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Maria P Mogavero,1,2,* Alessandro Silvani,3,* Giuseppe Lanza,4,5 Lourdes M DelRosso,6 Luigi Ferini-Strambi,1,2 Raffaele Ferri4 1Vita-Salute San Raffaele University, Milan, Italy; 2Sleep Disorders Center, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy; 3PRISM Lab, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 4Sleep Research Centre, Oasi Research Institute - IRCCS, Troina, Italy; 5Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy; 6Pulmonary and Sleep Medicine, University of California San Francisco-Fresno, Fresno, CA, USA*These authors contributed equally to this workCorrespondence: Raffaele Ferri, Sleep Research Centre, Oasi Research Institute – IRCCS, Troina, 94018, Italy, Tel +39 0935 936111, Fax +39 0935 936231, Email rferri@oasi.en.itAbstract: After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions.Keywords: insomnia, orexin, hypocretin, orexin receptor antagonist, dual orexin receptor antagonists, selective orexin receptor antagonists

Davide Sparasci,1 Francesco Fanfulla,2 Raffaele Ferri,3 Debora Aricò,3 Daniela Distefano,4 Emanuele Pravatà,4 Raphael Heinzer,5 José Haba-Rubio,5 Mathieu Berger,5 Gianna Carla Riccitelli,6– 8 Claudio Gobbi,6,8 Chiara Zecca,6,8,* Mauro Manconi1,8,* 1Sleep Medicine Unit, Neurocenter of Southern Switzerland, Lugano, Switzerland; 2Sleep Medicine Unit, Istituti Clinici Scientifici Maugeri, IRCCS, Scientific Institute of Pavia, Pavia, Italy; 3Sleep Research Centre; Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy; 4Neuroradiology Clinic, Ospedale Regionale di Lugano, Neurocenter of Southern Switzerland, Lugano, Switzerland; 5Center for Investigation and Research in Sleep (CIRS), Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland; 6Multiple Sclerosis Center, Neurocenter of Southern Switzerland, Lugano, Switzerland; 7Neuropsychology and Behavioural Neurology Research Unit, Neurocenter of Southern Switzerland, Lugano, Switzerland; 8Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland*These authors contributed equally to this workCorrespondence: Raffaele Ferri, Sleep Research Centre; Department of Neurology I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Via Conte Ruggero 73, Troina, 94018, Italy, Email rferri@oasi.en.itBackground: Multiple sclerosis (MS) represents a risk factor for sleep disorders, but there are conflicting results about the prevalence and severity of sleep-related breathing disorders (SRBD) in MS. Most available data come from self-administered questionnaires.Objective: To conduct a polysomnographic study in MS focused on SRBD, compared to a group of healthy controls (HC), also considering the neuroimaging findings. To evaluate the impact of SRBD on vigilance, fatigue and depression in MS.Methods: In this cross-sectional, observational, instrumental study, 67 MS patients (men/women: 20/47; mean age: 50.6± 8.2 years) underwent PSG and maintenance of wakefulness test. Findings were compared to 67 age-, sex-, BMI-matched HC, by using parametric (Student’s t-test) and nonparametric statistics (chi-squared test). A subgroup analysis was then performed, evaluating the influence of brainstem (mesencephalic, pontine and medullary) lesions at neuroimaging on instrumental and clinical data: MS patients with at least one brainstem lesion vs MS patients without vs HC.Results: The frequency of SRBD was comparable in MS patients and HC. No MS patient had a central apnea index ≥ 2/h. The respiratory disturbance index (RDI) did not correlate to clinical parameters such as fatigue and depression. Patients with MS were drowsier than HC (47% vs 26%, p = 0.019) and showed a worse sleep pattern, in terms of duration, efficiency and architecture.Conclusion: Our study does not provide evidence of an association between MS-specific symptoms such as fatigue, sleepiness, depression and central or obstructive apneas, even in the presence of brainstem lesions.Keywords: sleep-related breathing disorders, multiple sclerosis, sleep quality, polysomnography

Stefania Mondello,1 Firas H Kobeissy,2 Yehia Mechref,2 Jingfu Zhao,3 Samer El Hayek,4 Kazem Zibara,5 Monica Moresco,6,7 Giuseppe Plazzi,6 Filomena II Cosentino,8 Raffaele Ferri8 1Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy; 2Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 3Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, 79409, USA; 4Department of Psychiatry, American University of Beirut, Beirut, Lebanon; 5Department of Biology, Faculty of Sciences-I, PRASE, DSST, Lebanese University, Beirut, Lebanon; 6Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy; 7IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; 8Sleep Research Centre, Oasi Research Institute - IRCCS, Troina, ItalyCorrespondence: Raffaele FerriSleep Research Centre, Oasi Research Institute - IRCCS, Troina, 94018, ItalyTel +39 0935 936111Fax +39 0935 936231Email rferri@oasi.en.itPurpose: We performed comparative proteomic analyses of blood of patients with RLS and healthy individuals aiming to identify potential biomarker and therapeutic target candidate for RLS.Patients and Methods: Blood serum samples from 12 patients with a clinical diagnosis of RLS (8 females and 4 males, with a mean age of 68.52 years) and 10 healthy controls (5 females and 5 males, with a mean age of 67.61 years) underwent proteomic profiling by liquid chromatography coupled with tandem mass spectrometry. Pathway analysis incorporating protein–protein interaction networks was carried out to identify pathological processes linked to the differentially expressed proteins.Results: We quantified 272 proteins in patients with RLS and healthy controls, of which 243 were shared. Five proteins – apolipoprotein C-II, leucine-rich alpha-2-glycoprotein 1, FLJ92374, extracellular matrix protein 1, and FLJ93143 – were substantially increased in RLS patients, whereas nine proteins – vitamin D-binding protein, FLJ78071, alpha-1-antitrypsin, CD5 antigen-like, haptoglobin, fibrinogen alpha chain, complement factor H-related protein 1, platelet factor 4, and plasma protease C1 inhibitor – were decreased. Bioinformatics analyses revealed that these proteins were linked to 1) inflammatory and immune response, and complement activation, 2) brain-related development, cell aging, and memory disorders, 3) pregnancy and associated complications, 4) myocardial infarction, and 5) reactive oxygen species generation and subsequent diabetes mellitus.Conclusion: Our findings shed light on the multifactorial nature of RLS and identified a set of circulating proteins that may have clinical importance as biomarkers and therapeutic targets.Keywords: idiopathic restless legs syndrome, biomarkers, LC-MS/MS, proteome, interactome

Mauro Manconi,1– 3 Raffaele Ferri4 1Sleep Medicine Unit, Neurocenter of Southern Switzerland, Lugano, Italy; 2Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland; 3Department of Neurology, University Hospital, Inselspital, Bern, Switzerland; 4Sleep Research Centre, Oasi Research Institute - IRCCS, Troina, ItalyCorrespondence: Mauro Manconi Email mauro.manconi@eoc.ch We have read with great interest the paper by Wang et al1 that shed a welcome spot of light on the intriguing and poorly addressed linkage between periodic limb movements (PLMS) and obstructive sleep apnea (OSA). With an elegant, despite retrospective, investigation, they tested the hypothesis that the OSA phenotype associated with low arousal threshold (ArTH) was a risk factor for the cooccurrence of OSA and PLMS. Once having rejected the null hypothesis, the authors confirmed their results in the independent large population of the MrOS study, and this is certainly a strength of the study. A second noteworthy methodological merit of the authors is to have used the new data-driven criteria to define the so-called respiratory-related leg movements (RRLM) proposed by the WASM taskforce.2 By using these criteria, all leg movements (LM) occurring within the time range from 2 s before to 10.25 s after the end of respiratory events were defined as RRLM. In addition, the authors repeated their analysis also using the standard AASM criteria (RRLM = LM overlapping or not separated by more than ±0.5 s from the end of the respiratory event).3 Since the recording of LM has become a standard procedure in accredited sleep labs, PLMS and RRLM are a frequent incidental finding and, besides their clinical significance possibly suggesting the existence of an underlying restless legs syndrome, the value of such motor components remains unclear as well as the option to treat them with dopamine agonists (DA). View the original paper by Wang and colleagues

Background: Individuals with Down syndrome generally show a floor effect on Wechsler Scales that is manifested by flat profiles and with many or all of the weighted scores on the subtests equal to 1. Method: The main aim of the present paper is to use the statistical Hessl method and the extended statistical method of Orsini, Pezzuti and Hulbert with a sample of individuals with Down syndrome (n = 128; 72 boys and 56 girls), to underline the variability of performance on Wechsler Intelligence Scale for Children-Fourth Edition subtests and indices, highlighting any strengths and weaknesses of this population that otherwise appear to be flattened. Results: Based on results using traditional transformation of raw scores into weighted scores, a very high percentage of subtests with weighted score of 1 occurred in the Down syndrome sample, with a floor effect and without any statistically significant difference between four core Wechsler Intelligence Scale for Children-Fourth Edition indices. The results, using traditional transformation, confirm a deep cognitive impairment of those with Down syndrome. Conversely, using the new statistical method, it is immediately apparent that the variability of the scores, both on subtests and indices, is wider with respect to the traditional method. Conclusion: Children with Down syndrome show a greater ability in the Verbal Comprehension Index than in the Working Memory Index.

ObjectivesWe aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD.MethodsThe consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]).ResultsSix inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies.ConclusionsThe IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

Claudia Dosi,1 Assia Riccioni,1 Martina della Corte,1 Luana Novelli,1 Raffaele Ferri,2 Oliviero Bruni1 1Department of Social and Developmental Psychology, Sapienza University, Rome, Italy; 2Sleep Research Centre, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy Abstract: The correlation and/or comorbidity between sleep disorders and headache has been reported in numerous studies, but the exact nature of the association between headache, disordered sleep, and underlying mechanisms remains poorly understood. The bidirectional association between sleep and headache is mediated by a temporal link (headache occurs during sleep, after sleep, and in relationship with sleep stages), by a quantitative relationship (excess, lack, bad quality, short duration of sleep may trigger headache), and by a reciprocal connection (headache may cause sleep disruption and may be associated with several sleep disturbances). This association is most evident for primary headache disorders, especially in childhood. A congenital alteration of neurotransmitter pathways (serotoninergic and dopaminergic) might predispose individuals to both disorders, presenting as sleep–wake rhythm disorder in infancy or as headache disorder later in childhood, as result of this neurotransmitter imbalance. Clinicians should be aware that a complete clinical evaluation of childhood headache includes a careful sleep history, taking into account that the treatment of sleep disturbances could lead to an improvement of headache symptoms and vice versa. Keywords: sleep, headache, migraine, childhood, adolescence