SAS CARE 1: Sleep architecture changes in a cohort of patients with Ischemic Stroke/TIA.

OBJECTIVE: Changes in sleep architecture following ischemic stroke have been poorly investigated. Our objective was to explore changes of sleep structure in patients with ischemic stroke or transient ischemic attack in order to verify a possible predictive value of sleep with respect to clinical outcome. METHODS: Patients recruited in the prospective SAS-CARE study received two polysomnographies (PSG) in the acute and chronic phases after stroke/TIA. Sleep parameters were compared between the two time-points and matched with a non-stroke population randomly selected from the HypnoLaus cohort. RESULTS: Of the 169 patients investigated with PSG in the acute phase, 104 were again studied 3 months after stroke symptom onset and compared with 162 controls. The acute phase of stroke/TIA was associated with sleep disruption, which significantly improved in the chronic phase, but remained worse than controls (total sleep time improve from 318.8 ± 90.8 to 348.4 ± 81.5 min, compared to 388.2 ± 71.3 in controls, sleep latency from 49.9 ± 58.4 to 27.9 min, compared to 20.2 ± 22 in controls, sleep efficiency from 58.2 ± 18.1% to 27.9 ± 36.4 min, compared to 83.4 ± 10.3% in controls, wakefulness after sleep onset percentage from 36.5 ± 17.3 to 29.3 ± 15.6, compared to 13.2 ± 9.2 in controls). The percentage of REM sleep was negatively associated with stroke severity, whereas stroke topography did not correlate with sleep parameters. CONCLUSIONS: This study confirmed a severe sleep disruption in the acute phase of stroke. Although a significant improvement of sleep quality was observed during the three months after stroke, sleep architecture did not normalize. In particular, sleep efficiency and REM sleep seem to be particularly affected by stroke in the acute phase, with a relative preservation of NREM sleep. We suggest that these sleep architecture changes represent a persistent marker of brain damage due to stroke. Further studies are needed to assess the relationship with stroke topographic and outcome.

Focal lesions induce large-scale percolation of sleep-like intracerebral activity in awake humans.

Focal cortical lesions are known to result in large-scale functional alterations involving distant areas; however, little is known about the electrophysiological mechanisms underlying these network effects. Here, we addressed this issue by analysing the short and long distance intracranial effects of controlled structural lesions in humans. The changes in Stereo-Electroencephalographic (SEEG) activity after Radiofrequency-Thermocoagulation (RFTC) recorded in 21 epileptic subjects were assessed with respect to baseline resting wakefulness and sleep activity. In addition, Cortico-Cortical Evoked Potentials (CCEPs) recorded before the lesion were employed to interpret these changes with respect to individual long-range connectivity patterns. We found that small structural ablations lead to the generation and large-scale propagation of sleep-like slow waves within the awake brain. These slow waves match those recorded in the same subjects during sleep, are prevalent in perilesional areas, but can percolate up to distances of 60 mm through specific long-range connections, as predicted by CCEPs. Given the known impact of slow waves on information processing and cortical plasticity, demonstrating their intrusion and percolation within the awake brain add key elements to our understanding of network dysfunction after cortical injuries.

The evolution of the narcolepsy concept in Russia: A historical view.

Following the first descriptions of narcolepsy with cataplexy by Westphal, Gelineau, and Fischer (1878-1880), Russian authors started to report on "narcolepsy cases" in 1894. It was, however, only in 1925 that Mankovsky reported a (postencephalitic) case, satisfying current diagnostic criteria for the disease. In the following 66 years (the last publication appeared in 1991), Russian authors including Davidenkov, Vein, and Yakhno made interesting contributions on the clinical features, neurophysiological correlates (e.g., sleep states and boundary dyscontrol), pathogenesis (e.g., hypothalamic origin), etiology (e.g., infectious, postvaccinal triggers, focal encephalitis), and treatment (e.g., use of sodium oxybate) of narcolepsy. Until recently, Pavlov's theory of narcolepsy as a "cortical excitatory-inhibitory phenomenon" strongly influenced the Russian view on the disease, contrasting with the current neurobiological insights acknowledged internationally. A Narcolepsy Network, including currently 10 member centers, was recently founded to promote knowledge, awareness, management, and research on this still poorly known disease in Russia.

The international European Academy of Neurology survey on neurological symptoms in patients with COVID-19 infection.

BACKGROUND AND PURPOSE: Although the main clinical features of COVID-19 infection are pulmonary, several associated neurological signs, symptoms and diseases are emerging. The incidence and characteristics of neurological complications are unclear. For this reason, the European Academy of Neurology (EAN) core COVID-19 Task Force initiated a survey on neurological symptoms observed in patients with COVID-19 infection. METHODS: A 17-question online survey was made available on the EAN website and distributed to EAN members and other worldwide physicians starting on 9 April 2020. RESULTS: By 27 April 2020, proper data were collected from 2343 responders (out of 4199), of whom 82.0% were neurologists, mostly from Europe. Most responders (74.7%) consulted patients with COVID-19 mainly in emergency rooms and in COVID-19 units. The majority (67.0%) had evaluated fewer than 10 patients with neurological manifestations of COVID-19 (neuro COVID-19). The most frequently reported neurological findings were headache (61.9%), myalgia (50.4%), anosmia (49.2%), ageusia (39.8%), impaired consciousness (29.3%) and psychomotor agitation (26.7%). Encephalopathy and acute cerebrovascular disorders were reported at 21.0%. Neurological manifestations were generally interpreted as being possibly related to COVID-19; they were most commonly recognized in patients with multiple general symptoms and occurred at any time during infection. CONCLUSION: Neurologists are currently and actively involved in the management of neurological issues related to the COVID-19 pandemic. This survey justifies setting up a prospective registry to better capture the prevalence of patients with neuro COVID-19, neurological disease characteristics and the contribution of neurological manifestations to outcome.

EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke.

BACKGROUND: Sleep disorders are highly prevalent in the general population and may be linked in a bidirectional fashion to stroke, which is one of the leading causes of morbidity and mortality. AIM: Four major scientific societies established a task force of experts in neurology, stroke, respiratory medicine, sleep medicine and methodology to critically evaluate the evidence regarding potential links and the impact of therapy. MATERIALS AND METHODS: Thirteen research questions were evaluated in a systematic literature search using a stepwise hierarchical approach: first, systematic reviews and meta-analyses; second, primary studies post-dating the systematic reviews/meta-analyses. A total of 445 studies were evaluated and 88 were included. Statements were generated regarding current evidence and clinical practice. RESULTS: Severe obstructive sleep apnoea (OSA) doubles the risk for incident stroke, especially in young to middle-aged patients. Continuous positive airway pressure (CPAP) may reduce stroke risk, especially in treatment-compliant patients. The prevalence of OSA is high in stroke patients and can be assessed by polygraphy. Severe OSA is a risk factor for recurrence of stroke and may be associated with stroke mortality, whilst CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, whilst the pharmacotherapy of insomnia may increase it. Periodic limb movements in sleep (PLMS), but not restless limb syndrome (RLS), may be associated with an increased risk of stroke. Preliminary data suggest a high frequency of post-stroke insomnia and RLS and their association with a less favourable stroke outcome, whilst treatment data are scarce. DISCUSSION/CONCLUSION: Overall, the evidence base is best for OSA relationship with stroke and supports active diagnosis and therapy. Research gaps remain especially regarding insomnia and RLS/PLMS relationships with stroke.

SAS CARE 2 - a randomized study of CPAP in patients with obstructive sleep disordered breathing following ischemic stroke or transient ischemic attack.

OBJECTIVE/BACKGROUND: The benefit of Continuous Positive Airway Pressure (CPAP) treatment following ischemic stroke in patients with obstructive sleep-disordered breathing (SDB) is unclear. We set out to investigate this open question in a randomized controlled trial as part of the SAS-CARE study. PATIENTS/METHODS: Non-sleepy patients (ESS < 10) with ischemic stroke or transient ischemic attack (TIA) and obstructive SDB (AHI ≥ 20) 3 months post-stroke were randomized 1:1 to CPAP treatment (CPAP+) or standard care. Primary outcome was the occurrence of vascular events (TIA/stroke, myocardial infarction/revascularization, hospitalization for heart failure or unstable angina) or death within 24 months post-stroke. Secondary outcomes included Modified Rankin Scale (mRS) and Barthel Index. RESULTS: Among 238 SAS-CARE patients 41 (17%) non-sleepy obstructive SDB patients were randomized to CPAP (n = 19) or standard care (n = 22). Most patients (80%) had stroke and were males (78%), mean age was 64 ± 7 years and mean NIHSS score 0.6 ± 1.0 (range: 0-5). The primary endpoint was met by one patient in the standard care arm (a new stroke). In an intent-to treat analysis disregarding adherence, this corresponds to an absolute risk difference of 4.5% or an NNT = 22. mRS and Barthel Index were stable and similar between arms. CPAP adherence was sufficient in 60% of evaluable patients at month 24. CONCLUSION: No benefit of CPAP started three months post-stroke was found in terms of new cardio- and cerebrovascular events over 2 years. This may be related to the small size of this study, the mild stoke severity, the exclusion of sleepy patients, the delayed start of treatment, and the overall low event rate.

Individual spindle detection and analysis in high-density recordings across the night and in thalamic stroke.

Sleep spindles are thalamocortical oscillations associated with several behavioural and clinical phenomena. In clinical populations, spindle activity has been shown to be reduced in schizophrenia, as well as after thalamic stroke. Automatic spindle detection algorithms present the only feasible way to systematically examine individual spindle characteristics. We took an established algorithm for spindle detection, and adapted it to high-density EEG sleep recordings. To illustrate the detection and analysis procedure, we examined how spindle characteristics changed across the night and introduced a linear mixed model approach applied to individual spindles in adults (n = 9). Next we examined spindle characteristics between a group of paramedian thalamic stroke patients (n = 9) and matched controls. We found a high spindle incidence rate and that, from early to late in the night, individual spindle power increased with the duration and globality of spindles; despite decreases in spindle incidence and peak-to-peak amplitude. In stroke patients, we found that only left-sided damage reduced individual spindle power. Furthermore, reduction was specific to posterior/fast spindles. Altogether, we demonstrate how state-of-the-art spindle detection techniques, applied to high-density recordings, and analysed using advanced statistical approaches can yield novel insights into how both normal and pathological circumstances affect sleep.

[Headache in the emergency department]. / Kopfschmerz in der Notaufnahme.

Headache is one of the most frequent symptoms leading to visits at the emergency department. Here, we aim at presenting a pragmatic algorithm for headache patients at the emergency department. The basic principle is taking a detailed history of the current headache with a focus on dynamics, phenotype and trigger factors as well as a possible preexisting headache. "Red flags" should be interrogated specifically. Hypotheses of the etiology of the headache should be generated in combination with the clinical examination (vital signs, neurological exam, otorhinolaryngological and ophthalmological exams) and should be tested appropriately with imaging, laboratory, cerebral spinal fluid studies and ultrasound. Secondary headache have to be treated with a causal approach, if necessary also symptomatically. When a secondary headache can be excluded, we recommend aiming for a primary headache diagnosis with subsequent specific therapy. When a headache patient can be discharged, we recommend scheduling a follow-up appointment to understand the development of a secondary headache and its cause. In case of a primary headache, optimizing prophylaxis and acute therapy is important to prevent future emergency department visits.

Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

Baclofen and gamma-hydroxybutyrate differentially altered behavior, EEG activity and sleep in rats.

OBJECTIVES: Animal and human studies have shown that sleep may have an impact on functional recovery after brain damage. Baclofen (Bac) and gamma-hydroxybutyrate (GHB) have been shown to induce physiological sleep in humans, however, their effects in rodents are unclear. The aim of this study is to characterize sleep and electroencelphalogram (EEG) after Bac and GHB administration in rats. We hypothesized that both drugs would induce physiological sleep. METHODS: Adult male Sprague-Dawley rats were implanted with EEG/electromyogram (EMG) electrodes for sleep recordings. Bac (10 or 20 mg/kg), GHB (150 or 300 mg/kg) or saline were injected 1 h after light and dark onset to evaluate time of day effect of the drugs. Vigilance states and EEG spectra were quantified. RESULTS: Bac and GHB induced a non-physiological state characterized by atypical behavior and an abnormal EEG pattern. After termination of this state, Bac was found to increase the duration of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep (∼90 and 10 min, respectively), reduce sleep fragmentation and affect NREM sleep episode frequency and duration (p<0.05). GHB had no major effect on vigilance states. Bac drastically increased EEG power density in NREM sleep in the frequencies 1.5-6.5 and 9.5-21.5 Hz compared to saline (p<0.05), while GHB enhanced power in the 1-5-Hz frequency band and reduced it in the 7-9-Hz band. Slow-wave activity in NREM sleep was enhanced 1.5-3-fold during the first 1-2 h following termination of the non-physiological state. The magnitude of drug effects was stronger during the dark phase. CONCLUSION: While both Bac and GHB induced a non-physiological resting state, only Bac facilitated and consolidated sleep, and promoted EEG delta oscillations thereafter. Hence, Bac can be considered a sleep-promoting drug and its effects on functional recovery after stroke can be evaluated both in humans and rats.

Is preeclampsia associated with restless legs syndrome?

OBJECTIVE: Restless legs syndrome (RLS) is a common neurologic disorder. Secondary RLS includes pregnancy and iron deficiency. Prevalence of RLS in pregnancy ranges from 11% to 27%. We aimed to assess the frequency and characteristics of RLS in pregnancy in a Peruvian population and to evaluate the possible pregnancy or delivery complications due to RLS. METHODS: We assessed 218 consecutive expectant mothers at the inpatient clinic of the Hospital San Bartolome in Lima, Peru. Assessment was performed by using the standard diagnostic criteria for RLS and by using a clinical and diagnostic interview. Questionnaires for RLS severity, idiopathic RLS (IRLS), and excessive daytime sleepiness (EDS) according to the Epworth sleepiness scale (ESS) were used. Blood examination was performed for hemoglobin and hematocrit. For comparison, RLS patients were matched for age and body mass index (BMI) with pregnant women without RLS. RESULTS: Out of 218 patients, 40 (18.4%) fulfilled diagnostic criteria for RLS. In RLS patients, prophylactic iron supplementation therapy during pregnancy was less frequently taken (P=.02). Pregnant women with RLS had a higher ESS score than pregnant controls (10.6 +/- 3.1 vs 7.6. +/- 3.6; P<.001). Preeclampsia was more frequent in RLS (7/40 vs 1/39; P=.03). CONCLUSIONS: In our study, RLS was frequent in pregnant Peruvian women, especially in those without prophylactic iron supplementation. RLS patients described more EDS. Preeclampsia was more common in RLS. Our study is the first study to indicate a possible association between RLS and preeclampsia.

Sleep deprivation before stroke is neuroprotective: a pre-ischemic conditioning related to sleep rebound.

BACKGROUND AND AIM: We have previously shown in a rat model of focal cerebral ischemia that sleep deprivation after stroke onset aggravates brain damage. Others reported that sleep deprivation prior to stroke is neuroprotective. The main aim of this study was to test the hypothesis that the neuroprotection may be related to an increase in sleep (sleep rebound) during the acute phase of stroke. METHODS: Male Sprague Dawley rats (n=36) were subjected to continuous polygraphic recordings for baseline, total sleep deprivation (TSD), and 24h after ischemia. TSD for 6h was performed by gentle handling and immediately followed by ischemia. Focal cerebral ischemia was induced by permanent occlusion of distal branches of the middle cerebral artery. Control experiments included ischemia without SD (nSD) and sham surgery with TSD (n=6/group). RESULTS: Shortly after stroke, the amount of slow wave sleep (SWS) and paradoxical sleep (PS) increased significantly (p<0.05) in the TSD/ischemia, resulting in an increase in the total sleep time by 30% compared to baseline, or by 20% compared with the nSD/ischemia group. The infarct volume decreased significantly by 50% in the TSD/ischemia compared to nSD group (p<0.02). Removal of sleep rebound by allowing TSD-rats sleep for 24h before ischemia eliminated the reduction in the infarct size. CONCLUSION PRESTROKE: Sleep deprivation results in sleep rebound and reduces brain damage. Sleep rebound may be causally related to the neuroprotection.

Guidance for the preparation of neurological management guidelines by EFNS scientific task forces - revised recommendations 2012.

This paper is meant to provide guidance to anyone wishing to write a neurological guideline for diagnosis or treatment, and is directed at the Scientist Panels and task forces of the European Federation of Neurological Societies (EFNS). It substitutes the previous guidance paper from 2004. It contains several new aspects: the guidance is now based on a change of the grading system for evidence and for the resulting recommendations, and has adopted The Grading of Recommendations, Assessment, Development and Evaluation system (GRADE). The process of grading the quality of evidence and strength of recommendations can now be improved and made more transparent. The task forces embarking on the development of a guideline must now make clearer and more transparent choices about outcomes considered most relevant when searching the literature and evaluating their findings. Thus, the outcomes chosen will be more critical, more patient-oriented and easier to translate into simple recommendations. This paper also provides updated practical recommendations for planning a guideline task force within the framework of the EFNS. Finally, this paper hopes to find the approval also by the relevant bodies of our future organization, the European Academy of Neurology.

Tumefactive demyelinating lesions during etanercept treatment requiring decompressive hemicraniectomy.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory and immunoregulatory cytokine involved in the pathogenesis of several autoimmune disorders. Etanercept, a TNF-α antagonist (anti-TNF-α) acting as a soluble TNF-α receptor, has been associated with neurological demyelinating disorders. This paper aims to report an unusual case showing tumefactive central nervous system (CNS) inflammatory demyelination in a patient in the course of TNF -α antagonist therapy, requiring decompressive hemicraniectomy. This report is based on magnetic resonance imaging (MRI) findings and histology. A biopsy confirmed the inflammatory demyelinating nature of the lesions. The clinical presentation is unusual due to the severity of the disease process, requiring decompressive hemicraniotomy with a clinically favorable outcome.

Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (­18 min (P = 0.02)) and WASO (­54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.

Long-term efficacy of sodium oxybate in 4 patients with chronic cluster headache.

BACKGROUND: Cluster headache (CH) manifests with periodic attacks of severe unilateral pain and autonomic symptoms. Nocturnal attacks may cause severe sleep disruption. In about 10%of cases, patients present with a chronic form (CCH), which is often medically intractable. Few attempts have been made to improve headache via pharmacologic modulation of sleep. METHODS: In an open-label study, 4 patients with CCH and disturbed sleep received increasing dosages of sodium oxybate (SO), a compound known to consolidate sleep and to increase slow-wave sleep. Response to SO was monitored by serial polysomnography, and actimetry, along with pain and sleep diaries. RESULTS: SO was effective in all 4 patients as shown by an immediate reduction in frequency (up to 90%) and intensity (>50%) of nocturnal pain attacks and improved sleep quality. These effects were long-lasting in 3 patients (mean 19 months, range 12-29 months) and transient (for 8 months) in one patient. Long-lasting improvement of daytime headaches was achieved with a latency of weeks in 2 patients. SO was safe, with mild to moderate adverse effects (dizziness, vomiting, amnesia, weight loss). CONCLUSION: SO may represent a new treatment option to reduce nocturnal and diurnal pain attacks and improve sleep quality in CCH. These data also suggest the interest of treating primary headache syndromes by sleep-manipulating substances. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that oral SO at night improves sleep and reduces the intensity and frequency of headaches in patients with CCH.

Sodium oxybate in narcolepsy with cataplexy: Zurich sleep center experience.

Sodium oxybate (SO; Xyrem®) has been approved in most countries for treatment of narcolepsy and cataplexy. In this study, we present a single-center experience of a series of 18 patients with narcolepsy with cataplexy (18/18 DQB1*0602 positive, 17/17 with low/absent cerebrospinal fluid hypocretin) in whom SO was prescribed. After 26 ± 13 months, 13/18 patients were still on SO at a mean dosage of 6.1 ± 1.2 g (in 8 of them in combination with stimulants). The following significant effects were observed: improved subjective sleepiness (12/13), cataplexy (13/13; median number of attacks from 20 to 1/month), hallucinations (8/10) and sleep paralysis (8/8); increase in mean sleep latency on the Maintenance of Wakefulness Test (from 5.5 to 17.4 min) and sleep/rest efficiency on actigraphy (from 61 to 76%); decrease in Epworth Sleepiness Scale score (from 18 to 14), sleep onset REM periods on the Multiple Sleep Latency Test (from 3.6 to 2.4) and errors in the Steer-Clear Test (from 11 to 2%). Five patients discontinued SO because of insufficient compliance (n = 2), lack of efficiency (n = 1) and side effects (n = 1). These data confirm and expand previous reports on the good effects and tolerability of SO as a treatment for narcolepsy with cataplexy.