Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by ...excessive daytime sleepiness and cataplexy, accompanied by sleep-wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02. Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep-wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the 'narcoleptic borderland', including narcolepsy type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed.
At present, the standard practices for home-based assessments of abnormal movements in Parkinson’s disease (PD) are based either on subjective tools or on objective measures that often fail to ...capture day-to-day fluctuations and long-term information in real-life conditions in a way that patient’s compliance and privacy are secured. The employment of wearable technologies in PD represents a great paradigm shift in healthcare remote diagnostics and therapeutics monitoring. However, their applicability in everyday clinical practice seems to be still limited. We carried out a systematic search across the Medline Database. In total, 246 publications, published until 1 June 2020, were identified. Among them, 26 reports met the inclusion criteria and were included in the present review. We focused more on clinically relevant aspects of wearables’ application including feasibility and efficacy of the assessment, the number, type and body position of the wearable devices, type of PD motor symptom, environment and duration of assessments and validation methodology. The aim of this review is to provide a systematic overview of the current knowledge and state-of-the-art of the home-based assessment of motor symptoms and fluctuations in PD patients using wearable technology, highlighting current problems and laying foundations for future works.
Daytime functioning is impaired in people with insomnia disorder. Currently available dual orexin receptor antagonists have shown efficacy in insomnia disorder, but do not address all aspects of this ...disease. We aimed to assess safety and efficacy of daridorexant, a novel orexin receptor antagonist, on night-time and daytime symptoms of insomnia.
We did two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials at 156 sites in 18 countries. Adults (aged ≥18 years) with insomnia disorder were randomly assigned using interactive response technology (1:1:1) to receive daridorexant 50 mg, 25 mg, or placebo (study 1) or daridorexant 25 mg, 10 mg, or placebo (study 2) every evening for 3 months. Participants, investigators, and site personnel were masked to treatment allocation. The primary endpoints were change from baseline in wake time after sleep onset (WASO) and latency to persistent sleep (LPS), measured by polysomnography, at months 1 and 3. The secondary endpoints were change from baseline in self-reported total sleep time and the sleepiness domain score of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) at months 1 and 3. Study-wise type I error rate (5%) was controlled for all pairwise comparisons. Efficacy was analysed in all randomly assigned participants, and safety in all participants who received at least one dose of treatment. The studies are registered at ClinicalTrials.gov, NCT03545191 (study 1) and NCT03575104 (study 2).
Between June 4, 2018 and Feb 25, 2020, 930 participants were randomly assigned to receive daridorexant 50 mg (n=310), daridorexant 25 mg (n=310), or placebo (n=310) in study 1. Between May 29, 2018, and May 14, 2020, 924 participants were randomly assigned to receive daridorexant 25 mg (n=309), daridorexant 10 mg (n=307), or placebo (n=308) in study 2. In study 1, WASO and LPS were significantly reduced among participants in the daridorexant 50 mg group compared with participants in the placebo group at month 1 (least squares mean LSM difference −22·8 min 95% CI −28·0 to −17·6, p<0·0001 for WASO; –11·4 min −16·0 to −6·7, p<0·0001 for LPS) and month 3 (−18·3 min −23·9 to −12·7, p<0·0001 for WASO; −11·7 min −16·3 to −7·0, p<0·0001 for LPS). WASO and LPS were significantly reduced among participants in the daridorexant 25 mg group compared with the placebo group at month 1 (LSM difference −12·2 min −17·4 to −7·0, p<0·0001 for WASO; –8·3 min −13·0 to −3·6, p=0·0005 for LPS) and month 3 (−11·9 min −17·5 to −6·2, p<0·0001 for WASO; −7·6 min −12·3 to −2·9, p=0·0015 for LPS). Compared with placebo, participants in the daridorexant 50 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 22·1 min 14·4 to 29·7, p<0·0001) and month 3 (19·8 min 10·6 to 28·9, p<0·0001), and IDSIQ sleepiness domain scores at month 1 (–1·8 –2·5 to –1·0, p<0·0001) and month 3 (–1·9 –2·9 to –0·9, p=0·0002). Compared with the placebo group, participants in the daridorexant 25 mg group had significantly improved self-reported total sleep time at month 1 (LSM difference 12·6 min 5·0 to 20·3, p=0·0013) and month 3 (9·9 min 0·8 to 19·1, p=0·033), but not IDSIQ sleepiness domain scores (–0·8 –1·5 to 0·01, p=0·055 at month 1; –1·0 –2·0 to 0·01, p=0·053 at month 3). In study 2, WASO was significantly reduced among participants in the daridorexant 25 mg group compared with participants in the placebo group at month 1 (LSM difference −11·6 min −17·6 to −5·6, p=0·0001) and month 3 (−10·3 min −17·0 to −3·5, p=0·0028), whereas no significant differences in LPS were observed at month 1 (–6·5 min –12·3 to –0·6, p=0·030) or month 3 (–9·0 –15·3 to –2·7, p=0·0053). Compared with the placebo group, participants in the daridorexant 25 mg group had significant improvement in self-reported total sleep time at month 1 (LSM difference 16·1 min 8·2 to 24·0, p<0·0001) and month 3 (19·1 10·1 to 28·0, p<0·0001), but not in IDSIQ sleepiness domain scores (–0·8 –1·6 to 0·1, p=0·073 at month 1; –1·3 –2·2 to –0·3, p=0·012 at month 3). Compared with the placebo group, no significant differences were observed among participants in the daridorexant 10 mg group for WASO (LSM difference –2·7 min –8·7 to 3·2, p=0·37 at month 1; –2·0 –8·7 to 4·8, p=0·57 at month 3), LPS (–2·6 min –8·4 to 3·2, p=0·38 at month 1; –3·2 min –9·5 to 3·1, p=0·32 at month 3), self-reported total sleep time (13·4 min 5·5 to 21·2, p=0·0009 at month 1; 13·6 min 4·7 to 22·5, p=0·0028 at month 3), nor IDSIQ sleepiness domain scores (–0·4 –1·3 to 0·4, p=0·30 at month 1; –0·7 –1·7 to 0·2, p=0·14 at month 3). Overall incidence of adverse events was comparable between treatment groups (116 38% of 308 participants in the daridorexant 50 mg group, 117 38% of 310 in the daridorexant 25 mg group, and 105 34% of 309 in the placebo group in study 1; 121 39% of 308 participants in the daridorexant 25 mg group, 117 38% of 306 in the daridorexant 10 mg group, and 100 33% of 306 in the placebo group). Nasopharyngitis and headache were the most common adverse events in all groups. One death (cardiac arrest) occurred in the daridorexant 25 mg group in study 1, which was not deemed to be treatment-related.
Daridorexant 25 mg and 50 mg improved sleep outcomes, and daridorexant 50 mg also improved daytime functioning, in people with insomnia disorder, with a favourable safety profile.
Idorsia Pharmaceuticals.
Abstract
Three papers currently published in SLEEP using two different mouse models of narcolepsy, including either Hcrt-tTa;TetO diptheria toxin-A (DTA) or Hypocretin knock-out (Hcrt-KO) mice, ...suggest important gender differences in narcolepsy expression. Specifically, these recent data corroborate previous findings in mice demonstrating that females show more cataplexy events and more total cataplexy expression than males. Moreover, in the neurotoxic DTA mouse model, females show earlier onset of cataplexy expression than males during active Hcrt cell loss. Finally, females show a doubling of cataplexy during estrous compared to other phases of the estrous cycle. These findings are reviewed in the broader context of prior published literature, including reported gender differences in Hcrt expression and hormonal influences on sleep and wakefulness. Although similar findings have not been reported in humans, a systematic evaluation of gender differences in human narcolepsy has yet to be performed. Taken together, these animal data suggest that more research exploring gender differences in human narcolepsy is warranted.
Sleep apnoea, one of the most common chronic diseases, is a risk factor for ischaemic stroke, stroke recurrence, and poor functional recovery after stroke. More than half of stroke survivors present ...with sleep apnoea during the acute phase after stroke, with obstructive sleep apnoea being the most common subtype. Following a stroke, sleep apnoea frequency and severity might decrease over time, but moderate to severe sleep apnoea is nevertheless present in up to a third of patients in the chronic phase after an ischaemic stroke. Over the past few decades evidence suggests that treatment for sleep apnoea is feasible during the acute phase of stroke and might favourably affect recovery and long-term outcomes. Nevertheless, sleep apnoea still remains underdiagnosed and untreated in many cases, due to challenges in the detection and prediction of post-stroke sleep apnoea, uncertainty as to the optimal timing for its diagnosis, and a scarcity of clear treatment guidelines (ie, uncertainty on when to treat and the optimal treatment strategy). Moreover, the pathophysiology of sleep apnoea associated with stroke, the proportion of stroke survivors with obstructive and central sleep apnoea, and the temporal evolution of sleep apnoea subtypes following stroke remain to be clarified. To address these shortcomings, the management of sleep apnoea associated with stroke should be integrated into a multidisciplinary diagnostic, treatment, and follow-up strategy.
Summary
Background and aim
Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence‐based guidelines ...for the management of narcolepsy in both adults and children.
Methods
The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU‐NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.
Results
A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults—scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults—SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children—scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children—SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient’s symptoms, comorbidities, tolerance and risk of potential drug interactions.
Conclusion
The management of narcolepsy involves non‐pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.
Management of narcolepsy involves both non‐pharmacological and pharmacological approaches. An increasing number of symptomatic treatment options for adults and children is available.
Functional recovery after stroke is associated with a remapping of neural circuits. This reorganization is often associated with low-frequency, high-amplitude oscillations in the peri-infarct zone in ...both rodents and humans. These oscillations are reminiscent of sleep slow waves (SW) and suggestive of a role for sleep in brain plasticity that occur during stroke recovery; however, direct evidence is missing. Using a stroke model in male mice, we showed that stroke was followed by a transient increase in NREM sleep accompanied by reduced amplitude and slope of ipsilateral NREM sleep SW. We next used 5 ms optical activation of Channelrhodopsin 2-expressing pyramidal neurons, or 200 ms silencing of Archeorhodopsin T-expressing pyramidal neurons, to generate local cortical UP, or DOWN, states, respectively, both sharing similarities with spontaneous NREM SW in freely moving mice. Importantly, we found that single optogenetically evoked SW (SW
) in the peri-infarct zone, randomly distributed during sleep, significantly improved fine motor movements of the limb corresponding to the sensorimotor stroke lesion site compared with spontaneous recovery and control conditions, while motor strength remained unchanged. In contrast, SW
during wakefulness had no effect. Furthermore, chronic SW
during sleep were associated with local axonal sprouting as revealed by the increase of anatomic presynaptic and postsynaptic markers in the peri-infarct zone and corresponding contralesional areas to cortical circuit reorganization during stroke recovery. These results support a role for sleep SW in cortical circuit plasticity and sensorimotor recovery after stroke and provide a clinically relevant framework for rehabilitation strategies using neuromodulation during sleep.
Brain stroke is one of the leading causes of death and major disabilities in the elderly worldwide. A better understanding of the pathophysiological mechanisms underlying spontaneous brain plasticity after stroke, together with an optimization of rehabilitative strategies, are essential to improve stroke treatments. Here, we investigate the role of optogenetically induced sleep slow waves in an animal model of ischemic stroke and identify sleep as a window for poststroke intervention that promotes neuroplasticity and facilitates sensorimotor recovery.
Ambient temperature (Ta) warming toward the high end of the thermoneutral zone (TNZ) preferentially increases rapid eye movement (REM) sleep over non-REM (NREM) sleep across species. The control and ...function of this temperature-induced REM sleep expression have remained unknown. Melanin-concentrating hormone (MCH) neurons play an important role in REM sleep control. We hypothesize that the MCH system may modulate REM sleep as a function of Ta. Here, we show that wild-type (WT) mice dynamically increased REM sleep durations specifically during warm Ta pulsing within the TNZ, compared to both the TNZ cool and baseline constant Ta conditions, without significantly affecting either wake or NREM sleep durations. However, genetically engineered MCH receptor-1 knockout (MCHR1-KO) mice showed no significant changes in REM sleep as a function of Ta, even with increased sleep pressure following a 4-h sleep deprivation. Using MCH-cre mice transduced with channelrhodopsin, we then optogenetically activated MCH neurons time locked with Ta warming, showing an increase in REM sleep expression beyond what Ta warming in yellow fluorescent protein (YFP) control mice achieved. Finally, in mice transduced with archaerhodopsin-T, semi-chronic optogenetic MCH neuronal silencing during Ta warming completely blocked the increase in REM sleep seen in YFP controls. These data demonstrate a previously unknown role for the MCH system in the dynamic output expression of REM sleep during Ta manipulation. These findings are consistent with the energy allocation hypothesis of sleep function, suggesting that endotherms have evolved neural circuits to opportunistically express REM sleep when the need for thermoregulatory defense is minimized.
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•Wild-type mice dynamically increase REM sleep with ambient temperature (Ta) warming•Optogenetic MCH activation overdrives REM sleep expression during Ta warming•Optogenetic MCH silencing or lack of MCH receptor blocks Ta modulation of REM sleep•The MCH system plays a critical role in modulating REM sleep as a function of Ta
The control and function of temperature-induced REM sleep modulation have remained unknown. Komagata et al. show that the melanin-concentrating hormone system within the lateral hypothalamus plays a critical role in the dynamic ability of the organism to opportunistically increase REM sleep when the need for core body temperature defense is minimized.
The aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on ...central disorders of hypersomnolence.
The ultimate goal for a sleep disorders classification is to be based on the underlying neurobiological causes of the disorders with clear implication for treatment or, ideally, prevention and or healing. The current ICSD classification, published in 2014, inevitably has important shortcomings, largely reflecting the lack of knowledge about the precise neurobiological mechanisms underlying the majority of sleep disorders we currently delineate. Despite a clear rationale for the present structure, there remain important limitations that make it difficult to apply in routine clinical practice. Moreover, there are indications that the current structure may even prevent us from gaining relevant new knowledge to better understand certain sleep disorders and their neurobiological causes.
We suggest the creation of a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence; containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity and sensitivity in the diagnostic context.
We propose and define three diagnostic categories (with levels of certainty):
1/“Narcolepsy” 2/“Idiopathic hypersomnia”, 3/“Idiopathic excessive sleepiness” (with subtypes).
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