Restless legs syndrome: From clinic to personalized medicine.

Restless legs syndrome (RLS) is a common neurological sensorimotor disorder that impairs sleep, mood and quality of life. RLS is defined by an urge to move the legs at rest that increases in the evening and at night, and is frequently associated with metabolic and cardiovascular diseases. Symptoms frequency, age at RLS onset, severity, familial history and consequences of RLS vary widely between patients. A genetic susceptibility, iron deficiency, dopamine deregulation, and possible hypo-adenosinergic state may play a role in the pathophysiology of RLS. Polysomnographic recordings found often periodic leg movements during sleep and wakefulness in patients with RLS. RLS can be classified as primary or comorbid with major diseases: iron deficiency, renal, neurological, rheumatological and lung diseases. First-line treatments are low-dose dopamine agonists, and alpha-2-delta ligands depending on the clinical context, and second/third line opiates for pharmacoresistant forms of RLS. Augmentation syndrome is a serious complication of dopamine agonists and should be prevented by using the recommended low dose. Despite an increase in knowledge, RLS is still underdiagnosed, poorly recognized, resulting in substantial individual health burden and socioeconomic coast, and education is urgently needed to increase awareness of this disabling disorder.

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.

Nocturnal agitation: From sleep state dissociation to sleep-related dissociative state.

Nocturnal agitation refers to a broad spectrum of symptoms from simple movements to aggressive behaviors with partial or complete loss of awareness. An accurate identification of its etiology is critical for appropriate therapeutic intervention. In children and young adults, distinguishing between non-rapid eye movement (NREM) sleep parasomnias and psychogenic non-parasomniac manifestations, a condition known as sleep-related dissociative disorder (SRDD), can be challenging. This review aims to summarize current clinical, neurophysiological, and epidemiological knowledge on NREM parasomnia and SRDD, and to present the pathophysiological hypotheses underlying these nocturnal manifestations. Sleepwalking, sleep terror and confusional arousals are the three main presentations of NREM parasomnias and share common clinical characteristics. Parasomniac episodes generally occur 30minutes to three hours after sleep-onset, they are usually short, lasting no more than few minutes and involve non-stereotyped, clumsy behaviors with frequent amnesia. The prevalence of NREM parasomnia decreases from 15-30% in children to 2-4% in adults. Parasomniac episodes are incomplete awakening from the deepest NREM sleep and are characterized by a dissociated brain activity, with a wake-like activation in motor and limbic structures and a preserved sleep in the fronto-parietal regions. SRDD is a less known condition characterized by dramatic, often very long episodes with frequent aggressive and potentially dangerous behaviors. SRDD episodes frequently occur in quiet wakefulness before falling asleep. These dissociative manifestations are frequently observed in the context of psychological trauma. The pathophysiology of SRDD is poorly understood but could involve transient changes in brain connectivity due to labile sleep-wake boundaries in predisposed individuals. We hypothesize that SRDD and NREM parasomnia are forms of sleep-related dissociative states favored by a sleep-wake state dissociation during sleep-onset and awakening process, respectively.

The multifaceted aspects of sleep and sleep-wake disorders following stroke.

Sleep-wake disorders (SWD) are acknowledged risk factors for both ischemic stroke and poor cardiovascular and functional outcome after stroke. SWD are frequent following stroke, with sleep apnea (SA) being the most frequent SWD affecting more than half of stroke survivors. While sleep disturbances and SWD are frequently reported in the acute phase, they may persist in the chronic phase after an ischemic stroke. Despite the frequency and risk associated with SWD following stroke, screening for SWD remains rare in the clinical setting, due to challenges in the assessment of post-stroke SWD, uncertainty regarding the optimal timing for their diagnosis, and a lack of clear treatment guidelines (i.e., when to treat and the optimal treatment strategy). However, little evidence support the feasibility of SWD treatment even in the acute phase of stroke and its favorable effect on long-term cardiovascular and functional outcomes. Thus, sleep health recommendations and SWD treatment should be systematically embedded in secondary stroke prevention strategy. We therefore propose that the management of SWD associated with stroke should rely on a multidisciplinary approach, with an integrated diagnostic, treatment, and follow-up strategy. The challenges in the field are to improve post-stroke SWD diagnosis, prognosis and treatment, through a better appraisal of their pathophysiology and temporal evolution.

[Potential teratogenicity of modafinil - Conflicting evidence, need for research]. / Tératogénicité potentielle du modafinil ­ des données contradictoires, un besoin de recherche.

Central disorders of hypersomnolence include narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia and hypersomnia associated with medical or mental disorders. Treatment is both non-pharmacological and pharmacological, including wake enhancing drugs and stimulants. One of the first-line treatment (modafinil, MODIODAL®) was the subject of a health authority alert in 2019 concerning a risk of major congenital malformations when taken during organogenesis. Since this date, three epidemiological studies have presented contradictory results. Given their methodological weaknesses, it is not possible at this stage to confirm or deny such a risk for the embryo and its nature if there is one. In clinical practice, because of these uncertainties, it is preferable if possible to suspend the treatment of a pregnant woman during the first 10 weeks from last menstrual period (organogenesis). There is an unmet clinical need for research to clarify the potential teratogenic impact of modafinil.

Socioeconomic impact of restless legs syndrome and inadequate restless legs syndrome management across European settings.

Restless legs syndrome (RLS) is one of the most common neurological disorders. It describes an irresistible urge to move the legs, mostly manifested in the evening and at night, which can lead to severe sleep disturbance. As part of the European Brain Council (EBC)-led Value-of-Treatment project, this study aimed at capturing the socioeconomic impact of RLS related to the inadequate diagnosis and treatment across different European healthcare settings. The economic burden of RLS was estimated using the published EBC framework of analysis in three separate European Union healthcare systems (France, Germany, and Italy). The RLS care pathway was mapped to identify the unmet needs of patients. Based on specific patient stories, the economic impact of correctly diagnosing RLS and changing between inadequate and target treatment was calculated using appropriate scenario analysis. RLS proved to be a significant personal and social burden, when epidemiological data, high prevalence of RLS, and its need for treatment are combined. By looking at the savings emerging from the provision of optimal care management (timely and correct diagnosis, evidence-based therapy, avoidance of therapy-related complications such as augmentation), the authors foresee substantial economic savings with the achievement of adequate diagnosis and treatment of RLS. Education about RLS is urgently needed for all subspecialties involved in RLS patient care as well as the general public. Equally important, the search for new causal treatment strategies should be intensified to reduce suffering and substantial societal cost.

Effects of an individualized exercise training program on severity markers of obstructive sleep apnea syndrome: a randomised controlled trial.

OBJECTIVE: Obstructive sleep apnea (OSA) is a high prevalent disorder with severe consequences including sleepiness, metabolic, and cardiovascular disorders. The aim of this study was to assess the effect of an individualized exercise-training (IET) program with educational sessions vs educational sessions alone on severity markers of OSA over an eight-week duration. METHODS: This was a randomised, controlled, parallel-design study. In sum, 64 patients with moderate-to-severe OSA (apnea-hypopnea index AHI 15-45/hour), low physical activity level (Voorrips<9), body-mass index (BMI) <40 kg/m2 were included in intervention group (IG) or control group (CG), and 54 patients finished the study. All underwent polysomnography (PSG), multiple sleep latency test (MSLT), constant workload exercise test, blood samples and fulfilled questionnaires twice. The primary endpoint was the change in apnea-hypopnea (AHI) at eight weeks from baseline. Main secondary endpoints were daytime sleepiness assessed by questionnaire and objective tests. RESULTS: No significant between-group differences were found for changes in AHI. A reduction in AHI was found in IG only (p = 0.005). Compared to CG, exercise training leads to a greater decrease in AHI during REM sleep (p = 0.0004), with a significant increase in mean daytime sleep latency (p = 0.02). Between-group differences were significant for weight reduction, severity of fatigue, insomnia and depressive symptoms with trend for sleepiness symptoms. CONCLUSIONS: In adult patients with moderate-to-severe OSA, IET did not decrease AHI compared to the control group but improved markers of severity of OSA, in particular AHI in rapid eye movement (REM) sleep and objective daytime sleepiness. Adding personalized exercise training to the management of patients with OSA should be considered. CLINICALTRIALS. GOV IDENTIFIER: NCT01256307.

Natural history of excessive daytime sleepiness: a population-based 5-year longitudinal study.

STUDY OBJECTIVES: To document the rates of persistent, remitted, and intermittent excessive daytime sleepiness (EDS) in a longitudinal 5-year community study of adults and to assess how changes in risk factors over time can predict improvement of daytime sleepiness (DS). METHODS: Participants were recruited in 2007-2008 as part of a population-based epidemiological study implemented in Canada. They completed postal assessments at baseline and at each yearly follow-up. An Epworth Sleepiness Scale total score >10 indicated clinically significant EDS; a 4-point reduction between two consecutive evaluations defined DS improvement. Socio-demographic, lifestyle, health characteristics, and sleep-related measures (e.g. insomnia symptoms, sleep duration, sleep medication) were self-reported at each time point. Cox proportional-hazard models were used to predict EDS and DS remissions over 5 years. RESULTS: Among the 2167 participants, 33% (n = 714) met criteria for EDS at baseline, of whom 33% had persistent EDS, 44% intermittent EDS, and 23% remitted EDS over the follow-up. Furthermore, 61.4% of 2167 initial participants had stable DS, 27.1% sustained DS improvement and 8.5% transient improvement over the follow-up. The main predictors of EDS remission or DS improvement were normal weight, taking less hypnotics, having hypertension, increased nighttime sleep duration, and decreased insomnia, and depressive symptoms. CONCLUSIONS: EDS waxes and wanes over time with frequent periods of remission and is influenced by behavioral characteristics and changes in psychological, metabolic, and nighttime sleep patterns. Targeting these predictors in future interventions is crucial to reduce DS in the general adult population.

Guidance to 2018 good practice: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma.

AIMS: Mobile Airways Sentinel NetworK (MASK) belongs to the Fondation Partenariale MACVIA-LR of Montpellier, France and aims to provide an active and healthy life to rhinitis sufferers and to those with asthma multimorbidity across the life cycle, whatever their gender or socio-economic status, in order to reduce health and social inequities incurred by the disease and to improve the digital transformation of health and care. The ultimate goal is to change the management strategy in chronic diseases. METHODS: MASK implements ICT technologies for individualized and predictive medicine to develop novel care pathways by a multi-disciplinary group centred around the patients. STAKEHOLDERS: Include patients, health care professionals (pharmacists and physicians), authorities, patient's associations, private and public sectors. RESULTS: MASK is deployed in 23 countries and 17 languages. 26,000 users have registered. EU GRANTS 2018: MASK is participating in EU projects (POLLAR: impact of air POLLution in Asthma and Rhinitis, EIT Health, DigitalHealthEurope, Euriphi and Vigour). LESSONS LEARNT: (i) Adherence to treatment is the major problem of allergic disease, (ii) Self-management strategies should be considerably expanded (behavioural), (iii) Change management is essential in allergic diseases, (iv) Education strategies should be reconsidered using a patient-centred approach and (v) Lessons learnt for allergic diseases can be expanded to chronic diseases.

French consensus: Augmentation syndrome in restless legs syndrome.

Augmentation syndrome is one of the most severe complications of RLS. It is characterised by a worsening of treated symptoms; principally an increase in the severity of symptoms and an earlier onset time. Augmentation syndrome occurs primarily with dopaminergic treatments. It is crucial for the patient to be sufficiently well informed to prevent its occurrence and the prescription of too high doses of dopaminergic agonists avoided. In the presence of augmentation syndrome confirmed using the diagnostic criteria, the specialist treating the restless legs syndrome should quickly modify the patient's treatment. In this article, our expert group proposes a practical strategy for the diagnosis, prevention and treatment of augmentation syndrome.

Prevalence of obstructive sleep apnoea in acute coronary syndrome: Routine screening in intensive coronary care units.

INTRODUCTION: Increased evidence has shown that, despite the maximum care afforded to patients admitted with acute coronary syndromes (ACS), a residual risk of mortality remains, in which obstructive sleep apnoea (OSA) appears to be a largely undiagnosed factor, particularly in the intensive cardiac care unit (ICCU). The purpose of this study is to determine whether the systematic screening for sleep-disordered breathing (SDB) is feasible and may be recommended. The aims of our study are to determine: (1) The estimated prevalence of OSA in patients admitted to the ICCU for ACS determined by a validated, user-friendly portable screening device; (2) The feasibility of the screening in this context; (3) To assess any negative impact of OSA on the severity of ACS. PATIENTS AND METHODS: This is an observational study of 101 patients admitted to the ICCU for ACS showing no clinical evidence of heart failure (HF). In the 24-72hours following admission, they underwent an overnight sleep study using a 3-channel portable screening device with automatic analysis. RESULTS: Sixty-two out of the 101 patients proved positive to the screening test, and its feasibility was acceptable. OSA patients tended to have greater peak levels of hs-cTnT (3685±3576ng/L versus 2830±3333ng/L, P=0.08) than the non-OSA group. Compared with the non-OSA group, OSA patients presented more severe ACS, with a greater average GRACE score at admission of 112.2±26.3 (versus 98.4±19.2, P<0.001). In the OSA group, we found a statistically significant inverse correlation between the apnoea-hypopnea index (AHI) and the left ventricular ejection fraction (LVEF) in the linear regression analysis (r=-0.26; P=0.037). CONCLUSIONS: A systematic screening of patients in the ICCU is acceptable. OSA is frequently found in the acute phase of ischaemic heart disease and its presence is associated with more severe ACS and a poorer left ventricle systolic function.

Incidence, worsening and risk factors of daytime sleepiness in a population-based 5-year longitudinal study.

Excessive daytime sleepiness (EDS) is highly prevalent in the general population; however little is known about its evolution and predictors. Our objectives were to document its natural history, provide estimates of its prevalence, incidence and persistence rates, and to identify predictors of increased daytime sleepiness (DS) in a longitudinal community study of 2157 adults over 5 years. Participants completed postal assessment at baseline and at each yearly follow-up. DS was evaluated by the Epworth Sleepiness scale (ESS). At baseline, 33% reported EDS (ESS > 10) with 33% of them reported persistent EDS. Of those without EDS at baseline, 28% developed incident EDS (15% were persistent) and 31% increased DS (augmentation ≥4-points between two consecutive evaluations). Younger age and depression were independent predictors of incident EDS and DS increase while lower coffee consumption, smoking, insomnia, tiredness and chronic pain were associated with incident EDS, and living alone with DS increase only. Persistent vs transient EDS or DS showed association with poor general health including metabolic diseases. Thus, sleepiness fluctuated over time and it was predicted by common lifestyle and psychological factors potentially modifiable. However, persistent sleepiness was associated with chronic medical diseases thus highlighting a homogeneous group at risk requiring a dedicated management.

French consensus. Idiopathic hypersomnia: Investigations and follow-up.

Idiopathic hypersomnia is a rare, central hypersomnia, recently identified and to date of unknown physiopathology. It is characterised by a more or less permanent, excessive daytime sleepiness, associated with long and unrefreshing naps. Night-time sleep is of good quality, excessive in quantity, associated with sleep inertia in the subtype previously described as "with long sleep time". Diagnosis of idiopathic hypersomnia is complex due to the absence of a quantifiable biomarker, the heterogeneous symptoms, which overlap with the clinical picture of type 2 narcolepsy, and its variable evolution over time. Detailed evaluation enables other frequent causes of somnolence, such as depression or sleep deprivation, to be eliminated. Polysomnography and multiple sleep latency tests (MSLT) are essential to rule out other sleep pathologies and to objectify excessive daytime sleepiness. Sometimes the MSLT do not show excessive sleepiness, hence a continued sleep recording of at least 24hours is necessary to show prolonged sleep (>11h/24h). In this article, we propose recommendations for the work-up to be carried out during diagnosis and follow-up for patients suffering from idiopathic hypersomnia.

French consensus. Hypersomnolence: Evaluation and diagnosis.

Sleepiness is one of the most frequently reported complaints in adults and children during specialised sleep consultations. It is responsible for an alteration that can be severe in quality of life, a lowering of academic or professional performance, and domestic or work accidents. Hypersomnolence is the first cause of road accidents on the highway, responsible for a third of fatal accidents. Furthermore its presence is associated with an increased risk of morbi-mortality related to cardiovascular and neurodegenerative pathologies. Hence, its represents a real public health issue. Recent revisions in international classifications have clarified confusing terminology, and the complaint of hypersomnia has now been replaced by the terms hypersomnolence or excessive sleepiness. It is clinically defined as an excessive quantity of sleep over 24hours, and/or by an alteration in the quality of arousal defined as incapacity to maintain a satisfactory level of vigilance during the day or in the morning on awakening (defined as sleep inertia). The evaluation of sleepiness requires a rigorous clinical approach, completed by subjective and objective measurements. The Epworth Sleep Scale, Multiple Sleep Latency Tests and the Maintenance of Wakefulness Test are the most studied and used in clinical practice. However, to date, no gold standard measurement of excessive sleepiness exists, and there are no quantifiable biological markers. It is therefore important to optimise our evaluation tools, improve our pathophysiological understanding of sleepiness, and define genetic and environmental risk factors.

French consensus. Type 1 and type 2 Narcolepsy: Investigations and follow-up.

In the new international classification of sleep disorders (ICSD-3), narcolepsy is differentiated into two distinct pathologies: type 1 narcolepsy (NT1) and type 2 narcolepsy (NT2). NT1 is characterised by periods of an irrepressible need to sleep, cataplexy (a sudden loss of muscle tone triggered by emotion) and in some cases the presence of symptoms such as hypnagogic hallucinations, sleep paralysis and disturbed night-time sleep. Its physiopathology is based on the loss of hypocretin neurons in the hypothalamus, seemingly connected to an auto-immune process. By definition, cataplexy is absent and the hypocretin levels in the CSF are normal in NT2. Confirming the diagnosis requires polysomnography and multiple sleep latency tests. The choice of further investigations is based on the presence or absence of typical cataplexy. Further investigations include HLA typing, lumbar puncture to measure the hypocretin level in the CSF, or even brain imagery in the case of narcolepsy suspected to be secondary to an underlying pathology. In this consensus we propose recommendations for the work-up to be carried out during diagnosis and follow-up for patients suffering from narcolepsy.

French consensus. Management of patients with hypersomnia: Which strategy?

Central hypersomnias principally involves type 1 narcolepsy (NT1), type 2 narcolepsy (NT2) and idiopathic hypersomnia (IH). Despite great progress made in understanding the physiopathology of NT1 with low cerebrospinal fluid hypocretin-1 levels, current treatment remains symptomatic. The same applies to NT2 and IH, for which the physiopathology is still largely unknown. Controlling excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed night-time sleep are key therapeutic targets in NT1. For IH and NT2, reducing EDS is the main objective. Based on European and American directives for the treatment of narcolepsy, we propose French recommendations for managing central hypersomnias as well as strategies in the case of drug-resistance. Stimulating treatments target EDS, and Modafinil is the first-line treatment. Other stimulants such as methylphenidate, pitolisant, and exceptionally dextro-amphetamine can be prescribed. Selective serotonin and noradrenaline reuptake inhibitor antidepressants are effective for the management of cataplexy in NT1. Sodium oxybate is an effective treatment for several symptoms, including EDS, cataplexy and disturbed night-time sleep. Treatment of central hypersomnia must also take into consideration frequent cardiovascular, metabolic and psychiatric comorbidities, particularly in NT1. New therapies are currently under study with the development of new stimulants and anti-cataplectics. The next few years will see innovative emerging therapies, based on a physiopathological approach, aiming to restore hypocretinergic transmission or to interrupt the autoimmune processes causing the loss of hypocretin neurons.

Absence of NMDA receptor antibodies in the rare association between Type 1 Narcolepsy and Psychosis.

Frequency and mechanisms underlying the association between narcolepsy type 1 (NT1) and psychosis remain unclear with potential role for a common immune pathway. We estimated the frequency of psychosis and its characteristics in NT1 at two European sleep centers (France, n = 381; Spain, n = 161) and measured IgG autoantibodies that recognize the GluN1 subunit of the NMDAR in 9 patients with NT1 with psychosis, and 25 NT1 patients without psychosis. Ten NT1 patients (6 in France, 4 in Spain) were diagnosed with comorbid psychosis, a frequency of 1.8%. One patient reported psychotic symptoms few months before narcolepsy onset, two patients few months after onset, and one patient one year after onset but after modafinil introduction. The six remaining patients reported long delays between NT1 and psychosis onset. Half the patients, mostly male adults, reported onset or worsening of psychotic symptoms after medication. We found no IgG antibodies to NR1/NR2B heteromers of the NMDARs in patients with NT1 with or without psychosis. To conclude, psychosis is rare in NT1, with limited evidence for a key impact of stimulants, and no association with anti-NMDAR antibodies. However, dramatic NT1 and schizophrenia exists especially in early onset NT1, which may lead to inappropriate diagnosis and management.

Parkinson's Disease Genetic Loci in Rapid Eye Movement Sleep Behavior Disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson's disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The SCARB2 rs6812193 (OR = 0.67, 95 % CI = 0.51-0.88, p = 0.004) and the MAPT rs12185268 (OR-0.43, 95 % CI-0.26-0.72, p = 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (n = 56), demonstrated that homozygous carriers of the USP25 rs2823357 SNP had progressed to synucleinopathies faster than others (log-rank p = 0.003, Breslow p = 0.005, Tarone-Ware p = 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies.