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.

Evaluation of hypersomnolence: From symptoms to diagnosis, a multidimensional approach.

Hypersomnolence is a major public health issue given its high frequency, its impact on academic/occupational functioning and on accidentology, as well as its heavy socio-economic burden. The positive and aetiological diagnosis is crucial, as it determines the therapeutic strategy. It must consider the following aspects: i) hypersomnolence is a complex concept referring to symptoms as varied as excessive daytime sleepiness, excessive need for sleep, sleep inertia, or drowsiness, all of which warrant specific dedicated investigations; ii) the boundary between physiological and abnormal hypersomnolence is blurred, since most symptoms can be encountered in the general population to varying degrees without being considered as pathological, meaning that their severity, frequency, context of occurrence and related impairment need to be carefully assessed; iii) investigation of hypersomnolence relies on scales/questionnaires as well as behavioural and neurophysiological tests, which measure one or more dimensions, keeping in mind the possible discrepancy between objective and subjective assessment; iv) aetiological reasoning is driven by knowledge of the main sleep regulation mechanisms, epidemiology, and associated symptoms. The need to assess hypersomnolence is growing, both for its management, and for assessing the efficacy of treatments. The landscape of tools available for investigating hypersomnolence is constantly evolving, in parallel with research into sleep physiology and technical advances. These investigations face the challenges of reconciling subjective perception and objective data, making tools accessible to as many people as possible and predicting the risk of accidents.

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.

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.