The neurophysiologic landscape of the sleep onset: a systematic review.

Background: The sleep onset process is an ill-defined complex process of transition from wakefulness to sleep, characterized by progressive modifications at the subjective, behavioural, cognitive, and physiological levels. To this date, there is no international consensus which could aid a principled characterisation of this process for clinical research purposes. The current review aims to systemise the current knowledge about the underlying mechanisms of the natural heterogeneity of this process. Methods: In this systematic review, studies investigating the process of the sleep onset from 1970 to 2022 were identified using electronic database searches of PsychINFO, MEDLINE, and Embase. Results: A total of 139 studies were included; 110 studies in healthy participants and 29 studies in participants with sleep disorders. Overall, there is a limited consensus across a body of research about what distinct biomarkers of the sleep onset constitute. Only sparse data exists on the physiology, neurophysiology and behavioural mechanisms of the sleep onset, with majority of studies concentrating on the non-rapid eye movement stage 2 (NREM 2) as a potentially better defined and a more reliable time point that separates sleep from the wake, on the sleep wake continuum. Conclusions: The neurophysiologic landscape of sleep onset bears a complex pattern associated with a multitude of behavioural and physiological markers and remains poorly understood. The methodological variation and a heterogenous definition of the wake-sleep transition in various studies to date is understandable, given that sleep onset is a process that has fluctuating and ill-defined boundaries. Nonetheless, the principled characterisation of the sleep onset process is needed which will allow for a greater conceptualisation of the mechanisms underlying this process, further influencing the efficacy of current treatments for sleep disorders.

Profile of sleep disturbances in patients with recurrent depressive disorder or bipolar affective disorder in a tertiary sleep disorders service.

Bidirectional relationship between sleep disturbances and affective disorders is increasingly recognised, but its underlying mechanisms are far from clear, and there is a scarcity of studies that report on sleep disturbances in recurrent depressive disorder (RDD) and bipolar affective disorder (BPAD). To address this, we conducted a retrospective study of polysomnographic and clinical records of patients presenting to a tertiary sleep disorders clinic with affective disorders. Sixty-three BPAD patients (32 female; mean age ± S.D.: 41.8 ± 12.4 years) and 126 age- and gender-matched RDD patients (62 female; 41.5 ± 12.8) were studied. Whilst no significant differences were observed in sleep macrostructure parameters between BPAD and RDD patients, major differences were observed in comorbid sleep and physical disorders, both of which were higher in BPAD patients. Two most prevalent sleep disorders, namely obstructive sleep apnoea (OSA) (BPAD 50.8.0% vs RDD 29.3%, P = 0.006) and insomnia (BPAD 34.9% vs RDD 15.0%, P = 0.005) were found to be strongly linked with BPAD. In summary, in our tertiary sleep clinic cohort, no overt differences in the sleep macrostructure between BPAD and RDD patients were demonstrated. However, OSA and insomnia, two most prevalent sleep disorders, were found significantly more prevalent in patients with BPAD, by comparison to RDD patients. Also, BPAD patients presented with significantly more severe OSA, and with higher overall physical co-morbidity. Thus, our findings suggest an unmet/hidden need for earlier diagnosis of those with BPAD.

The effect of a change from face-to-face to remote positive airway pressure education for patients with sleep apnoea during the coronavirus disease-2019 pandemic: a prospective cohort study.

Background: The coronavirus disease-2019 (COVID-19) pandemic and national lockdowns necessitated a change in service delivery including positive airway pressure (PAP) education protocols, with no data on how this may impact subsequent PAP adherence. We aim to quantify adherence of PAP initiated during the COVID-19 pandemic and compare the effects of remote versus face-to-face (FTF) education in patients with obstructive sleep apnoea (OSA). Methods: This prospective cohort study in a tertiary National Health Service (NHS) hospital sleep disorders centre in London, United Kingdom, included 141 patients aged >18 years with newly diagnosed OSA initiating PAP during the COVID-19 pandemic; 71 patients receiving standard FTF education compared to 70 patients educated on PAP remotely at the start of lockdown. Results: Adherence over a consecutive 30-day period within the first three months of PAP usage was measured, secondary outcomes included average nightly usage, usage per nights used, percentage of nights used, and percentage of nights used for ≥4 hours. In 141 patients (two-thirds male, 56% of at least 45 years of age and 48.9% sleepy at baseline), 114 patients (81%) were diagnosed with moderate or severe OSA. 54 patients (38.3%) achieved good adherence (≥70% of nights with ≥4 hours usage), with an average of 4.7 hours of PAP usage per night used. Patients receiving FTF PAP education had a comparable level of good adherence (38% versus 38.6%, P=0.915), and hours per nights used (4.7 versus 4.6 h/night, P=0.711) to remotely educated patients. More severe OSA, lower mask leak, and a nasal mask were associated with achieving good PAP adherence. Conclusions: PAP adherence of newly diagnosed individuals with OSA during the COVID-19 pandemic was modest at 38.30%, and not significantly affected by remote PAP education delivery.

Nocturnal visual hallucinations in patients with disorders of arousal: a novel behavioral and EEG pattern.

AIM: To investigate clinical and video-polysomnography (VPSG) findings of hallucinatory experiences in patients suffering from disorders of arousal (DOA) in the absence of other pathologies. METHODS: The authors retrospectively reviewed the records of 370 adults with DOA. Thirty (8.1%) patients concomitantly reported complex nocturnal visual hallucinations. VPSG recordings were scrutinized, and motor behavioral and electroencephalogram (EEG) patterns were classified according to previous descriptions of DOA. RESULTS: Thirty DOA patients reported seeing images of objects, people, and animals; either distorted, static, or mobile. The images disappeared with increased illumination in 80% of patients, and 23.3% reported preceding dream imagery. In addition to the classical DOA patterns on VPSG, a distinct pattern of behavioral and EEG manifestation associated with complex hallucinatory episodes was identified in 16 (53.3%) DOA patients. This consisted of low-voltage mixed-frequency EEG activity before eye opening that persisted while patients were observed staring or visually tracking before the onset of motor behavior. CONCLUSION: A novel, distinct behavioral and EEG pattern in patients with DOA and history of reported complex nocturnal visual hallucinations was identified. This may represent a unique phenotype of dissociation between sleep states that merits further investigation.

TADMaster: a comprehensive web-based tool for the analysis of topologically associated domains.

BACKGROUND: Chromosome conformation capture and its derivatives have provided substantial genetic data for understanding how chromatin self-organizes. These techniques have identified regions of high intrasequence interactions called topologically associated domains (TADs). TADs are structural and functional units that shape chromosomes and influence genomic expression. Many of these domains differ across cell development and can be impacted by diseases. Thus, analysis of the identified domains can provide insight into genome regulation. Hence, there are many approaches to identifying such domains across many cell lines. Despite the availability of multiple tools for TAD detection, TAD callers' speed, flexibility, result inconsistency, and reproducibility remain challenges in this research area. RESULTS: In this work, we developed a computational webserver called TADMaster that provides an analysis suite to directly evaluate the concordance level and robustness of two or more TAD data on any given genome region. The suite provides multiple visual and quantitative metrics to compare the identified domains' number, size, and various comparisons of shared domains, domain boundaries, and domain overlap. CONCLUSIONS: TADMaster is an efficient and easy-to-use web application that provides a set of consensus and unique TADs to inform the choice of TADs. It can be accessed at http://tadmaster.io and is also available as a containerized application that can be deployed and run locally on any platform or operating system.

The maternal-fetal transfer of passive immunity as a mechanism of transplacental nanoparticle drug delivery for prenatal therapies.

Nanoparticles administered into the maternal circulation and across the placenta are a potential clinical therapy to treat congenital diseases. The mechanism by which nanoparticles can safely cross the placenta for targeted drug delivery to the fetus remains poorly understood. We demonstrate that the maternal-fetal transfer of passive immunity through the neonatal Fc Receptor (FcRn) can induce the transplacental transfer of chitosan nanoparticles modifed with IgG antibodies (414 ± 27 nm). The transfer of FITC-tagged IgG-modified chitosan nanoparticles was 2.8 times higher (p = 0.0264) compared to similarly-sized unmodified chitosan nanoparticles (375 ± 17 nm). Co-administration of free IgG competitively diminished the transplacental transfer of IgG-modified nanoparticles, yet unmodified nanoparticles remained unaffected. Colocalization of the FcRn and the IgG-modified chitosan nanoparticles were observed with confocal microscopy. Barrier function before and after nanoparticle administration remained intact as determined by TEER (75-79 Ω cm2) and immmunofluorescence of ZO-1 tight junction proteins. The results provide insight into the clinical applications of nanoparticles for prenatal therapies using the mechanism of the maternal-fetal transfer of passive immunity.

Restricted truncal sagittal movements of rapid eye movement behaviour disorder.

Unlike sleep-walkers, patients with rapid-eye-movement-behaviour disorder (RBD) rarely leave the bed during the re-enactment of their dreams. RBD movements may be independent of spatial co-ordinates of the 'outside-world', and instead rely on (allocentric) brain-generated virtual space-maps, as evident by patients' limited truncal/axial movements. To confirm this, a semiology analysis of video-polysomnography records of 38 RBD patients was undertaken and paradoxically restricted truncal/thoraco-lumbar movements during complex dream re-enactments demonstrated.

Comprehensive deletion landscape of CRISPR-Cas9 identifies minimal RNA-guided DNA-binding modules.

Proteins evolve through the modular rearrangement of elements known as domains. Extant, multidomain proteins are hypothesized to be the result of domain accretion, but there has been limited experimental validation of this idea. Here, we introduce a technique for genetic minimization by iterative size-exclusion and recombination (MISER) for comprehensively making all possible deletions of a protein. Using MISER, we generate a deletion landscape for the CRISPR protein Cas9. We find that the catalytically-dead Streptococcus pyogenes Cas9 can tolerate large single deletions in the REC2, REC3, HNH, and RuvC domains, while still functioning in vitro and in vivo, and that these deletions can be stacked together to engineer minimal, DNA-binding effector proteins. In total, our results demonstrate that extant proteins retain significant modularity from the accretion process and, as genetic size is a major limitation for viral delivery systems, establish a general technique to improve genome editing and gene therapy-based therapeutics.

A Novel Group Cognitive Behavioral Therapy Approach to Adult Non-rapid Eye Movement Parasomnias.

Background: Following the success of Cognitive Behavioral Therapy (CBT) for insomnia, there has been a growing recognition that similar treatment approaches might be equally beneficial for other major sleep disorders, including non-rapid eye movement (NREM) parasomnias. We have developed a novel, group-based, CBT-program for NREM parasomnias (CBT-NREMP), with the primary aim of reducing NREM parasomnia severity with relatively few treatment sessions. Methods: We investigated the effectiveness of CBT-NREMP in 46 retrospectively-identified patients, who completed five outpatient therapy sessions. The outcomes pre- and post- CBT-NREMP treatment on clinical measures of insomnia (Insomnia Severity Index), NREM parasomnias (Paris Arousal Disorders Severity Scale) and anxiety and depression (Hospital Anxiety and Depression Scale), were retrospectively collected and analyzed. In order to investigate the temporal stability of CBT-NREMP, we also assessed a subgroup of 8 patients during the 3 to 6 months follow-up period. Results: CBT-NREMP led to a reduction in clinical measures of NREM parasomnia, insomnia, and anxiety and depression severities [pre- vs. post-CBT-NREMP scores: P (Insomnia Severity Index) = 0.000054; P (Paris Arousal Disorders Severity Scale) = 0.00032; P (Hospital Anxiety and Depression Scale) = 0.037]. Improvements in clinical measures of NREM parasomnia and insomnia severities were similarly recorded for a subgroup of eight patients at follow-up, demonstrating that patients continued to improve post CBT-NREMP. Conclusion: Our findings suggest that group CBT-NREMP intervention is a safe, effective and promising treatment for NREM parasomnia, especially when precipitating and perpetuating factors are behaviorally and psychologically driven. Future randomized controlled trials are now required to robustly confirm these findings.

Cyclic alternating pattern in obstructive sleep apnea: A preliminary study.

Obstructive sleep apnea is linked to cardiovascular disease, metabolic disorders and dementia. The precise nature of the association between respiratory events in obstructive sleep apnea, cortical or subcortical arousals, and cognitive, autonomic and oxidative stress consequences remains incompletely elucidated. Previous studies have aimed to understand the relationship between obstructive sleep apnea and arousal patterns, as defined by the cyclic alternating pattern, but results have been inconsistent, in part likely due to the presence of associated comorbidities. To better define this relationship, we analysed cyclic alternating patterns in patients with obstructive sleep apnea without any additional comorbidities. We identified 18 adult male, non-obese subjects with obstructive sleep apnea and no other comorbidities or medication history, who underwent whole-night electroencephalography and polysomnography. Cyclic alternating pattern analysis was performed and verified by certified somnologists. Pairwise linear regression analysis demonstrated an inverse relationship between obstructive sleep apnea severity and cyclic alternating pattern subtype A1, and a direct correlation with cyclic alternating pattern subtype A3. Cyclic alternating pattern subtypes A1 prevail in milder obstructive sleep apnea phenotype, whilst cyclic alternating pattern subtypes A2 and A3 overcome among moderate-to-severe obstructive sleep apnea patients. The milder obstructive sleep apnea group also presented higher sleep efficiency, and increased percentages of non-rapid eye movement stage 3 and rapid eye movement sleep, as well as longer cyclic alternating pattern sequences in N3, while severe obstructive sleep apnea patients spent more time in lighter sleep stages. These results imply/suggest a balance between cyclic alternating pattern's adaptive and maladaptive arousal processes in obstructive sleep apnea of differing severities. In milder obstructive sleep apnea (apnea-hypopnea index < 20), sleep continuity may be reinforced by cyclic alternating pattern subtype A1, whereas in more severe obstructive sleep apnea, decompensation of these sleep-stabilizing mechanisms may occur and more intrusive cyclic alternating pattern fluctuations disrupt sleep circuitry.

Cognitive-Behavioral Therapy for Obsessive-Compulsive Disorder: 2021 Update.

In this update of a previous review, the authors discuss cognitive-behavioral therapy (CBT) with exposure and response prevention for obsessive-compulsive disorder (OCD). This efficacious modality avoids side effects common to psychotropic medication and reduces risk of relapse once treatment has ended. Psychotherapy involves identification and ranking of stimuli that provoke obsessions, exposure to these stimuli while preventing compulsions, and cognitive restructuring. The family of the OCD patient plays a significant role in treatment. This article includes expanded research on family-focused CBT and treatment of pediatric OCD. The family's accommodation and emotional response to a patient's symptoms may interfere with therapy and perpetuate the disorder. The treatment of pediatric OCD involves the same considerations. However, the form of obsessions and compulsions may differ and therapeutic techniques are modified to make them age appropriate.

Periodic limb movements during sleep: a narrative review.

OBJECTIVE: Using narrative review techniques, this paper evaluates the evidence for separable underlying patho-mechanisms of periodic limb movements (PLMs) to separable PLM motor patterns and phenotypes, in order to elucidate potential new treatment modalities. BACKGROUND: Periodic limb movement disorder (PLMD) is estimated to occur in 5-8% of the paediatric population and 4-11% of the general adult population. Due to significant sleep fragmentation, PLMD can lead to functional impairment, including hyperactivity and delayed language development in children, and poor concentration and work performance in adults. Longitudinal data demonstrate that those with PLMD are at greater risk of depression and anxiety, and a 4-fold greater risk of developing dementia. PLMD has been extensively studied over the past two decades, and several key insights into the genetic, pathophysiological, and neural correlates have been proposed. Amongst these proposals is the concept of separable PLM phenotypes, proposed on the basis of nocturnal features such as the ratio of limb movements and distribution throughout the night. PLM phenotype and presentation, however, varies significantly depending on the scoring utilized and the nocturnal features examined, across age, and co-morbid clinical conditions. Furthermore, associations between these phenotypes with major neurologic and psychiatric disorders remain controversial. METHODS: In order to elucidate potential divergent biological pathways that may help clarify important new treatment modalities, this paper utilizes narrative review and evaluates the evidence linking PLM motor patterns and phenotypes with hypothesised underlying patho-mechanisms. Distinctive, underlying patho-mechanisms include: a pure motor mechanism originating in the spinal cord, iron deficiency, dopamine system dysfunction, thalamic glutamatergic hyperactivity, and a more cortical-subcortical interplay. In support of the latter hypothesis, PLM rhythmicity appears tightly linked to the microarchitecture of sleep, not dissimilarly to the apnoeic/hypopneic events seen in obstructive sleep apnea (OSA). CONCLUSIONS: This review closes with a proposal for greater investigation into the identification of potential, divergent biological pathways. To do so would require prospective, multimodal imaging clinical studies which may delineate differential responses to treatment in restless legs syndrome (RLS) without PLMS and PLMS without RLS. This could pave the way toward important new treatment modalities.

From Emergency Department Visit to Readmission After Esophagectomy: Analysis of Burden and Risk Factors.

BACKGROUND: Frequent emergency department (ED) visits occur after esophagectomy. We aimed to identify the incidence of and risk factors for conversion from ED visit to inpatient admission. METHODS: A retrospective cohort study was performed of consecutive esophagectomies at a tertiary Canadian center (1999 to 2014). Multivariable regression analyses identified factors associated with conversion from ED visit to admission. RESULTS: There were 520 esophagectomies with 6% inhospital mortality (n = 31). Of those discharged, 29.7% (n = 145) had one or more emergency visit and 43.4% (n = 63) of these patients were readmitted to the hospital. First-time ED visits resulted in inpatient conversion 23.4% of the time (n = 34); successive ED visits resulted in increasing conversion. On multivariable analysis, anastomotic leak (adjusted odds ratio 2.45; 95% confidence interval, 1 to 6.01; P = .05) was independently associated with higher odds of conversion to admission. Sensitivity analysis using Poisson regression to model conversion as a rate identified that living in regions further away was associated with lower conversion rate to admission (risk ratio 0.35; 95% confidence interval, 0.13 to 0.94; P = .04). CONCLUSIONS: Although postesophagectomy ED utilization is high, the majority of visits do not convert to admission. With each increasing ED visit, likelihood of converting to admission increases. Anastomotic leakage was associated with higher odds of conversion to admission, possibly related to development of strictures. Access to urgent outpatient endoscopy may help reduce the incidence of ED visits and admission. Although living in regions further away is associated with lower conversion rates to admission at the index hospital, that may be due to patients utilizing closer local hospitals.

Apnoea-hypopnoea-index comparing the 2007 and 2012 American Academy of Sleep Medicine criteria in chronic obstructive pulmonary disease/obstructive sleep apnoea overlap syndrome.

BACKGROUND: In 2007 and 2012, the American Academy of Sleep Medicine (AASM) updated their scoring criteria for nocturnal respiratory events. We hypothesised that this could have led to changes in the apnoea-hypopnoea index (AHI) of patients with chronic obstructive pulmonary disease (COPD)/obstructive sleep apnoea (OSA) overlap syndrome. METHODS: In a retrospective study, polysomnographic (PSG) recordings of 34 patients with COPD/OSA overlap syndrome were independently analysed using the AASM criteria from 2007 (AASM2007) and 2012 (AASM2012). The primary outcome was the difference in AHI, the secondary outcomes were frequency of hypopnoeas, diagnosis of overlap syndrome and differences between the AASM 2007 recommended (AASM2007Rec) and altered (AASM2007Alt) classifications. Data are presented as mean (standard deviation) if normally distributed, and as median (interquartile range) if non-normally distributed. RESULTS: The PSGs of 34 elderly [aged 67 (7.0) years] and predominantly male (m:f, 31:3) patients with COPD [FEV1%pred 48.4% (19.6%)] were analysed. The AHI using AASM2007Rec criteria was 5.9 (2.0, 15.1) events/hour vs. 20.4 (11.5, 28.0) events/hour using the 2012 criteria (P<0.001); with the AASM2007Alt criteria, the AHI was 15.0 (9.3, 26.3) events/hour (P<0.001). Using the 2012 classification, the number of scored hypopnoeas increased by +48% compared to the AASM2007Rec criteria (P<0.001), 92% of these events were associated with arousal. Although statistically non-significant, using the AASM2007Alt classification, 12% of our cohort would not have been diagnosed with COPD/OSA overlap syndrome (P=0.114), this was also the case for 47% of the cohort when the AASM2007Rec classification was used (P<0.01). CONCLUSIONS: The use of the AASM2012 scoring rules results in a significantly higher AHI compared to the AASM2007 criteria in patients with COPD/OSA overlap syndrome, mostly due to an increased number of arousal-associated hypopnoeas. These observations are important for the definition of the COPD/OSA overlap syndrome.

Suspected Succinylcholine-Induced Masseter Muscle Rigidity During Rapid Sequence Intubation in the Air Medical Setting.

Trismus, or masseter muscle rigidity, is a rare but previously described complication of succinylcholine-induced neuromuscular blockade. We present a case report that details unique aspects of suspected masseter muscle rigidity in the prehospital setting air medical setting after attempted rapid sequence intubation with succinylcholine. We then discuss the need for knowledge base of this life-threatening and rarely described syndrome as well as the importance of working through a differential diagnosis and specific trismus-focused airway algorithm. Trismus, or masseter muscle rigidity (MMR), is a rare but previously described complication of succinylcholine-induced neuromuscular blockade. It has been cited in anesthesia and emergency medicine literature as a potentially life-threatening complication and requires prompt intervention. This case report details a unique case of suspected MMR in the prehospital setting after attempted rapid sequence intubation (RSI) with succinylcholine performed by an experienced aeromedical flight crew.

Co-activation of rhythms during alpha band oscillations as an interictal biomarker of exploding head syndrome.

BACKGROUND: Exploding head syndrome is a rarely reported benign sensory parasomnia that may nonetheless have significant impact on patients' quality of life and their perceived well-being. To date, the mechanisms underlying attacks, characterised by a painless perception of abrupt, loud noises at transitional sleep-wake or wake-sleep states, are by and large unclear. METHODS AND RESULTS: In order to address the current gap in the knowledge of potential underlying pathophysiology, a retrospective case-control study of polysomnographic recordings of patients presenting to a tertiary sleep disorders clinic with exploding head syndrome was conducted. Interictal (non-attack associated) electroencephalographic biomarkers were investigated by performing macrostructural and event-related dynamic spectral analyses of the whole-night EEG. In patients with exploding head syndrome, additional oscillatory activity was recorded during wakefulness and at sleep/wake periods. This activity differed in its frequency, topography and source from the alpha rhythm that it accompanied. CONCLUSION: Based on these preliminary findings, we hypothesise that at times of sleep-wake transition in patients with exploding head syndrome, aberrant attentional processing may lead to amplification and modulation of external sensory stimuli.

Cotard parasomnia: le délire de negation that occur during the sleep-wake dissociation?

None: Unpleasant dreamlike mentation can occur during non-rapid eye movement parasomnias, leading to associated panic attacks. The mentations are rarely remembered and are likely underreported. However, they may lead to significant personal distress and, if not addressed, may contribute to poorer clinical outcomes. Cotard le délire de negation are very rare nihilistic delusions, historically described with psychotic disorders. Their association with a variety of neurologic disorders, including migraine and cluster-headache, has also been reported. Here we present three cases of Cotard parasomnia during which distinct states of consciousness defined by nihilistic ideation occurred. Patients described believing they are dead or dying, while unable to perceive or experience their bodies in whole, or in part, as their own. A source analysis of the electroencephalographic fingerprint of these mentations suggests right-hemispheric hypoactivity subsequent to confusional arousals. Mechanistically, an aberrant activation of two major intrinsic brain networks of wakefulness, the salience network and the default mode network, is argued.

Cotard's Parasomnia: Le Délire de Negation that occur during the Sleep-Wake Dissociation?

NONE: Unpleasant dreamlike mentation can occur during NREM parasomnias, leading to associated panic attacks. The mentations are rarely remembered, and are likely underreported. However, they may lead to significant personal distress, and if not addressed, may contribute to poorer clinical outcomes. Cotard's 'Le Délire de Negation', are very rare nihilistic delusions, historically described with psychotic disorders. Their association with variety of neurologic disorders, including migraine and cluster-headache, has also been reported. Here we present three cases of Cotard's parasomnia during which distinct states of consciousness defined by nihilistic ideation are reported. Patients described believing to be dead or dying, whilst unable to perceive or experience their bodies in whole, or in part, as their own. The source analysis of electroencephalographic fingerprint of these mentations suggests right hemispheric hypoactivity subsequent to confusional arousals. Mechanistically, an aberrant activation of two major intrinsic brain networks of wakefulness, the salience and the default-mode-network is argued.

Adherence to wakefulness promoting medication in patients with narcolepsy.

OBJECTIVE: Narcolepsy management usually requires lifelong pharmacotherapy. However, we know little about adherence to prescribed treatment in narcolepsy. We assessed adherence to wakefulness-promoting agents in narcolepsy patients. PATIENTS AND METHODS: We retrospectively assessed adherence to wakefulness promoting medication in patients with narcolepsy using the Medicines Possession Ratio (MPR). Three levels of adherence were defined: poor (≤50%), intermediate (51-79%), and good (≥80%). Refractory daytime sleepiness was defined as an Epworth sleepiness scale (ESS) score >12 despite trialling at least three wakefulness-promoting agents. We compared demographic and clinical factors, and prescribed medications between patients, stratified by levels of adherence, as well as by presence or not of refractory sleepiness. RESULTS: We included 116 patients with narcolepsy (54.3% female, mean age 39.4 (±14) years). In sum, 93 (80.2%) patients had a diagnosis of narcolepsy type 1 (NT1), and 23 (19.8%) of type 2 (NT2). Suboptimal symptom control was common: 39.8% had refractory sleepiness, and 47.3% of NT1 patients had persistent cataplexy. Good adherence was seen in only 55.2% of patients, while 12.9% were intermediately and 31.9% poorly adherent. Patients with poor adherence were more likely to have a diagnosis of NT2, but adherence did not vary according to gender, age, the presence of psychiatric co-morbidity, or the presence of apparent intractable symptoms. Levels of good adherence to therapy were no better in patients with refractory sleepiness than in those with satisfactory symptom control (56.5% vs 54.3%; p = 0.81). CONCLUSION: Suboptimal adherence to prescribed therapy is common in narcolepsy patients, including those with apparent intractable symptoms, and particularly in patients with NT2.