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.
Sleep-disordered breathing (SDB) and sleep-wake disturbances (SWD) are highly prevalent in stroke patients. Recent studies suggest that they represent both a risk factor and a consequence of stroke ...and affect stroke recovery, outcome, and recurrence.
Review of literature.
Several studies have proven SDB to represent an independent risk factor for stroke. Sleep studies in TIA and stroke patients are recommended in view of the very high prevalence (>50%) of SDB (Class IIb, level of evidence B). Treatment of obstructive SDB with continuous positive airway pressure is recommended given the strength of the increasing evidence in support of a positive effect on outcome (Class IIb, level of evidence B). Oxygen, biphasic positive airway pressure, and adaptive servoventilation may be considered in patients with central SDB. Recently, both reduced and increased sleep duration, as well as hypersomnia, insomnia, and restless legs syndrome (RLS), were also suggested to increase stroke risk. Mainly experimental studies found that SWD may in addition impair neuroplasticity processes and functional stroke recovery. Treatment of SWD with hypnotics and sedative antidepressants (insomnia), activating antidepressants or stimulants (hypersomnia), dopaminergic drugs (RLS), and clonazepam (parasomnias) are based on single case observations and should be used with caution.
SDB and SWD increase the risk of stroke in the general population and affect short- and long-term stroke recovery and outcome. Current knowledge supports the systematic implementation of clinical procedures for the diagnosis and treatment of poststroke SDB and SWD on stroke units.
Clinical sleep scoring involves a tedious visual review of overnight polysomnograms by a human expert, according to official standards. It could appear then a suitable task for modern artificial ...intelligence algorithms. Indeed, machine learning algorithms have been applied to sleep scoring for many years. As a result, several software products offer nowadays automated or semi-automated scoring services. However, the vast majority of the sleep physicians do not use them. Very recently, thanks to the increased computational power, deep learning has also been employed with promising results. Machine learning algorithms can undoubtedly reach a high accuracy in specific situations, but there are many difficulties in their introduction in the daily routine. In this review, the latest approaches that are applying deep learning for facilitating and accelerating sleep scoring are thoroughly analyzed and compared with the state of the art methods. Then the obstacles in introducing automated sleep scoring in the clinical practice are examined. Deep learning algorithm capabilities of learning from a highly heterogeneous dataset, in terms both of human data and of scorers, are very promising and should be further investigated.
Neurological disorders account for a large and increasing health burden worldwide, as shown in the Global Burden of Diseases (GBD) Study 2016. Unpacking how this burden varies regionally and ...nationally is important to inform public health policy and prevention strategies. The population in the EU is older than that of the WHO European region (western, central, and eastern Europe) and even older than the global population, suggesting that it might be particularly vulnerable to an increasing burden of age-related neurological disorders. We aimed to compare the burden of neurological disorders in the EU between 1990 and 2017 with those of the WHO European region and worldwide.
The burden of neurological disorders was calculated for the year 2017 as incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability for the countries in the EU and the WHO European region, totally and, separately. Diseases analysed were Alzheimer's disease and other dementias, epilepsy, headache (migraine and tension-type headache), multiple sclerosis, Parkinson's disease, brain cancer, motor neuron diseases, neuroinfectious diseases, and stroke. Data are presented as totals and by sex, age, year, location and socio-demographic context, and shown as counts and rates.
In 2017, the total number of DALYs attributable to neurological disorders was 21·0 million (95% uncertainty interval 18·5–23·9) in the EU and 41·1 million (36·7–45·9) in the WHO European region, and the total number of deaths was 1·1 million (1·09–1·14) in the EU and 1·97 million (1·95–2·01) in the WHO European region. In the EU, neurological disorders ranked third after cardiovascular diseases and cancers representing 13·3% (10·3–17·1) of total DALYs and 19·5% (18·0–21·3) of total deaths. Stroke, dementias, and headache were the three commonest causes of DALYs in the EU. Stroke was also the leading cause of DALYs in the WHO European region. During the study period we found a substantial increase in the all-age burden of neurodegenerative diseases, despite a substantial decrease in the rates of stroke and infections. The burden of neurological disorders in Europe was higher in men than in women, peaked in individuals aged 80–84 years, and varied substantially with WHO European region and country. All-age DALYs, deaths, and prevalence of neurological disorders increased in all-age measures, but decreased when using age-standardised measures in all but three countries (Azerbaijan, Turkmenistan, and Uzbekistan). The decrease was mostly attributed to the reduction of premature mortality despite an overall increase in the number of DALYs.
Neurological disorders are the third most common cause of disability and premature death in the EU and their prevalence and burden will likely increase with the progressive ageing of the European population. Greater attention to neurological diseases must be paid by health authorities for prevention and care. The data presented here suggest different priorities for health service development and resource allocation in different countries.
European Academy of Neurology.
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.
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.
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.
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