. Scheduled naps and sleep hygiene are essential to minimize the dose of medications. Much progress has been seen in the pharmacological treatment of narcolepsy with new stimulants, different presentations of oxybate, and recent studies with orexin agonists. Narcolepsy is a rare disease that needs to be more understood and highlighted to avoid delayed diagnosis and severe disabilities in patients.

A narcolepsia é um distúrbio primário do sistema nervoso central resultante das interações genéticas, ambientais e imunológicas definidas como sonolência diurna excessiva mais cataplexia, alucinações, paralisia do sono e fragmentação do sono. A fisiopatologia não é completamente conhecida, mas a interação entre predisposição genética, exposição ambiental e componente imunológico com consequente deficiência de hipocretina-1 é o modelo para explicar a narcolepsia tipo I. O mecanismo da narcolepsia tipo II é menos compreendido. Há um atraso de mais de dez anos para o diagnóstico da narcolepsia em todo o mundo. Pacientes com narcolepsia apresentam muitas comorbidades com impacto negativo na qualidade de vida. O tratamento da narcolepsia deve conter uma abordagem educativa para a família, colegas de trabalho e pacientes. Cochilos programados e higiene do sono são importantes para minimizar a dose dos medicamentos. Muito progresso foi observado no tratamento farmacológico da narcolepsia com novos estimulantes, diferentes apresentações de oxibato e estudos recentes com agonistas de orexina. A narcolepsia é uma doença rara que precisa ser mais compreendida e destacada para evitar atrasos no diagnóstico e incapacidades graves nos pacientes.

A vertebrate family without a functional Hypocretin/Orexin arousal system.

The Hypocretin/Orexin signaling pathway suppresses sleep and promotes arousal, whereas the loss of Hypocretin/Orexin results in narcolepsy, including the involuntary loss of muscle tone (cataplexy).1 Here, we show that the South Asian fish species Chromobotia macracanthus exhibits a sleep-like state during which individuals stop swimming and rest on their side. Strikingly, we discovered that the Hypocretin/Orexin system is pseudogenized in C. macracanthus, but in contrast to Hypocretin-deficient mammals, C. macracanthus does not suffer from sudden behavioral arrests. Similarly, zebrafish mutations in hypocretin/orexin show no evident signs of cataplectic-like episodes. Notably, four additional species in the Botiidae family also lack a functional Hypocretin/Orexin system. These findings identify the first vertebrate family that does not rely on a functional Hypocretin/Orexin system for the regulation of sleep and arousal.

Making sense of narcolepsy: A qualitative exploration of how persons with narcolepsy perceive symptoms and their illness experience.

INTRODUCTION: Understanding how persons with narcolepsy conceptualize symptoms, daily impact and illness experience is key to facilitating dialogue between patients and healthcare professionals. These concepts are usually explored from the perspective of healthcare professionals/researchers and rarely from the perspective of those with narcolepsy. METHODS: 127 self-reported persons with narcolepsy were recruited from an Australian patient support group. A short demographic survey was completed. All agreed to participate in a subsequent 1:1 semi-structured interview. Saturation was reached after 24 interviews (mean age = 33 years (SD 11) with 44% reporting cataplexy). A multidisciplinary team of researchers/clinicians analyzed interview transcripts using thematic analysis. RESULTS: Participants perceived physical fatigue, sleepiness, and two separate experiences of 'falling asleep/sleep attacks' as distinct symptoms rather than a multidimensional construct (i.e. excessive daytime sleepiness). We also identified two experiences of cataplexy, one triggered by acute emotion and another by a stressor. Participants determined their narcolepsy to be 'well-managed' by the level of functional impairment rather than the frequency of any symptom. Almost all participants described experiencing anticipated stigma and internalized or 'self-' stigma, likely stemming from societal devaluation of sleep and the conflation of sleepiness with laziness. CONCLUSION: Descriptions of common symptoms often differed between participants and the existing literature. These differences likely impact patient-physician communication, with both parties utilizing the same terminology to communicate different concepts. The characterization of stigma in narcolepsy presents opportunities for future research exploring the impact and possible development of interventions to reduce the substantial psychological comorbidity in persons with narcolepsy.

Identification of bidirectional causal links between gut microbiota and narcolepsy type 1 using Mendelian randomization.

STUDY OBJECTIVES: Narcolepsy type 1 (NT1), characterized by cataplexy and orexin deficiency, is a rare and frequently debilitating neurological disorder. It has been noted to have connections with the gut microbiota, yet the exact causal relationships remain unclear. METHODS: We conducted a comprehensive bidirectional Mendelian randomization (MR) study to rigorously investigate the causal links between the gut microbiota and NT1, utilizing genetic datasets from the MiBioGen consortium and FinnGen consortium, respectively. The inverse-variance weighted (IVW) method was employed to obtain the primary MR estimates, supplemented by several alternative methods as well as sensitivity analyses including Cochran's Q, MR-Egger, MR pleiotropy residual sum and outlier, leave-one-out, and genetic colocalization. RESULTS: Our findings indicated that an increased relative abundance of five genera including Blautia (p = 4.47E-5), Collinsella (p = 0.036), Gordonibacter (p = 0.047), Hungatella (p = 0.015), and Lachnospiraceae UCG010 (p = 0.027) may be associated with a decreased risk of NT1. Conversely, an increased relative abundance of class Betaproteobacteria (p = 0.032), genus Alloprevotella (p = 0.009), and genus Ruminiclostridium6 (p = 0.029) may potentially heighten the risk of NT1. The onset of NT1 may lead to a decrease in the relative abundance of genus Eubacterium eligens group (p = 0.022), while a increase in the family Family XI (p = 0.009), genus Hungatella (p = 0.005), genus Prevotella (p = 0.013), and unknown genus id.2001 (p = 0.019). These findings remained robust under all sensitivity analyses. CONCLUSIONS: Our results offer robust evidence for the bidirectional causal links between particular gut microbial taxa and NT1, underscoring the significance of the microbiota-gut-brain axis in the pathological process of NT1.

Vagus nerve stimulation for the treatment of narcolepsy.

BACKGROUND AND OBJECTIVE: No study on neurostimulation in narcolepsy is available until now. Arousal- and wake-promoting effects of vagus nerve stimulation (VNS) have been demonstrated in animal experiments and are well-known as side effects of VNS therapy in epilepsy and depression. The objective was to evaluate the therapeutic effect of VNS on daily sleepiness and cataplexies in narcolepsy. METHODS: In our open-label prospective comparative study, we included narcolepsy patients who were treated with VNS because of depression or epilepsy and compared them to controls without narcolepsy treated with VNS for depression or epilepsy (18 patients in each group, aged 31.5 ± 8.2 years). We evaluated daily sleepiness (Epworth Sleepiness Scale, ESS) and the number of cataplexies per week before the implantation of VNS and at three and six month follow-ups. RESULTS: Compared to baseline (ESS: 15.9 ± 2.5) patients with narcolepsy showed a significant improvement on ESS after three months (11.2 ± 3.3, p < 0.05) and six months (9.6 ± 2.8, p < 0.001) and a trend to reduction of cataplexies. No significant ESS-improvement was observed in patients without narcolepsy (14.9 ± 3.9, 13.6 ± 3.7, 13.2 ± 3.5, p = 0.2 at baseline, three and six months, correspondingly). Side effects did not differ between the study groups. CONCLUSION: In this first evaluation of VNS in narcolepsy, we found a significant improvement of daily sleepiness due to this type of neurostimulation. VNS could be a promising non-medical treatment in narcolepsy.

The Burden of Narcolepsy in Adults: A Population Sampling Study Using Personal Media.

OBJECTIVE: To obtain insight in the spectrum of narcolepsy symptoms and associated burden in a large cohort of patients. METHODS: We used the Narcolepsy Monitor, a mobile app, to easily rate the presence and burden of 20 narcolepsy symptoms. Baseline measures were obtained and analyzed from 746 users aged between 18 and 75 years with a reported diagnosis of narcolepsy. RESULTS: Median age was 33.0 years (IQR 25.0-43.0), median Ullanlinna Narcolepsy Scale 19 (IQR 14.0-26.0), 78% reported using narcolepsy pharmacotherapy. Excessive daytime sleepiness (97.2%) and lack of energy were most often present (95.0%) and most often caused a high burden (79.7% and 76.1% respectively). Cognitive symptoms (concentration 93.0%, memory 91.4%) and psychiatric symptoms (mood 76.8%, anxiety/panic 76.4%) were relatively often reported to be present and burdensome. Conversely, sleep paralysis and cataplexy were least often reported as highly bothersome. Females experienced a higher burden for anxiety/panic, memory, and lack of energy. CONCLUSIONS: This study supports the notion of an elaborate narcolepsy symptom spectrum. Each symptom's contribution to the experienced burden varied, but lesser-known symptoms did significantly add to this as well. This emphasizes the need to not only focus treatment on the classical core symptoms of narcolepsy.

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. RESULTS: 22 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). DISCUSSION: Daytime 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.

Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy.

STUDY OBJECTIVES: We examined body mass index (BMI) changes associated with sodium oxybate treatment (SXB) in pediatric patients with narcolepsy with cataplexy who participated in a double-blind, placebo-controlled, randomized withdrawal study and an open-label continuation period. METHODS: Participants were aged 7-16 years at screening. SXB-naive participants titrated to twice-nightly dosing of SXB then entered a 2-week stable-dose period; participants taking SXB at study entry entered a 3-week stable-dose period. After a 2-week randomized withdrawal period, all participants entered an open-label safety period (OLP; main study duration: ≤ 52 weeks). Participants who completed the OLP were allowed to enter the open-label continuation period (an additional 1-2 years). BMI percentile categories were defined as underweight (< 5th), normal (5th to < 85th), overweight (≥ 85th to < 95th), and obese (≥ 95th). RESULTS: Median BMI percentile decreased from baseline to OLP week 52 in SXB-naive participants who were normal weight at baseline (decreased from 77.0 to 35.0) or overweight/obese at baseline (98.0 to 86.7). Median BMI percentile decreased to a lesser extent in participants taking twice-nightly SXB at study entry who were normal weight at baseline (54.6 to 53.0) or overweight/obese at baseline (96.5 to 88.9). Shifts in BMI category from baseline to week 52 were sometimes noted. In SXB-naive participants, 9/10 (90.0%) who were overweight became normal weight, 7/25 (28.0%) who were obese became normal weight, 3/25 (12.0%) who were obese became overweight, and 1/16 (6.3%) who was normal weight became obese. In participants taking SXB at baseline, 5/8 (62.5%) who were overweight became normal weight, 3/6 (50.0%) who were obese became overweight, 1/14 (7.1%) who was normal weight became overweight, and 2/14 (14.3%) who were normal weight became underweight. Median BMI percentiles at months 6 and 12 of the open-label continuation period were similar to those at OLP end (OLP week 52). In SXB-naive participants, the evident BMI z-score decrease over time was relative to the screening values. CONCLUSIONS: Decreases in BMI percentile and z-score, and downward shifts in BMI category, were observed within 1 year of SXB treatment in pediatric participants with narcolepsy with cataplexy. BMI decreases plateaued after approximately 1 year. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of Xyrem With an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects With Narcolepsy With Cataplexy; URL: https://clinicaltrials.gov/study/NCT02221869; Identifier: NCT02221869. CITATION: Dauvilliers Y, Lammers GJ, Lecendreux M, et al. Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy. J Clin Sleep Med. 2024;20(3):445-454.

Headache improves with armodafinil.

This case report recounts the details of a patient diagnosed with narcolepsy and cataplexy whose headaches improved once treatment with armodafinil began. The clinical significance of this report lies in the fact that armodafinil is known to cause headaches, at least initially. But perhaps through a reduced need for caffeine and/or a regulation of sleep/wake, armodafinil may reduce headache frequency and severity. CITATION: Barone DA. Headache improves with armodafinil. J Clin Sleep Med. 2024;20(3):469-470.

Neural Control of REM Sleep and Motor Atonia: Current Perspectives.

PURPOSE OF REVIEW: Since the formal discovery of rapid eye movement (REM) sleep in 1953, we have gained a vast amount of knowledge regarding the specific populations of neurons, their connections, and synaptic mechanisms regulating this stage of sleep and its accompanying features. This article discusses REM sleep circuits and their dysfunction, specifically emphasizing recent studies using conditional genetic tools. RECENT FINDINGS: Sublaterodorsal nucleus (SLD) in the dorsolateral pons, especially the glutamatergic subpopulation in this region (SLDGlut), are shown to be indispensable for REM sleep. These neurons appear to be single REM generators in the rodent brain and may initiate and orchestrate all REM sleep events, including cortical and hippocampal activation and muscle atonia through distinct pathways. However, several cell groups in the brainstem and hypothalamus may influence SLDGlut neuron activity, thereby modulating REM sleep timing, amounts, and architecture. Damage to SLDGlut neurons or their projections involved in muscle atonia leads to REM behavior disorder, whereas the abnormal activation of this pathway during wakefulness may underlie cataplexy in narcolepsy. Despite some opposing views, it has become evident that SLDGlut neurons are the sole generators of REM sleep and its associated characteristics. Further research should prioritize a deeper understanding of their cellular, synaptic, and molecular properties, as well as the mechanisms that trigger their activation during cataplexy and make them susceptible in RBD.

Once-nightly sodium oxybate (FT218) improved symptoms of disrupted nighttime sleep in people with narcolepsy: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a published article in the journal CNS Drugs. Narcolepsy is a rare sleep condition. Most people with narcolepsy experience disrupted nighttime sleep and have poor quality of sleep. Sometimes these symptoms are not easily diagnosed as a symptom of narcolepsy. Sodium oxybate is an approved treatment for narcolepsy. The only version of sodium oxybate that was available until 2023 required people to take their sodium oxybate at bedtime and then again in the middle of the night. The US Food and Drug Administration (FDA for short) has approved a once-nightly bedtime dose of sodium oxybate (ON-SXB for short, also known as FT218 or LUMRYZ™) to treat symptoms of narcolepsy in adults. These symptoms are daytime sleepiness and cataplexy, which is an episode of sudden muscle weakness. The once-nightly bedtime dose of ON-SXB removes the need for a middle-of-the-night dose of sodium oxybate. The REST-ON clinical study compared ON-SXB to a placebo (a substance that contains no medicine) to determine if it was better at treating symptoms of disrupted nighttime sleep associated with narcolepsy. This summary looks at whether; ON-SXB was better than placebo at treating symptoms of disrupted nighttime sleep. WHAT WERE THE RESULTS?: Compared to people who took placebo, people who took ON-SXB had fewer number of changes from deeper to lighter sleep stages and woke up less during the night. They also reported that they slept better at night and felt more refreshed when waking up in the morning. People with narcolepsy sometimes take alerting agents to help with sleepiness during the day, but alerting agents can cause difficulty sleeping at night. This study showed that people who took ON-SXB had better nighttime sleep even if they were taking alerting agents during the day. The most common side effects of ON-SXB included dizziness, nausea (feeling sick to your stomach), vomiting, headache, and bedwetting. WHAT DO THE RESULTS MEAN?: A once-nightly bedtime dose of ON-SXB is a narcolepsy treatment option for people without the need for a middle-of-the-night dose of sodium oxybate.

Narcolepsy type 1 and Sydenham chorea - Report of 3 cases and review of the literature.

OBJECTIVES/BACKGROUND: Narcolepsy type 1 (NT1) is an immune-mediated disorder characterized by excessive daytime sleepiness, cataplexy, low levels of hypocretin-1 in the cerebrospinal fluid, and a strong association with the HLA DQB1*06:02 allele. There is evidence for streptococcal infections as one pathogenic factor that may lead to NT1 as part of a multifactorial pathogenesis. Elevated titers of Antistreptolysin-O antibodies and increased inflammatory activity in response to streptococci antigens have been described in patients with NT1. Sydenham chorea (SC) results from a post-streptococcal autoimmune process targeting basal ganglia neurons. Despite this common trigger, SC has been interpreted as a misdiagnosis in a few described cases of patients who were first diagnosed with SC and later with NT1. Our goal was to analyze the association between SC and NT1. PATIENTS/METHODS: We reviewed the literature and report three patients from three European sleep centers who were diagnosed with both SC and NT1 within a few months. RESULTS: We describe the cases of one male (age 10) and two female (age 22 and 10) patients. CONCLUSIONS: We argue that in those cases both diagnoses are justified, unlike reports of previous cases in which SC was considered a misdiagnosis in patients with NT1. It remains, however, unclear if the conditions occur independently or if there is an overlap disorder- an SC-like subtype of narcolepsy with a particular sequence of symptoms. Further studies need to clarify the causality of the relationship and the pathophysiology of the reported rare association.

Deficiency of orexin signaling during sleep is involved in abnormal REM sleep architecture in narcolepsy.

Narcolepsy is a sleep disorder caused by deficiency of orexin signaling. However, the neural mechanisms by which deficient orexin signaling causes the abnormal rapid eye movement (REM) sleep characteristics of narcolepsy, such as cataplexy and frequent transitions to REM states, are not fully understood. Here, we determined the activity dynamics of orexin neurons during sleep that suppress the abnormal REM sleep architecture of narcolepsy. Orexin neurons were highly active during wakefulness, showed intermittent synchronous activity during non-REM (NREM) sleep, were quiescent prior to the transition from NREM to REM sleep, and a small subpopulation of these cells was active during REM sleep. Orexin neurons that lacked orexin peptides were less active during REM sleep and were mostly silent during cataplexy. Optogenetic inhibition of orexin neurons established that the activity dynamics of these cells during NREM sleep regulate NREM-REM sleep transitions. Inhibition of orexin neurons during REM sleep increased subsequent REM sleep in "orexin intact" mice and subsequent cataplexy in mice lacking orexin peptides, indicating that the activity of a subpopulation of orexin neurons during the preceding REM sleep suppresses subsequent REM sleep and cataplexy. Thus, these results identify how deficient orexin signaling during sleep results in the abnormal REM sleep architecture characteristic of narcolepsy.

Status Cataplecticus Induced by an Abrupt Duloxetine Withdrawal-A Case Report.

ABSTRACT: In persons with narcolepsy type 1, sudden withdrawal of antidepressants can cause status cataplecticus. We describe a 77-year-old female patient with long-standing history of narcolepsy type 1 complaining of recurrent short sudden episodes of whole-body paralysis, with preserved consciousness and memory. Episodes started an hour after her family invited her to celebrate Mother's Day. One week prior, patient had abruptly discontinued duloxetine. Cataplectic episodes resolved within 24 hours after resumption of duloxetine and treatment of hypokalemia. Status cataplecticus has been reported after withdrawal of venlafaxine, fluoxetine, and clomipramine. This is the first report of status cataplecticus due to duloxetine withdrawal. We review the pathophysiology of antidepressant withdrawal-induced status cataplecticus. In persons with narcolepsy type 1, physicians discontinuing any antidepressant should counsel on adverse effects of antidepressant withdrawal and reduce the dose in tapering manner.

Validation of the Brazilian Portuguese version of the Stanford cataplexy questionnaire.

INTRODUCTION: Cataplexy is a sudden and involuntary episode of loss of muscle tone during wakefulness. Cataplexy cannot be easily recognized when clinical features are atypical or when the physician is unfamiliar with its characteristics. The unstructured clinical interview is the only standard diagnostic method, but the use of a targeted questionnaire can help in the diagnosis of cataplexy. METHODS: The Stanford cataplexy questionnaire is a self-administered 51-question questionnaire. This validation consisted of an initial translation and back-translation of the questionnaire from English into Brazilian Portuguese, followed by a pilot study with 10 participants for the cultural adaptation of the scale. RESULTS: 155 consecutive patients aged 18-85 completed the questionnaire. The Brazilian version of the Stanford cataplexy questionnaire showed similar results to the original version with good metric properties (area under the curve), high internal consistency (Cronbach's alpha equal to 0.87), good reliability and reproducibility. CONCLUSIONS: The Brazilian Portuguese version of the Stanford Cataplexy questionnaire presented good accuracy satisfactory psychometric properties in identifying cataplexy.

The role of orexinergic system in the regulation of cataplexy.

Loss of orexin/hypocretin causes serious sleep disorder; narcolepsy. Cataplexy is the most striking symptom of narcolepsy, characterized by abrupt muscle paralysis induced by emotional stimuli, and has been considered pathological activation of REM sleep atonia system. Clinical treatments for cataplexy/narcolepsy and early pharmacological studies in narcoleptic dogs tell us about the involvement of monoaminergic and cholinergic systems in the control of cataplexy/narcolepsy. Muscle atonia may be induced by activation of REM sleep-atonia generating system in the brainstem. Emotional stimuli may be processed in the limbic systems including the amygdala, nucleus accumbens, and medial prefrontal cortex. It is now considered that orexin/hypocretin prevents cataplexy by modulating the activity of different points of cataplexy-inducing circuit, including monoaminergic/cholinergic systems, muscle atonia-generating systems, and emotion-related systems. This review will describe the recent advances in understanding the neural mechanisms controlling cataplexy, with a focus on the involvement of orexin/hypocretin system, and will discuss future experimental strategies that will lead to further understanding and treatment of this disease.

Narcolepsies, update in 2023.

Narcolepsy type 1 (NT1) and type 2 (NT2), also known as narcolepsy with and without cataplexy, are sleep disorders that benefited from major scientific advances over the last two decades. NT1 is caused by the loss of hypothalamic neurons producing orexin/hypocretin, a neurotransmitter regulating sleep and wake, which can be measured in the cerebrospinal fluid (CSF). A low CSF level of hypocretin-1/orexin-A is a highly specific and sensitive biomarker, sufficient to diagnose NT1. Orexin-deficiency is responsible for the main NT1 symptoms: sleepiness, cataplexy, disrupted nocturnal sleep, sleep-related hallucinations, and sleep paralysis. In the absence of a lumbar puncture, the diagnosis is based on neurophysiological tests (nocturnal and diurnal) and the presence of the pathognomonic symptom cataplexy. In the revised version of the International Classification of sleep Disorders, 3rd edition (ICSD-3-TR), a sleep onset rapid eye movement sleep (REM) period (SOREMP) (i.e. rapid occurrence of REM sleep) during the previous polysomnography may replace the diurnal multiple sleep latency test, when clear-cut cataplexy is present. A nocturnal SOREMP is very specific but not sensitive enough, and the diagnosis of cataplexy is usually based on clinical interview. It is thus of crucial importance to define typical versus atypical cataplectic attacks, and a list of clinical features and related degrees of certainty is proposed in this paper (expert opinion). The time frame of at least three months of evolution of sleepiness to diagnose NT1 was removed in the ICSD-3-TR, when clear-cut cataplexy or orexin-deficiency are established. However, it was kept for NT2 diagnosis, a less well-characterized disorder with unknown clinical course and absence of biolo biomarkers; sleep deprivation, shift working and substances intake being major differential diagnoses. Treatment of narcolepsy is nowadays only symptomatic, but the upcoming arrival of non-peptide orexin receptor-2 agonists should be a revolution in the management of these rare sleep diseases.

A unique association? A narcolepsy type 1 case comorbid with Primary Biliary Cholangitis.

The aim of the study was to present a woman affected of a narcolepsy with cataplexy (narcolepsy type 1) comorbid with an asymptomatic Primary Biliary Cholangitis (PBC). The HLA haplotype was DRB1*15:01, DQA1*01:02, DQB1*06:02. The allele DQB1*06:02 has been considered until now protective for PBC and dual pathology has not been published. We think the important clinical message of the Case would be of continuing to monitor adults with narcolepsy type 1 for late complications that may be associated with other autoimmune conditions. Clinicians should be aware of the relationship between Narcolepsy and PBC. This highlights the need for screening and management in these individuals.

Pharmacological options for narcolepsy: are they the way forward?

INTRODUCTION: Narcolepsy is an under-recognized, rare neurologic disorder of hypersomnolence that is associated with increased mortality and medical and psychiatric co-morbidities. Narcolepsy exerts a substantial economic burden on patients and society. There is currently no cure, and life-long symptomatic therapy is needed. Available drugs do not modify the disease course. AREAS COVERED: This manuscript provides an overview of narcolepsy symptoms, diagnosis, pathophysiology, current pharmacotherapies, and emerging treatments. Gaps and unresolved issues in diagnosis and management of narcolepsy are discussed to answer whether pharmacological options are the way forward. EXPERT OPINION: Diagnostic criteria for narcolepsy (ICSD-3) need revision and greater clarity. Improved recognition of cataplexy and other symptoms through educational outreach, new biomarkers, improved test scoring through artificial intelligence algorithms, and use of machine learning may facilitate earlier diagnosis and treatment. Pharmacological options need improved symptomatic therapy in addition to targeted therapies that address the loss of hypocretin signaling. Optimal narcolepsy care also needs a better understanding of the pathophysiology, recognition of the different phenotypes in narcolepsy, identification of at-risk individuals and early recognition of symptoms, better diagnostic tools, and a database for research and disease monitoring of treatment, side-effects, and comorbidities.

Sleep Disorders in Childhood.

OBJECTIVE: This article provides a comprehensive review of pediatric sleep disorders including the clinical features, diagnosis, and treatment of sleep-disordered breathing, insomnia, parasomnias, restless sleep disorder, restless legs syndrome, narcolepsy in childhood, and Kleine-Levin syndrome. LATEST DEVELOPMENTS: Our understanding of pediatric sleep pathophysiology continues to evolve, and diagnostic and treatment modalities have expanded. A low-sodium oxybate formulation was approved in July 2020 in the United States to treat cataplexy and excessive daytime sleepiness in patients 7 years old and older with narcolepsy. A validated pediatric hypersomnolence survey for pediatric narcolepsy and idiopathic hypersomnia with high sensitivity, specificity, and interrater reliability is now available. ESSENTIAL POINTS: The clinical presentation, diagnostics, and treatment of children with sleep disorders differ from those of adults. Untreated sleep disorders in childhood can lead to adverse physical and psychological consequences in adults. Correctly diagnosing and treating sleep disorders in youth can prevent a significant burden of disease in adulthood.